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Important: This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Breast cancer


Table of Contents

GENERAL INFORMATION
CELLULAR CLASSIFICATION
STAGE INFORMATION
Inflammatory breast cancer
TREATMENT OPTION OVERVIEW
BREAST CANCER IN SITU
Intraductal carcinoma
Lobular carcinoma in situ
STAGE I BREAST CANCER
Primary therapy
Adjuvant therapy
Timing of primary and adjuvant therapy
Chemotherapy
Radiation and chemotherapy
Initial surgical management
Adjuvant therapy
STAGE II BREAST CANCER
Primary therapy
Adjuvant therapy: stage II positive nodes
Adjuvant therapy: stage II negative nodes
Timing of primary and adjuvant therapy
Chemotherapy
Radiation and chemotherapy
Initial surgical management
Adjuvant therapy
STAGE III BREAST CANCER
Stage IIIA
Stage IIIB (locally advanced, including inflammatory)
STAGE IV BREAST CANCER
INFLAMMATORY BREAST CANCER
RECURRENT BREAST CANCER

GENERAL INFORMATION

(Separate summaries containing information on prevention of breast cancer, screening for breast cancer, breast cancer and pregnancy, and male breast cancer are also available in PDQ.)

Breast cancer, which is highly treatable by surgery, radiation therapy, chemotherapy, and hormonal therapy, is most often curable when detected in early stages. Mammography is the most important screening modality for the early detection of breast cancer. Breast magnetic resonance imaging is under study as a diagnostic tool.[1] Prognosis and selection of therapy are influenced by the age of the patient,[2] stage of the disease, pathologic characteristics of the primary tumor including the presence of tumor necrosis,[3] estrogen-receptor (ER) and progesterone-receptor (PR) levels in the tumor tissue,[4] and measures of proliferative capacity, as well as by menopausal status and general health. Since criteria of menopausal status vary widely, age older than 50 years can be substituted as a definition of the postmenopausal state. Overweight patients may have a poorer prognosis.[5] Prognosis may also vary by race, with blacks, and to a lesser extent Hispanics, having a poorer prognosis than whites.[6,7] Breast cancer is classified into a variety of cell types, but only a few of these affect prognosis or selection of therapy. Rarely, the breast may be involved by other tumors such as melanoma, lymphoma, or sarcoma.

Female relatives of patients with breast cancer may have an increased risk of the disease. Age-specific risk estimates are available to help counsel these women and to design screening strategies for them.[8,9] It is estimated that approximately 5% of all women with breast cancer may have germ-line mutation(s) in a gene (BRCA1) localized to chromosome 17q21. Their relatives, if carriers of the BRCA1 mutation(s), have an increased lifetime risk of breast cancer with many of the breast cancers occurring prior to age 50 years. Specific mutations of the BRCA1 gene may be more common in certain ethnic groups.[10] Ovarian cancer risk is also elevated in patients with the BRCA1 mutation.[11] A second gene, BRCA2, has been localized to chromosome 13q12-13. BRCA2 confers a high risk of breast cancer and, to a lesser extent, ovarian cancer.[12] As practical assays are developed and validated, such detectable genetic abnormalities may be used to screen members of high-risk families.[13-17] Refer to the PDQ summaries on screening for breast cancer and prevention of breast cancer for more information.

Hormonal contraceptives have been associated with a slight increase in the risk of breast cancer in a large overview analysis of 54 epidemiologic studies.[18] The relative risk does vary with time from last use; current users have a relative risk of 1.24. For women who have not taken contraceptives for 1 to 4 years, the risk is 1.16 and for women who have not taken contraceptives for 5 to 9 years, the risk falls to 1.07. For women who have not taken contraceptives for 10 years, there appears to be no increased risk of breast cancer.

Patient management following initial suspicion of breast cancer generally includes confirmation of the diagnosis, evaluation of stage of disease, and selection of therapy. Diagnosis may be confirmed by aspiration cytology, core needle biopsy with a stereotactic or ultrasound technique for nonpalpable lesions, or incisional or excisional biopsy. At the time the tumor tissue is surgically removed, part of it should be processed for determination of ER and PR levels. Assay procedures are technically demanding, and the laboratory should use appropriate quality control procedures.[19] Charcoal, enzyme immunoassay, or enzyme immunocytochemical assays may be done.[20-22]

Although anatomic stage (size of primary tumor, axillary node status) remains an important prognostic factor,[23-26] other histologic and biologic characteristics may have predictive value.[27,28] Studies from the National Surgical Adjuvant Breast and Bowel Project (NSABP) [19] and the International Breast Cancer Study Group (IBCSG) [29] have shown that tumor nuclear grade and histologic grade, respectively, are important indicators of outcome following adjuvant therapy for breast cancer. Morphologically determined tumor necrosis may be a prognostic variable for early recurrence.[3] However, the prognostic significance of these pathologic factors outside these study groups is unclear. In addition, the IBCSG has reported that serial sectioning of ipsilateral axillary lymph nodes judged to be disease-free after routine histologic examination reveals micrometastases in 9% of breast cancer patients and may identify a higher-risk "node-negative" population,[30] confirming reports by Friedman et al.[31] There is substantial evidence that ER status and measures of proliferative capacity of the primary tumor (thymidine labeling index or flow cytometric measurements of S-phase and ploidy) may have important independent predictive value.[32-35] In stage II disease, the PR status may have greater prognostic value than the ER status.[36] Tumor microvessel density, c-erbB-2, c-myc, p53 expression, and peritumoral lymphatic vessel invasion may also be prognostic indicators in patients with breast cancer.[37-44]

Several retrospective reviews demonstrate a significantly better disease-free survival for premenopausal women with breast cancer and positive axillary lymph nodes operated on during the luteal phase (days 15-36) as compared to those operated on during the follicular phase (days 0-14) of their menstrual cycle.[45-47] However, several other studies have failed to confirm this finding or have found opposite results.[48-51] Because of the inconsistent results of these studies, it would be premature to mandate a modification in the scheduling of breast cancer operations according to the patient's menstrual cycle.

Pathologically, breast cancer is frequently a multicentric disease. However, clinical diagnosis of 2 or more primary cancers in a single breast is uncommon.[52] Similarly, simultaneous bilateral breast cancer is unusual. It is more common in patients with infiltrating lobular carcinoma. Patients who have breast cancer should have bilateral mammography at the time of diagnosis to rule out synchronous disease. They should also continue to have regular breast physical examinations and mammography to detect either asynchronous disease in the ipsilateral breast in those patients treated with breast- conserving surgery and radiation therapy or a second primary cancer in the contralateral breast.[53] The risk of a primary breast cancer in the contralateral breast is significant, approximately 1% per year.[28,54] Patient age of less than 55 years at the time of diagnosis or lobular tumor histology appear to increase this risk to 1.5%.[55] The development of a contralateral breast cancer is associated with an increased risk of distant recurrence.[56]

Some retrospective studies suggest that perioperative blood transfusion impairs survival in breast cancer patients.[57] Although other retrospective studies have not confirmed the association between transfusion and prognosis,[58] limiting the transfusion of blood to breast cancer patients whenever medically feasible seems prudent. A modified radical mastectomy rarely requires blood transfusion if performed by an experienced surgeon, even when combined with submuscular insertion of an implant to restore breast contour. When breast contour following modified radical mastectomy is to be restored using a tissue flap, the need for blood transfusions should be anticipated. Provision for autologous blood transfusions in that setting is recommended.

Even when standard therapy is effective, patients with breast cancer are appropriately considered as candidates for clinical trials designed to improve therapeutic results and decrease the morbidity of treatment. There is convincing evidence from randomized trials that periodic follow-up with bone scans, liver sonography, chest x-rays, and blood tests of liver function do not improve survival or quality of life when compared to routine physical examinations.[59,60] Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected.[60] Based on these data, some investigators feel acceptable follow-up for asymptomatic patients after completion of their treatment of stages I-III breast cancer can be limited to physical examination along with annual mammography. In patients treated with lumpectomy and radiation, the detection of in-breast recurrence by physical examination and/or mammography can lead to curative mastectomy. In 1 series of 30 patients who failed locally after lumpectomy plus radiation therapy and who underwent salvage mastectomy, no distant recurrences were seen later than 6 years after initial local failure, and the disease-free survival following salvage mastectomy was 58% at 5 years and 50% at 10 years.[61-65] The intensity of follow-up and the appropriateness of screening tests after the completion of primary treatment of stages I-III breast cancer remain controversial.

Increasingly, hormone replacement therapy (HRT) is prescribed for many postmenopausal women in the United States both to decrease acute menopausal symptoms and to promote long term health benefits. More precise quantitation of those latter benefits with current HRT regimens is presently under study (Women's Health Initiative Trial), but the benefits are potentially important. A study involving 121,000 nurses has shown that HRT taken for 5 years is associated with a reduced risk of coronary artery disease deaths as well as death from cancer. After 10 years of HRT, the magnitude of the reduction in risk of death is partially attenuated due to an increased risk of death in women taking HRT for more than 10 years.[66,67]

With rising numbers of breast cancer survivors, many of whom are entering menopause prematurely due to adjuvant hormonal or chemotherapy treatment, HRT for these women poses a dilemma. HRT is generally not used for women with breast cancer because estrogen is a proven growth factor for most breast cancer cells in the laboratory. However, a review of the literature makes several pertinent observations based on clinical trials.[68,69] In addition, the prognosis of women who took HRT before developing breast cancer appears better than that of women with no such exposure. This may be a result of increased surveillance leading to detection of tumors at an earlier stage and may not be a result of the HRT.[70] Neither pregnancy after breast cancer nor the use of oral contraceptive pills before a diagnosis of breast cancer has been shown to adversely impact survival when controlled for stage of disease. These findings provide the rationale for prospective clinical trials testing the impact of HRT on breast cancer recurrence and on the development of new tumors. Such research is planned in carefully selected women with breast cancer at relatively low risk of relapse. The routine use of HRT should await these results.[69]

Results of a large chemoprevention trial, NSABP P-1, have been published.[71] The study involved 13,366 high-risk premenopausal and postmenopausal women who took tamoxifen or placebo in a double-blind fashion for 5 years. The data showed that women who took tamoxifen for 5 years had a 50% decrease in invasive and non-invasive breast cancer, compared to women who took placebo. Toxic effects were primarily development of endometrial cancer and vascular events. The numbers of each event are small, and the incidence is about 1 to 2 cases per 1,000 women. Other side effects were hot flashes and vaginal discharge. High-risk women, as defined by the trial, may consider taking 20 milligrams of tamoxifen daily for 5 years as a preventative for breast cancer development after weighing both the risks and benefits. Two smaller European studies have been published which do not show the same beneficial effects of tamoxifen. However, the study populations were smaller, and the populations and trial designs are not comparable to the P-1 study.[72,73] Refer to the PDQ prevention of breast cancer summary for more information.

Bilateral prophylactic mastectomy is an alternative preventive approach for women at high risk for breast cancer. Controversy has long existed over the indication for this procedure. Results of a retrospective study of 639 women with a family history of breast cancer who underwent bilateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993 provide evidence that prophylactic surgery is effective.[74] The women were categorized into moderate- and high-risk groups according to the number, relationship, and age at onset of family members with breast cancer. In both risk groups, the incidence of breast cancer was reduced by as much as 90% and the death rate also appeared to be substantially reduced. The actual number of cases of breast cancer in the study population was 2, compared to a predicted number of 20 if prophylactic mastectomy had not been done.[75][Level of evidence: 3iiDi] Therefore, although prophylactic mastectomy was associated with a reduction of cases of breast cancer, the majority of women who underwent the procedure would not have developed breast cancer. Total mastectomy with breast reconstruction is currently the procedure of choice when prophylactic surgery is considered. Refer to the PDQ summaries on prevention of breast cancer and genetics of breast and ovarian cancer for more information.

References:

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  27. Tandon AK, Clark GM, Chamness GC, et al.: Cathepsin D and prognosis in breast cancer. New England Journal of Medicine 322(5): 297-302, 1990.

  28. Rosen PP, Groshen S, Kinne DW, et al.: Factors influencing prognosis in node-negative breast carcinoma: analysis of 767 T1N0M0/T2N0M0 patients with long-term follow-up. Journal of Clinical Oncology 11(11): 2090-2100, 1993.

  29. Davis BW, Gelber RD, Goldhirsch A, et al.: Prognostic significance of tumor grade in clinical trials of adjuvant therapy for breast cancer with axillary lymph node metastasis. Cancer 58(12): 2662-2670, 1986.

  30. International (Ludwig) Breast Cancer Study Group: Prognostic importance of occult axillary lymph node micrometastases from breast cancers. Lancet 335(8705): 1565-1568, 1990.

  31. Friedman S, Bertin F, Mouriesse H, et al.: Importance of tumor cells in axillary node sinus margins ('clandestine' metastases) discovered by serial sectioning in operable breast carcinoma. Acta Oncologica 27(5): 483-487, 1988.

  32. Sigurdsson H, Baldetorp B, Borg A, et al.: Indicators of prognosis in node-negative breast cancer. New England Journal of Medicine 322(15): 1045-1053, 1990.

  33. Fisher B, Gunduz N, Constantino J, et al.: DNA flow cytometric analysis of primary operable breast cancer: relation of ploidy and s-phase fraction to outcome of patients in NSABP B-04. Cancer 68(5): 1465-1475, 1991.

  34. Wenger CR, Beardslee S, Owens MA, et al.: DNA ploidy, S-phase, and steroid receptors in more than 127,000 breast cancer patients. Breast Cancer Research and Treatment 28(1): 9-20, 1993.

  35. Allred DC, Clark GM, Tandon AK, et al.: HER-2/neu in node-negative breast cancer: prognostic significance of overexpression influenced by the presence of in situ carcinoma. Journal of Clinical Oncology 10(4): 599-605, 1992.

  36. Clark GM, McGuire WL, Hubay CA, et al.: Progesterone receptors as a prognostic factor in stage II breast cancer. New England Journal of Medicine 309(22): 1343-1347, 1983.

  37. Berns EM, Klijn JG, van Putten WL, et al.: c-myc amplification is a better prognostic factor than HER2/neu amplification in primary breast cancer. Cancer Research 52(5): 1107-1113, 1992.

  38. Paik S, Hazan R, Fisher ER, et al.: Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. Journal of Clinical Oncology 8(1): 103-112, 1990.

  39. Toikkanen S, Helin H, Isola J, et al.: Prognostic significance of HER-2 oncoprotein expression in breast cancer: a 30-year follow-up. Journal of Clinical Oncology 10(7): 1044-1048, 1992.

  40. Gusterson BA, Gelber RD, Goldhirsch A, et al.: Prognostic importance of c-erbB-2 expression in breast cancer. Journal of Clinical Oncology 10(7): 1049-1056, 1992.

  41. Gasparini G, Weidner N, Bevilacqua P, et al.: Tumor microvessel density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma. Journal of Clinical Oncology 12(3): 454-466, 1994.

  42. Muss HB, Thor AD, Berry DA, et al.: c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. New England Journal of Medicine 330(8): 1260-1266, 1994.

  43. Press MF, Bernstein L, Thomas PA, et al.: HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. Journal of Clinical Oncology 15(8): 2894-2904, 1997.

  44. Elledge RM, Green S, Ciocca D, et al.: HER-2 expression and response to tamoxifen in estrogen receptor-positive breast cancer: a Southwest Oncology Group study. Clinical Cancer Research 4(1): 7-12, 1998.

  45. Veronesi U, Luini A, Mariani L, et al.: Effect of menstrual phase on surgical treatment of breast cancer. Lancet 343(8912): 1545-1547, 1994.

  46. Badwe RA, Gregory WM, Chaudary MA, et al.: Timing of surgery during menstrual cycle and survival of premenopausal women with operable breast cancer. Lancet 337(8752): 1261-1264, 1991.

  47. Senie RT, Rosen PP, Rhodes P, et al.: Timing of breast cancer excision during the menstrual cycle influences duration of disease-free survival. Annals of Internal Medicine 115(5): 337-342, 1991.

  48. McGuire WL, Hilsenbeck S, Clark GM: Optimal mastectomy timing. Journal of the National Cancer Institute 84(5): 346-348, 1992.

  49. Gnant MF, Seifert M, Jakesz R, et al.: Breast cancer and timing of surgery during menstrual cycle: a 5-year analysis of 385 pre-menopausal women. International Journal of Cancer 52(5): 707-712, 1992.

  50. Nathan B, Bates T, Anbazhagan R, et al.: Timing of surgery for breast cancer in relation to the menstrual cycle and survival of premenopausal women. British Journal of Surgery 80(1): 43, 1993.

  51. Hagen AA, Hrushesky WJ: Menstrual timing of breast cancer surgery. American Journal of Surgery 104(3): 245-261, 1998.

  52. de la Rochefordiere A, Asselain B, Scholl S, et al.: Simultaneous bilateral breast carcinomas: a retrospective review of 149 cases. International Journal of Radiation Oncology, Biology, Physics 30(1): 35-41, 1994.

  53. Orel SG, Troupin RH, Patterson EA, et al.: Breast cancer recurrence after lumpectomy and irradiation: role of mammography in detection. Radiology 183(1): 201-206, 1992.

  54. Gustafsson A, Tartter PI, Brower ST, et al.: Prognosis of patients with bilateral carcinoma of the breast. Journal of the American College of Surgeons 178(2): 111-116, 1994.

  55. Broet P, de la Rochefordiere A, Scholl SM, et al.: Contralateral breast cancer: annual incidence and risk parameters. Journal of Clinical Oncology 13(7): 1578-1583, 1995.

  56. Healey EA, Cook EF, Orav EJ, et al.: Contralateral breast cancer: clinical characteristics and impact on prognosis. Journal of Clinical Oncology 11(8): 1545-1552, 1993.

  57. Crowe JP, Gordon NH, Fry DE, et al.: Breast cancer survival and perioperative blood transfusion. Surgery 106(5): 836-841, 1989.

  58. Kieckbusch ME, O'Fallon JR, Ahmann DL, et al.: Blood transfusion exposure does not influence survival in patients with carcinoma of the breast. Transfusion 29(6): 500-504, 1989.

  59. The GIVIO Investigators: Impact of follow-up testing on survival and health-related quality of life in breast cancer patients: a multicenter randomized controlled trial. Journal of the American Medical Association 271(20): 1587-1592, 1994.

  60. Del Turco MR, Palli D, Cariddi A, et al.: Intensive diagnostic follow-up after treatment of primary breast cancer: a randomized trial. Journal of the American Medical Association 271(20): 1593-1597, 1994.

  61. Aberizk WJ, Silver B, Henderson IC, et al.: The use of radiotherapy for treatment of isolated locoregional recurrence of breast carcinoma after mastectomy. Cancer 58(6): 1214-1218, 1986.

  62. Recht A, Hayes DF: Specific sites of metastatic disease and emergencies: local recurrence. In: Harris Jr, Hellman S, Henderson IC, et al., Eds.: Breast Diseases. Philadelphia: J.B. Lippincott, 1987, pp 508-524.

  63. Abner AL, Recht A, Eberlein T, et al.: Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. Journal of Clinical Oncology 11(1): 44-48, 1993.

  64. Haffty BG, Fischer D, Rose M, et al.: Prognostic factors for local recurrence in the conservatively treated breast cancer patient: a cautious interpretation of the data. Journal of Clinical Oncology 9(6): 997-1003, 1991.

  65. Haffty BG, Fischer D, Beinfield M, et al.: Prognosis following local recurrence in the conservatively treated breast cancer patient. International Journal of Radiation Oncology, Biology, Physics 21(2): 293-298, 1991.

  66. Grodstein F, Stampfer MJ, Colditz GA, et al.: Postmenopausal hormone therapy and mortality. New England Journal of Medicine 336(25): 1769-1775, 1997.

  67. Brinton LA, Schairer C: Postmenopausal hormone-replacement therapy: time for a reappraisal? New England Journal of Medicine 336(25): 1821-1822, 1997.

  68. Cobleigh MA, Berris RF, Bush T, et al.: Estrogen replacement therapy in breast cancer survivors - a time for change: Breast Cancer Committees of the Eastern Cooperative Oncology Group. Journal of the American Medical Association 272(7): 540-545, 1994.

  69. Roy JA, Sawka CA, Pritchard KI: Hormone replacement therapy in women with breast cancer: do the risks outweigh the benefits? Journal of Clinical Oncology 14(3): 997-1006, 1996.

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  73. Powles T, Eeles R, Ashley S, et al.: Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 352(9122): 98-101, 1998.

  74. Hartmann LC, Schaid DJ, Woods JE, et al.: Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. New England Journal of Medicine 340(2): 77-84, 1999.

  75. Eisen A, Weber BL: Prophylactic mastectomy--the price of fear. New England Journal of Medicine 340(2): 137-138, 1999.


CELLULAR CLASSIFICATION

Infiltrating or invasive ductal cancer is the most common cell type, comprising 70% to 80% of all cases.

Lobular carcinoma involves both breasts more frequently than other histologic types.

Inflammatory carcinoma is a clinicopathologic entity characterized by diffuse brawny induration of the skin of the breast with an erysipeloid edge, usually without an underlying palpable mass.[1] Radiologically there may be a detectable mass and characteristic thickening of the skin over the breast. This clinical presentation is due to tumor embolization of dermal lymphatics with engorgement of superficial capillaries. Inflammatory carcinoma is classified as T4d.

The following is a list of breast cancer histologic classifications:[1]

carcinoma, NOS (not otherwise specified)
ductal

intraductal (in situ)
invasive with predominant intraductal component
invasive, NOS
comedo
inflammatory
medullary with lymphocytic infiltrate
mucinous (colloid)
papillary
scirrhous
tubular
other
lobular
in situ
invasive with predominant in situ component
invasive [2]
nipple
Paget's disease, NOS
Paget's disease with intraductal carcinoma
Paget's disease with invasive ductal carcinoma
other
undifferentiated carcinoma

The following are tumor subtypes that occur in the breast but are not considered to be typical breast cancers:

cystosarcoma phyllodes

Cystosarcoma phyllodes is a rare variant of breast cancer generally treated
with wide local excision. Although most patients are cured with such
treatment, the risk of developing local recurrence or metastases is related
to infiltrating margins, degree of stromal mitotic activity, nuclear
pleomorphism, and stromal overgrowth.[3]
angiosarcoma primary lymphoma

References:

  1. Breast. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 171-180.

  2. Yeatman TJ, Cantor AB, Smith TJ, et al.: Tumor biology of infiltrating lobular carcinoma: implications for management. Annals of Surgery 222(4): 549-561, 1995.

  3. Reinfuss M, Mitus J, Duda K, et al.: The treatment and prognosis of patients with phyllodes tumor of the breast: an analysis of 170 cases. Cancer 77(5): 910-916, 1996.


STAGE INFORMATION

This staging system provides a strategy for grouping patients with respect to prognosis. Therapeutic decisions are formulated in part according to staging categories but primarily according to lymph node status, estrogen- and progesterone-receptor levels in the tumor tissue, menopausal status, and the general health of the patient.




The American Joint Committee on Cancer (AJCC) has designated staging by TNM

classification.[1]



-- TNM definitions --

Primary tumor (T):

  TX:  Primary tumor cannot be assessed

  T0:  No evidence of primary tumor

  Tis: Carcinoma in situ; intraductal carcinoma, lobular carcinoma in situ, or

       Paget's disease of the nipple with no associated tumor.

       Note: Paget's disease associated with a tumor is classified according to

       the size of the tumor.

  T1:  Tumor 2.0 cm or less in greatest dimension

    T1mic: Microinvasion 0.1 cm or less in greatest dimension

    T1a: Tumor more than 0.1 but not more than 0.5 cm in greatest dimension

    T1b: Tumor more than 0.5 cm but not more than 1.0 cm in greatest dimension

    T1c: Tumor more than 1.0 cm but not more than 2.0 cm in greatest dimension

  T2:  Tumor more than 2.0 cm but not more than 5.0 cm in greatest dimension

  T3:  Tumor more than 5.0 cm in greatest dimension

  T4:  Tumor of any size with direct extension to (a) chest wall or (b) skin,

       only as described below.

       Note: Chest wall includes ribs, intercostal muscles, and serratus

       anterior muscle but not pectoral muscle.

    T4a: Extension to chest wall

    T4b: Edema (including peau d'orange) or ulceration of the skin of the

         breast or satellite skin nodules confined to the same breast

    T4c: Both of the above (T4a and T4b)

    T4d: Inflammatory carcinoma



Regional lymph nodes (N):

  NX: Regional lymph nodes cannot be assessed (e.g., previously removed)

  N0: No regional lymph node metastasis

  N1: Metastasis to movable ipsilateral axillary lymph node(s)

  N2: Metastasis to ipsilateral axillary lymph node(s) fixed to each other or

      to other structures

  N3: Metastasis to ipsilateral internal mammary lymph node(s)



Pathologic classification (pN):

  pNX: Regional lymph nodes cannot be assessed (not removed for pathologic

       study or previously removed)

  pN0: No regional lymph node metastasis

  pN1: Metastasis to movable ipsilateral axillary lymph node(s)

    pN1a: Only micrometastasis (none larger than 0.2 cm)

    pN1b: Metastasis to lymph node(s), any larger than 0.2 cm

      pN1bi:   Metastasis in 1 to 3 lymph nodes, any more than 0.2 cm and all

               less than 2.0 cm in greatest dimension

      pN1bii:  Metastasis to 4 or more lymph nodes, any more than 0.2 cm and

               all less than 2.0 cm in greatest dimension

      pN1biii: Extension of tumor beyond the capsule of a lymph node

               metastasis less than 2.0 cm in greatest dimension

      pN1biv:  Metastasis to a lymph node 2.0 cm or more in greatest dimension

  pN2: Metastasis to ipsilateral axillary lymph node(s) fixed to each other

       or to other structures

  pN3: Metastasis to ipsilateral internal mammary lymph node(s)



Distant metastasis (M):

  MX: Presence of distant metastasis cannot be assessed

  M0: No distant metastasis 

  M1: Distant metastasis present (includes metastasis to ipsilateral

      supraclavicular lymph nodes)



-- AJCC stage groupings --



-- Stage 0 --

  Tis, N0, M0



-- Stage I --

  T1,* N0, M0



*T1 includes T1mic



-- Stage IIA --

  T0, N1, M0

  T1,* N1,** M0

  T2, N0, M0



*T1 includes T1mic

**The prognosis of patients with pN1a disease is similar to that of patients

with pN0 disease.



-- Stage IIB --

  T2, N1, M0

  T3, N0, M0



-- Stage IIIA --

  T0, N2, M0

  T1,* N2, M0

  T2, N2, M0

  T3, N1, M0

  T3, N2, M0



*T1 includes T1mic



-- Stage IIIB --

  T4, Any N, M0

  Any T, N3, M0



-- Stage IV --

  Any T, Any N, M1


Inflammatory breast cancer

Inflammatory carcinoma is a clinicopathologic entity characterized by diffuse brawny induration of the skin of the breast with an erysipeloid edge, usually without an underlying palpable mass. Radiologically there may be a detectable mass and characteristic thickening of the skin over the breast. The clinical presentation is due to tumor embolization of dermal lymphatics or to capillary congestion. Inflammatory carcinoma is classified T4d.

References:

  1. Breast. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 171-180.


TREATMENT OPTION OVERVIEW

The choice of breast cancer treatment is influenced by tumor stage and estrogen- and progesterone-receptor levels and by patient age and menopausal status. All newly diagnosed patients with breast cancer may appropriately be considered as candidates for 1 of the numerous ongoing clinical trials designed to improve survival and decrease the morbidity of current conventional treatment.

A separate summary containing information on breast cancer and pregnancy is also available in PDQ.

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.


BREAST CANCER IN SITU

Carcinoma in situ is classified as either intraductal carcinoma in situ (DCIS) arising from ductal epithelium or lobular carcinoma in situ (LCIS) arising from the epithelium of the lobules.[1] With the increasing use of screening mammography, noninvasive cancers are more frequently diagnosed and now constitute 15% to 20% of all breast cancers. DCIS usually presents as microcalcifications or as a soft-tissue abnormality.[2] There are several histologic subtypes: micropapillary, papillary, solid, cribriform, and comedocarcinoma. Some evidence suggests that comedocarcinoma may be more aggressive and associated with a higher probability of microinvasion.[3] LCIS is usually an incidental finding when a biopsy is done for some other abnormality. Data suggest that LCIS is a risk factor for invasive cancer.[4] Because it may be difficult to distinguish DCIS from atypical hyperplasia and because certain forms of DCIS may be confused with LCIS, it may be helpful to obtain a second histopathologic interpretation of the biopsy specimen.


Intraductal carcinoma

The customary treatment of DCIS was previously mastectomy. This treatment results in a combined local and distant recurrence rate of 1% to 2%. Experience with breast-conserving surgery and radiation therapy suggests that it is a reasonable alternative. Breast cancer recurrence rates of 9% to 21% are seen, and one-half of these recurrences are invasive carcinomas. Salvage of recurrences with mastectomy is feasible, and survival remains excellent and comparable to primary mastectomy.[5] Although no randomized comparisons of mastectomy versus breast-conserving surgery plus breast irradiation have been done, the National Surgical Adjuvant Breast and Bowel Project (NSABP) study B- 17 randomly assigned 818 women with localized DCIS and negative margins following excisional biopsy to breast irradiation (50 Gy) or no further therapy.[6-8] On both treatment arms, 80% of the patients were diagnosed by mammography and 70% had small lesions (</=1.0 centimeter). In the irradiated group, 8-year event-free survival was improved, due entirely to a decrease in ipsilateral breast cancers. At 8 years, the cumulative incidence of recurrent DCIS was reduced by radiation from 13.4% to 8.2% (P=.007), and, more importantly, occurrence of invasive cancer decreased from 13.4% to 3.9% (P<.001). Overall, 14 deaths (1.1%) from breast cancer have been reported thus far in this trial. The NSABP investigators concluded that local excision and breast irradiation are acceptable alternatives to mastectomy for treatment of localized DCIS.

To determine whether patients at high risk for recurrence could be identified, the NSABP analyzed the pathologic material submitted for central review from 573 of the original cohort of 818 women randomized in B-17.[9] Only the absence of clear tumor margins and moderate to marked comedonecrosis were independent predictors of ipsilateral breast tumor recurrence. However, even among cases with these risk factors, the rate of recurrence after local excision and irradiation was not sufficiently increased to make mastectomy necessarily preferable to complete local excision and irradiation.

In addition to the B-17 randomized study results, several retrospective, nonrandomized series from single institutions have demonstrated that there is a low ipsilateral recurrence rate following local excision alone in carefully selected cases. Recurrence and the occurrence of invasive cancer appear to decrease with the addition of breast irradiation, even for the lowest-risk lesions, and this knowledge should be factored into the decision-making process of those choosing excision alone. There is much debate among pathologists over how to best identify low-risk DCIS lesions. Several pathologic staging systems have been developed and tested retrospectively, but consensus recommendations have not been achieved.[10-13] The Van Nuys Prognostic Index (VNPI) was used to conduct a retrospective analysis of 333 patients treated with either excision alone or excision and radiation, with a median follow-up of 79 months. The index requires independent, prospective validation prior to its adoption as a paradigm for treatment.[14]

Patients with nonpalpable lesions and microcalcifications detected on mammography who are considered for breast-conserving treatment should undergo careful mammographic evaluation prior to biopsy, followed by needle localization biopsy. Radiography of the oriented specimen should be performed to confirm that the lesion has been excised and to direct pathologic sampling. A pathologist should give a careful gross description of the excised specimen and should ink the specimen margins before sectioning to facilitate margin evaluation on permanent section. The relation between the calcifications and the lesion and the distance from the tumor to the inked margins of resection should be described. Following biopsy, mammography should be repeated to confirm that all suspicious microcalcifications have been removed. If residual microcalcifications are seen on post-biopsy mammography, the primary site should be re-excised prior to beginning radiation therapy. The choice of treatment when there is margin involvement by tumor is a controversial issue. Frequently, if the original excision reveals positive margins, a re-excision is done. Then, the extent of disease in the re-excision is evaluated and a decision is made as to whether radiation therapy or mastectomy is appropriate. A simultaneous low axillary dissection is not recommended, as positive lymph nodes are rare.[15] Those patients with invasive disease in whom lymph node involvement is documented should be managed as described under stage II.

Patients with persistent microscopic involvement of margins after local excision or with a diagnosis of DCIS and evidence of suspicious, diffuse microcalcifications have usually been treated with mastectomy. The NSABP has completed accrual to a trial (B-24) comparing 2 treatment options for these patients. In this trial, 1,800 women with such lesions were randomly assigned, following local excision, to receive either irradiation plus tamoxifen or irradiation plus placebo, but the results are not yet available. There is no defined role for chemotherapy for the treatment of DCIS lesions, and hormonal therapy is under clinical evaluation.

Surgical and radiotherapeutic techniques are extremely important in obtaining an optimal therapeutic result and satisfactory cosmesis. The availability of specialized equipment and radiation oncologists with expertise using these techniques should be considered in the selection of treatment. Radiation side effects that can be minimized with careful attention to technique include: myocardial damage for left-sided breast lesions, radiation pneumonitis, arm edema, brachial plexopathy, and the risk of second malignancies. Sarcomas in the treatment port and secondary leukemias are very rare.[16] One report suggests an increase in contralateral breast cancer for women under the age of 45 who have received radiation. Modern techniques to minimize radiation dose to the contralateral breast should be used to keep the absolute risk as low as possible.[17,18]


Lobular carcinoma in situ

LCIS is a controversial term; some prefer to call this lesion "lobular neoplasia." The lesion is generally widely distributed throughout the breast and is frequently bilateral. Data suggest that LCIS is a risk factor for invasive cancer.[4] With 5-year follow-up, results from a large prospective study from the NSABP of 182 patients with LCIS suggest that the risk of developing invasive breast cancer after excisional biopsy alone is much lower.[4] In this study, there was a 2.2% incidence of invasive ipsilateral breast tumor recurrence and a 1.1% incidence of contralateral breast tumor occurrence. Data from retrospective studies with 25-year follow-up suggest that the patient with LCIS has a 25% chance of developing an invasive cancer (either lobular or, more commonly, infiltrating duct cancer) in either breast within 25 years. The incidence of subsequent cancer is not related to the extent of focal areas of LCIS within the breast. The clinical management of the patient with LCIS is controversial; options include no treatment after biopsy with careful follow-up (physical examination and mammography) or bilateral prophylactic mastectomies. Axillary lymph node dissection is not necessary for the in situ lesion. Many physicians favor periodic examination and mammography without further surgery, provided the patient is aware of the risk of developing invasive cancer and is also aware of the possibility of developing metastatic cancer before a clinical diagnosis is established.[19,20] Patients who have undergone local excision for LCIS are eligible for a large multicenter clinical trial of tamoxifen to prevent development of invasive cancer.[21]

For patients with either LCIS or DCIS who opt for a total mastectomy, reconstructive surgery may be used. It may be done at the time of the mastectomy (immediate reconstruction) or at some subsequent time (delayed reconstruction) in an attempt to restore the anatomical deficit of the mastectomy.[22-25] Breast contour can be restored either by the submuscular insertion of an artificial implant (saline-filled) or by a rectus muscle or other flap. Both procedures offer satisfactory cosmetic results. Insertion of an artificial implant is a relatively simple procedure. A saline-filled tissue expander can be inserted beneath the pectoral muscle. Saline is used to expand it during a period of weeks or months until the desired volume is obtained. The tissue expander is then replaced by a permanent implant. Rectus muscle flaps, which offer a better cosmetic result, require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required. There is no consistent evidence that a silicone implant induces cancer or autoimmune disease. Problems associated with silicone implants include contracture of the capsule around the implant causing hardening and pain, rupture of the implant with release of the silicone gel, and infection.[26-28] In rare instances, either procedure could make a local recurrence of cancer more difficult to detect. Following breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes either in the adjuvant setting or when local disease recurs. Although this does not adversely affect outcome, cosmesis may be affected and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.[27] The use of silicone implants for breast augmentation may make the early detection of breast cancer more difficult by obscuring and compressing breast parenchyma.[26,28,29] The Food and Drug Administration (FDA) has announced that silicone breast implants will be available only through controlled clinical studies. Women who wish to undergo reconstructive surgery following mastectomy will be assured access to those studies. However, the FDA has placed no restrictions on the use of saline-filled breast implants, which may constitute a reasonable alternative.

Standard treatment options for intraductal carcinoma (DCIS):[30-35]

1. Total mastectomy.

2. Breast-conserving surgery with radiation therapy.

Under clinical evaluation:
Lumpectomy with radiation therapy with or without tamoxifen. The NSABP has
completed accrual to a trial (B-24) for which women were randomly
assigned, following local resection, to receive either radiation plus
tamoxifen or radiation plus placebo, but the results are not yet available.

Women who opt for local excision alone or lumpectomy with radiation therapy for DCIS should have careful follow-up with regular mammography and physical examination to detect asynchronous disease in breast tissue recurring in the ipsilateral breast.[36] Women treated with radiation therapy or mastectomy should also have regular physical and mammographic examinations of the contralateral breast because of the risk of a second primary.

Treatment options for lobular carcinoma in situ (LCIS):[37-39]

1. Long-term periodic examination with yearly mammography and follow-up after biopsy without further therapy.[40]

2. A large multicenter clinical trial of tamoxifen to prevent development of invasive cancer.

3. Bilateral total mastectomy.

References:

  1. Ariel IM, Cleary JB, Eds.: Breast Cancer - Diagnosis and Treatment. New York: McGraw-Hill, 1987.

  2. Fonseca R, Hartmann LC, Petersen IA, et al.: Ductal carcinoma in situ of the breast. Annals of Internal Medicine 127(11): 1013-1022, 1997.

  3. Patchefsky AS, Schwartz GF, Finkelstein SD, et al.: Heterogeneity of intraductal carcinoma of the breast. Cancer 63(4): 731-741, 1989.

  4. Fisher ER, Costantino J, Fisher B, et al.: Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17. Cancer 78(7): 1403-1416, 1996.

  5. Solin LJ, Fourquet A, McCormick B, et al.: Salvage treatment for local recurrence following breast-conserving surgery and definitive irradiation for ductal carcinoma in situ (intraductal carcinoma) of the breast. International Journal of Radiation Oncology, Biology, Physics 30(1): 3-9, 1994.

  6. Fisher B, Costantino J, Redmond C, et al.: Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. New England Journal of Medicine 328(22): 1581-1586, 1993.

  7. Fisher B, Dignam J, Wolmark N, et al.: Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from the National Surgical Adjuvant Breast and Bowel Project B-17. Journal of Clinical Oncology 16(2): 441-452, 1998.

  8. Amichetti M, Caffo O, Richetti A, et al.: Ten-year results of treatment of ductal carcinoma in situ (DCIS) of the breast with conservative surgery and radiotherapy. European Journal of Cancer 33(10): 1559-1565, 1997.

  9. Fisher ER, Costantino J, Fisher B, et al.: Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) protocol B-17. Cancer 75(6): 1310-1319, 1995.

  10. Page DL, Lagios MD: Pathologic analysis of the National Surgical Adjuvant Breast Project (NSABP) B-17 trial: unanswered questions remaining unanswered considering current concepts of ductal carcinoma in situ. Cancer 75(6): 1219-1222, 1995.

  11. Fisher ER, Costantino J, Fisher B, et al.: Response - blunting the counterpoint. Cancer 75(6): 1223-1227, 1995.

  12. Holland R, Peterse JL, Millis RR, et al.: Ductal carcinoma in situ: a proposal for a new classification. Seminars in Diagnostic Pathology 11(3): 167-180, 1994.

  13. Silverstein MJ, Poller DN, Waisman JR, et al.: Prognostic classification of breast ductal carcinoma-in-situ. Lancet 345(8958): 1154-1157, 1995.

  14. Silverstein MJ, Lagios MD, Craig PH, et al.: A prognostic index for ductal carcinoma in situ of the breast. Cancer 77(11): 2267-2274, 1996.

  15. Silverstein MJ, Gierson ED, Colburn WJ, et al.: Axillary lymphadenectomy for intraductal carcinoma of the breast. Surgery, Gynecology and Obstetrics 172(3): 211-214, 1991.

  16. Karlsson P, Holmberg E, Samuelsson A, et al.: Soft tissue sarcoma after treatment for breast cancer--a Swedish population-based study. European Journal of Cancer 34(13): 2068-2075, 1998.

  17. Boice JD, Harvey EB, Blettner M, et al.: Cancer in the contralateral breast after radiotherapy for breast cancer. New England Journal of Medicine 326(12): 781-785, 1992.

  18. Fraass BA, Roberson PL, Lichter AS: Dose to the contralateral breast due to primary breast irradiation. International Journal of Radiation Oncology, Biology, Physics 11(3): 485-497, 1985.

  19. Frykberg ER, Santiago F, Betsill WL, et al.: Lobular carcinoma in situ of the breast. Surgery, Gynecology and Obstetrics 164(3): 285-301, 1987.

  20. Ciatto S, Cataliotti L, Cardona G, et al.: Risk of infiltrating breast cancer subsequent to lobular carcinoma in situ. Tumori 78(4): 244-246, 1992.

  21. Wolmark N, National Surgical Adjuvant Breast and Bowel Project: Randomized, Placebo-Controlled Clinical Trial to Determine the Worth of Tamoxifen for Preventing Breast Cancer (Summary Last Modified 01/98), NSABP-P-1, clinical trial, closed, 09/30/1997.

  22. Feller WF, Holt R, Spear S, et al.: Modified radical mastectomy with immediate breast reconstruction. American Surgeon 52(3): 129-133, 1986.

  23. Cunningham BL: Breast reconstruction following mastectomy. In: Najarian JS, Delaney JP, Eds.: Advances in Breast and Endocrine Surgery. Chicago: Year Book Medical Publishers, 1986, pp 213-226.

  24. Scanlon EF.: The role of reconstruction in breast cancer. Cancer 68(Suppl 5): 1144-1147, 1991.

  25. Hang-Fu L, Snyderman RK.: State-of-the-art breast reconstruction. Cancer 68(Suppl 5): 1148-1156, 1991.

  26. Council on Scientific Affairs, American Medical Association: Silicone gel breast implants. Journal of the American Medical Association 270(21): 2602-2606, 1993.

  27. Kuske RR, Schuster R, Klein E, et al.: Radiotherapy and breast reconstruction: clinical results and dosimetry. International Journal of Radiation Oncology, Biology, Physics 21(2): 339-346, 1991.

  28. Bridges AJ, Vasey FB: Silicone breast implants: history, safety, and potential complications. Archives of Internal Medicine 153(23): 2638-2644, 1993.

  29. Kessler DA, Merkatz RB, Schapiro R: A call for higher standards for breast implants. Journal of the American Medical Association 270(21): 2607-2608, 1993.

  30. Stotter AT, McNeese M, Oswald MJ, et al.: The role of limited surgery with irradiation in primary treatment of ductal in situ breast cancer. International Journal of Radiation Oncology, Biology, Physics 18(2): 283-287, 1990.

  31. Bornstein BA, Recht A, Connolly JL, et al.: Results of treating ductal carcinoma in situ of the breast with conservative surgery and radiation therapy. Cancer 67(7): 7-13, 1991.

  32. McCormick B, Rosen PP, Kinne D, et al.: Duct carcinoma in situ of the breast: an analysis of local control after conservation surgery and radiotherapy. International Journal of Radiation Oncology, Biology, Physics 21(2): 289-292, 1991.

  33. Silverstein MJ, Waisman JR, Gierson ED, et al.: Radiation therapy for intraductal carcinoma. Is it an equal alternative? Archives of Surgery 126(4): 424-428, 1991.

  34. Schnitt SJ, Silen W, Sadowsky NL, et al.: Ductal carcinoma in situ (intraductal carcinoma) of the breast. New England Journal of Medicine 318(14): 898-903, 1988.

  35. Solin LJ, Fowble BL, Yeh I, et al.: Microinvasive ductal carcinoma of the breast treated with breast-conserving surgery and definitive irradiation. International Journal of Radiation Oncology, Biology, Physics 23(5): 961-968, 1992.

  36. Orel SG, Troupin RH, Patterson EA, et al.: Breast cancer recurrence after lumpectomy and irradiation: role of mammography in detection. Radiology 183(1): 201-206, 1992.

  37. Walt AJ, Simon M, Swanson GM: The continuing dilemma of lobular carcinoma in situ. Archives of Surgery 127(8): 904-909, 1992.

  38. Rosen PP: Lobular Carcinoma In Situ and Intraductal Carcinoma of the Breast. In: McDivitt RW, Okerman MA, Ozzello L, et al., Eds.: The Breast Book. Baltimore: Williams and Wilkens, 1984, pp 59-105.

  39. Osborne MP, Hoda SA: Current management of lobular carcinoma in situ of the breast. Oncology (Huntington NY) 8(2): 45-49, 1994.

  40. Jager JJ, Langendijk JA, Dohmen JP, et al.: Mammography in the follow-up after breast-conserving treatment in cancer of the breast: suitability for mammographic interpretation, validity and interobserver variation. British Journal of Radiology 68(811): 754-760, 1995.


STAGE I BREAST CANCER

Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information.


Primary therapy

Stage I breast cancer is often curable with a variety of surgical procedures. However, 10 to 20 year follow-up of patients managed with surgery alone now reveals that as many as 21% may ultimately relapse.[1] Surgical procedures that conserve a major portion of the involved breast, followed by radiation therapy, provide tumor control equivalent to more extensive surgical procedures. The diagnostic biopsy and the surgical procedure that will be used as initial treatment are often performed as 2 separate procedures. After the presence of a malignancy is confirmed and the histology is determined, treatment options should be discussed with the patient before definitive therapy is recommended. Estrogen-receptor (ER) and progesterone-receptor (PR) status should always be determined for the primary tumor.[2]

In many cases, the diagnosis of breast carcinoma using core needle biopsy, fine needle aspiration cytology, or stereotactic core needle biopsy may be sufficient to confirm malignancy. Core needle biopsy is now used in many centers because it provides a large enough specimen for immunocytochemical analysis. It is then appropriate to discuss the therapeutic options to help the patient with the treatment decision. Surgical options include mastectomy, mastectomy with reconstruction, or breast-conserving surgery (i.e., lumpectomy, quadrantectomy) plus radiation therapy. Survival is equivalent with any of these options as documented in prospective randomized trials.[3-10] Selection of the appropriate therapeutic approach depends on the location and size of the lesion, breast size, patient age, appearance of the mammogram, and how the patient feels about preservation of the breast.

Whether young women with germ-line mutations or strong family histories are good candidates for breast-conserving therapy is currently uncertain. Retrospective studies indicate no difference in local failure rates or overall survival when women with strong family histories are compared to similarly treated women without such histories.[11,12][Level of evidence: 3iiiD] However, the group with a positive family history does appear more likely to develop contralateral breast cancer within 5 years.[11] This risk for contralateral tumors may be even greater in women who are positive for BRCA1 and BRCA2 mutations.[13][Level of evidence: 3iiiDi] In view of the available evidence indicating no difference in outcome, women with strong family histories are candidates for breast-conserving treatment. For women with germ- line mutations, further study of breast-conserving treatment is needed.

An axillary lymph node dissection should be performed for histologic study since approximately one-third of patients with clinically negative nodes will have histologic involvement and would be candidates for additional treatment as per stage II with positive axillary nodes. Although most authorities agree that an axillary node dissection in the presence of clinically negative nodes is a necessary staging procedure, controversy exists as to the extent of the procedure because of long-term morbidity (arm discomfort and swelling) associated with an axillary node dissection. Mammographically detected tumors less than or equal to 5 millimeters have an incidence of axillary node involvement ranging from 0% to 3%. This low incidence of nodal involvement may obviate the routine use of axillary dissection in this group of patients.[14] [Level of evidence: 3iii] Whether entire areas of potentially lymph-node-bearing tissue should be removed or whether staging can be accomplished by excision of a specific number of nodes is questioned. In an effort to decrease the morbidity of axillary lymphadenectomy while maintaining accurate staging, several investigators have studied lymphatic mapping and sentinel lymph node (SLN) biopsy in women with invasive breast cancer.[15-17] SLN is defined as the first node in the lymphatic basin that receives primary lymphatic flow. Studies have demonstrated the ability of peritumoral injection of technetium-labeled sulfur colloid alone, or with vital blue dye to identify the SLN in 92% to 98% of patients. These preliminary reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete axillary lymph node dissection. The identification of a SLN without metastatic disease would obviate the need for complete axillary lymphadenectomy. Larger trials must confirm these data before this technique is routinely incorporated into the surgical treatment of breast cancer. Data also suggest that the level of lymph node involvement (I versus II versus III) does not add independent prognostic information to the total number of positive axillary nodes.[18] In addition, ER status, PR status, tumor size, and measures of proliferative capacity (thymidine labeling index, flow cytometry for measurement of S-phase and ploidy) are highly predictive for risk of relapse in the node-negative patient.[1,19,20] Some patients with stage I tumors appear to be at low risk of relapse (for example, those with tumor size less than 1.0 centimeter or with more favorable histologic tumor types, e.g., medullary, mucinous, papillary, tubular) and may not require postoperative adjuvant hormonal therapy or chemotherapy.[21-23] High histologic grade of tumor and high rate of mitosis may identify a high-risk subset of patients with T1 lesions less than 1.0 centimeter.[24] A review of 20 years' experience illustrates the prognostic significance of tumor size and histologic grade in stage I tumors.[25]


Adjuvant therapy

Because a substantial number of patients with node-negative breast cancer ultimately have disease recurrence, several prospective randomized trials have studied adjuvant chemotherapy or hormonal therapy in node-negative breast cancer. Early trials using tamoxifen, including the Nolvadex Adjuvant Trial Organization (NATO) trial [26] and the Scottish trial,[27] suggested disease-free and overall survival benefit for node-negative patients but data were inconclusive. A small randomized trial comparing adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) versus no adjuvant therapy demonstrated improved disease-free and overall survival for poor-prognosis node-negative patients treated with CMF.[28,29]

Three large trials by the National Surgical Adjuvant Breast and Bowel Project (NSABP) have demonstrated significant improvement in disease-free survival after 5 years of follow-up for ER-negative patients treated with adjuvant chemotherapy (methotrexate, fluorouracil (5-FU), and leucovorin) [30,31] and for ER-positive patients treated with adjuvant tamoxifen.[32] Both of these large randomized trials demonstrate an early significant benefit for adjuvant therapy in these groups of node-negative breast cancer patients. In both studies, premenopausal and postmenopausal patients benefitted. NSABP protocol B-20 compared tamoxifen alone to tamoxifen plus chemotherapy (CMF or sequential methotrexate and 5-FU) in patients with node-negative, ER-positive breast cancer. Throughout 5 years of follow-up, the chemotherapy plus tamoxifen regimen resulted in a 91% disease-free survival and a 96% overall survival versus an 87% disease-free survival and a 94% overall survival from tamoxifen alone.[33] An improvement in overall survival has been demonstrated at 5 years in postmenopausal ER-negative women treated with chemotherapy.[34] These trials, coupled with the 3 earlier trials and another intergroup adjuvant chemotherapy trial (INT-0011), demonstrated the efficacy of adjuvant treatment.[35,36]

The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) performed a meta-analysis of systemic treatment of early breast cancer by hormonal, cytotoxic, or biologic therapy methods in randomized trials involving 75,000 women with stage I or II carcinoma who were premenopausal or postmenopausal. In stage I and II postmenopausal women who were ER-positive, tamoxifen at 20 milligrams daily for at least 2 years (or perhaps longer) was found to prevent recurrent disease and increase survival, with the benefits of initial treatment persisting up to 10 years. Some evidence indicates that ER-negative women could receive similar benefits with tamoxifen treatment.[37] There is a decreased incidence of carcinoma in the contralateral breast and decreased cardiovascular mortality in women treated with tamoxifen, based on retrospective analyses. This overview was updated with results presented at a meeting in Oxford in 1995. The analysis of 37,000 patients who received adjuvant tamoxifen versus those who did not receive tamoxifen was published in 1998.[38] The tamoxifen results show a highly significant trend towards greater effect with longer treatment (1 year versus 2 years versus 5 years). The proportional mortality reductions were 12% for 1 year, 17% for 2 years, and 26% for 5 years. The improvement in survival increased throughout the first 10 years. The absolute improvement in 10-year survival rates with 5 years of tamoxifen was 10.9% for node-positive women and 5.6% for node-negative women (both statistically significant). These benefits were present in both pre- and postmenopausal women. The mortality reduction was not statistically significant in ER-negative patients. There was a decreased incidence of contralateral breast cancer, increased incidence of endometrial cancer, and no effect on colorectal cancer. The effect on cardiovascular mortality could not be reliably interpreted due to the small number of events.

Cytotoxic chemotherapy in the EBCTCG, usually with CMF for 6 to 12 months, was shown to decrease recurrences and increase survival in both premenopausal and postmenopausal women with stages I and II disease.[31] The role of ovarian ablation in women younger than 50 years of age was also analyzed. It was found to produce a survival benefit comparable to that seen with chemotherapy in premenopausal women. This has raised the question again of whether a portion of the impact of systemic chemotherapy is through an endocrine mechanism - ovarian ablation. Such a mechanism of action has been postulated in several trials.[39] In a single study, a 12-week chemotherapy regimen induced menopause less frequently than a 36-week regimen and was associated with poorer survival.[40] An additional data-derived analysis of ovarian ablation and chemotherapy postulated an additive effect.[41] The EBCTCG by an indirect analysis also postulated that there would be an additive effect of tamoxifen and cytotoxic chemotherapy in postmenopausal women.[37,42] However, individual randomized trials have generally had inadequate sample sizes to detect the small improvement suggested by the EBCTCG meta-analysis. Even when restricted to node-positive, ER-positive, premenopausal patients, a study of 314 patients was unable to detect a benefit for the addition of oophorectomy to adjuvant chemotherapy.[43] Larger trials testing this concept have completed enrollment and should be able to address this question more definitively. An intergroup trial (INT-0142) in the United States, coordinated by the Eastern Cooperative Oncology Group (E-3193), is evaluating whether oophorectomy is additive to tamoxifen in node-negative, ER-positive or PR-positive, premenopausal women.[44] The ongoing International Breast Cancer Trial VIII compares combination CMF with ovarian suppression (CMF versus goserelin versus sequential CMF and goserelin).[45]

The use of adjuvant tamoxifen has been associated with certain toxic effects. The most important is the development of endometrial cancer which, in large clinical trials, has been reported to occur at a rate that is 2 to 7 times greater than that observed in untreated women.[46-49] A population-based observational study of women with breast cancer who took tamoxifen as adjuvant therapy for 2 years showed no increased risk of ovarian or endometrial cancer and a significant decrease in the risk of developing contralateral breast cancer.[50] There has been some concern raised about increased risk of gastrointestinal malignancy, but these findings are tentative and further study is needed.[51]

Adjuvant chemotherapy is associated with several well-characterized side effects that vary according to the individual drugs used in each regimen. Common side effects include nausea and vomiting, myelosuppression, alopecia, and mucositis. Less common, but serious, side effects include heart failure (if an anthracycline is used), thromboembolic events, and premature menopause.[52]

Adjuvant combinations of tamoxifen and chemotherapy administered concurrently to enhance efficacy may also have enhanced toxic effects. A single study randomly assigned postmenopausal, node-positive, ER-positive women to receive tamoxifen (30 milligrams per day for 2 years) plus CMF (intravenously for 6 months) (n = 353) or tamoxifen alone (n = 352).[52] Of the women receiving combined chemohormonal therapy, 13.6% developed 1 or more thromboembolic events compared with 2.6% in the tamoxifen-alone group (P<.0001). There were also significantly more women on combined treatment who developed severe thromboembolic events (grade 3-5), most of which (39 of 54) occurred while women were actually receiving chemotherapy. However, not all studies that compared concurrent chemotherapy plus tamoxifen with tamoxifen alone have reported rates as high as these. In NSABP B-16, a study that compared tamoxifen (20 milligrams per day for 5 years) plus chemotherapy with doxorubicin plus cyclophosphamide (4 cycles) with tamoxifen alone, 4.9% of the women on combined treatment had thromboembolic events versus 2.1% of women on tamoxifen alone.[53]

Results from the NSABP Protocol B-14, which evaluated 5 years versus 10 years of adjuvant tamoxifen for early-stage breast cancer, indicate no advantage for continuation of tamoxifen beyond 5 years in women with node-negative, ER- positive breast cancers.[54] In view of the proven benefits of 5 years of adjuvant tamoxifen, this treatment should continue to be administered whenever appropriate to women with early-stage breast cancer. The optimal duration of tamoxifen treatment of node-positive patients is unknown. There are no data to suggest that more than 5 years of tamoxifen is beneficial. Therefore, it has been recommended that adjuvant tamoxifen be discontinued after 5 years in all patients. This controversial issue is being studied in ongoing clinical trials.[55-57]

If ER status is used to select adjuvant treatment, the study should be performed in a well-established, skilled laboratory, and ER-indeterminate patients (either because of inadequate tissue sample or equivocal results) should be considered separately. Immunohistochemical assays appear to be at least as reliable as standard ligand-binding assays in predicting response to adjuvant endocrine therapy.[58]


Timing of primary and adjuvant therapy


Chemotherapy

A randomized clinical trial (NSABP B-18) has been performed to evaluate the worth of preoperative chemotherapy in the management of patients with stage I and II breast cancer. After preoperative therapy with 4 cycles of doxorubicin and cyclophosphamide, 80% of the assessable patients had a reduction in tumor size by at least 50%, and 36% had a complete clinical response. More patients treated with preoperative chemotherapy were able to have breast conservation procedures as compared to those patients in the postoperative chemotherapy group (68% versus 60%). Twenty-seven percent of the women in the preoperative therapy group for whom a mastectomy had been planned before randomization underwent a lumpectomy. There was, however, no significant difference in the disease-free, distant disease-free, or overall survival in the patients receiving preoperative chemotherapy as compared to those receiving postoperative chemotherapy.[59][Level of evidence 1iiA] Preoperative chemotherapy may be beneficial in women who desire breast conservation surgery but who would otherwise not be considered candidates due to the size of their tumor.


Radiation and chemotherapy

The optimal sequence of adjuvant chemotherapy and radiation therapy after breast-conserving surgery was studied in a randomized trial.[60] Patients received either chemotherapy first (n=122) consisting of CMFP (cyclophosphamide, methotrexate, fluorouracil, prednisone) plus doxorubicin repeated every 21 days for 4 cycles followed by breast irradiation, or breast irradiation first (n=122) followed by the same chemotherapy. With a median follow-up of 5 years, overall survival was 73% for the radiation-first group and 81% for the chemotherapy-first group (P=0.11). The 5-year crude rates of first recurrence by site in the radiation therapy-first and chemotherapy-first groups, respectively, were 5% and 14% for local recurrence and 32% and 20% for distant or regional recurrence or both. This difference in the pattern of recurrence was of borderline significance (P=0.07). Further analyses revealed that differences in recurrence patterns persisted for most subgroups with the exception of those that had either negative tumor margins or 1 to 3 positive lymph nodes. For these 2 subgroups, sequence assignment made little difference in local or distant recurrence rates, although the statistical power of these subgroup analyses is low. Potential explanations for the increase in distant recurrence noted in the radiation therapy-first group are that chemotherapy was delayed a median of 17 weeks after surgery and that this group received lower chemotherapy dosages due to increased myelosuppression.

Two additional randomized trials,[61,62] while not specifically designed to address the timing of radiation therapy and adjuvant chemotherapy, do add useful information. In the NSABP B-15 trial, patients undergoing breast- conserving surgery received either 1 course of CMF (cyclophosphamide, methotrexate, fluorouracil; n=194) and then received radiation therapy followed by 5 additional cycles of CMF or they received 4 cycles of AC (doxorubicin, cyclophosphamide; n=199) followed by radiation therapy. No differences in disease-free survival, distant disease-free survival, and overall survival were observed between these 2 arms. The International Breast Cancer Study Group (IBCSG) trials VI and VII also varied the timing of radiation therapy with CMF adjuvant chemotherapy.[62] These studies showed that delays in radiation therapy after surgery from 2 to 7 months had no effect on the rate of local recurrence.

Based on the above studies, delaying radiation therapy for several months after breast-conserving surgery until the completion of adjuvant chemotherapy appears safe and may be preferable for patients at high risk of distant dissemination.

Patients on tamoxifen should have routine follow-up pelvic examinations and should be evaluated further if there is any abnormal uterine bleeding. Although 1 retrospective study raised concern that endometrial cancers in women on tamoxifen (40 milligrams per day) had a worse outcome and were characterized by higher grade lesions and a more advanced stage than in women not treated with tamoxifen, other larger studies using standard tamoxifen doses (20 milligrams per day) have failed to demonstrate this finding.[46,63,64] Similar to estrogen, tamoxifen produces endometrial hyperplasia which can be a premalignant change. In a cohort of women without a history of breast cancer randomized to receive tamoxifen or placebo on the British Pilot Breast Cancer Prevention Trial, 16% of those on tamoxifen developed atypical hyperplasia at varying times from the start of treatment (range 3-75 months, median 24 months) while no cases occurred on the control arm.[65] The value of endometrial biopsy, hysteroscopy, and transvaginal ultrasound as screening tools is unclear.[66,67]

Other toxic effects noted with tamoxifen include thromboembolic phenomena, which occurred with an increased frequency of approximately 1% in women on the NSABP trial.[34] Clotting factor changes have been reported in controlled studies of prolonged tamoxifen use at standard doses; antithrombin III, fibrinogen, and platelet counts have been minimally reduced in patients receiving tamoxifen. The relationship of these counts to thromboembolic phenomena is not clear.[68] Patients should be watched for this complication. An additional potential problem is the development of benign ovarian cysts, which occurred in about 10% of women in a single study.[69] Physicians should be aware of this side effect during the annual pelvic examination that is required for women receiving tamoxifen. The relationship between tamoxifen and ovarian tumors requires further study.[70] Short-term toxic effects of tamoxifen in postmenopausal women may include vasomotor symptoms and gynecologic symptoms (vaginal discharge or irritation).[71] Clonidine can ameliorate hot flashes in some patients.[72] Tamoxifen therapy may also be associated with certain beneficial estrogenic effects including decreased total and low-density lipoprotein levels.[73,74] A large controlled Swedish trial has shown a decreased incidence of cardiac disease in postmenopausal women taking tamoxifen. Results were better for women taking tamoxifen for 5 years than in those taking it for 2 years.[75] In another trial, the risk of fatal myocardial infarction was significantly decreased in patients receiving adjuvant tamoxifen for 5 years versus those treated with surgery alone.[74] In NSABP B-14, there was not a statistically significant difference in the number of deaths from coronary heart disease in patients receiving tamoxifen versus placebo.[76] The NSABP B-14 trial has also shown a decrease in heart disease deaths in women who have taken tamoxifen for 5 years.[76] There are now 3 large controlled trials that have shown a decrease in heart disease.[74-76] Controlled studies have associated long-term tamoxifen use with preservation of bone mineral density of the lumbar spine in postmenopausal women.[77-79] In premenopausal women, there may be decreased bone mineral density.[80] Ophthalmologic toxic effects have been reported in patients receiving tamoxifen; such patients who complain of visual problems should be assessed carefully.[81,82] Because the teratogenic potential of tamoxifen is unknown, contraception should be discussed with patients who are premenopausal or of childbearing age and are candidates for treatment with this drug. The usual tamoxifen dosage is 10 milligrams twice daily, but evidence suggests that 20 milligrams once daily is bioequivalent.[83]

Treatment options:

Standard:


Initial surgical management

The surgical procedure for initial treatment depends on the location and size of the lesion, analysis of the mammogram, breast size, patient age, and how the patient feels about preservation of the breast. The primary advantage of breast-conserving surgery (i.e., lumpectomy) plus radiation therapy is cosmesis with breast preservation. Long-term, prospective, randomized studies indicate that survival is equivalent with either modified radical mastectomy or breast- conserving surgery plus radiation therapy.[3-9] All histologic types of invasive breast cancer may be well-treated with breast-conserving surgery plus radiation therapy.[84] The rate of local recurrence in the breast varies with the surgical technique used (lumpectomy, quadrantectomy, segmental mastectomy, and others). It is lowest with extensive local resections such as quadrantectomy [9] and highest with gross total excision.[7] The risk of in- breast recurrence is higher in patients younger than 35 years of age. The use of adjuvant therapy, whether chemotherapy or hormonal therapy, lowers the risk for in-breast recurrence.[3,9]

There is debate as to whether completely clear microscopic margins are necessary.[85-87] Investigators have shown that in patients with positive, [88] close, or unknown margins after an excisional biopsy, large tumors (T2 lesions), positive axillary nodes, tumors with an extensive intraductal component,[89] detectability of the tumor by palpation, and lobular histology correlate with a higher likelihood of finding persistent tumor on re-excision. Patients whose tumors have these characteristics may benefit from a more generous initial excision to avoid the need for a re-excision.[90,91]

Preoperative chemotherapy may be beneficial in women who desire breast conservation surgery but who would otherwise not be considered candidates due to the size of their tumor. A randomized clinical trial (NSABP B-18) has been performed to evaluate the worth of preoperative chemotherapy in the management of patients with stage I and II breast cancer. After preoperative therapy with 4 cycles of doxorubicin and cyclophosphamide, 80% of the assessable patients had a reduction in tumor size by at least 50%, and 36% had a complete clinical response. More patients treated with preoperative chemotherapy were able to have breast conservation procedures as compared to those patients in the postoperative chemotherapy group (68% versus 60%). Twenty-seven percent of the women in the preoperative therapy group for whom a mastectomy had been planned before randomization underwent a lumpectomy. There was, however, no significant difference in the disease-free, distant disease-free, or overall survival in the patients receiving preoperative chemotherapy as compared to those receiving postoperative chemotherapy.[59][Level of evidence 1iiA]

Surgical and radiotherapeutic techniques are extremely important in obtaining an optimal therapeutic result and satisfactory cosmesis. Radiation therapy consists of external-beam radiation to the entire breast. Some of the randomized trials have employed a boost to the primary site,[7,8] others have not.[3] A randomized trial has shown that a 10 Gy boost reduces the risk of early local recurrence (3.6% versus 4.5%, P=0.044).[92][Level of evidence: 1iiDii] If a boost is used, it can be given either with an interstitial radioactive implant or by external-beam radiation, generally with electrons. Axillary radiation is generally not required in patients who have had axillary dissections and may increase the risk of arm edema.[93,94] In patients with 4 or more positive nodes, the addition of supraclavicular radiation results in low rates of supraclavicular nodal recurrence.[93,94] Radiation side effects that can be minimized with careful attention to technique include radiation pneumonitis, arm edema, brachial plexopathy, and the risk of second malignancies. Sarcomas in the treatment field and secondary leukemias are very rare. One report suggests an increase in contralateral breast cancer for women younger than 45 years of age who have received chest wall irradiation after mastectomy.[95] There is no increased risk of contralateral breast cancer for women 45 years of age and older who receive radiation therapy.[96] Modern techniques to minimize the radiation dose to the contralateral breast should be used to keep the absolute risk as low as possible.[97] In nonsmokers, the risk of lung cancer as a result of radiation exposure during treatment of breast cancer is minimal when modern dosimetry techniques are used. Smokers, however, may have an increased risk of lung cancer in the ipsilateral lung.[98]

An overview of randomized studies of surgery alone or with radiation has been done. Since this overview covers studies of radiation therapy after mastectomy, studies of radiation therapy after breast-conserving surgery (i.e., lumpectomy), and studies with start dates from 1949 to 1985, it includes a variety of surgical and radiotherapeutic techniques and adjuvant chemotherapeutic and hormonal treatments.[99][Level of evidence: 1iiA] No clear differences in overall survival were seen between the arms at 10 years. Radiation therapy was associated with a reduced risk of death due to breast cancer (odds ratio, 0.94, 95% confidence interval, 0.88-1.00, p=0.03). However, an increase in non-breast cancer deaths was seen in patients who received radiation (odds ratio 1.24, 95% confidence interval, 1.09-1.42, p=0.002). The absolute increase in risk was particularly greater in women older than 60 years of age (15.3% versus 11.1%) than in women younger than 50 years of age (2.5% versus 2.0%). A separate analysis of the Stockholm and Oslo trials, which were of mastectomy with radiation therapy, was included in the meta-analysis and showed that the increase in non-breast cancer deaths was related to an increase in cardiac mortality, seen in women with cancers of the left breast who had large volumes of the myocardium included in the radiation portals.[100] No increased cardiac mortality was seen in either the Danish or the British Columbian trials, which were more recent trials of mastectomy with chemotherapy followed by radiation therapy. However, these trials included only premenopausal women who would be at lower baseline risk and did not have follow-up for as long as the trials in which the risk was manifest.[100,101]

Two population-based analyses have also revealed an increase in cardiac mortality, primarily in women with cancers of the left breast. One analysis, of 206,523 women in the SEER database, revealed that the overall relative risk for fatal myocardial infarction in cancers of the left breast was 1.17 (95% confidence interval, 1.01-1.36).[102][Level of evidence: 3iB] However, in comparison to the meta-analysis, this risk was seen primarily in women younger than 60 years of age (relative risk=1.98, 95% confidence interval, 1.31-.97). The second analysis, of 54,617 breast cancer patients reported to the Swedish Cancer Registry, revealed a higher mortality due to myocardial infarction in women with cancers of the left breast versus cancers of the right breast (relative risk=1.09, 95% confidence interval, 1.02-1.17).[103][Level of evidence: 3iB] No overall mortality differences were seen. Limitations of these 2 analyses were that radiation treatment, dose, fraction, and technique information were not documented.

It will be important to determine whether this cardiac mortality can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals. Additionally, measures to lower the baseline absolute risk of cardiac disease, such as smoking cessation and lowering of cholesterol levels, may be of benefit in lowering mortality. In reference to technique, a single institution reported no statistically significant increase in cardiac mortality for women with lesions of the left breast in a series of 745 patients irradiated for breast conservation and followed for 12 years.[104][Level of evidence: 3iiiB] However, the study was not sufficiently large to exclude an increase in cardiac mortality in the range described above. Limiting cardiac volume is technically more challenging when treating internal mammary nodes. An ongoing European Organization for Research and Treatment of Cancer study is addressing the issue of the usefulness of this treatment. Long-term, large scale studies of modern radiotherapeutic techniques combined with current, aggressive chemotherapeutic regimens (particularly those containing doxorubicin and taxol) may be necessary to better define the benefits and risks of current combined modality therapies in the post-mastectomy and breast-conservation setting.

Women who opt for radiation therapy should be followed carefully with regular mammography and physical examination to detect asynchronous disease in remaining breast tissue in the ipsilateral breast.[105,106] Women treated with radiation therapy or mastectomy should also have regular physical and mammographic examinations of the contralateral breast because of the risk of a second primary tumor. Women who have initially undergone radiation and who develop a primary tumor in the contralateral breast may be treated with breast- conserving surgery plus radiation therapy for this second tumor with excellent cosmetic results. The development of a contralateral breast cancer is associated with an increased risk of distant recurrence.[107]

Breast-conserving surgery alone without radiation has been compared with breast-conserving surgery followed by radiation in 4 prospective randomized trials.[3,9,108-110] All of the trials demonstrate a higher in-breast recurrence rate overall with breast-conserving surgery alone. No subset has been identified that did not benefit from the addition of radiation. In a report of the NSABP-B06 trial, distant disease-free survival was worse in the node-negative group treated with lumpectomy alone.[3]

Proposals have been made to treat elderly patients with tamoxifen alone and with no surgery. This approach has unacceptably high local recurrence rates and outside of a clinical trial setting should be used only in patients who are not candidates for mastectomy or for breast-conserving surgery plus radiation therapy or for those who refuse these options.[111-113] A study is underway in which patients treated with lumpectomy plus tamoxifen are randomly assigned to receive or not to receive radiation therapy.[114] One report showed that treatment with lumpectomy and radiation in women 65 years of age and older produces survival and freedom-from-recurrence rates similar to those of women younger than 65 years of age.[115]

For patients who opt for a total mastectomy, reconstructive surgery may be used. It may be done at the time of the mastectomy (immediate reconstruction) or at some subsequent time (delayed reconstruction) in an attempt to restore the anatomical deficit of the mastectomy.[116-119] Breast contour can be restored either by the submuscular insertion of an artificial implant (saline-filled) or by a rectus muscle or other flap. Both procedures offer satisfactory cosmetic results. Insertion of an artificial implant is a relatively simple procedure. A saline-filled tissue expander can be inserted beneath the pectoral muscle. Saline is used to expand it during a period of weeks or months until the desired volume is obtained. The tissue expander is then replaced by a permanent implant. Rectus muscle flaps, which offer a better cosmetic result, require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required. There is no convincing evidence that a silicone implant induces cancer or autoimmune disease. Problems associated with silicone implants include contracture of the capsule around the implant causing hardening and pain, rupture of the implant with release of the silicone gel, and infection.[120-122] In rare instances, either procedure could make a local recurrence of cancer more difficult to detect. Following breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes either in the adjuvant setting or when local disease recurs. Although this does not adversely affect outcome, cosmesis may be affected, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.[121] The use of silicone implants for breast augmentation may make the early detection of breast cancer more difficult by obscuring and compressing breast parenchyma.[120,122,123] The Food and Drug Administration (FDA) has announced that silicone breast implants will be available only through controlled clinical studies. Women who wish to undergo reconstructive surgery following mastectomy will be assured access to those studies. However, the FDA has placed no restrictions on the use of saline-filled breast implants, which may constitute a reasonable alternative.

The surgical procedures include:

1. Breast-conserving surgery (lumpectomy, quadrantectomy, or segmental mastectomy) with separate axillary node dissection and radiation therapy to the breast.[3,9]

2. Modified radical or total mastectomy with axillary dissection.[9,124,125]


Adjuvant therapy

1. For suitable ER-negative patients, adjuvant chemotherapy with a proven effective regimen.[28,30] There is continuing controversy concerning the routine use of adjuvant chemotherapy in all patients with ER-negative, node-negative cancers. Patients with a poor prognosis (manifested by poor nuclear differentiation, tumor necrosis, and tumor size >2.0 centimeters) are reasonable candidates for adjuvant chemotherapy. A number of studies have been reported, however, that indicate that a group of patients with small tumors who probably would not benefit from adjuvant chemotherapy could be identified. These include patients with more favorable histologic types of breast cancer, with tumors less than 1.0 centimeter in size, and with diploid tumors with less than a 6% to 10% fraction of cells in S phase.[1]

2. For ER-positive patients, adjuvant chemotherapy [30,35] or tamoxifen (20 milligrams daily).[32,34]

In completed trials, adjuvant therapy was initiated within 6 weeks of surgery. Whether adjuvant therapy is effective if initiated at a later time is unknown.

Under clinical evaluation:

1. Studies of the value of more aggressive adjuvant chemotherapy for subsets of patients with unfavorable prognostic factors.[126,127]

2. No adjuvant therapy for selected subsets of patients with favorable prognostic factors.

3. Studies of the role of ovarian ablation or suppression for premenopausal ER-positive patients.[128,129]

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  83. Buzdar AU, Hortobagyi GN, Frye D, et al.: Bioequivalence of 20-mg once-daily tamoxifen relative to 10-mg twice-daily tamoxifen regimens for breast cancer. Journal of Clinical Oncology 12(1): 50-54, 1994.

  84. Weiss MC, Fowble BL, Solin LJ, et al.: Outcome of conservative therapy for invasive breast cancer by histologic subtype. International Journal of Radiation Oncology, Biology, Physics 23(5): 941-947, 1992.

  85. Schmidt-Ullrich R, Wazer DE, Tercilla O, et al.: Tumor margin assessment as a guide to optimal conservation surgery and irradiation in early stage breast carcinoma. International Journal of Radiation Oncology, Biology, Physics 17(4): 733-738, 1989.

  86. Solin LJ, Fowble BL, Schultz DJ, et al.: The significance of the pathology margins of the tumor excision on the outcome of patients treated with definitive irradiation for early stage breast cancer. International Journal of Radiation Oncology, Biology, Physics 21(2): 279-287, 1991.

  87. Wazer DE, DiPetrillo T, Schmidt-Ullrich R, et al.: Factors influencing cosmetic outcome and complication risk after conservative surgery and radiotherapy for early-stage breast carcinoma. Journal of Clinical Oncology 10(3): 356-363, 1992.

  88. DiBiase SJ, Komarnicky LT, Schwartz GF, et al.: The number of positive margins influences the outcome of women treated with breast preservation for early stage breast carcinoma. Cancer 82(11): 2212-2220, 1998.

  89. Holland R, Connolly JL, Gelman RS, et al.: The presence of an extensive intraductal component following a limited excision correlates with prominent residual disease in the remainder of the breast. Journal of Clinical Oncology 8(1): 113-118, 1990.

  90. Jardines L, Fowble B, Schultz D, et al.: Factors associated with a positive reexcision after excisional biopsy for invasive breast cancer. Surgery 118(5): 803-809, 1995.

  91. Renton SC, Gazet JC, Ford HT, et al.: The importance of the resection margin in conservative surgery for breast cancer. European Journal of Surgical Oncology 22(1): 17-22, 1996.

  92. Romestaing P, Lehingue Y, Carrie C, et al.: Role of a 10-Gy boost in the conservative treatment of early breast cancer: results of a randomized clinical trial in Lyon, France. Journal of Clinical Oncology 15(3): 963-968, 1997.

  93. Recht A, Pierce SM, Abner A, et al.: Regional nodal failure after conservative surgery and radiotherapy for early-stage breast carcinoma. Journal of Clinical Oncology 9(6): 988-996, 1991.

  94. Mehta K, Haffty BG: Long-term outcome in patients with four or more positive lymph nodes treated with conservative surgery and radiation therapy. International Journal of Radiation Oncology, Biology, Physics 35(4): 679-685, 1996.

  95. Boice JD, Harvey EB, Blettner M, et al.: Cancer in the contralateral breast after radiotherapy for breast cancer. New England Journal of Medicine 326(12): 781-785, 1992.

  96. Storm HH, Andersson M, Boice JD, et al.: Adjuvant radiotherapy and risk of contralateral breast cancer. Journal of the National Cancer Institute 84(16): 1245-1250, 1992.

  97. Fraass BA, Roberson PL, Lichter AS: Dose to the contralateral breast due to primary breast irradiation. International Journal of Radiation Oncology, Biology, Physics 11(3): 485-497, 1985.

  98. Inskip PD, Stovall M, Flannery JT: Lung cancer risk and radiation dose among women treated for breast cancer. Journal of the National Cancer Institute 86(13): 983-988, 1994.

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  101. Overgaard M, Hansen PS, Overgaard J, et al.: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. New England Journal of Medicine 337(14): 949-955, 1997.

  102. Paszat LF, Mackillop WJ, Groome PA, et al.: Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the Surveillance, Epidemiology, and End-Results cancer registries. Journal of Clinical Oncology 16(8): 2625-2631, 1998.

  103. Rutqvist LE, Johansson H: Mortality by laterality of the primary tumour among 55,000 breast cancer patients from the Swedish Cancer Registry. British Journal of Cancer 61(6): 866-868, 1990.

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  105. Orel SG, Troupin RH, Patterson EA, et al.: Breast cancer recurrence after lumpectomy and irradiation: role of mammography in detection. Radiology 183(1): 201-206, 1992.

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STAGE II BREAST CANCER

Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information.


Primary therapy

Stage II breast cancer is curable with a range of accepted surgical procedures. Surgical approaches that conserve a portion of the breast, followed by radiation therapy, can provide survival rates equivalent to more extensive surgery. The diagnostic biopsy and surgical procedure that will be used as primary treatment should be performed as 2 separate procedures. After the presence of a malignancy is confirmed and histology is determined, treatment options should be discussed with the patient before a definitive therapeutic procedure is recommended. Estrogen-receptor (ER) and progesterone-receptor (PR) protein status should be determined for the primary tumor.[1]

In many cases, the diagnosis of breast carcinoma using core needle biopsy or fine needle aspiration cytology may be sufficient to confirm malignancy. It is then appropriate to discuss the therapeutic options to help the patient with the treatment decision. The surgeon may then proceed with a single, sequential procedure that includes biopsy, frozen section confirmation of carcinoma, and the surgery elected by the patient.

Surgical options include mastectomy, mastectomy with reconstruction, or breast- conserving surgery (i.e., lumpectomy) plus radiation therapy. Survival is equivalent with any of these options as documented in randomized prospective trials.[2-8] Selection of the appropriate therapeutic approach depends on the location and size of the lesion, analysis of the mammogram, breast size, patient age, and how the patient feels about preserving the breast. An axillary lymph node dissection should be done for staging purposes. In the situation of clinically positive nodes, the axillary dissection may have some local therapeutic benefit.

Postoperative chest wall radiation therapy after mastectomy is not given routinely to all node-positive women. It should be considered in patients who are thought to be in a high-risk group for local-regional failure. Radiation therapy can decrease local-regional recurrence in this group, even among those patients who receive adjuvant chemotherapy.[9-11] Patients at highest risk include those with 4 or more positive nodes, with grossly evident nodal extracapsular nodal extension, or with involved or very close, deep margins of resection of the primary tumor. Patients at somewhat lower risk include those with 1 to 3 involved nodes, in whom other features such as large primary tumor size and/or adverse tumor prognostic factors, including extensive lymphatic/vascular space invasion, should be assessed to determine the level of risk of chest or regional nodal recurrence before postoperative radiation can be recommended.

The indications for postoperative chest wall and regional nodal radiation therapy are undergoing reassessment prompted by publication of 2 trials of combined chemotherapy and radiation with prolonged follow-up in which an overall survival advantage was observed. In the Danish Breast Cancer Cooperative Group protocol 82b, 1708 premenopausal women who were node-positive or T3 N0 or had skin or pectoral fascial invasion, were randomized to receive either cyclophosphamide plus methotrexate plus fluorouracil (CMF) and radiation, or CMF alone after mastectomy. At 10 years, local regional recurrence (9% versus 32%, P<0.001) and overall survival (54% versus 45%, P<0.001) favored the combined arm.[12][Level of evidence: 1iiA] Of note, axillary recurrence was higher in this trial than is typically seen, possibly as a result of the low average number of nodes removed. A similar but smaller trial from British Columbian of 318 premenopausal node-positive women, with 15-year follow-up, showed a trend which did not reach statistical significance: 54% versus 46% (P=0.07).[13][Level of evidence: 1iiA]

These 2 trials need to be placed in the context of the totality of evidence available on this issue. An update of a meta-analysis by the Early Breast Cancer Trialists Collaborative Group comparing radiation therapy after surgery to surgery alone, which included earlier results from the Danish and British Columbian trials, revealed no clear differences in overall survival at 10 years.[12][Level of evidence: 1iiA] A decrease in deaths as a result of breast cancer in patients who received radiation therapy was seen (odds ratio 0.94, 95% confidence interval, 0.88-1.00, P=0.03). Information on toxic effects of treatment is provided later in this section under treatment options.


Adjuvant therapy: stage II positive nodes

Adjuvant combination chemotherapy has been found to prolong the disease-free interval and survival for pre- and postmenopausal patients with positive nodes.[14] The standard duration of administration of such chemotherapy does not exceed 6 months. For node-positive, postmenopausal women with hormone-receptor-positive tumors, adjuvant hormonal therapy with tamoxifen prolongs disease-free interval and overall survival. In this setting, tamoxifen is typically given for up to 5 years.

Cyclophosphamide plus doxorubicin (CA) and cyclophosphamide, methotrexate, and fluorouracil (CMF) seem to produce similar results in terms of disease-free survival in both premenopausal and postmenopausal patients, but there are differences in toxic effects that may influence the choice of regimen.[15] Long term follow-up of women who received cyclophosphamide-containing adjuvant chemotherapy for treatment of breast cancer indicates that the incidence of other solid tumors and secondary leukemia is not much higher than that in the general population.[16] In a trial by the National Surgical Adjuvant Breast and Bowel Project (NSABP-B-16), node-positive women 50 to 59 years of age who were PR-positive and women 60 years of age and older irrespective of receptor status had improved disease-free and overall survival when treated with tamoxifen and chemotherapy (doxorubicin plus cyclophosphamide) compared to those treated with tamoxifen alone.[17] A report from the Eastern Cooperative Oncology Group (ECOG), comparing CMFP and CMFPT to surgery alone in node-positive postmenopausal patients, demonstrated disease-free survival benefit for CMFP chemotherapy in ER-negative patients, but overall survival was not prolonged at the time of analysis. CMFPT, given for 1 year, failed to improve either disease-free or overall survival compared to surgery alone. ER- positive women experienced no benefit on either regimen.[18] A Southwest Oncology Group (SWOG) study of node-positive, postmenopausal, ER-positive women compared tamoxifen alone to CMFVP and CMFVP + tamoxifen. CMFVP alone or in combination with tamoxifen was not superior to tamoxifen alone. In both the SWOG and ECOG studies, the small number of patients entered into these studies may have limited the ability to detect small but important differences. Another small study has indicated that disease-free survival may be increased with prolonged therapy with tamoxifen and 1 year of CMFVP chemotherapy.[19,20] A multicenter study comparing CMF with fluorouracil, epirubicin, and cyclophosphamide (FEC) in premenopausal women shows no difference in overall survival or in relapse-free survival between the 2 treatment groups at 4.5 years.[21] However, another trial compared FEC given on a day 1, day 8 schedule with CMF given on the same schedule. Patients treated with the FEC regimen had superior relapse-free (63% versus 53%; P=.009) and overall (77% versus 70%; P=.03) survival at 5 years. Quality of life during treatment was more adversely affected by FEC, but both groups of patients had equal quality of life at 1 year.[22][Level of evidence: 1iiA] The design of the trial does not allow for a determination of whether anthracycline or dose-intensity or both is responsible for the improved outcome. A trial by Cancer and Leukemia Group B randomized both pre- and post-menopausal, ER-positive and ER-negative, node-positive women to receive cyclophosphamide plus 1 of 2 dose levels of doxorubicin followed by either paclitaxel or no paclitaxel. After chemotherapy, patients with ER-positive tumors were offered a planned course of tamoxifen for 5 years. Preliminary results, in abstract form only, demonstrate no difference in disease-free or overall survival related to the dose of doxorubicin; however, the addition of paclitaxel improved both the disease-free and overall survival, from 86% to 90% and 95% to 97%, respectively.[23][Level of evidence: 1iiDi]

The optimal timing of initiation of adjuvant therapy is uncertain. A single study addressed the use of perioperative adjuvant chemotherapy in node-positive patients. It showed no advantage in disease-free survival when a single cycle of perioperative chemotherapy was given in addition to standard therapy initiated 4 weeks after surgery.[24] A single cycle of immediate postoperative chemotherapy alone was inferior.[25] With regard to duration of therapy, the 10-year survival rate for both premenopausal and postmenopausal women receiving either 6 or 12 cycles of CMF has been shown to be identical.[9]


Adjuvant therapy: stage II negative nodes

Patients with stage IIA, node-negative breast cancer (T2 N0 M0) generally have a lower risk of recurrence than node-positive patients. Relapse may be related to a number of factors, including tumor size. In an analysis of patients with T2 N0 M0 breast cancer, there was a 33% chance of recurrence at 20 years for patients with T = 2.1 to 3.0 centimeters compared to 44% for T = 3.1 to 5.0 centimeters.[26] Because a substantial number of patients with node-negative breast cancer ultimately have disease recurrence, several prospective randomized trials have studied adjuvant chemotherapy or hormonal therapy in node-negative breast cancer. Early trials, including the Nolvadex Adjuvant Trial Organization (NATO) trial [27] and the Scottish trial,[28] suggested disease-free and overall survival benefit for node-negative patients, but data were inconclusive. A small randomized trial comparing adjuvant chemotherapy with CMF versus no adjuvant therapy showed improved disease-free and overall survival for poor-prognosis node-negative patients treated with CMF.[27-29]

Two large trials by the NSABP have demonstrated substantial improvement in disease-free survival after 4 years follow-up for ER-negative patients treated with chemotherapy (methotrexate, fluorouracil, and leucovorin) [30] and for ER-positive patients treated with tamoxifen.[31] Both of these large randomized trials demonstrate an early substantial benefit for adjuvant therapy in these groups of node-negative breast cancer patients, although an improvement in overall survival has not been demonstrated. In both studies, pre- and postmenopausal patients benefitted. These trials, coupled with the 3 earlier trials and another intergroup adjuvant chemotherapy trial (INT-0011), demonstrated the efficacy of adjuvant treatment.[32,33]

The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) performed a meta-analysis of systemic treatment of early breast cancer by hormonal, cytotoxic, or biologic therapy methods in randomized trials involving 75,000 women with stage I or II carcinoma who were pre- or postmenopausal. In stage I and II postmenopausal women who were ER-positive, tamoxifen at 20 milligrams daily for at least 2 years (or perhaps longer) was found to prevent recurrent disease and increase survival, with the benefits of initial treatment persisting up to 10 years. Some evidence indicates that ER-negative, postmenopausal women could receive similar benefits with tamoxifen treatment.[34] There is a decreased incidence of carcinoma in the contralateral breast and decreased cardiovascular mortality in women treated with tamoxifen. This overview was updated with results presented at a meeting in Oxford in 1995. The analysis of 37,000 patients who received adjuvant tamoxifen versus those who did not receive tamoxifen was published in 1998.[35] The tamoxifen results show a highly significant trend towards greater effect with longer treatment (1 year versus 2 years versus 5 years). The proportional mortality reductions were 12% for 1 year, 17% for 2 years, and 26% for 5 years. The improvement in survival increased throughout the first 10 years. The absolute improvement in 10-year survival rates with 5 years of tamoxifen was 10.9% for node-positive women and 5.6% for node-negative women (both statistically significant). These benefits were present in both pre- and postmenopausal women. The mortality reduction was not statistically significant in estrogen-receptor-negative patients. There was a decreased incidence of contralateral breast cancer, increased incidence of endometrial cancer, and no effect on colorectal cancer. The effect on cardiovascular mortality could not be reliably interpreted due to the small number of events.

Cytotoxic chemotherapy in the EBCTCG, usually with CMF for 6 to 12 months, was shown to decrease recurrences and increase survival in both premenopausal and postmenopausal women with stages I and II disease.[14,34] The role of ovarian ablation in women younger than 50 years of age was also analyzed. It was found to produce a survival benefit comparable to that seen with chemotherapy in premenopausal women. This has raised the question again of whether a portion of the impact of systemic chemotherapy is through an endocrine mechanism - ovarian ablation. Such a mechanism of action has been postulated in several trials.[36] In a single study, a 12-week chemotherapy regimen induced menopause less frequently than a 36-week regimen and was associated with poorer survival.[37] An additional data-derived analysis of ovarian ablation and chemotherapy postulated an additive effect.

In the only direct comparison of CMF versus ovarian ablation, disease-free and overall survival rates were identical in 332 premenopausal women with stage II disease.[38] It has been postulated that there should be an additive effect of tamoxifen and cytotoxic chemotherapy in postmenopausal women.[34,14] Clinical trials that address these issues are ongoing.

The use of adjuvant tamoxifen has been associated with certain toxic effects. The most important is the development of endometrial cancer which, in large clinical trials, has been reported to occur at a rate that is 2 to 7 times greater than that observed in untreated women.[39-42] Because of this, patients on tamoxifen should have routine follow-up pelvic examinations and should be examined further if there is any abnormal uterine bleeding. Although 1 retrospective study raised concern that endometrial cancers in women on tamoxifen (40 milligrams per day) had a worse outcome and were characterized by higher grade lesions and a more advanced stage than in women not treated with tamoxifen, other larger studies using standard tamoxifen doses (20 milligrams per day) have failed to demonstrate this finding.[39,43,44]

Similar to estrogen, tamoxifen produces endometrial hyperplasia which can be a premalignant change. In a randomized cohort of patients on tamoxifen or placebo, recruited from the British Pilot Breast Cancer Prevention Trial, 16% of those on tamoxifen developed atypical hyperplasia at varying times from the start of treatment (range 3-75 months, median 24 months) while no cases occurred on the control arm.[45] The value of endometrial biopsy, hysteroscopy, and transvaginal ultrasound as screening tools is unclear.[46,47]

Adjuvant chemotherapy is associated with several well-characterized side effects that vary according to the individual drugs used in each regimen. Common side effects include nausea and vomiting, myelosuppression, alopecia, and mucositis. Less common, but serious, side effects include heart failure (if an anthracycline is used), thromboembolic events, and premature menopause.[48]

Adjuvant combinations of tamoxifen and chemotherapy administered concurrently to enhance efficacy may also have enhanced toxic effects. A single study randomly assigned postmenopausal, node-positive, ER-positive women to receive tamoxifen (30 milligrams per day for 2 years) plus CMF (intravenously for 6 months) (n=353) or tamoxifen alone (n=352).[48] Of the women receiving combined chemohormonal therapy, 13.6% developed 1 or more thromboembolic events compared with 2.6% in the tamoxifen-alone group (P<.0001). There were also significantly more women on combined treatment who developed severe thromboembolic events (grade 3-5), most of which (39 of 54) occurred while women were actually receiving chemotherapy. However, not all studies that compared concurrent chemotherapy plus tamoxifen with tamoxifen alone have reported rates as high as these. In NSABP B-16, a study that compared tamoxifen (20 milligrams per day for 5 years) plus chemotherapy with doxorubicin plus cyclophosphamide (4 cycles) with tamoxifen alone, 4.9% of the women on combined treatment had thromboembolic events versus 2.1% of women on tamoxifen alone.[17] If combined therapy is selected, whether tamoxifen should be given concurrently or following the completion of chemotherapy is also unknown. An Intergroup U.S. Study (INT-0100) has directly posed this question (tamoxifen alone versus cyclophosphamide, doxorubicin, and fluorouracil (CAF) and concurrent tamoxifen versus CAF followed by tamoxifen).[20]

Results from the NSABP Protocol B-14, which evaluated 5 years versus 10 years of adjuvant tamoxifen for early-stage breast cancer, indicate no advantage for continuation of tamoxifen beyond 5 years in women with node-negative, ER- positive breast cancers.[49] In view of the proven benefits of 5 years of adjuvant tamoxifen, this treatment should continue to be administered whenever appropriate to women with early-stage breast cancer. However, the new data suggest that more than 5 years of adjuvant treatment is not warranted in routine clinical practice in this patient population. For node-positive patients, there are no data to suggest that more than 5 years of tamoxifen is beneficial. Therefore, it has been recommended that adjuvant tamoxifen be discontinued after 5 years in all patients. This issue is being studied in ongoing clinical trials.

If ER status is used to select adjuvant treatment, the study should be performed in a well-established, skilled laboratory, and ER-indeterminate patients (either because of inadequate tissue sample or equivocal results) should be considered separately. Immunohistochemical assays appear to be at least as reliable as standard ligand-binding assays in predicting response to adjuvant endocrine therapy.[50]


Timing of primary and adjuvant therapy


Chemotherapy

A randomized clinical trial (NSABP B-18) has been performed to evaluate the worth of preoperative chemotherapy in the management of patients with stage I and II breast cancer. After preoperative therapy with 4 cycles of doxorubicin and cyclophosphamide, 80% of the assessable patients had a reduction in tumor size by at least 50%, and 36% had a complete clinical response. More patients treated with preoperative chemotherapy were able to have breast conservation procedures as compared to those patients in the postoperative chemotherapy group (68% versus 60%). Twenty-seven percent of the women in the preoperative therapy group for whom a mastectomy had been planned before randomization underwent a lumpectomy. There was, however, no significant difference in the disease-free, distant disease-free, or overall survival in the patients receiving preoperative chemotherapy as compared to those receiving postoperative chemotherapy.[51][Level of evidence 1iiA] Preoperative chemotherapy may be beneficial in women who desire breast conservation surgery but who would otherwise not be considered candidates due to the size of their tumor.


Radiation and chemotherapy

The optimal sequence of adjuvant chemotherapy and radiation therapy after breast-conserving surgery was studied in a randomized trial.[52] Patients received either chemotherapy first (n=122) consisting of CMFP (cyclophosphamide, methotrexate, fluorouracil, prednisone) plus doxorubicin repeated every 21 days for 4 cycles followed by breast irradiation or breast irradiation first (n=122) followed by the same chemotherapy. With a median follow-up of 5 years, overall survival was 73% for the radiation-first group and 81% for the chemotherapy-first group (P=0.11). The 5-year crude rates of first recurrence by site in the radiation therapy-first and chemotherapy-first groups, respectively, were 5% and 14% for local recurrence and 32% and 20% for distant or regional recurrence or both. This difference in the pattern of recurrence was of borderline significance (p=0.07). Further analyses revealed that differences in recurrence patterns persisted for most subgroups with the exception of those that had either negative tumor margins or 1 to 3 positive lymph nodes. For these 2 subgroups, sequence assignment made little difference in local or distant recurrence rates, although the statistical power of these subgroup analyses is low. Potential explanations for the increase in distant recurrence noted in the radiation therapy-first group are that chemotherapy was delayed a median of 17 weeks after surgery and that this group received lower chemotherapy dosages due to increased myelosuppression.

Two additional randomized trials,[15,53] while not specifically designed to address the timing of radiation therapy and adjuvant chemotherapy, do add useful information. In the NSABP B-15 trial, patients undergoing breast- conserving surgery received either 1 course of CMF (cyclophosphamide, methotrexate, fluorouracil; n=194) and then received radiation therapy followed by 5 additional cycles of CMF or they received 4 cycles of AC (doxorubicin, cyclophosphamide; n=199) followed by radiation therapy. No differences in disease-free survival, distant disease-free survival, and overall survival were observed between these 2 arms. The International Breast Cancer Study Group (IBCSG) trials VI and VII also varied the timing of radiation therapy with CMF adjuvant chemotherapy.[53] These studies showed that delays in radiation therapy after surgery from 2 to 7 months had no effect on the rate of local recurrence.

Based on the above studies, delaying radiation therapy for several months after breast-conserving surgery until the completion of adjuvant chemotherapy appears safe and may be preferable for patients at high risk of distant dissemination. Other toxic effects noted with tamoxifen include thromboembolic phenomena, which occurred with an increased frequency of approximately 1% in women in the NSABP trial.[32] Clotting factor changes have been reported in controlled studies of prolonged tamoxifen use at standard doses; antithrombin III, fibrinogen, and platelet counts have been minimally reduced in patients receiving tamoxifen. The relationship of these counts to thromboembolic phenomena is not clear.[54] Patients should be watched for this complication. An additional potential problem is the development of benign ovarian cysts, which occurred in about 10% of women in a single study.[55] Physicians should be aware of this side effect during the annual pelvic examination that is required for women receiving tamoxifen. The relationship between tamoxifen and ovarian tumors requires further study.[56] Short-term toxic effects of tamoxifen in postmenopausal women may include vasomotor symptoms and gynecologic symptoms (vaginal discharge or irritation).[57] Clonidine can ameliorate hot flashes in some patients.[58] Tamoxifen therapy may also be associated with certain beneficial estrogenic effects, including decreased total and low-density lipoprotein levels.[59,60] A large controlled Swedish trial has shown a decreased incidence of cardiac disease in postmenopausal women taking tamoxifen. Results were better for women taking tamoxifen for 5 years than in those taking it for 2 years.[61] In another trial, the risk of fatal myocardial infarction was significantly decreased in patients receiving adjuvant tamoxifen for 5 years versus those treated with surgery alone.[60] Controlled studies have associated long-term tamoxifen use with preservation of bone mineral density of the lumbar spine in postmenopausal women.[62-64] In premenopausal women, there may be decreased bone mineral density.[65] Ophthalmologic toxic effects have been reported in patients receiving tamoxifen; such patients who complain of visual problems should be assessed carefully.[66] Because the teratogenic potential of tamoxifen is unknown, contraception should be discussed with patients who are premenopausal or of childbearing age and are candidates for treatment with this drug. The usual tamoxifen dosage is 10 milligrams twice daily, but evidence suggests that 20 milligrams once daily is bioequivalent.[67]

Treatment options:

Standard:


Initial surgical management

The surgical procedure for initial treatment depends on the location and size of the lesion, analysis of the mammogram, breast size, patient age, and how the patient feels about preservation of the breast. The primary advantage of breast-conserving surgery (i.e., lumpectomy) plus radiation therapy is cosmesis with breast preservation. Long-term, prospective, randomized studies indicate that survival is equivalent with either modified radical mastectomy or breast- conserving surgery plus radiation therapy.[2-8] All histologic types of invasive breast cancer may be well-treated with breast-conserving surgery plus radiation therapy.[68] The rate of local recurrence in the breast varies with the surgical technique used. It is lowest with extensive local resections, such as the quadrantectomy,[7] and highest with gross total excision.[3] The risk of in-breast recurrence is higher in patients younger than 35 years of age. The use of adjuvant therapy, whether chemotherapy or hormonal therapy, lowers the risk for in-breast recurrence.[2,7]

There is debate as to whether completely clear microscopic margins are necessary.[69-71] A group from the Joint Center for Radiation Therapy and other investigators have used extensive intraductal component (EIC) as a histopathologic marker to determine extent of resection.[72-76] If EIC is prominently present in grossly normal adjacent breast tissue, a more extensive resection to remove residual intraductal carcinoma is performed. If this would leave a cosmetically unacceptable result, a mastectomy is done. Other investigators have shown that in patients with positive, close, or unknown margins after an excisional biopsy, large tumors (T2 lesions), positive axillary nodes, detectability of the tumor by palpation, and lobular histology correlate with a higher likelihood of finding persistent tumor on re-excision. Patients whose tumors have these characteristics may benefit from a more generous initial excision to avoid the need for a re-excision.[77,78]

Preoperative chemotherapy may be beneficial in women who desire breast conservation surgery but who would otherwise not be considered candidates due to the size of their tumor. A randomized clinical trial (NSABP B-18) has been performed to evaluate the worth of preoperative chemotherapy in the management of patients with stage I and II breast cancer. After preoperative therapy with 4 cycles of doxorubicin and cyclophosphamide, 80% of the assessable patients had a reduction in tumor size by at least 50%, and 36% had a complete clinical response. More patients treated with preoperative chemotherapy were able to have breast conservation procedures as compared to those patients in the postoperative chemotherapy group (68% versus 60%). Twenty-seven percent of the women in the preoperative therapy group for whom a mastectomy had been planned before randomization underwent a lumpectomy. There was, however, no significant difference in the disease-free, distant disease-free, or overall survival in the patients receiving preoperative chemotherapy as compared to those receiving postoperative chemotherapy.[51][Level of evidence 1iiA]

Surgical and radiotherapeutic techniques are extremely important in obtaining an optimal therapeutic result and satisfactory cosmesis. Radiation therapy consists of external-beam radiation to the entire breast. Some of the randomized trials have employed a boost to the primary site,[3,8] others have not.[2] A randomized trial from Lyon has shown that a 10 Gy boost reduces the risk of early local recurrence (3.6% versus 4.5%, P=0.044).[79][Level of evidence: 1iiDii] If a boost is used, it can be given either with an interstitial radioactive implant or by external-beam radiation, generally with electrons. Axillary radiation may not be required in patients who have had axillary dissections.[80,81] In patients with 4 or more positive nodes, the addition of supraclavicular radiation results in low rates of supraclavicular nodal recurrence.[80,81] Radiation side effects that can be minimized with careful attention to technique include myocardial damage for lesions of the left breast, radiation pneumonitis, arm edema, brachial plexopathy, and the risk of second malignancies. Sarcomas in the treatment field and secondary leukemias are very rare. One report suggests an increase in contralateral breast cancer for women younger than 45 years of age who have received chest wall radiation after mastectomy.[82] There is no increased risk of contralateral breast cancer for women 45 years of age and older who receive radiation therapy.[83] Modern techniques to minimize the radiation dose to the contralateral breast should be used to keep the absolute risk as low as possible.[84] In nonsmokers, the risk of lung cancer as a result of radiation exposure during treatment of breast cancer is minimal when modern dosimetry techniques are used. Smokers, however, may have an increased risk of lung cancer in the ipsilateral lung.[85]

Women who opt for radiation therapy should be followed carefully with regular mammography and physical examination to detect recurrent or asynchronous disease in remaining breast tissue in the ipsilateral breast.[86,87] In patients treated with lumpectomy and radiation, detection of in-breast recurrence by physical examination and/or mammography can lead to curative mastectomy. In 1 series of 30 patients who had a local recurrence in the breast after lumpectomy plus radiation therapy and who underwent salvage mastectomy, no distant recurrences were seen later than 6 years after initial local failure, and the disease-free survival following salvage mastectomy was 58% at 5 years and 50% at 10 years.[88-92] Women treated with radiation therapy or mastectomy should also have regular physical and mammographic examinations of the contralateral breast because of the risk of a second primary tumor. Women who have initially undergone radiation and who develop a primary tumor in the contralateral breast may be treated with breast-conserving surgery plus radiation therapy for this second tumor with excellent cosmetic results. The development of a contralateral breast cancer is associated with an increased risk of recurrence.[93]

Breast-conserving surgery alone without radiation has been compared with breast-conserving surgery followed by radiation in 4 prospective randomized trials.[2,7,94,95] All of the trials demonstrate a higher in-breast recurrence rate overall with breast-conserving surgery alone. No subset has been identified that did not benefit from the addition of radiation. In a report of the NSABP-B06 trial, distant disease-free survival was worse in the node- negative group treated with lumpectomy alone.[2]

Proposals have been made to treat elderly patients with tamoxifen alone and with no surgery. This approach has unacceptably high local recurrence rates and outside of a clinical trial setting should be used only in patients who are not candidates for mastectomy or for breast-conserving surgery plus radiation therapy or for those who refuse these options.[96,97] A study is underway in which patients treated with lumpectomy plus tamoxifen are randomly assigned to receive or not to receive radiation therapy.[98] One report showed that treatment with lumpectomy and radiation in women 65 years of age and older produces survival and freedom-from-recurrence rates similar to those of women younger than 65 years of age.[99]

For patients who opt for a total mastectomy, reconstructive surgery may be used. It may be done at the time of the mastectomy (immediate reconstruction) or at some subsequent time (delayed reconstruction) in an attempt to restore the anatomical deficit of the mastectomy.[100-103] Breast contour can be restored either by the submuscular insertion of an artificial implant (saline-filled) or by a rectus muscle or other flap. Both procedures offer satisfactory cosmetic results. Insertion of an artificial implant is a relatively simple procedure. A saline-filled tissue expander can be inserted beneath the pectoral muscle. Saline is used to expand it during a period of weeks or months until the desired volume is obtained. The tissue expander is then replaced by a permanent implant. Rectus muscle flaps, which offer a better cosmetic result, require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required. There is no convincing evidence that a silicone implant induces cancer or autoimmune disease. Problems associated with silicone implants include contracture of the capsule around the implant causing hardening and pain, rupture of the implant with release of the silicone gel, and infection.[104-106] In rare instances, either procedure could make a local recurrence of cancer more difficult to detect. Following breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes either in the adjuvant setting or when local disease recurs. Although this does not adversely affect outcome, cosmesis may be affected, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.[105] The use of silicone implants for breast augmentation may make the early detection of breast cancer more difficult by obscuring and compressing breast parenchyma.[104,106,107] The Food and Drug Administration (FDA) has announced that silicone breast implants will be available only through controlled clinical studies. Women who wish to undergo reconstructive surgery following mastectomy will be assured access to those studies. However, the FDA has placed no restrictions on the use of saline-filled breast implants, which may constitute a reasonable alternative.

The surgical procedures include:

1. Breast-conserving surgery (lumpectomy, quadrantectomy, or segmental mastectomy) with separate axillary node dissection and radiation therapy to the breast.[2,7]

2. Modified radical or total mastectomy with axillary dissection.[7,108,109]

Radiation therapy to the chest wall and regional nodes should be considered for patients at high risk of local-regional recurrence, including those with known residual disease or 4 or more involved nodes.[110]


Adjuvant therapy

1. Following the treatment used to control local disease, adjuvant combination chemotherapy is given to reduce the rate of recurrence and improve survival in pre- and postmenopausal node-positive patients. Many different drug regimens have been developed. Numerous studies have shown that combination chemotherapy is superior to single-agent treatment, and single-agent adjuvant chemotherapy should be avoided outside a clinical trial. The drug combinations listed have been tested and provide therapeutic benefit. Not all have been compared to an untreated control group in prospective randomized trials.[111]
CMF: cyclophosphamide + methotrexate + fluorouracil.[112,113]
Various recognized combinations of cyclophosphamide, doxorubicin, and
fluorouracil.[114]
CA +/- tamoxifen: cyclophosphamide + doxorubicin +/-
tamoxifen.[15,17]

Dose intensity: Retrospective analyses have indicated that the intensity of dose delivery may be important in the clinical outcome. The results of a study suggest that drug doses should not be reduced arbitrarily.[115] Dose intensity is expressed in milligrams per square meter per week. Analyses of trials using a combination of drugs have, in general, given equal weight to the "effective drugs" and have assigned a zero value if a given "standard drug" is not used in a particular regimen. Therefore, there is some degree of subjectivity to these analyses. Nevertheless, using such analyses, response rate (in advanced breast cancer) and freedom from relapse (in stage II breast cancer) have increased with increasing dose intensity. The steepest relationship between dose intensity and outcome has been observed at dose intensities of less than 0.8. Physicians should avoid arbitrary reductions in dose intensity.[116-118] One clinical trial has evaluated the use of actual versus ideal body weight in patients receiving chemotherapy. Obese patients treated at doses appropriate for their actual weight had no greater toxic effects.[119]

2. Following the treatment used to control local disease, adjuvant endocrine therapy with tamoxifen alone is given to reduce the rate of recurrence and improve survival in postmenopausal patients with lymph node involvement and positive hormone receptors. Tamoxifen, either alone or combined with chemotherapy, prolongs disease-free survival when administered for 24 months as adjuvant therapy to postmenopausal women with axillary lymph node metastases. In a large trial of 3887 postmenopausal women with node-positive and node-negative breast cancer randomized to receive either 2 or 5 years of adjuvant tamoxifen, the longer duration of tamoxifen appeared to improve disease-free and overall survival.[120]

3. In node-negative patients:

For ER-negative patients or ER-positive patients with large tumors,
adjuvant chemotherapy with a proven effective regimen.[29,30]
For ER-positive patients, adjuvant chemotherapy [30,32] and/or tamoxifen
(20 milligrams daily).[31,42] Data indicate that the combination may
be superior to tamoxifen alone.[121]

Data from the NSABP-B-16 protocol indicate that patients 50 years of age and older who have hormonally responsive, node-positive tumors treated with chemotherapy (AC) and tamoxifen had a significantly increased disease-free and overall survival when compared with patients given tamoxifen alone. There was no apparent drug interaction between chemotherapy and tamoxifen.[17]

In completed trials, adjuvant therapy was initiated within 6 weeks of surgery. Whether adjuvant therapy is effective if initiated at a later time is unknown.

Under clinical evaluation:

1. Data indicate that primary (neoadjuvant) chemotherapy does allow breast-conserving therapy in patients whose lesion and breast size would not otherwise have allowed this option.[122-125] This NSABP study also reported a significantly decreased incidence of positive nodes in patients receiving preoperative therapy compared to postoperative chemotherapy. Preliminary reports, however, do not show a disease-free survival or overall survival benefit with preoperative chemotherapy.[126]

2. Clinical trials of high-dose chemotherapy with bone marrow transplantation in women with more than 10 positive lymph nodes and in those with 4 to 9 positive lymph nodes.[127,128] Preliminary reports, published only in abstract form, from 2 clinical trials comparing conventional chemotherapy to high-dose chemotherapy with bone marrow transplant or stem cell support in high-risk patients in the adjuvant setting indicate no overall or event-free survival benefit from the high-dose chemotherapy with bone marrow transplant or stem cell support.[129][Level of evidence: 1iiA];[130][Level of evidence: 1iiA] One small trial, also published only in abstract form, showed a statistical survival benefit from high-dose chemotherapy when compared to conventional chemotherapy.[131][Level of evidence: 1iiA] While further follow-up of these studies is required to resolve the role of high-dose consolidation therapy in this setting, the information to date does not support the use of high-dose chemotherapy outside the context of a randomized clinical trial. Women will also need to consider the substantial toxic effects incurred by high-dose chemotherapy including the possibility of treatment-related death, which occured in about 5% of women in these trials.[129]

3. While substantial advances have been made in the past 5 years, the search for optimal adjuvant therapy continues to evolve for all subsets of patients. For this reason, all patients and their physicians are strongly encouraged to participate in controlled clinical trials. [132-135]

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  80. Recht A, Pierce SM, Abner A, et al.: Regional nodal failure after conservative surgery and radiotherapy for early-stage breast carcinoma. Journal of Clinical Oncology 9(6): 988-996, 1991.

  81. Mehta K, Haffty BG: Long-term outcome in patients with four or more positive lymph nodes treated with conservative surgery and radiation therapy. International Journal of Radiation Oncology, Biology, Physics 35(4): 679-685, 1996.

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  83. Storm HH, Andersson M, Boice JD, et al.: Adjuvant radiotherapy and risk of contralateral breast cancer. Journal of the National Cancer Institute 84(16): 1245-1250, 1992.

  84. Fraass BA, Roberson PL, Lichter AS: Dose to the contralateral breast due to primary breast irradiation. International Journal of Radiation Oncology, Biology, Physics 11(3): 485-497, 1985.

  85. Inskip PD, Stovall M, Flannery JT: Lung cancer risk and radiation dose among women treated for breast cancer. Journal of the National Cancer Institute 86(13): 983-988, 1994.

  86. Orel SG, Troupin RH, Patterson EA, et al.: Breast cancer recurrence after lumpectomy and irradiation: role of mammography in detection. Radiology 183(1): 201-206, 1992.

  87. Jager JJ, Langendijk JA, Dohmen JP, et al.: Mammography in the follow-up after breast-conserving treatment in cancer of the breast: suitability for mammographic interpretation, validity and interobserver variation. British Journal of Radiology 68(811): 754-760, 1995.

  88. Aberizk WJ, Silver B, Henderson IC, et al.: The use of radiotherapy for treatment of isolated locoregional recurrence of breast carcinoma after mastectomy. Cancer 58(6): 1214-1218, 1986.

  89. Recht A, Hayes DF: Specific sites of metastatic disease and emergencies: local recurrence. In: Harris Jr, Hellman S, Henderson IC, et al., Eds.: Breast Diseases. Philadelphia: J.B. Lippincott, 1987, pp 508-524.

  90. Abner AL, Recht A, Eberlein T, et al.: Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. Journal of Clinical Oncology 11(1): 44-48, 1993.

  91. Haffty BG, Fischer D, Rose M, et al.: Prognostic factors for local recurrence in the conservatively treated breast cancer patient: a cautious interpretation of the data. Journal of Clinical Oncology 9(6): 997-1003, 1991.

  92. Haffty BG, Fischer D, Beinfield M, et al.: Prognosis following local recurrence in the conservatively treated breast cancer patient. International Journal of Radiation Oncology, Biology, Physics 21(2): 293-298, 1991.

  93. Healey EA, Cook EF, Orav EJ, et al.: Contralateral breast cancer: clinical characteristics and impact on prognosis. Journal of Clinical Oncology 11(8): 1545-1552, 1993.

  94. Veronesi U, Luini A, Del Vecchio M, et al.: Radiotherapy after breast-preserving surgery in women with localized cancer of the breast. New England Journal of Medicine 328(22): 1587-1591, 1993.

  95. Clark RM, McCulloch PB, Levine MN, et al.: Randomized clinical trial to assess the effectiveness of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer. Journal of the National Cancer Institute 84(9): 683-689, 1992.

  96. Akhtar SS, Allan SG, Rodger A, et al.: A 10-year experience of tamoxifen as primary treatment of breast cancer in 100 elderly and frail patients. European Journal of Surgical Oncology 17(1): 30-35, 1991.

  97. Gazet JC, Ford HT, Coombes RC, et al.: Prospective randomized trial of tamoxifen vs surgery in elderly patients with breast cancer. European Journal of Surgical Oncology 20(3): 207-214, 1994.

  98. Hughes KS, Cancer and Leukemia Group B: Phase III Randomized Study of Adjuvant Tamoxifen with vs without Radiotherapy Following Lumpectomy for Carcinoma of the Breast No Greater Than 2 cm with Clinically Negative Axillary Nodes in Women Age 70 and Over (Summary Last Modified 05/1999), CLB-9343, clinical trial, closed, 02/26/1999.

  99. Solin LJ, Schultz DJ, Fowble BL: Ten-year results of the treatment of early-stage breast carcinoma in elderly women using breast-conserving surgery and definitive breast irradiation. International Journal of Radiation Oncology, Biology, Physics 33(1): 45-51, 1995.

  100. Feller WF, Holt R, Spear S, et al.: Modified radical mastectomy with immediate breast reconstruction. American Surgeon 52(3): 129-133, 1986.

  101. Cunningham BL: Breast reconstruction following mastectomy. In: Najarian JS, Delaney JP, Eds.: Advances in Breast and Endocrine Surgery. Chicago: Year Book Medical Publishers, 1986, pp 213-226.

  102. Scanlon EF.: The role of reconstruction in breast cancer. Cancer 68(Suppl 5): 1144-1147, 1991.

  103. Hang-Fu L, Snyderman RK.: State-of-the-art breast reconstruction. Cancer 68(Suppl 5): 1148-1156, 1991.

  104. Council on Scientific Affairs, American Medical Association: Silicone gel breast implants. Journal of the American Medical Association 270(21): 2602-2606, 1993.

  105. Kuske RR, Schuster R, Klein E, et al.: Radiotherapy and breast reconstruction: clinical results and dosimetry. International Journal of Radiation Oncology, Biology, Physics 21(2): 339-346, 1991.

  106. Bridges AJ, Vasey FB: Silicone breast implants: history, safety, and potential complications. Archives of Internal Medicine 153(23): 2638-2644, 1993.

  107. Kessler DA, Merkatz RB, Schapiro R: A call for higher standards for breast implants. Journal of the American Medical Association 270(21): 2607-2608, 1993.

  108. Fisher B, Redmond C, Fisher ER, et al.: Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. New England Journal of Medicine 312(11): 674-681, 1985.

  109. Martin JK, van Heerden JA, Taylor WF, et al.: Is modified radical mastectomy really equivalent to radical mastectomy in treatment of carcinoma of the breast? Cancer 57(3): 510-518, 1986.

  110. Diab SG, Hilsenbeck SG, de Moor C, et al.: Radiation therapy and survival in breast cancer patients with 10 or more positive axillary lymph nodes treated with mastectomy. Journal of Clinical Oncology 16(5): 1655-1660, 1998.

  111. Jones SE, Moon TE, Bonadonna G, et al.: Comparison of different trials of adjuvant chemotherapy in stage II breast cancer using a natural history data base. American Journal of Clinical Oncology 10(5): 387-395, 1987.

  112. Tancini G, Bonadonna G, Valagussa P, et al.: Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles. Journal of Clinical Oncology 1(1): 2-10, 1983.

  113. Bonadonna G, Brusamolino E, Valagussa P, et al.: Combination chemotherapy as an adjuvant treatment in operable breast cancer. New England Journal of Medicine 294(8): 405-410, 1976.

  114. Buzdar AU, Kau SW, Smith TL, et al.: Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. American Journal of Clinical Oncology 12(2): 123-128, 1989.

  115. Budman DR, Berry DA, et al. for the Cancer and Leukemia Group B: Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. Journal of the National Cancer Institute 90(16): 1205-1211, 1998.

  116. Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. Journal of Clinical Oncology 4(8): 1162-1170, 1986.

  117. Focan C, Andrien JM, Closon MT, et al.: Dose-response relationship of epirubicin-based first-line chemotherapy for advanced breast cancer: a prospective randomized trial. Journal of Clinical Oncology 11(7): 1253-1263, 1993.

  118. Hryniuk WM: Average relative dose intensity and the impact on design of clinical trials. Seminars in Oncology 14(1): 65-74, 1987.

  119. Rosner GL, Hargis JB, Hollis DR, et al.: Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: results from Cancer and Leukemia Group B study 8541. Journal of Clinical Oncology 14(11): 3000-3008, 1996.

  120. Swedish Breast Cancer Cooperative Group: Randomized trial of 2 versus 5 years of adjuvant tamoxifen in postmenopausal early-stage breast cancer. Proceedings of the American Society of Clinical Oncology 15: A-171, 126, 1996.

  121. Fisher B, Dignam J, Wolmark N, et al.: Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. Journal of the National Cancer Institute 89(22): 1673-1682, 1997.

  122. Bonadonna G, Veronesi U, Brambilla C, et al.: Primary chemotherapy to avoid mastectomy in tumors with diameters of three centimeters or more. Journal of the National Cancer Institute 82(19): 1539-1545, 1990.

  123. Powles TJ, Hickish TF, Markris A, et al.: Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. Journal of Clinical Oncology 13(3): 547-552, 1995.

  124. Fisher B, Brown A, Mamounas E, et al.: Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. Journal of Clinical Oncology 15(7): 2483-2493, 1997.

  125. Bonadonna G, Valagussa P, Brambilla C, et al.: Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. Journal of Clinical Oncology 16(1): 93-100, 1998.

  126. Fisher B, Brown A, Mamounas E, et al.: Effect of preoperative therapy for primary breast cancer (BC) on local-regional disease, disease-free survival (DFS) and survival (S): results from NSABP B-18. Proceedings of the American Society of Clinical Oncology 16: A-449, 127a, 1997.

  127. Peters WP, Cancer and Leukemia Group B: NCI HIGH PRIORITY CLINICAL TRIAL --- Phase III Randomized Comparison of High-Dose Chemotherapy with Autologous Marrow and Peripheral Stem Cell Support vs Standard-Dose Chemotherapy Following Adjuvant Chemotherapy in Women with Stage II/IIIA Breast Cancer with at Least 10 Positive Axillary Nodes (Summary Last Modified 09/98), CLB-9082, clinical trial, closed, 05/29/1998.

  128. Tallman MS, Eastern Cooperative Oncology Group: NCI HIGH PRIORITY CLINICAL TRIAL --- Phase III Randomized Study of Adjuvant CAF (Cyclophosphamide/Doxorubicin/Fluorouracil) vs Adjuvant CAF Followed by Intensification with High-Dose Cyclophosphamide/Thiotepa plus Autologous Stem Cell Rescue in Women with Stage II/III Breast Cancer At High Risk of Recurrence (Summary Last Modified 12/98), EST-2190, clinical trial, closed, 08/03/1998.

  129. Peters W, Rosner G, et al. for CALGB, SWOG, and NCIC: A prospective, randomized comparison of two doses of combination alkylating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): preliminary results of CALGB 9082/SWOG 9114/NCIC MA-13. Proceedings of the American Society of Clinical Oncology 18: A2, 1a, 1999.

  130. The Scandinavian Breast Cancer Study Group 9401: Results from a randomized adjuvant breast cancer study with high dose chemotherapy with CTCb supported by autologous bone marrow stem cells versus dose escalated and tailored FEC therapy. Proceedings of the American Society of Clinical Oncology 18: A3, 2a, 1999.

  131. Bezwoda WR: Randomised, controlled trial of high dose chemotherapy (HD-CNVp) versus standard dose (CAF) chemotherapy for high risk, surgically treated, primary breast cancer. Proceedings of the American Society of Clinical Oncology 18: A4, 2a, 1999.

  132. Henderson IC, Cancer and Leukemia Group B: Phase III Randomized Study of Adjuvant CA (Cyclophosphamide/Doxorubicin) Comparing Standard- vs Intermediate- vs High-Dose Doxorubicin, with vs without Subsequent Paclitaxel, in Women with Node-Positive Breast Cancer (Summary Last Modified 08/97), CLB-9344, clinical trial, closed, 04/16/1997.

  133. Figlin RA, Southwest Oncology Group: Phase III Randomized Study of Adjuvant Chemotherapy with High-Dose Doxorubicn/Cyclophosphamide vs Doxorubicin Followed by Cyclophosphamide in Women with High-Risk Breast Cancer and 0-3 Positive Nodes (Summary Last Modified 07/97), SWOG-9313, clinical trial, closed, 05/02/1997.

  134. Cobleigh MA, Eastern Cooperative Oncology Group: Phase III Randomized Study of Adjuvant Tamoxifen/Fenretinide vs Tamoxifen/Placebo in Postmenopausal Women with Receptor-Positive Breast Cancer (Summary Last Modified 07/1999), E-EB193, clinical trial, active, 10/04/1995.

  135. Mamounas T, National Surgical Adjuvant Breast and Bowel Project: Phase III Randomized Study of Paclitaxel vs No Further Chemotherapy Following Doxorubicin/Cyclophosphamide for Resected Node-Positive Breast Cancer (Summary Last Modified 07/98), NSABP-B-28, clinical trial, closed, 05/22/1998.


STAGE III BREAST CANCER

Stage III (locally advanced) breast cancer is further classified into stage IIIA and stage IIIB disease. Stage IIIA disease is often operable when axillary lymph nodes are mobile. However, if the lymph nodes are fixed or if the tumor is very large, neoadjuvant chemotherapy is indicated to shrink the tumor before surgery.


Stage IIIA

Treatment options:

Standard:

1. In operable cases, 1 of the following surgical procedures for initial treatment:

Modified radical mastectomy.

Radical mastectomy.

2. Because of the high risk of local recurrence for this stage, radiation therapy should be considered as part of the overall treatment plan:
Postoperative external-beam irradiation to the chest wall. A boost can
be given if clinically indicated for positive or close margins.

3. Chemotherapy regimens with or without hormones are given in conjunction with the above surgical and radiotherapeutic procedures. Chemotherapy can be given prior to surgery in cases where primary resection is not feasible or is technically difficult. Some equally effective combination chemotherapy regimens commonly used are:

CMF: cyclophosphamide + methotrexate + fluorouracil.[1]

CAF: cyclophosphamide + doxorubicin + fluorouracil.[2,3]

CA: cyclophosphamide + doxorubicin.[4]

Under clinical evaluation:
1. Clinical trials evaluating the role of combination chemotherapy with or without hormonal manipulation are ongoing.[5,6] Preliminary data indicate that neoadjuvant preoperative chemotherapy may allow breast conservation therapy in patients whose lesion and breast size would not have allowed this option.[7-9]

2. High-dose chemotherapy with hematopoietic stem cell support.


Stage IIIB (locally advanced, including inflammatory)

The treatment of inflammatory breast cancer is similar to options for stage IIIB or IV breast cancer.[10,11]

In stage IIIB breast cancer, initial surgery is generally limited to biopsy. Removal of residual tumor may be performed if a good response is achieved with chemotherapy with or without radiation therapy.

Treatment options:
Standard:

1. Core needle biopsy, fine-needle aspiration or incisional biopsy for diagnosis and receptor protein assay followed by preoperative chemotherapy. If the patient has a good response, local therapy with surgery and/or irradiation is recommended. If the response is poor, palliative radiation therapy may be recommended.

2. Chemotherapy regimens with or without hormones are given in conjunction with the above surgical and radiotherapeutic procedures. Chemotherapy can be given prior to surgery in cases where primary resection is not feasible or is technically difficult. Commonly used chemotherapy regimens include:

CMF: cyclophosphamide + methotrexate + fluorouracil.

CAF: cyclophosphamide + doxorubicin + fluorouracil.

CA: cyclophosphamide + doxorubicin.

3. If combination chemotherapy is contraindicated, pretreatment with tamoxifen may be recommended for patients whose tumors are positive for estrogen- and progesterone-receptor proteins.

Under clinical evaluation:

1. Phase II studies evaluating newly developed chemotherapeutic or biologic agents may be considered for patients whose local disease is not controllable by standard measures.

2. High-dose chemotherapy with hematopoietic cell support.

References:

  1. Tancini G, Bonadonna G, Valagussa P, et al.: Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles. Journal of Clinical Oncology 1(1): 2-10, 1983.

  2. Buzdar AU, Kau SW, Smith TL, et al.: Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. American Journal of Clinical Oncology 12(2): 123-128, 1989.

  3. Buzdar AU, Smith TL, Powell KC, et al.: Effect of timing of initiation of adjuvant chemotherapy on disease-free survival in breast cancer. Breast Cancer Research and Treatment 2(2): 163-169, 1982.

  4. Fisher B, Redmond C, Fisher ER, et al.: A summary of findings from NSABP: trials of adjuvant therapy. In: Jones SE, Salmon SE, Eds.: Adjuvant Therapy of Cancer IV. New York: Grune and Stratton, Inc., 1984, pp 185-194.

  5. Mamounas T, National Surgical Adjuvant Breast and Bowel Project: Phase III Randomized Study of Paclitaxel vs No Further Chemotherapy Following Doxorubicin/Cyclophosphamide for Resected Node-Positive Breast Cancer (Summary Last Modified 07/98), NSABP-B-28, clinical trial, closed, 05/22/1998.

  6. Henderson IC, Cancer and Leukemia Group B: Phase III Randomized Study of Adjuvant CA (Cyclophosphamide/Doxorubicin) Comparing Standard- vs Intermediate- vs High-Dose Doxorubicin, with vs without Subsequent Paclitaxel, in Women with Node-Positive Breast Cancer (Summary Last Modified 08/97), CLB-9344, clinical trial, closed, 04/16/1997.

  7. Bonadonna G, Veronesi U, Brambilla C, et al.: Primary chemotherapy to avoid mastectomy in tumors with diameters of three centimeters or more. Journal of the National Cancer Institute 82(19): 1539-1545, 1990.

  8. Sener SF, Imperato JP, Khandekar JD, et al.: Achieving local control for inflammatory carcinoma of the breast. Surgery, Gynecology and Obstetrics 175(2): 141-144, 1992.

  9. Smith IE, Walsh G, Jones A, et al.: High complete remission rates with primary neoadjuvant infusional chemotherapy for large early breast cancer. Journal of Clinical Oncology 13(2): 424-429, 1995.

  10. Moore MP, Ihde JK, Crowe JP, et al.: Inflammatory breast cancer. Archives of Surgery 126(3): 304-306, 1991.

  11. Ueno NT, Buzdar AU, Singletary SE, et al.: Combined-modality treatment of inflammatory breast carcinoma: twenty years of experience at M. D. Anderson Cancer Center. Cancer Chemotherapy and Pharmacology 40(4): 321-329, 1997.


STAGE IV BREAST CANCER

Stage IV breast cancer is often responsive to treatment with durable complete remissions attainable in 10% to 20% of patients, although long disease-free survival indicative of cure is rare.[1-3]

Diagnostic surgical procedures are generally limited to those that will permit the determination of histology and estrogen-receptor (ER) and progesterone- receptor (PR) levels. Control of local disease is usually achieved with either surgery or radiation therapy. External-beam irradiation also has a major role in the palliation of symptoms, particularly pain caused by bone metastases.

Patients with bone metastases should be considered for available trials studying the role of bisphosphonates in reducing skeletal morbidity in those with bony metastases. Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity in patients receiving this class of drugs.[4,5] The majority of patients with stage IV breast cancer will respond to a standard chemotherapy regimen used as initial treatment. However, all eligible patients with stage IV breast cancer should be considered for ongoing clinical trials designed to improve therapeutic results in this disease.[6,7] For patients with disease progression after an anthracycline-containing regimen, paclitaxel and docetaxel have produced clinically useful responses. In studies of refractory metastatic breast cancer, response rates to these agents have ranged from 6% to 48% for paclitaxel and from 53% to 57% for docetaxel. However, these agents are associated with substantial toxic effects, including severe neutropenia, fever, complete alopecia, stomatitis, myalgia, neuropathy, asthenia, and rare cases of allergic reactions. In addition, docetaxel can cause cumulative dose-related fluid retention and symptomatic pleural effusions.[8-11]

The optimal treatment duration for patients with responsive or stable disease has been studied by several groups. For patients who attain a complete response to initial therapy, 2 randomized trials have shown a prolonged disease-free survival from immediate treatment with a different chemotherapy regimen compared to observation with treatment upon relapse.[12][Level of evidence: 1iiA];[13][Level of evidence; 1iiA] However, neither of these studies showed an improvement in overall survival for patients who received immediate treatment, and in a single study,[13] survival was actually worse in the immediately-treated group. Similarly, no difference in survival was noted when patients with partial response or stable disease after initial therapy were randomized to either a different chemotherapy versus observation [14] or to a different chemotherapy regimen given at higher versus lower doses.[15][Level of evidence: 1iiA] These 4 studies indicate that different combination regimens of additional chemotherapy immediately following a patient's best response to an induction chemotherapy regimen does not improve survival. In view of the lack of a standard approach, patients requiring second-line regimens are good candidates for clinical trials.

The potential for doxorubicin-induced cardiotoxicity should be considered in the selection of chemotherapeutic regimens for an individual patient. Recognized risk factors for cardiac toxicity include advanced age, prior chest- wall irradiation, prior anthracycline exposure, hypertension, diabetes, and known underlying heart disease. The cardioprotective drug dexrazoxane has been shown in controlled studies to decrease the risk of doxorubicin-induced cardiac toxicity. The use of this agent has permitted patients to receive greater cumulative doses of doxorubicin and allowed patients with cardiac risk factors to receive doxorubicin.[16-19] Dexrazoxane has a similar protective effect in patients receiving epirubicin.[20] The risks of cardiac toxicity may also be reduced by administering doxorubicin as a continuous intravenous infusion.[21]

Treatment options:

Standard:

1. A biopsy to determine histology and ER and PR levels. External-beam radiation therapy or a palliative mastectomy may be recommended to control local disease.

2. If visceral disease is minimal or absent and ER and PR status is positive, hormonal therapy is an excellent first treatment.

Tamoxifen, toremifene, or oophorectomy (surgical, radiation, or chemical
with LHRH agonists) [22] can be used for premenopausal patients.[23,24]

For patients who relapse following a period of response or prolonged stability on initial hormone therapy, either megestrol acetate (40 milligrams 4 times per day), anastrozole (1 milligram daily),[25] or letrozole [26] (2.5 milligrams) can be valuable palliative treatment.[27,28] Megestrol is associated with weight gain, which may be an undesirable side effect.

3. If visceral disease is present or ER and PR status is negative, 1 of the following combination chemotherapy regimens will produce equivalent results:

CMF: cyclophosphamide + methotrexate + fluorouracil.[29]

CAF: cyclophosphamide + doxorubicin + fluorouracil.[30]

CA: cyclophosphamide + doxorubicin.[31]

Under clinical evaluation:
1. If visceral disease is absent and ER and PR status is positive, clinical trials evaluating the role of hormonal therapy should be considered as first treatment.[32]

2. If visceral disease is present or ER and PR status is negative, clinical trials evaluating the role of combination chemotherapy with and without hormonal therapy should be considered as first treatment.

3. Studies evaluating newly developed chemotherapeutic or biologic agents should also be considered.[8-11,33-37]

4. High-dose chemotherapy with hematopoietic stem cell support.[38,39] A study, published in abstract form only, comparing high-dose chemotherapy with stem cell support to conventional maintenance chemotherapy in patients with metastatic disease indicates no overall or relapse-free survival benefit in patients with high-dose chemotherapy with stem cell support, compared to conventional maintenance.[40][Level of evidence: 1iiA]

References:

  1. Perry MC, Kardinal CG, Korzun AH, et al.: Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081. Journal of Clinical Oncology 5(10): 1534-1545, 1987.

  2. Tannock IF: Treating the patient, not just the cancer. New England Journal of Medicine 317(24): 1534-1535, 1987.

  3. Dhodapkar MV, Ingle JN, Cha SS, et al.: Prognostic factors in elderly women with metastatic breast cancer treated with tamoxifen: an analysis of patients entered on four prospective clinical trials. Cancer 77(4): 683-690, 1996.

  4. Paterson AH, Powles TJ, Kanis JA, et al.: Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. Journal of Clinical Oncology 11(1): 59-65, 1993.

  5. Hortobagyi GN, Theriault RL, Lipton A, et al.: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Journal of Clinical Oncology 16(6): 2038-2044, 1998.

  6. Livingston RB, Southwest Oncology Group: NCI HIGH PRIORITY CLINICAL TRIAL --- Phase III Randomized Comparison of Marrow Ablation with STAMP V (High-Dose CTX/TSPA/CDBCA) and Autologous Stem Cell Rescue vs Standard Chemotherapy in Patients with Poor-Prognosis Advanced Breast Carcinoma (Summary Last Modified 08/93), SWOG-9115, clinical trial, closed, 01/01/1994.

  7. Taylor CW, Southwest Oncology Group: Phase III Randomized Comparison of Surgical Oophorectomy vs Medical Oophorectomy with Goserelin in Premenopausal Women with Metastatic, ER-Positive or PR-Positive Carcinoma of the Breast (Summary Last Modified 02/95), SWOG-8692, clinical trial, closed, 07/15/1995.

  8. Seidman AD, Reichman BS, Crown JP, et al.: Paclitaxel as second and subsequent therapy for metastatic breast cancer: activity independent of prior anthracycline response. Journal of Clinical Oncology 13(5): 1152-1159, 1995.

  9. Gianni L, Munzone E, Capri G, et al.: Paclitaxel in metastatic breast cancer: a trial of two doses by a 3-hour infusion in patients with disease recurrence after prior therapy with anthracyclines. Journal of the National Cancer Institute 87(15): 1169-1175, 1995.

  10. Ravdin PM, Burris HA, Cook G, et al.: Phase II trial of docetaxel in advanced anthracycline-resistant or anthracenedione-resistant breast cancer. Journal of Clinical Oncology 13(12): 2879-2885, 1995.

  11. Valero V, Holmes FA, Walters RS, et al.: Phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. Journal of Clinical Oncology 13(12): 2886-2894, 1995.

  12. Falkson G, Gelman RS, Pandya KJ, et al.: Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment. Journal of Clinical Oncology 16(5): 1669-1676, 1998.

  13. Peters WP, Jones RB, Vrendenburgh J, et al.: A large, prospective, randomized trial of high-dose combination alkylating agents (CPB) with autologous cellular support (ABMS) as consolidation for patients with metastatic breast cancer achieving complete remission after intensive doxorubicin-based induction therapy (AFM). Proceedings of the American Society of Clinical Oncology 15: A-149, 121, 1996.

  14. Muss HB, Case LD, Richards F II, et al.: Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. New England Journal of Medicine 325(19): 1342-1348, 1991.

  15. Falkson G, Gelman RS, Glick J, et al.: Metastatic breast cancer: higher versus low dose maintenance treatment when only a partial response or a no change status is obtained following doxorubicin induction treatment: an Eastern Cooperative Oncology Group study. Annals of Oncology 3(9): 768-770, 1992.

  16. Speyer JL, Green MD, Zeleniuch-Jacquotte A, et al.: ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. Journal of Clinical Oncology 10(1): 117-127, 1992.

  17. Piga A, Francini G, Pein F, et al.: Cardioprotection by Cardioxane (dexrazoxane) in breast cancer patients at increased risk for anthracycline induced cardiotoxicity. Proceedings of the American Association for Cancer Research 34: A-1359, 228, 1993.

  18. Swain SM, Whaley FS, Gerber MC, et al.: Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. Journal of Clinical Oncology 15(4): 1333-1340, 1997.

  19. Swain SM, Whaley FS, Gerber MC, et al.: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. Journal of Clinical Oncology 15(4): 1318-1332, 1997.

  20. Venturini M, Michelotti A, Del Mastro L, et al.: Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. Journal of Clinical Oncology 14(12): 3112-3120, 1996.

  21. Hortobagyi GN, Frye D, Buzdar AU, et al.: Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer 63(1):37-45, 1989.

  22. Hayes DF, Van Zyl JA, Hacking A, et al.: Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. Journal of Clinical Oncology 13(10): 2556-2566, 1995.

  23. Ingle JN, Krook JE, Green SJ, et al.: Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer. Journal of Clinical Oncology 4(2): 178-185, 1986.

  24. Goldberg RM, Loprinzi CL, O'Fallon JR, et al.: Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. Journal of Clinical Oncology 12(1): 155-158, 1994.

  25. Buzdar AU, Jones SE, Vogel CL, et al.: A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma. Cancer 79(4): 730-739, 1997.

  26. Dombernowsky P, Smith I, Falkson G, et al.: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. Journal of Clinical Oncology 16(2): 453-461, 1998.

  27. Jonat W, Howell A, Blomqvist C, et al.: A randomised trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer. European Journal of Cancer 32A(3): 404-412, 1996.

  28. Gershanovich M, Chaudri HA, et al., for the Letrozole International Trial Group (AR/BC3): Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Annals of Oncology 9(6): 639-645, 1998.

  29. Tormey DC, Gelman R, Band PR, et al.: Comparison of induction chemotherapies for metastatic breast cancer: an Eastern Cooperative Oncology Group trial. Cancer 50(7): 1235-1244, 1982.

  30. Smalley RV, Lefante J, Bartolucci A, et al.: A comparison of cyclophosphamide, Adriamycin, and 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine and prednisone (CMFVP) in patients with advanced breast cancer: a Southeastern Cancer Study Group project. Breast Cancer Research and Treatment 3(2): 209-220, 1983.

  31. Tranum BL, McDonald B, Thigpen T, et al.: Adriamycin combinations in advanced breast cancer: a Southwest Oncology Group study. Cancer 49(5): 835-839, 1982.

  32. Rubens RD, Tinson CL, Coleman RE, et al.: Prednisolone improves the response to primary endocrine treatment for advanced breast cancer. British Journal of Cancer 58(5): 626-630, 1988.

  33. Brandt SJ, Peters WP, Atwater SK, et al.: Effect of recombinant human granulocyte-macrophage colony-stimulating factor on hematopoietic reconstitution after high-dose chemotherapy and autologous bone marrow transplantation. New England Journal of Medicine 318(14): 869-876, 1988.

  34. Perez JE, Machiavelli M, Leone BA, et al.: Ifosfamide and mitoxantrone as first-line chemotherapy for metastatic breast cancer. Journal of Clinical Oncology 11(3): 461-466, 1993.

  35. Margolin KA, Doroshow JH, Akman SA, et al.: Effective initial therapy of advanced breast cancer with fluorouracil and high-dose, continuous infusion calcium leucovorin. Journal of Clinical Oncology 10(8): 1278-1283, 1992.

  36. Crown J: A review of the efficacy and safety of docetaxel as monotherapy in metastatic breast cancer. Seminars in Oncology 26(1 suppl 3): 5-9, 1999.

  37. Nabholtz JM, Senn HJ, et al., for the 304 Study Group: Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. Journal of Clinical Oncology 17(5): 1413-1424, 1999.

  38. Bezwoda WR, Seymour L, Dansey RD: High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: a randomized trial. Journal of Clinical Oncology 13(10): 2483-2489, 1995.

  39. Kennedy MJ: High-dose chemotherapy of breast cancer: is the question answered? Journal of Clinical Oncology 13(10): 2477-2479, 1995.

  40. Stadtmauer EA, O'Neill A, Goldstein LJ, et al.: Phase III randomized trial of high-dose chemotherapy (HDC) and stem cell support (SCT) shows no difference in overall survival or severe toxicity compared to maintenance chemotherapy with cyclophosphamide, methotrexate and 5-fluorourcil (CMF) for women with metastatic breast cancer who are responding to conventional induction chemotherapy: the 'Philadelphia' Intergroup study (PBT-1). Proceedings of the American Society of Clinical Oncology 18: A1, 1a, 1999.


INFLAMMATORY BREAST CANCER

The treatment of inflammatory breast cancer is similar to options for stage IIIB or IV breast cancer.[1,2]

References:

  1. Moore MP, Ihde JK, Crowe JP, et al.: Inflammatory breast cancer. Archives of Surgery 126(3): 304-306, 1991.

  2. Lopez MJ, Porter KA: Inflammatory breast cancer. Surgical Clinics of North America 76(2): 411-429, 1996.


RECURRENT BREAST CANCER

Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information.

Recurrent breast cancer is often responsive to therapy although treatment is rarely curative at this stage of the disease. Radiation therapy has a major role in the palliation of locally recurrent disease and symptoms such as pain due to bone metastases. The estrogen-receptor (ER) and progesterone-receptor (PR) levels at the time of recurrence and previous treatment should be considered in selecting therapy. ER levels may change at time of recurrence.[1] In a single study, 36% of ER-positive tumors lost receptor positivity when remeasured at time of recurrence. If ER and PR status is unknown or positive, then the site(s) of recurrence, disease-free interval, response to previous treatment, and menopausal status are useful in selecting chemotherapy or hormonal therapy.[2]

The results of 1 long-term trial indicate that between 10% and 20% of patients will have locally recurrent disease in the breast between 1 and 9 years after breast conservation surgery plus radiation therapy.[3] The patient's age alone (younger than or older than 65 years) is not an independent predictor of response to or toxic effects from doxorubicin-based chemotherapy.[4] Local recurrence is usually the harbinger of widespread disease but, in a subset of patients, may be the only site of recurrence. For patients in this subset, surgery and/or radiation therapy may be curative.[5-7] Patients with chest wall recurrences of less than 3 centimeters, axillary and internal mammary node recurrence (not supraclavicular, which has a poorer survival), and a greater than 2-year disease-free interval prior to resection have the best chance for prolonged survival.[7] The 5-year disease-free survival rate (i.e., without further local or distant relapse) in 1 series of such patients was 25%, with a 10-year rate of 15%.[5] The locoregional control rate was 57% at 10 years.

The prognosis following breast cancer recurrence after lumpectomy plus radiation therapy is much better than that following chest-wall recurrence after mastectomy. Only 9% to 25% of patients undergoing lumpectomy plus radiation therapy will be found to have distant metastases or locally extensive disease preventing mastectomy at the time of recurrence. In 1 series of 30 patients who had a local recurrence in the breast after lumpectomy plus radiation therapy and who underwent salvage mastectomy, no distant recurrences were seen later than 6 years after initial local failure, and the disease-free survival following salvage mastectomy was 58% at 5 years and 50% at 10 years.[8-12]

All patients with recurrent breast cancer should be considered candidates for 1 of the ongoing clinical trials testing newly developed chemotherapeutic and biologic agents in phase II studies. For patients with recurrence after an anthracycline-containing regimen, paclitaxel has been approved by the Food and Drug Administration (FDA) for second-line therapy and docetaxel received formal approval by the FDA.[13]

For patients with disease progression after an anthracycline-containing regimen, paclitaxel and docetaxel have produced significant second-line responses. In studies of refractory metastatic breast cancer, response rates to these agents have ranged from 6% to 48% for paclitaxel and from 53% to 57% for docetaxel. In addition, docetaxel can cause cumulative dose-related fluid retention.[14-17] This can be minimized with the administration of dexamethasone for 3 days beginning the day prior to treatment.

Drugs that have also been approved for treatment of refractory breast cancer include vinorelbine and capecitabine. Capecitabine has demonstrated activity in patients with breast cancer resistant to treatment with paclitaxel.[18]]Level of evidence: 3iiiD] In a single series, 8 of 44 patients (18%) with disease progression while taking paclitaxel responded to docetaxel.[19] Vinorelbine has demonstrated activity in patients who relapse after treatment with an anthracycline-containing regimen [20] and has been effective in producing palliation as first- and second-line treatment in advanced breast cancer.[21]

The potential for doxorubicin-induced cardiotoxicity should be considered in the selection of chemotherapeutic regimens for an individual patient. Recognized risk factors for cardiac toxicity include advanced age, prior chest- wall irradiation, prior anthracycline exposure, hypertension, diabetes, and known underlying heart disease. The cardioprotective drug dexrazoxane has been shown in controlled studies to decrease the risk of doxorubicin-induced cardiac toxicity. The use of this agent has permitted patients to receive greater cumulative doses of doxorubicin and allowed patients with cardiac risk factors to receive doxorubicin.[22,23] The risks of cardiac toxicity may also be reduced by administering doxorubicin as a continuous intravenous infusion.[24]

Treatment options:

1. If visceral disease is absent or is not bulky and confined to 1 organ (e.g., nodular pulmonary metastases) in an asymptomatic patient, and ER and PR status is positive or unknown:

Tamoxifen, toremifene, or oophorectomy (or chemical castration with
luteinizing hormone-releasing hormone (LHRH) agonists [25]) for
premenopausal patients.[26]

Tamoxifen or toremifene for postmenopausal patients.

2. Surgery and/or radiation therapy if recurrence is localized or visceral.[5,27]

3. Patients who respond to additive hormonal therapy and then relapse should be considered for other forms of hormonal therapy such as those therapies in (1) above not previously used or:

Aromatase inhibitors anastrozole,[28,29] letrozole,[30] or vorozole.[31]

Progesterone therapy with megestrol acetate at a dose of 160

milligrams per day.[32]

Androgen therapy for pre- and postmenopausal patients.

LHRH agonists for premenopausal patients.

Aminoglutethimide.[33,34]

Selected patients with an initial response to hormone therapy, generally those with soft tissue disease and/or hormone-receptor-positive disease, may have a response to withdrawal of the hormonal therapy of an average duration of 10 months, at which time another hormonal therapy can be instituted.[35]

4. If visceral disease is present and ER and PR status is negative:

CMF: cyclophosphamide + methotrexate + fluorouracil.[36]

CAF: cyclophosphamide + doxorubicin + fluorouracil.[37]

CA: cyclophosphamide + doxorubicin.[38]

5. Patients may be retreated with the same regimen of CMF used during adjuvant therapy, especially if the relapse occurs 1 or more years after adjuvant therapy. In a single study, results were similar to those of patients who had no prior treatment with CMF.[39][Level of evidence: 3iiiD]

6. Studies evaluating newly developed chemotherapeutic or biologic agents should also be considered.[40,41]

References:

  1. Kuukasjarvi T, Kononen J, Helin H, et al.: Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. Journal of Clinical Oncology 14(9): 2584-2589, 1996.

  2. Perry MC, Kardinal CG, Korzun AH, et al.: Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081. Journal of Clinical Oncology 5(10): 1534-1545, 1987.

  3. Lichter AS, Lippman ME, Danforth DN, et al.: Mastectomy versus breast-conserving therapy in the treatment of stage I and II carcinoma of the breast: a randomized trial at the National Cancer Institute. Journal of Clinical Oncology 10(6): 976-983, 1992.

  4. Ibrahim NK, Frye DK, Buzdar AU, et al.: Doxorubicin-based chemotherapy in elderly patients with metastatic breast cancer: tolerance and outcome. Archives of Internal Medicine 156(8): 882-888, 1996.

  5. Halverson KJ, Perez CA, Kuske RR, et al: Isolated local-regional recurrence of breast cancer following mastectomy: radiotherapeutic management. International Journal of Radiation Oncology, Biology, Physics 19(4): 851-858, 1990.

  6. Schwaibold F, Fowble BL, Solin LJ, et al.: The results of radiation therapy for isolated local regional recurrence after mastectomy. International Journal of Radiation Oncology, Biology, Physics 21(2): 299-310, 1991.

  7. Halverson KJ, Perez CA, Kuske RR, et al.: Survival following locoregional recurrence of breast cancer: univariate and multivariate analysis. International Journal of Radiation Oncology, Biology, Physics 23(2): 285-291, 1992.

  8. Aberizk WJ, Silver B, Henderson IC, et al.: The use of radiotherapy for treatment of isolated locoregional recurrence of breast carcinoma after mastectomy. Cancer 58(6): 1214-1218, 1986.

  9. Recht A, Hayes DF: Specific sites of metastatic disease and emergencies: local recurrence. In: Harris Jr, Hellman S, Henderson IC, et al., Eds.: Breast Diseases. Philadelphia: J.B. Lippincott, 1987, pp 508-524.

  10. Abner AL, Recht A, Eberlein T, et al.: Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. Journal of Clinical Oncology 11(1): 44-48, 1993.

  11. Haffty BG, Fischer D, Rose M, et al.: Prognostic factors for local recurrence in the conservatively treated breast cancer patient: a cautious interpretation of the data. Journal of Clinical Oncology 9(6): 997-1003, 1991.

  12. Haffty BG, Fischer D, Beinfield M, et al.: Prognosis following local recurrence in the conservatively treated breast cancer patient. International Journal of Radiation Oncology, Biology, Physics 21(2): 293-298, 1991.

  13. Hudis CA, Seidman AD, Crown JP, et al.: Phase II and pharmacologic study of docetaxel as initial chemotherapy for metastatic breast cancer. Journal of Clinical Oncology 14(1): 58-65, 1996.

  14. Seidman AD, Reichman BS, Crown JP, et al.: Paclitaxel as second and subsequent therapy for metastatic breast cancer: activity independent of prior anthracycline response. Journal of Clinical Oncology 13(5): 1152-1159, 1995.

  15. Gianni L, Munzone E, Capri G, et al.: Paclitaxel in metastatic breast cancer: a trial of two doses by a 3-hour infusion in patients with disease recurrence after prior therapy with anthracyclines. Journal of the National Cancer Institute 87(15): 1169-1175, 1995.

  16. Ravdin PM, Burris HA, Cook G, et al.: Phase II trial of docetaxel in advanced anthracycline-resistant or anthracenedione-resistant breast cancer. Journal of Clinical Oncology 13(12): 2879-2885, 1995.

  17. Valero V, Holmes FA, Walters RS, et al.: Phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. Journal of Clinical Oncology 13(12): 2886-2894, 1995.

  18. Blum JL, Jones SE, Buzdar AU, et al.: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. Journal of Clinical Oncology 17(2): 485-493, 1999.

  19. Valero V, Jones SE, Von Hoff DD, et al.: A phase II study of docetaxel in patients with paclitaxel-resistant metastatic breast cancer. Journal of Clinical Oncology 16(10): 3362-3368, 1998.

  20. Jones S, Winer E, Vogel C, et al.: Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. Journal of Clinical Oncology 13(10): 2567-2574, 1995.

  21. Weber BL, Vogel C, Jones S, et al.: Intravenous vinorelbine as first-line and second-line therapy in advanced breast cancer. Journal of Clinical Oncology 13(11): 2722-2730, 1995.

  22. Speyer JL, Green MD, Zeleniuch-Jacquotte A, et al.: ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. Journal of Clinical Oncology 10(1): 117-127, 1992.

  23. Piga A, Francini G, Pein F, et al.: Cardioprotection by Cardioxane (dexrazoxane) in breast cancer patients at increased risk for anthracycline induced cardiotoxicity. Proceedings of the American Association for Cancer Research 34: A-1359, 228, 1993.

  24. Hortobagyi GN, Frye D, Buzdar AU, et al.: Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer 63(1):37-45, 1989.

  25. Taylor CW, Green S, Dalton WS, et al.: Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study. Journal of Clinical Oncology 16(3): 994-999, 1998.

  26. Ingle JN, Krook JE, Green SJ, et al.: Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer. Journal of Clinical Oncology 4(2): 178-185, 1986.

  27. Lanza LA, Natarajan G, Roth JA, et al.: Long-term survival after resection of pulmonary metastases from carcinoma of the breast. Annals of Thoracic Surgery 54(2): 244-248, 1992.

  28. Jonat W, Howell A, Blomqvist C, et al.: A randomised trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer. European Journal of Cancer 32A(3): 404-412, 1996.

  29. Buzdar A, Jonat W, Howell A, et al.: Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Journal of Clinical Oncology 14(7): 2000-2011, 1996.

  30. Dombernowsky P, Smith I, Falkson G, et al.: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. Journal of Clinical Oncology 16(2): 453-461, 1998.

  31. Goss PE, Winer EP, Tannock IF, et al.: Randomized phase III trial comparing the new potent and selective third-generation aromatase inhibitor vorozole with megestrol acetate in postmenopausal advanced breast cancer patients. Journal of Clinical Oncology 17(1): 52-63, 1999.

  32. Kornblith AB, Hollis DR, Zuckerman E, et al.: Effect of megestrol acetate on quality of life in a dose-response trial in women with advanced breast cancer. Journal of Clinical Oncology 11(11): 2081-2089, 1993.

  33. Cocconi G, Bisagni G, Ceci G, et al.: Low-dose aminoglutethimide with and without hydrocortisone replacement as a first-line endocrine treatment in advanced breast cancer: a prospective randomized trial of the Italian Oncology Group for Clinical Research. Journal of Clinical Oncology 10(6): 984-989, 1992.

  34. Gale KE, Andersen JW, Tormey DC, et al.: Hormonal treatment for metastatic breast cancer: an Eastern Cooperative Oncology Group phase III trial comparing aminoglutethimide to tamoxifen. Cancer 73(2): 354-361, 1994.

  35. Howell A, Dodwell DJ, Anderson H, et al.: Response after withdrawal of tamoxifen and progestogens in advanced breast cancer. Annals of Oncology 3(8): 611-617, 1992.

  36. Tormey DC, Gelman R, Band PR, et al.: Comparison of induction chemotherapies for metastatic breast cancer: an Eastern Cooperative Oncology Group trial. Cancer 50(7): 1235-1244, 1982.

  37. Smalley RV, Lefante J, Bartolucci A, et al.: A comparison of cyclophosphamide, Adriamycin, and 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine and prednisone (CMFVP) in patients with advanced breast cancer: a Southeastern Cancer Study Group project. Breast Cancer Research and Treatment 3(2): 209-220, 1983.

  38. Tranum BL, McDonald B, Thigpen T, et al.: Adriamycin combinations in advanced breast cancer: a Southwest Oncology Group study. Cancer 49(5): 835-839, 1982.

  39. Castiglione-Gertsch M, Tattersall M, Hacking A, et al.: Retreating recurrent breast cancer with the same CMF-containing regimen used as adjuvant therapy. European Journal of Cancer 33(14): 2321-2325, 1997.

  40. Crown J: A review of the efficacy and safety of docetaxel as monotherapy in metastatic breast cancer. Seminars in Oncology 26(1 suppl 3): 5-9, 1999.

  41. Nabholtz JM, Senn HJ, et al., for the 304 Study Group: Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. Journal of Clinical Oncology 17(5): 1413-1424, 1999.

Date Last Modified: 11/1999



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