Benefit of Extended Adjuvant Endocrine Therapy Remains Unknown

Partner | Cancer Centers | <b>UCSF Helen Diller Family Comprehensive Cancer Center</b>

In a presentation during an OncLive® State of the Science Summit™, Melanie Majure, MD, discussed the duration of endocrine-directed therapy for estrogen receptor–positive breast cancer.

Melanie Majure, MD

Patients with hormone receptor (HR)-positive breast cancer generally have a good prognosis, said Melanie Majure, MD. However, more work needs to be done since greater than 50% of patients’ disease recurs after 5 years, she added.

Clinical and pathologic factors are known to be prognostic, but they do not reliably predict benefit from extended endocrine therapy. “You can see as these tumors get larger, and more lymph nodes are involved, that risk continues to rise,” explained Majure.

In a presentation during the 2018 OncLive® State of the Science Summit™ on Breast Cancer, Majure, a clinical instructor in the Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed the duration of endocrine-directed therapy for estrogen receptor (ER)—positive disease.

Tamoxifen has demonstrated a significant survival benefit for patients with early-stage breast cancer. However, the risk of recurrence remains, Majure said. The development of aromatase inhibitors (AIs) provided additional benefit, in terms of reduction in recurrence, as well as a mortality benefit, explained Majure. Multiple trials have investigated extended endocrine therapy, including ATLAS, aTTOm, MA.17R, and NSABP B-42.

The ATLAS and aTTOm studies were very similar in design and outcomes, Majure said. Patients on these trials were randomized either to be on observation for 5 years or to receive 5 more years of tamoxifen. Those on extended tamoxifen therapy had an absolute benefit in their disease-free survival (DFS).

In MA.17, patients received 5 years of tamoxifen and then were randomized to either placebo or an AI for 5 years. Some benefit in DFS was observed with an AI in this trial as well, Majure stated. In light of these results, the MA.17R study investigated extended adjuvant therapy with an AI to 10 years after treatment for early-stage HR-positive breast cancer.

Extended AI therapy with letrozole led to a reduction in the risk of recurrence by more than one-third without added toxicities or impact on quality of life. At 5 years, DFS for patients who received letrozole was 95% compared with 91% for placebo (P = .01).1 Although there was a higher rate of bone-related toxic events with letrozole versus placebo, Majure noted that there was a reduction in contralateral breast cancers with extended letrozole. The rate of new contralateral breast cancer was 13% versus 31% for letrozole and placebo, respectively.

Findings from the NSABP B-42 study, however, indicated that extended letrozole in patients with early-stage HR-positive breast cancer did not yield statically significant improvement in DFS or overall survival (OS). The study randomized 3923 patients, and only 62.5% of patients on placebo and 60.3% of patients on letrozole completed all 5 years of therapy.2

In the last few years, there have been 3 trials of extended endocrine therapy of note, said Majure: DATA, IDEAL, and SOLE. The DATA trial investigated 3 versus 6 years of anastrozole after 2 to 3 years of tamoxifen. This was a higher-risk population, noted Majure, as 55% of patients had ≥T2 disease, 67% were node-positive, 81% had grade 2/3 tumors, and 90% were HER2-negative.3 There was a small increase in benefit for those with ER-positive, progesterone receptor—positive disease with positive lymph nodes.

“In this population of almost 2000 patients, compliance was not so great either, similar to some of these other studies,” said Majure. “What you see is no improvement in 5-year DFS.”

IDEAL enrolled patients who had received 5 years of endocrine therapy, and they were randomized to 2.5 versus 5 years of letrozole. This study, Majure said, also did not improve DFS. However, a subgroup analysis suggested a benefit with 5 years of letrozole for patients with node-positive disease.

“The MA.17R trial showed some benefit ... Then there were several others that did not show an improvement in DFS,” said Majure. “What do we make of this?”

Genomic Factors

Majure said that a final important study is the SOLE trial, which investigated the role of intermittent letrozole following 4 to 6 years of endocrine therapy. Findings showed that there was no difference in DFS, which Majure said this suggests that taking breaks from anti-estrogen therapy is a viable option. Having treatment breaks improved quality of life, she added.Optimization of candidate selection for extended AI therapy is based on genomics, Majure said. “Genomic classifiers that predict risk of late recurrence and/or benefit from extended endocrine therapy may help to further optimize the selection of patients for extended AI therapy,” she said. Breast Cancer Index (BCI), MammaPrint, Oncotype DX, EndoPredict assay, PAM50 risk of recurrence (ROR) score, and 21-Gene Recurrence Score are gene expression profiles that have been shown to predict risk of later recurrence in ER-positive, HER2- negative breast cancer. These do not, however, indicate whether extending endocrine therapy is of benefit to an individual patient.

While a high score on BCI was associated with a 67% reduction in the risk of recurrence when used in the MA.17 trial, Majure says that this tool needs to be further validated. In summary, Majure said that extended duration of endocrine therapy reduces the risk of recurrence and contralateral breast cancer in unselected populations. Additionally, extended duration of endocrine therapy has not been shown to significantly prolong OS, except in the ATLAS and aTTom trials.

Premenopausal Patients

“The number needed to treat is around 30 to 40 to prevent 1 event, and closer to 100 to prevent 1 metastatic event,” said Majure. “Extended duration increases drug-specific toxicities, and assessment of potential risks and benefits is important before recommending extended adjuvant AI therapy.”To close out her presentation, Majure touched on the optimal adjuvant treatment for premenopausal patients with HR-positive early breast cancer. Women who develop chemotherapy- induced ovarian function suppression (OFS) have a reduced risk of relapse, but apart from cytotoxic effects, chemotherapy can also have endocrine effects in ER-positive disease through a change in ovarian function. The likelihood of chemotherapy-induced OFS is correlated with older age, and is less likely in women aged <35 years of age, said Majure.

At the 2018 ASCO Annual Meeting, Meredith M. Regan, ScD, of the Dana-Farber Cancer Institute, presented a composite risk and Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the SOFT and TEXT trials of premenopausal patients with HR-positive early breast cancer.4 This analysis combined standard clinical pathologic features into a single value for each patient. Once this composite risk was determined, it was stratified by risk and then analyzed by STEPP.

“Among premenopausal women in SOFT and TEXT with HR-positive, HER2-negative cancers, magnitude of absolute improvement in 8-year freedom from distant recurrence varied widely according to risk of recurrence,” Majure noted. “For women at significant risk for recurrence based on their combined clinical pathologic features, exemestane plus OFS is a more effective endocrine therapy than tamoxifen plus OFS, or tamoxifen alone. Those at higher risk may experience 10% to 15% improvement with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone.”


  1. Goss PE, Ingle JN, Pritchard KI, et al. A randomized trial (MA.17R) of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer. J Clin Oncol. 2016;34(18 suppl; abstr LBA1). doi: 10.1200/JCO.2016.34.18_suppl.LBA1.
  2. Mamounas EP, Bandos H, Lembersky BC, et al. A randomized, double-blinded, placebo-controlled clinical trial to evaluate extended adjuvant endocrine therapy (5 years of letrozole) in postmenopausal women with hormone-receptor positive breast cancer who have completed previous adjuvant endocrine therapy: initial results of NRG oncology/NSABP B-42. In: Proceedings from the 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, Texas. Abstract S1-05.
  3. Tjan-Heijnen VC, Van Hellemond IE, Peer PG, et al. First results from the multi- center phase III DATA study comparing 3 versus 6 years of anastrozole after 2-3 years of tamoxifen in postmenopausal women with hormone receptor-positive early breast cancer. In: Proceedings from the 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016e; San Antonio, Texas. Abstract S1-03.
  4. Regan MM, Francis PA, Pagani O, et al. Absolute improvements in freedom from distant recurrence with adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) HER2-negative breast cancer (BC): results from TEXT and SOFT. J Clin Oncol. 2018;36(suppl; abstr 503).