Reduction Not Only in Recurrences, but Also in Mortality, Observed for Exemestane Plus Ovarian Function Suppression in Premenopausal Women with Hormone Receptor Positive EBC

After a median follow-up of 13 years, SOFT and TEXT investigators reported a sustained improvement in long-term outcomes, such as disease-free survival (DFS), and for the first time an improvement in overall survival (OS) for premenopausal women with hormone receptor positive early breast cancer (EBC) through incorporation of ovarian function suppression as a component of endocrine treatment. Based on the data from a combined analysis of SOFT and TEXT, ovarian function suppression with an aromatase inhibitor should become the preferred initial hormonal therapy recommendation for all premenopausal women with high-risk (e.g. grade 3, T2, and age < 35 years) hormone receptor positive EBC. The findings published on 15 December 2022 in the Journal of Clinical Oncology provide guidance for selecting patients for whom exemestane should be preferred over tamoxifen in the setting of ovarian function suppression.

The SOFT and TEXT combined analysis assessed the role of the aromatase inhibitor exemestane versus tamoxifen in premenopausal women with hormone receptor positive EBC receiving ovarian function suppression. The analysis after a 9 year of median follow-up showed sustained improvements with exemestane plus ovarian function suppression versus tamoxifen plus ovarian function suppression in DFS (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.67 to 0.90) and distant recurrence-free interval (DRFI), but not in OS (HR 0.98; 95% CI 0.79 to 1.22).

Given the potential late recurrences of hormone receptor positive breast cancer and late emergent survival benefit of adjuvant aromatase inhibitors versus tamoxifen in postmenopausal women, the investigators now report the late treatment effects on DRFI and OS and benefits in women with HER2-negative tumours and in those at high risk of disease relapse.

In the intention-to-treat (ITT) population, the 12-year DFS with 4.6% absolute improvement (HR 0.79, 95% CI 0.70 to 0.90; p < 0.001) and DRFI with 1.8% absolute improvement (HR 0.83, 95% CI 0.70 to 0.98; p = 0.03), but not OS 90.1% versus 89.1% (HR 0.93, 95% CI 0.78 to 1.11), continued to be significantly improved for patients assigned to exemestane plus ovarian function suppression over tamoxifen plus ovarian function suppression.

Among patients with HER2-negative tumours (86.0% of the ITT population), the absolute improvement in 12-year OS with exemestane plus ovarian function suppression was 2.0% (HR 0.85, 95% CI 0.70 to 1.04) and 3.3% in those who received chemotherapy (45.9% of the ITT population).

Benefit in OS was clinically significant in patients with high-risk disease, e.g. women age < 35 years (4.0%) and those with tumours > 2 cm (4.5%) or grade 3 (5.5%).

Treatment effects on recurrence tended to attenuate over time, being strongest in years 0 to 5 with no further improvement after ≥ 10 years. OS was excellent with both treatments, not improved by exemestane plus ovarian function suppression; the lack of survival benefit from exemestane plus ovarian function suppression is at least in part attributable to early emergent, persistent favourable outcomes with tamoxifen plus ovarian function suppressions in the HER2-positive subgroup. Deaths without breast cancer or second (non-breast) cancer were rare and not higher with exemestane. Similar findings, reported in the postmenopausal meta-analysis of adjuvant aromatase inhibitors versus tamoxifen, contrast data of increased cardiovascular deaths in premenopausal women undergoing oophorectomy and are reassuring for the safety of 5-year aromatase inhibitor plus ovarian function suppression in premenopausal patients.

No OS benefit with exemestane plus ovarian function suppression was evident in women at lower risk of relapse not receiving adjuvant chemotherapy. Given the burden of treatment intensification on quality of life, proper selection of women most likely to benefit is paramount.

On 9 December 2022, the SOFT investigators reported separately, also in the Journal of Clinical Oncology, the study long term outcomes and emphasized that benefit remains from including ovarian function suppression in adjuvant endocrine treatment, with an absolute improvement in OS more apparent with higher baseline risk of recurrence.

In an accompanied editorial, the editorialists stated that long-term follow-up requires persistence and patience, but the field does not remain static, so some may question the relevance of these results given the changes in adjuvant treatment landscape since SOFT and TEXT were launched. Approximately 15% of participants enroled had HER2 overexpressing tumours with inconsistent use of HER2-targeted treatment. The use of chemotherapy has also evolved. Most patients with lymph node positive disease (91.7% in SOFT and 79.3% in TEXT) received chemotherapy; none received a cyclin-dependent kinase inhibitor. Whether changes in HER2-targeted therapy, use of chemotherapy, or addition of a cyclin-dependent kinase inhibitor alter the proportional benefit of ovarian suppression is unknown.

Despite these uncertainties, improvements in OS cannot and should not be ignored. Ovarian suppression with an aromatase inhibitor should become the preferred initial hormonal treatment recommendation for all premenopausal women with high-risk hormone receptor positive EBC. The editorialists favour a stepwise approach, first initiating and evaluating side effects of ovarian suppression alone and then adding an aromatase inhibitor. In case of intolerable side effects, reversion to tamoxifen alone, or with continued ovarian suppression remains an option and is certainly preferable to discontinuation of all anti-oestrogen treatments. Ovarian suppression should not be considered a mandate for patients with lower risk disease where the long-term side effects outweigh the benefits according to the editorialists.

The findings were previously presented at the San Antonio 2021 Breast Cancer Symposium in San Antonio, TX, US (7-11 December 2021).

SOFT and TEXT are sponsored by ETOP IBCSG Partners Foundation. Studies conduct were supported by Pfizer; Pfizer and Ipsen provided the study drugs.

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