Aromatase-Inhibitors: Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years

Original Article
Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years

Paul E. Goss, M.D., Ph.D., James N. Ingle, M.D., Kathleen I. Pritchard, M.D., Nicholas J. Robert, M.D., Hyman Muss, M.D., Julie Gralow, M.D., Karen Gelmon, M.D., Tim Whelan, B.M., B.Ch., Kathrin Strasser-Weippl, M.D., Sheldon Rubin, M.D., Keren Sturtz, M.D., Antonio C. Wolff, M.D., Eric Winer, M.D., Clifford Hudis, M.D., Alison Stopeck, M.D., J. Thaddeus Beck, M.D., Judith S. Kaur, M.D., Kate Whelan, M.Sc., Dongsheng Tu, Ph.D., and Wendy R. Parulekar, M.D.

N Engl J Med 2016; 375:209-219July 21, 2016DOI: 10.1056/NEJMoa1604700

Background

Treatment with an aromatase inhibitor for 5 years as up-front monotherapy or after tamoxifen therapy is the treatment of choice for hormone-receptor–positive early breast cancer in postmenopausal women. Extending treatment with an aromatase inhibitor to 10 years may further reduce the risk of breast-cancer recurrence.

Methods

We conducted a double-blind, placebo-controlled trial to assess the effect of the extended use of letrozole for an additional 5 years. Our primary end point was disease-free survival.

Results

We enrolled 1918 women. After a median follow-up of 6.3 years, there were 165 events involving disease recurrence or the occurrence of contralateral breast cancer (67 with letrozole and 98 with placebo) and 200 deaths (100 in each group). The 5-year disease-free survival rate was 95% (95% confidence interval [CI], 93 to 96) with letrozole and 91% (95% CI; 89 to 93) with placebo (hazard ratio for disease recurrence or the occurrence of contralateral breast cancer, 0.66; P=0.01 by a two-sided log-rank test stratified according to nodal status, prior adjuvant chemotherapy, the interval from the last dose of aromatase-inhibitor therapy, and the duration of treatment with tamoxifen). The rate of 5-year overall survival was 93% (95% CI, 92 to 95) with letrozole and 94% (95% CI, 92 to 95) with placebo (hazard ratio, 0.97; P=0.83). The annual incidence rate of contralateral breast cancer in the letrozole group was 0.21% (95% CI, 0.10 to 0.32), and the rate in the placebo group was 0.49% (95% CI, 0.32 to 0.67) (hazard ratio, 0.42; P=0.007). Bone-related toxic effects occurred more frequently among patients receiving letrozole than among those receiving placebo, including a higher incidence of bone pain, bone fractures, and new-onset osteoporosis. No significant differences between letrozole and placebo were observed in scores on most subscales measuring quality of life.

Conclusions

The extension of treatment with an adjuvant aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than those with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo. (Funded by the Canadian Cancer Society and others; ClinicalTrials.gov numbers, NCT00003140 and NCT00754845.)

Supported by grants from the Canadian Cancer Society Research Institute (021039 and 015469), the National Cancer Institute (CA180888, CA189953, CA180828, CA13612, CA37981, CA077202, CA180863, CA67753, CA189805 [to Dr. Sturtz], CA16116, CA180802 [to Dr. Wolff], CA16116, and CA180802 [to Dr. Robert]), the Canadian Cancer Trials Group (CA077202 and CA180863), the ECOG-ACRIN Cancer Research Group (CA180820 and CA21115), and Novartis Pharmaceuticals. Dr. Goss was funded in part by the Avon Foundation.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Dr. Pritchard reports receiving fees for serving on advisory boards from AstraZeneca, Pfizer, Roche, Amgen, Novartis, GlaxoSmithKline and Eisai, consulting fees from Pfizer and Novartis, and lecture fees from Novartis; Dr. Muss, serving as an uncompensated consultant and advisor to Pfizer and HarborPath and serving on the board of directors of HarborPath; Dr. Gralow, serving on data safety and monitoring committees for Novartis and Roche-Genentech and on a steering committee for Roche-Genentech; Dr. Whelan, receiving fees for serving on an advisory board from Genomic Health and fees for testing reagents from NanoString; Dr. Winer, receiving grant support through his institution from Novartis; Dr. Hudis, receiving consulting fees and fees for serving on advisory boards from Novartis, Pfizer, and AstraZeneca; and Dr. Stopeck, receiving consulting fees from Amgen, Genentech, and BioMarin and honoraria from Amgen and serving on a data safety and monitoring committee for Pfizer and a steering committee for Sandoz. No other potential conflict of interest relevant to this article was reported.

This article was published on June 5, 2016, and last updated on June 28, 2016, at NEJM.org.

We thank Jessica St. Louis for her administrative support in the preparation and submission of an earlier version of this manuscript.