Conference Coverage

Trial updates will help tailor endocrine therapy for premenopausal breast cancer



– Adjuvant endocrine therapies improve outcomes of premenopausal breast cancer in the long term, with absolute benefit varying somewhat by therapy and by patient and disease characteristics, according to planned updates of a pair of pivotal phase 3 trials.

The trials – TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) – are coordinated by the International Breast Cancer Study Group and together randomized more than 5,000 premenopausal women with early hormone receptor–positive breast cancer to 5 years of various types of adjuvant endocrine therapy. Their initial results, reported several years ago, form part of treatment guidelines that are used worldwide.

Dr. Gini Fleming

Dr. Gini Fleming

In an updated joint analysis of TEXT and SOFT, benefit of the aromatase inhibitor (AI) exemestane plus ovarian function suppression (OFS) over the selective estrogen-receptor modulator tamoxifen plus OFS was sustained, with a 4.0% absolute gain in 8-year disease-free survival, investigators reported at the San Antonio Breast Cancer Symposium. And in an updated analysis of SOFT, the benefit of tamoxifen plus OFS over tamoxifen alone became significant, with a 4.2% absolute gain in 8-year disease-free survival.

Relative benefits for various outcomes were generally similar across subgroups, but absolute benefits were greater for women having certain features increasing risk for poor outcomes.

Clinical implications

These updates, along with other emerging data, can be used to optimize endocrine therapy for younger women with breast cancer, according to invited discussant Ann H. Partridge, MD, of Dana Farber Cancer Institute in Boston.

“For higher-risk disease, we should be considering OFS. At this point in time, I don’t think HER2 status alone should drive this decision,” she commented. “If you are getting OFS, what do we do, AI versus tamoxifen? Well, we do see a large improvement in disease-free survival [with AIs], so many women will want to use AIs. Yet tamoxifen is still reasonable, especially in light of the survival data.”

Data on switch strategies and extended-duration therapy are generally lacking at present for the premenopausal population, Dr. Partridge noted. “That’s something that we still need to extrapolate from data that’s predominantly in postmenopausal women.”

Another compelling question is whether OFS can be used instead of chemo for some patients. “We are increasingly recognizing that women with higher-risk anatomy and lower-risk biology having endocrine-responsive tumors may get more bang for the buck from the optimizing of hormonal therapy, and chemo may not add much,” she said.

Both short- and long-term toxicities of the various endocrine therapies and, for aromatase inhibitors, the potential for breakthrough (return of estradiol levels to premenopausal levels) also need to be considered, Dr. Partridge stressed. “And ultimately, patient preference and tolerance are key. After all, the best treatment is the one the patient will take.”

“We need to follow these women on TEXT and SOFT very long term. It would be a crime not to follow these women further out,” she maintained. “We need to conduct real-world comparative effectiveness research to understand the risks and benefits of OFS more fully in our survivors. Then, as we start to suppress more ovaries in more women with breast cancer, we need to be aware clinically of these risks, and we need to share this awareness with their primary care providers because we need to optimize in particular their cardiovascular risk factors, and screen and treat for potential comorbidities that they may be at higher risk for.”

Joint TEXT and SOFT update

Initial results of the joint TEXT and SOFT analysis, reported after a median follow-up of 5.7 years, showed that exemestane plus OFS was superior to tamoxifen plus OFS for the primary outcome, providing a significant 3.8% absolute gain in 5-year disease-free survival (N Engl J Med. 2014;371:107-18).

The updated joint analysis, now with a median follow-up of 9 years and based on data from 4,690 women, showed that the 8-year rate of disease-free survival was 86.8% with exemestane plus OFS versus 82.8% with tamoxifen plus OFS (hazard ratio, 0.77; P = .0006), for a similar absolute benefit of 4.0%, reported Prudence Francis, MD, of the University of Melbourne, head of Medical Oncology in the Breast Service at the Peter MacCallum Cancer Centre, Melbourne.

In stratified analysis, absolute benefit tended to be greater among women in TEXT who received chemotherapy (6.0%); intermediate among women in TEXT who did not receive chemotherapy (3.7%) and women in SOFT who received prior chemotherapy (3.7%); and less among women in SOFT who did not receive chemotherapy (1.9%).

Exemestane plus OFS was also superior to tamoxifen plus OFS in terms of breast cancer–free interval, with an absolute 4.1% benefit (P = .0002), and distant recurrence–free interval, with an absolute 2.1% benefit (P = .02). Overall survival did not differ significantly between arms.

Among the 86% of patients with HER2-negative disease, exemestane plus OFS netted an absolute disease-free survival gain of 5.4% and an absolute distant recurrence–free interval gain of 3.4%. There was a consistent relative treatment benefit across subgroups, but larger absolute benefit, on the order of 5%-9%, in women given chemotherapy and in those younger than 35 years.

“Results for the HER2-positive subgroup require further investigation,” Dr. Francis said. “The trials enrolled both before and after the routine use of adjuvant trastuzumab, and a significant proportion of the patients with HER2-positive breast cancer did not receive adjuvant HER2-targeted therapy.”

In the entire joint-analysis population, exemestane plus OFS was associated with higher rates of musculoskeletal events of grade 3 or 4 (11% vs. 6%) and osteoporosis of grade 2-4 (15% vs. 7%), while tamoxifen plus OFS was associated with a higher rate of thrombosis/embolism of grade 2-4 (2.3% vs. 1.2%) and more cases of endometrial cancer (9 vs. 4 cases). At 4 years, early discontinuation of oral endocrine therapy was greater for exemestane than for tamoxifen (25% vs. 19%).

“After longer follow-up, with a median of 9 years, the combined analysis results confirm a statistically significant improvement in disease outcomes with exemestane plus ovarian suppression. As is critical given the long natural history of estrogen receptor–positive breast cancer, follow-up in these trials is currently continuing,” Dr. Francis summarized.

“To optimally translate the observed absolute trial improvements into clinical practice, oncologists need to discuss and weigh the potential benefits and toxicities in each individual patient who is premenopausal with hormone receptor–positive breast cancer,” she recommended.

Session attendee Hope S. Rugo, MD, of the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, noted that exemestane had superior benefit despite the 25% rate of early discontinuation. “I wonder if one of the interpretations of that, given the toxicity of this therapy for very young women, is that we need some but maybe not so much. Maybe they don’t need 5 years altogether,” she said.

“The fact that they stopped their assigned endocrine therapy doesn’t mean that they didn’t continue any therapy. They may have switched over to tamoxifen or they may have decided they wanted to have a baby or there may have been many other things,” Dr. Francis replied, noting that analyses sorting out the reasons for early discontinuation are planned.

Session attendee Mark E. Sherman, MD, of the Mayo Clinic, Jacksonville, Fla., asked, “Do you have any ability to test for tamoxifen metabolites? It’s possible that a third to a half of patients got reduced benefit from that drug.”

Banked samples are available and a substudy is planned, according to Dr. Francis. “We haven’t got data on that yet, but yes, we are analyzing that.”


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