Although women with early-stage hormone receptor–positive breast cancer have low recurrence rates initially, they have a constant and unrelenting risk of relapse that extends up to 15 years despite the use of adjuvant therapy. Increasing evidence supports the use of extended endocrine therapy with either tamoxifen or an aromatase inhibitor (AI) after 5 years of initial adjuvant tamoxifen to reduce breast cancer recurrence and mortality. However, the optimal total duration of AI therapy, as well as the ideal timing of sequencing from tamoxifen to an AI, is still unclear. Potential strategies differ depending on a woman’s menopausal status at the time of her initial diagnosis. Individual patient clinical factors and preferences can help with decision making until further data emerge on prolonged AI use and on potential biomarkers that can be used to tailor adjuvant endocrine treatment.
Existing Guidelines for Adjuvant Endocrine Therapy in Women Who Are Postmenopausal at Diagnosis
According to current guidelines, many options are available for women who are postmenopausal at diagnosis. The 2010 ASCO guidelines recommend that all postmenopausal women consider taking an AI at some point during their treatment because of the small but real (< 5%) absolute reduction in risk of recurrence with their use compared with tamoxifen; however, the ASCO guidelines acknowledge that there is no overall survival benefit for AIs over tamoxifen. They advocate treatment with AIs as either initial adjuvant therapy or after 2 to 3 years of tamoxifen, stating that “switching at 2–3 years (sequential) is recommended, but switching at 5 years is also supported by available data (extended).” The NCCN guidelines, by comparison, list as equivalent options for postmenopausal women the use of AIs as initial adjuvant therapy, as sequential therapy following 2 to 3 years of tamoxifen, and as extended therapy following 4.5 to 6 years of tamoxifen. They also state that the use of tamoxifen alone for 5 to 10 years in women who are postmenopausal at diagnosis should be reserved for those who decline or have a contraindication to AIs. In contrast, the St. Gallen panelists “strongly believed that some postmenopausal women could be treated with tamoxifen alone”—although they strongly supported starting therapy with an AI in high-risk women. All guidelines are in agreement that there is no definitive evidence at this time to support offering more than 5 years of AI therapy, although the St. Gallen panel was divided on this issue. Further, all the guidelines acknowledge that there are no data comparing an AI for 5 years, an AI for 5 years following tamoxifen for 5 years, and 10 years of tamoxifen.
Several factors drive the strong recommendation to incorporate at least some AI therapy into the adjuvant treatment of women who are postmenopausal at diagnosis. First, the majority of the sequential AI trials and all the extended adjuvant trials randomized women after completion of 2 to 5 years of tamoxifen, and thus, in effect, excluded patients with early recurrence. This represents a potentially important difference in study patient populations, compared with the primary adjuvant trials of upfront AI use vs tamoxifen. Second, compared with 5 years of tamoxifen, adjuvant AI use (primary/sequential/extended use) improves DFS and lowers the risks of breast cancer recurrence (distant and locoregional) and contralateral breast cancer.
The MA.17/BIG 1-97 trial (Table 2) was a double-blind placebo-controlled trial designed to test the effectiveness of 5 years of letrozole in ER-positive breast cancer patients who had completed 4 to 6 years of adjuvant tamoxifen therapy. At the time of initial analysis for this study—at a median follow-up of 2.4 years—extended adjuvant letrozole treatment after tamoxifen had significantly reduced recurrence risk (HR, 0.57; 95% CI, 0.43–0.75; P = .00008) for patients with early-stage breast cancer. This led to an early unblinding of the study, followed by an extremely high crossover rate from the placebo to the letrozole group of more than 60%. Despite this, an exploratory analysis adjusting for the treatment crossover still showed both a DFS and an overall survival benefit for letrozole compared with placebo.
Unlike the extended tamoxifen trials in which no signal emerged of specific patient subgroups that would benefit from extended tamoxifen, some of the adjuvant AI trials have provided clues about patient subsets that could benefit from prolonged therapy. Interestingly, in the MA.17/BIG 1-97 trial, although all women were postmenopausal at randomization to letrozole or placebo after completion of tamoxifen, a minority of participants (877 of 4,289 patients) were premenopausal at the time of their primary diagnosis. In this small group of premenopausal women who became postmenopausal while receiving tamoxifen, the benefit of extended letrozole therapy seemed more pronounced than in the women who were postmenopausal at diagnosis.
Other AI trials were prematurely closed to accrual when the initial results of the MA.17/BIG 1-97 trial were reported. One of these studies, the NSABP B-33 trial, was a double-blind trial of exemestane vs placebo as extended adjuvant therapy for postmenopausal women who were disease-free after 5 years of adjuvant tamoxifen. Subset analysis of NSABP B-33 indicated that patients who were less than 60 years of age, had larger tumors, had positive lymph nodes, or had prior adjuvant chemotherapy seemed to benefit more from extended adjuvant therapy. Thus, choosing to use extended adjuvant AI dosing strategies in higher-risk patients seems prudent. Certainly this seems wise for high-risk women who start on tamoxifen at a premenopausal age and become postmenopausal during treatment. However, women who are postmenopausal at diagnosis and have high-risk features present a conundrum, because all guidelines advocate starting with a primary AI in these patients, and there are not yet data to support more than 5 years of AI therapy.
In contrast, the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 6a trial (see Table 2) showed that extended anastrozole after tamoxifen reduced total recurrences (HR, 0.62; 95% CI, 0.40–0.96; P = .031) and distant recurrences (HR, 0.53; 95% CI, 0.29–0.96; P = .034). Much as in the tamoxifen trials, subgroup analysis showed that the benefit seemed independent of age, nodal status, and ER positivity. However, there did seem to be a lack of benefit with extended AI therapy in the obese women who participated in this trial compared with the normal-weight women.
Trials of Longer-Duration AI Therapy
At this time, there is no evidence to support prescribing more than 5 years of AI therapy. Results are eagerly awaited from a number of trials, now closed to enrollment, that are examining this issue in women with early-stage breast cancer (Table 3). The MA.17R trial randomly assigned women to treatment with letrozole or to placebo after completion of 5 years of an adjuvant AI (either as initial therapy or after tamoxifen, including in women who participated in the MA.17 study). Similarly, the NSABP B-42 trial randomized patients who had completed 5 years of hormonal therapy (either with an AI, or sequential therapy of tamoxifen followed by an AI) to 5 years of letrozole or placebo. The ABCSG-16/SALSA (Secondary Adjuvant Long-Term Study With Arimidex) study randomly assigned postmenopausal women who had had 4 to 6 years of prior endocrine therapy to extended adjuvant treatment with anastrozole for either 2 years or 5 years. The Study of Letrozole Extension (SOLE)/International Breast Cancer Study Group (IBCSG) 35-07 randomly assigned women who had completed 4 to 6 years of any prior endocrine therapy to receive 5 years of letrozole dosed either continuously or intermittently. The Different Durations of Anastrozole and Tamoxifen (DATA) trial randomly assigned women to either 5 years or 3 years of anastrozole after 5 years of any endocrine therapy. Finally, the Letrozole Adjuvant Therapy Duration (LEAD) study randomly assigned women to treatment with letrozole for either 5 years or 2 to 3 years—after 2 to 3 years of tamoxifen. In aggregate, these trials should provide guidance about longer durations of AI therapy.
Biomarkers of Late Recurrence at Diagnosis or of Hormone Resistance
The use of biomarkers that may be able to predict late recurrence at diagnosis, and the emergence of biomarkers of hormone resistance that develops over time, will hopefully assist with clinical decision making in the future. One assay that has been shown to predict late recurrence in ER-positive patients is the Breast Cancer Index (BCI). BCI is a multi-gene test that includes the two-gene ratio HOXB13:IL17BR (H/I) and the Molecular Grade Index (MGI), which was originally validated in a tamoxifen-treated cohort from Stockholm and was confirmed in a different multi-institutional cohort from the United States. A low BCI score was associated with high distant recurrence–free survival (DRFS) at 0–5 years and at > 5 years, and thus seemed to have prognostic value for late recurrence. Additionally, a recent study evaluated the ability of multi-gene assays to predict early and late recurrence using archival tumor blocks from the TransATAC (translational arm of the Arimidex, Tamoxifen, Alone or in Combination trial) tissue bank for postmenopausal women with ER-positive breast cancer, in which a 21-gene recurrence score (RS) and immunohistochemical (IHC4) values had been previously ascertained. Although all of the assays were prognostic for early distant recurrence, only the BCI linear model (BCI-L) was significantly prognostic for risk of late distant recurrence (BCI-L HR, 1.95; 95% CI, 1.22–3.14; P = .0048; 21-gene RS HR, 1.13; 95% CI, 0.82–1.56; P = .47; IHC4 HR, 1.30; 95% CI, 0.88–1.94; P = .20). These findings of a prognostic value of BCI score for late recurrence in samples from a large randomized study are compelling and warrant further investigations into the test’s potential for prediction of extended adjuvant treatment benefit.
New evidence now supports improved recurrence and breast cancer mortality outcomes with continued tamoxifen for up to 10 years in women of any age, and such long-duration therapy is especially important for women who remain premenopausal after their first 5 years of tamoxifen. If women are found to be postmenopausal after the first 5 years of tamoxifen, one can recommend an additional 5 years of tamoxifen or 5 years of an AI, depending on patient preference, compliance, and tolerance. For postmenopausal women, there is no difference in overall survival between tamoxifen and AI therapy, and the absolute reduction in recurrence is small (< 5%). It is therefore advisable to try to treat all postmenopausal patients with an AI at some point during their adjuvant therapy, with careful attention to toxicity and baseline risk. Data from trials looking at prolonged AI therapy beyond 5 years are needed to determine the optimal total duration of AI therapy. Current strategies for postmenopausal women include initial adjuvant AI therapy, sequential AI therapy after 2 to 3 years of tamoxifen, or extended AI use after 5 years of tamoxifen. Patient risk factors, compliance, toxicity, medical comorbidities, and patient preference can be considered in deciding among these strategies.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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