Estrogen receptor–positive breast cancer is the most common type of breast cancer, diagnosed in more than 2.3 million women around the world each year, including more than 200,000 in the United States alone. Adjuvant endocrine therapy is a mainstay of treatment for these millions of women and is a major contributor to their long-term survival.
The optimal duration of adjuvant endocrine treatment in women with breast cancer has long been debated. For decades, 5 years was the ‘standard’ recommendation. However, women with estrogen receptor–positive breast cancer remain at jeopardy for recurrence, despite 5 years of adjuvant treatment.1 Indeed, more than half of recurrences arise beyond the 5-year timeframe.
Dario Trapani, MD
Harold J. Burstein, MD, PhD, FASCO
Anatomic stage is the biggest determinant of late recurrence: the risk of such recurrences for estrogen receptor–positive breast cancers is around 10% for stage I tumors, but it increases to more than 30% in higher-stage presentations with extensive lymph node involvement. Biologic factors also affect the risk of late recurrence; high-grade tumors and tumors with ‘luminal B’ features pose greater jeopardy for late recurrence.
Late recurrences seem to be driven by “dormant” disseminated tumor cells shedding from the primary breast cancer into the bloodstream; these cells are able to “hibernate” (ie, stay in a G0-G1 cell-cycle arrest) for a long period and possibly reside cloaked within normal tissues and organs for extended periods. Changed conditions, from microenvironmental signals to immune surveillance and acquisition of resistance to endocrine therapy, may trigger a reversion of the dormancy state, resulting in clinically relevant disease recurrences. For all these reasons, the idea of extending endocrine therapy to improve long-term outcomes has been a compelling notion.
Case for Prolonged Adjuvant Endocrine Therapy
Previous clinical trials have demonstrated that adjuvant endocrine treatments taken for prolonged periods (up to 7 or 10 years) may result in a disease-free survival benefit, with a relative gain of 28% to 49% for extended treatment with aromatase inhibitors.2 This translates to an absolute risk reduction of disease recurrence from 9.5% to 7% and of distant recurrence from 6.1% to 5.1%, as reported in the large Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis.2
The absolute benefit seems to increase as the tumor risk increases, and it is magnified with extensive lymph node involvement (ie, high-risk disease presentation) and may be more pronounced in women initially treated with tamoxifen and then switched to an aromatase inhibitor. The 5-year absolute risk reduction of recurrence is around 1.1% in women with no nodal involvement, but it rises to around 7.7% when four or more axillary lymph nodes are affected. Based on these trials, longer durations of treatment up to 10 years have become standard for women who have node-positive, estrogen receptor–positive breast cancers and who have tolerated therapy with sufficiently modest side effects.
Potential Benefit of Intermediate Duration of Adjuvant Endocrine Therapy
The jump from 5 years to 10 years of treatment skipped over the question: Would an intermediate, longer duration of treatment prove sufficient? New data suggest that may be the case for many patients. The Austrian ABCSG-16/SALSA study,3 summarized in this issue of The ASCO Post, is a prospective, phase III clinical trial that randomly assigned postmenopausal women with estrogen receptor–positive breast cancer who had received 5 years of endocrine therapy to ongoing treatment with either 2 or 5 more years of the aromatase inhibitor anastrozole. Thus, the study compared a total of about 7 years of treatment with about 10 years of treatment.
The study showed no difference in disease-free survival or overall survival; at 8 years, the rates were 73.6% vs 73.9% and 87.5% vs 87.3% in the 7-year and 10-year groups. The lack of significant difference was consistent across prespecified subgroups, including in women with (up to three) positive lymph nodes (30.8% of the study population) and regardless of previous tamoxifen, aromatase inhibitor, or (neo)adjuvant chemotherapy. Notably, only 7.3% had received 5 years of an aromatase inhibitor alone before the randomization. The 7-year extended regimen appeared to be safer than the 10-year regimen, since the longer regimen was associated with a 35% increase in osteoporotic bone fractures.
Ongoing Search for Optimal Duration of Therapy
The Italian GIM4 trial is the latest study to analyze the optimal treatment duration.4 It enrolled women who had received 2 to 3 years of adjuvant tamoxifen; they were randomly assigned to receive 2 to 3 (standard) or 5 (extended) years of treatment with the aromatase inhibitor letrozole, effectively comparing a total duration of treatment of 5 years vs 7 years. With long follow-up of up to 12 years, there was a significant improvement in disease-free survival from 62% to 67% with the extended endocrine therapy, corresponding to a relative disease-free survival gain of 22%. Of note, there was also emerging evidence of a survival benefit, as the 12-year overall survival rate improved from 84% to 88% with the longer course of treatment. An increased risk of osteoporosis was also reported with the extended strategy, consistent with previous studies.
ABCSG-16/SALSA and GIM4 are important contributions to the prior studies of extended adjuvant endocrine therapy for postmenopausal women. Collectively, they provide evidence in support of an extended adjuvant treatment of 7 to 8 years in total as the ‘optimal duration’ for women with average-risk breast cancers. The benefit of 7 to 8 years of extended adjuvant therapy seems to be confirmed for women with stage I and II breast cancer previously exposed to initial treatment with tamoxifen and then switched to an aromatase inhibitor. What is less clear is to what extent the results can be extrapolated to high-risk disease presentations—for example, in patients with extensive lymph node involvement or higher-risk stage II cancers—and whether women who began initial treatment upfront with an aromatase inhibitor for a total exposure of 5 years would derive the same magnitude of benefit compared with women initially treated with tamoxifen.
Tailored Approach Based on Anatomic and Biologic Risks
We think these recent data are important for clinicians and women with breast cancer and offer a tailored approach based on anatomic and biologic risks. For postmenopausal women with stage I breast cancer, who have lower-risk histologic features or genomic risk scores, 5 years of adjuvant endocrine treatment is likely sufficient, particularly if that includes an aromatase inhibitor at some point. For patients with stage II cancers or limited nodal involvement, they suggest that a treatment course of around 7 years is likely to offer an advantage over 5 years. And, finally, for women with higher-risk tumors by virtue of stage or adverse biology, longer durations of around 10 years remain the standard recommendation. As always, it is important to weigh the benefits of longer treatment against the well-known side effects of therapy, such as arthralgias, osteoporosis, hair thinning, and genitourinary health. Hopefully, patients and clinicians can use these data to make well-informed, data-driven, shared decisions about the best course of therapy.
Dr. Trapani and Dr. Burstein are employed at the Dana-Farber Cancer Institute, Harvard Medical School, Boston.
DISCLOSURE: Dr. Trapani and Dr. Burstein reported no conflicts of interest.
REFERENCES
1. Burstein HJ, Lacchetti C, Anderson H, et al: Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: ASCO clinical practice guideline focused update. J Clin Oncol 37:423-438, 2019.
2. Gray R, Early Breast Cancer Trialists’ Collaborative Group: Effects of prolonging adjuvant aromatase inhibitor therapy beyond 5 years on recurrence and cause-specific mortality. 2018 San Antonio Breast Cancer Symposium. Abstract GS3-03. Presented December 6, 2018.
3. Gnant M, Fitzal F, Rinnerthaler G, et al: Duration of adjuvant aromatase-inhibitor therapy in postmenopausal breast cancer. N Engl J Med 385:395-405, 2021.
4. Del Mastro L, Mansutti M, Bisagni G, et al: Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early-stage breast cancer. Lancet Oncol 22:1458-1467, 2021.
