Distinct HER2- breast cancer traits among subethnic Hispanics of South Florida

Introduction: Studies with representative numbers of the predominant Caribbean and South American subethnic Hispanics of South Florida (SHFL) are limited. This study explored traits potentially linked to breast cancer susceptibility risk among SHFL, which comprise 45% of Sylvester Cancer Center's breast cancer patients. Methods: A cohort of 971 SHFL females with breast cancer records between 1/1/2019 and 12/1/2024 was extracted from our medical record database. Data included age, ethnicity, menopausal state, cancer stage, menarche age, BRCA variants, hormone receptors (HR) and HER2 status. Human Epidermal growth factor Receptor-2 negative (HER2-) tumors (n=802) were re-evaluated for reclassification to HER2-Low using criteria: HER2 immunohistochemistry (IHC) = 1+ or 2+ with fluorescence in-situ hybridization (FISH) negative. Association of risk factors with Triple-Negative Breast Cancer (TNBC) vs non-TNBC (defined as positivity for HR and/or HER2) was assessed using logistic regression. Multiplicity in univariable analysis was reported by Q-values (p-values adjusted for false discovery rate). Results: At diagnosis, 47% of the cohort was pre-menopausal, with 25% aged ≤45 and 13% aged ≤40. Among those diagnosed with stage 4, 24% were also aged ≤45. 71% of HR+/HER2- tumors were reclassified to HER2-Low, along with 50% of all TNBC. Univariable logistic analysis showed that younger ages (≤45 vs >45: OR=1.69, 95%CI: 1.11-2.56; q=0.042) and greater BRCA burden (1-unit increase OR=2.70, 95%CI: 1.38-5.28; q=0.017) were significantly associated with TNBC. Multivariable analysis including age, HER2-, HER2-Low, BRCA and interaction terms revealed significant positive interaction between BRCA and TNBC (p interaction =0.018) which was weakened in HER2-Low tumors. Later cancer stages were associated with less years of estrogen exposure when compared to stages 0/1 (p=0.008 for stages 2/3 and p=0.038 for stage 4). Prevalence of early menarche (age <10) was 7% whereas late menarche (age >14) was 14%. Conclusions: Our findings reveal distinct patterns and novel associations of BRCA burden, HER2-Low patterns, estrogen exposure and ages at diagnosis and menarche in SHFL with breast cancer. For instance, in contrast to the usual association of breast cancer with older women, nearly half of our cohort was pre-menopausal, with one quarter aged 45 or younger. This is concerning as younger patients may not be old enough to benefit from preventive mammograms and are more likely to have TNBC (the most aggressive tumors with the least treatment options). Reclassification of most HER2- tumors into HER2-Low potentially expands their therapy options to include the first trastuzumab-based therapy for HER2-Low. A weakened interaction of BRCA with TNBC in HER2-Low suggests distinct genetic basis compared to HER2- IHC=0 tumors. Lastly, prevalence of both early and late menarches was elevated compared to the general population.