Abstract P4-14-01: Estrogen levels in premenopausal patients (pts) with hormone-receptor positive (HR+) early breast cancer (BC) receiving adjuvant triptorelin (Trip) plus exemestane (E) or tamoxifen (T) in the SOFT trial: SOFT-EST substudy final analysis
Authors: Bellet M , Gray K , Francis P , Láng I , Ciruelos E , Lluch A , Ángel Climent M , Catalán G , Avella A , Bohn U , González-Martin A , Zaman K , Ferrer R , Azaro A , Rajasekaran A , De la Peña L , Fleming G , Regan MM 
Published: May 2019

Abstract
Background: Optimal endocrine therapy for premenopausal pts with early HR+ BC may depend on complete estrogen suppression with GnRH analog, which is crucial when using concurrent aromatase inhibitors (AIs). SOFT-EST is a prospective substudy of the phase 3 SOFT trial aiming to describe estradiol (E2), estrone (E1) and estrone sulphate (E1S) during the first 4 years (y) of monthly Trip+E/T and to assess if there were suboptimally estrogen suppressed (SES) pts in the E+Trip group. Secondary objectives included associations of baseline (BL) factors with SES, early SES with later SES, and SES with disease-free survival (DFS; exploratory objective).
Methods: Patients from select centers who consented and enrolled in SOFT, selected Trip as ovarian function suppression method, and were randomized to E+Trip or T+Trip were eligible for SOFT-EST until the accrual goal (120 pts: 90 E+Trip; 30 T+Trip). Prem status for SOFT eligibility was based on local E2. Blood sampling timepoints were 0, 3, 6, 12, 18, 24, 36 & 48 months (m) until Trip stopped. Serum estrogens were measured centrally by high specificity/sensitivity GC/MSMS and were not available during the study. For 4y analyses, SES was defined as E2 levels &gt;2.72 pg/mL in ≥2 post-BL samples (E2 levels not consistent with postmenopausal (PM) status on AIs [Smith IE, JCO 2006]), or vaginal bleeding &gt;3m after Trip start, or pregnancy. We explored 2 additional cutoffs: &gt;10 pg/mL (clearly inconsistent with PM status on AIs) and &gt;20 pg/mL (inconsistent with GnRH analog-related PM status). The analysis is intention-to-treat based on E/T assignment; as-treated analyses are forthcoming.
Results: From Mar 2009 to Jan 2011,109 pts (E/T=83/26) started Trip and had ≥2 samples drawn. In pts assigned E+Trip, median reductions from BL in E1, E2 and E1S were &gt;95% at all timepoints and significantly lower than in T+Trip. Post-BL E2 geometric mean ranged 0.8-1.3 pg/mL in E+Trip and 16.5-18.3 pg/mL in T+Trip. 21 (25%), 11 (13%) and 6 (7%) pts assigned to E+Trip had E2&gt;2.72, &gt;10, and &gt;20 pg/mL in ≥2 post BL samples or vaginal bleeding (n=3), respectively. Early SES [(≥1 E2 value &gt;2.72 pg/mL or vaginal bleeding in the firsty] predicted later SES [≥1 E2 value &gt;2.72 or vaginal bleeding thereafter (n=1); p&lt;0.001]. BL factors related to SES were higher E2, lower FSH and lower LH values (p=0.02, p&lt;0.01, p&lt;0.01 respectively). 12m FSH levels were not related to SES. In pts assigned E+Trip, after 6y median follow-up, DFS events were seen in 0 of 21 pts with SES vs 5 of 62 pts without SES.
Conclusions: Most pts on E+Trip had a profound E2 drop consistent with postmenopausal status on AI, but &gt;20% assigned to E+Trip had ≥2 E2 values &gt;2.72 pg/mL and 4% had vaginal bleeding, with those having higher E2, lower FSH/LH at BL being at higher risk. SES at 12m predicted subsequent SES. Few DFS events limit the ability to assess clinical relevance of SES with disease outcomes.
BL characteristicsN-109Prior chemo60 (55%)Amenorrhea39 (36%)Age &lt;35y8 (7%) Median (range)Age, y44 (25-53)BMI, kg/m224 (22-28)Estrogen (pg/mL) E252 (7-119)E141 (24-70)E1S894 (304-1320)FSH/LH (IU/L) FSH15 (7-47)LH11 (6-26)
Citation Format: Bellet M, Gray K, Francis P, Láng I, Ciruelos E, Lluch A, Ángel Climent M, Catalán G, Avella A, Bohn U, González-Martin A, Zaman K, Ferrer R, Azaro A, Rajasekaran A, De la Peña L, Fleming G, Regan MM. Estrogen levels in premenopausal patients (pts) with hormone-receptor positive (HR+) early breast cancer (BC) receiving adjuvant triptorelin (Trip) plus exemestane (E) or tamoxifen (T) in the SOFT trial: SOFT-EST substudy final analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-01.