Adjuvant Ovarian Suppression in Premenopausal Breast Cancer

Abstract

BACKGROUND Suppression of ovarian estrogen production reduces the recurrence of hormone-receptor– positive early breast cancer in premenopausal women, but its value when added to tamoxifen is uncertain. METHODS We randomly assigned 3066 premenopausal women, stratified according to prior receipt or nonreceipt of chemotherapy, to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The primary analysis tested the hypothesis that tamoxifen plus ovarian suppression would improve disease-free survival, as compared with tamoxifen alone. In the primary analysis, 46.7% of the patients had not received chemotherapy previously, and 53.3% had received chemotherapy and remained premenopausal. RESULTS After a median follow-up of 67 months, the estimated disease-free survival rate at 5 years was 86.6% in the tamoxifen–ovarian suppression group and 84.7% in the tamoxifen group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.83; 95% confidence interval [CI], 0.66 to 1.04; P = 0.10). Multivariable allowance for prognostic factors suggested a greater treatment effect with tamoxifen plus ovarian suppression than with tamoxifen alone (hazard ratio, 0.78; 95% CI, 0.62 to 0.98). Most recurrences occurred in patients who had received prior chemotherapy, among whom the rate of freedom from breast cancer at 5 years was 82.5% in the tamoxifen–ovarian suppression group and 78.0% in the tamoxifen group (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02). At 5 years, the rate of freedom from breast cancer was 85.7% in the exemestane–ovarian suppression group (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87). CONCLUSIONS Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes. Further improvement was seen with the use of exemestane plus ovarian suppression. (Funded by Pfizer and others; SOFT ClinicalTrials.gov number, NCT00066690.)

Adjuvant ovarian suppression for resected breast cancer: 2017 critical assessment

“…Six months after the TEXT publication, the primary analysis for SOFT gave us the results for the control group relevant for most North American physicians, the group whose hormonal therapy was TAM alone [1]. The DFS advantage for TAM plus OFS compared to TAM alone (the primary study endpoint) just failed to achieve statistical significance.…”

“…The surrogate endpoints used in the first two SOFT and TEXT publications [1,2] (DFS and BCFI) include too many events that are generally well treated and rarely fatal (local recurrences, new invasive cancers in breast and other primary sites). Surrogate endpoints that censor deaths without prior breast cancer events are very good for generating hypotheses and honing analyses, but are not appropriate for advising patients, because the humans as a rule prefer to defer death, regardless of its cause.…”

“…The issue is not whether OFS is active, but whether OFS has sufficient activity when it is added to the multiple agents of modern adjuvant therapy of resected breast cancer to justify its use, despite its considerable subjective and objective toxicities. The published result of the key modern ''positive'' adjuvant OFS study (SOFT [1], with its associated study, TEXT [2]) has limitations in its data and analysis that make the extent of the benefit and confidence in the magnitude of the benefit uncertain. Further follow-up may fail to prove a significant benefit in reduction in distant metastases (which ultimately lead to death from breast cancer) and improvement in overall survival (OS).…”

General St. Gallen-2015 guidelines for the treatment of early breast cancer (adapted by the experts of the Russian Society of Breast Oncologists)

“…Напротив, среди пациенток, остающихся в пременопаузе после цитотоксической химиотерапии, добавле-ние OFS улучшает результаты в сравнении с одним тамоксифеном, в то время как комбинация эксеместа-на и подавления функции яичников была еще более эффективной. Выгода от подавления функции яичников оказалась особенно значительна среди молодых пациенток [3] Снижение риска прежде-временного угасания функции яичников, индуцированного химиотерапией…”

“…Разра-ботка эффективных, но менее дорогих видов лечения является важным приоритетом [2]. Панель экспертов одобрила результаты нескольких недавно проведен-ных клинических испытаний, включая SOFT и TEXT, проясняющие роль супрессии овариальной функции (ovarian function suppression, OFS) в комбинации с та-моксифеном или эксеместаном в эндокринотерапии пременопаузальных пациенток, а также испытание POEMS, подтверждающее протективную ценность лютеинизирующего гормона рилизинг-гормона (ЛГРГ) для сохранения овариальной функции при проведении адъювантной цитотоксической овариэк-томии [3][4][5]. Всплыл странный парадокс в обоснова-нии локальных видов лечения.…”