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After definitive local therapy is completed, it is important to plan for adjuvant systemic therapy. The use of chemotherapy, hormonal therapy, and targeted therapy before or after definitive local therapy has had a significant effect on the management and outcomes of breast cancers. All women with node-positive disease and a significant percentage of node-negative women with tumors that are hormone receptor negative or >1 cm in size benefit from chemotherapy. The choice of agents to be used for chemotherapy and hormonal therapy should be guided by the patient’s age, concomitant medical issues, positive or negative axillary lymph node involvement, and the status of the hormone receptors and HER2. Estimation of risk of recurrence and death should be assessed. Adjuvant! Online is a validated model that estimates DFS and OS based on age, comorbidity, tumor size and grade, hormone receptor status, and number of involved lymph nodes (34). Additionally, Oncotype Dx, Mammaprint, and other assays can help stratify risk for hormone receptor–positive, node-negative patients (35).
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Historical Perspective
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Studies in the 1960s and 1970s evaluated whether single-agent chemotherapy after local therapy had any benefit compared with observation alone. The single agents studied included cyclophosphamide, thiotepa, and melphalan. Most reports documented that single agents have modest or no effect on DFS. Subsequently, the focus shifted to polychemotherapy, with most trials evaluating variations of the three-drug regimen of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or similar anthracycline-containing regimens (36,37).
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These polychemotherapy regimens clearly showed a greater benefit in DFS and OS, but it was often unclear to clinicians which regimens were superior or equivalent. The Oxford Overview in 1998 helped clarity this issue by reviewing data from about 18,000 women in 47 trials that compared polychemotherapy or no chemotherapy, about 6,000 women in 11 trials that compared longer versus shorter polychemotherapy, and about 6,000 women in 11 trials of anthracycline-containing regimens versus CMF (38). The final interpretation concluded that adjuvant polychemotherapy for patients under 50 years of age resulted in an absolute improvement in 10-year survival of 7% to 11%, whereas the overall 10-year survival benefit was 2% to 3% for patients age 50 to 69 years.
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The 1998 Oxford Overview further demonstrated that anthracycline-containing regimens were superior to CMF. There was a statistically significant 12% reduction in risk of recurrence for anthracycline-containing regimens, a 2.7% decrease in mortality, and a 3.2% decrease in relapse. The information gained from this important systematic analysis began a shift toward administration of anthracycline-based regimens for adjuvant therapy of breast cancer.
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Official recommendations have been made based on the above data. These were presented at the National Institutes of Health Consensus Development Conference in 2000 and suggested an anthracycline be included as part of breast cancer adjuvant therapy. Several studies have investigated the role of HER2/neu in the positive response to anthracyclines. Both the Cancer and Leukemia Group B (CALGB) 8082 and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-11 studies have shown a benefit in DFS in patients who overexpressed HER2/neu and received anthracycline therapy (39,40).
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Evaluation of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) began in 1974 at the University of Texas MD Anderson Cancer Center (MDACC). For 1,107 women with node-positive disease, the results were favorable. The 10-year DFS was 72% for patients with 1 to 3 positive nodes, 55% for patients with 4 to 10 positive nodes, and 36% for those with >10 positive nodes (41).
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Investigations addressing accelerating the delivery of anthracyclines in a dose-dense manner are discussed later.
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The role of taxanes for breast cancer treatment was first investigated in metastatic disease. In randomized trials, paclitaxel and docetaxel improved response rates, duration of response, and OS (42). These positive results prompted their investigation in early-stage breast cancer. Several major studies contributed to the current use of taxanes in the adjuvant setting. The CALGB 9344 study evaluated the addition of paclitaxel to doxorubicin and cyclophosphamide (AC) and showed improvements versus placebo in DFS and OS at 69 months of 70% versus 65% and 80% versus 77%, respectively.
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The use of docetaxel was evaluated by the Breast Cancer International Research Group (BCIRG) 001 trial, which compared TAC (docetaxel plus AC) versus FAC for the adjuvant treatment of node-positive breast cancer. There was a significant difference in DFS and a trend in OS suggesting docetaxel could reduce the risk of recurrence of breast cancer in the adjuvant setting compared to the standard FAC regimen. However, with the higher rates of myelosuppression and febrile neutropenia seen with TAC, the use of this regimen requires extensive supportive care, including utilization of granulocyte colony-stimulating growth factor (43,44)
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The Eastern Cooperative Oncology Group (ECOG) E1199 trial attempted to define the more effective adjuvant taxane and the optimal schedule of administration (45). All patients received a standard dose and schedule of doxorubicin and cyclophosphamide and were randomized to receive paclitaxel (175 mg/m2) every 3 weeks for four cycles, paclitaxel (80 mg/m2) every week for 12 doses, docetaxel (100 mg/m2) every 3 weeks for four cycles, or docetaxel (35 mg/m2) every week for 12 doses. Weekly paclitaxel compared to every 3 weeks was better, with an odds ratio of 1.27 for DFS (P = .006) and 1.32 for OS (P = .01). No significant difference existed between paclitaxel and docetaxel. Paclitaxel every 3 weeks was no longer recommended after this trial (Fig. 27-1).
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The US09735 trial was a randomized study that compared four cycles of standard-dose AC with four cycles of docetaxel (75 mg/m2) and cyclophosphamide (TC) (600 mg/m2). Most patients (84.3%) were younger than 65 years old, and 48% were node negative. At a median follow-up of 7 years, there was a significant difference in DFS between TC and AC (81% vs 75%; hazard ratio, 0.74). Additionally, there was a significant difference in OS (87% vs 82%). Febrile neutropenia in older patients was 8% with TC and 4% with AC (46). This indicates that TC is a treatment option but should be used with caution in higher risk cancers given the large percentage of young node-negative patients in the study.
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The correlation between the endocrine system and breast cancer was first recognized more than 100 years ago. Beatson first described bilateral oophorectomy in treating inoperable cases of breast cancer (47). However, the true understanding of the biological mechanisms that cause estrogen to stimulate the growth of hormone receptor–positive tumors is more recent. Jensen first identified the ER and led subsequent cloning of ER and PR. This knowledge has enabled the development of multiple therapies. Many of these therapies have varying mechanisms of action, but all have the common goal of decreasing estrogen availability for hormone receptor–positive malignancies.
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In the late 1970s, tamoxifen was shown to be effective for the treatment of metastatic breast cancer. This form of treatment was well received, because data from trials showed that patients experienced fewer side effects than they did with traditional chemotherapy or with old fashioned endocrine therapy (high-dose estrogens, androgens, adrenalectomy, or hypophysectomy). The proven efficacy of tamoxifen in the metastatic setting enabled its study for adjuvant use.
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Tamoxifen was the first targeted drug to be used as an endocrine treatment for early breast cancer. An early placebo-controlled trial of tamoxifen as adjuvant therapy for early breast cancer, NATO, showed that 2 years of tamoxifen treatment reduced treatment failure at 21 months compared with control (14.2% vs 20.5%, respectively) (48). Since then, the efficacy of tamoxifen in the adjuvant treatment of primary breast cancer has been demonstrated repeatedly.
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Since tamoxifen became available over 35 years ago, a large number of trials investigated its efficacy and tolerability in the treatment of primary breast cancer. Although some individual trials are too small to justify firm conclusions, a meta-analysis has increased confidence in the effectiveness of tamoxifen in improving DFS and OS. Additionally, large cooperative group (NSABP B-14) and international randomized trials (Stockholm and Scottish trials) of tamoxifen versus placebo have demonstrated a clear benefit in DFS and OS (49,50,51).
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An overview of 55 trials studying adjuvant tamoxifen for 1, 2, or 5 years versus no treatment in patients with primary breast cancer showed that tamoxifen treatment produced highly significant benefits in terms of both recurrence of first events and mortality in the hormone receptor–positive population. The reductions in recurrence were 21%, 28%, and 50%, and the reductions in death rate were 14%, 18%, and 28% for 1, 2, and 5 years of tamoxifen treatment, respectively (P < .00001 for each). Tamoxifen treatment for 1, 2, and 5 years also reduced the incidence of contralateral breast cancer by 13%, 26%, and 47%, respectively (52). The benefits occurred almost exclusively in the hormone receptor–positive population. Tamoxifen improves the 10-year survival of women who have ER-positive or ER-unknown tumors.
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Further clarification of the optimal treatment duration of tamoxifen was investigated in two large trials: ATTOM (Adjuvant Tamoxifen Treatment Offers More) and ATLAS (Adjuvant Tamoxifen—Longer Against Shorter).
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The ATLAS trial enrolled women with early breast cancer who had completed 5 years of tamoxifen and randomly assigned the women to either continue tamoxifen for 10 years or stop at 5 years (53). The risk of recurrence during years 5 to 14 was 21.4% versus 25.1% for women who continued tamoxifen versus those who did not. Breast cancer mortality during years 5 to 14 for women who continued tamoxifen versus the control group was 12.2% and 15.0%, respectively. Pulmonary embolus and endometrial cancer occurred significantly more frequently in the extended tamoxifen group (Fig. 27-2).
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The ATTOM trial had a similar design to ATLAS (54). Women randomized to continue tamoxifen, versus those who stopped tamoxifen, had significantly less breast cancer recurrence (580 of 3,468 patients vs 672 of 3,485 patients, P = .003) and significantly decreased breast cancer mortality (392 of 3,468 patients vs 443 of 3,485 patients, P = .050). Combining the two trials strengthens the statistical significance of recurrence (P < .0001), breast cancer mortality (P = .002), and OS (P = .005).
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The addition of chemotherapy in intermediate- or high-risk groups is recommended (55). The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overviews in 1990 showed that chemotherapy in combination with tamoxifen had a beneficial effect in premenopausal women. The 1998 EBCTCG overview (52) showed that the benefits of chemotherapy combined with tamoxifen in patients with ER-positive disease occurred irrespective of age or menopausal status. The benefits of chemotherapy in terms of contralateral breast cancer and improved survival also occurred irrespective of age or menopausal status.
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It was not until recently that the appropriate sequence of chemotherapy and hormonal therapy was definitively documented. One difficulty was that evidence had existed in experimental systems that tamoxifen could antagonize the cytotoxic effects of particular chemotherapeutic agents.
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One particular study was designed to address the specific timing of tamoxifen therapy (56). Patients were divided among three groups: tamoxifen alone, FAC chemotherapy followed by tamoxifen, and concomitant FAC and tamoxifen. Patients were followed up for a median of 8.5 years. The estimated DFS was 67% in the sequential treatment group compared with 62% in the concurrent treatment group.
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Although tamoxifen has proven efficacy for the treatment of hormone receptor–positive breast cancer both alone and in combination with chemotherapy, its usefulness is in part curtailed by its partial estrogen agonist activity. The documented negative secondary effects of tamoxifen include an increased incidence of endometrial cancer, uterine sarcoma, and thromboembolic disease. Thus, there is great interest in exploring other endocrine therapies.
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In women whose ovarian function has ceased, the primary remaining estrogen source is the conversion of adrenal androgens to estrogens in peripheral tissues by the cytochrome P450 enzyme aromatase. Aromatase inhibitors (AIs) reduce the availability of estrogen by inhibiting the aromatase enzyme and are indicated for the treatment of breast cancer in postmenopausal women whose ovarian function has ceased (57). The first-generation AI aminoglutethimide became available 25 years ago but was limited by excessive toxicity. Newer generation selective AIs, including anastrozole, letrozole, fadrozole, and exemestane, are now available for the treatment of metastatic breast cancer and in the adjuvant setting. Common side effects of all AIs include hot flashes, osteoporosis, arthritis, and joint and muscle pains.
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Based on the antitumor activity of the third-generation AIs in the setting of metastatic disease, these drugs were evaluated in the adjuvant setting. The ATAC (Arimidex [anastrozole], Tamoxifen, Alone or in Combination) trial was a double-blind, multicenter study of postmenopausal women with invasive operable breast cancer who had completed primary therapy and were eligible for adjuvant treatment. They were randomized to tamoxifen, anastrozole, or a combination of the two (58). Time to recurrence was significantly longer with anastrozole versus tamoxifen in the overall population, with a larger benefit seen in the hormone receptor–positive population. A reduction in the incidence of contralateral breast cancers favored anastrozole, with statistical significance in the hormone receptor–positive population. The DFS estimates at 4 years were 86.9% and 84.5% for anastrozole and tamoxifen, respectively (59).
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Anastrozole was associated with significantly fewer withdrawals from treatment than tamoxifen (21.9% vs 26.0%, P = .0002) and significantly fewer withdrawals due to adverse events (7.8% vs 11.1%, P < .0001). Anastrozole also resulted in a lower incidence of hot flashes, vaginal discharge, and vaginal bleeding (P < .0001 for each), of ischemic cerebrovascular events and thromboembolic events (P = .0006 for each), including deep venous thrombosis (P = .02), and of endometrial cancer (P = .02). Tamoxifen resulted in a lower incidence of musculoskeletal disorders (including myalgias and arthralgias) and fractures (P < .0001 for both). The tolerability results in the updated analysis showed no major difference from those seen in the first analysis (60).
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A meta-analysis published in 2010 reviewed the use of AIs versus tamoxifen in postmenopausal women with ER-positive tumors. This review compared AIs as initial monotherapy to tamoxifen monotherapy or as a hormone switch after 2 to 3 years of tamoxifen for a total of 5 years. The conclusion was that AI therapy was associated with a lower rate of recurrence when used as an initial monotherapy or after 2 to 3 years of tamoxifen when compared to tamoxifen monotherapy (61).
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It is postulated that tamoxifen might stop being effective because breast cancer cells develop resistance to tamoxifen, dependence on tamoxifen, or great sensitivity to circulating estrogen. Consequently, the use AIs after tamoxifen was investigated. The MA-17 trial showed that the addition of letrozole after 5 years of tamoxifen resulted in a significant improvement in DFS (62).
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The Breast International Group (BIG) 1-98 trial compared letrozole versus tamoxifen in postmenopausal hormone receptor–positive women and was later amended to include two sequential strategies using letrozole either before or after tamoxifen for a total of 5 years. The results showed that upfront AI reduced the risk of recurrence and improved DFS better than upfront tamoxifen and better than either switching strategy (63,64).
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Another double-blind randomized trial investigated the use of exemestane to complete the 5 years of adjuvant endocrine treatment after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer (65). The results showed that exemestane improved the absolute benefit in DFS by 4.7% Thus, exemestane therapy following 2 to 3 years of tamoxifen significantly improved DFS.
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The above data for therapy beyond 5 years of tamoxifen is becoming more convincing, and AIs should be considered as extended therapy for high-risk postmenopausal patients. In general, outcomes with antiestrogen therapies are hindered by noncompliance, with 20% to 50% nonadherence rates. This is the same difficulty faced in other disease states, and a cancer diagnosis does not necessarily command optimal compliance with oral therapy. Many barriers influence compliance including medication cost, access to mail-order pharmacies, and a lack of understanding of the benefits of such medicine. A population-based study performed in British Columbia noted that adherence was still difficult even when these oral agents were given free of charge in a country with a national formulary system. Patients who are on oral medication should be followed regularly, and compliance should be reinforced as highly important, as shown in multiple studies, even when drug cost is not a barrier (66).
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Ovarian Ablation and Suppression
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The use of oophorectomy or ovarian irradiation to cause ovarian ablation is an efficacious method for treating early-stage disease in premenopausal patients. The 1996 meta-analysis by the EBCTCG demonstrated that for women below age 50 there was a distinct advantage in OS and DFS when they were treated with ovarian ablation versus no adjuvant therapy. In addition, the outcomes for these patients were similar to those who received the CMF regimen. The ZEBRA trial displayed similar results in hormone receptor–positive patients when comparing a luteinizing hormone–releasing hormone (LH-RH) analog, goserelin, to CMF (67).
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The TEXT and SOFT trials were designed to determine the value of the addition of adjuvant ovarian suppression to tamoxifen or exemestane in premenopausal hormone receptor–positive breast cancer patients. The patients were randomized to receive tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression for 5 years. In the total population, the addition of ovarian suppression to tamoxifen did not produce a significant benefit. However, in the high-risk cohort who received chemotherapy, ovarian suppression plus tamoxifen improved outcomes when compared to tamoxifen alone. The combined analysis also showed that 5-year DFS with adjuvant endocrine therapy with exemestane was significantly more effective than tamoxifen when ovarian suppression was added. Longer follow-up is needed to evaluate survival data (68,69).
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Ovarian suppression does come at significant costs because the adverse effects are not trivial. In these trials, women receiving ovarian suppression developed significant hot flashes, vaginal dryness, depression, and possible long-term health implications like hypertension, diabetes, and osteoporosis.
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HER2 Targeted Therapy
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Trastuzumab is a high-affinity humanized monoclonal antibody that recognizes the HER2/neu receptor and is a targeted therapeutic for tumors that overexpress this growth factor receptor. Trastuzumab has been evaluated extensively in the HER2/neu-overexpressing metastatic setting and has been shown to be effective as a single agent both before (70) and after chemotherap, (71) and in combination with multiple agents (72). One notable side effect has been a high rate of cardiotoxicity, particularly when trastuzumab is combined with anthracycline-based chemotherapy. This is due in part to overlapping toxicities and the long half-life of trastuzumab (up to 32 days). The toxicity rarely occurs in patients without a history of cardiac disease and not previously or simultaneously exposed to chemotherapy, especially anthracyclines (73).
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Therefore trastuzumab was an accepted and standard therapy for metastatic breast cancer that overexpresses HER2/neu. The safety and efficacy of trastuzumab-based therapy were then established for earlier stage breast cancer with the NSABP B-31 and North Central Cancer Treatment Group (NCCTG) N9831 trials, where patients received AC plus paclitaxel with the addition of trastuzumab versus placebo.
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The joint analysis of these trials showed an absolute difference in DFS of 12% at 3 years and a 33% reduction in the risk of death (P = .015) (74). An updated analysis with a mean time of 8.4 years on study showed a 37% relative improvement in OS (95% confidence interval [CI], 0.54-0.73; P < .001) and an increase in 10-year OS from 75.2% to 84% (75).
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The BCIRG 006 trial was designed to evaluate the efficacy and safety of docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH) (32). Patients were randomly assigned to standard doses of doxorubicin and cyclophosphamide followed by docetaxel (100 mg/m2) every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-TH), or docetaxel (75 mg/m2) and carboplatin (area under the curve [AUC] 6 mg/mL/min) plus 52 weeks of trastuzumab (TCH). At a median follow-up of 65 months, the 5-year estimated DFS was 75% for patients receiving AC-T, 84% with AC-T, and 81% with TCH. Estimated rates of OS were 87%, 92%, and 91%, respectively. All trastuzumab regimens were statistically superior for DFS and OS to nontrastuzumab regimens. There were significant difference in both DFS and OS between AC-TH and TCH. Rates of cardiac dysfunction were significantly higher with AC-TH compared with TCH (P = .001).
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The PHARE trial attempted to answer the appropriate duration for trastuzumab by comparing 6 versus 12 months of adjuvant therapy. After a median follow-up of 42.5 months, the 2-year DFS rate was 93.8% for the 12-month group versus 91.1% for the 6-month group, with a hazard ratio of 1.28 (95% CI, 1.05-1.56). These results support continuing with the standard of care of 1 year of trastuzumab (76).
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The HERA trial was also designed to answer the question regarding the optimal duration of trastuzumab. Patients were assigned to observation or 1 or 2 years of trastuzumab. Patients were allowed a variety of standard neoadjuvant or adjuvant chemotherapies and had node-positive or high-risk node-negative disease. A recent update includes mature data from patients receiving trastuzumab for 2 years. Comparing 1 year of trastuzumab versus observation revealed a hazard ratio of 0.76 (95% CI, 0.67-0.86; P < .0001) for DFS and 0.76 (95% CI, 0.65-0.88; P = .0005) for OS despite significant (52%) crossover. No significant differences in DFS or OS were noted between the 1- and 2-year groups (31).