4.3. Concurrent or sequential ovarian function suppression

Breast cancer treatment guidelines recommend that higher risk premenopausal patients should receive ovarian function suppression as part of adjuvant endocrine therapy. However, if chemotherapy is also given, until recently, it was uncertain whether concurrent or sequential sequential ovarian function suppression (OFS) initiation has any detrimental effect on prognosis or menstruation resumption.

Recently, in a phase 3, open-label, parallel, randomized controlled trial, 216 premenopausal patients younger than 45 years with invasive ER+ breast cancer were randomized at a 1:1 ratio to receive (neo)adjuvant chemotherapy combined with sequential or simultaneous GnRHa treatment between July 2009 to May 2013 [53]. All patients were advised to receive GnRHa for at least 2 years. The rates of early menopause were 22.8% (21/92) in the sequential group and 23.1% (18/78) in the simultaneous group (simultaneous vs. sequential: OR 1.01; P = 0.969; age-adjusted OR 1.13; P = 0.737). The median menstruation resumption period was 12.0 months and 10.3 months for the sequential and simultaneous groups, respectively (HR 0.83; P = 0.274; age-adjusted HR 0.90; P = 0.567). During a median follow-up time of 56.9 months (IQR 49.5–72.4 months), there were no significant differences in disease-free survival (P = 0.290) or in overall survival (P = 0.514) between the two groups.

In an exploratory analysis of phase III TEXT and SOFT trials, 1872 patients who received adjuvant chemotherapy for HR+, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated GnRHa triptorelin were analyzed [54]. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, landmark analysis was implemented to re-define BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 months in TEXT and 8.1 months from enrollment to landmark in SOFT). The median duration of adjuvant chemotherapy was 18 weeks in both groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. After postlandmark median follow-up of about 5 years, post-landmark BCFI was found to be statistically similar between concurrent use of triptorelin with chemotherapy and sequential use of triptorelin after chemotherapy, either in the overall population (HR = 1.11; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women < 40 years at diagnosis (HR = 1.13) who are less likely to develop chemotherapy-induced amenorrhea.

Because the sequential use of GnRHa and chemotherapy showed similar ovarian preservation and survival outcomes when compared with simultaneous use ER+ premenopausal patients, addition of GnRHa to oncologic treatment can probably be delayed until menstruation resumption after chemotherapy. However, based on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, concurrent administration of OFS with chemotherapy is neither detrimental nor beneficial effect on the efficacy of adjuvant therapy which includes chemotherapy, with limited statistical power especially for the subgroup < 40 years.
