Germline and somatic DNA damage repair gene mutations and overall survival in metastatic pancreatic adenocarcinoma patients treated with FOLFIRINOX

Amikar Sehdev, Olumide Gbolahan, Brad A. Hancock, Melissa Stanley, Safi Shahda, Jun Wan, Howard Wu, Milan Radovich, Bert H. O'Neil

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with lack of predictive biomarkers. We conducted a study to assess DNA damage repair (DDR) gene mutations as a predictive biomarker in PDAC patients treated with FOLFIRINOX. Experimental Design: Indiana University Simon Cancer Center pancreatic cancer database was used to identify patients with metastatic PDAC, treated with FOLFIRINOX and had tissue available for DNA sequencing. Baseline demographic, clinical, and pathologic information was gathered. DNA isolation and targeted sequencing was performed using the Ion AmpliSeq protocol. Overall survival (OS) analysis was conducted using Kaplan–Meier, logistic regression and Cox proportional hazard methods. Multivariate models were adjusted for age, gender, margin status, CA 19-9, adjuvant chemotherapy, tumor and nodal stage. Results: Overall, 36 patients were sequenced. DDR gene mutations were found in 12 patients. Mutations were seen in BRCA1 (N ¼ 7), BRCA2 (N ¼ 5), PALB2 (N ¼ 3), MSH2 (N ¼ 1), and FANCF (N ¼ 1) of all the DDR genes sequenced. Median age was 65.5 years, 58% were male, 97.2% were Caucasian and 51.4% had any family history of cancer. The median OS was near significantly superior in those with DDR gene mutations present vs. absent [14 vs. 5 months; HR, 0.58; 95% confidence interval (CI), 0.29–1.14; log-rank P ¼ 0.08]. Multivariate logistic (OR, 1.47; 95% CI, 1.04–2.06; P ¼ 0.04) and Cox regression (HR, 0.37; 95% CI, 0.15–0.94; P ¼ 0.04) showed presence of DDR gene mutations was associated with improved OS. Conclusions: In a single institution, retrospective study, we found that the presence of DDR gene mutations are associated with improved OS in PDAC patients treated with FOLFIRINOX.

Original languageEnglish (US)
Pages (from-to)6204-6211
Number of pages8
JournalClinical Cancer Research
Volume24
Issue number24
DOIs
StatePublished - Dec 15 2018

Fingerprint

DNA Repair
DNA Damage
Adenocarcinoma
Mutation
Survival
Genes
Confidence Intervals
Neoplasms
Biomarkers
Adjuvant Chemotherapy
Survival Analysis
Pancreatic Neoplasms
DNA Sequence Analysis
Research Design
Retrospective Studies
Logistic Models
Demography
Databases
Ions
DNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Germline and somatic DNA damage repair gene mutations and overall survival in metastatic pancreatic adenocarcinoma patients treated with FOLFIRINOX. / Sehdev, Amikar; Gbolahan, Olumide; Hancock, Brad A.; Stanley, Melissa; Shahda, Safi; Wan, Jun; Wu, Howard; Radovich, Milan; O'Neil, Bert H.

In: Clinical Cancer Research, Vol. 24, No. 24, 15.12.2018, p. 6204-6211.

Research output: Contribution to journalArticle

Sehdev, Amikar ; Gbolahan, Olumide ; Hancock, Brad A. ; Stanley, Melissa ; Shahda, Safi ; Wan, Jun ; Wu, Howard ; Radovich, Milan ; O'Neil, Bert H. / Germline and somatic DNA damage repair gene mutations and overall survival in metastatic pancreatic adenocarcinoma patients treated with FOLFIRINOX. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 24. pp. 6204-6211.
@article{7a639bdd141846c7bf9bff3cefb2a763,
title = "Germline and somatic DNA damage repair gene mutations and overall survival in metastatic pancreatic adenocarcinoma patients treated with FOLFIRINOX",
abstract = "Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with lack of predictive biomarkers. We conducted a study to assess DNA damage repair (DDR) gene mutations as a predictive biomarker in PDAC patients treated with FOLFIRINOX. Experimental Design: Indiana University Simon Cancer Center pancreatic cancer database was used to identify patients with metastatic PDAC, treated with FOLFIRINOX and had tissue available for DNA sequencing. Baseline demographic, clinical, and pathologic information was gathered. DNA isolation and targeted sequencing was performed using the Ion AmpliSeq protocol. Overall survival (OS) analysis was conducted using Kaplan–Meier, logistic regression and Cox proportional hazard methods. Multivariate models were adjusted for age, gender, margin status, CA 19-9, adjuvant chemotherapy, tumor and nodal stage. Results: Overall, 36 patients were sequenced. DDR gene mutations were found in 12 patients. Mutations were seen in BRCA1 (N ¼ 7), BRCA2 (N ¼ 5), PALB2 (N ¼ 3), MSH2 (N ¼ 1), and FANCF (N ¼ 1) of all the DDR genes sequenced. Median age was 65.5 years, 58{\%} were male, 97.2{\%} were Caucasian and 51.4{\%} had any family history of cancer. The median OS was near significantly superior in those with DDR gene mutations present vs. absent [14 vs. 5 months; HR, 0.58; 95{\%} confidence interval (CI), 0.29–1.14; log-rank P ¼ 0.08]. Multivariate logistic (OR, 1.47; 95{\%} CI, 1.04–2.06; P ¼ 0.04) and Cox regression (HR, 0.37; 95{\%} CI, 0.15–0.94; P ¼ 0.04) showed presence of DDR gene mutations was associated with improved OS. Conclusions: In a single institution, retrospective study, we found that the presence of DDR gene mutations are associated with improved OS in PDAC patients treated with FOLFIRINOX.",
author = "Amikar Sehdev and Olumide Gbolahan and Hancock, {Brad A.} and Melissa Stanley and Safi Shahda and Jun Wan and Howard Wu and Milan Radovich and O'Neil, {Bert H.}",
year = "2018",
month = "12",
day = "15",
doi = "10.1158/1078-0432.CCR-18-1472",
language = "English (US)",
volume = "24",
pages = "6204--6211",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "24",

}

TY - JOUR

T1 - Germline and somatic DNA damage repair gene mutations and overall survival in metastatic pancreatic adenocarcinoma patients treated with FOLFIRINOX

AU - Sehdev, Amikar

AU - Gbolahan, Olumide

AU - Hancock, Brad A.

AU - Stanley, Melissa

AU - Shahda, Safi

AU - Wan, Jun

AU - Wu, Howard

AU - Radovich, Milan

AU - O'Neil, Bert H.

PY - 2018/12/15

Y1 - 2018/12/15

N2 - Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with lack of predictive biomarkers. We conducted a study to assess DNA damage repair (DDR) gene mutations as a predictive biomarker in PDAC patients treated with FOLFIRINOX. Experimental Design: Indiana University Simon Cancer Center pancreatic cancer database was used to identify patients with metastatic PDAC, treated with FOLFIRINOX and had tissue available for DNA sequencing. Baseline demographic, clinical, and pathologic information was gathered. DNA isolation and targeted sequencing was performed using the Ion AmpliSeq protocol. Overall survival (OS) analysis was conducted using Kaplan–Meier, logistic regression and Cox proportional hazard methods. Multivariate models were adjusted for age, gender, margin status, CA 19-9, adjuvant chemotherapy, tumor and nodal stage. Results: Overall, 36 patients were sequenced. DDR gene mutations were found in 12 patients. Mutations were seen in BRCA1 (N ¼ 7), BRCA2 (N ¼ 5), PALB2 (N ¼ 3), MSH2 (N ¼ 1), and FANCF (N ¼ 1) of all the DDR genes sequenced. Median age was 65.5 years, 58% were male, 97.2% were Caucasian and 51.4% had any family history of cancer. The median OS was near significantly superior in those with DDR gene mutations present vs. absent [14 vs. 5 months; HR, 0.58; 95% confidence interval (CI), 0.29–1.14; log-rank P ¼ 0.08]. Multivariate logistic (OR, 1.47; 95% CI, 1.04–2.06; P ¼ 0.04) and Cox regression (HR, 0.37; 95% CI, 0.15–0.94; P ¼ 0.04) showed presence of DDR gene mutations was associated with improved OS. Conclusions: In a single institution, retrospective study, we found that the presence of DDR gene mutations are associated with improved OS in PDAC patients treated with FOLFIRINOX.

AB - Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with lack of predictive biomarkers. We conducted a study to assess DNA damage repair (DDR) gene mutations as a predictive biomarker in PDAC patients treated with FOLFIRINOX. Experimental Design: Indiana University Simon Cancer Center pancreatic cancer database was used to identify patients with metastatic PDAC, treated with FOLFIRINOX and had tissue available for DNA sequencing. Baseline demographic, clinical, and pathologic information was gathered. DNA isolation and targeted sequencing was performed using the Ion AmpliSeq protocol. Overall survival (OS) analysis was conducted using Kaplan–Meier, logistic regression and Cox proportional hazard methods. Multivariate models were adjusted for age, gender, margin status, CA 19-9, adjuvant chemotherapy, tumor and nodal stage. Results: Overall, 36 patients were sequenced. DDR gene mutations were found in 12 patients. Mutations were seen in BRCA1 (N ¼ 7), BRCA2 (N ¼ 5), PALB2 (N ¼ 3), MSH2 (N ¼ 1), and FANCF (N ¼ 1) of all the DDR genes sequenced. Median age was 65.5 years, 58% were male, 97.2% were Caucasian and 51.4% had any family history of cancer. The median OS was near significantly superior in those with DDR gene mutations present vs. absent [14 vs. 5 months; HR, 0.58; 95% confidence interval (CI), 0.29–1.14; log-rank P ¼ 0.08]. Multivariate logistic (OR, 1.47; 95% CI, 1.04–2.06; P ¼ 0.04) and Cox regression (HR, 0.37; 95% CI, 0.15–0.94; P ¼ 0.04) showed presence of DDR gene mutations was associated with improved OS. Conclusions: In a single institution, retrospective study, we found that the presence of DDR gene mutations are associated with improved OS in PDAC patients treated with FOLFIRINOX.

UR - http://www.scopus.com/inward/record.url?scp=85058474379&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058474379&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-18-1472

DO - 10.1158/1078-0432.CCR-18-1472

M3 - Article

VL - 24

SP - 6204

EP - 6211

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 24

ER -