Neighborhood disadvantage and correlation with differences in somatic mutations in a real-world breast cancer cohort.

Abstract

577 Background: African compared to European genetic ancestry is associated with lower prevalence of clinically actionable alterations despite comparable overall prevalence of driver alterations by ancestry group. This likely contributes to breast cancer (BC) disparity. A limitation of prior ancestry studies is lack of neighborhood-level disadvantage (ND) data, a contributor to BC disparity. The objective of this study was to investigate associations between ND and somatic mutations in a real-world BC cohort. Methods: Somatic mutations from primary and metastatic BC samples and genetic ancestry data were identified from MSK IMPACT (FDA-authorized sequencing panel). Samples sequenced between 2015-2025 were annotated and linked with census-tract level socioeconomic status (Yost Index 1-100; higher reflects increasing ND). Multivariate logistic regression analyzed associations between ND and somatic mutations, adjusting for covariates (FDR p<0.05). Results: 6703 samples (62% primary, 38% metastatic) were analyzed. Mean age was 60 (SD 13). Mean Yost was 26 (SD 24). 67% had ER+/HER2- disease, 9.7% had ER+/HER2+, 5.1% had ER-/HER2+, and 19% had ER-/HER2-. Adjusting for age, BMI, ancestry, and subtype, patients from ND had lower odds of CDH1 (OR 0.99, 95% CI 0.98- 0.99, p<0.001), BRCA1 (OR 0.96, 95% CI 0.94-0.99, p=0.021), and AKT1 (OR 0.98, 95% CI 0.97- 0.99, p=0.006) somatic mutations in metastatic samples. Conclusions: We identify novel associations between ND and somatic mutations. Notably, patients with ND had lower odds of actionable BRCA1 and AKT1 mutations. This highlights the importance of ensuring patients of diverse ancestry and ND have equitable inclusion in clinical sequencing workflows to improve identification of actionable mutations in all populations. Genetic ancestry (GA) and somatic mutational frequency by Yost.     TotalN=6703 1 Yost 1-20(Most Advantaged)N=3601 1 Yost 21-40N=1539 1 Yost 41-60N=826 1 Yost 61-80N=477 1 Yost 81-100(Most Disadvantaged) N=260 1 p-value 2 European GA* 0.75(0.36) 0.83(0.30) 0.72(0.38) 0.64(0.39) 0.58(0.39) 0.42(0.35) <0.001 African GA* 0.12(0.27) 0.04(0.16) 0.15(0.30) 0.21(0.34) 0.25(0.36) 0.44(0.38) <0.001 East Asian GA* 0.05(0.21) 0.05(0.21) 0.06(0.22) 0.06(0.21) 0.07(0.23) 0.04(0.17) <0.001 South Asian GA* 0.06(0.16) 0.06(0.17) 0.05(0.15) 0.06(0.17) 0.04(0.12) 0.03(0.08) <0.001 Native American GA* 0.03(0.10) 0.01(0.07) 0.03(0.10) 0.04(0.12) 0.06(0.16) 0.08(0.17) <0.001 Mutational Frequency, metastases N=2536 1 N=1403 1 N=584 1 N=311 1 N=165 1 N=73 1 p-value 2 ^ CDH1 341(13%) 220(16%) 66(11%) 26(8.4%) 18(11%) 11(15%) <0.001 AKT1 127(5.0%) 74(5.3%) 34(5.8%) 12(3.9%) 4(2.4%) 3(4.1%) 0.006 BRCA1 21(0.8%) 13(0.9%) 7(1.2%) 1(0.3%) 0(0%) 0(0%) 0.021 *Calculated using >3,000 common SNP markers. ^MVA, control for age, BMI, ancestry, subtype. 1 Mean (SD), n (%). 2 Pearson’s Chi 2 test; Kruskal-Wallis rank sum test; Fisher’s exact test.