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

Caitlin A. McIntyre, Sharon A. Lawrence, Allison L. Richards, Joanne F. Chou, Winston Wong, Marinela Capanu, Michael F. Berger, Mark T.A. Donoghue, Kenneth H. Yu, Anna M. Varghese, David P. Kelsen, Wungki Park, Vinod P. Balachandran, T. Peter Kingham, Michael I. D’Angelica, Jeffrey A. Drebin, William R. Jarnagin, Christine A. Iacobuzio-Donahue, Peter J. Allen, Eileen M. O’Reilly

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3939-3949
Number of pages11
JournalCancer
Volume126
Issue number17
DOIs
StatePublished - Sep 1 2020
Externally publishedYes

Keywords

  • driver gene alterations
  • homologous recombination
  • pancreatic ductal adenocarcinoma
  • resection
  • survival outcomes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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