Dataset Information

Clinico-genomic Characterization of ATM and HRD in Pancreas Cancer: Application for Practice.

ABSTRACT:

Purpose

Characterizing germline and somatic ATM variants (gATMm, sATMm) zygosity and their contribution to homologous recombination deficiency (HRD) is important for therapeutic strategy 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 variants 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 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.

SUBMITTER: Park W

PROVIDER: S-EPMC9634347 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

Clinico-genomic Characterization of ATM and HRD in Pancreas Cancer: Application for Practice.

Park Wungki W O'Connor Catherine A CA Bandlamudi Chaitanya C Forman Daniella D Chou Joanne F JF Umeda Shigeaki S Reyngold Marsha M Varghese Anna M AM Keane Fergus F Balogun Fiyinfolu F Yu Kenneth H KH Kelsen David P DP Crane Christopher C Capanu Marinela M Iacobuzio-Donahue Christine C O'Reilly Eileen M EM

Clinical cancer research : an official journal of the American Association for Cancer Research 20221101 21

<h4>Purpose</h4>Characterizing germline and somatic ATM variants (gATMm, sATMm) zygosity and their contribution to homologous recombination deficiency (HRD) is important for therapeutic strategy in pancreatic ductal adenocarcinoma (PDAC).<h4>Experimental design</h4>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.<h4>Results</h4>Forty-six p ...[more]

PMID: 36040493

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Project description:The chemotherapy backbone for patients with high-grade advanced epithelial ovarian cancer (HG-AOC) is carboplatin and paclitaxel followed by a maintenance therapy either with bevacizumab, with a PARP inhibitor, or with a combination of both, which is defined by the presence of a homologous recombination deficiency (HRD) and by the BRCA1/2 status. This study included patients with a primary diagnosis of HG-AOC treated between December 2019 and December 2021. The HRD status was measured using the Myriad myChoice® test on all the patients with an indication for tumor HRD testing. Germline testing was conducted on all the patients using the TruRisk® panel as recommended by the national guidelines. HRD testing was requested for 190 patients, and, for 163 patients (85.8%), an HRD test result was available. An HRD test result could not be reported in 27 patients due to an insufficient tumor yield. The median time that it took to receive the HRD test results was 37 days (range of 8-97). In total, an HRD was present in 44.7% (73/163) of the patients based on a GIS ≥ 42 in 42.9% of the patients and based on a tumor BRCA1/2 mutation in 3 cases (all with a GIS < 42). The germline testing results were available for 148 patients, and, in 18 patients (12.2%), a deleterious germline mutation was detected. Of the 27 patients without sufficient HRD testing, BRCA1/2 germline testing results were available for 19 patients (70.4%), and a deleterious germline mutation was detected in 2 patients (7.4%). The implementation of HRD testing is feasible, and the results become available for treatment decisions in a timely manner for most patients. The prerequisite for HRD testing with the Myriad myChoice® test is a sufficient amount of tumor tissue. The cotesting of HRD and BRCA1/2 germline testing should be aimed for in order to enable optimal and timely treatment decisions on maintenance therapy as well as to test patients on whom the HRD test will not be evaluable.

Dataset Information

Clinico-genomic Characterization of ATM and HRD in Pancreas Cancer: Application for Practice.

Purpose

Experimental design

Results

Conclusions

Publications

Clinico-genomic Characterization of ATM and HRD in Pancreas Cancer: Application for Practice.

Similar Datasets

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