Characterization of genomic alterations between local breast cancers and cutaneous metastases.

1038 Background: Cutaneous metastases (CM) are a distinct manifestation of advanced breast cancer (BC), yet their genomic alterations (GA) relative to primary tumors are incompletely defined. In this study, we aimed to identify similarities and differences between GA in local BC and CM. Methods: Local BC and CM were profiled by comprehensive next-generation sequencing (FoundationOne CDx). Genomic biomarkers included tumor mutational burden (TMB), microsatellite instability (MSI), homologous recombination deficiency signature (HRDsig), reported as a laboratory professional service, and GA prevalence. Odds ratios (ORs) for enrichment in local BC versus CM were calculated using Fisher’s Exact Test with false discovery rate (FDR) correction. Results: Across 14,769 BC and 1,731 CM cases, most had TMB-low (&lt;10 mutations/Megabase; 94% vs 90%), were not MSI-high (99%), and were HRDsig-negative (83% vs 87%), respectively. Among BC cases, the most prevalent GA included TP53 (54.1%), PIK3CA (34.5%), MYC (20.9%), RAD21 (19.0%), CCND1 (16.7%), and recurrent 11q13/8p12 amplicon–associated genes ( FGF19 , FGF3 , FGF4 , NSD3 , ZNF703 , and FGFR1 ; each 13–15%). Among CM cases, the most prevalent GA included TP53 (48.4%), PIK3CA (37.6%), MYC (22.7%), and RAD21 (20.0%), and also CDH1 (18.8%) and ESR1 (12.5%). Multiple genes differed significantly in prevalence between BC and CM, including enrichment of ESR1 , CDH1 , NOTCH1 , MAP3K1 , CTNNA1 , CBFB , NFE2L2 , AKT1 , BRAF , and GATA4 in CM, and higher frequencies of TP53 , MCL1 and KDM5A in BC biopsies (Table 1). In addition, several therapeutically relevant GA were observed at lower but clinically meaningful frequencies between BC and CM, such as alterations in the PI3K/AKT pathway beyond PIK3CA , including AKT2 (1.8% vs 2.4%), AKT3 (3.2% vs 3.6%), and PTEN (13.1% vs 13.0%); DNA damage repair genes, including BRCA1 (3.9% vs 2.7%), BRCA2 (4.1% vs 3.9%), PALB2 (1.1% vs 0.8%), RAD51 ( RAD51B/C/D combined 1.3% vs 1.1%), ATM (2.6% vs 1.9%), ATR (0.9% vs 0.7%), CHEK1 (0.1% vs 0%), and CHEK2 (1.5% vs 2.2%); and additional potentially actionable GA, such as the MTAP (4.0% vs 3.8%), SMARCA4 (1.0% vs 0.8%), CCNE1 (4.2% vs 5.3%), and ERBB2 (11.1% vs 11.3%) genes in local BC and CM biopsies, respectively. Conclusions: CM largely retain the GA profile of local BC, but may exhibit distinct enrichment of alterations in estrogen signaling, likely from selective pressure, cell adhesion, possibly due to more frequent lobular CDH1 -mutated BC involving skin, and oncogenic pathways. A substantial proportion of both BC and CM samples harbor targetable GA, underscoring opportunities for precision therapy not only in advanced disease, but also in early stages. Clinically significant genes with significant differences between local BC and CM. Gene BC (%) CM (%) Odds Ratio (CM vs BC) p-value (FDR adjusted) TP53 54.1 48.4 0.79 &lt;0.001 CDH1 11.4 18.8 1.80 &lt;0.001 ESR1 4.7 12.5 2.89 &lt;0.001 <jats:td colspan