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Pairing ovarian function suppression (OFS) with an aromatase inhibitor significantly reduced the risk of premenopausal breast cancer recurrence but did not improve overall survival (OS) versus a tamoxifen strategy, long-term follow-up from two randomized trials showed.

After a median follow-up of 13 years, exemestane plus OFS led to a 12-year disease-free survival (DFS) rate of 80.5% versus 75.9% for tamoxifen plus OFS and a distant recurrence-free interval (DRFI) rate of 88.4% versus 86.6%, both of which achieved statistical significance. A 1% absolute difference in OS (90.1% vs 89.1%) was not statistically significant.

Subgroup analyses showed a nonsignificant 2% improvement in OS among patients with HER2-negative breast cancer. The largest improvement in OS occurred in small high-risk subgroups, such as patients younger than 35 and those with larger, higher-grade tumors. Higher OS benefits also occurred in patients treated with chemotherapy, irrespective of hormonal therapy, reported Olivia Pagani, MD, of Hospital Riviera-Chablais in Rennaz, Switzerland, and co-authors in the .

"Treatment effects on recurrence tended to attenuate over time, being strongest in years 0-5 with no further improvement after ≥10 years," the authors wrote. "Overall survival was excellent with both treatments, not improved by exemestane plus OFS ... the lack of survival benefit from exemestane plus OFS is at least in part attributable to early emergent, persistent favorable outcomes with tamoxifen plus OFS in the HER2-positive subgroup."

"No overall survival benefit with exemestane plus OFS was evident in women at lower risk of relapse not receiving chemotherapy," they added. "Given the burden of treatment intensification on quality of life, proper selection of women most likely to benefit is paramount."

The long-term benefits of adding a CDK4/6 inhibitor to adjuvant endocrine therapy remain unknown at this point, Pagani and co-authors noted.

Considerable uncertainty surround the long-term follow-up data from the SOFT and TEXT trials, said the authors of an . Use of HER2-targeted agents was inconsistent among the 15% of patients with HER2-positive tumors. Patients with node-positive disease received chemotherapy, but not a CDK4/6 inhibitor.

"Despite these uncertainties, improvements in OS cannot and should not be ignored," wrote Roisin Connolly, MBBCh, MD, of University College Cork in Ireland, and Kathy Miller, MD, of Indiana University's Melvin and Bren Simon Comprehensive Cancer Center in Bloomington. "Ovarian suppression with an aromatase inhibitor should become the preferred initial hormone therapy recommendation for all premenopausal women with high-risk ... ER [estrogen receptor]-positive breast cancer."

"We favor a stepwise approach, first initiating and evaluating toxicity with ovarian suppression alone and then adding an aromatase inhibitor," they added. "Should toxicity be intolerable, reversion to tamoxifen alone, or with continued ovarian suppression, remains an option and is certainly preferable to discontinuation of all anti-estrogen therapies. Ovarian suppression should not be considered a mandate for patients with lower-risk disease where the long-term toxicities outweigh the benefits."

Connolly and Miller suggested greater focus on maximizing the well-being of premenopausal patients with ER-positive breast cancer. Borrowing from the concept of tailored treatment decisions, they raised the prospect of "personalized survivorship care pathways spanning supported self-management (lower risk) and expert-led supportive care (moderate/high risk)."

Noting that management of ER-positive breast cancer requires "playing the long game," Connolly and Miller said tailored survivorship care "has the potential to optimally support women in the years after initiation of endocrine therapy, maximizing adherence and long-term outcomes regardless of the specific anti-estrogen therapy."

The combined analysis of SOFT and TEXT included 4,690 premenopausal women with hormone receptor (HR)-positive early breast cancer randomized to 5 years of adjuvant exemestane-OFS or tamoxifen-OFS. A after 9 years of follow-up showed improvement in DFS and DRFI, but not OS. The update evaluated all three outcomes after an additional 4 years of follow-up.

The update showed an absolute improvement in DFS of 4.6% with exemestane, representing a 21% reduction in the hazard ratio (95% CI 0.70-0.90, P<0.001) and an absolute improvement in DRFI of 1.8%, equivalent to a 17% reduction in the hazard (95% CI 0.70-0.98, P=0.03). The 1% difference in OS represented a 7% reduction in the hazard (95% CI 0.78-1.11).

In a subgroup analysis, the 86% of patients who had HER2-negative tumors had a 2% improvement in OS, and the 46% of patients who received chemotherapy had an OS benefit of 3.3% with exemestane. The largest absolute benefits occurred among high-risk patients, including those younger than 35 (4.0%), those with tumors >2 cm (4.5%), or those with grade 3 tumors (5.5%).

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