Paesmans, Marianne

ImportanceYoung women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers.ObjectiveTo investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers.Design, Setting, and ParticipantsInternational, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023.ExposurePregnancy after breast cancer.Main Outcomes and MeasuresPrimary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer–specific survival, overall survival, pregnancy, and fetal and obstetric outcomes.ResultsOf 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (≥37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer–specific survival and overall survival.Conclusions and RelevanceIn this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival.Trial RegistrationClinicalTrials.gov Identifier: NCT03673306

522 Background: Our preclinical findings suggest a role for the mevalonate pathway (MVA) in treatment resistance in HER2+ BC by providing alternative growth and survival signaling to bypass potent HER2 blockade, which could be overcome by the MVA inhibitors statins and nitrogen-containing bisphosphonates (NBs). Here we explored the effect of MVA inhibitors’ use on pts’ outcomes in the ALTTO trial (BIG2-06; NCT00490139). Methods: In the ALTTO trial, 8381 pts with HER2+ BC were randomized to 1 year of adjuvant lapatinib (L), trastuzumab (T), L+T, or T→L. All pts with documented treatment start with statins or NBs < 1 year after randomization were considered as MVA inhibitors users. Survival curves, with a median follow-up of 6.9 years, for disease-free survival (DFS), distant relapse-free interval (DRFI), BC-specific survival (BCSS), and overall survival (OS) according to MVA inhibitors use were estimated by the Kaplan Meier method and Log-rank test. All multivariate survival analyses employed a Cox proportional hazards regression model, adjusting for tumor size, nodal status, hormonal receptor (HoR), menopausal status, BMI, timing of chemo, and randomization arm. We considered interactions terms in Cox’s model between MVA inhibitors use and randomization arm, hormonal status, and BMI group. Results: Among the 8381 pts included in this study, 493 and 299 were statins or NBs users, respectively. Table 1 summarizes the significant differences in pts’ characteristics according to MVA inhibitors use ( P <.005). In multivariate survival analyses, only NBs use was associated independently with better BCSS (HR, 0.44; 95% CI, 0.23 - 0.84; P = 0.014). Statin use was not independently associated with prognosis but only in interaction with pts characteristics: worse DFS, BCSS and OS in pts treated with L+T, worse DRFI and OS in pts treated with HoR+ BC (respective interaction P-values <0.05 in the Cox’s model). Conclusions: NBs independently predicted improved BC-specific outcome in pts with HER2+ BC treated with adjuvant anti-HER2 therapy. Statin use was associated with an inferior outcome in pts with HoR+ disease and/or those treated with L+T. Whether this inferior association in statin users may reflect the underlying predisposition factors that can weaken the efficacy of anti-HER2 treatments and whether this effect was observed only in the L+T arm due to the more potent inhibition of the HER2 signaling pathway remain open questions. Further clinical investigations on the impact of MVA inhibitors on the outcome of pts with HER2+ BC are warranted. [Table: see text]

524 Background: PREDICT+ is a widely used, free, online tool based on traditional clinico-pathological features, including HER2, developed to predict individual mortality of EBC pts and to aid clinical decision making for adjuvant therapy. However, its prognostic role in HER2+ EBC pts treated with chemotherapy (CT) and anti-HER2 therapies remains unclear. We aimed to investigate the prognostic performance of PREDICT+ in HER2+ EBC pts enrolled in the ALTTO trial. Methods: ALTTO is a phase III study evaluating adjuvant lapatinib (L) +/- trastuzumab (T) vs. T alone in pts with HER2+ EBC. Pts enrolled in the ALTTO trial and receiving T-based therapy started concurrently with CT were eligible for this analysis. We calculated PREDICT+ estimates using variables extracted from ALTTO database, blinded to pts outcomes. The prognostic performance of PREDICT+ was evaluated by assessing its calibration and discriminatory accuracy. For calibration, median predicted 5-year (5-yr) overall survival (OS) was compared to observed 5-yr OS. For discriminatory accuracy, the area under the receiver-operator characteristic (AUC under the ROC) curve and corresponding 95% confidence intervals (CI) for predicted 5-yr OS were calculated. Subgroup analyses were performed according to type of anti-HER2 therapy, type of CT, age, hormone receptor (HR) status, nodal status and tumor size. Results: This analysis included 2,794 pts. After a median follow-up of 6.0 years (IQR, 5.8-6.7), 182 deaths were observed. Overall, PREDICT+ underestimated 5-yr OS by 6.7% (95% CI, 5.8-7.6): observed 5-year OS was 94.7% vs. predicted 88.0%. The underestimation was consistent across all subgroups (Table). For discriminatory accuracy, AUC under the ROC curve was 73.7% (95%CI 69.7-77.8) in the overall population, ranging between 61.7% and 77.7% across the analysed subgroups. Conclusions: In HER2+ EBC pts enrolled in the ALTTO trial, the PREDICT+ score highly underestimated OS. The low performance of this prognostic tool was consistent across all pts subgroups. PREDICT+ should be used with caution to give prognostic estimation in HER2+ EBC pts treated in the modern era with effective chemotherapy and anti-HER2 targeted therapies.[Table: see text]