The most recent ASCO Clinical Practice Guideline update—summarized in this issue of The ASCO Post—represents the latest chapter in the ongoing evolution of adjuvant endocrine therapy for hormone-sensitive breast cancer.1 Rather than including a comprehensive review of the 2010 guidelines, this update focuses on the duration of tamoxifen therapy. With each change in guidelines, clinicians are likely to ask three important questions: (1) What happened? (2) How should my practice change? and (3) Are we done yet?
What Happened?
Long ago, patients enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial who were completing 5 years of therapy were offered re-randomization to an additional 5 years of tamoxifen vs placebo. Disease-free survival, relapse-free survival, and overall survival all favored placebo, though only the difference in disease-free survival reached statistical significance.2
Though the efficacy results were surprising, the toxicity results were entirely predictable—longer duration of therapy brought more toxicity. In the absence of any suggestion of benefit and with the real and documented increased toxicity, guidance at the time appropriately recommended that tamoxifen therapy be limited to 5 years’ duration.
Many researchers urged caution, pointing out that NSABP B-14 was a relatively small trial limited to patients with a low risk of recurrence (~1,150 patients enrolled, 243 disease-free events reported). They suggested that B-14 provided, at best, a preliminary estimate rather than a definitive answer.
While much of the focus of hormone therapy investigations over the ensuing decade shifted to the aromatase inhibitors, the ATLAS and aTTom trials soldiered on, re-addressing the tamoxifen duration question and contributing more than 10 times the number of patients enrolled in B-14 to the analysis.3,4 The result was clear: longer treatment (at least up to 10 years) does increase the risk of significant toxicity, but also reduces the risk of recurrence. Importantly, longer duration of tamoxifen decreased the risk of death from any cause, providing irrefutable confirmation that the benefit outweighs the risk.
How Should My Practice Change?
The change in guidelines is most directly applicable to those patients who remain premenopausal after 5 years of tamoxifen therapy. If observation off therapy was an uncomfortable option, patients and their treating physicians faced a difficult choice of continuing tamoxifen or pursuing ovarian suppression (either alone or with an aromatase inhibitor), recognizing that both choices brought toxicity and had no proven benefit. Those patients should be offered the option of continuing tamoxifen for another 5 years.
We should also be mindful of the broader implications. Patients who become amenorrheic during tamoxifen therapy also now have a choice for extended therapy—either continue tamoxifen or change to an aromatase inhibitor. Many postmenopausal patients find the aromatase inhibitors difficult to tolerate, with up to 25% discontinuing therapy due to toxicity in some studies.5 Postmenopausal patients unable to tolerate the aromatase inhibitors should be offered extended-duration tamoxifen.
Are We Done Yet?
We are clearly not done yet. Hormone-sensitive breast cancer has an extremely long natural history with a low but constant rate of recurrence over at least 15 years.6 Quick answers in trials with limited follow-up or a small number of events will always require caution. The benefit of therapeutic interventions may not be apparent until 7 to 8 years after diagnosis,7 and may take even longer to reach statistical significance.
Questions remain regarding the optimal duration (and schedule) of the aromatase inhibitors and the role of ovarian suppression. Since the guideline panel met to review the ATLAS and ATTom trial data, the combined analysis of the TEXT and SOFT trials suggested that ovarian suppression and exemestane reduced recurrence compared to ovarian suppression and tamoxifen.8 Additional analyses of the SOFT trial to clarify the impact of ovarian suppression are expected within the next year. The understanding of the impact of breast cancer molecular subtype on the benefit of various hormone therapy strategies is in its infancy.
In short, patience will remain a virtue when it comes to the management of hormone-sensitive early breast cancer. Since up to 40% of patients discontinue hormone therapy before completing even 5 years (often without the knowledge of their treating physician),9,10 the benefit from enhancing adherence is likely to far outweigh the incremental benefits reported in any of the trials reported thus far. Perhaps the “optimal” hormone therapy might be described most simply as “the hormone therapy the patient can and will continue to take.” ■
Disclosure: Dr. Miller reported no potential conflicts of interest.
References
1. Burstein HJ, Temin S, Anderson H, et al: Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol 32:2255-2269, 2014.
2. Fisher B, Dignam J, Bryant J, et al: Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 93:684-690, 2001.
3. Davies C, Pan H, Godwin J, et al: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381:805-816, 2013.
4. Gray R, Rea D, Handley K, et al: ATTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol 31(suppl):Abstract 5, 2013.
5. Henry NL, Skaar TC, Dantzer J, et al: Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer. Breast Cancer Res Treat 138:807-816, 2013.
6. Saphner T, Tormey DC, Gray R: Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14:2738-2746, 1996.
7. Albain KS, Barlow WE, Ravdin PM, et al: Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet 374:2055-2063, 2009.
8. Pagani O, Regan M, Walley BA, et al: Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Joint analysis of IBCSG TEXT and SOFT trials. J Clin Oncol 32(suppl):Abstract LBA1, 2014.
9. Partridge AH, Wang PS, Winer EP, et al: Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol 21:602-606, 2003.
10. Partridge AH, LaFountain A, Mayer E, et al: Adherence to initial adjuvant anastrozole therapy among women with early-stage breast cancer. J Clin Oncol 26:556-562, 2008.
Dr. Miller is Professor of Medicine at Indiana University Melvin and Bren Simon Cancer Center, Indianapolis.
