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! 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.
Chemotherapy. Multiagent therapy with CMF (cyclophosphamide, methotrexate(Drug information on methotrexate), and fluorouracil(Drug information on fluorouracil) [5-FU]), CMFP (cyclophosphamide, methotrexate, 5-FU, and prednisone(Drug information on prednisone)), AC (Adriamycin [doxorubicin] and cyclophosphamide(Drug information on 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(Drug information on 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 National Cancer Institute of Canada (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(Drug information on 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(Drug information on 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. Study investigators concluded that weekly paclitaxel given after standard adjuvant AC improved disease-free and overall survival in women with breast cancer. As compared with standard therapy (ie, paclitaxel given every 3 weeks), the odds ratio for disease-free survival was 1.27 among those receiving weekly paclitaxel (P = .006), 1.23 among those receiving docetaxel every 3 weeks (P = .02), and 1.09 among those receiving weekly docetaxel (P = .29), with an odds ratio > 1 favoring the groups receiving experimental therapy. Weekly paclitaxel was also associated with improved overall survival (odds ratio = 1.32; P = .01). An exploratory analysis of a subgroup of patients with HER2-negative tumors found similar improvements in disease-free and overall survival with weekly paclitaxel, regardless of hormone-receptor expression. Grade 2, 3, or 4 neuropathy was more frequent with use of weekly paclitaxel (27%) than with paclitaxel given every 3 weeks (20%).
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(Drug information on 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 was 65% for the AC-treated cohort and 70% for the AC-plus-paclitaxel treatment group, and overall survival was 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(Drug information on 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). 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.
Adjuvant chemotherapy regimens in node-positive breast cancerIn 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(Drug information on 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 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(Drug information on 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) (Shulman LN et al: 33rd Annual San Antonio Breast Cancer Symposium, December 8-12, 2010, abstract S6-3).
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.
Sidebar: The EBCTCG recently published an update 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, estrogen receptor [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 cyclophosphamide, methotrexate, and fluorouracil (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 (relative risk [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+ 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 (Early Breast Cancer Trialists' Collaborative Group et al: Lancet 379:432–444, 2012).
Sidebar: NSABP B-38 is a phase III randomized trial designed to assess whether adjuvant dose-dense (DD) AC → paclitaxel (P) plus gemcitabine(Drug information on gemcitabine) (G, Gemzar) (with the regimen being A 60 mg/m2 and C 600 mg/m2 q2 wks × 4 followed by P 175 mg/m2 + G 2,000 mg/m2 q2 wks × 4) will be superior to DD AC→P (A 60 mg/m2 and C 600 mg/m2 q2 wks × 4 followed by P 175 mg/m2 q2 wks × 4), as well as to TAC (docetaxel [T, Taxotere] 75 mg/m2, doxorubicin [A, Adriamycin] 50 mg/m2, cyclophosphamide [C] 500 mg/m2 q3wks × 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 DD AC→PG group was 80.6% compared with 82.2% in DD AC→P group (HR = 1.1; P = .27) and 80.1 % (HR = 0.97; P = .71) in 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 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. 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 in 12%, 26%, 33%, respectively, and transfusions in 3.7%, 6.3%, 9.4%, respectively) (Swain S et al: J Clin Oncol 30[suppl]: abstr LBA1000, 2012).
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, ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) 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(Drug information on 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 (HR)-positive tumors is the subject of several ongoing clinical trials.
In the SOFT (Suppression of Ovarian Function Trial) study, following adjuvant chemotherapy, tamoxifen alone is being compared with tamoxifen plus ovarian function suppression/ablation vs ovarian function suppression plus an aromatase inhibitor (exemestane [Aromasin]). The role of ovarian suppression and aromatase inhibitors in this setting is being further investigated by the TEXT (Tamoxifen and Exemestane Trial) study, which is comparing ovarian suppression with the LHRH analog triptorelin(Drug information on triptorelin) (Trelstar) plus tamoxifen vs triptorelin plus exemestane(Drug information on exemestane).
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(Drug information on zoledronic acid) (Zometa) to adjuvant endocrine therapy significantly improved clinical outcomes beyond endocrine therapy alone. In Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12, a phase III randomized study of 1,800 premenopausal women with stage I-II disease undergoing ovarian suppression with goserelin, therapy with tamoxifen or anastrozole(Drug information on 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 5-year follow-up, disease-free survival was 98.2%. Investigators concluded that some premenopausal women with early breast cancer may achieve a strong treatment benefit without receiving chemotherapy.
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 (AI) 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+ 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 HR-positive), but there was no difference in overall survival (HR = 0.97, HR-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(Drug information on 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 I-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 to 1.21, and the tamoxifen-followed-by-letrozole arm had an HR of 1.05, with a 99% CI of 0.84 to 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 to 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 (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 recently were reported, indicating 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 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).
The Z-FAST (Zometa-Femara Adjuvant Synergy Trial) study 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 osteonecrosis of the jaw cases 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.
Several questions on the optimal use of aromatase inhibitors remain, and we must await completion of ongoing trials and/or development of new trials for answers. For instance, neither the optimal timing nor the duration of aromatase inhibitor therapy has been established, and the role of biomarkers in selecting optimal endocrine therapy remains controversial. Furthermore, long-term effects of aromatase therapy, including osteoporosis, have not yet been well characterized.
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 (CHF) 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 CHF, and 1 died of cardiac causes) and 4.1% in the trastuzumab group (31 patients had CHF). Of the 31 women in the trastuzumab group who had CHF, 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, 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 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 CHF, 0.8% vs 0%; confirmed significant left ventricular ejection fraction [LVEF] 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(Drug information on 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 CHF 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 CHF 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.
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 (AIs), 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.
