Alterations in driver genes are predictive of survival in patients with resected pancreatic ductal adenocarcinoma Journal Article


Authors: McIntyre, C. A.; Lawrence, S. A.; Richards, A. L.; Chou, J. F.; Wong, W.; Capanu, M.; Berger, M. F.; Donoghue, M. T. A.; Yu, K. H.; Varghese, A. M.; Kelsen, D. P.; Park, W.; Balachandran, V. P.; Kingham, T. P.; D’Angelica, M. I.; Drebin, J. A.; Jarnagin, W. R.; Iacobuzio-Donahue, C. A.; Allen, P. J.; O’Reilly, E. M.
Article Title: Alterations in driver genes are predictive of survival in patients with resected pancreatic ductal adenocarcinoma
Abstract: Background: KRAS, TP53, CDKN2A, and SMAD4 are established driver genes in pancreatic ductal adenocarcinoma (PDAC). This study was aimed at determining whether the mutational status of driver genes and those involved in DNA repair pathways are associated with clinical outcomes for individuals who undergo resection. Methods: Eligible individuals were those who underwent resection of PDAC and consented to targeted sequencing of their primary tumor via Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). Genomic alterations were determined on the basis of MSK-IMPACT results from formalin-fixed, paraffin-embedded samples. Associations between genomic alterations and clinical outcomes were assessed. Results: Targeted sequencing was performed on 283 primary tumors resected between 2004 and 2017. The median follow-up was 23 months among survivors. Alterations in KRAS and TP53 were associated with worse overall survival (OS) in comparison to wild type (median for KRAS, 38.8 months [95% CI, 33.0-45.5 months] vs 91.0 months [95% CI, 34.8 months to not available (NA)]; P =.043; median for TP53, 37.4 months [95% CI, 32.1-42.8 months] vs 65.0 months [95% CI, 33.0 months to NA]; P =.035). KRAS G12D mutations were associated with worse OS (median, 31.6 months [95% CI, 25.3-45.5 months] vs 39.2 months [95% CI, 37.4-75.2 months]; P =.012). TP53 truncating mutations (median, 39.6 months [95% CI, 32.4-75.2 months] vs 33.9 months [95% CI, 24.0-39.0 months]; P =.020) and those associated with loss of heterozygosity (median, 26.6 months [95% CI, 21.6-44.2 months] vs 39.2 months [95% CI, 34.5-49.1 months]; P =.048) had decreased OS. TP53 alterations were independently associated with OS in a multivariate analysis (hazard ratio, 1.54; 95% CI, 1.01-2.33; P =.042). Individuals with germline alterations in homologous recombination deficiency (HRD) genes had improved OS in comparison with those without them (median, not reached vs 37.0 months; 95% CI, 33.0-49.8 months; P =.035). Conclusions: In patients with resected PDAC, genomic alterations in KRAS and TP53 are associated with worse outcomes, whereas alterations in HRD genes are associated with a favorable prognosis. Further studies are needed to better define these alterations as biomarkers in resected PDAC. © 2020 American Cancer Society
Keywords: homologous recombination; resection; pancreatic ductal adenocarcinoma; survival outcomes; driver gene alterations
Journal Title: Cancer
Volume: 126
Issue: 17
ISSN: 0008-543X
Publisher: Wiley Blackwell  
Date Published: 2020-09-01
Start Page: 3939
End Page: 3949
Language: English
DOI: 10.1002/cncr.33038
PUBMED: 32573775
PROVIDER: scopus
PMCID: PMC7424538
DOI/URL:
Notes: Article -- Export Date: 1 September 2020 -- Source: Scopus
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Joanne Fu-Lou Chou
    336 Chou
  2. Anna Mary Varghese
    146 Varghese
  3. Marinela Capanu
    389 Capanu
  4. Peter Allen
    501 Allen
  5. Kenneth Ho-Ming Yu
    165 Yu
  6. William R Jarnagin
    911 Jarnagin
  7. T Peter Kingham
    620 Kingham
  8. Eileen O'Reilly
    794 O'Reilly
  9. Michael Forman Berger
    770 Berger
  10. David P Kelsen
    538 Kelsen
  11. Jeffrey Adam Drebin
    168 Drebin
  12. Wungki Park
    99 Park
  13. Winston Wong
    29 Wong