In English | En español
Questions About Cancer? 1-800-4-CANCER

Breast Cancer Treatment (PDQ®)

  • Last Modified: 07/11/2014

Page Options

  • Print This Page
  • Print This Document
  • View Entire Document
  • Email This Document

Stage I, II, IIIA, and Operable IIIC Breast Cancer

Primary Therapy
        Local-regional treatment
        Axillary lymph node surgery
        Breast reconstruction
Adjuvant Radiation Therapy
        Post-breast conservation surgery
        Postmastectomy
        Late toxic effects of radiation
Adjuvant Systemic Therapy
        Hormone therapy
        Chemotherapy
        Bisphosphonates
        Monoclonal antibodies
Timing of Primary and Adjuvant Therapy
        Postoperative adjuvant chemotherapy
        Preoperative neoadjuvant chemotherapy
        Bevacizumab
        Adjuvant radiation and chemotherapy
        Timing of surgery
        Chemotherapy risks
        Chemotherapy and tamoxifen risks
Treatment Options
        Primary therapy
Current Clinical Trials



Primary Therapy

Local-regional treatment

Stage I, II, IIIA, and operable IIIC breast cancer often requires a multimodality approach to treatment. Irrespective of the eventual procedure selected, the diagnostic biopsy and surgical procedure that will be used as primary treatment should be performed as two separate procedures. In many cases, the diagnosis of breast carcinoma is made by core needle biopsy. After the presence of a malignancy is confirmed, treatment options should be discussed with the patient before a therapeutic procedure is selected. Estrogen-receptor (ER) and progesterone-receptor (PR) protein status and human epidermal growth factor receptor 2 (HER2/neu) status should be determined for the primary tumor.[1] Additional pathologic characteristics, including grade and proliferative activity may also be of value.[2-5]

Options for surgical management of the primary tumor include breast-conserving surgery plus radiation therapy, mastectomy plus reconstruction, and mastectomy alone. Surgical staging of the axilla should also be performed. Survival is equivalent with any of these options as documented in randomized prospective trials (including the European Organization for Research and Treatment of Cancer's trial [EORTC-10801]).[6-13] Selection of a local therapeutic approach depends on the location and size of the lesion, analysis of the mammogram, breast size, and the patient’s attitude toward preserving the breast. The presence of multifocal disease in the breast or a history of collagen vascular disease are relative contraindications to breast-conserving therapy.[14] A retrospective study of 753 patients who were divided into three groups based on receptor status (ER-positive or PR-positive; ER-negative and PR-negative but HER2/neu-positive; and ER-negative, PR-negative, and HER2/neu-negative [triple-negative]) found no differences in disease control within the breast in patients treated with standard breast-conserving surgery; however, there are not yet substantive data to support this finding.[15]

All histologic types of invasive breast cancer may be treated with breast-conserving surgery plus radiation therapy.[16] The rate of local recurrence in the breast with conservative treatment is low and varies slightly with the surgical technique used (e.g., lumpectomy, quadrantectomy, segmental mastectomy, and others). Whether completely clear microscopic margins are necessary is debatable.[17-19]

Retrospective studies have shown the following examples of tumor characteristics to correlate with a greater likelihood of finding persistent tumor on re-excision:

  • Large tumors (T2 lesions).
  • Positive axillary nodes.
  • Tumors with an extensive intraductal component.[20]
  • Palpable tumors.
  • Lobular histology.

Patients whose tumors have these characteristics may benefit from a more generous initial excision to avoid the need for a re-excision.[21,22]

Radiation therapy (as part of breast-conserving local therapy) consists of postoperative external-beam radiation therapy (EBRT) to the entire breast with doses of 45 Gy to 50 Gy, in 1.8 Gy to 2.0 Gy daily fractions over a 5-week period. Shorter hypofractionation schemes achieve comparable results.[23-25] A further radiation boost is commonly given to the tumor bed. Two randomized trials conducted in Europe have shown that using boosts of 10 Gy to 16 Gy reduces the risk of local recurrence from 4.6% to 3.6% at 3 years (P = .044),[26][Level of evidence: 1iiDiii] and from 7.3% to 4.3% at 5 years (P < .001), respectively.[27][Level of evidence: 1iiDiii] If a boost is used, it can be delivered either by EBRT, generally with electrons, or by using an interstitial radioactive implant.[28]

The age of the patient should not be a determining factor in the selection of breast-conserving treatment versus mastectomy. A study has shown that treatment with lumpectomy and radiation therapy in women 65 years and older produces survival and freedom-from-recurrence rates similar to those of women younger than 65 years.[29] Whether young women with germ-line mutations or strong family histories are good candidates for breast-conserving therapy is not certain. Retrospective studies indicate no difference in local failure rates or overall survival (OS) when women with strong family histories are compared with similarly treated women without such histories.[30,31][Level of evidence: 3iiiDii] The group with a positive family history, however, does appear more likely to develop contralateral breast cancer within 5 years.[30] This risk for contralateral tumors may be even greater in women who are positive for BRCA1 and BRCA2 mutations.[32][Level of evidence: 3iiiDii] Because of the available evidence indicating no difference in outcome, women with strong family histories should be considered candidates for breast-conserving treatment. For women with germ-line mutations in BRCA1 and BRCA2, further study of breast-conserving treatment is needed.

Breast-conserving surgery alone without radiation therapy has been compared with breast-conserving surgery followed by radiation therapy in six prospective randomized trials (including the National Surgical Adjuvant Breast and Bowel Project's trial [NSABP-B-06] and the Cancer and Leukemia Group B's trial [CLB-9343]).[6,33-37] In two of these trials, all patients also received adjuvant tamoxifen.[36,37] Every trial demonstrated a lower in-breast recurrence rate with radiation therapy, and this effect was present in all patient subgroups. In some groups, for example, women with receptor-positive small tumors [36] and those older than 70 years,[38] the absolute reduction in the rate of recurrence was small (<5%). The limited impact of radiation therapy in this group of women was also reported in a confirmatory observational study looking at in-breast control rates using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database.[39] The impact of radiation therapy on local control was additionally clarified by showing that healthy women aged 70 to 79 years were most likely to benefit from radiation therapy (number needed to treat [NNT] to prevent one event = 21–22 patients) when compared with women aged 80 years or older or to those who have comorbidities (NNT = 61–125 patients).[39] The administration of radiation therapy may be associated with short-term morbidity, inconvenience, and potential long-term complications.[38]

Axillary lymph node surgery

The axillary lymph nodes should be staged to aid in determining prognosis and therapy. Sentinel lymph node (SLN) biopsy is the initial standard axillary staging procedure performed in women with invasive breast cancer. The SLN is defined as any node that receives drainage directly from the primary tumor; therefore, allowing for more than one SLN, which is often the case. Studies have shown that the injection of technetium-labeled sulfur colloid, vital blue dye, or both around the tumor or biopsy cavity, or in the subareolar area, and subsequent drainage of these compounds to the axilla results in the identification of the SLN in 92% to 98% of patients.[40,41] These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete axillary lymph node dissection (ALND).[42-45]

A multicenter randomized phase III trial of 5,611 patients randomly assigned to either SLN plus ALND or to SLN resection alone with ALND only if the SLNs were positive showed no detectable difference in OS, disease-free survival (DFS), and regional control. OS was 91.8% versus 90.3% for SLN plus ALND and SLN resection alone, respectively (P = .12).[46][Level of evidence: 1iiA]

Similarly, a single-center randomized trial of 532 patients with T1 carcinomas undergoing either SLN biopsy plus complete axillary dissection or SLN biopsy alone showed, after a median follow-up of 78 months, no difference in 5-year DFS (92.9% in the SLN biopsy without routine axillary dissection group vs. 88.9% in patients having axillary dissection irrespective of SLN findings, P = .1).[47][Level of evidence: 1iiDii]

The reported false-negative rates of SLN biopsy using axillary node dissection as the gold standard range from 0% to 15% with an average of 8.8%.[48] The success rate varies with the surgeon’s experience and with the primary tumor characteristics. In general, studies have restricted the use of SLN biopsy to women with T1 and T2 disease, without evidence of multifocal involvement or clinically positive lymph nodes. SLN biopsy alone is associated with less morbidity than axillary lymphadenectomy. In a randomized trial of 1,031 women that compared SLN biopsy followed by axillary dissection when the SLN was positive with axillary dissection in all patients, quality of life at 1 year (as assessed by the frequency of patients experiencing a clinically significant deterioration in the Trial Outcome Index of the Functional Assessment of Cancer Therapy-Breast scale) was superior in the SLN biopsy group (23% vs. 35% deteriorating in the SLN biopsy vs. axillary dissection groups, respectively; P = .001).[49][Level of evidence 1iiC] Arm function was also better in the SLN group. The NSABP-B-32 (NCT00003830) trial, a randomized study of 5,611 women, found the same results with respect to accuracy and technical success.[50] Based on this body of evidence, SLN biopsy is the standard initial surgical staging procedure of the axilla for women with invasive breast cancer.

A multicenter, randomized clinical trial sought to determine whether ALND is required after an SLN biopsy reveals an SLN metastasis of breast cancer.[51] This phase III noninferiority trial planned to randomly assign 1,900 women with clinical T1–T2 invasive breast cancer without palpable adenopathy and with one to two SLNs containing metastases identified by frozen section to undergo ALND versus no further axillary treatment. All patients underwent lumpectomy, tangential whole-breast irradiation, and appropriate systemic therapy, and OS was the primary endpoint. Because of enrollment challenges, a total of 891 women out of a target enrollment of 1,900 women were randomly assigned to one of the two treatment arms. At a median follow-up of 6.3 years, 5-year OS was 91.8% (95% confidence interval [CI], 89.1%–94.5%) with ALND and 92.5% (95% CI, 90.0–95.1%) with SLN biopsy alone. The secondary endpoint of 5-year disease-free survival (DFS) was 82.2% (95% CI, 78.3%–86.3%) with ALND and 83.9% (95% CI, 80.2%–87.9%) with SLN biopsy alone.[51][Level of evidence: 1iiA] In a second, similarly designed trial, 929 women with breast tumors smaller than 5 cm and SLN involvement smaller than 2 mm were randomly assigned to receive or not receive axillary lymph node dissection. Patients without axillary dissection had fewer DFS events (hazard ratio [HR], 0.78; 95% CI, 0.55–1.11). No difference in OS was observed.[52][Level of evidence: 1iiA] On the basis of the results of these trials, the medical necessity of ALND after a positive SLN biopsy in patients with limited SLN-positive breast cancer treated with breast conservation, radiation, and systemic therapy is called into question.

For patients who require an ALND, the standard evaluation usually involves only a level I and II dissection, thereby removing a satisfactory number of nodes for evaluation (i.e., 6–10 at least), while reducing morbidity from the procedure. Several groups have attempted to define a population of women in whom the probability of nodal metastasis is low enough to preclude axillary node biopsy. In these single-institution case series, the prevalence of positive nodes in patients with T1a tumors ranged from 9% to 16%.[53,54] In another series, the incidence of axillary node relapse in patients with T1a tumors treated without ALND was 2%.[55][Level of evidence: 3iiiA] Because the axillary node status remains the most important predictor of outcome in breast cancer patients, insufficient evidence is available to recommend that lymph node staging can be omitted in most patients with invasive breast cancer.

Breast reconstruction

For patients who opt for a total mastectomy, reconstructive surgery may be used at the time of the mastectomy (i.e., immediate reconstruction) or at some subsequent time (i.e., delayed reconstruction).[56-59] Breast contour can be restored by the submuscular insertion of an artificial implant (saline-filled) or a rectus muscle or other flap. If a saline implant is used, a tissue expander can be inserted beneath the pectoral muscle. Saline is injected into the expander to stretch the tissues for a period of weeks or months until the desired volume is obtained. The tissue expander is then replaced by a permanent implant. (Visit the U. S. Food and Drug Administration's (FDA's) Web site for more information on breast implants.) Rectus muscle flaps require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required.

Following breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes either in the adjuvant setting or if local disease recurs. Radiation therapy following reconstruction with a breast prosthesis may affect cosmesis, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.[60]

Adjuvant Radiation Therapy

Radiation therapy is regularly employed after breast-conserving surgery. Radiation therapy also can be indicated for postmastectomy patients. The main goal of adjuvant radiation therapy is to eradicate residual disease thus reducing local recurrence.[61]

Post-breast conservation surgery

For women who are treated with breast-conserving surgery without radiation therapy, the risk of recurrence in the conserved breast is substantial (>20%) even in confirmed axillary lymph node-negative women. Thus, whole-breast radiation therapy after breast-conserving surgery is recommended.[62]

Although all trials assessing the role of radiation therapy in breast-conserving therapy have shown highly statistically significant reductions in local recurrence rate, no single trial has demonstrated a statistically significant reduction in mortality. However, a 2011 meta-analysis of 17 clinical trials performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), which included over 10,000 women with early stage breast cancer supported whole-breast radiation therapy after breast-conserving surgery.[63] Whole-breast radiation therapy resulted in a significant reduction in the 10-year risk of recurrence compared with breast-conserving surgery alone (19% vs. 35%, respectively; relative risk (RR), 0.52; 95% CI, 0.48–0.56) and a significant reduction in the 15-year risk of breast cancer death (21% vs. 25%; RR, 0.82; 95% CI, 0.75–0.90).[63][Level of evidence: 1iiA]

With regard to radiation dosing and schedule, conventional whole-breast radiation therapy is delivered to the whole breast (with or without regional lymph nodes) in 1.8 Gy to 2 Gy daily fractions over about 5 to 6 weeks to a total dose of 45 Gy to 50 Gy. However, some studies show that a shorter fractionation schedule of 42.5 Gy over 3 to 4 weeks is a reasonable alternative for some breast cancer patients. A randomized, noninferiority trial of 1,234 patients with node-negative invasive breast cancer analyzed locoregional recurrence rates with conventional whole-breast radiation therapy versus a shorter fractionation schedule.[64] The 10-year locoregional relapse rate among women who received shorter fractionation was not inferior to conventional whole-breast radiation therapy (6.2% vs. 6.7%, respectively with absolute difference, 0.5 percentage points; 95% CI, −2.5 to 3.5).[64][Level of evidence: 1iiDii]

Similarly, a combined analysis of the randomized United Kingdom Standardisation of Breast Radiotherapy trials (START), (START-A [ISRCTN59368779]) and START-B [ISRCTN59368779]), which collectively randomly assigned 4,451 women with completely excised invasive (pT1–3a, pN0–1, M0) early stage breast cancer after breast-conserving surgery to conventional whole-breast radiation therapy dosing versus shorter fractionation, revealed no difference in a 10-year locoregional relapse rate.[65] Additional studies are needed to determine whether shorter fractionation is appropriate for women with higher nodal disease burden.[65][Level of evidence: 1iiDii]

Postmastectomy

Postoperative chest wall and regional lymph node adjuvant radiation therapy has traditionally been given to selected patients considered at high risk for local-regional failure following mastectomy. Radiation therapy can decrease local-regional recurrence in this group, even among those patients who receive adjuvant chemotherapy.[66] Patients at highest risk for local recurrence include those with four or more positive axillary nodes, grossly evident extracapsular nodal extension, large primary tumors, and very close or positive deep margins of resection of the primary tumor.[67-69]

Patients with one to three involved nodes without any of the previously noted risk factors are at low risk of local recurrence, and the value of routine use of adjuvant radiation therapy in this setting has been unclear. The 2005 EBCTCG update indicates, however, that radiation therapy is beneficial, regardless of the number of lymph nodes involved.[61][Level of evidence: 1iiA] For women with node-positive disease postmastectomy and axillary clearance, radiation therapy reduced the 5-year local recurrence risk from 23% to 6% (absolute gain, 17%; 95%CI, 15.2%–18.8%). This translated into a significant (P = .002) reduction in breast cancer mortality, 54.7% versus 60.1% with an absolute gain of 5.4% (95% CI, 2.9%–7.9%). In subgroup analyses, the 5-year local recurrence rate was reduced by 12% (95% CI, 8.0%–16%) for women with one to three involved lymph nodes and by 14% (95% CI, 10%–18%) for women with four or more involved lymph nodes. In contrast, for women with node-negative disease, the absolute reduction in 5-year local recurrence was only 4% (P = .002; 95% CI, 1.8%–6.2%), and there was not a statistically significant reduction in 15-year breast cancer mortality in these patients (absolute gain, 1.0%; P > .1 95%; CI, -0.8%–2.8%). Further, an analysis of NSABP trials showed that even in patients with large (>5 cm) primary tumors, when axillary nodes were negative, the risk of isolated locoregional recurrence was low enough (7.1%) that routine locoregional radiation therapy was not warranted.[70]

Late toxic effects of radiation

Late toxic effects of radiation therapy, though uncommon, can include radiation pneumonitis, cardiac events, arm edema, brachial plexopathy, and the risk of second malignancies. Such toxic effects can be minimized with current radiation delivery techniques and with careful delineation of the target volume.

In a retrospective analysis of 1,624 women treated with conservative surgery and adjuvant breast radiation at a single institution, the overall incidence of symptomatic radiation pneumonitis was 1.0% at a median follow-up of 77 months.[71] The incidence of pneumonitis increased to 3.0% with the use of a supraclavicular radiation field and to 8.8% when concurrent chemotherapy was administered. The incidence was only 1.3% in patients who received sequential chemotherapy.[71][Level of evidence: 3iii]

Controversy existed as to whether adjuvant radiation therapy to the left chest wall or breast, with or without inclusion of the regional lymphatics, had an association with increased cardiac mortality. In women treated with radiation therapy before 1980, an increased cardiac death rate was noted after 10 to 15 years, compared with women with nonradiated or right-side-only radiated breast cancer.[66,72-74] This was probably caused by the radiation received by the left myocardium.

Modern radiation therapy techniques introduced in the 1990s minimized deep radiation to the underlying myocardium when left-sided chest wall or left-breast radiation was used. Cardiac mortality decreased accordingly.[75,76] At this time, cardiac mortality was also decreasing in the United States.

An analysis of SEER data from 1973 to 1989 reviewing deaths caused by ischemic heart disease in women who received breast or chest wall radiation showed that since 1980, no increased death rate resulting from ischemic heart disease in women who received left chest wall or breast radiation was found.[77,78][Level of evidence: 3iB]

Lymphedema consequent to cancer management remains a major quality-of-life concern for breast cancer patients. Single-modality treatment of the axilla (surgery or radiation) is associated with a low incidence of arm edema. Axillary radiation therapy can increase the risk of arm edema in patients who received axillary dissection from 2% to 10% with dissection alone to 13% to 18% with adjuvant radiation therapy.[79-81] (Refer to the PDQ summary on Lymphedema for more information.)

Radiation injury to the brachial plexus following adjuvant nodal radiation therapy is a rare clinical entity for breast cancer patients. In a single-institution study using current radiation techniques, 449 breast cancer patients treated with postoperative radiation therapy to the breast and regional lymphatics were followed for 5.5 years to assess the rate of brachial plexus injury.[82] The diagnosis of such injury was made clinically with computerized tomography to distinguish radiation injury from tumor recurrence. When 54 Gy in 30 fractions was delivered to the regional nodes, the incidence of symptomatic brachial plexus injury was 1.0% compared with 5.9% when increased fraction sizes (45 Gy in 15 fractions) were used.

The rate of second malignancies following adjuvant radiation therapy is very low. Sarcomas in the treated field are rare, with the long-term risk at 0.2% at 10 years.[83] One report suggests an increase in contralateral breast cancer for women younger than 45 years who have received chest wall radiation therapy after mastectomy.[84] No increased risk of contralateral breast cancer occurs for women 45 years and older who receive radiation therapy.[85] Techniques to minimize the radiation dose to the contralateral breast should be used to keep the absolute risk as low as possible.[86] In nonsmokers, the risk of lung cancer as a result of radiation exposure during treatment is minimal when current dosimetry techniques are used. Smokers, however, may have a small increased risk of lung cancer in the ipsilateral lung.[87]

Adjuvant Systemic Therapy

Stage and molecular features determine the need for adjuvant systemic therapy and the choice of modalities used. For example, ER-positive and/or PR–positive patients will receive hormone therapy. HER2 overexpression is an indication for using adjuvant trastuzumab, usually in combination with chemotherapy. When neither HER2 overexpression (e.g., triple negative, which is common in the basal-like tumors) nor hormone receptors are present, adjuvant therapy relies on chemotherapeutic regimens, which are often combined with experimental targeted approaches.

Hormone therapy

If ER status is used to select adjuvant treatment, the study should be performed in a well-established, skilled laboratory. Immunohistochemical assays appear to be at least as reliable as standard ligand-binding assays in predicting response to adjuvant endocrine therapy.[88]

Tamoxifen

The EBCTCG performed a meta-analysis of systemic treatment of early breast cancer by hormone, cytotoxic, or biologic therapy methods in randomized trials involving 144,939 women with stage I or stage II breast cancer. The most recent analysis, which included information on 80,273 women in 71 trials of adjuvant tamoxifen, was published in 2005.[89] In this analysis, the benefit of tamoxifen was found to be restricted to women with ER-positive or ER-unknown breast tumors. In these women, the 15-year absolute reductions in recurrence and mortality associated with 5 years of use were 12% and 9%, respectively.[89][Level of evidence: 1iiA]

Allocation to approximately 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31%, largely irrespective of the use of chemotherapy and of age (<50 years, 50–69 years, ≥70 years), PR status, or other tumor characteristics.[89] This EBCTCG meta-analysis also confirmed the benefit of adjuvant tamoxifen in ER-positive premenopausal women.[89] Women younger than 50 years obtained a degree of benefit from 5 years of tamoxifen similar to that obtained by older women. In addition, the proportional reductions in both recurrence and mortality associated with tamoxifen use were similar in women with either node-negative or node-positive breast cancer, but the absolute improvement in survival at 10 years was greater in the latter group (5.3% vs. 12.5% with 5 years of use).[89][Level of evidence: 1iiA] Similar results were found in the IBCSG-13-93 trial.[90] Of 1,246 women with stage II disease, only the women with ER-positive disease benefited from tamoxifen.

The optimal duration of tamoxifen use has been addressed by the EBCTCG meta-analysis and by several large randomized trials.[89,91-94] Results from the EBCTCG meta-analysis show a highly significant advantage of 5 years versus 1 to 2 years of tamoxifen with respect to the risk of recurrence (proportionate reduction, 15.2%; P <.001) and a less significant advantage with respect to mortality (proportionate reduction, 7.9%; P = .01).[89]

Whether the optimal duration of adjuvant tamoxifen therapy in premenopausal women is 5 years or 10 years is controversial. Results from the NSABP-B-14 study, which compared a 5-year regimen to a 10-year regimen of adjuvant tamoxifen for women with early stage breast cancer, indicated no advantage for continuation of tamoxifen beyond 5 years in women with node-negative, ER-positive breast cancer.[91][Level of evidence: 1iA] Another trial demonstrated the equivalence of 5 years and 10 years of therapy.[92][Level of evidence: 1iiDii] In both trials, there was a trend toward a worse outcome associated with a longer duration of treatment.

In the EST-5181 trial, node-positive women who had already received 5 years of tamoxifen following chemotherapy were randomly assigned to continue therapy or observation.[93] In the ER-positive subgroup, a longer time to relapse was associated with continued tamoxifen use, but no improvement in OS was observed.

Long-term follow-up of the Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trial, which randomly assigned 12,894 women with early breast cancer between 1996 and 2005, revealed that 10 years of tamoxifen reduced the risk of breast cancer recurrence (617 recurrences vs. 711 recurrences, 10 years vs. 5 years, respectively; P = .002), reduced breast-cancer mortality (331 deaths vs. 397 deaths, P= .01), and reduced overall mortality (639 deaths vs. 722 deaths, P = .01).[94][Level of Evidence: 1iiA]. Of note, from the time of the original breast cancer diagnosis, the benefits of 10 years of therapy were less extreme before than after year 10. At 15 years from the time of diagnosis, breast cancer mortality was 15% versus 12.2%, at 10 years and 5 years, respectively. Compared with 5 years, 10 years of tamoxifen therapy increased the risks of the following:

  • Pulmonary embolus RR, 1.87 (95% CI, 1.13–3.07, P = .01).
  • Stroke RR, 1.06 (0.83–1.36).
  • Ischemic heart disease RR, 0.76 (0.6–0.95, P = .02).
  • Endometrial cancer RR, 1.74 (1.30–2.34, P = .0002).

Notably, the cumulative risk of endometrial cancer during years 5 to 14 from breast cancer diagnosis was 3.1% for women who received 10 years of tamoxifen versus 1.6% for women who received 5 years of tamoxifen. The mortality for years 5 to 14 was 12.2 versus 15 for an absolute mortality reduction of 2.8%.

These trials raise important questions about the optimal duration of endocrine therapy. Of note, the long-term ATLAS data are applicable for women who remain premenopausal after 5 years of tamoxifen therapy. Randomized clinical trial data support the use of aromatase inhibitors in postmenopausal women. (Refer to the Aromatase Inhibitors section of this summary for more information.) For women who remain premenopausal after 5 years of tamoxifen, discussion with the patient about the risks and benefits of extending tamoxifen therapy should occur. Because of the conflict in data, the optimal duration is controversial.

(Refer to the Letrozole section in the Aromatase inhibitors section of this summary for more information.)

Tamoxifen and chemotherapy

That chemotherapy should add to the effect of tamoxifen in postmenopausal women has been postulated.[95,96] In a trial (NSABP-B-16) of node-positive women older than 50 years with hormone receptor–positive tumors, 3-year DFS and OS rates were better in those who received doxorubicin, cyclophosphamide, and tamoxifen versus tamoxifen alone (DFS was 84% vs. 67%; P = .004; OS was 93% vs. 85%; P = .04).[97][Level of evidence: 1iiA] The NSABP-B-20 study compared tamoxifen alone with tamoxifen plus chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [5-FU] [CMF] or sequential methotrexate and 5-FU) in women with node-negative, ER-positive breast cancer.[98] After 12 years of follow-up, the chemotherapy plus tamoxifen regimen resulted in 89% DFS and 87% OS compared with a 79% DFS and 83% OS with tamoxifen alone.[98][Level of evidence: 1iiA]

In another study of postmenopausal women with node-positive disease, tamoxifen alone was compared with tamoxifen plus three different schedules of CMF. A small, DFS advantage was conferred by the addition of early CMF to tamoxifen in women with ER-positive disease.[99][Level of evidence: 1iiDii] However, another study in a similar patient population, in which women were randomly assigned to receive adjuvant tamoxifen with or without CMF, showed no benefit in the chemotherapy arm; in this study, intravenous (IV) (day 1 every 3 weeks) rather than oral cyclophosphamide was used.[100][Level of evidence: 1iiA] The overall results of the available evidence suggest that the addition of chemotherapy to tamoxifen in postmenopausal women with ER-positive disease results in a significant, but small, survival advantage.

Tamoxifen toxic effects

The use of adjuvant tamoxifen has been associated with certain toxic effects. The most important effect is the development of endometrial cancer which, in large clinical trials, has been reported to occur at a rate that is two times to seven times greater than that observed in untreated women.[101-104] Women taking tamoxifen should be evaluated by a gynecologist if they experience any abnormal uterine bleeding. Although one retrospective study raised concern that endometrial cancers in women taking tamoxifen (40 mg/day) had a worse outcome and were characterized by higher-grade lesions and a more advanced stage than endometrial cancers in women not treated with tamoxifen, other larger studies using standard tamoxifen doses (20 mg/day) have not supported this finding.[101,105,106] Similar to estrogen, tamoxifen produces endometrial hyperplasia, which can be a premalignant change. In a cohort of women without a history of breast cancer who were randomly assigned 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 months–75 months; median, 24 months), while no cases occurred on the control arm.[107] The value of endometrial biopsy, hysteroscopy, and transvaginal ultrasound as screening tools is unclear.[108,109] Of concern is an increased risk of gastrointestinal malignancy after tamoxifen therapy, but these findings are tentative, and further study is needed.[110]

Tamoxifen use is also associated with an increased incidence of deep venous thrombosis and pulmonary emboli. In several adjuvant studies, the incidence ranged from 1% to 2%.[91,97,111-113] Clotting factor changes have been observed in controlled studies of prolonged tamoxifen use at standard doses; antithrombin III, fibrinogen, and platelet counts have been reported to be minimally reduced in patients receiving tamoxifen.[114] The relationship of these changes to thromboembolic phenomena is not clear. Tamoxifen use may also be associated with an increased risk of strokes.[113,115,116] In the NSABP Breast Cancer Prevention Trial (NSABP-P-1), this increase was not statistically significant.[115]

Another potential problem is the development of benign ovarian cysts, which occurred in about 10% of women in a single study.[117] The relationship between tamoxifen and ovarian tumors requires further study.[118] Short-term toxic effects of tamoxifen use may include vasomotor symptoms and gynecologic symptoms (e.g., vaginal discharge or irritation).[119] (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information.) Ophthalmologic toxic effects have also been reported in patients receiving tamoxifen; patients who complain of visual problems should be assessed carefully.[120-122] 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.

Tamoxifen therapy may also be associated with certain beneficial estrogenic effects, including decreased total and low-density lipoprotein levels.[123,124] 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 for women taking it for 2 years.[125] 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.[124] In the NSABP-B-14 study, the annual death rate due to coronary heart disease was lower in the tamoxifen group than in the placebo group (0.62 per 1,000 vs. 0.94 per 1,000), but this difference was not statistically significant.[126] To date, three large controlled trials have shown a decrease in heart disease.[124-126]

Controlled studies have associated long-term tamoxifen use with preservation of bone mineral density of the lumbar spine in postmenopausal women.[127-129] In premenopausal women, decreased bone mineral density is a possibility.[130]

Ovarian ablation, tamoxifen, and chemotherapy

The EBCTCG meta-analysis included almost 8,000 premenopausal women who were randomly assigned to undergo ovarian ablation with surgery or radiation therapy (4,317) or ovarian suppression with luteinizing hormone-releasing hormone (LHRH) agonists (3,408). Overall, ovarian ablation or suppression reduced the absolute risk of recurrence at 15 years by 4.3% (P < .001) and the risk of death from breast cancer by 3.2% (P = .004).[89] No evidence showed that the relative benefit of suppression differed from that of ablation, but the benefit of either was less in patients who received chemotherapy.[131][Level of evidence: 1iiA]

A single study of more than 300 patients that compared cyclophosphamide, methotrexate, 5-FU, and prednisone (CMFP) with the same chemotherapy regimen plus surgical oophorectomy showed no additional survival benefit from oophorectomy.[132][Level of evidence: 1iiA] Three trials (including the International Breast Cancer Study Group's trial [IBCSG-VIII] and the Eastern Cooperative Oncology Group's trial [EST-5188]) involving more than 3,000 patients assessed the impact on DFS and OS from the use of an LHRH analog (in one trial, 50% of the patients had radiation oophorectomy rather than an LHRH analog) in addition to chemotherapy.[131,133,134][Level of evidence: 1iiA] None of the trials identified a statistically significant benefit in OS or DFS from ovarian suppression.

As an adjuvant strategy, ovarian ablation has also been compared with chemotherapy in premenopausal women. In a direct comparison of surgical or radiation ablation and CMF, DFS and OS rates were identical in 332 premenopausal women with stage II disease.[135][Level of evidence: 1iiA] A trial of 599 premenopausal node-positive patients found leuprorelin acetate to be similar to CMF with respect to DFS and OS.[136] A Danish trial compared ovarian ablation or suppression to CMF (nine cycles IV every 3 weeks) in premenopausal, ER-positive women and found no difference in OS or DFS in the two study groups.[137,138] The study did not have tamoxifen as an adjuvant arm and also did not use taxanes or anthracyclines. Results may have been different with these two contemporary modifications to the study. A trial of CMF versus tamoxifen plus ovarian ablation (e.g., by surgery, radiation therapy, or gonadotropin-releasing hormone) in premenopausal or perimenopausal women with receptor-positive tumors has been reported.[139][Level of evidence: 1iiA] In this small trial, which did not meet its target accrual, the combination of tamoxifen and ovarian ablation provided comparable DFS and OS rates. In three larger trials in which medical ovarian ablation with goserelin was used, the impact of goserelin alone on DFS was found to be comparable to CMF in the subgroup of ER+ patients,[131,140][Level of evidence: 2Dii] whereas the combination of goserelin and tamoxifen was associated with prolonged DFS compared with CMF alone.[141][Level of evidence: 1iiDii] Whether tamoxifen or aromatase inhibitors add to ovarian ablation, and the elucidation of the optimal roles for endocrine manipulation and chemotherapy in receptor-positive premenopausal women, require further evaluation.[142] These issues are the subject of several trials.

In summary, the weight of evidence suggests that ovarian ablation should not be routinely added to systemic therapy with chemotherapy and/or tamoxifen.[131,133,134,143] Ovarian ablation alone should not be routinely used as an alternative to any other systemic therapy.[135-138,143] Further results of research studies prospectively evaluating the role of adjuvant ovarian ablation are awaited.

Aromatase inhibitors

Based on DFS advantage as described below, aromatase inhibitors have become the first-line adjuvant therapy for postmenopausal women; however, because there is no demonstrated survival advantage to aromatase inhibitors, tamoxifen remains a reasonable alternative.[144,145]

Anastrozole

A large, randomized trial of 9,366 patients has compared the use of the aromatase inhibitor anastrozole and the combination of anastrozole and tamoxifen with tamoxifen alone as adjuvant therapy for postmenopausal patients with node-negative and node-positive disease.[146,147] Most (84%) of the patients in the study were hormone-receptor positive. Slightly more than 20% had received chemotherapy. With a median follow-up of 33.3 months, no benefit was observed for the combination arm relative to tamoxifen. Patients on anastrozole, however, had a significantly longer DFS (HR, 0.83) than those on tamoxifen. In an analysis conducted when all but 8% of the patients had completed protocol therapy at a follow-up of 68 months,[147] the benefit of anastrozole relative to tamoxifen with respect to DFS was slightly less (HR, 0.87; 95% CI, 0.78–0.96; P = .01). A greater benefit was seen in hormone receptor-positive patients (HR, 0.83; 95% CI, .73–0.94; P = .05). There was an improvement in time to recurrence (HR, 0.79; 95% CI, 0.70–0.90; P = .005), distant DFS (HR, 0.86; 95% CI, 0.74–0.99; P = .04) and contralateral breast cancer (42% reduction; P = .01) in patients who received anastrozole.[147][Level of evidence: 1iDii] No difference was shown in OS (HR, 0.97; 95% CI, 0.85–1.12; P = .7 ). Arthralgia and fractures were reported significantly more often in patients who received anastrozole, whereas hot flushes, vaginal bleeding and discharge, endometrial cancer, ischemic cerebrovascular events, venous thromboembolic and deep venous thromboembolic events were more common in patients who received tamoxifen.[147] An American Society of Clinical Oncology (ASCO) Technology Assessment panel has commented on the implications of these results.[148,149]

Three trials examined the effect of switching to anastrozole to complete a total of 5 years of therapy after 2 to 3 years of tamoxifen.[150-152] One study, which included 448 patients, demonstrated a statistically significant reduction in DFS (HR, 0.35; 95% CI, 0.18–0.68; P = .001) but no difference in OS.[150][Level of evidence: 1iiA] The other two trials were reported together.[151] A total of 3,224 patients were randomly assigned after 2 years of tamoxifen to continue tamoxifen for a total of 5 years or to take anastrozole for 3 years. After a median follow-up of 78 months, an improvement in all-cause mortality (HR, 0.61; 95% CI, 0.42–0.88; P = .007) was observed.[152]

A meta-analysis of these three studies showed that patients who switched to anastrozole had significant improvements in DFS (HR, 0.59; 95% CI, 0.48–0.74; P < .001), event-free survival (EFS) (HR, 0.55; 95% CI, 0.42–0.71; P < .001), distant DFS (HR, 0.61; 95% CI, 0.45–0.83; P= .002), and OS (HR, 0.71; 95% CI, 0.52–0.98; P = .04) compared with the patients who remained on tamoxifen.[153]

Letrozole

A large double-blinded randomized trial of 8,010 postmenopausal women with hormone receptor-positive breast cancer compared the use of letrozole versus tamoxifen given continuously for 5 years or with crossover with the alternate drug at 2 years.[154] In an updated analysis from the Breast International Group (IBCSG-1-98) including only the 4,922 women who received tamoxifen or letrozole for 5 years, at a median follow-up time of 51 months, DFS was significantly superior in patients treated with letrozole (HR, 0.82; 95% CI, 0.71–0.95; P = .007; 5-year DFS, 84.0% vs. 81.1%).[155][Level of evidence: 1iDii] OS was not significantly different (HR, 0.91; 95% CI, 0.75–1.11; P = .35). Patients on letrozole had significantly fewer thromboembolic events, endometrial pathology, hot flashes, night sweating, and less vaginal bleeding. Patients on tamoxifen had significantly fewer bone fractures, arthralgia, hypercholesterolemia, and cardiac events other than ischemic heart disease and cardiac failures.[155]

A large, double-blinded, randomized trial (CAN-NCIC-MA17 [NCT00003140]) of 5,187 patients compared the use of letrozole with a placebo in receptor-positive postmenopausal women who received tamoxifen for approximately 5 (4.5–6.0) years.[156] After the first planned interim analysis, when median follow-up for patients on study was 2.4 years, the results were unblinded because of a highly significant (P < .008) difference in DFS (HR, 0.57) favoring the letrozole arm.[156][Level of evidence: 1iDii] After 3 years of follow-up, 4.8% of the women on the letrozole arm had developed recurrent disease or new primaries versus 9.8% on the placebo arm (95% CI for the difference, 2.7%–7.3%). Women on letrozole had significantly more hot flashes, arthritis, arthralgia and myalgia, but less vaginal bleeding. New diagnoses of osteoporosis were more frequent on letrozole (5.8% vs. 4.5%), though the difference was not statistically significant (P = .07). Because of the early unblinding of the study, longer-term comparative data on the risks and benefits of letrozole in this setting will not be available.[157,158] An updated analysis including all events prior to unblinding confirmed the results of the interim analysis.[159] In addition, a statistically significant improvement in distant DFS was found for patients on letrozole (HR, 0.60; 95% CI, 0.43–0.84; P = .002). Although no significant difference was found in the total study population, the node-positive patients on letrozole also experienced a statistically significant improvement in OS (HR, 0.61; 95% CI, 0.38–0.98; P = .04), though the P value was not corrected for multiple comparisons. An ASCO Technology Assessment panel has commented on the implications of these results.[148,149]

Exemestane

A large, double-blinded, randomized trial (EORTC-10967 [ICCG-96OEXE031-C1396-BIG9702]) of 4,742 patients compared continuing tamoxifen with switching to exemestane for a total of 5 years of therapy in women who had received 2 to 3 years of tamoxifen.[160,161] After the second planned interim analysis, when median follow-up for patients on the study was 30.6 months, the results were released because of a highly significant (P < .005) difference in DFS (HR, 0.68) favoring the exemestane arm.[160][Level of evidence: 1iDii] After a median follow-up of 55.7 months, the HR for DFS was 0.76 (95% CI, 0.66–0.88; P = .001) in favor of exemestane.[162] At 2.5 years after random assignment, 3.3% fewer patients on exemestane had developed a DFS event (95% CI, 1.6–4.9). The HR for OS was 0.85 (95% CI, 0.7–1.02; P = .08).[162][Level of evidence: 1iA] Women on exemestane had significantly more arthralgia, diarrhea, hypertension, fractures, arthritis, musculoskeletal pain, carpal tunnel syndrome, insomnia, and osteoporosis, but women on tamoxifen had significantly more gynecologic symptoms, muscle cramps, vaginal bleeding and discharge, thromboembolic disease, endometrial hyperplasia, and uterine polyps. (Refer to the PDQ summary on Gastrointestinal Complications for information on diarrhea and for information on insomnia, refer to the PDQ summary on Sleep Disorders.)

A large, randomized trial of 9,779 patients compared DFS of postmenopausal women with hormone receptor–positive breast cancer between initial treatment with sequential tamoxifen for 2.5 to 3 years followed by exemestane for a total of 5 years versus exemestane alone for 5 years.[163] The primary endpoints were DFS at 2.75 years and 5.0 years. Five-year DFS was 85% in the sequential group and 86% in the exemestane-alone group (HR, 0.97; 95% CI, 0.88–1.08; P = .60).[163][Level of evidence: 1iDii] The results of this trial support the use of exemestane, either sequentially after tamoxifen or as initial treatment for early-stage hormone receptor–positive breast cancer in postmenopausal women.

The mild androgen activity of exemestane prompted a randomized trial to evaluate whether exemestane might be preferable to anastrozole, in terms of its efficacy and toxicity, as upfront therapy for postmenopausal women diagnosed with hormone receptor-positive breast cancer.[164][Level of evidence: 1iiA] The MA27 (NCT00066573) trial randomly assigned 7,576 postmenopausal women to receive 5 years of anastrozole versus exemestane. At a median follow-up of 4.1 years, no difference in efficacy was seen.

Chemotherapy

Overview of Chemotherapy

Standard chemotherapy regimens for the adjuvant treatment of operable breast cancer that is given in the modern era are described in Table 6. There is no evidence favoring any regimen as superior to another. Therefore, any of these standard regimens is acceptable therapy.

Benefit of chemotherapy

Some of the most important data on the benefit of adjuvant chemotherapy came from the EBCTCG, which meets every 5 years to review data from global breast cancer trials. The year 2000 overview analysis (published in 2005) summarized the results of randomized adjuvant trials initiated by 1995.[89] The analyses of adjuvant chemotherapy involved 28,764 women participating in 60 trials of combination chemotherapy (polychemotherapy) versus no chemotherapy, 14,470 women in 17 trials of anthracycline-containing versus CMF-type chemotherapy, and 6,125 women in 11 trials of longer versus shorter chemotherapy duration.

For women younger than 50 years, polychemotherapy reduced the annual risk of disease relapse and death from breast cancer by 37% and 30%, respectively. This translated into a 10% absolute improvement in 15-year survival (HR, 42% vs. 32%). For women aged 50 to 69 years, the annual risk of relapse or death from breast cancer was decreased by 19% and 12%, respectively. This translated into a 3% absolute gain in 15-year survival (HR, 50% vs. 47%). The absolute gain in survival for polychemotherapy versus no adjuvant therapy in women younger than 50 was twice as great at 15 years as it was at 5 years (10% vs. 4.7%), while the main effect on disease recurrence was seen in the first 5 years.[89] The 15-year cumulative reduction in mortality from 6 months of an anthracycline-based regimen (e.g., fluorouracil, doxorubicin, cyclophosphamide [FAC] or fluorouracil, epirubicin, cyclophosphamide [FEC]) was 38% in women younger than 50 years, and 20% in those aged 50 to 60 years. The meta-analysis also showed that the reduction in risk of recurrence was similar in the presence or absence of tamoxifen, irrespective of age (<50 years vs. 50–69 years), though the result did not attain statistical significance in those randomly assigned women younger than 50 years. This finding, however, is most likely the result of the relatively small number of younger women in trials of combined chemoendocrine therapy. Few women older than 70 years had been studied, and specific conclusions could not be reached in this group. Importantly, these data were derived from clinical trials in which patients were not selected for adjuvant therapy according to ER status, and they were initiated before the advent of taxane-containing, dose-dense, or trastuzumab-based therapy.[89] As a result, they may not reflect treatment outcomes based on evolving treatment patterns.

Results of individual trials are generally in agreement with the conclusions of the meta-analysis. The NSABP-B-13 study demonstrated a benefit for chemotherapy with sequential methotrexate and 5-FU versus surgery alone in patients with node-negative, ER-negative tumors.[97,98,165,166][Level of evidence: 1iiA]

Table 6. Standard Adjuvant Chemotherapy Regimens for Stage I, II, IIIA, and Operable IIIC HER2/neu Non-Overexpressing Breast Cancer
Regimen Cycle Number and Duration (d) Cytoxan (mg/m²) 5-FU (mg/m²) Doxorubicin (mg/m²) Paclitaxel/Docetaxel (mg/m²) 
AC = cyclophosphamide, doxorubicin; AC-T = cyclophosphamide, doxorubicin, taxol; CAF = cyclophosphamide, doxorubicin, fluorouracil; d = day; D = docetaxel; IV = intravenously; P = paclitaxel; T = taxol; TAC = docetaxel, doxorubicin and cyclophosphamide; TC = docetaxel and cyclophosphamide; 5-FU = fluorouracil.
CAF [163]6 × 21500, IV d 1500, IV d 150, IV d 1
AC [166]4 × 21600, IV d 160, IV d 1
Dose-dense AC-T [179]4 (AC), 4 (T) ×14600, IV d 160, IV d 1P: 175, IV d 1
TAC [193, 194]6 × 21500, IV d 150, IV d 1D: 75, IV d 1
TC [195]4 x 21600, IV d 1D: 75, IV d 1

Adjuvant chemotherapy 1970s to 2000: Anthracycline-based regimens versus CMF

The EBCTCG meta-analysis analyzed 11 trials that began in 1976 through 1989 in which women were randomly assigned to receive regimens containing anthracyclines (e.g., doxorubicin or epirubicin) versus CMF alone. The EBCTCG overview analysis directly compared anthracycline-containing regimens (mostly 6 months of FEC or FAC) with CMF (either oral or IV) in approximately 14,000 women, 64% of whom were younger than 50 years.[89] Compared with CMF, anthracycline-based regimens were associated with a modest but statistically significant 11% proportional reduction in the annual risk of disease recurrence, and a 16% reduction in the annual risk of death. In each case, the absolute difference in outcomes between anthracycline-based and CMF-type chemotherapy was about 3% at 5 years and 4% at 10 years.[167][Level of evidence: 1iiA]

The largest direct comparison of cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) (six cycles) versus CMF (six cycles) occurred in a U.S. Intergroup study (SWOG-8897), which was not included in the meta-analysis.[168] In this study, 2,691 patients were randomly assigned to receive CAF or CMF with a second random assignment to 5 years of tamoxifen versus no tamoxifen. Ten-year follow-up estimates indicated that CAF was not significantly better than CMF (P = .13) for the primary outcome of DFS (77% vs. 75%; HR, 1.09; 95% CI, 0.94–1.27). CAF had slightly better OS than CMF (85% vs. 82%, HR, 1.19 for CMF vs. CAF; 95% CI, 0.99–1.43), though values were statistically significant in the planned one-sided test (P = .03). Toxicity was greater with CAF and did not increase with tamoxifen. Overall, tamoxifen had no benefit (DFS, P = .16; OS, P = .37), but the tamoxifen effect differed by high-risk groups. For high-risk node-positive patients, tamoxifen was beneficial (DFS: HR, 1.32 for no tamoxifen vs. tamoxifen; 95% CI, 1.09–1.61; P = .003; OS: HR, 1.26; 95% CI, 0.99–1.61; P = .03) but not for high-risk node-negative patients (DFS: HR, 0.81 for no tamoxifen vs. tamoxifen; 95% CI, 0.64–1.03; OS: HR, 0.79; 95% CI, 0.60–1.05). The conclusion of this trial was that CAF did not improve DFS, compared with CMF; and, there was a slight effect on OS. Given greater toxicity, CAF cannot be concluded to be superior to CMF. Tamoxifen was effective in high-risk node-positive disease but not in high-risk node-negative disease.[168][Level of evidence: 1iiA]

Several investigators have attempted to improve outcomes by combining CMF and anthracycline-containing regimens. Two Italian studies have evaluated these regimens.[169,170] In one study, 490 premenopausal and postmenopausal women with one to three axillary lymph nodes were randomly assigned to receive CMF (12 cycles) or CMF (eight cycles) followed by doxorubicin (four cycles).[169] After a median observation of 17.5 years, no statistically significant difference was documented in the first study (relapse-free survival [RFS], HR, 1.06; total survival, HR, 1.03). In contrast, the delivery of doxorubicin first, followed by CMF significantly reduced the risk of disease relapse (HR, 0.68; 95% CI, 0.54–0.87; P =.0017) and death (HR, 0.74; 95% CI, 0.57–0.95; P = .018) compared with the alternating regimen. In the other study, 403 premenopausal and postmenopausal women with four or more positive axillary lymph nodes were randomly assigned to receive doxorubicin (four cycles) followed by CMF (eight cycles) or CMF (two cycles) alternating with doxorubicin (one cycle) for a total of 12 cycles.[170] Women who received doxorubicin followed by CMF had better RFS (42% vs. 28%; P = .002) and OS (58% vs. 44%; P = .002).[170][Level of evidence: 1iiA]

The NSABP-B-15 trial randomly assigned 2,194 patients with axillary node-positive breast cancer and tumors determined nonresponsive to tamoxifen to doxorubicin and cyclophosphamide (AC) (four cycles), CMF (six cycles), or AC (four cycles) followed after a 6-month delay by CMF (three cycles).[171] No differences were seen in DFS or OS among the three groups.[171][Level of evidence: 1iiA] This study has also shown no difference in survival rates between four cycles of AC and six cycles of CMF.

The results of these various studies comparing and combining CMF and anthracycline-containing regimens suggest a slight advantage for the anthracycline regimens in both premenopausal and postmenopausal patients. Uncertainty remains, however, about whether there is an advantage to combining both regimens.

Evidence suggests that particular tumor characteristics may predict anthracycline-responsiveness. Data from retrospective analyses of randomized clinical trials suggest that, in patients with node-positive breast cancer, the benefit from standard-dose versus lower-dose adjuvant CAF,[2] or the addition of doxorubicin to the adjuvant regimen,[3] is restricted to those patients whose tumors overexpress HER2/neu.[Level of evidence: 1iiA] A retrospective analysis of the HER2/neu status of 710 premenopausal, node-positive women was undertaken to see the effects of adjuvant chemotherapy with CMF or cyclophosphamide, epirubicin, and fluorouracil (CEF).[172][Level of evidence: 2A] HER2/neu was measured using fluorescence in situ hybridization, polymerase chain reaction, and immunohistochemical methods. The study confirmed previous data indicating that the amplification of HER2/neu was associated with a decrease in RFS and OS. In patients with HER2/neu amplification, the RFS and OS were increased by CEF. In the absence of HER2/neu amplification, CEF and CMF were similar to RFS (HR for relapse, 0.91; 95% CI, 0.71–1.18; P = .049) and OS (HR for death, 1.06; 95% CI, 0.83–1.44; P = .68). Similar results were seen in a meta-analysis that included 5,354 patients in whom HER2 status was known from eight randomized trials (including the one just described) comparing anthracycline-containing regimens with nonanthracycline-containing regimens.[173]

Adjuvant Chemotherapy 2000s to Present: The role of adding taxanes to adjuvant therapy

A number of trials have addressed the benefit of adding a taxane (paclitaxel or docetaxel) to an anthracycline-based adjuvant chemotherapy regimen. A literature-based meta-analysis of 13 such studies demonstrated that the inclusion of a taxane improved both DFS and OS (DFS: HR, 0.83; 95% CI, 0.79–0.87; P < .001; OS: HR, 0.85; 95% CI, 0.79–0.91; P < .001).[174][Level of evidence: 1iiA] Five-year absolute survival differences were 5% for DFS and 3% for OS in favor of taxane-containing regimens. There were no differences in benefit observed in patient subsets defined by nodal status, hormone receptor status, or age/menopausal status. There was also no apparent difference in efficacy between the two agents. However, none of the studies reviewed involved a direct comparison between paclitaxel and docetaxel.

An Eastern Cooperative Oncology Group–led intergroup trial (E1199 [NCT00004125]) involving 4,950 patients compared, in a factorial design, two schedules (weekly and every 3 weeks) of the two drugs (docetaxel vs. paclitaxel) following standard-dose AC chemotherapy given every 3 weeks.[175][Level of evidence: 1iiA] There was no difference observed in the overall comparison with regard to DFS of docetaxel to paclitaxel (odds ratio [OR], 1.03; 95% CI, 0.91–1.16; P = .61) or between the 1-week and 3-week schedules (OR, 1.06; 95% CI, 0.94–1.20; P = .33). However, there was a significant interaction between the drug administered and schedule for both DFS (0.003) and OS (0.01). Thus, compared with paclitaxel given every 3 weeks, paclitaxel given weekly improved both DFS (OR, 1.27; 95% CI, 1.01–1.57; P = .006) and OS (OR, 1.32; 95% CI, 1.02–1.72; P = .01). Docetaxel given every 3 weeks was also superior in DFS to paclitaxel given every 3 weeks (OR, 1.23; 95% CI, 1.00–1.52; P = .02), but the difference was not statistically significant for OS (OR, 1.13; 95% CI, 0.88–1.46; P = .25). Docetaxel given weekly was not superior to paclitaxel given every 3 weeks. There was no stated a priori basis for expecting that varying the schedule of administration would have opposite effects for the two drugs. Thus, these results are hypothesis generating and should be confirmed.

A U.S. Intergroup study (CLB-9344) randomly assigned women with node-positive tumors to three dose levels of doxorubicin (60, 75, and 90 mg/m2) and a fixed dose of cyclophosphamide (600 mg/m2) every 3 weeks for four cycles. After AC chemotherapy, patients were randomly assigned for a second time to paclitaxel (175 mg/m2) every 3 weeks for four cycles versus no further therapy, and women with ER-positive tumors also received tamoxifen for 5 years. Although the dose-escalation of doxorubicin was not beneficial, the addition of paclitaxel resulted in statistically significant improvements in DFS (5%) and OS (3%).[176][Level of evidence: 1iiA] The results of a second trial (NSABP-B-28) have also been reported.[177] This trial randomly assigned 3,060 women with node-positive breast cancer to four cycles of postoperative AC or four cycles of AC followed by four cycles of paclitaxel. All women older than 50 years, and those younger than 50 years with receptor-positive disease, received tamoxifen. In this trial, DFS was significantly improved by the addition of paclitaxel (HR, 0.83; 95% CI, 0.72–0.96; P = .006; 5-year DFS, 76% vs. 72%). The difference in OS was small (HR, 0.93), however, and not statistically significant (P = .46).[177][Level of evidence: 1iiA]

The regimen of FAC compared with docetaxel plus doxorubicin and cyclophosphamide (TAC) has been studied in 1,491 women with node-positive disease in the Breast Cancer International Research Group's (BCIRG-001) trial. Six cycles of either regimen were given as adjuvant postoperative therapy. A 75% DFS rate existed at 5 years in the TAC group, compared with a 68% survival in the FAC group (P = .001). TAC was associated with a 30% overall lower risk of death (5% absolute difference) than FAC (HR, .70; 98% CI, 0.53–0.91; P < .008). Anemia, neutropenia, febrile neutropenia, and infections were more common in the TAC group. No deaths were associated with infections in either group.[178,179][Level of evidence: 1iiA] (Refer to the PDQ summary on Fatigue for information on anemia.)

Dose-intensity, dose-density, and high-dose chemotherapy

Retrospective and some prospective data support the view that physicians should avoid arbitrary reductions in dose intensity.[180,181] The data for the benefit of dose escalation in breast cancer, however, are more controversial. The CLB-8541 trial compared three dose intensities of CAF in 1,550 patients with node-positive breast cancer. Patients received either CAF (300/30/300 mg/m2 every 4 weeks for four cycles; low-dose arm), CAF (400/40/400 mg/m2 every 4 weeks for six cycles; moderate-dose arm), or CAF (600/60/600 mg/m2 every 4 weeks for four cycles; high-dose arm). The high-dose arm had twice the dose intensity and twice the drug dose as the low-dose arm. The moderate-dose arm had 66% of the dose intensity as the high-dose arm but the same total drug dose. At a median follow-up of 9 years, DFS and OS on the high-dose and intermediate-dose arms were superior to the corresponding survival measures on the low-dose arm (P = .001) with no difference in these measures between the high-dose and intermediate-dose arms.[180][Level of evidence: 1iiA] The higher dose levels used in this trial are currently considered standard, so it is unclear whether this trial is supportive of the value of dose intensity or, rather, supportive of the concept of a threshold level below which treatment becomes ineffective.

Other trials have clearly escalated doses beyond the standard range. The NSABP-B-22 and NSABP-B-25 trials, for example, escalated the dose of cyclophosphamide to 1,200 mg/m2 (without granulocyte-colony stimulating factor [G-CSF]) and 2,400 mg/m2 (with G-CSF), respectively, with no significant advantage observed in DFS or OS compared with the standard dose of 600 mg/m2.[182,183][Level of evidence: 1iiA]

A U.S. Intergroup study (CLB-9344) randomly assigned women with node-positive tumors to three dose levels of doxorubicin (60, 75, and 90 mg/m2). Following treatment with doxorubicin, a second random assignment occurred to paclitaxel or to no further therapy. After chemotherapy, patients with ER-positive tumors were offered a planned course of tamoxifen for 5 years. No difference in DFS related to the dose of doxorubicin was found.[176] In contrast, a Canadian trial (CAN-NCIC-MA5) in which cyclophosphamide, epirubicin, and 5-FU (CEF) were given to a total dose of 720 mg/m2 for a period of six 4-week cycles demonstrated at a median follow-up of 10 years for live patients, a 10-year RFS of 52% for patients who received CEF compared with 45% for CMF patients (HR for CMF vs. CEF, 1.31; stratified log-rank, P = .007).[184] The 10-year OS for patients who received CEF and CMF was 62% and 58%, respectively (HR for CMF vs. CEF, 1.18; stratified log-rank, P = .085). The rates of acute leukemia have not changed since the original report, whereas the rates of congestive heart failure were slightly higher (four patients [1.1%] in the CEF group vs. one patient [0.3%] in the CMF group).[184][Level of evidence: 1iiA] The design of the trial does not allow a determination of whether anthracycline or dose-intensity or both is responsible for the improved outcome. A French trial showed that higher doses of epirubicin led to a high survival rate in women with poor-prognosis disease.[185] A randomized trial that increased duration of epirubicin did not lead to increased survival at 10 years in node-positive premenopausal women.[186]

A U.S. Intergroup trial (CLB-9741) compared, in a 2 × 2 factorial design, the use of adriamycin, cyclophosphamide, and paclitaxel concurrently (adriamycin and cyclophosphamide followed by paclitaxel) versus sequentially (adriamycin followed by paclitaxel followed by cyclophosphamide), given every 3 weeks or every 2 weeks with filgrastim, in 2,005 node-positive premenopausal and postmenopausal patients.[187] At a median follow-up of 68 months, dose-dense treatment improved the primary end point, DFS in all patient population (HR, 0.80; P =.018) but not OS (HR, 0.85; P =.12). There was no interaction between density and sequence. Severe neutropenia was less frequent in patients who received the dose-dense regimens.[187,188] Grade 2 anemia (hemoglobin <10g/dL) was more frequent in the adriamycin and cyclophosphamide followed by paclitaxel every 2 weeks' arm (P < .001). At cycle five, this same arm had the lowest nadir hemoglobin of 10.7 g/dL, 0.9 g/dL lower than the other arms. Also, epoetin alpha use was highest in this arm compared with the three other arms (P = .013). In conclusion, dose-dense adriamycin and cyclophosphamide followed by paclitaxel every 14 days in C2 was associated with a greater incidence of moderate anemia, higher use of epoetin alpha, and more red cell transfusions than the other arms.[189][Level of evidence: 1iiA]

Several clinical trials (including EST-2190) have tested high-dose chemotherapy with bone marrow transplant (BMT) or stem cell support in women with more than ten positive lymph nodes and in women with four to nine positive lymph nodes.[190-197] A prospective, randomized trial of 403 patients testing the use of two tandem high-dose chemotherapy courses demonstrated a statistically significant (P = .02) difference in 5-year survival (75% vs. 70%) with a 49-month median follow-up.[196][Level of evidence: 1iiA] The remaining trials comparing conventional chemotherapy to high-dose chemotherapy with BMT or stem cell support in high-risk patients in the adjuvant setting indicated no OS or EFS benefit from the high-dose chemotherapy with BMT or stem cell support.[190-195,197-199][Level of evidence: 1iiA] The information to date does not support the use of high-dose chemotherapy outside the context of a randomized clinical trial.

Also, a systematic review of nine randomized, controlled trials comparing the effectiveness of high-dose chemotherapy and autograft with conventional chemotherapy for women with early poor prognosis breast cancer was performed.[197] In total 1,758 women were randomly assigned to receive high-dose chemotherapy with autograft, and 1,767 women were randomly assigned to receive conventional chemotherapy. There were 48 noncancer-related deaths on the high-dose arm and four on the conventional-dose arm (RR, 7.74; 95% CI, 3.43–17.50). There was no statistically significant difference in OS between women who received high-dose chemotherapy with autograft and women who received conventional chemotherapy, either at 3 years (RR, 1.02; 95% CI, 0.98–1.06), or at 5 years (RR, 0.98; 95% CI, 0.93–1.05). There was a statistically significant benefit in EFS at 3 years for the group who received high-dose chemotherapy (RR, 1.11; 95% CI, 1.05–1.18). However, this significance was lost at 5 years (RR, 1.00; 95% CI, 0.92–1.08).[197]

Docetaxel and cyclophosphamide

The regimen of docetaxel and cyclophosphamide (TC) compared with AC was studied in 1,016 women with stage I or stage II invasive breast cancer. Patients were randomly assigned to receive four cycles of either TC or AC as adjuvant postoperative therapy. At 5 years, DFS was statistically significantly superior for TC compared with AC (86% vs. 80%, HR, 0.67; 95% CI, 0.50–0.94; P = .015).[200][Level of evidence: 1iiA] At the time of the original report, OS was not statistically significantly improved. However, a 7-year update of results for DFS and OS demonstrated that four cycles of TC was superior to standard AC for both DFS and OS.[201][Level of evidence: 1iiA]. At 7 years, DFS was significantly superior for TC compared with AC (81% vs. 75%, HR, 0.74; 95% CI, 0.56–0.98; P = .033). At 7 years, OS was significantly superior for TC compared with AC (87% vs. 82%, HR, 0.69; 95% CI, 0.50–0.97; P = .032). With TC, patients had fewer cardiac-related toxic effects but other side effects included more myalgia, arthralgia, edema, and febrile neutropenia compared with AC.

Bisphosphonates

The role of bisphosphonates as part of adjuvant therapy for early stage breast cancer is unclear. The ABCSG-12 (NCT00295646) trial was a 2 × 2 factorial-design randomized trial that assigned 1,803 premenopausal patients with ER-positive breast cancer to receive ovarian function suppression with goserelin and tamoxifen versus goserelin and anastrozole. These patients then underwent a second random assignment to receive zoledronic acid (4 mg IV every 6 months) versus no zoledronic acid.[202][Level of evidence: 1iiA] There was no significant difference in DFS between the anastrozole and tamoxifen groups. However, the addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in a relative reduction of 36% in the risk of disease progression (HR, 0.64; P = .01) but did not significantly reduce the risk of death. Similar results were obtained in the trial (NCT00171340) in which 1,065 postmenopausal women received letrozole and were randomly assigned to receive zoledronic acid (4 mg IV every 6 months) immediately or only after the development of bone loss or fractures. Immediate administration of zoledronic acid resulted in a 34% improvement in DFS (HR, 0.66; 95% CI, 0.44–0.97, P = .035) but did not affect OS.[203][Level of evidence: 1iiA]

While bisphosphonates appear to improve DFS in a population with low-to-intermediate-risk breast cancer, this benefit does not appear to be seen in all patients with breast cancer. The AZURE trial was a randomized, phase III trial that assigned 3,660 patients with stage II or III breast cancer to receive chemotherapy and/or hormone therapy with or without zoledronic acid.[204][Level of evidence: 1iiA] At a median follow-up of 59 months, there was no significant benefit in the DFS in both groups (77% in each group; HR, 0.98; P = .79). OS was also similar, at 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted HR, 0.85; P = .07).

Based on the conflicting results of these trials, the exact role for bisphosphonates in adjuvant therapy for breast cancer is controversial. An ongoing phase III trial (NCT01077154) is examining the activity of the bone-modifying agent, denosumab, in stage II and III breast cancer.

Monoclonal antibodies

Several phase III clinical trials have addressed the role of the anti-HER2/neu antibody, trastuzumab, as adjuvant therapy for patients with HER2-overexpressing cancers.

In the HERceptin Adjuvant (HERA) (BIG-01-01 [NCT00045032]) trial, which is the largest study (5,090 patients), trastuzumab was given every 3 weeks within 7 weeks of the completion of primary therapy that included, for most patients, an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively, plus or minus locoregional radiation therapy.[205][Level of evidence: 1iiA] Also, 3,387 patients were enrolled in a comparison regimen of 1 year of trastuzumab (1,694 patients) versus observation (1,693 patients).[205] Of these patients, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor (ER and PR)-negative disease. Patients who were treated with 1 year of trastuzumab experienced a 46% lower risk of a first event (HR, 0.54; 95% CI, 0.43–0.67; P < .001), corresponding to an absolute DFS benefit of 8.4% at 2 years (95% CI, 2.1–14.8). The updated results at 23.5 months' follow-up showed an unadjusted HR for the risk of death with trastuzumab compared with observation of 0.66 (95% CI, 0.47–0.91; P = .0115), corresponding to an absolute OS benefit of 2.7%.[206] There were 218 DFS events reported with trastuzumab compared with 321 DFS events reported with observation. The unadjusted HR for the risk of an event with trastuzumab was 0.64 (0.54–0.76; P < .001), corresponding to an absolute DFS benefit of 6.3%. After a median follow-up of 8 years, the results of the comparison of 1 year versus 2 years of trastuzumab were analyzed.[207] No difference in DFS was found between the groups (HR, 0.99; 95% CI, 0.85–1.14; P = .86).[207][Level of evidence: 1iiA] The benefit of 1 year of trastuzumab over observation persisted, despite crossover of 52% of the patients on observation (HR, 0.76; 95% CI, 0.65–0.88; P = .0005).[207][Level of evidence: 1iiA]

In the combined analysis of the NSABP-B-31 (NCT00004067) and Intergroup NCCTG-N9831 trials, trastuzumab was given weekly, concurrently, or immediately after the paclitaxel component of the AC with paclitaxel regimen.[208][Level of evidence: 1iiA] The HERA results were confirmed in a joint analysis of the two studies, with a combined enrollment of 3,676 patients, that demonstrated a highly significant improvement in DFS (HR, 0.48; P < .001; 3-year DFS, 87% vs. 75%), as well as a significant improvement in OS (HR, 0.67; P = .015; 3-year OS, 94.3% vs. 91.7%; 4-year OS, 91.4% vs. 86.6%).[209] Patients treated with trastuzumab experienced a longer DFS with a 52% lower risk of a DFS event (HR, 0.48; 95% CI, 0.39–0.59; P < .001), corresponding to an absolute difference in DFS of 11.8% at 3 years and 18% at 4 years. The risk of distant recurrence was 53% lower (HR, 0.47; 95%CI, 0.37–0.61; P < .001) in patients treated with trastuzumab, and the risk of death was 33% lower (HR, 0.67; 95%CI, 0.48–0.93; P = .015) in these patients.

In the BCIRG-006 (NCT00021255) trial, 3,222 women with early stage HER2-overexpressing breast cancer were randomly assigned to receive AC followed by docetaxel (AC-T) versus AC followed by docetaxel plus trastuzumab (AC-T plus trastuzumab) versus docetaxel, carboplatin, plus trastuzumab (TCH, a nonanthracycline-containing regimen).[210][Level of Evidence: 1iiA] A significant benefit with respect to DFS and OS was seen in both groups treated with trastuzumab-containing regimens compared with the control group that did not receive trastuzumab. The control group had a 5-year DFS rate of 75% and an OS rate of 87%. For patients receiving AC-T plus trastuzumab, the 5-year DFS rate was 84% (HR for the comparison with AC-T, 0.64; P < .001), and the OS rate was 92% (HR, 0.63; P < .001). For patients receiving TCH, the 5-year DFS rate was 81% (HR, 0.75; P = .04), and the OS rate was 91% (HR, 0.77; P = .04).

The authors stated that there was no significant difference in DFS or OS between the two trastuzumab-containing regimens. However, the study was not powered to detect equivalence between the two trastuzumab-containing regimens. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH) group (P < .001). These trial findings raise the question of whether anthracyclines are needed for the adjuvant treatment of HER2-overexpressing breast cancer. The group receiving AC-trastuzumab showed a small but not statistically significant benefit over TCH. This trial supports the use of TCH as an alternative adjuvant regimen for women with early-stage HER2-overexpressing breast cancer, particularly in those with concerns about cardiac toxic effects.

The AVENTIS-TAX-GMA-302 study was a three-arm large trial containing two anthracycline arms (AC-D: doxorubicin, cyclophosphamide, docetaxel or AC-DH: doxorubicin, cyclophosphamide, docetaxel, and trastuzumab) and a nonanthracycline one (DCbH: docetaxel, carboplatin, trastuzumab).[211] In its second interim efficacy analysis with a median follow-up of 36 months, there were 462 DFS events and 185 deaths. For DFS, the HR was 0.61 for patients in the AC-DH arm (95% CI, 0.48–0.76; P < .001) and 0.67 for patients in the DCbH arm (95% CI, 0.54–0.83; P = .003), compared with the AC-D arm. This translated to absolute benefits (from years 2 to 4) of 6% and 5%, respectively with the addition of trastuzumab. Nevertheless, longer follow-up is needed in patients in the DCbH arm to warrant the omission of anthracyclines in these patients.

The Finland Herceptin (FINHER) study assessed the impact of a much shorter course of trastuzumab.[212] In this trial, 232 women younger than 67 years with node-positive or high-risk (>2 cm tumor size) node-negative HER2-overexpressing breast cancer were given nine weekly infusions of trastuzumab concurrently with docetaxel or vinorelbine followed by FEC. At a 3-year median follow-up, the risk of recurrence and/or death was significantly reduced in patients receiving trastuzumab (HR, 0.41; P = .01; 95% CI, 0.21–0.83; 3 year DFS, 89% vs. 78%). The difference in OS (HR, 0.41) was not statistically significant (P = .07; 95% CI, 0.16–1.08).[212][Level of evidence: 1iiA]

In contrast, a recent French trial failed to demonstrate that 6 months of adjuvant trastuzumab was noninferior to 12 months of treatment. A 2-year DFS rate was 93.8% (95% CI, 92.6–94.9) in the 12-month group and 91.1% (89.7–92.4) in the 6-month group (HR, 1.28; 95% CI, 1.05–1.56; noninferiority, P = .29). The authors concluded that 12 months should remain the standard duration of trastuzumab adjuvant therapy.[213][Level of evidence: 1iiA]

A number of studies have evaluated the use of subcutaneous (SQ) trastuzumab in the neoadjuvant and adjuvant settings and are described in the Timing of Adjuvant and Primary Therapy section of this summary.

Lapatinib

Lapatinib is a small molecule tyrosine kinase inhibitor that is capable of dual-receptor inhibition of both epidermal growth factor receptor and HER2. In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (ALTTO [NCT00553358]), the role of lapatinib (in combination with, in sequence to, in comparison with, or as an alternative to trastuzumab) in the adjuvant setting is being investigated. In phase I/II studies as a single agent, lapatinib has resulted in objective responses between 4.3% and 7.8% in HER2-positive patients who had progressed on multiple trastuzumab-containing regimens with a substantial number having stable disease at 4 months (34%–41%) and 6 months (18%–21%).[214] In a phase III trial (GSK-EGF100151), lapatinib plus capecitabine was superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab.[215] The HR for time to progression was 0.49 (95% CI, 0.34–0.71; P < .001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group.

The combination of lapatinib and trastuzumab in the ALTTO trial is further supported by a demonstration that lapatinib combined with trastuzumab confers a significantly improved progression-free survival in patients with metastatic breast cancer who experience progression on prior trastuzumab-containing treatment when compared with lapatinib alone.[216]

In September 2011, the ALTTO trial was amended to discontinue the lapatinib alone arm of the trial. The Independent Data Monitoring Committee of the trial determined that the patients assigned to the lapatinib alone arm were not likely to do as well as the patients assigned to the trastuzumab alone control arm. Final results of this trial are pending.

Cardiac toxic effects with adjuvant trastuzumab

In the HERA (BIG-01-01) trial, severe congestive heart failure (CHF) (New York Heart Association class III–IV) occurred in 0.6% of patients treated with trastuzumab.[205] Symptomatic CHF occurred in 1.7% and 0.06% of patients in the trastuzumab and observation arms, respectively. Fifty-one patients experienced a confirmed left ventricular ejection fraction (LVEF) decrease (defined as an ejection fraction decrease of >10 points from baseline to an LVEF <50%) with trastuzumab, which recovered or stabilized within 3 to 6 weeks of initial treatment in 86% of cases. In the NSABP B-31 (NCT00004067) trial, 31 of 850 patients in the trastuzumab arm had confirmed symptomatic cardiac events, compared with 5 of 814 patients in the control arm.[217] The 3-year cumulative incidence of cardiac events for trastuzumab-treated patients was 4.1%, compared with 0.8% of patients in the control arm (95% CI, 1.7%–4.9%). Asymptomatic decline in LVEF (defined by >10% decline or to 55%) occurred in 17% of patients in the trastuzumab arm (95% CI, 15%–20%) and 34% of patients in the control arm (95%CI, 31%–38%), with a HR, 2.1 (95%CI, 1.7–2.6; P < .001). In the NCCTG-N9831 trial, 39 cardiac events were reported in the three arms over a 3-year period. The 3-year cumulative incidence of cardiac events in arm A was 0.35% (no trastuzumab), arm B, 3.5% (trastuzumab following paclitaxel) and arm C, 2.5% (trastuzumab concomitant with paclitaxel).

In the AVENTIS-TAX-GMA-302 (BCIRG 006) trial, clinically symptomatic cardiac events were detected in 0.38% of patients in the AC-D arm, 1.87% of patients in the AC-DH arm, and 0.37% of patients in the DCbH arm.[211] There was also a statistically significant higher incidence of asymptomatic and persistent decrease in LVEF in the AC-DH arm than with either the AC-D or DCbH arms. No cardiac deaths were reported in the AVENTIS-TAX-GMA-302 trial.

In the FINHER trial, none of the patients who received trastuzumab experienced clinically significant cardiac events. In fact, LVEF was preserved in all of the women receiving trastuzumab, but the number of patients receiving adjuvant trastuzumab was very low.

A number of studies have also evaluated newer anti-HER2 therapies (e.g., lapatinib, pertuzumab) and combinations of anti-HER2 therapy (dual blockade) in both the early breast cancer and metastatic settings. These studies have incorporated close monitoring of LVEF. A pooled analysis of cardiac safety in 598 patients with cancer treated with pertuzumab was performed using data supplied by Roche and Genentech. Asymptomatic left ventricular systolic dysfunction was observed in 6.9% of patients receiving pertuzumab alone (n = 331; 95% CI, 4.5–10.2), 3.4% of patients receiving pertuzumab in combination with a nonanthracycline-containing chemotherapy (n = 175; 95% CI, 1.3–7.3), and 6.5% of patients receiving pertuzumab in combination with trastuzumab (n = 93; 95% CI, 2.4–13.5). Symptomatic heart failure was observed in 1 (0.3%), 2 (1.1%), and 1 (1.1%) patients, respectively.[218][Level of evidence: 3iiiD]

A meta-analysis of six studies reported no increased risk of cardiac toxic effects with dual blockade of the HER2 pathway.[219][Level of evidence: 1iiA] The overall incidence results for CHF in the combined anti-HER2 therapy and the anti-HER2 monotherapy were 0.88% (95% CI, 0.47–1.64%) and 1.49% (95% CI, 0.98–2.23%). The incidence of LVEF decline was 3.1% (95% CI, 2.2–4.4%) and 2.9% (95% CI, 2.1–4.1%), respectively. The OR of CHF between anti-HER2 combination and monotherapy was 0.58 (95% CI, 0.26–1.27, P = .17) while the OR of LVEF decline was 0.88 (95% CI, 0.53–1.48, P = .64). This meta-analysis suggests comparable cardiac toxicity between anti-HER2 combination therapy and anti-HER2 monotherapy. However, a number of limitations are noted within this analysis including the heterogeneity of the agents and disease settings evaluated, and that the data are trial level versus patient-level data.

Treatment options for HER2-positive early breast cancer:

  • Standard treatment is 1 year of adjuvant trastuzumab therapy. Results of the 1 year versus 2 years of trastuzumab of the HERA trial are awaited, as are the results of the Protocol of Herceptin Adjuvant with Reduced Exposure (INCA-PHARE [NCT00381901]) trial, which compared 1 year versus 6 months of adjuvant trastuzumab.
Timing of Primary and Adjuvant Therapy

Postoperative adjuvant chemotherapy

The optimal time to initiate adjuvant therapy is uncertain. A single study that addressed the use of perioperative adjuvant chemotherapy in node-positive patients showed no advantage in DFS when a single cycle of perioperative chemotherapy was given in addition to standard therapy initiated 4 weeks after surgery.[220] A single cycle of immediate postoperative chemotherapy alone was inferior.[221]

Preoperative neoadjuvant chemotherapy

A randomized clinical trial (NSABP-B-18) has been performed to evaluate preoperative chemotherapy in the management of patients with stage I or stage II breast cancer.[222] After preoperative therapy with four cycles of doxorubicin and cyclophosphamide, 80% of the assessable patients had a reduction in tumor size of at least 50%, and 36% of the patients had a complete clinical response. More patients treated with preoperative chemotherapy were able to have breast-conserving procedures as compared with those patients in the postoperative chemotherapy group (68% vs. 60%). Twenty-seven percent of the women in the preoperative therapy group for whom a mastectomy had been planned prior to being randomly assigned underwent a lumpectomy. No statistically significant difference existed, however, in DFS, distant DFS, or OS in the patients who received preoperative chemotherapy as compared with those who received postoperative chemotherapy.[222-224][Level of evidence: 1iiA]

An EORTC randomized trial (EORTC-10902) likewise demonstrated no improvement in DFS or OS, but showed an increased frequency of conservative surgery with the use of preoperative versus postoperative FEC chemotherapy.[225][Level of evidence: 1iiA] Preoperative chemotherapy may be beneficial in women who desire breast-conserving surgery but who would otherwise not be considered candidates because of the size of their tumor. In a meta-analysis including all trials that compared the use of the same chemotherapy preoperatively and postoperatively, the use of preoperative chemotherapy was associated with a higher rate of local recurrence.[226] Although preoperative chemotherapy affects the results of SLN biopsy, one small study indicated that SLN biopsy technique was feasible in this setting.[227] However, the results of two prospective studies (NCT02031042 and NCT00881361) indicate that SLN biopsy is associated with false-negative rates of 14.2% and 12.6%, respectively, when undertaken after neoadjuvant chemotherapy in patients who convert from a clinically positive to a clinically negative axillary status.[228,229][Level of evidence: 3iiD] These rates are higher than those observed when SLN biopsy is done before adjuvant chemotherapy. The role of this procedure in the neoadjuvant setting is uncertain.

HER2-directed therapies

Trastuzumab

In HER2-overexpressed disease, pilot studies have demonstrated remarkable clinical and pathologic responses when trastuzumab is given preoperatively in combination with chemotherapy.[230] A randomized phase III study (NOAH) in patients with HER2-positive locally advanced or inflammatory breast cancers confirmed that the addition of concurrent neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy with sequential doxorubicin plus paclitaxel followed by CMF resulted not only in improved clinical responses (87% vs. 74%) and pathologic responses (breast and axilla, 38% vs. 19%) but also in EFS, the primary outcome.[231] This was defined as the time from random assignment to disease recurrence or progression—whether local, regional, distant, or contralateral—or death from any cause.

At 3 years, of all of the patients, 71% (95% CI, 61–78) showed improvement in EFS with trastuzumab versus 56% without trastuzumab (95% CI, 46–65), HR, 0.59 (95% CI, 0.38–0.90, P = .013), thereby favoring the addition of trastuzumab. The 3-year OS was 87% versus 79% at the time of the report (P = .114, not significant). Symptomatic cardiac failure developed in two patients receiving concurrent doxorubicin and trastuzumab for two cycles. Close cardiac monitoring of (LVEF and the total dose of doxorubicin not exceeding 180 mg/m2 accounted for the relatively low number of declines in LVEF and only two cardiac events. (See the Cardiac toxic effects with adjuvant trastuzumab section in this summary.)[231][Level of evidence: 1iiD]

A phase III (Z1041 [NCT00513292]) trial randomly assigned patients with operable HER2-positive breast cancer to receive trastuzumab sequential to or concurrent with the anthracycline component (fluorouracil, epirubicin, cyclophosphamide) of the neoadjuvant chemotherapy regimen. All patients received trastuzumab concurrent with paclitaxel. There was no significant difference in pathological complete response (pCR) in the breast between the arms (56.5% sequential, 54.2% concurrent; difference 2.3% with 95% CI, -9.3–13.9). In addition, asymptomatic declines in LVEF during neoadjuvant chemotherapy were identified in similar proportions of patients in each arm. The conclusion was that concurrent administration of trastuzumab with anthracyclines is not warranted based on these findings.[232][Level of evidence: 1iiDiv]

A phase III (HannaH [NCT00950300]) trial also demonstrated that the pharmacokinetics and efficacy of neoadjuvant SQ trastuzumab is noninferior to the IV formulation. This international, open-label trial (n = 596) randomly assigned women with operable, locally advanced, or inflammatory HER2-positive breast cancer to neoadjuvant chemotherapy (anthracycline/taxane-based), concurrent with either SQ-administered or IV-administered trastuzumab every 3 weeks before surgery. Patients received adjuvant trastuzumab to complete 1 year of therapy. The pCR rates between the arms differed by 4.7% (95% CI, 4.0–13.4); 40.7% in the IV-administered group versus 45.4% in the SQ-administered group, demonstrating noninferiority for the SQ formulation. Data regarding the DFS and OS differences between the arms are not yet available.[233][Level of evidence: 1iiD]

PrefHer (NCT01401166) (n = 248) was a randomized, cross-over design trial in which all patients were randomly assigned to receive four cycles of 600 mg, fixed-dose, SQ-administered, adjuvant trastuzumab followed by four cycles of standard IV-administered trastuzumab, or the reverse sequence. Almost all patients preferred the SQ formulation; the primary endpoint was the proportion of patients indicating an overall preference for SQ-administered or IV-administered trastuzumab, which was assessed by patient interview.[213][Level of evidence: 1iiC] An ongoing trial, SafeHer, is evaluating the safety of self-administered versus clinician-administered SQ trastuzumab. SQ trastuzumab is approved for use in Europe in early and late stage breast cancer.

Pertuzumab

Pertuzumab, in combination with trastuzumab with or without chemotherapy, has been evaluated in two clinical trials. In the open-label, randomized, phase II NeoSPHERE trial (NCT00545688),[234] 417 women with tumors that were larger than 2 cm or node-positive, and who had HER2-positive breast cancer, were randomly assigned to one of four preoperative regimens:

  1. Docetaxel plus trastuzumab.
  2. Docetaxel plus trastuzumab and pertuzumab.
  3. Pertuzumab plus trastuzumab.
  4. Docetaxel plus pertuzumab.

The pCR rates were 29%, 46%, 17%, and 24%, respectively.[234][Level of evidence: 1iiDiv] Therefore, the highest pCR rate was seen in the preoperative treatment arm with dual HER2 blockade plus chemotherapy. The addition of pertuzumab to the docetaxel plus trastuzumab combination did not appear to increase toxic effects, including the risk of cardiac adverse events.

The open-label, randomized, phase II TRYPHAENA trial (NCT00976989) sought to evaluate the tolerability and activity associated with trastuzumab and pertuzumab.[235][Level of evidence: 1iiDiv] All 225 women with tumors that were larger than 2 cm or node-positive, and who had operable, locally advanced, or inflammatory HER2-positive breast cancer, were randomly assigned to one of three preoperative regimens:

  1. Concurrent FEC plus trastuzumab plus pertuzumab (×3) followed by concurrent docetaxel plus trastuzumab plus pertuzumab.
  2. FEC alone (×3) followed by concurrent docetaxel plus trastuzumab plus pertuzumab (×3).
  3. Concurrent docetaxel and carboplatin plus trastuzumab plus pertuzumab (×6).

The pCR rate was equivalent across all three treatment arms (62%, 57%, and 66%, respectively.) All three arms were associated with a low incidence of cardiac adverse events of 5% or less.

On the basis of these studies, the FDA granted accelerated approval for the use of pertuzumab as part of neoadjuvant treatment for women with early-stage, HER2-positive breast cancer. The FDA approved no more than 3 to 6 cycles of pertuzumab. The ongoing APHINITY trial (NCT01358877), a randomized, phase III, adjuvant study for women with HER2-positive breast cancer, is the confirmatory trial for this accelerated approval. Results are expected in 2016.

Lapatinib

The role of lapatinib in the neoadjuvant setting was examined in the GeparQuinto [NCT00567554] trial.[236] This phase III trial randomly assigned women with HER2-positive early stage breast cancer to receive chemotherapy with trastuzumab versus chemotherapy with lapatinib with pCR as the primary endpoint.[236][Level of Evidence: 1iiDiv] pCR in the chemotherapy and lapatinib arm was significantly lower than it was with chemotherapy and trastuzumab (22.7% vs. 30.3%; P = .04). Other endpoints of DFS, RFS, and OS have not been reported. The results do not support the use of single-agent lapatinib with chemotherapy in the neoadjuvant setting.

Neoadjuvant therapy with dual HER2 inhibition was studied in the NeoALTTO [NCT00553358] trial.[237][Level of evidence: 1iiDiv] This phase III trial randomly assigned 455 women with HER2-positive early stage breast cancer (tumor size >2 cm) to receive neoadjuvant lapatinib compared with neoadjuvant trastuzumab compared with neoadjuvant lapatinib plus trastuzumab. This anti-HER2 therapy was given alone for 6 weeks and then weekly paclitaxel was added to the regimen for an additional 12 weeks for all enrolled patients. The primary endpoint of this study was pCR. pCR was significantly higher in the lapatinib plus trastuzumab combination arm (51.3%; 95% CI, 43.1–59.5) than in the trastuzumab alone arm (29.5%; 95% CI, 22.4–37.5). No significant difference in pCR was seen between the lapatinib (24.7%, 95% CI, 18.1–32.3) and trastuzumab groups (difference -4.8%, -17.6–8.2; P = -.34).

The DFS, RFS, and OS rates have not been reported in this trial. pCR rates, while hypothesis-generating, do not substitute for these other efficacy endpoints. Interestingly, there was a numerical but not a statistically significant difference in pCR rate in patients observed in a phase III (NSABP B-41 [NCT00486668]) trial in which women with operable HER2-positive breast cancer were randomly assigned to doxorubicin and cyclophosphamide, followed by paclitaxel concurrent with trastuzumab (52.5%, 95% CI, 44.9–59.5), lapatinib (53.2%, 95% CI, 45.4–60.3), or the combination of trastuzumab and lapatinib (62%, 95% CI, 54.3–68.8; P = .095).[238][Level of evidence: 1iiDiv] Results from the similarly designed, ongoing, CALGB-40601 (NCT00770809) trial are pending. More definitive efficacy data will also be provided by the phase III ALLTO trial that is randomly assigning women to trastuzumab or trastuzumab plus lapatinib in the adjuvant setting.

Bevacizumab

At present, there is no established role for the use of bevacizumab as part of neoadjuvant chemotherapy for breast cancer. Bevacizumab is a monoclonal antibody that works against vascular endothelial growth factor A and has shown some degree of efficacy in the metastatic setting. Two randomized, phase III clinical trials of chemotherapy with or without bevacizumab have reported results. [239,240]

One trial randomly assigned 1,206 patients with primary operable HER2-negative breast cancer to receive chemotherapy with or without bevacizumab.[239] The addition of bevacizumab significantly increased the rate of pCR (28.2% without bevacizumab vs. 34.5% with bevacizumab, P = .02).[239][Level of evidence: 1iiDiv] However, the addition of bevacizumab increased the rates of hypertension, cardiac toxicity, hand-foot syndrome, and mucositis.

Another study randomly assigned 1,948 patients with operable HER2-negative breast cancer to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel with or without concomitant bevacizumab.[240] The addition of bevacizumab in this study also significantly increased the rate of pCR (14.9% without bevacizumab vs. 18.4% with bevacizumab, P = .003).[240][Level of evidence: 1iiDiv] Similarly to other clinical trials, the addition of bevacizumab increased the toxic effects, with higher rates of febrile neutropenia, mucositis, hand-foot syndrome, infection, and hypertension, but it did not increase surgical complications. A preplanned subgroup analysis subsequently revealed that the addition of bevacizumab to neoadjuvant chemotherapy significantly increased the pCR rate from 27.9% to 39.3% in patients with triple-negative breast cancer (P = .003).[241][Level of evidence: 1iiDii]

Of note, OS and DFS outcomes were not reported in either clinical trial.[239,240] Based on these results, bevacizumab should not be used in the treatment of operable breast cancer. Caution should be used in interpreting pCR as a primary clinical outcome. However, further study of bevacizumab for the treatment of operable breast cancer may be warranted.

Adjuvant radiation and chemotherapy

The optimal sequence of adjuvant chemotherapy and radiation therapy after breast-conserving surgery was studied in a randomized trial.[242] Patients received either chemotherapy first (n = 122), consisting of CMFP plus doxorubicin repeated every 21 days for four cycles, followed by breast radiation, or breast radiation first (n = 122), followed by the same chemotherapy. With a median follow-up of 5 years, OS was 73% for the radiation-first group and 81% for the chemotherapy-first group (P = .11).[242][Level of evidence: 1iiA] The 5-year crude rates of first recurrence by site in the radiation-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 statistical significance (P = .07). Further analyses revealed that differences in recurrence patterns persisted for most subgroups with the exception of those who had either negative tumor margins or one to three positive lymph nodes. For these two subgroups, sequence assignment made little difference in local or distant recurrence rates, though the statistical power of these subgroup analyses was low. Potential explanations for the increase in distant recurrence noted in the radiation therapy-first group are that chemotherapy was delayed for a median of 17 weeks after surgery, and that this group received lower chemotherapy dosages due to increased myelosuppression.

Two additional randomized trials, though not specifically designed to address the timing of radiation therapy and adjuvant chemotherapy, do add useful information.[171,243] In the NSABP-B-15 trial, patients who had undergone breast-conserving surgery received either one course of CMF (n = 194) followed by radiation therapy followed by five additional cycles of CMF, or they received four cycles of AC (n = 199) followed by radiation therapy. No differences in DFS, distant DFS, and OS were observed between these two arms.[171][Level of evidence: 1iiA] The International Breast Cancer Study Group trials VI and VII also varied the timing of radiation therapy with CMF adjuvant chemotherapy.[243] These studies showed that delays from 2 to 7 months in radiation therapy after surgery had no effect on the rate of local recurrence. These findings have been confirmed in a meta-analysis.[244][Level of evidence: 1iiA]

Based on the above studies, delaying radiation therapy for several months after breast-conserving surgery until the completion of adjuvant chemotherapy does not appear to have a negative impact on overall outcome. Additionally, initiating chemotherapy soon after breast-conserving therapy may be preferable for patients at high risk of distant dissemination.

In an unplanned analysis of patients treated on a phase III trial evaluating the benefit of adding trastuzumab in HER2/neu-positive breast cancer patients, there was no associated increase in acute adverse events or frequency of cardiac events in patients who received concurrent adjuvant radiation therapy and trastuzumab.[245] Therefore, delivering radiation therapy concomitantly with trastuzumab appears to be safe and avoids additional delay in radiation therapy treatment initiation.

Timing of surgery

Several retrospective reviews have indicated that statistically significantly better DFS is achieved for premenopausal women with breast cancer and positive axillary lymph nodes if breast surgery is performed during the luteal phase (days 15–36) as compared with the follicular phase (days 0–14) of the menstrual cycle.[246-248][Level of evidence: 1iiA]; [249] Several other studies, however, have failed to support this finding or have found opposite results.[250-252]; [253][Level of evidence: 1iiA] Because of the inconsistent findings 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. A prospectively controlled trial (UCLA-9810046) has been completed but is not yet analyzed.

Chemotherapy risks

Adjuvant chemotherapy is associated with several well-characterized toxic effects that vary according to the individual drugs used in each regimen. Common toxic effects include nausea and vomiting, myelosuppression, alopecia, and mucositis. Less common, but serious, toxic effects include heart failure (if an anthracycline is used), thromboembolic events,[254] and premature menopause.[255] (Refer to the PDQ summary on Nausea and Vomiting and for information on mucositis, refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation; for information on symptoms associated with premature menopause, refer to the PDQ summary on Hot Flashes and Night Sweats.)

Cognitive impairment has been reported to occur after the administration of some chemotherapy regimens.[256] However, data on this topic from prospective, randomized studies are lacking.

The EBCTCG meta-analysis revealed that women who received adjuvant combination chemotherapy did have a 20% (standard deviation = 10) reduction in the annual odds of developing contralateral breast cancer.[167] This small proportional reduction translated into an absolute benefit that was only marginally statistically significant, but it indicates that chemotherapy does not increase the risk of contralateral disease. In addition, the analysis showed no statistically significant increase in deaths attributed to other cancers or to vascular causes among all women randomly assigned to receive chemotherapy. The use of anthracycline-containing regimens, however—particularly those containing an increased dose of cyclophosphamide—has been associated with a cumulative risk of developing acute leukemia of 0.2% to 1.7% at 5 years.[257,258] This risk increases to more than 4% in patients receiving high cumulative doses of both epirubicin (>720 mg/m2) and cyclophosphamide (>6,300 mg/m2).[259]

Chemotherapy and tamoxifen risks

Adjuvant combinations of tamoxifen and chemotherapy administered concurrently to enhance efficacy may also have enhanced toxic effects. A single study randomly assigned postmenopausal women with node-positive, ER-positive tumors to receive tamoxifen (30 mg/day for 2 years) plus CMF (IV for 6 months) (n = 353) or tamoxifen alone (n = 352).[254] Of the women receiving combined chemohormonal therapy, 13.6% developed one or more thromboembolic events compared with 2.6% in the tamoxifen-alone group (P < .001). Also, statistically significantly more women were on combined treatment who developed severe thromboembolic events (grade 3–5), most of which (39 of 54) occurred while the women were actually receiving chemotherapy. Not all studies that compared concurrent chemotherapy plus tamoxifen with tamoxifen alone, however, have reported such high rates. In the NSABP-B-16 study that compared tamoxifen (20 mg/day for 5 years) plus chemotherapy with doxorubicin plus cyclophosphamide (four cycles) with tamoxifen alone, 4.9% of the women on combined treatment had thromboembolic events versus 2.1% of women on tamoxifen alone.[97] Whether tamoxifen should be given concurrently or after the completion of chemotherapy was addressed in an Intergroup trial (INT-0100 [NCT00929591], formerly SWOG-8814) that compared the concurrent and sequential administration of CAF and tamoxifen in postmenopausal hormone receptor-positive patients. Sequential administration resulted in superior DFS that was significant at 8 years (67% vs. 62%; P = .045).[260][Level of evidence: 1iiDii]

Candidates for whom adjuvant therapy may not be necessary include individuals with small primary tumors (<1 cm) and negative axillary nodes who have an excellent prognosis, with nearly 90% of patients alive and free of disease at 20 years in one series.[261] A U.S. Intergroup study (SWOG-8897) observed patients off treatment with tumors of low risk (tumors too small for biochemical ER/PR assay) and uncertain-risk (tumors <2 cm, ER-positive and PR-positive, and low S-phase fractions). This low-risk and uncertain-risk subset had a 96% 5-year survival rate without adjuvant therapy. Whether this group of patients would derive long-term benefit from tamoxifen for either its adjuvant or preventive effects remains uncertain. Clearly, this group has a risk of developing a new breast cancer that would meet the eligibility criteria that were used in the Breast Cancer Prevention Trial that demonstrated a benefit with tamoxifen.

Proposals have been made to treat elderly patients with tamoxifen alone and without surgery. This approach has unacceptably high local failure rates and, outside of a clinical trial setting, should be used only for patients who are not candidates for mastectomy or breast-conserving surgery plus radiation therapy, or for those who refuse these options.[262-264]

Treatment Options

Primary therapy

Local-regional treatment:

  • Breast-conserving therapy (lumpectomy, breast radiation, and surgical staging of the axilla).

  • Modified radical mastectomy (removal of the entire breast with level I–II axillary dissection) with or without breast reconstruction.

  • Sentinel node biopsy.

Adjuvant radiation therapy postmastectomy in axillary node-positive tumors:

  • For one to three nodes: unclear role for regional radiation (infra/supraclavicular nodes, internal mammary nodes, axillary nodes, and chest wall).

  • For more than four nodes or extranodal involvement: regional radiation is advised.

Adjuvant systemic therapy:

An International Consensus Panel proposed a three-tiered risk classification for patients with negative axillary lymph nodes.[55] This classification, with some modification, is described below:

Table 7. Risk Categories for Women With Node-Negative Breast Cancer
 Low Risk (Has All Listed Factors)  Intermediate Risk (Risk Classified Between the Other Two Categories)  High Risk (Has at Least One Listed Factor) 
ER = estrogen receptor; PR = progesterone receptor
Tumor size= 1 cm1–2 cm>2 cm
ER or PR statuspositivepositivenegative
Tumor gradegrade 1grade 1–2grade 2–3

The original Consensus Panel classification also required that women be 35 years or older to be included in the low-risk group and included women 35 years and younger in the high-risk group, based admittedly on indirect evidence. Traditionally, certain uncommon histologies (e.g., tubular, medullary, and mucinous) have also been associated with favorable prognosis and may be considered as low-risk factors. Some additional tumor characteristics that may eventually prove helpful in the prognosis of node-negative disease include the tumor proliferative fraction (S-phase) and the level of HER2/neu expression.

Regardless of how one chooses to characterize node-negative tumors, evidence from clinical trials suggests that various types of adjuvant therapies benefit certain subgroups of patients with these kinds of tumors. The same is true for women with node-positive breast cancer. What has become clear after reviewing results from multiple breast cancer treatment trials is that hormone therapy and chemotherapy regimens generally offer the same proportional benefit to women irrespective of their axillary lymph node status. The selection of therapy is most appropriately based upon knowledge of an individual’s risk of tumor recurrence balanced against the short-term and long-term risks of adjuvant treatment. This approach should allow clinicians to help individuals to determine if the gains anticipated from treatment are reasonable for their particular situation. The treatment options presented below should be modified based upon both patient and tumor characteristics.

Table 8. Adjuvant Systemic Treatment Options for Women With Axillary Node-Negative Breast Cancer
Patient Group Low Risk  Intermediate Risk High Risk 
Premenopausal, ER-positive or PR-positiveNone or tamoxifenTamoxifen plus chemotherapy, tamoxifen alone, ovarian ablation, GnRH analogaChemotherapy plus tamoxifen, chemotherapy plus ablation or GnRH analog*, chemotherapy plus tamoxifen plus ovarian ablation or GnRH*, or ovarian ablation alone or with tamoxifen or GnRH alone or with tamoxifen
Premenopausal, ER-negative or PR-negativeChemotherapy
Postmenopausal, ER-positive or PR-positiveNone or upfront AI or tamoxifen followed by AIUpfront AI or tamoxifen followed by AI +/- chemotherapyUpfront AI or tamoxifen followed by AI +/- chemotherapy
Postmenopausal, ER-negative or PR-negativeChemotherapy

AI = aromatase inhibitor; ER = estrogen receptor; GnRH = gonadotropin-releasing hormone; PR = progesterone receptor
aNote: This treatment option is under clinical evaluation.

Table 9. Treatment Options for Women With Axillary Node-Positive Breast Cancer
Patient Group  Treatments 
Premenopausal, ER-positive or PR-positiveChemotherapy plus tamoxifen, chemotherapy plus ovarian ablation/GnRH analog, chemotherapy plus tamoxifen plus ovarian ablation/GnRH analoga, ovarian ablation alone or with tamoxifen or GnRH alone or with tamoxifen
Premenopausal, ER-negative or PR-negativeChemotherapy
Postmenopausal, ER-positive or PR-positiveUpfront AI or tamoxifen followed by AI plus chemotherapy, upfront AI or tamoxifen followed by AI alone
Postmenopausal, ER-negative or PR-negativeChemotherapy

AI= aromatase inhibitors; ER = estrogen receptor; GnRH = gonadotropin-releasing hormone; PR = progesterone receptor
a Note: This treatment option is under clinical evaluation.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I breast cancer, stage II breast cancer, stage IIIA breast cancer and stage IIIC breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  1. Fisher B, Fisher ER, Redmond C, et al.: Tumor nuclear grade, estrogen receptor, and progesterone receptor: their value alone or in combination as indicators of outcome following adjuvant therapy for breast cancer. Breast Cancer Res Treat 7 (3): 147-60, 1986.  [PUBMED Abstract]

  2. Thor AD, Berry DA, Budman DR, et al.: erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 90 (18): 1346-60, 1998.  [PUBMED Abstract]

  3. Paik S, Bryant J, Park C, et al.: erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 90 (18): 1361-70, 1998.  [PUBMED Abstract]

  4. Hutchins L, Green S, Ravdin P, et al.: CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node negative patients: first results of intergroup trial INT 0102. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A2, 1a, 1998. 

  5. Simpson JF, Gray R, Dressler LG, et al.: Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189. J Clin Oncol 18 (10): 2059-69, 2000.  [PUBMED Abstract]

  6. Fisher B, Anderson S, Bryant J, et al.: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347 (16): 1233-41, 2002.  [PUBMED Abstract]

  7. Blichert-Toft M, Rose C, Andersen JA, et al.: Danish randomized trial comparing breast conservation therapy with mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative Group. J Natl Cancer Inst Monogr (11): 19-25, 1992.  [PUBMED Abstract]

  8. van Dongen JA, Bartelink H, Fentiman IS, et al.: Randomized clinical trial to assess the value of breast-conserving therapy in stage I and II breast cancer, EORTC 10801 trial. J Natl Cancer Inst Monogr (11): 15-8, 1992.  [PUBMED Abstract]

  9. Sarrazin D, Lê MG, Arriagada R, et al.: Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 14 (3): 177-84, 1989.  [PUBMED Abstract]

  10. Jacobson JA, Danforth DN, Cowan KH, et al.: Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 332 (14): 907-11, 1995.  [PUBMED Abstract]

  11. Veronesi U, Cascinelli N, Mariani L, et al.: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347 (16): 1227-32, 2002.  [PUBMED Abstract]

  12. Veronesi U, Salvadori B, Luini A, et al.: Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomised trials on 1,973 patients. Eur J Cancer 31A (10): 1574-9, 1995.  [PUBMED Abstract]

  13. van Dongen JA, Voogd AC, Fentiman IS, et al.: Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 92 (14): 1143-50, 2000.  [PUBMED Abstract]

  14. Abrams JS, Phillips PH, Friedman MA: Meeting highlights: a reappraisal of research results for the local treatment of early stage breast cancer. J Natl Cancer Inst 87 (24): 1837-45, 1995.  [PUBMED Abstract]

  15. Freedman GM, Anderson PR, Li T, et al.: Locoregional recurrence of triple-negative breast cancer after breast-conserving surgery and radiation. Cancer 115 (5): 946-51, 2009.  [PUBMED Abstract]

  16. Weiss MC, Fowble BL, Solin LJ, et al.: Outcome of conservative therapy for invasive breast cancer by histologic subtype. Int J Radiat Oncol Biol Phys 23 (5): 941-7, 1992.  [PUBMED Abstract]

  17. 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. Int J Radiat Oncol Biol Phys 17 (4): 733-8, 1989.  [PUBMED Abstract]

  18. 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. Int J Radiat Oncol Biol Phys 21 (2): 279-87, 1991.  [PUBMED Abstract]

  19. Wazer DE, Schmidt-Ullrich RK, Schmid CH, et al.: The value of breast lumpectomy margin assessment as a predictor of residual tumor burden. Int J Radiat Oncol Biol Phys 38 (2): 291-9, 1997.  [PUBMED Abstract]

  20. Holland R, Connolly JL, Gelman R, et al.: The presence of an extensive intraductal component following a limited excision correlates with prominent residual disease in the remainder of the breast. J Clin Oncol 8 (1): 113-8, 1990.  [PUBMED Abstract]

  21. Jardines L, Fowble B, Schultz D, et al.: Factors associated with a positive reexcision after excisional biopsy for invasive breast cancer. Surgery 118 (5): 803-9, 1995.  [PUBMED Abstract]

  22. Renton SC, Gazet JC, Ford HT, et al.: The importance of the resection margin in conservative surgery for breast cancer. Eur J Surg Oncol 22 (1): 17-22, 1996.  [PUBMED Abstract]

  23. Whelan TJ, MacKenzie RG, Levine M, et al.: A randomized trial comparing two fractionation schedules for breast irradiation postlumpectomy in node-negative breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 19: A-5, 2a, 2000. 

  24. Whelan T, MacKenzie R, Julian J, et al.: Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst 94 (15): 1143-50, 2002.  [PUBMED Abstract]

  25. Owen JR, Ashton A, Bliss JM, et al.: Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol 7 (6): 467-71, 2006.  [PUBMED Abstract]

  26. 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. J Clin Oncol 15 (3): 963-8, 1997.  [PUBMED Abstract]

  27. Bartelink H, Horiot JC, Poortmans P, et al.: Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 345 (19): 1378-87, 2001.  [PUBMED Abstract]

  28. Wazer DE, Kramer B, Schmid C, et al.: Factors determining outcome in patients treated with interstitial implantation as a radiation boost for breast conservation therapy. Int J Radiat Oncol Biol Phys 39 (2): 381-93, 1997.  [PUBMED Abstract]

  29. 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. Int J Radiat Oncol Biol Phys 33 (1): 45-51, 1995.  [PUBMED Abstract]

  30. Chabner E, Nixon A, Gelman R, et al.: Family history and treatment outcome in young women after breast-conserving surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 16 (6): 2045-51, 1998.  [PUBMED Abstract]

  31. Haas JA, Schultz DJ, Peterson ME, et al.: An analysis of age and family history on outcome after breast-conservation treatment: the University of Pennsylvania experience. Cancer J Sci Am 4 (5): 308-15, 1998 Sep-Oct.  [PUBMED Abstract]

  32. Robson M, Gilewski T, Haas B, et al.: BRCA-associated breast cancer in young women. J Clin Oncol 16 (5): 1642-9, 1998.  [PUBMED Abstract]

  33. Veronesi U, Luini A, Del Vecchio M, et al.: Radiotherapy after breast-preserving surgery in women with localized cancer of the breast. N Engl J Med 328 (22): 1587-91, 1993.  [PUBMED Abstract]

  34. Liljegren G, Holmberg L, Bergh J, et al.: 10-Year results after sector resection with or without postoperative radiotherapy for stage I breast cancer: a randomized trial. J Clin Oncol 17 (8): 2326-33, 1999.  [PUBMED Abstract]

  35. 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. J Natl Cancer Inst 84 (9): 683-9, 1992.  [PUBMED Abstract]

  36. Fyles AW, McCready DR, Manchul LA, et al.: Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 351 (10): 963-70, 2004.  [PUBMED Abstract]

  37. Hughes KS, Schnaper LA, Berry D, et al.: Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 351 (10): 971-7, 2004.  [PUBMED Abstract]

  38. Smith IE, Ross GM: Breast radiotherapy after lumpectomy--no longer always necessary. N Engl J Med 351 (10): 1021-3, 2004.  [PUBMED Abstract]

  39. Smith BD, Gross CP, Smith GL, et al.: Effectiveness of radiation therapy for older women with early breast cancer. J Natl Cancer Inst 98 (10): 681-90, 2006.  [PUBMED Abstract]

  40. Kern KA: Sentinel lymph node mapping in breast cancer using subareolar injection of blue dye. J Am Coll Surg 189 (6): 539-45, 1999.  [PUBMED Abstract]

  41. Rubio IT, Korourian S, Cowan C, et al.: Sentinel lymph node biopsy for staging breast cancer. Am J Surg 176 (6): 532-7, 1998.  [PUBMED Abstract]

  42. Veronesi U, Paganelli G, Galimberti V, et al.: Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 349 (9069): 1864-7, 1997.  [PUBMED Abstract]

  43. Albertini JJ, Lyman GH, Cox C, et al.: Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 276 (22): 1818-22, 1996.  [PUBMED Abstract]

  44. Krag D, Weaver D, Ashikaga T, et al.: The sentinel node in breast cancer--a multicenter validation study. N Engl J Med 339 (14): 941-6, 1998.  [PUBMED Abstract]

  45. Veronesi U, Paganelli G, Viale G, et al.: Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer Inst 91 (4): 368-73, 1999.  [PUBMED Abstract]

  46. Krag DN, Anderson SJ, Julian TB, et al.: Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol 11 (10): 927-33, 2010.  [PUBMED Abstract]

  47. Veronesi U, Paganelli G, Viale G, et al.: Sentinel-lymph-node biopsy as a staging procedure in breast cancer: update of a randomised controlled study. Lancet Oncol 7 (12): 983-90, 2006.  [PUBMED Abstract]

  48. Lyman GH, Giuliano AE, Somerfield MR, et al.: American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol 23 (30): 7703-20, 2005.  [PUBMED Abstract]

  49. Mansel RE, Fallowfield L, Kissin M, et al.: Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial. J Natl Cancer Inst 98 (9): 599-609, 2006.  [PUBMED Abstract]

  50. Krag DN, Anderson SJ, Julian TB, et al.: Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial. Lancet Oncol 8 (10): 881-8, 2007.  [PUBMED Abstract]

  51. Giuliano AE, Hunt KK, Ballman KV, et al.: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 305 (6): 569-75, 2011.  [PUBMED Abstract]

  52. Galimberti V, Cole BF, Zurrida S, et al.: Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol 14 (4): 297-305, 2013.  [PUBMED Abstract]

  53. Barth RJ Jr, Danforth DN Jr, Venzon DJ, et al.: Level of axillary involvement by lymph node metastases from breast cancer is not an independent predictor of survival. Arch Surg 126 (5): 574-7, 1991.  [PUBMED Abstract]

  54. Rivadeneira DE, Simmons RM, Christos PJ, et al.: Predictive factors associated with axillary lymph node metastases in T1a and T1b breast carcinomas: analysis in more than 900 patients. J Am Coll Surg 191 (1): 1-6; discussion 6-8, 2000.  [PUBMED Abstract]

  55. Greco M, Agresti R, Cascinelli N, et al.: Breast cancer patients treated without axillary surgery: clinical implications and biologic analysis. Ann Surg 232 (1): 1-7, 2000.  [PUBMED Abstract]

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

  57. Scanlon EF: The role of reconstruction in breast cancer. Cancer 68 (5 Suppl): 1144-7, 1991.  [PUBMED Abstract]

  58. Hang-Fu L, Snyderman RK: State-of-the-art breast reconstruction. Cancer 68 (5 Suppl): 1148-56, 1991.  [PUBMED Abstract]

  59. Feller WF, Holt R, Spear S, et al.: Modified radical mastectomy with immediate breast reconstruction. Am Surg 52 (3): 129-33, 1986.  [PUBMED Abstract]

  60. Kuske RR, Schuster R, Klein E, et al.: Radiotherapy and breast reconstruction: clinical results and dosimetry. Int J Radiat Oncol Biol Phys 21 (2): 339-46, 1991.  [PUBMED Abstract]

  61. Clarke M, Collins R, Darby S, et al.: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 366 (9503): 2087-106, 2005.  [PUBMED Abstract]

  62. Eifel P, Axelson JA, Costa J, et al.: National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst 93 (13): 979-89, 2001.  [PUBMED Abstract]

  63. Darby S, McGale P, Correa C, et al.: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378 (9804): 1707-16, 2011.  [PUBMED Abstract]

  64. Whelan TJ, Pignol JP, Levine MN, et al.: Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 362 (6): 513-20, 2010.  [PUBMED Abstract]

  65. Haviland JS, Owen JR, Dewar JA, et al.: The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol 14 (11): 1086-94, 2013.  [PUBMED Abstract]

  66. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 355 (9217): 1757-70, 2000.  [PUBMED Abstract]

  67. Ragaz J, Jackson SM, Le N, et al.: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337 (14): 956-62, 1997.  [PUBMED Abstract]

  68. Overgaard M, Hansen PS, Overgaard J, et al.: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 337 (14): 949-55, 1997.  [PUBMED Abstract]

  69. Fowble B, Gray R, Gilchrist K, et al.: Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy. J Clin Oncol 6 (7): 1107-17, 1988.  [PUBMED Abstract]

  70. Taghian AG, Jeong JH, Mamounas EP, et al.: Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol 24 (24): 3927-32, 2006.  [PUBMED Abstract]

  71. Lingos TI, Recht A, Vicini F, et al.: Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys 21 (2): 355-60, 1991.  [PUBMED Abstract]

  72. 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. J Clin Oncol 16 (8): 2625-31, 1998.  [PUBMED Abstract]

  73. Rutqvist LE, Johansson H: Mortality by laterality of the primary tumour among 55,000 breast cancer patients from the Swedish Cancer Registry. Br J Cancer 61 (6): 866-8, 1990.  [PUBMED Abstract]

  74. Darby SC, McGale P, Taylor CW, et al.: Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol 6 (8): 557-65, 2005.  [PUBMED Abstract]

  75. Højris I, Overgaard M, Christensen JJ, et al.: Morbidity and mortality of ischaemic heart disease in high-risk breast-cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: analysis of DBCG 82b and 82c randomised trials. Radiotherapy Committee of the Danish Breast Cancer Cooperative Group. Lancet 354 (9188): 1425-30, 1999.  [PUBMED Abstract]

  76. Nixon AJ, Manola J, Gelman R, et al.: No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques. J Clin Oncol 16 (4): 1374-9, 1998.  [PUBMED Abstract]

  77. Giordano SH, Kuo YF, Freeman JL, et al.: Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 97 (6): 419-24, 2005.  [PUBMED Abstract]

  78. Harris EE, Correa C, Hwang WT, et al.: Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment. J Clin Oncol 24 (25): 4100-6, 2006.  [PUBMED Abstract]

  79. Meek AG: Breast radiotherapy and lymphedema. Cancer 83 (12 Suppl American): 2788-97, 1998.  [PUBMED Abstract]

  80. Larson D, Weinstein M, Goldberg I, et al.: Edema of the arm as a function of the extent of axillary surgery in patients with stage I-II carcinoma of the breast treated with primary radiotherapy. Int J Radiat Oncol Biol Phys 12 (9): 1575-82, 1986.  [PUBMED Abstract]

  81. Swedborg I, Wallgren A: The effect of pre- and postmastectomy radiotherapy on the degree of edema, shoulder-joint mobility, and gripping force. Cancer 47 (5): 877-81, 1981.  [PUBMED Abstract]

  82. Powell S, Cooke J, Parsons C: Radiation-induced brachial plexus injury: follow-up of two different fractionation schedules. Radiother Oncol 18 (3): 213-20, 1990.  [PUBMED Abstract]

  83. Taghian A, de Vathaire F, Terrier P, et al.: Long-term risk of sarcoma following radiation treatment for breast cancer. Int J Radiat Oncol Biol Phys 21 (2): 361-7, 1991.  [PUBMED Abstract]

  84. Boice JD Jr, Harvey EB, Blettner M, et al.: Cancer in the contralateral breast after radiotherapy for breast cancer. N Engl J Med 326 (12): 781-5, 1992.  [PUBMED Abstract]

  85. Storm HH, Andersson M, Boice JD Jr, et al.: Adjuvant radiotherapy and risk of contralateral breast cancer. J Natl Cancer Inst 84 (16): 1245-50, 1992.  [PUBMED Abstract]

  86. Fraass BA, Roberson PL, Lichter AS: Dose to the contralateral breast due to primary breast irradiation. Int J Radiat Oncol Biol Phys 11 (3): 485-97, 1985.  [PUBMED Abstract]

  87. Inskip PD, Stovall M, Flannery JT: Lung cancer risk and radiation dose among women treated for breast cancer. J Natl Cancer Inst 86 (13): 983-8, 1994.  [PUBMED Abstract]

  88. Harvey JM, Clark GM, Osborne CK, et al.: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17 (5): 1474-81, 1999.  [PUBMED Abstract]

  89. Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365 (9472): 1687-717, 2005.  [PUBMED Abstract]

  90. Colleoni M, Gelber S, Goldhirsch A, et al.: Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol 24 (9): 1332-41, 2006.  [PUBMED Abstract]

  91. Fisher B, Dignam J, Bryant J, et al.: Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 93 (9): 684-90, 2001.  [PUBMED Abstract]

  92. Stewart HJ, Prescott RJ, Forrest AP: Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years. J Natl Cancer Inst 93 (6): 456-62, 2001.  [PUBMED Abstract]

  93. Tormey DC, Gray R, Falkson HC: Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group. J Natl Cancer Inst 88 (24): 1828-33, 1996.  [PUBMED Abstract]

  94. Davies C, Pan H, Godwin J, et al.: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381 (9869): 805-16, 2013.  [PUBMED Abstract]

  95. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists' Collaborative Group. Lancet 339 (8784): 1-15, 1992.  [PUBMED Abstract]

  96. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists' Collaborative Group. Lancet 339 (8785): 71-85, 1992.  [PUBMED Abstract]

  97. Fisher B, Redmond C, Legault-Poisson S, et al.: Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol 8 (6): 1005-18, 1990.  [PUBMED Abstract]

  98. Fisher B, Jeong JH, Bryant J, et al.: Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet 364 (9437): 858-68, 2004.  [PUBMED Abstract]

  99. Effectiveness of adjuvant chemotherapy in combination with tamoxifen for node-positive postmenopausal breast cancer patients. International Breast Cancer Study Group. J Clin Oncol 15 (4): 1385-94, 1997.  [PUBMED Abstract]

  100. Pritchard KI, Paterson AH, Fine S, et al.: Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site Group. J Clin Oncol 15 (6): 2302-11, 1997.  [PUBMED Abstract]

  101. Fornander T, Rutqvist LE, Cedermark B, et al.: Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1 (8630): 117-20, 1989.  [PUBMED Abstract]

  102. Magriples U, Naftolin F, Schwartz PE, et al.: High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. J Clin Oncol 11 (3): 485-90, 1993.  [PUBMED Abstract]

  103. Fisher B, Costantino JP, Redmond CK, et al.: Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86 (7): 527-37, 1994.  [PUBMED Abstract]

  104. van Leeuwen FE, Benraadt J, Coebergh JW, et al.: Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet 343 (8895): 448-52, 1994.  [PUBMED Abstract]

  105. Barakat RR, Wong G, Curtin JP, et al.: Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with a higher incidence of adverse histologic features. Gynecol Oncol 55 (2): 164-8, 1994.  [PUBMED Abstract]

  106. Cuenca RE, Giachino J, Arredondo MA, et al.: Endometrial carcinoma associated with breast carcinoma: low incidence with tamoxifen use. Cancer 77 (10): 2058-63, 1996.  [PUBMED Abstract]

  107. Kedar RP, Bourne TH, Powles TJ, et al.: Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet 343 (8909): 1318-21, 1994.  [PUBMED Abstract]

  108. Neven P, De Muylder X, Van Belle Y, et al.: Tamoxifen and the uterus. Br Med J 309 (6965): 1313-1314, 1994. 

  109. Bertelli G, Venturini M, Del Mastro L, et al.: Tamoxifen and the endometrium: findings of pelvic ultrasound examination and endometrial biopsy in asymptomatic breast cancer patients. Breast Cancer Res Treat 47 (1): 41-6, 1998.  [PUBMED Abstract]

  110. Rutqvist LE, Johansson H, Signomklao T, et al.: Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. Stockholm Breast Cancer Study Group. J Natl Cancer Inst 87 (9): 645-51, 1995.  [PUBMED Abstract]

  111. Fisher B, Dignam J, Wolmark N, et al.: Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89 (22): 1673-82, 1997.  [PUBMED Abstract]

  112. Fisher B, Dignam J, Wolmark N, et al.: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353 (9169): 1993-2000, 1999.  [PUBMED Abstract]

  113. Saphner T, Tormey DC, Gray R: Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol 9 (2): 286-94, 1991.  [PUBMED Abstract]

  114. Love RR, Surawicz TS, Williams EC: Antithrombin III level, fibrinogen level, and platelet count changes with adjuvant tamoxifen therapy. Arch Intern Med 152 (2): 317-20, 1992.  [PUBMED Abstract]

  115. Fisher B, Costantino JP, Wickerham DL, et al.: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90 (18): 1371-88, 1998.  [PUBMED Abstract]

  116. Dignam JJ, Fisher B: Occurrence of stroke with tamoxifen in NSABP B-24. Lancet 355 (9206): 848-9, 2000.  [PUBMED Abstract]

  117. Shushan A, Peretz T, Uziely B, et al.: Ovarian cysts in premenopausal and postmenopausal tamoxifen-treated women with breast cancer. Am J Obstet Gynecol 174 (1 Pt 1): 141-4, 1996.  [PUBMED Abstract]

  118. Cohen I, Beyth Y, Tepper R, et al.: Ovarian tumors in postmenopausal breast cancer patients treated with tamoxifen. Gynecol Oncol 60 (1): 54-8, 1996.  [PUBMED Abstract]

  119. Love RR, Cameron L, Connell BL, et al.: Symptoms associated with tamoxifen treatment in postmenopausal women. Arch Intern Med 151 (9): 1842-7, 1991.  [PUBMED Abstract]

  120. Bentley CR, Davies G, Aclimandos WA: Tamoxifen retinopathy: a rare but serious complication. BMJ 304 (6825): 495-6, 1992.  [PUBMED Abstract]

  121. Nayfield SG, Gorin MB: Tamoxifen-associated eye disease. A review. J Clin Oncol 14 (3): 1018-26, 1996.  [PUBMED Abstract]

  122. Noureddin BN, Seoud M, Bashshur Z, et al.: Ocular toxicity in low-dose tamoxifen: a prospective study. Eye 13 ( Pt 6): 729-33, 1999.  [PUBMED Abstract]

  123. Love RR, Wiebe DA, Newcomb PA, et al.: Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med 115 (11): 860-4, 1991.  [PUBMED Abstract]

  124. McDonald CC, Stewart HJ: Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. The Scottish Breast Cancer Committee. BMJ 303 (6800): 435-7, 1991.  [PUBMED Abstract]

  125. Rutqvist LE, Mattsson A: Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. The Stockholm Breast Cancer Study Group. J Natl Cancer Inst 85 (17): 1398-406, 1993.  [PUBMED Abstract]

  126. Costantino JP, Kuller LH, Ives DG, et al.: Coronary heart disease mortality and adjuvant tamoxifen therapy. J Natl Cancer Inst 89 (11): 776-82, 1997.  [PUBMED Abstract]

  127. Love RR, Mazess RB, Barden HS, et al.: Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326 (13): 852-6, 1992.  [PUBMED Abstract]

  128. Kristensen B, Ejlertsen B, Dalgaard P, et al.: Tamoxifen and bone metabolism in postmenopausal low-risk breast cancer patients: a randomized study. J Clin Oncol 12 (5): 992-7, 1994.  [PUBMED Abstract]

  129. Love RR, Barden HS, Mazess RB, et al.: Effect of tamoxifen on lumbar spine bone mineral density in postmenopausal women after 5 years. Arch Intern Med 154 (22): 2585-8, 1994.  [PUBMED Abstract]

  130. Powles TJ, Hickish T, Kanis JA, et al.: Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 14 (1): 78-84, 1996.  [PUBMED Abstract]

  131. Castiglione-Gertsch M, O'Neill A, Price KN, et al.: Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst 95 (24): 1833-46, 2003.  [PUBMED Abstract]

  132. Chemotherapy with or without oophorectomy in high-risk premenopausal patients with operable breast cancer. Ludwig Breast Cancer Study Group. J Clin Oncol 3 (8): 1059-67, 1985.  [PUBMED Abstract]

  133. Arriagada R, Lê MG, Spielmann M, et al.: Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy. Ann Oncol 16 (3): 389-96, 2005.  [PUBMED Abstract]

  134. Davidson NE, O'Neill AM, Vukov AM, et al.: Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188). J Clin Oncol 23 (25): 5973-82, 2005.  [PUBMED Abstract]

  135. Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: the Scottish trial. Scottish Cancer Trials Breast Group and ICRF Breast Unit, Guy's Hospital, London. Lancet 341 (8856): 1293-8, 1993.  [PUBMED Abstract]

  136. Schmid P, Untch M, Kossé V, et al.: Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol 25 (18): 2509-15, 2007.  [PUBMED Abstract]

  137. Ejlertsen B, Mouridsen HT, Jensen MB, et al.: Similar efficacy for ovarian ablation compared with cyclophosphamide, methotrexate, and fluorouracil: from a randomized comparison of premenopausal patients with node-positive, hormone receptor-positive breast cancer. J Clin Oncol 24 (31): 4956-62, 2006.  [PUBMED Abstract]

  138. Wolff AC, Davidson NE: Still waiting after 110 years: the optimal use of ovarian ablation as adjuvant therapy for breast cancer. J Clin Oncol 24 (31): 4949-51, 2006.  [PUBMED Abstract]

  139. Boccardo F, Rubagotti A, Amoroso D, et al.: Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial. boccardo@hp380.ist.unige.it. J Clin Oncol 18 (14): 2718-27, 2000.  [PUBMED Abstract]

  140. Jonat W, Kaufmann M, Sauerbrei W, et al.: Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 20 (24): 4628-35, 2002.  [PUBMED Abstract]

  141. Jakesz R, Hausmaninger H, Kubista E, et al.: Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol 20 (24): 4621-7, 2002.  [PUBMED Abstract]

  142. Pritchard KI: Adjuvant therapy for premenopausal women with breast cancer: is it time for another paradigm shift? J Clin Oncol 20 (24): 4611-4, 2002.  [PUBMED Abstract]

  143. Eisen A, Messersmith J, Franek M, et al.: Adjuvant ovarian ablation in the treatment of premenopausal women with early stage invasive breast cancer. Ontario, Canada: Cancer Care, 2010. Evidence-based Series # 1-9: Section 1. Available online. Last accessed June 13, 2012. 

  144. Mouridsen H, Giobbie-Hurder A, Goldhirsch A, et al.: Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med 361 (8): 766-76, 2009.  [PUBMED Abstract]

  145. Burstein HJ, Prestrud AA, Seidenfeld J, et al.: American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 28 (23): 3784-96, 2010.  [PUBMED Abstract]

  146. The ATAC Trialists' Group. Arimidex, tamoxifen alone or in combination: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359 (9324): 2131-9, 2002.  [PUBMED Abstract]

  147. Howell A, Cuzick J, Baum M, et al.: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365 (9453): 60-2, 2005.  [PUBMED Abstract]

  148. Winer EP, Hudis C, Burstein HJ, et al.: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002. J Clin Oncol 20 (15): 3317-27, 2002.  [PUBMED Abstract]

  149. Winer EP, Hudis C, Burstein HJ, et al.: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 23 (3): 619-29, 2005.  [PUBMED Abstract]

  150. Boccardo F, Rubagotti A, Guglielmini P, et al.: Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial. Ann Oncol 17 (Suppl 7): vii10-4, 2006.  [PUBMED Abstract]

  151. Jakesz R, Jonat W, Gnant M, et al.: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366 (9484): 455-62, 2005 Aug 6-12.  [PUBMED Abstract]

  152. Boccardo F, Rubagotti A, Aldrighetti D, et al.: Switching to an aromatase inhibitor provides mortality benefit in early breast carcinoma: pooled analysis of 2 consecutive trials. Cancer 109 (6): 1060-7, 2007.  [PUBMED Abstract]

  153. Jonat W, Gnant M, Boccardo F, et al.: Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta-analysis. Lancet Oncol 7 (12): 991-6, 2006.  [PUBMED Abstract]

  154. Thürlimann B, Keshaviah A, Coates AS, et al.: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353 (26): 2747-57, 2005.  [PUBMED Abstract]

  155. Coates AS, Keshaviah A, Thürlimann B, et al.: Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 25 (5): 486-92, 2007.  [PUBMED Abstract]

  156. Goss PE, Ingle JN, Martino S, et al.: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349 (19): 1793-802, 2003.  [PUBMED Abstract]

  157. Bryant J, Wolmark N: Letrozole after tamoxifen for breast cancer--what is the price of success? N Engl J Med 349 (19): 1855-7, 2003.  [PUBMED Abstract]

  158. Burstein HJ: Beyond tamoxifen--extending endocrine treatment for early-stage breast cancer. N Engl J Med 349 (19): 1857-9, 2003.  [PUBMED Abstract]

  159. Goss PE, Ingle JN, Martino S, et al.: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97 (17): 1262-71, 2005.  [PUBMED Abstract]

  160. Coombes RC, Hall E, Gibson LJ, et al.: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350 (11): 1081-92, 2004.  [PUBMED Abstract]

  161. Piccart-Gebhart MJ: New stars in the sky of treatment for early breast cancer. N Engl J Med 350 (11): 1140-2, 2004.  [PUBMED Abstract]

  162. Coombes RC, Kilburn LS, Snowdon CF, et al.: Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 369 (9561): 559-70, 2007.  [PUBMED Abstract]

  163. van de Velde CJ, Rea D, Seynaeve C, et al.: Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 377 (9762): 321-31, 2011.  [PUBMED Abstract]

  164. Goss PE, Ingle JN, Pritchard KI, et al.: Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol 31 (11): 1398-404, 2013.  [PUBMED Abstract]

  165. Fisher B, Jeong JH, Anderson S, et al.: Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst 96 (24): 1823-31, 2004.  [PUBMED Abstract]

  166. Mansour EG, Gray R, Shatila AH, et al.: Survival advantage of adjuvant chemotherapy in high-risk node-negative breast cancer: ten-year analysis--an intergroup study. J Clin Oncol 16 (11): 3486-92, 1998.  [PUBMED Abstract]

  167. Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 352 (9132): 930-42, 1998.  [PUBMED Abstract]

  168. Hutchins LF, Green SJ, Ravdin PM, et al.: Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol 23 (33): 8313-21, 2005.  [PUBMED Abstract]

  169. Bonadonna G, Zambetti M, Moliterni A, et al.: Clinical relevance of different sequencing of doxorubicin and cyclophosphamide, methotrexate, and Fluorouracil in operable breast cancer. J Clin Oncol 22 (9): 1614-20, 2004.  [PUBMED Abstract]

  170. Bonadonna G, Zambetti M, Valagussa P: Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten-year results. JAMA 273 (7): 542-7, 1995.  [PUBMED Abstract]

  171. Fisher B, Brown AM, Dimitrov NV, et al.: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8 (9): 1483-96, 1990.  [PUBMED Abstract]

  172. Pritchard KI, Shepherd LE, O'Malley FP, et al.: HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354 (20): 2103-11, 2006.  [PUBMED Abstract]

  173. Gennari A, Sormani MP, Pronzato P, et al.: HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 100 (1): 14-20, 2008.  [PUBMED Abstract]

  174. De Laurentiis M, Cancello G, D'Agostino D, et al.: Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol 26 (1): 44-53, 2008.  [PUBMED Abstract]

  175. Sparano JA, Wang M, Martino S, et al.: Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358 (16): 1663-71, 2008.  [PUBMED Abstract]

  176. Henderson IC, Berry DA, Demetri GD, et al.: Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21 (6): 976-83, 2003.  [PUBMED Abstract]

  177. Mamounas EP, Bryant J, Lembersky B, et al.: Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 23 (16): 3686-96, 2005.  [PUBMED Abstract]

  178. Martin M, Pienkowski T, Mackey J, et al.: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352 (22): 2302-13, 2005.  [PUBMED Abstract]

  179. Perez EA: TAC--a new standard in adjuvant therapy for breast cancer? N Engl J Med 352 (22): 2346-8, 2005.  [PUBMED Abstract]

  180. Budman DR, Berry DA, Cirrincione CT, et al.: Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst 90 (16): 1205-11, 1998.  [PUBMED Abstract]

  181. Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4 (8): 1162-70, 1986.  [PUBMED Abstract]

  182. Fisher B, Anderson S, Wickerham DL, et al.: Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 15 (5): 1858-69, 1997.  [PUBMED Abstract]

  183. Fisher B, Anderson S, DeCillis A, et al.: Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 17 (11): 3374-88, 1999.  [PUBMED Abstract]

  184. Levine MN, Pritchard KI, Bramwell VH, et al.: Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol 23 (22): 5166-70, 2005.  [PUBMED Abstract]

  185. Bonneterre J, Roché H, Kerbrat P, et al.: Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol 23 (12): 2686-93, 2005.  [PUBMED Abstract]

  186. Fumoleau P, Kerbrat P, Romestaing P, et al.: Randomized trial comparing six versus three cycles of epirubicin-based adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up results of the French Adjuvant Study Group 01 trial. J Clin Oncol 21 (2): 298-305, 2003.  [PUBMED Abstract]

  187. Citron ML, Berry DA, Cirrincione C, et al.: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21 (8): 1431-9, 2003.  [PUBMED Abstract]

  188. Hudis C, Citron M, Berry D, et al.: Five year follow-up of INT C9741: dose-dense (DD) chemotherapy (CRx) is safe and effective. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-41, 2005. 

  189. Citron ML, Berry DA, Cirrincione C, et al.: Dose-dense (DD) AC followed by paclitaxel is associated with moderate, frequent anemia compared to sequential (S) and/or less DD treatment: update by CALGB on Breast Cancer Intergroup Trial C9741 with ECOG, SWOG, & NCCTG. [Abstract] J Clin Oncol 23 (Suppl 16): A-620, 33s, 2005. 

  190. Tallman MS, Gray R, Robert NJ, et al.: Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med 349 (1): 17-26, 2003.  [PUBMED Abstract]

  191. Bergh J, Wiklund T, Erikstein B, et al.: Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study. Lancet 356 (9239): 1384-91, 2000.  [PUBMED Abstract]

  192. Hortobagyi GN, Buzdar AU, Theriault RL, et al.: Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst 92 (3): 225-33, 2000.  [PUBMED Abstract]

  193. Rodenhuis S, Bontenbal M, Beex LV, et al.: High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med 349 (1): 7-16, 2003.  [PUBMED Abstract]

  194. Schrama JG, Faneyte IF, Schornagel JH, et al.: Randomized trial of high-dose chemotherapy and hematopoietic progenitor-cell support in operable breast cancer with extensive lymph node involvement: final analysis with 7 years of follow-up. Ann Oncol 13 (5): 689-98, 2002.  [PUBMED Abstract]

  195. Coombes RC, Howell A, Emson M, et al.: High dose chemotherapy and autologous stem cell transplantation as adjuvant therapy for primary breast cancer patients with four or more lymph nodes involved: long-term results of an international randomised trial. Ann Oncol 16 (5): 726-34, 2005.  [PUBMED Abstract]

  196. Nitz UA, Mohrmann S, Fischer J, et al.: Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial. Lancet 366 (9501): 1935-44, 2005.  [PUBMED Abstract]

  197. Zander AR, Kröger N, Schmoor C, et al.: High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial. J Clin Oncol 22 (12): 2273-83, 2004.  [PUBMED Abstract]

  198. Peters WP, Rosner GL, Vredenburgh JJ, et al.: Prospective, randomized comparison of high-dose chemotherapy with stem-cell support versus intermediate-dose chemotherapy after surgery and adjuvant chemotherapy in women with high-risk primary breast cancer: a report of CALGB 9082, SWOG 9114, and NCIC MA-13. J Clin Oncol 23 (10): 2191-200, 2005.  [PUBMED Abstract]

  199. Moore HC, Green SJ, Gralow JR, et al.: Intensive dose-dense compared with high-dose adjuvant chemotherapy for high-risk operable breast cancer: Southwest Oncology Group/Intergroup study 9623. J Clin Oncol 25 (13): 1677-82, 2007.  [PUBMED Abstract]

  200. Jones SE, Savin MA, Holmes FA, et al.: Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 24 (34): 5381-7, 2006.  [PUBMED Abstract]

  201. Jones S, Holmes FA, O'Shaughnessy J, et al.: Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol 27 (8): 1177-83, 2009.  [PUBMED Abstract]

  202. Gnant M, Mlineritsch B, Schippinger W, et al.: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360 (7): 679-91, 2009.  [PUBMED Abstract]

  203. Coleman R, de Boer R, Eidtmann H, et al.: Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol 24 (2): 398-405, 2013.  [PUBMED Abstract]

  204. Coleman RE, Marshall H, Cameron D, et al.: Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 365 (15): 1396-405, 2011.  [PUBMED Abstract]

  205. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353 (16): 1659-72, 2005.  [PUBMED Abstract]

  206. Smith I, Procter M, Gelber RD, et al.: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369 (9555): 29-36, 2007.  [PUBMED Abstract]

  207. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al.: 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 382 (9897): 1021-8, 2013.  [PUBMED Abstract]

  208. Romond EH, Perez EA, Bryant J, et al.: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353 (16): 1673-84, 2005.  [PUBMED Abstract]

  209. Perez E, Romond E, Suman V, et al.: Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patiens with HER2-positive breast cancer. [Abstract] J Clin Oncol 25 (Suppl 18): 512, 6s, 2007. 

  210. Slamon D, Eiermann W, Robert N, et al.: Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365 (14): 1273-83, 2011.  [PUBMED Abstract]

  211. Slamon D, Eiermann W, Robert N, et al.: BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC->T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC->TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients. [Abstract] 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, Texas. A-52, 2006. 

  212. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al.: Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354 (8): 809-20, 2006.  [PUBMED Abstract]

  213. Pivot X, Romieu G, Debled M, et al.: 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol 14 (8): 741-8, 2013.  [PUBMED Abstract]

  214. Burris HA 3rd: Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist 9 (Suppl 3): 10-5, 2004.  [PUBMED Abstract]

  215. Geyer CE, Forster J, Lindquist D, et al.: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355 (26): 2733-43, 2006.  [PUBMED Abstract]

  216. Blackwell KL, Burstein HJ, Storniolo AM, et al.: Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 28 (7): 1124-30, 2010.  [PUBMED Abstract]

  217. Tan-Chiu E, Yothers G, Romond E, et al.: Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23 (31): 7811-9, 2005.  [PUBMED Abstract]

  218. Lenihan D, Suter T, Brammer M, et al.: Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab. Ann Oncol 23 (3): 791-800, 2012.  [PUBMED Abstract]

  219. Valachis A, Nearchou A, Lind P, et al.: Lapatinib, trastuzumab or the combination added to preoperative chemotherapy for breast cancer: a meta-analysis of randomized evidence. Breast Cancer Res Treat 135 (3): 655-62, 2012.  [PUBMED Abstract]

  220. Combination adjuvant chemotherapy for node-positive breast cancer. Inadequacy of a single perioperative cycle. The Ludwig Breast Cancer Study Group. N Engl J Med 319 (11): 677-83, 1988.  [PUBMED Abstract]

  221. Clahsen PC, van de Velde CJ, Julien JP, et al.: Improved local control and disease-free survival after perioperative chemotherapy for early-stage breast cancer. A European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group Study. J Clin Oncol 14 (3): 745-53, 1996.  [PUBMED Abstract]

  222. Fisher B, Bryant J, Wolmark N, et al.: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16 (8): 2672-85, 1998.  [PUBMED Abstract]

  223. Fisher ER, Wang J, Bryant J, et al.: Pathobiology of preoperative chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer 95 (4): 681-95, 2002.  [PUBMED Abstract]

  224. Rastogi P, Anderson SJ, Bear HD, et al.: Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26 (5): 778-85, 2008.  [PUBMED Abstract]

  225. van der Hage JA, van de Velde CJ, Julien JP, et al.: Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 19 (22): 4224-37, 2001.  [PUBMED Abstract]

  226. Mauri D, Pavlidis N, Ioannidis JP: Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 97 (3): 188-94, 2005.  [PUBMED Abstract]

  227. Haid A, Tausch C, Lang A, et al.: Is sentinel lymph node biopsy reliable and indicated after preoperative chemotherapy in patients with breast carcinoma? Cancer 92 (5): 1080-4, 2001.  [PUBMED Abstract]

  228. Kuehn T, Bauerfeind I, Fehm T, et al.: Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol 14 (7): 609-18, 2013.  [PUBMED Abstract]

  229. Boughey JC, Suman VJ, Mittendorf EA, et al.: Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA 310 (14): 1455-61, 2013.  [PUBMED Abstract]

  230. Buzdar AU, Ibrahim NK, Francis D, et al.: Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23 (16): 3676-85, 2005.  [PUBMED Abstract]

  231. Gianni L, Eiermann W, Semiglazov V, et al.: Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 375 (9712): 377-84, 2010.  [PUBMED Abstract]

  232. Buzdar AU, Suman VJ, Meric-Bernstam F, et al.: Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol 14 (13): 1317-25, 2013.  [PUBMED Abstract]

  233. Ismael G, Hegg R, Muehlbauer S, et al.: Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol 13 (9): 869-78, 2012.  [PUBMED Abstract]

  234. Gianni L, Pienkowski T, Im YH, et al.: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13 (1): 25-32, 2012.  [PUBMED Abstract]

  235. Schneeweiss A, Chia S, Hickish T, et al.: Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24 (9): 2278-84, 2013.  [PUBMED Abstract]

  236. Untch M, Loibl S, Bischoff J, et al.: Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol 13 (2): 135-44, 2012.  [PUBMED Abstract]

  237. Baselga J, Bradbury I, Eidtmann H, et al.: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379 (9816): 633-40, 2012.  [PUBMED Abstract]

  238. Robidoux A, Tang G, Rastogi P, et al.: Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol 14 (12): 1183-92, 2013.  [PUBMED Abstract]

  239. Bear HD, Tang G, Rastogi P, et al.: Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 366 (4): 310-20, 2012.  [PUBMED Abstract]

  240. von Minckwitz G, Eidtmann H, Rezai M, et al.: Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 366 (4): 299-309, 2012.  [PUBMED Abstract]

  241. Gerber B, Loibl S, Eidtmann H, et al.: Neoadjuvant bevacizumab and anthracycline-taxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44). Ann Oncol 24 (12): 2978-84, 2013.  [PUBMED Abstract]

  242. Recht A, Come SE, Henderson IC, et al.: The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334 (21): 1356-61, 1996.  [PUBMED Abstract]

  243. Wallgren A, Bernier J, Gelber RD, et al.: Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. International Breast Cancer Study Group. Int J Radiat Oncol Biol Phys 35 (4): 649-59, 1996.  [PUBMED Abstract]

  244. Hickey BE, Francis DP, Lehman M: Sequencing of chemotherapy and radiotherapy for early breast cancer. Cochrane Database Syst Rev 4: CD005212, 2013.  [PUBMED Abstract]

  245. Halyard MY, Pisansky TM, Dueck AC, et al.: Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG Phase III Trial N9831. J Clin Oncol 27 (16): 2638-44, 2009.  [PUBMED Abstract]

  246. Veronesi U, Luini A, Mariani L, et al.: Effect of menstrual phase on surgical treatment of breast cancer. Lancet 343 (8912): 1545-7, 1994.  [PUBMED Abstract]

  247. 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): 1261-4, 1991.  [PUBMED Abstract]

  248. Senie RT, Rosen PP, Rhodes P, et al.: Timing of breast cancer excision during the menstrual cycle influences duration of disease-free survival. Ann Intern Med 115 (5): 337-42, 1991.  [PUBMED Abstract]

  249. Goldhirsch A, Gelber RD, Castiglione M, et al.: Menstrual cycle and timing of breast surgery in premenopausal node-positive breast cancer: results of the International Breast Cancer Study Group (IBCSG) Trial VI. Ann Oncol 8 (8): 751-6, 1997.  [PUBMED Abstract]

  250. McGuire WL, Hilsenbeck S, Clark GM: Optimal mastectomy timing. J Natl Cancer Inst 84 (5): 346-8, 1992.  [PUBMED Abstract]

  251. 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. Br J Surg 80 (1): 43, 1993.  [PUBMED Abstract]

  252. Brown GS, Kramer S, Brady L, et al.: Primary irradiation of stage I and stage II adenocarcinoma of the breast. Int J Radiat Oncol Biol Phys 2 (11-12): 1145-8, 1977 Nov-Dec.  [PUBMED Abstract]

  253. Hagen AA, Hrushesky WJ: Menstrual timing of breast cancer surgery. Am J Surg 175 (3): 245-61, 1998.  [PUBMED Abstract]

  254. Pritchard KI, Paterson AH, Paul NA, et al.: Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. J Clin Oncol 14 (10): 2731-7, 1996.  [PUBMED Abstract]

  255. Shapiro CL, Manola J, Leboff M: Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol 19 (14): 3306-11, 2001.  [PUBMED Abstract]

  256. Schagen SB, Muller MJ, Boogerd W, et al.: Change in cognitive function after chemotherapy: a prospective longitudinal study in breast cancer patients. J Natl Cancer Inst 98 (23): 1742-5, 2006.  [PUBMED Abstract]

  257. Smith RE, Bryant J, DeCillis A, et al.: Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol 21 (7): 1195-204, 2003.  [PUBMED Abstract]

  258. Crump M, Tu D, Shepherd L, et al.: Risk of acute leukemia following epirubicin-based adjuvant chemotherapy: a report from the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21 (16): 3066-71, 2003.  [PUBMED Abstract]

  259. Praga C, Bergh J, Bliss J, et al.: Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol 23 (18): 4179-91, 2005.  [PUBMED Abstract]

  260. Albain KS, Green SJ, Ravdin PM, et al.: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814). [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-143, 2002. 

  261. Rosen PP, Groshen S, Saigo PE, et al.: Pathological prognostic factors in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma: a study of 644 patients with median follow-up of 18 years. J Clin Oncol 7 (9): 1239-51, 1989.  [PUBMED Abstract]

  262. Gazet JC, Ford HT, Coombes RC, et al.: Prospective randomized trial of tamoxifen vs surgery in elderly patients with breast cancer. Eur J Surg Oncol 20 (3): 207-14, 1994.  [PUBMED Abstract]

  263. 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. Eur J Surg Oncol 17 (1): 30-5, 1991.  [PUBMED Abstract]

  264. Dixon JM: Treatment of elderly patients with breast cancer. BMJ 304 (6833): 996-7, 1992.  [PUBMED Abstract]