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Benefit of Extended Adjuvant Endocrine Therapy Remains Unknown

Angelica Welch
Published: Monday, Oct 29, 2018

Melanie Majure, MD
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?”

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