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Germline and Somatic DNA Damage Repair Gene Mutations and Overall Survival in Metastatic Pancreatic Adenocarcinoma Patients Trea

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Published OnlineFirst August 21, 2018; DOI: 10.1158/1078-0432.CCR-18-1472 Precision Medicine and Imaging Clinical Cancer Research Germline and Somatic DNA Damage Repair Gene Mutations and Overall Survival in Metastatic Pancreatic Adenocarcinoma Patients Treated with FOLFIRINOX Amikar Sehdev1,2,3, Olumide Gbolahan1, Brad A. Hancock4, Melissa Stanley1, Safi Shahda1, Jun Wan5, Howard H. Wu4, Milan Radovich6, and Bert H. O'Neil1 Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a Results: Overall, 36 patients were sequenced. DDR gene lethal cancer with lack of predictive biomarkers. We con- mutations were found in 12 patients. Mutations were seen ducted a study to assess DNA damage repair (DDR) gene in BRCA1 (N ¼ 7), BRCA2 (N ¼ 5), PALB2 (N ¼ 3), MSH2 mutations as a predictive biomarker in PDAC patients (N ¼ 1), and FANCF (N ¼ 1) of all the DDR genes treated with FOLFIRINOX. sequenced. Median age was 65.5 years, 58% were male, Experimental Design: Indiana University Simon Cancer 97.2% were Caucasian and 51.4% had any family history Center pancreatic cancer database was used to identify of cancer. The median OS was near significantly superior patients with metastatic PDAC, treated with FOLFIRINOX in those with DDR gene mutations present vs. absent and had tissue available for DNA sequencing. Baseline [14 vs. 5 months; HR, 0.58; 95% confidence interval (CI), demographic, clinical, and pathologic information was 0.29–1.14; log-rank P ¼ 0.08]. Multivariate logistic (OR, gathered. DNA isolation and targeted sequencing was 1.47; 95% CI, 1.04–2.06; P ¼ 0.04) and Cox regression (HR, performed using the Ion AmpliSeq protocol. Overall sur- 0.37; 95% CI, 0.15–0.94; P ¼ 0.04) showed presence of vival (OS) analysis was conducted using Kaplan–Meier, DDR gene mutations was associated with improved OS. logistic regression and Cox proportional hazard methods. Conclusions: In a single institution, retrospective study, Multivariate models were adjusted for age, gender, margin we found that the presence of DDR gene mutations are status, CA 19-9, adjuvant chemotherapy, tumor and nodal associated with improved OS in PDAC patients treated with stage. FOLFIRINOX. Clin Cancer Res; 24(24); 6204–11. Ó2018 AACR. Introduction alterations, makes each PDAC rather distinctive. These altera- tions can be divided into required (nearly universally seen; Pancreatic ductal adenocarcinoma (PDAC) remains a lethal such as, KRAS, and CDKN2A), frequently mutated (occurring cancer with a 5-year survival rate of less than 5% overall (1) and in more than 25% of tumors; such as, SMAD4, TP53, and 15% to 20% for early-stage resectable disease (2). Moreover, NCOA3) and low frequency mutations (occurring in less than PDAC is projected to become the second leading cause of 25% of tumors; such as RB1, BRCA2 and ERBB2; refs. 5, 6). cancer-related mortality in the United States within a decade Low-frequency mutations, including mutations in DNA dam- (3). Genome stability is compromised in all cancers, including age repair (DDR) pathways, provide a very heterogeneous PDAC and can be broadly categorized into chromosomal mutational background that gives each PDAC a unique molec- instability (CIN) and microsatellite instability (MIN; refs. 4, ular signature. 5). The spectrum of altered genes, as well as the types of DDR pathways play an important role in the cellular response to platinum chemotherapy. FOLFIRINOX (5-Fluorouracil, 1 leucovorin, irinotecan and oxaliplatin) is a platinum based Department of Medicine, Indiana University School of Medicine, Indianapolis, chemotherapeutic regimen that has shown an unprecedented Indiana. 2Center for Health Services Research, Regenstrief Institute, Indianapolis, Indiana. 3Richard M. Fairbanks School of Public Health, Indiana University, improvement in median overall survival (OS) of PDAC to 11.1 Indianapolis, Indiana. 4Department of Pathology and Laboratory Medicine, months (7). However, not all PDAC patients respond to FOL- Indiana University School of Medicine, Indianapolis, Indiana. 5Department of FIRINOX chemotherapy; objective response rate is around 32% Medical and Molecular Genetics, Indiana University School of Medicine, India- (7). Chemotherapy resistance mechanisms are multifactorial, 6 napolis, Indiana. Department of Surgery, Division of General Surgery, Indiana but alterations in DDR pathways such as nucleotide excision University School of Medicine, Indianapolis, Indiana. repair (NER), mismatch repair (MMR), and BRCA pathways (8) Corresponding Author: Amikar Sehdev, Indiana University—Purdue University likely contribute significantly. For example, the excision repair Indianapolis, 535 Barnhill Drive, RT 130B, Indianapolis, IN 46202. Phone: 317-274- cross-complementation group 1 (ERCC1) protein is a key com- 0320; Fax: 317-948-9954; E-mail: [email protected] ponent of nucleotide excision repair pathway. High expression doi: 10.1158/1078-0432.CCR-18-1472 of ERCC1 has been associated in multiple studies with acquired Ó2018 American Association for Cancer Research. or intrinsic resistance to platinum drugs (8, 9). Similarly, loss of 6204 Clin Cancer Res; 24(24) December 15, 2018 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst August 21, 2018; DOI: 10.1158/1078-0432.CCR-18-1472 DNA Repair Gene Mutations and Survival in Pancreatic Cancer baseline carbohydrate antigen 19-9 (CA 19-9), history of surgical Translational Relevance resection, type of surgical resection (R0 or R1), adjuvant chemo- Emerging data suggest that DNA damage repair (DDR) gene therapy, pathological tumor and nodal stage were collected. mutations may be predictive of response to platinum-based The start date of FOLFIRINOX and date of death were collected chemotherapy in some cancers; however, the role of these for OS calculation. mutations in pancreatic adenocarcinoma (PDAC) is unknown. FOLFIRINOX (5-Fluorouracil, leucovorin, irinote- DNA-extraction can and oxaliplatin) is a platinum-based chemotherapeutic Matched tumor-normal paired tissue sections with 20% regimen that is commonly used as first-line treatment tumor cellularity were selected for DNA isolation. The sections of patients with advanced PDAC. However, the efficacy of were scraped from glass slides using microtome blades and the FOLFIRINOX is limited by its high toxicities and low objective QIAamp DNA FFPE Tissue Kit (56404, Qiagen) was used for DNA response rate. Currently, there is no predictive biomarker isolation. to select patients for treatment with FOLFIRINOX. In this Next-generation sequencing for germline and somatic study, we report that the presence of DDR gene mutations is mutations associated with improved OS in metastatic PDAC patients Germline mutation testing was done using adjacent normal treated with FOLFIRINOX. These results will need to be further tissue whereas somatic mutation testing was done using tumor tested in a larger study and may serve to select PDAC patients tissue. Sequencing libraries were constructed using the Ion for treatment with FOLFIRINOX. AmpliSeq Kit for Chef DL8 (A29024, Thermo Scientific) in conjunction with the Ion Comprehensive Cancer Panel Primer Pool (4477685, Thermo Scientific). Templates were prepared on the Ion Chef using the Ion P1 Hi-Q Chef Kit (A27198, function of MMR genes (mainly MLH1 and MSH2) has been Thermo Scientific). Templates were sequenced to at least associated with resistance to platinum compounds (10). Finally, 500XmeancoverageontheIonProtonsequencerusingaP1 BRCA1 and BRCA2 genes have established roles in DNA repair Chip v3 (A26771, Thermo Scientific). Genomic data (BAM and chemotherapy sensitivity (11, 12). However, these data files) were uploaded to Ion Reporter (Thermo Scientific) for come from either preclinical studies or clinical studies done in somatic variant and copy-number calling. Ingenuity Variant other cancer types and the role of DDR pathway gene alterations Analysis (Qiagen) was also used for second-level annotation. on the efficacy of FOLFIRINOX in PDAC is not well known. The primary objective of this study was to assess the effect of Statistical analyses mutations in DDR genes (BRCA1, BRCA2, PALB2, CHEK1, Descriptive statistics were used to summarize the baseline CHEK2, RAD51, MLH1, MSH2, ERCC1, ERCC4, PARP1, FANCF, characteristics and mutations in DDR genes (BRCA1, BRCA2, PALB2, CHEK1, CHEK2, RAD51, MLH1, MSH2, ERCC1, ERCC4, ATR and MDC1) on the OS of patients with metastatic PDAC PARP1, FANCF, ATR and MDC1 treated with FOLFIRINOX. ). The study cohort was then divided in to those with and without germline and somatic mutations in DDR genes. Baseline characteristics were compared Materials and Methods between the two groups (DDR gene mutations present vs. absent) Study population and patient selection using x2 test for categorical variables and Student t test for Patients were selected from the Indiana University Simon continuous variables. Cancer Center pancreatic cancer database, which is a large Two statistical approaches were used for data analyses. First, Institutional review board (IRB) approved high quality pro- we analyzed the data using logistic regression analysis as in a spective and retrospective data collection repository (13). The case–control study to investigate the association between main inclusion criterion (to allow for adequate available DDR gene mutations and OS (categorized as above and below tissue) for the study was histologic diagnosis of recurrent 3rd quartile). Our goal here was to see whether PDAC patients
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