Abstract P1-05-21: Prognostic implications of oncogenetic pathway alterations in advanced male breast cancer

Abstract Background: Male breast cancer (MaBC) represents a rare entity, accounting for only 1% of all BC cases. In a previous work, we reported that MaBC recapitulates a unique mutational repertoire, harboring a distinct immune and genomic landscape across BC clinical subtypes. However, prognostic implications of pathway alterations in MaBC have not been reported before, leaving uncertainty regarding their significance and clinical actionability in MaBC, and similarity with female BC (FeBC) counterparts. In this work, we analyzed the prognostic implication of single gene alterations on MaBC-related survival. Methods: 17,759 breast tumors were tested by next-generation sequencing (NextSeq; WES, NovaSeq) and whole-transcriptome sequencing (NovaSeq; Caris Life Sciences, Phoenix, AZ). Real world overall survival (OS) was obtained from insurance claims and calculated from treatment start to last contact using Kaplan-Meier estimates. Statistical significance was determined by chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q<0.05). Results: Of 17,759 BC patients, there were 226 (1.3%) MaBC and 17,533 (98.7%) FeBC. In FeBC, GATA3 mutations (MT) were associated with better OS post-endocrine therapy (mOS: 49.6 vs. 43.1 months, HR 0.83, 95% CI 0.71-0.9, p<0.01) compared to GATA3 wild type (WT); whereas in MaBC, GATA3-MT was not associated with survival post-endocrine therapy (mOS: 54.8 vs. 60.8 months, HR 1.4, 95% CI 0.63-3.2, p=0.39) compared to GATA3-WT. The presence of TP53 mutations was adversely associated in FeBC, with a trend in MaBC. Poorer outcomes in TP53-MT vs WT were observed in FeBC patients post-endocrine therapy (FeBC: ΔmOS 25.2 months, HR 1.7, 95% CI 1.6-1.7, p<0.01 vs MaBC: ΔmOS 16.3 months, HR 1.08 95% CI 0.43-2.7, p=0.85), with CDK4/6 inhibitor (FeBC: ΔmOS 18.2 months, HR 1.7, 95% CI 1.6-1.9, p<0.01 vs MaBC: ΔmOS 19.5 months, HR 1.35, 95% CI 0.46-2.7, p=0.57) and in the post-chemotherapy setting (FeBC: ΔmOS 18 months HR 1.3, 95% CI 1.3-1.4, p<0.01 vs MaBC: ΔmOS 34 months HR 1.7, 95% CI 0.93-3.4, p=0.07). Additionally, CDH1, BRCA2 and PIK3CA mutations appeared to have no prognostic role in both MaBC and FeBC. The proportion of HR+/HER2- subtype was 72.12% in MaBC and 54% in FeBC. The results in the HR+/HER2-MaBC subgroup were consistent with those reported from the overall cohort. The number of HR+/HER2- MaBC with mutations in ESR1 (n=7), AKT1 (n=2), PTEN (n=8), mTOR (n=0), CDK4 (n=0), Rb1 (n=2), as well as other cancer susceptibility genes were very infrequent. Conclusions: MaBC may recapitulate a unique tumorigenic trajectory that differs from FeBC, as suggested by the dissimilar prognostic significance of selected genomic alterations. These data warrant further confirmation toward the goal of understanding sex-defined differences in BC and potential for tailored therapeutic strategies. Citation Format: Dario Trapani, Sachin Kumar Deshmukh, Sharon Wu, Joanne Xiu, Daniel L. Abravanel, Priya Jayachandran, Nancy U. Lin, Giuseppe Curigliano, Philip Spanheimer, Milan Radovich, Stephanie L. Graff, Maryam Lustberg, George W. Sledge Jr, Sara M. Tolaney, Jose P. Leone. Prognostic implications of oncogenetic pathway alterations in advanced male breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-05-21.