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:
Notes: Article -- Export Date: 3 August 2020 -- Source: Scopus
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MSK Authors
  1. Joanne Fu-Lou Chou
    215 Chou
  2. Timothy Chan
    271 Chan
  3. Simon Nicholas Powell
    199 Powell
  4. Mark E Robson
    488 Robson
  5. Nadeem Riaz
    271 Riaz
  6. James Joseph Harding
    120 Harding
  7. Ghassan Abou-Alfa
    328 Abou-Alfa
  8. Liying Zhang
    113 Zhang
  9. Marinela Capanu
    275 Capanu
  10. Kenneth Ho-Ming Yu
    109 Yu
  11. Eileen O'Reilly
    461 O'Reilly
  12. Michael Forman Berger
    522 Berger
  13. David P Kelsen
    446 Kelsen
  14. Nikolaus D Schultz
    283 Schultz
  15. Xin Pei
    106 Pei
  16. Danny Nejad Khalil
    23 Khalil
  17. Jorge Sergio Reis
    403 Reis
  18. Vladimir Makarov
    44 Makarov
  19. Imane El Dika
    26 El Dika
  20. Wungki Park
    15 Park
  21. Winston Wong
    8 Wong
  22. Jiapeng Chen
    1 Chen