Stage II Breast Cancer

Overview

This chapter focuses on the treatment of stage II breast cancer, which encompasses malignancies with primary tumors > 2 cm in their greatest dimension that involve ipsilateral axillary lymph nodes as well as tumors up to 5 cm without nodal involvement.

Stage II breast cancer is further subdivided into stages IIA and IIB. Patients classified as having stage IIA breast cancer include those with T0-1, N1, and T2, N0 disease. Stage IIB breast cancer includes patients with T2, N1, and T3, N0 disease. Therefore, this patient population is more heterogeneous than are the populations with stages 0 and I disease. The pretreatment evaluation and type of treatment offered to patients with stage II breast cancer are based on tumor size, nodal status, status of receptors for estrogen and human epidermal growth factor receptor 2 (HER2, HER2/neu) and Oncotype DX recurrence score.

Treatment

Surgical and Radiation Treatment

Multiple studies have demonstrated that patients with stage II breast cancer who are treated with either breast-conservation therapy (lumpectomy and radiation therapy) or modified radical mastectomy have similar disease-free and overall survival rates.

Breast-conservation therapy

The optimal extent of local surgery has yet to be determined and, in the literature, has ranged from excisional biopsy to quadrantectomy. A consensus statement issued by the National Cancer Institute (NCI) recommended that the breast cancer be completely excised with negative surgical margins and that a level I-II axillary lymph node dissection be performed. Patients should subsequently be treated with adjuvant breast irradiation.

Patients with tumors > 4 to 5 cm may not be optimal candidates for breast conservation due to the risk of significant residual tumor burden and the potential for a poor cosmetic result following lumpectomy (or partial mastectomy). Neoadjuvant chemotherapy, typically used for locally advanced breast cancer, is increasingly used in earlier stage, operable breast cancers to reduce the size of the primary tumor and allow for breast-conserving therapy.

In a study of more than 300 patients treated with neoadjuvant chemotherapy at the MD Anderson Cancer Center, promising results were reported. At a median follow-up of 60 months, the 5-year actuarial rates of ipsilateral breast tumor recurrence (IBTR)-free and locoregional recurrence–free survival were 95% and 91%, respectively. The authors concluded that breast-conservation therapy after neoadjuvant chemotherapy results in acceptably low rates of recurrence-free survival in appropriately selected patients, even those with T3 or T4 disease. Advanced nodal involvement at diagnosis, residual tumor larger than 2 cm, multifocal residual disease, and lymphovascular space invasion predict higher rates of recurrence.

In some patients, preoperative chemotherapy produces a sufficient reduction in tumor size that allows patients to receive breast-conserving therapy. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial showed that preoperative doxorubicin-based chemotherapy decreases tumor size by > 50% in approximately 90% of operable breast cancers, resulting in a greater frequency of lumpectomy.

In a subsequent trial, NSABP B-27, women with invasive breast cancer were randomized to receive 4 cycles of preoperative AC (Adriamycin [doxorubicin] and cyclophosphamide) chemotherapy followed by surgery, or 4 cycles of preoperative AC followed by 4 cycles of docetaxel (Taxotere) then surgery, or 4 cycles of preoperative AC followed by surgery then by 4 cycles of postoperative docetaxel. A higher rate of complete pathologic response was seen at surgery in patients treated with AC followed by docetaxel vs AC alone. There were no significant differences in disease-free and overall survival between the treatment groups. However, those with a complete pathologic response in the breast had significant improvements in disease-free survival (hazard ratio [HR] = 0.45; P < .001) and overall survival (HR = 0.33; P < .001) compared with those who had residual disease after preoperative chemotherapy. Because preoperative chemotherapy does not have a negative impact on survival, the preoperative approach is a reasonable option and has gained favor among many patients.

Preoperative chemotherapy had an ability to convert patients requiring mastectomy to candidates for breast-conserving surgery. However, there was an increase in local recurrence in the “converted” group vs those deemed eligible initially for breast-conserving surgery.

Patients undergoing sentinel lymph node biopsy. A prospective study designed to determine the survival impact of micrometastases in the sentinel nodes of patients with invasive breast cancer included 790 patients who underwent sentinel node biopsy. The investigators found no significant difference in 8-year disease-free or overall survival among patients with micrometastatic tumor deposits in sentinel nodes defined as being pN0(i+) or pN1mic when compared with patients having negative sentinel nodes. The true significance of these micrometastatic deposits is still unclear, but it may help to better define groups of patients who should receive maximum adjuvant medical or surgical therapy or who could avoid additional therapy.

Although helpful in prognosis and treatment planning, completion axillary dissection after a positive sentinel node biopsy may not be required for small tumors and in the absence of lymphovascular invasion. Factors affecting the rate of positive nonsentinel nodes and the necessity of axillary dissection following a positive sentinel lymph node resection were evaluated in NSABP B-32. Women with operable invasive breast cancer and clinically negative nodes were randomized to undergo sentinel node resection with immediate conventional axillary dissection (group 1) or without axillary dissection (group 2). Patients in group 2 who had positive sentinel nodes underwent axillary dissection. Data from 1,166 patients with positive sentinel nodes that were available for multivariate analysis (595 from group 1; 571 from group 2) indicated that a significantly higher percentage of patients in group 2 had positive nonsentinel nodes than did those in group 1 (41.5% vs 35.5%; P = .032). Clinical tumor size was a significant predictor for positive nonsentinel nodes (P = .001). Percentages of patients having positive nonsentinel nodes were significantly increased by the number of positive sentinel nodes, and lymphovascular invasion was a significant predictor for positive nonsentinel nodes. The percentages of patients with positive nonsentinel nodes significantly decreased with increases in the number of hot spots identified and the number of sentinel nodes removed.

The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial is a randomized, multicenter trial designed to determine the effects of completion axillary node dissection on survival of patients with clinical T1 or T2 N0 M0 breast cancer who have one to two positive sentinel nodes. Patients were treated with lumpectomy with whole breast irradiation and adjuvant systemic therapy. Clinical and tumor characteristics were similar between a group of 445 patients randomized to axillary lymph node dissection (ALND) and a group of 446 patients randomized to sentinel lymph node dissection (SLND) alone. At a median follow-up of 6.3 years, locoregional recurrences were uncommon, occurring in 3.1% of ALND and 1.6% of SLND patients (P = .11). Only age (≤ 50 years) and higher Bloom-Richardson scores were associated with locoregional recurrence by multivariate analysis. Number of positive sentinel nodes, size of the sentinel node metastasis, and number of lymph nodes removed were not associated with locoregional recurrence. The omission of ALND in this group of patients did not result in inferior survival. The 5-year overall survival was 91.8% (95% confidence interval [CI], 89.1–94.5) with ALND and 92.5% (95% CI, 90–95.1) with SLND alone; 5-year disease-free survival was 82.2% (95% CI, 78.3–86.3) with ALND and 83.9% (95% CI, 80.2–87.9) with SLND alone. A drawback of this study is its early closure and accrual of less than one-half of the targeted enrollment population; nonetheless, its findings have immediate implications for clinical practice. It is important to note that the Z0011 trial did not include patients undergoing mastectomy, lumpectomy without radiotherapy, partial-breast irradiation, or neoadjuvant therapy. In those patients, ALND remains standard practice when SLND identifies a positive SLN.

The timing of sentinel node biopsy in patients undergoing preoperative chemotherapy is controversial. Preoperative chemotherapy can sterilize the axillary nodes and lead to errors in determining nodal involvement. ACOSOG 1071 was designed to determine the application of SLN surgery for staging the axilla following chemotherapy for women who initially had node-positive cN1 breast cancer. The primary objective of the trial was to determine if the false-negative rate (FNR) for SLN surgery with two or more LNs examined following chemotherapy in women initially presenting with biopsy-proven cN1 breast cancer was greater than 10%. A total of 756 women were enrolled, with 649 patients undergoing neoadjuvant chemotherapy followed by both SLN surgery and ALND. Of these 649, a total of 525 patients had two or more SLNs removed. In 39 patients, cancer was not identified in the SLNs but was found in lymph nodes obtained with ALND, resulting in an FNR of 12.6% (90% Bayesian credible interval, 9.85% to 16.05%). Their findings suggest that surgeons cannot reliably detect by SLN procedures all axillary lymph node metastases in patients with cN1 breast cancer following chemotherapy. The authors further concluded that for SLND to become an alternative to ALND in this patient population, changes in approach and patient selection that result in greater sensitivity would be necessary.

Radiation therapy after breast-conserving surgery

For patients with stages I and II breast cancer, radiation therapy following lumpectomy remains an acceptable standard of care. Randomized trials and single-institution experiences have consistently demonstrated a significant reduction in local relapse rates for radiotherapy following breast-conserving surgery. Furthermore, small but significant differences in distant metastasis and disease-free survival have been observed in randomized trials comparing lumpectomy alone with lumpectomy and radiation therapy for patients with invasive breast cancer.

Based on the results of a number of retrospective, single-institution experiences as well as several prospective, randomized clinical trials, breast-conserving surgery followed by radiation therapy to the intact breast is now considered standard treatment for the majority of patients with stage II invasive breast cancer.

An update from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) metaanalysis focused on 10,801 women enrolled in 17 randomized trials of radiotherapy vs no radiotherapy after breast-conserving surgery and relates the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk. Overall, radiotherapy reduced the 10-year risk of any first recurrence from 35% to 19.3% (P < .001) and reduced the 15-year risk of breast cancer death from 25.2% to 21.4% (P < .001). In women with pN+ disease (n = 1,050), radiotherapy reduced the 10-year recurrence risk from 63.7% to 42.5% (P < .001) and the 15-year risk of breast cancer death from 51.3% to 42.8% (P = .01).

Radiation dose and protocol. Radiation dose to the intact breast follows the same guidelines used in patients with stages 0 and I disease, described in the previous chapter.

Regional nodal irradiation (RNI). For patients who undergo ALND and are found to have negative lymph nodes, RNI may be employed if the patient has high risk factors such as triple-negative disease, an undissected axilla, or inner/medial quadrant tumors. For patients with positive lymph nodes, radiation therapy to the supraclavicular fossa and/or internal mammary chain may be considered on an individualized basis.

RNI should be administered using careful treatment-planning techniques to minimize the dose delivered to the underlying heart and lungs. Prophylactic nodal irradiation to doses of 45 to 50 Gy results in a high rate of regional nodal control and may improve disease-free survival in subsets of patients.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA20 trial evaluated addition of RNI to whole breast irradiation (WBI) following breast-conserving surgery. Whelan et al reported that women with high-risk node-negative or node-positive breast cancer treated with breast-conserving surgery and adjuvant chemotherapy and/or endocrine therapy were randomized to WBI (50 Gy in 25 fractions +/− boost irradiation) or WBI plus RNI (with RNI at 45 Gy, in 25 fractions) to the internal mammary, supraclavicular, and high axillary lymph nodes. A total of 1,832 women were randomly assigned to WBI + RNI (n = 916) or WBI (n = 916). Median follow-up was 62 months. In the study population, 85% of the women had one to three positive nodes, 91% received adjuvant chemotherapy, and 71% got adjuvant endocrine therapy. Compared with WBI alone, WBI + RNI was associated with an improvement in isolated locoregional disease–free survival (HR = .59; P = .02; 5-year risk 94.5% vs 96.8%, respectively), distant disease–free survival (HR = .64; P = .002; 5-year risk 87% vs 92.4%, respectively), disease-free survival (HR = .68; P = .003; 5-year risk 84% vs 89.7%, respectively), and overall survival (HR = .76; P = .07; 5-year risk 90.7% vs 92.3%, respectively). WBI + RNI in comparison to WBI was associated with an increase in grade 2 or greater pneumonitis (1.3% and 0.2% respectively; P = .01) and lymphedema (7.3% and 4.1% respectively; P = .004).

Radiation therapy after mastectomy

Available data suggest that in patients with positive postmastectomy margins, chest wall fixation, primary tumors > 5 cm, or involvement of four or more lymph nodes at the time of mastectomy, the risk of locoregional failure remains significantly high enough for postmastectomy radiation therapy to be considered.

Several prospective, randomized trials have evaluated the role of postmastectomy radiotherapy in addition to chemotherapy. Most of these trials have been limited to patients with pathologic stage II disease or with T3 or T4 primary lesions. All of these trials have shown an improvement in locoregional control with the addition of adjuvant irradiation, and several recent trials have demonstrated a disease-free and overall survival advantage in selected patients. Clinical practice guidelines developed by the American Society of Clinical Oncology (ASCO) support routine use of postmastectomy radiation therapy for women with stage III or T3 disease or those who have four or more involved axillary lymph nodes.

Most ongoing trials evaluating dose-intensive chemotherapy routinely include postmastectomy radiation therapy to the chest wall and/or regional lymph nodes to minimize locoregional recurrence.

Current recommendations. There is no clearly defined role for postmastectomy irradiation in patients with small (T1 or T2) primary tumors and negative nodes. For patients with one to three positive nodes, postmastectomy radiation therapy may be considered to lower the rate of local relapse and improve disease-free survival, although the benefit is less than that of patients with four or more positive nodes. However, based on the NCIC-CTG MA20 trial, addition of RNI in node-positive patients is beneficial in terms of locoregional control and disease-free survival. For patients with four or more positive lymph nodes, with or without a large primary tumor, postmastectomy radiation therapy should be considered to lower the rate of local relapse and improve disease-free survival. For patients who are younger, or who have T1 or T2 tumors, one to three positive nodes, poorly differentiated subtypes, or lymphovascular invasion, postmastectomy radiation therapy may have a benefit with respect to disease-free and overall survival. However, controversies and uncertainties regarding this issue remain, and individualized decision-making based on the patient’s overall condition and specific risk factors is reasonable.

The EBCTCG conducted a meta-analysis of 8,135 women randomly assigned to treatment groups during 1964 through 1986 in 22 trials of radiotherapy to the chest wall and regional lymph nodes after mastectomy and axillary surgery vs the same surgery but no radiotherapy. In women who underwent axillary dissection and had no positive nodes (n = 700), radiotherapy did not affect locoregional recurrence or breast cancer mortality. In women who underwent axillary dissection and had one to three positive nodes (n = 1,314), radiotherapy reduced locoregional recurrence (2P < .00001), overall recurrence (2P = .00006), and breast cancer mortality (2P = .01), even in the setting of chemotherapy. Notably, the unirradiated women in these trials with one to three positive nodes had an absolute 10-year risk of overall recurrence of 45.7%, which was reduced to 34.2% by their radiotherapy, so their absolute gain was 11.5%. For 1,772 women with axillary dissection and four or more positive nodes, radiotherapy reduced locoregional recurrence (2P < .00001), overall recurrence (2P = .0003), and breast cancer mortality (relative risk [RR] = 0·87; 95% CI, 0.77–0.99; 2P = .04).

Minimizing pulmonary and cardiac toxicities. Early trials employing postmastectomy radiation therapy showed that the modest improvement in breast cancer mortality was offset by an excess risk of cardiovascular deaths, presumably due to the radiation treatment techniques used, that resulted in delivery of relatively high radiation doses to the heart. Recent trials employing more modern radiation therapy techniques have not demonstrated an excess of cardiac morbidity and, hence, have shown a slight improvement in overall survival due to a decrease in breast cancer deaths. Thus, in any patient being considered for postmastectomy radiation therapy, efforts should be made to treat the areas at risk while minimizing the dose to the underlying heart and lungs.

Radiation dose and protocol. The available literature suggests that doses of 4,500 to 5,000 cGy should be sufficient to control subclinical microscopic disease in the postmastectomy setting. Electron-beam boosts to areas of positive margins and/or gross residual disease reaching doses of about 6,000 cGy and delivered to sites of gross disease, may be considered. At present, in the United States, it is not standard of care to consider hypofractionated regimens in the setting of postmastectomy radiation therapy.

In patients who have undergone axillary lymph node dissection, even in those with multiple positive nodes, treatment of the axillae does not appear to be necessary in the absence of gross residual disease. Treatment of the supraclavicular and/or internal mammary chain should employ techniques and field arrangements that minimize overlap between adjacent fields and decrease the dose to underlying cardiac and pulmonary structures. When treating patients who underwent neoadjuvant chemotherapy who only underwent SLN surgery, care should be taken to comprehensively treat the regional lymph nodes based on the NCIC MA.20 and EORTC trials.

There are two prospective cooperative group trials that will help determine the role of the optimal local therapy after neoadjuvant chemotherapy. The Alliance for Clinical Trials in Oncology cooperative group (formerly known as the American College of Surgeons Oncology Group, Cancer and Leukemia Group B, and North Central Cancer Treatment Group) trial A011202 examines the role of local therapy in the management of the axilla in patients with residual node-positive disease after neoadjuvant chemotherapy. Patients with cT1-3 N1 disease treated with neoadjuvant chemotherapy will be enrolled, and patients with positive sentinel nodes will be randomly assigned to axillary radiation or completion axillary lymph node dissection. All patients will receive radiation to the breast or chest wall and to the undissected supraclavicular and level III axillary nodes. A companion study by the NRG Oncology group (formerly known as the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group) trial 9353 examines the role of local therapy in the management of the axilla in patients who convert to node-negative after neoadjuvant chemotherapy. Patients with cT1-3 N1 disease treated with neoadjuvant chemotherapy will be enrolled and those with negative sentinel nodes will be randomly assigned to comprehensive nodal irradiation or no nodal irradiation. All patients will receive radiation to the breast or chest wall.

Medical Treatment

Medical management of local disease depends on clinical and pathologic staging. Systemic therapy is indicated only for invasive (infiltrating) breast cancers.

A discussion of the sequencing of chemotherapy and irradiation and hormonal therapy with irradiation is provided in the previous chapter.

Treatment regimens

Systemic adjuvant therapy has been shown to decrease the risk of recurrence and in some cases also the risk of death. Systemic therapy may be divided into chemotherapy and endocrine (hormonal) therapy. Chemotherapy often involves use of combination regimens, given for 4 to 8 cycles. It is most often delivered after primary surgery for breast cancer and before radiation therapy for those who are candidates for irradiation.

A study comparing two decision aids found that the 21-gene assay (Oncotype DX) was more accurate than were the classic clinicopathologic features and therapy utilized in Adjuvant! Online in predicting recurrence among 465 women with hormone receptor–positive operable breast cancer and zero to three positive axillary nodes who were treated with chemohormonal therapy. Recurrence score highly significantly predicted recurrence of both node-negative and node-positive disease (P < .001) when adjusted for other clinical variables. Recurrence score also was more accurate than were clinical variables at predicting recurrence when integrated by an algorithm modeled after Adjuvant! Online that was adjusted to 5-year outcomes. The 5-year recurrence rate was 5% or less for the 46% of patients with a low recurrence score (< 18). The investigators concluded that the 21-gene assay may be used to select low-risk vs high-risk patients for specific chemotherapy regimens and clinical trials.

A multicenter study found that the recurrence score assay impacts medical oncologists’ adjuvant treatment recommendations and patient treatment choice. The largest change due to recurrence score assay results was conversion from the medical oncologist’s pretest recommendation for chemotherapy plus hormonal therapy to post-test recommendation for hormone therapy alone, and the recurrence score results often increased medical oncologists’ confidence in their treatment recommendation. Patient anxiety and decisional conflict were significantly lower after recurrence score results were known.

Apart from Oncotype DX, other multigene tests being used clinically to predict recurrence risk and guide adjuvant chemotherapy decisions include MammaPrint and PAM50. Prospective clinical trials are ongoing to further validate these assays. The TAILORx trial uses the Oncotype DX recurrence score to assign estrogen receptor (ER)-positive, node-negative patients to chemotherapy plus hormonal therapy vs hormonal therapy alone. The RxPONDER (SWOG S1007) trial uses Oncotype DX in a similar approach but for patients with one to three node-positive nodes. The MINDACT trial uses MammaPrint and Adjuvant! Online for treatment arm assignments. MINDACT has very broad eligibility criteria and two secondary randomizations for selecting chemotherapy and hormonal therapy regimens. Genome sequencing may potentially identify the molecular abnormalities that underlie the poor risk identified by multigene tests and provide potential new targets for therapy.

Chemotherapy. Multiagent therapy with CMF (cyclophosphamide, methotrexate, and fluorouracil [5-FU]), CMFP (cyclophosphamide, methotrexate, 5-FU, and prednisone), AC (Adriamycin [doxorubicin] and cyclophosphamide), and MF (sequential methotrexate and 5-FU) has been used in patients with node-negative disease (see Table 2 in the “Stages 0 and I Breast Cancer” chapter).

For node-positive disease, systemic chemotherapy has changed over the past few decades. Anthracycline-containing regimens have been shown to be of greater benefit than non–anthracycline-containing regimens (eg, CMF). Epirubicin (Ellence) was approved by the US Food and Drug Administration (FDA) for use in combination chemotherapy, in CEF (cyclophosphamide, epirubicin, and 5-FU) for adjuvant treatment of patients with node-positive breast cancer following resection of the primary tumor.

In a pivotal trial conducted by the NCIC, premenopausal women with node-positive breast cancer were randomly allocated to receive either CEF or CMF, administered monthly for 6 months. With a median follow-up of 59 months, the 5-year relapse-free survival rates were 53% and 63% (P = .009), and 5-year survival rates were 70% and 77% (P = .03) for CMF and CEF, respectively.

Several trials have also shown the benefit of incorporating taxanes (paclitaxel and docetaxel [Taxotere]) in the adjuvant treatment of node-positive breast cancer, and these drugs are now routinely used in this setting. Taxanes can either be given in combination with an anthracycline or sequentially, either before or after an anthracycline. They can also be given in combination with other drugs such as cyclophosphamide.

The E1199 trial compared paclitaxel with docetaxel and therapeutic schedules (ie, every 3 weeks vs weekly) in the adjuvant therapy of operable breast cancer. In all, 4,950 eligible patients with lymph node–positive or high-risk (tumor > 2 cm), node-negative breast cancer received 4 cycles of AC and then were randomized to receive IV paclitaxel or docetaxel given at 3-week intervals for 4 cycles or at 1-week intervals for 12 cycles. With a median follow-up of 12.1 years, adjuvant weekly paclitaxel (HR = 0.84; 95% CI, 0.73–0.96) and every-3-week docetaxel (HR = 0.79; 95% CI, 0.68–0.90) were associated with significantly improved disease-free survival compared to every-3-week paclitaxel when given sequentially following AC. Exploratory analysis in triple-negative breast cancer (n = 1,025) showed that the most effective taxane regimen was weekly paclitaxel, with an improvement in the 10-year disease-free survival rate from 59% to 69% and improvement in the overall survival rate from 66% to 75%. Among hormone-positive, HER2-negative/unknown disease (n = 2,785), the trend for improved outcomes initially seen at 5 years were not consistently observed. Furthermore, strong associations with inferior outcomes were observed for obese women and black race, independent of obesity.

The Breast Cancer International Research Group (BCIRG) compared TAC (Taxotere [docetaxel], AC) with the FAC regimen (5-FU, AC) in 1,480 women with node-positive breast cancer (BCIRG 001/TAX 316). At a median follow-up of 55 months, the estimated 5-year disease-free survival was 75% for patients treated with TAC vs 68% for those treated with FAC. This represents a statistically significant reduction in the risk of relapse [P = .001]). Furthermore, treatment with TAC resulted in a statistically significant reduction in the risk of death (30%; P = .008). The improvement in both disease-free and overall survival was confirmed in the 10-year follow-up analysis of the BCIRG 001 trial (disease-free survival: HR = 0.80; 95% CI, 0.68–0.93; P = .0043 and overall survival: HR = 0.74; 95% CI, 0.61–0.90; P = .002). Although there was more febrile neutropenia with TAC, it was ameliorated with growth factor support. The rate of grade 3/4 congestive heart failure was greater in the TAC vs FAC group (3.5% vs 2.3%), as was the incidence of acute myeloid leukemia (four patients treated with TAC and two patients treated with FAC).

In the Cancer and Leukemia Group B (CALGB) trial 9344, a total of 3,121 women with operable, node-positive breast cancer were randomized to receive three different doses of doxorubicin with a standard dose of cyclophosphamide, followed by either no further therapy or 4 cycles of paclitaxel (at 175 mg/m²). This study did not show any substantial benefit from dose escalation of doxorubicin. However, the addition of 4 cycles of paclitaxel improved disease-free and overall survival. At 5 years, the disease-free survival rates were 65% for the AC-treated cohort and 70% for the AC-plus-paclitaxel treatment group, and overall survival rates were 77% and 80%, respectively. An unplanned subset analysis showed that the majority of the benefit was seen in patients with estrogen receptor-negative tumors. Tamoxifen was given to 94% of patients with hormone receptor-positive tumors. Toxicity was modest with the addition of 4 cycles of paclitaxel.

Jones et al previously reported that 4 cycles of docetaxel and cyclophosphamide (TC) improved overall survival when compared with 4 cycles of AC in early breast cancer. Updated results of this study as well as the impact of age, hormone receptor status, and HER2 status on outcome and toxicity were published. Of note, 16% of patients in this trial were > 65 years. The median age in women under the age of 65 was 50 years (range, 27–64 years) and for women over age 65 was 69 years (range, 65–77 years). Baseline characteristics in the two age subgroups generally were well matched, except that older women tended to have more lymph node involvement. At a median of 7 years follow-up, the difference in disease-free survival between the TC and AC groups was significant (81% vs 75%, respectively; P = .033; HR = 0.74; 95% CI, 0.56–0.98), as was the difference in overall survival (87% vs 82%; P = .032; HR = 0.69; 95% CI, 0.50–0.97). The TC regimen was superior in both older and younger patients. Older women experienced more febrile neutropenia with TC and more anemia with AC. However, studies comparing TC with an anthracycline-and-taxane containing regimen (ie, TAC) are ongoing.

TABLE 1: Adjuvant chemotherapy regimens in node-positive breast cancer

In NSABP B-28, the addition of paclitaxel (225 mg/m²) did not initially result in improvement of either disease-free or overall survival. However, with longer follow-up (median, 67 months), improvement in disease-free survival in favor of AC followed by paclitaxel has emerged.

• Dose-dense treatment-CALGB 9741 tested two novel concepts: dose density and sequential therapy. A total of 2,005 women with operable, node-positive breast cancer were randomly assigned to receive one of the following regimens: (1) sequential Adriamycin (A) for four doses followed by Taxol (paclitaxel; T) for four doses followed by cyclophosphamide (C) for four doses, with doses every 3 weeks; (2) sequential A for four doses followed by T for four doses followed by C for four doses, every 2 weeks with filgrastim (Neupogen); (3) concurrent AC for four doses followed by T for four doses, every 3 weeks; or (4) concurrent AC for four doses followed by T for four doses, every 2 weeks with filgrastim. At a median follow-up of 36 months, there was an improvement in disease-free survival (risk ratio = 0.74; P = .01) and overall survival (risk ratio = 0.69; P = .013) in favor of dose density. Four-year disease-free survival was 82% for the dose-dense regimens and 75% for the others. There was no difference in disease-free or overall survival between the concurrent (dose-dense) and sequential schedules. Severe neutropenia was less frequent in patients who received the dose-dense treatments with granulocyte colony-stimulating factor (GCSF) support. Therefore, the trial demonstrated that administering chemotherapy sequentially is as effective as concurrent administration, but outcomes are improved with dose-dense regimens (administered every 2 weeks).

The CALGB 40101 study was a 2 × 2 factorial phase III trial designed to evaluate whether the efficacy of paclitaxel (80 mg/m²/wk) is equivalent to a regimen of standard-dose AC with a reduced rate of toxicity. In addition, the study was designed to evaluate whether 6 cycles of adjuvant chemotherapy was superior to 4 cycles. The primary endpoint was relapse-free survival, and overall survival was a secondary endpoint. The study, reported by Shulman et al at the 2010 San Antonio Breast Cancer Symposium, enrolled 3,174 women with low-risk, operable breast cancer and 0–3 positive nodes, stratified for estrogen receptor/progesterone receptor (ER/PR) and human epidermal growth factor receptor 2 (HER2, HER2/neu) status. Patients with hormone receptor–positive disease received appropriate endocrine therapy and patients with HER2-positive disease also received trastuzumab after its approval for adjuvant therapy. At a median follow-up of 4.6 years, the relapse-free survival and overall survival rates were equivalent with the 4 and 6 chemotherapy cycles, and there was no differences in outcomes according to ER and HER2 status. In general, paclitaxel was generally better tolerated than AC. Paclitaxel was associated with lower rates of neutropenia, febrile neutropenia, and anemia but with higher rates of neuropathy. For each of the regimens, the 4-cycle treatment course was associated with an equal or a lower incidence of grade 3/4 toxicities compared with the 6-cycle treatment course. Overall, there were 10 patients (< 1%) who experienced a grade 3 to 5 cardiac adverse event, usually in those who received AC. There were 6 patients who developed acute myeloid leukemia (n = 5) or myelodysplastic syndromes (n = 1) during the follow-up period. The rates of breast cancer–related deaths were comparable between the 4- and 6-cycle arms (63.1% vs 58.8%, respectively).

The dosages, schedules, and frequencies of chemotherapy regimens used for node-positive breast cancer are detailed in Table 1. Other regimens also used in node-negative (“Stages 0 and I Breast Cancer” chapter) and/or metastatic disease (“Stages III and IV Breast Cancer” chapter) are listed in their respective chapters.

• Recommendations-All patients with stage II breast cancer should be considered for systemic adjuvant therapy. Adjuvant chemotherapy in node-positive breast cancer improves disease-free and overall survival by 24% and 15%, respectively. Risk reductions for multiagent chemotherapy are proportionately the same in patients with node-negative and node-positive disease.

Chemotherapy for women 50 years of age and older is similar to that for younger women. However, multiagent chemotherapy affords the greatest benefit in women younger than age 50 with respect to reductions in the risk of recurrence and death from breast cancer. For instance, CMF or AC chemotherapy improves disease-free survival in women aged 50 to 69 by 18%, vs 33% for women younger than age 50. Limited data are available from randomized trials regarding women aged 70 and older. However, in the absence of comorbidity, such as heart, renal, or liver disease, systemic adjuvant therapy can be offered to women > 70 years old.

The EBCTCG published an update in 2012 on the benefit of adjuvant chemotherapy regimens, including the taxanes. The update assessed the relevance of scheduled drug dosage and investigated whether any of the available patient or tumor characteristics (eg, age, nodal status, tumor differentiation, ER status, use of tamoxifen) affect the proportional reductions in breast cancer recurrence and death with use of modern chemotherapy. For this analysis, individual-patient-data meta-analyses of the randomized trials were used, comparing: any taxane-plus-anthracycline-based regimen vs the same, or more, non-taxane chemotherapy (n = 44,000); one anthracycline-based regimen vs another (n = 7,000) or vs CMF (n = 18,000); and polychemotherapy vs no chemotherapy (n = 32,000).

In trials adding 4 separate cycles of a taxane to a fixed anthracycline-based control regimen, breast cancer mortality was reduced (RR 0.86, standard error [SE] 0.04, 2P = .0005); however, in trials with 4 such extra cycles of a taxane counterbalanced in controls by extra cycles of other cytotoxic drugs, there was no significant difference (RR 0.94, SE 0.06, 2P = .33). Trials with CMF-treated controls showed that standard 4AC and standard CMF were equivalent (RR 0.98, SE 0.05, 2P = .67), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC were superior to standard CMF (RR 0.78, SE 0.06, 2P = .0004). Trials of polychemotherapy vs no chemotherapy also suggested greater mortality reductions with CAF (RR 0.64, SE 0.09, 2P < .0001) than with standard 4AC (RR 0.78, SE 0.09, 2P = .01) or standard CMF (RR 0.76, SE 0.05, 2P < .0001). In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were not significantly affected by age, nodal status, tumor diameter or differentiation, ER status, or tamoxifen use. Hence, largely independent of age (up to at least 70 years) or the tumor characteristics, some taxane-plus-anthracycline–based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. Overall 10-year mortality differences depend on absolute risks without chemotherapy (which, for ER-positive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implies low absolute benefit, but information was lacking about tumor gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both.

NSABP B-38 is a phase III randomized trial designed to assess whether adjuvant dose-dense (DD) AC → paclitaxel (P) plus gemcitabine (G, Gemzar) (with the regimen being A 60 mg/m² and C 600 mg/m² q2wk × 4 followed by P 175 mg/m² + G 2,000 mg/m² q2wk × 4) will be superior to DD AC→P (A 60 mg/m² and C 600 mg/m² q2 wk × 4 followed by P 175 mg/m² q2 wk × 4), as well as to TAC (docetaxel [T, Taxotere] 75 mg/m², doxorubicin [A, Adriamycin] 50 mg/m², cyclophosphamide [C] 500 mg/m² q3wk × 6) in disease-free survival, and to compare the relative disease-free survival of patients treated with TAC vs DD AC→P. A total of 4,894 women were randomized: 1,630 to TAC, 1,634 to DD AC→P, and 1,630 to DD AC→PG. Among the treated women, 52% were postmenopausal, 65% had one to three positive nodes, and 80% had hormone receptor–positive breast cancer. Log-rank tests were used for pair-wise comparisons of disease-free and overall survival (a secondary endpoint) among the three treatment arms.

With 64 months median follow-up, the addition of G to DD AC→P did not improve outcomes, and no significant differences in efficacy endpoints were identified between DD AC→P and TAC. The 5-year disease-free survival in the DD AC→PG group was 80.6% compared with 82.2% in the DD AC→P group (HR = 1.1; P = .27) and 80.1 % (HR = 0.97; P = .71) in the TAC group. The 5-year overall survival was 90.8% in the DD AC→PG group compared with 89.1% (HR = .89; P = .25) in the DD AC→P group and 89.6 % (HR = 0.90; P = .32) in the TAC group. The HR for disease-free and overall survival of DD AC→P vs TAC were 0.89 (P = .14) and 1.01 (P = .92), respectively. There were no significant differences in 5-year disease-free survival between DD AC→PG and DD AC→P (80.6% vs 82.2%; HR = 1.07; P = .41), between DD AC→PG and TAC (80.6% vs 80.1%; HR = 0.93; P = .39), in 5-year overall survival between DD AC→PG and DD AC→P (90.8% vs 89.1%; HR = 0.85; P = .13), between DD AC→PG and TAC (90.8% vs 89.6%; HR = 0.86; P = .17), or between DD AC→P vs TAC for disease-free survival (HR = 0.87; P = .07) and overall survival (HR = 1.01; P = .96).

Toxicity profiles differed between the treatment arms. Compared with the DD regimens, patients treated with TAC had more febrile neutropenia (grade 3/4: 9% vs 4%; P < .001) as well as diarrhea (grade 3/4: 8% vs 2%; P < .001). In contrast, TAC was associated with the least sensory neuropathy (grade 3/4: < 1% with TAC vs 7% and 6% with DD AC→PG and DD AC→P, respectively; P < .001) and anemia (Hgb was < 10 g/dL in 12%, 26%, and 33%, respectively, and transfusions were needed in 3.7%, 6.3%, and 9.4%, respectively). Grade 3 and 4 toxicities for TAC, DD AC→P, and DD AC→PG, respectively, were febrile neutropenia (9%, 3%, and 3%; P < .001), sensory neuropathy (< 1%, 7%, and 6%; P < .001), and diarrhea (7%, 2%, and 2%; P < .001). Exploratory analyses for erythropoiesis-stimulating agents showed no association with disease-free survival events (HR = 1.02; P = .95)

Sidebar: The NSABP B-36 study initially had a 2 × 2 factorial design, but ultimately became a two-arm randomization among 6 cycles of FEC-100 compared with the standard 4 cycles of AC for adjuvant treatment of patients with high-risk node-negative disease. A total of 2,722 patients were randomized, and the two treatment arms were well balanced in terms of age, tumor characteristics, and type of surgery (lumpectomy vs mastectomy), as well as receipt of trastuzuamb for patients with HER2-positive disease. With a median follow-up of 7 years, disease-free survival was almost identical between the two treatment groups: approximately 82% (HR = 1.03; P = .74). Overall survival differences were not statistically significant at 91.2% vs 92% for AC vs FEC, respectively (HR = 0.94; P = .65). Cases of symptomatic congestive heart failure were rare in both arms. There were more toxicities observed in the FEC treatment arm, the most common grade 3/4 toxicities being febrile neutropenia (9.4% vs 3.7%) and fatigue (8.4% vs 3.6%). The investigators concluded that 6 cycles of anthracycline-based regimens in node-negative breast cancer is unnecessary and leads to more toxicities (Jacobs SA et al: 37th SABCS, December 9–13, 2014. Abstract S3-02).

Endocrine therapy

The EBCTCG overview analyses demonstrated a significant advantage with the addition of tamoxifen (20 mg/d oral) for 5 years to the adjuvant therapy regimen of women with ER-positive breast cancer, regardless of age. Treatment with tamoxifen reduced the risk of death by 14% in women younger than age 50 and by 27% in those 50 years of age and older. Long-term follow-up from the NSABP conclusively demonstrates that there is no benefit to continuing tamoxifen therapy beyond 5 years. However, results from much larger studies have recently reported that a longer duration of tamoxifen may be more beneficial than 5 years of therapy.

From 1996 to 2005, the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial randomized 11,500 women (59% ER-positive, 41% untested) who had completed about 5 years of adjuvant tamoxifen to 5 more years of tamoxifen vs stopping. Less than 1% of patients had switched to any other adjuvant hormonal therapy in the trial treatment period. At a mean follow-up of 4.2 years, the annual recurrence rate in each treatment group was approximately constant during and after the 5-year trial treatment period. Approximately 1,500 recurrences have been reported. A total of about 1,300 occurred during years 5 to 9, but only about 200 occurred during years 10 to 14. Overall, the recurrence rate was significantly lower among patients allocated to continue tamoxifen. There was no significant heterogeneity in the recurrence rate reduction with respect to ER status, time period, age, or nodal status at diagnosis. Breast cancer mortality and overall mortality rates were lower among those allocated to continue tamoxifen, but were not statistically significant. Further follow-up is needed to reliably assess the longer-term effects on recurrence and the net effects on mortality.

Premenopausal women. Approximately 60% of premenopausal women with primary breast cancer have ER-positive tumors. For this group of patients, the benefit of adjuvant endocrine therapy, either tamoxifen or ovarian ablation, was established in the EBCTCG overview. For premenopausal women, however, the long-term morbidity associated with permanent ovarian suppression may be significant. Ovarian suppression with luteinizing hormone-releasing hormone (LHRH) analogs offers an alternative to permanent ovarian ablation, which is potentially reversible on cessation of therapy.

The ZEBRA (Zoladex Early Breast Cancer Research Association) trial is a randomized study that directly compares goserelin (Zoladex) monotherapy with CMF in premenopausal women 50 years of age and younger with node-positive, stage II breast cancer. The study included 1,614 patients: 797 randomized to receive goserelin and 817 to receive CMF. ER status was known for 92.5% of patients and 80% had ER-positive tumors.

At a median follow-up of 6 years, the ER-positive patients treated with goserelin fared comparably to those who received CMF in terms of disease-free survival (HR = 1.01; P = .94) and overall survival (HR = 0.99; P = .92). Not surprisingly, CMF was superior to goserelin in patients with ER-negative tumors. The onset of amenorrhea occurred on average 6 months sooner with goserelin than with CMF. More than 95% of patients on goserelin were amenorrheic vs 59% of patients receiving CMF. Reversibility of amenorrhea was greater for goserelin. One year after cessation of goserelin treatment, 23% remained amenorrheic vs 77% of CMF recipients.

Several studies have compared adjuvant chemotherapy with combined endocrine therapies, consisting of tamoxifen for 5 years and an LHRH agonist for 2 to 3 years, in premenopausal women. Overall, combination endocrine treatment yielded better results than did chemotherapy alone. Whether a strategy of combined endocrine therapy is better than tamoxifen alone, either with or without chemotherapy, in premenopausal patients with hormone receptor–positive tumors is the subject of several ongoing clinical trials.

Two randomized, phase III studies, SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial) investigated the role of ovarian suppression plus tamoxifen vs anaromatase inhibitor, exemestane, in the adjuvant therapy of premenopausal women with hormone receptor–positive breast cancer. Primary analysis of the combined data from both trials (n = 4,690) were reported by Pagani et al. With a median follow-up of 68 months, disease-free survival at 5 years was 91.1 in the exemestane-OFS group compared to 87.3% in the tamoxifen-OFS group (HR = 0.72; 95% CI, 0.60–0.85; P < .001). Overall survival was not statistically different between the two groups (HR = 1.14; 95% CI, 0.86–1.51; P = .37); however, conclusions about overall survival are premature at this early point in follow-up of hormone receptor–positive disease. The side effect profile of exemestane-OFS mirrors that seen with use of aromatase inhibitors in postmenopausal women.

Sidebar: Additional results from SOFT, specifically the comparison between tamoxifen monotherapy vs tamoxifen-OFS was recently presented at the SABCS annual meeting. For this analysis, 2,033 women were included, 53% of whom received chemotherapy in addition to the assigned hormonal therapy. The median age was 43 years, 35% had node-positive disease, 32% had tumors > 2 cm, 22% had grade 3 tumors, and 12% had HER2-positive disease. Results showed that the overall study population did not benefit from the addition of OFS to tamoxifen. The 5-year disease-free survival was 84.7% for tamoxifen alone vs 86.6% for tamoxifen-OFS (HR = 0.83; 95% CI, 0.66–1.04; P = .10). There was a 19% relative reduction in breast cancer recurrence between the tamoxifen-OFS group vs tamoxifen alone (P = .09). Women who were < 35 years of age (11.5% of the study population) had the most striking benefit from OFS. It is hoped that ongoing translational studies would help to further identify which groups of patients would derive the most benefit from OFS (Francis P, presenting for SOFT investigators. 37th SABCS, December 9–13, 2014. Abstract S3-08).

Whether combined endocrine therapies alone may be sufficient to achieve excellent outcomes without chemotherapy was investigated in the PERCHE (Premenopausal Endocrine Responsive Chemotherapy) trial. Chemotherapy use was determined by randomization; unfortunately, the trial closed due to inadequate accrual. In the TEXT clinical trial, in which chemotherapy use was chosen by the physician, lymph node status was the predominant determinant of chemotherapy use (88% of treated node-positive vs 46% of node-negative patients). Geography, patient age, and tumor size and grade were also determinants, but degree of receptor positivity and HER2 status were not. Currently, almost all premenopausal women with lymph node–positive, HR-positive breast cancer receive chemotherapy.

In premenopausal women with early breast cancer, addition of zoledronic acid (Zometa) to adjuvant endocrine therapy significantly improved clinical outcomes beyond endocrine therapy alone. In the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 trial, a phase III randomized study of 1,801 premenopausal women with stage I–II disease undergoing ovarian suppression with goserelin, therapy with tamoxifen or anastrozole (Arimidex) plus zoledronic acid reduced the risk of disease-free survival events by 36% and relapse-free survival by 35% vs endocrine therapy alone (P = .011 and P = .015, respectively). At a median follow-up of 62 months, Gnant et al reported that zoledronic acid reduced the risk of disease-free survival events (relapse) overall (HR = 0.68; 95% CI, 0.51–0.91; P = .009), although the difference was not significant in the tamoxifen (HR = 0.67; 95% CI, 0.44–1.03; P = .067) and anastrozole (HR = 0.68; 95% CI, 0.45–1.02; P = .061) arms assessed separately. Zoledronic acid did not significantly affect risk of death (HR = 0.67; 95% CI, 0.41–1.07; P = .09). There was no difference in disease-free survival between patients on tamoxifen alone vs anastrozole alone (HR = 1.08; 95% CI, 0.81–1.44; P = .591), but overall survival was worse with anastrozole than with tamoxifen (46 vs 27 deaths; HR = 1.75; 95% CI, 1.08–2.83; P = .02). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. Bone pain was reported in 601 patients (33%; 349 patients on zoledronic acid vs 252 not on the drug), fatigue in 361 (20%; 192 vs 169), headache in 280 (16%; 147 vs 133), and arthralgia in 266 (15%; 145 vs 121). The authors concluded there were persistent benefits with zoledronic acid and support its addition to adjuvant endocrine therapy in premenopausal patients with early-stage breast cancer.

Postmenopausal women. For many years, tamoxifen has been the gold standard adjuvant endocrine therapy for postmenopausal women with hormone receptor–positive tumors. However, after third-generation aromatase inhibitors demonstrated superior activity in metastatic breast cancer, large randomized clinical trials were initiated in patients with early-stage breast cancer to evaluate these drugs compared with tamoxifen, in combination with tamoxifen, and sequentially with tamoxifen.

The AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial is one of the largest phase III studies of adjuvant bisphosphonates designed to determine whether treatment with zoledronic acid (ZA) added to standard adjuvant therapy improves disease-free survival in a broader range of patients with stage II/III breast cancer. A total of 3,360 patients were randomized to receive chemotherapy and/or endocrine therapy (ET) with or without 4 mg ZA intravenously every 3 to 4 weeks for six doses, then three doses monthly × 8 and six doses monthly × 5 to complete 5 years of treatment. With a median follow-up of 59 months, there have been 752 disease-free survival events (ZA = 377 vs control = 375; HR = 0.98; 95% CI, 0.85–1.13; P = .79).

The numbers of deaths-243 in the ZA group and 276 in the control group-were also similar, resulting in overall survival rates of 85.4% in the ZA group and 83.1% in the control group (adjusted HR = 0.85; 95% CI, 0.72–1.01; P = .07). Subgroup analysis of premenopausal, ER-positive patients (n = 1,185), approximating the ABCSG 12 population, also gave no indication of benefit from ZA. Serious adverse events were similar in both treatment arms. There were 17 confirmed cases of osteonecrosis of the jaw (cumulative incidence, 1.1%; 95% CI, 0.6–1.7; P < .001) and 9 suspected cases; there were no cases in the control group. Rates of other adverse effects were similar in the two study groups.

ATAC (Arimidex, Tamoxifen, Alone or in Combination) was the first large, randomized trial demonstrating the superiority of an aromatase inhibitor over tamoxifen in the adjuvant treatment of postmenopausal women with HR-positive breast cancer. After the initial ATAC analyses, the combination arm was closed because of low efficacy.

ATAC has shown that anastrozole (n = 3,125) is significantly more effective than tamoxifen (n = 3,116) in preventing recurrences and is better tolerated but associated with a higher risk of fractures on treatment. After treatment completion, fractures and serious adverse events continued to be collected in a blinded fashion.

At a median follow-up of 100 months, the ATAC trial showed significant improvement for anastrozole compared with tamoxifen for disease-free survival, time to recurrence, time to distant recurrence, and contralateral breast cancer. In the HR-positive population, the results showing this benefit with anastrozole were: disease-free survival (HR = 0.85; 95% CI, 0.76–0.94; P = .003), time to recurrence (HR = 0.76; 95% CI, 0.67–0.87; P = .0001); time to distant recurrence (HR = 0.84; 95% CI, 0.72–0.97; P = .022); and incidence of new contralateral breast cancer (HR = 0.6; 95% CI, 0.42–0.85; P = .004). Absolute differences for anastrozole vs tamoxifen increased over time, and hazard rates remained lower on anastrozole compared with tamoxifen after treatment completion. Breast cancer deaths were nonsignificantly fewer with anastrozole than with tamoxifen (351 vs 380 intent-to-treat; 246 vs 268 hormone receptor–positive), but there was no difference in overall survival (HR = 0.97, hormone receptor–positive). After treatment completion, fracture rates for anastrozole and tamoxifen were similar, and safety benefits were maintained. Myocardial infarction rates among patients were identical to those seen on or off treatment, and endometrial cancer rates remained lower for anastrozole than for tamoxifen off treatment. No new safety concerns were seen. These data confirm the long-term superior efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer.

Exploratory analysis from the ATAC trial investigated the impact of body mass index (BMI) on recurrence and the relative benefit of anastrozole vs tamoxifen according to baseline BMI. Overall, women with a high BMI (> 35 kg/m²) at baseline had more recurrences than women with a low BMI (< 23 kg/m²; adjusted HR = 1.39; 95% CI, 1.06–1.82; P [heterogeneity] = .03) and significantly more distant recurrences (adjusted HR = 1.46; 95% CI, 1.07–1.61; P [heterogeneity] = .01). The relative benefit of anastrozole vs tamoxifen was nonsignificantly better in thin women vs overweight women. Recurrence rates were lower for anastrozole than tamoxifen for all BMI quintiles. These results confirm the poorer prognosis of obese women with early-stage breast cancer and suggest that the relative efficacy of anastrozole compared with tamoxifen is greater in thin postmenopausal women. Requiring independent confirmation is the concept that higher doses or more complete inhibitors might be more effective in overweight women.

The use of an aromatase inhibitor as upfront adjuvant endocrine therapy for postmenopausal women with HR-positive breast cancer was confirmed in the Breast International Group (BIG) 1-98 trial. This study compared letrozole (Femara) with tamoxifen for 5 years as adjuvant endocrine therapy for this patient population. At a median follow-up time of 51 months for the monotherapy (non-crossover) arms, 352 disease-free survival events among 2,463 women receiving letrozole and 418 events among 2,459 women receiving tamoxifen were observed. This reflected an 18% reduction in the risk of an event (HR = 0.82; 95% CI, 0.71–0.95; P = .007). No predefined subsets showed differential benefit. Adverse events were similar to those noted in previous reports, with patients on tamoxifen experiencing more thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding, and those on letrozole experiencing more bone fractures, arthralgia, low-grade hypercholesterolemia, and cardiovascular events other than ischemia and cardiac failure. The present updated analysis yielded results that were similar to those from the previous primary analysis but more directly comparable with results from other trials of continuous therapy using a single endocrine agent. The BIG 1-98 trial was later modified to include a crossover for both agents.

Goss et al reported on a subset of women in the MA17 trial who were premenopausal at initial diagnosis and in whom subsequent menopause, prior to randomization, may have influenced their outcome on extended adjuvant letrozole. Women randomized to MA17 were divided into two groups: (1) premenopausal: women < 50 years of age who underwent bilateral oophorectomy when tamoxifen treatment was started or women < 50 years of age at the start of tamoxifen treatment who became amenorrheic during adjuvant chemotherapy or tamoxifen treatment; and (2) postmenopausal. Disease-free survival from time of randomization for women in these two groups was compared; 889 women were identified as premenopausal and 4,277 were identified as postmenopausal. The interaction between treatment and menopausal status was statistically significant for disease-free survival (P = .02), indicating that women diagnosed with premenopausal breast cancer had significantly greater benefit (HR = 0.25; 95% CI, 0.12–0.51) with letrozole treatment in terms of disease-free survival than those with postmenopausal status (HR = 0.69; 95% CI, 0.52–0.91). Letrozole was well tolerated in premenopausal women. These data indicate that women who are premenopausal at diagnosis but become postmenopausal any time before or during adjuvant tamoxifen should be considered for extended adjuvant therapy with letrozole.

At a median follow-up of 71 months after randomization in the BIG 1-98 study, the letrozole monotherapy arm was compared with the sequential-therapy arms. In terms of disease-free survival, there was no difference between the letrozole monotherapy, tamoxifen sequenced to letrozole, or letrozole-followed-by-tamoxifen arms. The letrozole-followed-by-tamoxifen arm had an HR of 0.96, with a 99% CI of 0.76–1.21, and the tamoxifen-followed-by-letrozole arm had an HR of 1.05, with a 99% CI of 0.84–1.32.

Other randomized trials have investigated the use of an aromatase inhibitor after tamoxifen. Two sequential strategies after tamoxifen were studied: (1) a switch to an aromatase inhibitor after 2 or 3 years of tamoxifen to complete a 5-year course of endocrine therapy, or (2) a switch to an aromatase inhibitor after 5 years of tamoxifen to complete 10 years of endocrine therapy, also called extended adjuvant therapy. With either strategy, use of an aromatase inhibitor after tamoxifen provided significant reduction in events (recurrence, contralateral breast cancer, or death).

In the IES (Intergroup Exemestane Study), 4,742 patients who had received 2 to 3 years of tamoxifen were randomized to receive either additional tamoxifen or a switch to exemestane to complete a 5-year course of endocrine therapy. After a median follow-up of 55.7 months, 809 events contributing to the analysis of disease-free survival had been reported (354 events in patients treated with exemestane, 455 in those who received tamoxifen); an unadjusted HR of 0.76 (95% CI, 0.66–0.88; P = .0001) was in favor of exemestane, with an absolute benefit of 3.3% (95% CI, 1.6–4.9) by the end of treatment (ie, 2.5 years after randomization). A total of 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group, with an unadjusted HR of 0.85 (95% CI, 0.71–1.02; P = .08) in the intent-to-treat group. When 122 patients with ER-negative disease were excluded, the HR was 0.83 (0.69–1; P = .05). Results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2 to 3 years on tamoxifen persist after treatment and translate into a modest improvement in overall survival.

Severe toxic events in patients on exemestane were rare, and toxicity profiles were generally similar to those previously reported for aromatase inhibitors. Patients who received exemestane reported fewer venous thromboembolic events than did those on tamoxifen. No other statistically significant differences in reported cardiovascular events (excluding venous thromboembolic events) were noted either on treatment or including the post-treatment period. Myocardial infarctions were rare and occurred in 31 (1.3%) exemestane-treated patients as compared with 19 (0.8%) tamoxifen-treated patients (P = .08). Any effect of treatment on the risk of myocardial infarction seemed largely restricted to patients with a history of hypertension. Musculoskeletal pain, carpal tunnel syndrome, joint stiffness, paresthesia, and arthralgia were reported more frequently in patients who switched to exemestane than in those who remained on tamoxifen. These effects emerged during the on-treatment period. In total, fractures occurred in 277 patients, but hip, spine, and wrist fractures were few. Including on-treatment and post-treatment follow-up, other types of fractures were more common in patients who switched to exemestane than in those on tamoxifen. Fewer clinically serious gynecologic events were reported in patients who switched to exemestane than in those on tamoxifen in the on-treatment period and throughout follow-up. The number of endometrial cancers did not differ significantly between the groups.

Three other randomized trials showed a benefit to switching to anastrozole after 2 to 3 years of tamoxifen treatment vs continued tamoxifen for a total of 5 years. The ITA (Italian Tamoxifen Arimidex) trial, with 448 patients enrolled and a median follow-up of 36 months, showed significant benefits in event-free survival (HR = 0.35; 95% CI, 0.20–0.63; P = .0002) and recurrence-free survival (HR = 0.35; 95% CI, 0.18–0.68; P = .001) in the women switched to anastrozole. There were 19 total events in the tamoxifen group (n = 225) and 10 in the anastrozole group (n = 223). The 3-year difference in recurrence-free survival was 5.8% (95% CI = 5.2–6.4). Significantly longer locoregional recurrence-free survival (HR = 0.15; 95% CI, 0.03–0.65; P = .003) was noted for the anastrozole group. The difference in distant recurrence-free survival approached statistical significance (HR = 0.49; 95% CI, 0.22–1.05; P = .06).

A combined analysis of the ABCSG Trial 8 and the ARNO (Arimidex-Nolvadex) 95 Trial, with 3,224 patients and a median follow-up of 28 months, investigated a similar strategy. It showed that sequential endocrine therapy with tamoxifen for 2 years followed by anastrozole for 3 years was superior to 5 years of tamoxifen in terms of event-free survival (HR = 0.6; 95% CI, 0.44–0.81; P = .0009) and distant recurrence–free survival (HR = 0.61; 95% CI, 0.42–0.87; P = .0067). No statistically significant difference in overall survival has emerged at this point (P = .16). Updated results from the ARNO 95 trial indicated that switching to anastrozole resulted in a significant reduction in the risk of disease recurrence (HR = 0.66; 95% CI, 0.44–1; P = .049) and improved overall survival.

In the MA17 trial, 5,187 postmenopausal women who had taken tamoxifen for 5 years were randomly assigned to receive either letrozole or placebo for an additional 5 years. At a median follow-up of 30 months, an updated analysis of MA17 was performed. It confirmed the results of the first interim analysis. There continued to be an improvement seen with letrozole in disease-free survival (HR = 0.58; 95% CI, 0.45–0.76; 2P < .001) and distant disease–free survival (HR = 0.60; 95% CI, 0.43–0.84; P = .002).

Bone effects. The third-generation aromatase inhibitors have been shown to reduce bone mineral density (BMD) when compared with tamoxifen in the advanced adjuvant and neoadjuvant settings in women with early breast cancer. Five-year results from the ATAC trial showed that patients treated with anastrozole had an annual decline in lumbar BMD of 2% during the first 2 years of treatment and of 1% in years 3 to 5.

The bone subprotocol of IBIS-II (International Breast Cancer Intervention Study-II) assessed changes in the BMD in postmenopausal women aged 40 to 70 years with a high risk of breast cancer who received anastrozole or placebo for 5 years. To date, of the 1,540 women in the prevention study, 613 have taken part in the bone subprotocol of the study. Of the 250 women whose lumbar spine and femoral neck BMD has been assessed at baseline and 1 year by dual-energy x-ray absorptiometry (DEXA) scans, 162 with normal BMD received only monitoring without bisphosphonate treatment, 59 osteopenic women were further randomized to receive either risedronate (Actonel) or placebo, and 29 osteoporotic women received treatment with risedronate. Data from this trial confirm the BMD losses observed with third-generation aromatase inhibitors in breast cancer patients, but it is also reassuring that BMD loss can be controlled if women receive DEXA scans at baseline and bisphosphonate treatment as needed along with aromatase inhibitors.

ABCSG-12, described previously in this chapter, is a randomized, open-label, phase III, four-arm trial comparing tamoxifen (20 mg/d orally) and goserelin (3.6 mg every 28 days SC) with or without zoledronic acid (4 mg IV every 6 months) vs anastrozole (1 mg/d PO) and goserelin with or without zoledronic acid for 3 years in premenopausal women with endocrine-responsive breast cancer. The median patient age at diagnosis was 44 years. In a BMD subprotocol, patients underwent serial BMD measurements at 0, 6, 12, 24, 36, and 60 months. Of 1,801 patients in the trial, 404 were prospectively included in a bone substudy. A total of 201 patients received adjuvant zoledronic acid together with their endocrine treatment, whereas 203 patients did not. After 3 years of treatment, patients who did not receive zoledronic acid showed a BMD loss of 11.3% as compared with baseline (P < .001). Bone loss was more pronounced if anastrozole was used in combination with goserelin as compared with tamoxifen (−13.6% vs −9%). At 60 months of follow-up (ie, 2 years after the completion of treatment), patients without zoledronic acid still showed impaired BMD as compared with baseline (−6.8%; P = .0005). In contrast, patients who received zoledronic acid showed unchanged BMD at 36 months (+ .3%; P = .85) and increased BMD at 60 months (+3.9%; P = .02).

Z-FAST (Zometa-Femara Adjuvant Synergy Trial) evaluated the efficacy and safety of zoledronic acid in preventing aromatase inhibitor–associated bone loss in postmenopausal women with early breast cancer who were receiving adjuvant letrozole therapy. A total of 602 patients with hormone receptor–positive early breast cancer starting letrozole were randomized to upfront zoledronic acid vs delayed zoledronic acid. The delayed group received zoledronic acid when either the post-baseline T-score decreased to below −2 or a clinical fracture occurred. All patients were treated with calcium and vitamin D.

The Z-FAST trial showed that the overall difference in the percentage change in BMD between the upfront and delayed zoledronic acid treatment groups, at both lumbar spine and total hip, progressively increased from baseline through 36 months. Therefore, administering zoledronic acid every 6 months for up to 36 months is effective in preventing bone loss associated with adjuvant aromatase inhibitor therapy in postmenopausal women with early breast cancer. At 36 months, the upfront zoledronic acid group (n = 189) showed a mean increase of 3.72% in lumbar spine BMD, whereas the delayed group (n = 188) showed a mean decrease of 2.95%, resulting in an absolute difference of 6.7% (P < .001). The upfront group (n = 189) showed a mean increase of 1.66% in total hip BMD, whereas the delayed group (n = 187) showed a mean decrease of 3.51%, resulting in an absolute difference of 5.2% (P < .001). The study was not designed to detect a significant difference in the fracture rate between treatment arms. Zoledronic acid was safe and well tolerated; no serious renal adverse events and no confirmed cases of osteonecrosis of the jaw were reported.

Recommendations. Guidelines from ASCO and the National Comprehensive Cancer Network (NCCN) highlight the appropriate use of aromatase inhibitors in postmenopausal women with hormone receptor-positive breast cancer. Aromatase inhibitors have a significant role in reduction of recurrence in early-stage breast cancer and should be included as part of the adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive disease. Using an aromatase inhibitor as upfront therapy or switching at some point after 2 to 3 years of tamoxifen is an acceptable strategy. Since the risk of breast cancer recurrence after completion of adjuvant endocrine therapy remains substantial, extended therapy with an aromatase inhibitor is another viable strategy for patients who are completing 5 years of tamoxifen. The extended use of adjuvant tamoxifen for 10 years rather than 5 years is also supported by two recently reported ongoing studies, the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial and the Adjuvant Tamoxifen - To Offer More? (aTTom) trial. Based on the results of ATLAS and aTTom, it would be reasonable in women who remain premenopausal after 5 years of adjuvant tamoxifen to have a discussion regarding the potential benefits of extending treatment to 10 years. Any such discussion should weigh the potential degree of benefit against the potential treatment side effects. In women who enter menopause during tamoxifen therapy, switching to an aromatase inhibitor or the use of an aromatase inhibitor upon completion of tamoxifen is another treatment option.

Sidebar: In the ATLAS trial, continuing tamoxifen to 10 years rather than stopping at 5 years produced a further reduction in recurrence and mortality, particularly after year 10, for women with ER-positive disease. Treatment allocation seemed to have no effect on breast cancer outcome among 1,248 women with ER-negative disease, and an intermediate effect among 4,800 women with unknown ER status. The cumulative risk of recurrence during years 5–14 was 21.4% for women allocated to continue versus 25.1% for controls; breast cancer mortality during years 5–14 was 12.2% for women allocated to continue versus 15% for controls (absolute mortality reduction 2.8%). Mortality without recurrence from causes other than breast cancer was not significantly affected by longer tamoxifen use. The cumulative risk of endometrial cancer during years 5–14 was 3.1% (mortality 0.4%) for women allocated to continue versus 1.6% (mortality 0.2%) for controls (absolute mortality increase 0.2%) (Davies C et al: Lancet 381:805–816, 2013).

In the aTTom study, which recruited 6,953 women, those randomized to continue tamoxifen had a significant reduction in breast cancer recurrence (RR 0.85; 95% CI, 0.76–0.95; P = .003), with an absolute difference of 4% at 15 years from randomization. There was a nonsignificant reduction in breast cancer mortality (RR 0.88; 95% CI, 0.77–1.01; P = .06), with an absolute difference of 3% at 15 years from randomization. There was no obvious effect on non–breast-cancer mortality (RR 0.95; 95% CI, 0.84–1.08; P = .4). There was a significant excess of endometrial cancer in those who continued on tamoxifen (2.9% versus 1.3%; RR 2.20; 95% CI, 1.31–2.34; P < .0001), as well as deaths from endometrial cancer (1.1% vs 0.6%; RR 1.83; 95% CI, 1.09–3.09; P = .02). (Gray RG et al: J Clin Oncol 31(suppl):Abstract 5, 2013).

In an analysis of the combined ATLAS and aTTom data (17,477 patients in total) there was a statistically significant reduction in breast cancer mortality (RR 0.85; 95% CI 0.77–0.94; P = .001) and improvement in overall survival (RR 0.91; 95% CI, 0.84–0.94; P = .008) with 10 years of tamoxifen.

Treatment of HER2-positive tumors

HER2-expressing breast cancers have been shown to have a worse outcome than their HER2-negative counterpart. Studies have demonstrated significant benefit from the addition of trastuzumab (Herceptin) to chemotherapy for both early-stage and metastatic breast cancer. In women with surgically resected breast cancer that overexpresses HER2, trastuzumab combined with chemotherapy improves disease-free and overall survival. Trastuzumab treatment decreases the risk of death by one-third (P = .015) in patients with HER2-positive breast cancer. Cardiac toxicity is a potential side effect of trastuzumab therapy and is more prevalent in patients previously treated with doxorubicin. Trastuzumab should not be administered concurrently with doxorubicin because of an increased risk of cardiac toxicity. New York Heart Association (NYHA) Class III or IV congestive heart failure or death from cardiac causes at 3 years was seen in 4.1% of patients treated with doxorubicin and trastuzumab in the B-31 trial and in 2.9% of patients in the N9831 trial.

Four major trials of trastuzumab in the adjuvant setting have been published. The NSABP B-31 and the North Central Cancer Treatment Group (NCCTG) N9831 trials were jointly analyzed to include a total of 3,351 HER2-positive patients, with a median follow-up of 2 years (2.4 years in trial B-31 and 1.5 years in trial N9831). Both trials included two similar treatment arms: adjuvant chemotherapy with AC followed by paclitaxel with or without weekly trastuzumab for 1 year. Although there were differences between the two studies, including a third treatment arm in N9831 (sequencing trastuzumab after paclitaxel) that was not included in the joint analysis, the common question addressed was the effect of adding trastuzumab to AC followed by paclitaxel.

There were 261 events in the control group and 133 events in the trastuzumab group. The HR for a first event in the trastuzumab group, as compared with the control group, was 0.48 (95% CI, 0.39–0.59; P < .001). The percentages of patients alive and disease-free at 3 years were 75.4% in the control group and 87.1% in the trastuzumab group (absolute difference, 11.8%; 95% CI, 8.1–15.4). At 4 years, the respective percentages were 67.1% and 85.3% (absolute difference: 18.2%; 95% CI, 12.7–23.7). Distant metastases were reported in 193 patients in the control group and 96 in the trastuzumab group. The HR for a first distant recurrence was 0.47 in the trastuzumab group as compared with the control group (95% CI, 0.37–0.61; (P < .001). At 3 years, 90.4% of women in the trastuzumab group were free of distant recurrence, as compared with 81.5% of women in the control group (absolute difference, 8.8%; 95% CI, 5.5–12.1); the respective rates at 4 years were 89.7% and 73.7% (absolute difference, 15.9%; 95% CI, 11.1–20.8). Both disease-free and overall survival were highly statistically significant for the trastuzumab-treated cohort.

Furthermore, there is an overall survival benefit to the addition of trastuzumab to chemotherapy. There were 62 deaths in the trastuzumab group, as compared with 92 deaths in the control group (HR = 0.67; 95% CI, 0.48–0.93; P = .015). The absolute survival rate at 3 years was 94.3% in the trastuzumab group and 91.7% in the control group (absolute difference, 2.5%; 95% CI, 0.1–5); at 4 years, the respective rates were 86.6% and 91% (absolute difference, 4.8%; 95% CI, 0.6–9). The principal adverse event associated with trastuzumab therapy among patients with prior exposure to anthracyclines is cardiac dysfunction.

In NSABP trial B-31, for patients initiated on trastuzumab therapy, the cumulative incidence of NYHA class III or IV CHF or death from cardiac causes at 3 years was 0.8% in the control group (4 patients had congestive heart failure, and 1 died of cardiac causes) and 4.1% in the trastuzumab group (31 patients had congestive heart failure). Of the 31 women in the trastuzumab group who had congestive heart failure, 27 have been followed for at least 6 months after the onset of heart failure, and only 1 reported persistent symptoms of heart failure at the most recent follow-up visit.

During treatment with paclitaxel alone or with trastuzumab, there was little imbalance between treatment groups in the incidence of any toxicity except for a higher incidence of left ventricular dysfunction in the trastuzumab group. Since the dramatic results are changing the way breast cancer is treated and many clinicians have adopted use of trastuzumab for similar groups of patients, the same monitoring used in these trials can be adopted in clinical practice to minimize cardiac toxicity. Additional toxicities were rare cases of interstitial pneumonitis, some of which appeared to be related to trastuzumab therapy. In trial B-31, four patients in the trastuzumab group had interstitial pneumonitis, and one of these patients died. In the N9831 trial, five patients in the trastuzumab group had grade 3+ pneumonitis or pulmonary infiltrates, and one of these patients died.

From May 2000 to April 2005 in the NCCTG N9831 trial, a total of 2,448 eligible women were enrolled for the comparison between Arm A: AC (doxorubicin [Adriamycin] plus cyclophosphamide) →T (paclitaxel [Taxol]) (n = 1,087) vs Arm B: AC→T→H (trastuzumab [Herceptin]) (n = 1,097). With 6-year median follow-up and 390 events, 5-year disease-free survival rates of 71.8% and 80.1% were seen for women in Arm A vs Arm B, respectively. Disease-free survival was significantly increased with trastuzumab added sequentially to paclitaxel (log-rank P < .001; arm B/arm A HR = 0.69; 95% CI, 0.57–0.85). Comparison of arm B (n = 954) and arm C (AC→T + H →H) (n = 949), with 6-year median follow-up and 313 events, revealed 5-year disease-free survival rates of 80.1% and 84.4% for Arms B and C, respectively. There was an increase in disease-free survival with concurrent trastuzumab and paclitaxel relative to sequential administration (Arm C/Arm B HR, 0.77; 99.9% CI, 0.53–1.11), but the P value (.02) did not cross the prespecified O’Brien-Fleming boundary (.00116) for the interim analysis. After adjusting for age, tumor size, number of positive nodes, and ER status, risk of disease progression was still found to be significantly decreased with the addition of trastuzumab following AC and then paclitaxel (P < .001; adjusted Arm B/Arm A HR, 0.67; 95% CI, 0.54–0.81). In summary, disease-free survival is significantly improved with the addition of 52 weeks of trastuzumab (sequentially or concurrently) to AC→T. There is a statistically significant 33% reduction in the risk of an event with the sequential addition of H following AC→T. There is a strong trend for a 25% reduction in the risk of an event with starting H concurrently with T rather than sequentially after T. Therefore, based on a positive risk/benefit ratio, the investigators recommend that trastuzumab be incorporated in a concurrent fashion with T chemotherapy.

The international HERA (HERceptin Adjuvant) trial had a different design. It assessed HER2-positive patients who received a variety of chemotherapeutic regimens and were randomized to observation vs 1 or 2 years of every-3-week trastuzumab. Results were reported for only the 1 year of trastuzumab arm vs the observation arm, which included 5,081 patients with 1-year medical follow-up. Similar to the previously mentioned joint analysis, there was a reduction in observed events (ie, recurrence of breast cancer in the contralateral breast, P < .001) in favor of trastuzumab. This represents an absolute benefit in terms of disease-free survival at 2 years of 8.4%. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs 37 with observation). Severe cardiotoxicity developed in 0.5% of the women who were treated with trastuzumab.

The incidence of cardiac adverse events was investigated in the HERA trial in patients treated with 1 year of trastuzumab; 1,698 patients were randomly assigned to observation and 1,703 randomly assigned to trastuzumab treatment; 94.1% of patients had been treated with anthracyclines. The incidence of discontinuation of trastuzumab because of cardiac disorders was 5.1%. At a median follow-up of 3.6 years, the incidence of cardiac endpoints remained low, though it was higher in the trastuzumab group than in the observation group (severe congestive heart failure, 0.8% vs 0%; confirmed significant left ventricular ejection fraction decreases, 3.6% vs 0.6%). In the trastuzumab group, 59 of 73 patients with a cardiac endpoint reached acute recovery; of these 59 patients, 52 were considered by the cardiac advisory board to have a favorable outcome from the cardiac endpoint. The cumulative incidence of any type of cardiac endpoint increases during the scheduled treatment period, but it remains relatively constant thereafter.

The BCIRG 006 study evaluated the benefit of adjuvant trastuzumab in 3,222 patients with HER2-positive breast cancer. Unique to this study was a nonanthracycline-containing regimen, which was expected to minimize the cardiotoxicity seen with trastuzumab (H) following anthracycline-based chemotherapy. There were three treatment arms: (1) AC (doxorubicin [Adriamycin] plus cyclophosphamide) followed by T (docetaxel [Taxotere]); (2) AC followed by TH (docetaxel plus trastuzumab [Herceptin]); and (3) TCH (docetaxel, carboplatin, trastuzumab).

At the latest analysis of BCIRG 006, a total of 656 disease-free survival events were observed (257 in the group receiving AC→T, 185 in the group receiving AC→T plus trastuzumab, and 214 in the group receiving TCH. During a median follow-up of 65 months, 348 patients had died. A significant benefit with respect to disease-free and overall survival was seen in both groups treated with trastuzumab-containing regimens, as compared with the group that received AC→T (standard therapy), which had a 5-year disease-free survival rate of 75% and an overall survival rate of 87%. For patients receiving AC→T plus trastuzumab, the 5-year rate of disease-free survival was 84% (HR for the comparison with AC→T, 0.64; P < .001), and the overall survival rate was 92% (HR = 0.63; P < .001). For patients receiving TCH, the 5-year rate of disease-free survival was 81% (HR = 0.75; P = .04), and the rate of overall survival was 91% (HR = 0.77; P = .04). In contrast, no significant difference in the rate of disease-free or overall survival was seen between the two trastuzumab-containing regimens. Benefit for trastuzumab was seen in both node-negative and node-positive patients; however, the benefit of trastuzumab was seen in node-positive patients at highest risk for recurrence (ie, those with at least four positive nodes), for whom the 5-year rate of disease-free survival was 73% in the group receiving AC→TH and 72% in the group receiving TCH, as compared with 61% in the group receiving AC→T (HR = 0.66; P = .002 for both comparisons). The incidence of congestive heart failure in the two trastuzumab-containing regimens was higher in the group receiving AC-T plus trastuzumab (2%) than in the AC→T group (0.7%) or the TCH group (0.4%); the incidence with AC→TH as compared with TCH was increased by a factor of 5. The difference in rates of congestive heart failure between the two trastuzumab-containing regimens significantly favored TCH over AC→TH (P < .001). Finally, acute leukemias developed in seven patients who were treated with anthracycline-based regimens and in one patient who was treated with TCH but subsequently received an anthracycline for the treatment of a B-cell lymphoma that occurred after her breast cancer.

There are unresolved questions about the adjuvant use of trastuzumab, including the optimal duration of treatment, and long-term safety in this setting. Studies are also ongoing to assess the benefit of additional and/or combined anti-HER2 therapy with trastuzumab in the adjuvant setting.

Sidebar: Pertuzumab in combination with trastuzumab and docetaxel for neoadjuvant use in HER2-positive early-stage breast cancer received accelerated approval by the US Food and Drug Administration (FDA) in October 2013. The primary study used to support this combination was a multicenter, randomized phase II trial, reported by Gianni et al, that evaluated four neoadjuvant regimens. Treatment-naive women with HER2-positive breast cancer were randomized prior to surgery (NeoSphere trial). A total of 417 eligible patients were randomly assigned (1:1:1:1) to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m², escalating, if tolerated, to 100 mg/m² every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response (pCR) in the breast. Results showed the highest pCR rate in the group treated with a combination of pertuzumab, trastuzumab, and docetaxel compared with the other three groups. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45.8% [95% CI = 36.1–55.7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29% [20.6–38.5]; P = .0141). Among women given pertuzumab plus docetaxel (group D), 23 of 96 (24% [15.8–33.7]) had a pathological complete response, as did 18 of 107 (16.8% [10.3–25.3]) given pertuzumab and trastuzumab (group C). The magnitude of improvement in the pCR rate was higher in patients with hormone receptor–negative cancers. A major adverse event with the addition of pertuzumab was the increased incidence of left ventricular cardiac dysfunction.

Sidebar: In a multicenter, open-label phase II study looking at the safety of pertuzumab in the neoadjuvant setting (TRYPHAENA study), patients with operable, locally advanced, or inflammatory breast cancer were randomized 1:1:1 to receive six neoadjuvant cycles q3wk (Arm A: 5-fluorouracil, epirubicin, cyclophosphamide [FEC] + H + P × 3 → docetaxel [T] + H + P × 3; Arm B: FEC × 3 → T + H + P × 3; Arm C: T + carboplatin + H [TCH] + P × 6). pCR was assessed at surgery and adjuvant therapy given to complete 1 year of H. A total of 225 patients were randomized. During neoadjuvant treatment, 2 patients (2.7%; Arm B) experienced symptomatic left ventricular systolic dysfunction (LVSD) and 11 patients (Arm A: 4 [5.6%]; Arm B: 4 [5.3%]; Arm C: 3 [3.9%]) had declines in left ventricular ejection fraction of ≥ 10% points from baseline to < 50%. Diarrhea was the most common adverse event. The combination of P with H and standard chemotherapy resulted in low rates of symptomatic LVSD (Schneeweiss NE et al: Ann Oncol 24:2278–2284, 2013).

Toxic effects of medical therapy

Chemotherapy. The most frequent acute toxicities are nausea/vomiting, alopecia, and hematologic side effects such as leukopenia and thrombocytopenia, as well as allergic reactions, cystitis, stomatitis, and nail/skin changes. Neutropenia, with its risk of infection, is a potentially life-threatening complication that requires prompt medical attention and broad-spectrum antibiotics until hematologic recovery occurs.

Other toxicities may include transient or permanent amenorrhea, infertility, early menopause, neuropathy, and leukemia. Amenorrhea is drug- and dose-related and is often permanent in women older than age 40. Recent evidence demonstrates that chemotherapy-induced ovarian failure in the adjuvant chemotherapy setting is associated with a high risk of rapid bone demineralization in the first 6 to 12 months after treatment. Thus, premenopausal women undergoing adjuvant chemotherapy must be closely evaluated to prevent the development of early osteoporosis. Cardiac failure, although rare, is potentially life-threatening and may be irreversible.

Endocrine therapy. Toxicities with tamoxifen or aromatase inhibitors include hot flashes, menstrual irregularities, vaginal discharge (tamoxifen), vaginal dryness (aromatase inhibitors), and weight gain. Thrombophlebitis and endometrial hyperplasia are more common with tamoxifen. Arthralgias, osteoporosis, and fractures are more common with aromatase inhibitors, although the incidence of hip fractures is low.

Follow-Up of Long-Term Survivors

There is no consensus among oncologists as to the appropriate and optimal follow-up routine for long-term breast cancer survivors. Recommendations for follow-up testing vary. The vast majority of relapses, both locoregional and distant, occur within the first 3 years. Surveillance is most intensive in the initial 5 years; thereafter, the frequency of follow-up visits and testing is reduced (Table 2).

Recommendations

History and physical examination

Surveillance methods include a detailed history and physical examination at each office visit. They are performed every 4 to 6 months for 5 years after completion of initial therapy, then annually thereafter. Patients at higher risk of recurrence or complications of treatment may require surveillance at shorter intervals. Patients who have been treated by mastectomy can be seen in the office annually after they have been disease-free for 5 years. Patients who were treated with breast-conserving surgery and radiotherapy can be followed at 6-month intervals until they have been disease-free for 6 to 8 years, after which time they can be assessed annually.

TABLE 2: Follow-up recommendations for asymptomatic long-term breast cancer survivors as per NCCN guidelines

Approximately 71% of breast cancer recurrences are detected by the patients themselves, and they will report a change in their symptoms when questioned carefully. In patients who are asymptomatic, physical examination will detect a recurrence in another 15%. Therefore, a patient’s complaint on history or a new finding on physical examination will lead to the detection of 86% of all recurrences.

Mammography

Mammography should be performed annually in all patients who have been treated for breast cancer. For patients who have undergone breast-conserving surgery, the first follow-up mammogram should be performed approximately 6 months after completion of radiation therapy. The risk of developing contralateral breast cancer is approximately 0.5% to 1% per year. In addition, approximately one-third of IBTRs in patients who have been treated by conservation surgery and radiotherapy are detected by mammography alone. As the time interval between the initial therapy and follow-up mammography increases, so does the likelihood that local breast recurrence will develop elsewhere in the breast rather than at the site of the initial primary lesion.

Chest x-ray

Routine chest radiographs detect between 2.3% and 19.5% of recurrences in asymptomatic patients and may be indicated on an annual basis.

Liver function tests

Liver function tests detect recurrences in relatively few asymptomatic patients, and their routine use has been questioned. However, these tests are relatively inexpensive, and it may not be unreasonable to obtain them annually.

Tumor markers

There is no evidence that tumor markers, such as carcinoembryonic assay, CA-15-3, and CA-57-29, provide an advantage in survival or palliation of recurrent disease in asymptomatic patients. Therefore, use of tumor markers to follow long-term breast cancer survivors is not recommended.

Bone scans

Postoperative bone scans are also not recommended in asymptomatic patients. In the NSABP B-09 trial, in which bone scans were regularly performed, occult disease was identified in only 0.4% of patients.

Liver and brain imaging

Imaging studies of the liver and brain are not indicated in asymptomatic patients. Position emission tomography scans are not routinely recommended. Their utility is primarily as an adjunct study, often to establish the extent of metastatic disease.

Pelvic examinations

Women with intact uteri who are taking tamoxifen should have yearly pelvic examinations because of their risk of tamoxifen-associated endometrial carcinoma, especially among postmenopausal women. The vast majority of women with tamoxifen-associated uterine carcinoma have early vaginal spotting, and any vaginal spotting should prompt rapid evaluation. However, since neither endometrial biopsy nor ultrasonography has demonstrated utility as a screening test in any population of women, routine use of these tests in asymptomatic women is not recommended.

Bone density

Premenopausal women who become permanently amenorrheic from adjuvant chemotherapy and postmenopausal women who are treated with an aromatase inhibitor are at increased risk for bone fracture from osteopenia/osteoporosis. These patients should undergo monitoring of bone health every 1 to 2 years.

Suggested Reading

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