Couch, F. J.

Abstract Introduction: Patients with ER+/HER2- breast cancer associated with germline pathogenic variants (PVs) in BRCA1, BRCA2 and CHEK2 exhibit distinct clinicopathological features compared to sporadic cases. However, the optimal endocrine therapy strategies for these patients remain undefined. The Breast Cancer Index (BCI) is a validated gene expression-based signature that stratifies patients based on the risk of overall (0-10 years) and late (post-5 years) distant recurrence and predicts the likelihood of benefit from extended endocrine therapy (EET) in early-stage, HR+ breast cancer. Here we utilize BCI to investigate endocrine sensitivity and the predicted EET benefit in a cohort of ER+/HER2- breast cancer patients with BRCA1, BRCA2 and CHEK2 PVs. Methods: BRCA1, BRCA2 and CHEK2 PV carriers with ER+/HER2- breast cancer diagnosed at Mayo Clinic between 1996 and 2024 at Mayo Clinic were identified from a registry tracking germline test result. For comparison, we utilized the BCI Registry, a prospective, multi-institutional tumor registry of patients with early-stage ER+/HER2- breast cancer undergoing BCI testing, regardless of germline PV status. The analysis was restricted to women with invasive, early-stage locoregional breast cancer and available pre-treatment tumor specimens. BCI testing was performed by RT-PCR blinded to clinical outcome. BCI prognostic and BCI predictive categories were compared between the Mayo Clinic germline PV cohort and the BCI Registry using descriptive statistics and Fisher’s exact test. Results: The final analysis included 123 PVcarriers (BRCA1: 36; BRCA2: 40; CHEK2: 47) from the MayoClinic cohort and 2,563 women from the BCI Registry. The proportion of patientsdiagnosed before age 50 was higher among PV carriers—52.8% in BRCA1,50.0% in BRCA2, and 21.3% in CHEK2—compared to 7.0% in the BCIRegistry. PV carriers were also more likely to be premenopausal andnode-positive at diagnosis. Based on BCI score, a significant higher proportionof BRCA1 (75.0%, p=0.002) andBRCA2 (70.0%, p=0.01) PV carriers wereclassified as high risk, compared to 48.5% of patients in the BCI Registry, butno significant difference was seen for CHEK2 PV carriers (46.8%,p=0.88). A significantly higher proportion of BRCA1 PV carriers werepredicted to benefit from EET compared to the BCI Registry cohort (77.8% vs.33.9%, p<0.001), whereas no significant differences in BCI Predictivecategories were observed for BRCA2 or CHEK2 PV carriers. Overall,compared to breast cancer cases in the BCI registry, a significant differencein the distribution of the combined BCI prognostic and predictive categorieswas noted for BRCA1 (p<0.001)and BRCA2 (p=0.02) PV carriers,but not for CHEK2 PV carriers (p=0.66). In particular, BRCA1 andBRCA2 PV carriers were enriched for high-risk tumors with a high likelihoodof EET benefit (66.7% and 37.5%, respectively vs 25.1%, p<0.001 and p=0.02),whereas only a small non-significant increase was observed for CHEK2 PVcarriers (29.8% vs 25.1%, p=0.66) compared to breast cancer cases in the BCIRegistry. Conclusions: Genomicclassification by BCI reveals distinct patterns of endocrine sensitivity andpredicted EET benefit among germline PV carriers, particularly in BRCA1and BRCA2 PV carriers. These findings warrant further investigation andmay inform personalized endocrine therapy strategies for women with germlinePV-associated ER+/HER2- breast cancer. Citation Format: S. Yadav, B. O'Neal, S. Yasir, N. Siuliukina, A. Karki, Y. Zhang, A. K. Anderson, K. Treuner, M. P. Goetz, F. J. Couch. Endocrine Sensitivity and Predicted Benefit of Extended Endocrine Therapy based on Breast Cancer Index (BCI) in BRCA1, BRCA2 and CHEK2 Pathogenic Variant Carriers with ER+/HER2- Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-08-25.

Abstract Background: Smoking, a known risk factor for numerous cancers, negatively impacts long-term survival in breast cancer (BC) survivors (Parada H Jr et al., 2017; Pierce et al., 2019). This study aims to characterize baseline smoking behaviors among breast cancer patients who self-reported smoking during an initial survey. Objectives: To assess attributes of patients self-reporting as current smokers near BC diagnosis, examining demographics, habits, quality of life, cancer treatments, comorbidities, and finances. Methods: Patients with newly diagnosed BC seen at Mayo Clinic Rochester between 2014-2024 were invited to enroll in the Mayo Clinic Breast Disease Registry. Consenting participants who completed self-reported questionnaires at baseline were included in this study. Smoking status and related variables at the time of survey completion were assessed via a baseline questionnaire, classifying participants as current, former, or never smokers. Of 3,959 participants completing baseline surveys, 3,729 were analyzed after excluding 103 with missing smoking data and 127 with their baseline survey returned >1-year post-diagnosis. Categorical variables were summarized with frequencies and percents, continuous variables with distributional statistics. Univariable associations with current smoking were assessed via two-sample t-tests (continuous) and chi-square or Fisher exact tests (categorical). Significant variables (p<0.05) were included in a multivariable logistic regression model. Results: Among 3,729 BC patients (mean age 58.3 years, SD 12.9), 99.1% were female, 97.1% White, and 98.7% non-Hispanic. Only 2.7% reported financial difficulty, 56.4% had a bachelor's degree or higher, 81.7% were married or equivalent, and 21.7% consumed ≥5 alcoholic drinks/week. Tumor stage distribution was as follows: Stage 0 (13.9%), Stage 1 (43.9%), Stage 2 (28.9%), Stage 3 (8.9%), and Stage 4 (4.5%); 33.8% received chemotherapy, 56.5% radiotherapy, 63.6% endocrine therapy, and 42.2% underwent mastectomy. Current smokers (2.6%, n = 95) had a median diagnosis age of 59.1 (IQR 31.8-87.1),with 32.6% consuming ≥5 drinks/week (vs. 21.5% in non-smokers, univariable p = 0.012), 69.5% with less than a Bachelor’s degree (vs. 42.9%, p<0.001), 9.6% facing financial difficulty (vs. 2.5%, p<0.001), and 10.5% diagnosed within 270-365 days after survey return (vs. 4.2%, p = 0.022). Tumor stage showed 47% with Stage 1 (vs. 43.7%, p = 0.245); 33.7% received chemotherapy, 60.0% radiotherapy, and 58.9% endocrine therapy. Current smokers had a mean smoking initiation age of 19.9 (SD 6.2), smoked 12.5 cigarettes/day (SD 7.9) for 32.8 years (SD 14.1), with mean 22.3 pack-years (SD 17.2).Univariable associations of demographic and clinical characteristics with current smoking showed Compared to never or former smokers, current smokers at the time of survey took a longer time to return their baseline survey (p = 0.022), were more likely to consume five or more alcoholic drinks per week (p = 0.012), were more likely to have difficulty paying their bills (p<0.001) and were less likely to obtain a Bachelor's degree or higher (p<0.001). These associations remained significant after multivariable adjustment. Conclusion: Current smoking (2.6%) soon after a BC diagnosis was independently associated with delayed survey return, higher alcohol use, financial difficulty, and lower education. Assessing smoking status and referring patients to smoking cessation programs are critical for addressing these risk factors and improving health outcomes. These findings highlight distinct socioeconomic and behavioral profiles among current smokers, suggesting potential targets for tailored interventions. Citation Format: S. Hirani, R. A. Vierkant, N. L. Larson, S. D. D’Andre, F. J. Couch, J. E. Olson, K. J. Ruddy. Identifying Smoking-Related Factors in Breast Cancer Patients: Mayo Clinic Registry Insight [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-04-18.