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Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection.


ABSTRACT:

Purpose

Genomic methods can identify homologous recombination deficiency (HRD). Rigorous evaluation of their outcome association to DNA damage response-targeted therapies like platinum in pancreatic ductal adenocarcinoma (PDAC) is essential in maximizing therapeutic outcome.

Experimental design

We evaluated progression-free survival (PFS) and overall survival (OS) of patients with advanced-stage PDAC, who had both germline- and somatic-targeted gene sequencing. Homologous recombination gene mutations (HRm) were evaluated: BRCA1, BRCA2, PALB2, ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1 HRm status was grouped as: (i) germline versus somatic; (ii) core (BRCAs and PALB2) versus non-core (other HRm); and (iii) monoallelic versus biallelic. Genomic instability was compared using large-scale state transition, signature 3, and tumor mutation burden.

Results

Among 262 patients, 50 (19%) had HRD (15% germline and 4% somatic). Both groups were analyzed together due to lack of difference in their genomic instability and outcome. Median [95% confidence interval (CI)] follow-up was 21.9 (1.4-57.0) months. Median OS and PFS were 15.5 (14.6-19) and 7 (6.1-8.1) months, respectively. Patients with HRD had improved PFS compared with no HRD when treated with first-line (1L) platinum [HR, 0.44 (95% CI: 0.29-0.67); P < 0.01], but not with 1L-non-platinum. Multivariate analysis showed HRD patients had improved OS regardless of their first-line treatment, but most had platinum exposure during their course. Biallelic HRm (11%) and core HRm (12%) had higher genomic instability, which translated to improved PFS on first-line platinum (1L-platinum) versus 1L-non-platinum.

Conclusions

Pathogenic HRm identifies HRD in patients with PDAC with the best outcome when treated with 1L-platinum. Biallelic HRm and core HRm further enriched benefit from 1L-platinum from HRD.

SUBMITTER: Park W 

PROVIDER: S-EPMC7380542 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection.

Park Wungki W   Chen Jiapeng J   Chou Joanne F JF   Varghese Anna M AM   Yu Kenneth H KH   Wong Winston W   Capanu Marinela M   Balachandran Vinod V   McIntyre Caitlin A CA   El Dika Imane I   Khalil Danny N DN   Harding James J JJ   Ghalehsari Nima N   McKinnell Zoe Z   Chalasani Sree B SB   Makarov Vladimir V   Selenica Pier P   Pei Xin X   Lecomte Nicolas N   Kelsen David P DP   Abou-Alfa Ghassan K GK   Robson Mark E ME   Zhang Liying L   Berger Michael F MF   Schultz Nikolaus N   Chan Timothy A TA   Powell Simon N SN   Reis-Filho Jorge S JS   Iacobuzio-Donahue Christine A CA   Riaz Nadeem N   O'Reilly Eileen M EM  

Clinical cancer research : an official journal of the American Association for Cancer Research 20200522 13


<h4>Purpose</h4>Genomic methods can identify homologous recombination deficiency (HRD). Rigorous evaluation of their outcome association to DNA damage response-targeted therapies like platinum in pancreatic ductal adenocarcinoma (PDAC) is essential in maximizing therapeutic outcome.<h4>Experimental design</h4>We evaluated progression-free survival (PFS) and overall survival (OS) of patients with advanced-stage PDAC, who had both germline- and somatic-targeted gene sequencing. Homologous recombin  ...[more]

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