Synapse - Genomic methods identify homologous recombination deficiency in pancreas adenocarcinoma and optimize treatment selection

Genomic methods identify homologous recombination deficiency in pancreas adenocarcinoma and optimize treatment selection Journal Article

Authors:	Park, W.; Chen, J.; Chou, J. F.; Varghese, A. M.; Yu, K. H.; Wong, W.; Capanu, M.; Balachandran, V.; McIntyre, C. A.; El Dika, I.; Khalil, D. N.; Harding, J. J.; Ghalehsari, N.; McKinnell, Z.; Chalasani, S. B.; Makarov, V.; Selenica, P.; Pei, X.; Lecomte, N.; Kelsen, D. P.; Abou-Alfa, G. K.; Robson, M. E.; Zhang, L.; Berger, M. F.; Schultz, N.; Chan, T. A.; Powell, S. N.; Reis-Filho, J. S.; Iacobuzio-Donahue, C. A.; Riaz, N.; O'Reilly, E. M.
Article Title:	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. ©2020 American Association for Cancer Research.
Journal Title:	Clinical Cancer Research
Volume:	26
Issue:	13
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2020-07-01
Start Page:	3239
End Page:	3247
Language:	English
DOI:	10.1158/1078-0432.Ccr-20-0418
PUBMED:	32444418
PROVIDER:	scopus
PMCID:	PMC7380542
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85087529675&doi=10.1158%2f1078-0432.CCR-20-0418&partnerID=40&md5=e6927945db9b835d348d61dd96bf7f7c
Notes:	Article -- Export Date: 3 August 2020 -- Source: Scopus