I am approaching the end of my general surgery residency and trying to decide on a sub-specialty going forward. Over the past 2 years I have found myself drawn to the field of breast surgery, in large part due to the large breadth of research being done in the field. Research in breast cancer has pioneered many of the current oncologic concepts and therapy that exist today for many cancers beyond breast cancer. However, we are far from having all the answers and are constantly trying to further our understanding of the disease. Additionally, patient desires, emotions, and fears play a large factor, oftentimes making treatment decisions more of an art than a science. A common theme that seems to emerge from much of the breast cancer research is the balance of risks and benefits, coupled with the patient’s concerns and preferences. Decisions are required at almost every stage of breast cancer treatment: Lumpectomy or mastectomy…or even bilateral mastectomies? Radiation or no radiation? Chemotherapy or no chemotherapy? Adjuvant endocrine therapy or no endocrine therapy? And now, another big question to be answered- how long should we continue that endocrine therapy?
While several previous studies have examined prolonged effects of extended adjuvant endocrine therapy, no study had specifically looked at extended aromatase-inhibitor therapy or duration of adjuvant endocrine therapy of more than 10 years. An recent article in NEJM by Goss et al. addresses this question with a double-blind, randomized, placebo-controlled trial. This study, the MA.17R trial, enrolled postmenopausal women with primary breast cancer who had previously received about 5 years of an adjuvant aromatase inhibitor, preceded by tamoxifen in the majority of women, and assigned them to either daily letrozole or placebo for 5 years. Randomization was stratified based on several potential confounding factors: lymph-node status, prior receipt of adjuvant chemotherapy, the interval between the last dose of aromatase inhibitor and randomization, and the duration of prior receipt of tamoxifen. The primary end point was disease-free survival, including any recurrence of breast cancer (local, regional, or metastatic) or the development of a new primary breast cancer.
1918 patients were randomized with 959 patients in each group. Baseline characteristics of age, stage, and prior adjuvant endocrine therapy were similar between the two groups. Overall daily adherence (assessed with questionnaires) was low, but similar between the two groups, 62.5% among those receiving letrozole and 62.3% among those receiving placebo. 5 year disease-free survival was 95% (95% confidence interval [CI], 93 to 96) in the letrozole group and 91% (95% CI, 89 to 93) in the placebo group. The hazard ratio for disease recurrence or the occurrence of contralateral breast cancer comparing letrozole to placebo was 0.66 (95% CI, 0.48 to 0.91; P=0.01). The results remained similar when looking at the previously specified stratification groups. There was no significant difference in overall survival between the 2 groups or when analyzing any of the prespecified subgroups. Extended letrozole therapy significantly reduced the annual incidence rate of contralateral breast cancer with an annual incidence rate of 0.21% in the letrozole group and 0.49% in the placebo group (P =0.007), with a hazard ratio of 0.42 (95% CI, 0.22 to 0.81).
Few women in both groups discontinued assigned treatment due to toxic effects (5.4% in the letrozole group vs. 3.7% in the placebo group) and non-bone related toxicity was low in both groups. However, there was a higher rate of bone fracture and new onset osteoporosis in the letrozole group as well as a higher mean loss of bone mineral density in the hip. The placebo group actually had an increase in bone mineral density in the hip and spine likely due to discontinuation of their prior endocrine therapy and concurrent use of bone-protecting medications, rates of which were high across both groups. Overall quality of life was similar for both groups.
While results of this study appear promising, there are some limitations to the interpretation. In the accompanying editorial, Drs. Chlebowski and Budoffoint out that the “the favorable side-effect profile in the MA.17R trial may be due to the self-selection of women who had limited side effects during previous treatment with letrozole.” Additionally, the greatest effect seems to be in preventing contralateral breast cancers as opposed to reducing recurrences and there was no effect on overall survival which Chlebowski and Budoff says “should not be surprising” as “the participants, who in most cases underwent randomization approximately 10 years after the time of diagnosis, have passed the peak risk of recurrence and a considerable proportion of their remaining risk as well.” Regardless of these caveats, the results of this study have potentially large implications for changing treatment in post-menopausal breast cancer. In the end, this will likely be another story of shared decision making as, per the editorialists, “oncologists and patients with breast cancer weigh the risks and benefits of the use of long-term adjuvant endocrine therapy.”
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Andrea Merrill, MD
Andrea was a 2015-2016 NEJM Group Editorial Fellow. She is currently in the middle of her General Surgery residency at Massachusetts General Hospital and is also conducting research focusing on improvements in breast cancer surgery. She plans to pursue a fellowship in Surgical Oncology at the completion of her residency.