Alterations in somatic driver genes are associated with response to neoadjuvant FOLFIRINOX in patients with localized pancreatic ductal adenocarcinoma Journal Article


Authors: Ecker, B. L.; Court, C. M.; Janssen, Q. P.; Tao, A. J.; D'Angelica, M. I.; Drebin, J. A.; Gonen, M.; O'Reilly, E. M.; Jarnagin, W. R.; Wei, A. C.; for the David M Rubenstein Center for Pancreatic Cancer Research Group at Memorial Sloan Kettering Cancer Center
Contributors: Walch, H. S.; Balachandran, V. P.; Crane, C. H.; Kingham, T. P.; Soares, K. C.; Iacobuzio-Donahue, C. A.; Vakiani, E.
Article Title: Alterations in somatic driver genes are associated with response to neoadjuvant FOLFIRINOX in patients with localized pancreatic ductal adenocarcinoma
Abstract: BACKGROUND: There is increased use of neoadjuvant fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the management of localized pancreatic ductal adenocarcinoma (PDAC), yet there are few validated biomarkers of treatment response. STUDY DESIGN: Consecutive patients (n = 196) with resectable, borderline resectable or locally advanced PDAC (2012-2019) receiving FOLFIRINOX as initial treatment and with targeted sequencing of a pretreatment biopsy were identified in a prospective institutional database. Genomic alterations were determined in the 4 driver mutations (KRAS, TP53, CDKN2A, SMAD4), and associations between genomic alterations and clinical outcomes were assessed. RESULTS: Alterations in KRAS (n = 172, 87.8%) and TP53 (n = 131, 66.8%) were common; alterations in CDKN2A (n = 49, 25.0%) and SMAD4 (n = 36, 18.4%) were less frequently observed. A total of 105 patients (53.6%) were able to undergo resection, of whom 8 (7.6%) had a complete/near-complete pathologic response. There were no somatic alterations associated with major pathologic response. Alterations in SMAD4 were associated with a lower rate of surgical resection (27.8% vs 59.4%, p < 0.001); this was additionally observed in a multivariable regression model accounting for resectability status (OR 0.35, 95% confidence interval [CI] 0.15-0.85). Thirty-three patients (16.8%) developed metastatic disease while on neoadjuvant therapy. SMAD4 alterations were associated with a significant risk of metastatic progression on therapy when controlling for resectability status (OR 3.31, 95% CI 1.44-7.60). CONCLUSIONS: SMAD4 alterations are associated with more frequent development of metastasis during neoadjuvant FOLFIRINOX and lower probability of reaching surgical resection. Evaluation of alternative chemotherapy regimens in patients with SMAD4 alterations will be important to distinguish whether this represents a prognostic or predictive biomarker. Copyright © 2022 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.
Keywords: retrospective studies; genetics; fluorouracil; neoadjuvant therapy; pancreatic neoplasms; cancer staging; antineoplastic agent; neoplasm staging; prospective study; prospective studies; adenocarcinoma; antineoplastic combined chemotherapy protocols; carcinoma, pancreatic ductal; pathology; retrospective study; irinotecan; pancreas carcinoma; folinic acid; pancreas tumor; oxaliplatin; protein p21; proto-oncogene proteins p21(ras); leucovorin; humans; human; folfirinox
Journal Title: Journal of the American College of Surgeons
Volume: 235
Issue: 2
ISSN: 1072-7515
Publisher: Elsevier Science, Inc.  
Date Published: 2022-08-01
Start Page: 342
End Page: 349
Language: English
DOI: 10.1097/xcs.0000000000000212
PUBMED: 35839413
PROVIDER: scopus
PMCID: PMC9319357
DOI/URL:
Notes: Article -- Export Date: 1 August 2022 -- Source: Scopus
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MSK Authors
  1. Mithat Gonen
    885 Gonen
  2. William R Jarnagin
    741 Jarnagin
  3. T Peter Kingham
    430 Kingham
  4. Eileen O'Reilly
    566 O'Reilly
  5. Efsevia Vakiani
    225 Vakiani
  6. Christopher   Crane
    123 Crane
  7. Jeffrey Adam Drebin
    80 Drebin
  8. Alice Chia-Chi Wei
    55 Wei
  9. Henry Stuart Walch
    26 Walch
  10. Kevin Cerqueira Soares
    32 Soares
  11. Colin Macdonald Court
    5 Court
  12. Brett Logan Ecker
    6 Ecker