PDQ® Treatment Health Professionals
(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. Prognosis and selection of therapy are influenced by the age of the patient, stage of the disease, pathologic characteristics of the primary tumor including the presence of tumor necrosis, estrogen-receptor (ER) and progesterone-receptor (PR) levels in the tumor tissue, 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. 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. Ovarian cancer risk is also elevated in patients with the BRCA1 mutation. 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. 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. 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. 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)  and the International Breast Cancer Study Group (IBCSG)  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. 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, confirming reports by Friedman et al. 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. 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. 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. 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%. The development of a contralateral breast cancer is associated with an increased risk of distant recurrence.
Some retrospective studies suggest that perioperative blood transfusion impairs survival in breast cancer patients. Although other retrospective studies have not confirmed the association between transfusion and prognosis, 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. 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. 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.
Results of a large chemoprevention trial, NSABP P-1, have been published. 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. 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.[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.
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. 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:
carcinoma, NOS (not otherwise specified)
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. -- 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 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.
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.
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. 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. 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. 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. 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.
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. 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. 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.
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. 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. 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]
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. 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. 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.
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. 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.
2. Breast-conserving surgery with radiation therapy.
2. A large multicenter clinical trial of tamoxifen to prevent development of invasive cancer.
3. Bilateral total mastectomy.
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.
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. 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.
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. This risk for contralateral tumors may be even greater in women who are positive for BRCA1 and BRCA2 mutations.[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. [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. 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. A review of 20 years' experience illustrates the prognostic significance of tumor size and histologic grade in stage I tumors.
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  and the Scottish trial, 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. 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. An improvement in overall survival has been demonstrated at 5 years in postmenopausal ER-negative women treated with chemotherapy. 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. 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. 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. 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. In a single study, a 12-week chemotherapy regimen induced menopause less frequently than a 36-week regimen and was associated with poorer survival. An additional data-derived analysis of ovarian ablation and chemotherapy postulated an additive effect. 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. 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. The ongoing International Breast Cancer Trial VIII compares combination CMF with ovarian suppression (CMF versus goserelin versus sequential CMF and goserelin).
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. There has been some concern raised about increased risk of gastrointestinal malignancy, but these findings are tentative and further study is needed.
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.
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). 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.
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. 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.
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.[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.
The optimal sequence of adjuvant chemotherapy and radiation therapy after breast-conserving surgery was studied in a randomized trial. 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. 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. 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. 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. 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. 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. Short-term toxic effects of tamoxifen in postmenopausal women may include vasomotor symptoms and gynecologic symptoms (vaginal discharge or irritation). Clonidine can ameliorate hot flashes in some patients. 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. 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. 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. The NSABP B-14 trial has also shown a decrease in heart disease deaths in women who have taken tamoxifen for 5 years. 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. 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.
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. 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  and highest with gross total excision. 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,  close, or unknown margins after an excisional biopsy, large tumors (T2 lesions), positive axillary nodes, tumors with an extensive intraductal component, 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.[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. 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).[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. There is no increased risk of contralateral breast cancer for women 45 years of age and older who receive radiation therapy. Modern techniques to minimize the radiation dose to the contralateral breast should be used to keep the absolute risk as low as possible. 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.
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.[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. 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).[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).[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.[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.
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.
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. 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.
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. 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:
Under clinical evaluation:
2. No adjuvant therapy for selected subsets of patients with favorable prognostic factors.