Leisha A Emens
Assistant Professor of Oncology
Nancy E Davidson
Professor of Oncology
Director, Breast Cancer Research Program
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
The Johns Hopkins University School of Medicine
Tamoxifen, a selective oestrogen receptor modulator (SERM) that can exert both an antagonistic and a partial agonistic effect on the oestrogen receptor (ER),(1) has been the gold standard for adjuvant hormonal manipulation in steroid hormone-receptor-positive breast cancer. The meta-analyses of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) revealed that 5 years of tamoxifen therapy after primary breast cancer surgery results in a 45% (standard deviation [SD] = 8%) relative reduction in disease recurrence and a 32% (SD = 10%) relative reduction in breast cancer-related deaths.(2) In addition to primary therapeutic resistance, an important limitation of tamoxifen therapy is the emergence of secondary therapeutic resistance, where the agonist activity of the drug comes to predominate and may perhaps promote the growth of breast tumour cells.(3–11) This is thought to potentially underlie the observation that women who receive more than 5 years of adjuvant tamoxifen therapy may have worse outcomes than those who receive 5 years only.(12–15)
Accordingly, newer targeted hormonal agents for breast cancer therapy have been developed. These include the third-generation aromatase (oestrogen synthetase) inhibitors anastrozole, letrozole and exemestane (which inhibit the peripheral conversion of androgens to oestrogen) and the selective oestrogen receptor destroyer (SERD) fulvestrant. While the role of SERDs in breast cancer management is not yet defined, aromatase inhibitors (AIs) have been widely adopted as first- or second-line endocrine therapy for postmenopausal women with hormone- dependent metastatic breast cancer.(16) Their favourable therapeutic index in metastatic disease has led to strong interest in extending their use to adjuvant therapy. Multiple clinical trials examining the potency of AIs alone and in sequence with tamoxifen are ongoing; two major studies have recently been published.
Aromatase inhibitors instead of tamoxifen
The first randomised evaluation of third-generation AIs as adjuvant therapy for postmenopausal women with early breast cancer was the Arimidex or Tamoxifen Alone or in Combination (ATAC) trial, which directly compared 5 years of anastrozole (1mg daily), tamoxifen (20mg daily) or both in 9,366 women with biopsy-proven, operable breast cancer.(17) In this study, 84% of women had tumours that expressed the ER and/or the progesterone receptor (PR). In the most recent update analysis, at a median follow-up of 47 months the 4-year disease-free survivals for anastrozole and tamoxifen were 86.9% and 84.5%, respectively, with a superior hazard ratio (HR) for anastrozole over tamoxifen (0.86, 95% CI 0.76–0.99, p=0.03).(18) No unexpected toxicities emerged, with musculoskeletal side-effects and bone fractures predominating with anastrozole and hot flashes, vaginal bleeding and/or discharge, vascular events and endometrial cancers associated with tamoxifen. Based on these data, the FDA approved the use of anastrozole for the adjuvant therapy of primary operable hormone- receptor-positive breast cancer in postmenopausal women.
Aromatase inhibitors in sequence with tamoxifen
The ATAC trial also assessed concomitant adjuvant tamoxifen and anastrozole therapy for hormone-dependent early breast cancer. Because there was no additional benefit with tamoxifen plus an AI, that arm of the study was discontinued.(17,18) The NCIC CTG MA-17 trial examined the role of sequential adjuvant hormonal therapy with approximately 5 years of tamoxifen followed by an additional 5 years of letrozole (2.5mg daily).(19) The trial was a double-blind, placebo-controlled, randomised, international study of 5,187 postmenopausal women with a history of histologically confirmed primary breast cancer that expressed ER, PR or both. All participants had previous tamoxifen therapy lasting 4.5–6 years, had been off tamoxifen therapy for 3 months or less and had no evidence of metastatic disease. At a median follow-up of 2.4 years, there were 207 events (local or distant recurrence, or a new contralateral breast cancer), 75 in the letrozole group and 132 in the placebo group. Corresponding estimated 4-year disease-free survival rates were 93% and 87%, respectively (p <-0.001). These data translate into a HR of 0.57 (95% CI 0.43–0.75, p=0.00008); the benefit was seen in women with either node-negative or node-positive disease. The unexpectedly early emergence of a significant benefit associated with letrozole led the data and safety monitoring committee to recommend unblinding the study and offering letrozole to women on the placebo arm.
Adjuvant AI therapy
These two trials support a role for adjuvant AI therapy in the management of early breast cancer. However, many important questions remain. Neither study has yet demonstrated a statistically significant overall survival benefit with either primary or sequential adjuvant AI therapy. As the follow-up of both studies is relatively short, few data are available on the long-term adverse effects of AI therapy. An accurate assessment of the risk/benefit ratio of adjuvant AI therapy is thus difficult. Indeed, a technology assessment panel convened by the American Society of Clinical Oncology in 2002 and 2003 concluded that the ATAC data are too premature to recommend an AI as first-line adjuvant hormonal therapy.(20) Moreover, the optimal duration of therapy with letrozole after tamoxifen is not clear, since participants in NCIC CTG MA-17 received AI therapy for only 2–3 years. Additionally, tamoxifen has a widely recognised carry-over effect, where there continues to be a 30% benefit during the 5-year period after tamoxifen therapy is discontinued.(21) Together, these data suggest that the appropriate integration and duration of endocrine therapies for the optimal management of early breast cancer is likely to be complex. Multiple international trials are ongoing that should provide additional data.(16)
In the meantime, what is the practising oncologist to do? It is reasonable to offer 5 years of tamoxifen as first-line hormonal therapy, reserving the use of first-line anastrozole therapy for women with a contraindication to tamoxifen therapy or those who develop breast cancer while taking a SERM (tamoxifen or raloxifene). After 5 years of tamoxifen, it is reasonable to offer 5 years of additional therapy with letrozole, realising that the true risks and benefits are not well defined. There are currently no data addressing the question of tamoxifen after 5 years of primary AI therapy. Regardless, it is clear that the use of AIs for early breast cancer is here to stay, and that new and maturing data will continue to redefine their role in adjuvant breast cancer therapy.
This work was supported in part by NIH K23 CA098498-01, DAMD 17-01-1-0281, the Maryland Cigarette Restitution Fund, the AVON Foundation and NIH P50 CA88843.
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