Association of germline ATM mutations and survival in pancreatic cancer

Purpose: Characterizing germline and somatic ATM variants (gATMm, sATMm), zygosity and their contribution to homologous recombination deficiency (HRD) is important for therapeutic strategy in pancreas ductal adenocarcinoma (PDAC). Methods: Clinico-genomic data for patients with PDAC and other cancers with ATM variants was abstracted. Genomic instability scores (GIS) were derived from ATM-mutant cancers and overall survival (OS) was evaluated. Results: Forty-six patients with PDAC and pathogenic ATM variants including 24 (52%) stage III/IV; gATMm (N=24) and sATMm (N=22). Twenty-seven (59%) had biallelic, 15 (33%) monoallelic, and 4 indeterminate (8%) variants. Median OS for advanced stage cohort at diagnosis (N=24) was 19.7 months (95% CI: 12.3-NR); 27.1 months (95% CI: 22.7-NR) for gATMm (n=11) and 12.3 months for sATMm (n=13) (95% CI: 11.9-NR)) for sATMm (p=0.025). GIS was computed for 33 patients with PDAC and compared to other ATM-mutant cancers enriched for HRD. The median was lower (median, 11; range, 2-29) relative to breast (18, 3-55) or ovarian (25, 3-56) ATM-mutant cancers (p<0.001 and p=0.003, respectively). Interestingly, biallelic pathogenic ATM variants were mutually exclusive with TP53. Other canonical driver gene (KRAS, CDKN2A, SMAD4) variants were less frequent in ATM-mutant PDAC. Conclusion: ATM variants in PDAC represent a distinct biologic group and appear to have favorable OS. Nonetheless, pathogenic ATM variants do not confer an HRD signature in PDAC and ATM should be considered as a non-core HR gene in this disease.

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Clinico-genomic Characterization ofATMand HRD in Pancreas Cancer: Application for Practice

Park

O’Connor

Bandlamudi

et al. 2022

Clinical Cancer Research

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Association of germline ATM mutations and survival in pancreatic cancer

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Clinico-genomic Characterization ofATMand HRD in Pancreas Cancer: Application for Practice

Clinico-genomic Characterization ofATMand HRD in Pancreas Cancer: Application for Practice

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