Breast Cancer Treatment (Professional) (cont.)
IN THIS ARTICLE
Stage I, II, IIIA, and Operable IIIC Breast Cancer
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. Additional pathologic characteristics, including grade and proliferative activity may also be of value.[2,3,4,5]
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]).[6,7,8,9,10,11,12,13] 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. A retrospective study of 753 patients who were divided into three groups based on receptor status (ER- or PR-positive; ER- and PR-negative but HER2/neu -positive; and ER-, PR-, 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.
All histologic types of invasive breast cancer may be treated with breast-conserving surgery plus radiation therapy. 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.[17,18,19]
Retrospective studies have shown the following examples of tumor characteristics to correlate with a greater likelihood of finding persistent tumor on re-excision:
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.[23,24,25] 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),[Level of evidence: 1iiDiii] and from 7.3% to 4.3% at 5 years (P < .001), respectively.[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.
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. 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. This risk for contralateral tumors may be even greater in women who are positive for BRCA1 and BRCA2 mutations.[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]).[6,33,34,35,36,37] 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  and those older than 70 years, 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. 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 to women aged 80 years or older or to those who have comorbidities (NNT = 61–125 patients). The administration of radiation therapy may be associated with short-term morbidity, inconvenience, and potential long-term complications.
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).[42,43,44,45]
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% in the SLN plus ALND and SLN alone, respectively (P = .12).[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).[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%. 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).[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. 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. 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% 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.[Level of evidence: 1iiA] On the basis of the results of this trial, 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%.[52,53] In another series, the incidence of axillary node relapse in patients with T1a tumors treated without ALND was 2%.[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.
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).[55,56,57,58] 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 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.
Adjuvant Radiation Therapy
Radiation therapy is regularly employed after breast-conservation 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.
Post-breast conservation surgery
For women who are treated with breast-conserving surgery, the most common site of local recurrence is the conserved breast itself. 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.
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, in the 2005 Early Breast Cancer Trialists' Collaborative Group's (EBCTCG) update, when all relevant trials were combined, 15-year breast cancer mortality was reduced from 35.9% to 30.5% in women receiving radiation therapy (absolute difference of 5.4%; 95% CI, 2.1%–8.7%; breast cancer death rate ratio 0.83; 95% CI, 0.75–0.91; P = .002). There was a similar effect on all-cause mortality.
Although adjuvant whole-breast radiation is standard treatment, no trials have addressed the role of regional lymph node radiation therapy in this setting. The National Cancer Institute of Canada's study (CAN-NCIC-MA20 [NCT00005957]) has closed, but until results are reported, decisions regarding the use of such therapy must rely on extrapolations from the postmastectomy setting and on knowledge of the local-regional recurrence rates following conservation therapy with axillary lymph node dissection for a given lesion.
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. 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.[63,64,65]
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.[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% confidence interval [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.
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. 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.[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.[62,68,69,70] 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.[71,72] 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.[73,74][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.[75,76,77] (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. 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. One report suggests an increase in contralateral breast cancer for women younger than 45 years who have received chest wall radiation therapy after mastectomy. No increased risk of contralateral breast cancer occurs for women 45 years and older who receive radiation therapy. Techniques to minimize the radiation dose to the contralateral breast should be used to keep the absolute risk as low as possible. In nonsmokers, the risk of lung cancer as a result of radiation exposure during treatment is minimal when current dosimetry techniques are used. Smokers, however, may have a small increased risk of lung cancer in the ipsilateral lung.
Adjuvant Systemic Therapy
Stage and molecular features determine the need for adjuvant systemic therapy and the choice of modalities used. For example, estrogen and/or progesterone receptor–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.
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.
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. 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.[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. This EBCTCG meta-analysis also confirmed the benefit of adjuvant tamoxifen in ER-positive premenopausal women. 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).[Level of evidence: 1iiA] Similar results were found in the IBCSG-13-93 trial. 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.[85,87,88,89,90] 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).
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.[Level of evidence: 1iA] Another trial demonstrated the equivalence of 5 years and 10 years of therapy.[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. 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 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).[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 to 5 years, 10 years of tamoxifen therapy increased the risks of the following:
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.
These trials raise important questions about the optimal duration of endocrine therapy. Of note, the long-term ATLAS data are really 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.
(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.[91,92] 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).[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. 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.[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.[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 (day 1 every 3 weeks) rather than oral cyclophosphamide was used.[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.[97,98,99,100] 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.[97,101,102] 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. The value of endometrial biopsy, hysteroscopy, and transvaginal ultrasound as screening tools is unclear.[104,105] Of concern is an increased risk of gastrointestinal malignancy after tamoxifen therapy, but these findings are tentative, and further study is needed.
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%.[87,93,107,108,109] 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. The relationship of these changes to thromboembolic phenomena is not clear. Tamoxifen use may also be associated with an increased risk of strokes.[109,111,112] In the NSABP Breast Cancer Prevention Trial (NSABP-P-1), this increase was not statistically significant.
Another potential problem is the development of benign ovarian cysts, which occurred in about 10% of women in a single study. The relationship between tamoxifen and ovarian tumors requires further study. Short-term toxic effects of tamoxifen use may include vasomotor symptoms and gynecologic symptoms (e.g., vaginal discharge or irritation). (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.[116,117,118] 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.[119,120] 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. In another trial, the risk of fatal myocardial infarction was significantly decreased in patients receiving adjuvant tamoxifen for 5 years versus those treated with surgery alone. In 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. To date, three large controlled trials have shown a decrease in heart disease.[120,121,122]
Controlled studies have associated long-term tamoxifen use with preservation of bone mineral density of the lumbar spine in postmenopausal women.[123,124,125] In premenopausal women, decreased bone mineral density is a possibility.
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). 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.[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.[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 analogue (in one trial, 50% of the patients had radiation oophorectomy rather than an LHRH analogue) in addition to chemotherapy.[127,129,130][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.[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. A Danish trial compared ovarian ablation or suppression to CMF (9 cycles intravenously every 3 weeks) in premenopausal, ER-positive women and found no difference in OS or DFS in the two study groups.[133,134] 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 [GnRH]) in premenopausal or perimenopausal women with receptor-positive tumors has been reported.[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,[127,136][Level of evidence: 2Dii] whereas the combination of goserelin and tamoxifen was associated with prolonged DFS compared with CMF alone.[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. 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.[127,129,130,139] Ovarian ablation alone should not be routinely used as an alternative to any other systemic therapy.[131,132,133,134,139] Further results of research studies prospectively evaluating the role of adjuvant ovarian ablation are awaited.
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.[140,141]
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.[142,143] 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 (hazard ratio [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, 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.[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. An American Society of Clinical Oncology (ASCO) Technology Assessment panel has commented on the implications of these results.[144,145]
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.[146,147,148] 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.[Level of evidence: 1iiA] The other two trials were reported together. A total of 3,224 patients were randomized 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.
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), 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.
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 to the alternate drug at 2 years. 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%).[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.
A large, double-blinded, randomized trial (CAN-NCIC-MA17 [NCT00003140]) of 5,187 patients compared the use of letrozole versus placebo in receptor-positive postmenopausal women who received tamoxifen for approximately 5 (4.5–6.0) years. 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.[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.[153,154] An updated analysis including all events prior to unblinding confirmed the results of the interim analysis. 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.[144,145]
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.[156,157] 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.[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. At 2.5 years after randomization, 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).[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. 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).[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.[Level of evidence: IiiA] The NCIC CTG MA.27 (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. Some differences in toxicities between the two drugs were seen. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent for patients on exemestane, while mild liver-function abnormalities and rare episodes of atrial fibrillation were less frequent for patients on anastrozole. Vasomotor and musculoskeletal symptoms were similar with both drugs. Based on the results of this trial, no specific aromatase inhibitor is considered superior as upfront therapy for postmenopausal women with hormone receptor-positive breast cancer.
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. 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. 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 to 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. 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.[93,94,161,162][Level of evidence: 1iiA]
Table 6. Standard Adjuvant Chemotherapy Regimens for Stage I, II, IIIA, and Operable IIICHER2/neuNon-Overexpressing Breast Cancer
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 randomized 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 under 50 years. Compared to 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.[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. In this study, 2,691 patients were randomized to receive CAF or CMF with a second randomization 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.[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.[165,166] In one study, 490 premenopausal and postmenopausal women with one to three axillary lymph nodes were randomized to receive CMF (12 cycles) or CMF (eight cycles) followed by doxorubicin (four cycles). 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 randomized 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. Women who received doxorubicin followed by CMF had better RFS (42% vs. 28%; P = .002) and OS (58% vs. 44%; P = .002).[Level of evidence: 1iiA]
The NSABP-B-15 trial randomized 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). No differences were seen in DFS or OS among the three groups.[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, or the addition of doxorubicin to the adjuvant regimen, 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).[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 non–anthracycline-containing regimens.
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 < .0001; OS: HR, 0.85; 95% CI, 0.79–0.91; P < .0001).[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.[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%).[Level of evidence: 1iiA] The results of a second trial, the NSABP-B-28 trial, have also been reported. 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 (hazard ratio [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).[Level of evidence: 1iiA]
The regimen of 5-FU, doxorubicin, and cyclophosphamide (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.[174,175][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.[176,177] 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.[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.[178,179][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 randomization 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. 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). 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).[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. A randomized trial that increased duration of epirubicin did not lead to increased survival at 10 years in node-positive premenopausal women.
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. 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.[183,184] 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.[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.[186,187,188,189,190,191,192,193] 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.[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.[186,187,188,189,190,191,193,194,195][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. 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).
Docetaxel and cyclophosphamide
The regimen of docetaxel and cyclophosphamide (TC) compared with doxorubicin plus cyclophosphamide (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).[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.[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 cardiotoxic effects but other side effects included more myalgia, arthralgia, edema, and febrile neutropenia compared with AC.
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+ breast cancer to receive ovarian function suppression with goserelin and tamoxifen versus goserelin and anastrozole. These patients then underwent a second randomization to receive zoledronic acid (4 mg intravenously every 6 months) versus no zoledronic acid.[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.
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.[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.
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 an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively plus or minus locoregional radiation therapy.[Level of evidence: 1iiA] Although the results of the comparison of 1 year versus 2 years of trastuzumab have not been released yet, there are available data for 3,387 patients (1,694 in the 1-year trastuzumab arm and 1,693 in the observation arm). 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 (hazard ratio [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%. 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%.
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.[Level of evidence: 1iiA] The 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%). 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).[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). 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. 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. 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).[Level of evidence: 1iiA]
Lapatinib is a small molecule tyrosine kinase inhibitor that is capable of dual-receptor inhibition of both EGFR 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 to, 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 ER2-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%). 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. The hazard ratio 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 to lapatinib alone.
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 NYHA class III–IV) occurred in 0.6% of patients treated with trastuzumab. 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 EF 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. 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. 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.
Treatment options for HER2-positive early breast cancer:
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. A single cycle of immediate postoperative chemotherapy alone was inferior.
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. 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-conservation 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.[213,214,215][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.[Level of evidence: 1iiA] Preoperative chemotherapy may be beneficial in women who desire breast conservation 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. Although preoperative chemotherapy affects the results of SLN biopsy, one small study indicated that SLN biopsy technique was feasible in this setting. Before SLN biopsy can replace complete axillary lymphadenectomy, randomized trials are needed to confirm that both procedures yield comparable survival rates.
In HER2-overexpressed disease, pilot studies have demonstrated remarkable clinical and pathologic responses when trastuzumab is given preoperatively in combination with chemotherapy. A randomized study in patients with HER2-positive locally advanced or inflammatory breast cancers confirmed that the addition of 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 (38% vs. 19%) but also in the primary outcome: event-free survival (EFS). 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 left ventricular ejection fraction (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.)[Level of evidence: 1iiD]
The role of lapatinib in the neoadjuvant setting was examined in the GeparQuinto [NCT00567554] trial. This phase III trial randomly assigned women with HER2-positive early stage breast cancer to receive chemotherapy with trastuzumab versus chemotherapy with lapatinib with pathologic complete response (pCR) as the primary endpoint.[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, relapse-free survival (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.[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).
It is important to note that DFS, RFS, and OS have not been reported in this trial. pCR rates, while hypothesis-generating, do not substitute for these other efficacy endpoints. Nevertheless, the results suggest that dual inhibition of HER2 by a monoclonal antibody and a tyrosine kinase should be further explored for patients with early stage HER2-positive breast cancer. Confirmatory results from the similarly designed, ongoing, CALGB-40601 (NCT00770809) trial are pending. More definitive efficacy data will be provided by the phase III ALLTO trial that is randomly assigning women to trastuzumab or trastuzumab plus lapatinib in the adjuvant setting.
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. [223,224]
One trial randomly assigned 1,206 patients with primary operable HER2-negative breast cancer to receive chemotherapy with or without bevacizumab. The addition of bevacizumab significantly increased the rate of pCR (28.2% without bevacizumab vs. 34.5% with bevacizumab, P = .02).[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. 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).[Level of evidence: 1iiDiv] Similarly to other clinical trials, the addition of bevacizumab increased toxicity, with higher rates of febrile neutropenia, mucositis, hand-foot syndrome, infection, and hypertension, but it did not increase surgical complications.
Of note, OS and DFS outcomes were not reported in either clinical trial.[223,224] 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. 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).[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 that 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.[167,226] 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.[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. These studies showed that delays from 2 to 7 months in radiation therapy after surgery had no effect on the rate of local recurrence.
Based on the above studies, delaying radiation therapy for several months after breast-conserving surgery until the completion of adjuvant chemotherapy 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 (AE) or frequency of cardiac events in patients who received concurrent adjuvant radiation therapy and trastuzumab. 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.[228,229,230][Level of evidence: 1iiA] Several other studies, however, have failed to support this finding or have found opposite results.[232,233,234,235][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.
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, and premature menopause. (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 Fever, Sweats, and Hot Flashes.)
Cognitive impairment has been reported to occur after the administration of some chemotherapy regimens. 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. 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.[239,240] 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).
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 (intravenously for 6 months) (n = 353) or tamoxifen alone (n = 352). 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. 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).[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. 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.[244,245,246]
Adjuvant radiation therapy postmastectomy in axillary node-positive tumors:
Adjuvant systemic therapy:
An International Consensus Panel proposed a three-tiered risk classification for patients with negative axillary lymph nodes. This classification, with some modification, is described below:
Table 7. Risk Categories for Women With Node-Negative Breast Cancer
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
Table 9. Treatment Options for Women With Axillary Node-Positive Breast Cancer
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.
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