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Clinico-genomic Characterization of ATM and HRD in Pancreas Cancer: Application for Practice
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DOI：10.1158/1078-0432.CCR-22-1483.png)
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Abstract
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Purpose: Characterizing germline and somatic ATM variants (gATMm, sATMm) zygosity and their contribution to homologous recombination deficiency (HRD) is important for therapeutic strat-egy in pancreatic ductal adenocarcinoma (PDAC).Experimental Design: Clinico-genomic data for patients with PDAC and other cancers with ATM variants were abstracted. Genomic instability scores (GIS) were derived from ATM-mutant cancers and overall survival (OS) was evaluated. Results: Forty-six patients had 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% confidence interval (CI): 12.3-not reached(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; P = 0.025). GIS was computed for 33 patients with PDAC and compared with 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 var-iants were mutually exclusive with TP53. Other canonical driver gene (KRAS, CDKN2A, SMAD4) variants were less frequent in ATM-mutant PDAC.Conclusions: ATM variants in PDAC represent a distinct bio-logic group and appear to have favorable OS. Nonetheless, path-ogenic ATM variants do not confer an HRD signature in PDAC and ATM should be considered as a non-core HR gene in this disease.
Keywords:
COLLOID CARCINOMA
SURVIVAL
MUTATIONS
ADENOCARCINOMA
BREAST
MULTICENTER
DEFICIENCY
LANDSCAPE
THERAPIES
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