Germline non- <i>BRCA1/2</i> mutations and clinico-radio-pathologic features of early-onset breast cancer patients in Thailand.

e22594 Background: BRCA1/2 mutations account for the majority of early-onset breast cancer (BC); however, nearly half of pathogenic/likely pathogenic (P/LP) variants involve non- BRCA1/2 genes, leading to diverse clinical profiles. Data on these mutations in the Southeast Asian population remain scarce. Methods: Female BC patients diagnosed before 45 years of age at our tertiary referral center were tested for germline mutations using next-generation sequencing from 2020 to 2024. Retrospective chart reviews were conducted to collect demographic and clinical data. Descriptive statistics were applied, and Pearson’s Chi-square, linear-by-linear association, and Fisher’s exact tests were used to compare clinical variables between P/LP carriers and non-carriers. Results: Among 408 patients underwent germline testing, the mean age was 35 years (range 18-44), 24% having extremely dense breasts on mammography, 68.2% stage I-II disease, 18.5% triple negative breast cancer (TNBC), and 7.8% HER2-enriched subtypes. Of these, 64 (15.7%) carried at least one P/LP variant, including 15 TP53 , 13 ATM , 8 PALB2 , 7 BARD1 , 7 RAD50 , 4 RAD51D , 4 BRIP1 , 2 NF1 , 1 CDH1 , 1 CHEK2 , 1 NF1 with ATM , 1 PALB2 with ATM . The P/LP group had a higher rate of BC family history in first-degree relatives (FDR) (24.2% vs 8.0%, p &lt; 0.001), FDR with BC before 45 years (11.7% vs 2.7%, p = 0.005), multiple primary BC (12.5% vs 4.7%, p = 0.036), and HER2-positive (36.5% vs 23.2%, p = 0.042) compared to non-carriers. Among HER2-positive cases, TP53 carriers were more likely to be HER2-positive than non-carriers (72.7% vs 23.2%, p &lt; 0.001). No differences were observed between P/LP carriers and non-carriers in TNBC (16.7% vs 18.9%, p = 0.7) or HER2-enriched subtypes (5.6% vs 8.2%, p = 0.5). However, BARD1 carriers showed a higher incidence of TNBC (66.7% vs 18.9%, p = 0.015). The ratio of extremely dense breasts was similar between P/LP carriers and non-carriers (28.0% vs 23.6%, p = 0.95). No significant differences were found between P/LP carriers and non-carriers in the distribution of invasive ductal carcinoma (IDC) versus DCIS-IDC (30.0% vs 32.8%, p = 0.8), high-grade versus non-high-grade tumors (37.0% vs 37.8%, p = 0.9), lymphovascular invasion (LVI) versus no LVI (33.3% vs 27.0%, p = 0.5), or positive versus negative lymph node status (23.3% vs 35.2%, p = 0.2). Conclusions: Our study highlights the characteristics of young BC patients carrying germline non- BRCA1/2 mutations, which may differ from those of well-characterized BRCA1/2 carriers. Although no significant differences in pathologic features were observed between P/LP carriers and non-carriers, certain mutations, TP53 and BARD1 , exhibit distinct receptor expression patterns that may influence prognosis. To better understand the heterogeneity and behavior of these mutations, larger and more diverse studies, particularly across different racial groups, are essential.