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Genetic Testing in Pancreatic Ductal Adenocarcinoma: Implications for Prevention and Treatment

      Abstract

      Purpose

      This article reviews the progress to date and future directions for investigation of germline and somatic genetic testing to inform pancreatic adenocarcinoma (PDAC) treatment, screening, and prevention strategies.

      Methods

      We searched PubMed to identify recent articles regarding genetic testing in pancreatic cancer, including both germline and somatic testing, and recent genome-wide association studies. References were specifically hand searched as relevant. Guidelines for testing and screening high-risk individuals were included. We searched clinicaltrials.gov to review the current landscape of active clinical trials.

      Findings

      Approximately 10% of PDACs are associated with an identified germline mutation. Although germline mutations may inform treatment options and identify high-risk individuals for screening in other cancers, the data on PDAC are only now emerging. For example, poly adenosine diphosphate ribose polymerase (PARP) inhibitors are under investigation for BRCA-associated PDAC. Somatic mutations have also been identified in PDAC. However, current data are limited regarding treatment for potential PDAC somatic driver mutations. Although erlotinib is used in PDAC, its use is not targeted based on a tumor marker. Many tyrosine kinase inhibitors targeted toward potential driver mutations and critical pathways are in development, including BRAF/MEK, ALK, and CDK4/6. A consensus on screening strategies for individuals at high risk for PDAC is still evolving because of the relatively low prevalence of the disease, the relative invasiveness of endoscopic procedures often used as part of screening, and the lack of a clear survival benefit.

      Implications

      Pancreatic cancer has been slower to move toward genomic testing, partially because of a lower prevalence of mutations and partially because of a limited effect of results on treatment choices outside a clinical trial. This is an area of active investigation, and we anticipate that there will be both preventive and therapeutic implications of driver mutations in the coming decade.

      Key words

      Introduction

      Clinical Background

      Although pancreatic adenocarcinoma (PDAC) contributes more than double its incidence rate (3% of new US cancer diagnoses per year) to cancer mortality (6.9% of US cancer deaths per year),
      Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD, 2015. http://seer.cancer.gov/csr/1975_2012/. Accessed October 25, 2015.
      most PDAC cases are not linked to identified germline mutations.

      Canto MI, Harinck F, Hruban RH, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013;62:339–347.

      However, somatic mutations, particularly in KRAS, are common.
      • Alexandrov L.B.
      • Nik-Zainal S.
      • Wedge D.C.
      • et al.
      Signatures of mutational processes in human cancer.
      Other risk factors, such as cigarette smoking, diabetes mellitus, and chronic pancreatitis, have consistent links to increased incidence of pancreatic cancer but with lower relative risks than for other malignant tumors.
      Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD, 2015. http://seer.cancer.gov/csr/1975_2012/. Accessed October 25, 2015.

      Ferlay J SI, Ervik M, Dikshit R, et al. Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer.

      Interestingly, PDAC has higher incidence rates in developed countries and among African Americans.
      Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD, 2015. http://seer.cancer.gov/csr/1975_2012/. Accessed October 25, 2015.
      Although survival has modestly improved in the past 30 years, the overall 5-year survival is still only 7.2% in 2012, up from 3.6% in 1995 and 3% in 1975. Even localized disease that may be resectable has a 5-year survival rate of only 27%.
      Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD, 2015. http://seer.cancer.gov/csr/1975_2012/. Accessed October 25, 2015.
      Despite decades of research on systemic therapy for advanced PDAC, only 2 combination cytotoxic chemotherapy regimens have produced a clinically meaningful survival benefit compared with single-agent gemcitabine in the first-line setting. The FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan, oxaliplatin) regimen improved survival (11.1 vs 6.8 months) and decreased degradation quality of life at 6 months (31% vs 61%) compared with gemcitabine alone.
      • Conroy T.
      • Desseigne F.
      • Ychou M.
      • et al.
      FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
      The combination of nab-paclitaxel and gemcitabine also improved survival relative to gemcitabine alone (8.5 months for the combination vs 6.7 months for gemcitabine).
      • Von Hoff D.D.
      • Ervin T.
      • Arena F.P.
      • et al.
      Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
      The only targeted agent approved for PDAC treatment, the oral EGFR inhibitor erlotinib, improved survival by approximately 10 days when added to gemcitabine (6.24 months for the combination vs 5.91 months for gemcitabine alone).
      • Moore M.J.
      • Goldstein D.
      • Hamm J.
      • et al.
      Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group.
      • Miksad R.A.
      • Schnipper L.
      • Goldstein M.
      Does a statistically significant survival benefit of erlotinib plus gemcitabine for advanced pancreatic cancer translate into clinical significance and value?.
      Although there may be some association with response, EGFR has not proven a useful clinical tool to predict a strong erlotinib response in PDAC.
      • Wang J.P.
      • Wu C.-Y.
      • Yeh Y.-C.
      • et al.
      Erlotinib is effective in pancreatic cancer with epidermal growth factor receptor mutations: a randomized, open-label, prospective trial.
      The choice in first-line treatment for advanced PDAC is often based on the patient’s performance status and the toxicity profile of the treatment regimens.
      We reviewed clinicaltrials.gov seeking active clinical trials for pancreatic cancer (accessed October 26, 2015). There are at least 90 early-stage studies of investigational therapeutic agents enrolling patients with pancreatic cancer. Most of these are early-stage, exploratory studies that include patients with a broad range of solid tumors. There are 15 later-stage studies specific to pancreatic cancer, some of which evaluate the efficacy of compounds already approved for other cancers. On the basis of historical drug development success rates,
      • DiMasi J.A.
      • Feldman L.
      • Seckler A.
      • et al.
      Trends in risks associated with new drug development: success rates for investigational drugs.
      it is likely that only a small proportion of these agents will be approved as anticancer therapies, and fewer still will provide clinical benefit for PDAC. Improved systemic therapy for PDAC remains a critical unmet need.

      Oncogenesis of PDAC

      Many PDACs appear to arise from pancreatic intraepithelial neoplasia (PanIN), an intraductal precursor lesion. As shown in Figure 1, an accumulation of genetic alterations occurs on the pathway from most well-defined PanINs to invasive carcinoma, a typical oncogenic progression.
      • Whitcomb D.C.
      • Shelton C.A.
      • Brand R.E.
      Genetics and Genetic Testing in Pancreatic Cancer.
      Genetic predisposition syndromes act to increase the risk of oncogenesis in a variety of ways, affecting DNA repair mechanisms, microsatellite stability, or mismatch repair mechanisms. KRAS mutations appear to be a key somatic alteration, with low rates in pancreatitis specimens and high rates in PDAC specimens. KRAS mutations may also be an early mutation in the PanIN pathway because it is found in 36% to 44% of low-grade PanIN samples but up to 87% of high-grade PanIN samples.
      • Lohr M.
      • Kloppel G.
      • Maisonneuve P.
      • et al.
      Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis.
      CDKN2A is another early mutation noted in PanIN lesions. Higher-grade PanIN lesions also have SMAD4 and p53 mutations.
      • Schutte M.
      • Hruban R.H.
      • Geradts J.
      • et al.
      Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas.
      • Maitra A.
      • Kern S.E.
      • Hruban R.H.
      Molecular pathogenesis of pancreatic cancer. Best practice & research.
      • Ranganathan P.
      • Harsha H.C.
      • Pandey A.
      Molecular alterations in exocrine neoplasms of the pancreas.
      Figure 1.
      Figure 1Pancreatic adenocarcinoma (PDAC) carcinogenesis model. Adapted from Whitcomb et al.
      • Whitcomb D.C.
      • Shelton C.A.
      • Brand R.E.
      Genetics and Genetic Testing in Pancreatic Cancer.
      Normal acinar cells acquire somatic mutations, leading to transformation to pancreatic intraepithelial neoplasia (PanIN). Cancer susceptibility genes may play a role, but for many people this process is due to external factors, such as local toxins and inflammation. Among the first abnormalities is the KRAS G12D mutation, which leads to KRAS activation. Further somatic mutations are acquired, particularly SMAD4 and CDKN2A, which are often seen in PDAC cells. Once dysplasia has progressed to form a carcinoma in situ, a vicious cycle of loss of DNA repair genes and loss of growth control genes leads to formation of PDAC. CIS = carcinoma in situ.
      Epigenetic alterations are also noted in PDAC. Hypermethylation is often a factor in tumor suppressor gene inactivation and increases with higher-stage pancreatic neoplasia. Overexpression of micro-RNAs is also seen in a distinct pattern in neoplastic pancreatic tissue versus normal pancreatic tissue. Although there is no current clinical application for these findings, further investigation of epigenetic markers may refine our understanding of PDAC oncogenesis and identify potential treatment targets.
      • Ranganathan P.
      • Harsha H.C.
      • Pandey A.
      Molecular alterations in exocrine neoplasms of the pancreas.
      • Fukushige S.
      • Horii A.
      Road to early detection of pancreatic cancer: Attempts to utilize epigenetic biomarkers.
      This article reviews the current status of germline and somatic genetic testing in PDAC, clinical applications, and future directions for investigation.

      Methods

      We performed an initial PubMed search for the terms pancreatic cancer genetics and pancreatic cancer genetic testing to identify the body of research in the last 10 years in particular. We then performed specific searches for each of the key proposed germline mutations and somatic driver mutations. Society guidelines were explicitly included. We searched clinicaltrials.gov for active clinical trials in pancreatic cancer.

      Discussion

      Testing for PDAC genetic mutations has 2 primary purposes: (1) germline testing to identify at-risk individuals and (2) somatic and germline testing to identify potential targets for treatment. Historically, routine PDAC germline testing has been hindered by an unclear definition of the target population of at-risk individuals and the absence of proven low-risk screening strategies. For example, PDAC is not included in the Amsterdam or Bethesda guidelines that define Lynch syndrome even though these individuals have a higher PDAC risk than the general population.
      • Vasen H.F.
      • Watson P.
      • Mecklin J.P.
      • et al.
      New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC.
      • Umar A.
      • Boland C.R.
      • Terdiman J.P.
      • et al.
      Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.
      Similarly, the role of PDAC screening for BRCA carriers remains unclear, despite increased rates of PDAC and clear screening guidelines for other BRCA-associated malignant tumors.
      • Brose M.S.
      • Rebbeck T.R.
      • Calzone K.A.
      • et al.
      Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program.
      Patients with an established germline mutation that places them at risk for PDAC often undergo screening with magnetic resonance imaging (MRI) or endoscopic ultrasonography (EUS). In addition, future possible preventive approaches could include therapeutics (cyclo-oxygenase [COX] 2 inhibitors, aspirin, metformin, angiotensin-converting enzyme inhibition, or angiotensin II receptor blockade) or even prophylactic pancreatectomy. For patients with an established diagnosis of PDAC, the presence of a germline mutation may indicate susceptibility to specific chemotherapeutic agents (eg, poly adenosine diphosphate ribose polymerase [PARP] inhibitor use in patients with BRCA) or increased risk associated with certain treatment modalities (eg, radiation therapy in Li Fraumeni syndrome). Pharmacogenomics is being studied to optimize irinotecan dosing in the commonly used FOLFIRI regimen. Somatic mutations are increasingly in use to target chemotherapeutic approaches to driver mutation pathways, such as HER-2, EGFR, BRAF/MEK, and PI3K. microsatellite instability (MSI) high status of the tumor may indicate susceptibility to Programmed cell death protein 1 (PD-1) or other immune checkpoint inhibition. Although most of these uses are still investigational, these pathways have proven fruitful in other malignant tumors. As more is learned about the pathogenesis of PDAC, information about germline and somatic mutations may provide important data to individualize and optimize treatment and screening strategies (Figure 2).
      Figure 2.
      Figure 2Types of genetic testing in pancreatic adenocarcinoma (PDAC) and implications for management. Items in italics are currently investigational. ACEi = angiotensin-converting enzyme inhibitors; ARB = angiotensin receptor blocker; COX = cyclo-oxygenase; EUS = endoscopic ultrasonography; GCC = guanylyl cyclase C; MRI = magnetic resonance imaging; MSI = microsatellite instability; PARP = poly adenosine diphosphate ribose polymerase.

      Germline PDAC Mutations

      During the 1970s and 1980s, multiple families were identified with a clear pattern of heritable PDAC.
      • Lynch H.T.
      • Fitzsimmons M.L.
      • Smyrk T.C.
      • et al.
      Familial pancreatic cancer: clinicopathologic study of 18 nuclear families.
      • Lynch H.T.
      • Fusaro R.M.
      Pancreatic cancer and the familial atypical multiple mole melanoma (FAMMM) syndrome.
      A recent observational study comparing 370 familial PDAC kindreds to 468 sporadic PDAC kindreds found a 32-fold increased risk of PDAC in those families with at least 3 affected members.
      • Klein A.P.
      • Brune K.A.
      • Petersen G.M.
      • et al.
      Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds.
      With the advent of advanced sequencing techniques, the causative germline mutation for some PDAC pedigrees was established in the mid-1990s: BRCA1,
      • Brose M.S.
      • Rebbeck T.R.
      • Calzone K.A.
      • et al.
      Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program.
      • Thompson D.
      • Easton D.F.
      Cancer Incidence in BRCA1 mutation carriers.
      HNPCC genes,
      • Lynch H.T.
      • Smyrk T.
      • Kern S.E.
      • et al.
      Familial pancreatic cancer: a review.
      familial atypical multiple mole melanoma (FAMMM)/CDKN2A,
      • Vasen H.F.
      • Gruis N.A.
      • Frants R.R.
      • et al.
      Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden).
      and Lynch syndrome
      • Lynch H.T.
      • Smyrk T.
      • Kern S.E.
      • et al.
      Familial pancreatic cancer: a review.
      genes (EPCAM, MLH1, MSH2, MSH6, and PMS2).
      In studies of roughly 1500 patients with PDAC with a positive family history referred for genetic testing by a variety of criteria, approximately 10% to 12% of patients have been found to have a germline mutation.

      Canto MI, Harinck F, Hruban RH, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013;62:339–347.

      • Hampel H.
      • Bennett R.L.
      • Buchanan A.
      • et al.
      A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
      Specific target genes include APC, BRCA1 and BRCA2, CDKN2A, the Lynch syndrome genes (EPCAM, MLH1, MSH2, MSH6, and PMS2), STK11, and TP53. Several commercial PDAC panels also include ATM, PALB2, and SPINK1. In the studies of patients with PDAC with high-risk family histories, the most commonly found mutations are BRCA2 (2.9%–17%), CDKN2A (2.5%–21%), and the Lynch genes (11%).
      • Salo-Mullen E.E.
      • O’Reilly E.M.
      • Kelsen D.P.
      • et al.
      Identification of germline genetic mutations in patients with pancreatic cancer.
      • Bartsch D.K.
      • Gress T.M.
      • Langer P.
      Familial pancreatic cancer: current knowledge.
      • Zhen D.B.
      • Rabe K.G.
      • Gallinger S.
      • et al.
      BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study.
      • Harinck F.
      • Kluijt I.
      • van der Stoep N.
      • et al.
      Indication for CDKN2A-mutation analysis in familial pancreatic cancer families without melanomas.
      A summary of these studies appears in Figure 3.
      Figure 3.
      Figure 3Identified germline mutations associated with pancreatic adenocarcinoma (PDAC).
      • Brose M.S.
      • Rebbeck T.R.
      • Calzone K.A.
      • et al.
      Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program.
      • Thompson D.
      • Easton D.F.
      Cancer Incidence in BRCA1 mutation carriers.
      • Vasen H.F.
      • Gruis N.A.
      • Frants R.R.
      • et al.
      Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden).
      • Bartsch D.K.
      • Gress T.M.
      • Langer P.
      Familial pancreatic cancer: current knowledge.
      • Holter S.
      • Borgida A.
      • Dodd A.
      • et al.
      Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma.
      • Syngal S.
      • Brand R.E.
      • Church J.M.
      • et al.
      ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
      • Giardiello F.M.
      • Offerhaus G.J.
      • Lee D.H.
      • et al.
      Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis.
      • Apostolou P.
      • Fostira F.
      Hereditary breast cancer: the era of new susceptibility genes.
      • Mateo J.
      • Carreira S.
      • Sandhu S.
      • et al.
      DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.
      • Hu C.
      • Hart S.N.
      • Bamlet W.R.
      • et al.
      Prevalence of pathogenic mutations in cancer predisposition genes among pancreatic cancer patients.
      • Mersch J.
      • Jackson M.A.
      • Park M.
      • et al.
      Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian.
      • Ferrone C.R.
      • Levine D.A.
      • Tang L.H.
      • et al.
      BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma.
      • van Asperen C.J.
      • Brohet R.M.
      • Meijers-Heijboer E.J.
      • et al.
      Cancer risks in BRCA2 families: estimates for sites other than breast and ovary.
      • Windsor J.A.
      An update on familial pancreatic cancer and the management of asymptomatic relatives.
      • Bhalla A.
      • Saif M.W.
      PARP-inhibitors in BRCA-associated pancreatic cancer.
      • Lynch H.T.
      • Brand R.E.
      • Hogg D.
      • et al.
      Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome.
      • McWilliams R.R.
      • Wieben E.D.
      • Rabe K.G.
      • et al.
      Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling.
      • de Snoo F.A.
      • Bishop D.T.
      • Bergman W.
      • et al.
      Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families.
      • Lynch H.T.
      • Fusaro R.M.
      • Lynch J.F.
      • et al.
      Pancreatic cancer and the FAMMM syndrome.
      • Aspinwall L.G.
      • Taber J.M.
      • Leaf S.L.
      • et al.
      Genetic testing for hereditary melanoma and pancreatic cancer: a longitudinal study of psychological outcome.
      • Kastrinos F.
      • Mukherjee B.
      • Tayob N.
      • et al.
      Risk of pancreatic cancer in families with Lynch syndrome.
      • Shimosegawa T.
      • Kume K.
      • Satoh K.
      Chronic pancreatitis and pancreatic cancer: prediction and mechanism.
      • Schubert S.
      • Traub F.
      • Brakensiek K.
      • et al.
      CFTR, SPINK1, PRSS1, and CTRC mutations are not associated with pancreatic cancer in German patients.
      • Giardiello F.M.
      • Brensinger J.D.
      • Tersmette A.C.
      • et al.
      Very high risk of cancer in familial Peutz-Jeghers syndrome.
      • Grover S.
      • Syngal S.
      Hereditary pancreatic cancer.
      • Ruijs M.W.
      • Verhoef S.
      • Rookus M.A.
      • et al.
      TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes.
      However, several studies have questioned the overall prevalence of these germline mutations among unselected patients with PDAC. One retrospective study of 290 patients with newly diagnosed PDAC in Ontario found an overall mutation prevalence of 3.8% (ATM, BRCA1, BRCA2, Lynch genes, TP53).
      • Grant R.C.
      • Selander I.
      • Connor A.A.
      • et al.
      Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer.
      A prospective study of 306 patients with newly diagnosed PDAC found 1% with BRCA1 mutations and 3.6% with BRCA2 mutations.
      • Holter S.
      • Borgida A.
      • Dodd A.
      • et al.
      Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma.
      Recent American College of Medical Genetics and Genomics guidelines recommend genetic testing referral for patients with PDAC of Ashkenazi Jewish heritage, multiple relatives affected by PDAC, or those patients with risk factors for Lynch syndrome, Peutz-Jeghers syndrome, or FAMMM.
      • Hampel H.
      • Bennett R.L.
      • Buchanan A.
      • et al.
      A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
      The American College of Gastroenterology (ACG) released similar genetic testing guidelines for PDAC patients with a suspicious family history.
      • Syngal S.
      • Brand R.E.
      • Church J.M.
      • et al.
      ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
      A summary of these guidelines can be found in Figure 4. Although germline testing for patients with PDAC with a high-risk family history has been endorsed, current knowledge is limited about the clinical utility of the information for the patient and the best practices for testing and screening of the patient’s family members.
      Figure 4.
      Figure 4Comparative summary of guidelines for pancreatic adenocarcinoma (PDAC) genetic testing.
      • Hampel H.
      • Bennett R.L.
      • Buchanan A.
      • et al.
      A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
      • Syngal S.
      • Brand R.E.
      • Church J.M.
      • et al.
      ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
      FAMMM = familial atypical multiple mole melanoma; N/A = not applicable.
      We review the specific evidence linking each of the 14 most commonly cited genetic mutations to the development of PDAC in the following sections.

      APC Gene (Familial Adenomatous Polyposis)

      The APC gene on 5q is part of the Wnt signaling pathway, acting as a tumor suppressor via its action on β-catenin.
      • Morin P.J.
      • Sparks A.B.
      • Korinek V.
      • et al.
      Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC.
      Germline mutation in APC leads to familial adenomatous polyposis, which is strongly associated with colon cancer. A retrospective review of 197 familial adenomatous polyposis kindreds revealed a slightly increased risk of PDAC.
      • Giardiello F.M.
      • Offerhaus G.J.
      • Lee D.H.
      • et al.
      Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis.
      Given the small magnitude of added risk, the ACG 2015 guidelines do not recommend APC testing for patients with PDAC.
      • Syngal S.
      • Brand R.E.
      • Church J.M.
      • et al.
      ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.

      ATM Gene (Ataxia-telangiectasia syndrome)

      ATM on 11q is involved in repair of DNA double-strand breaks. Mutations in ATM are associated with ataxia-telangiectasia syndrome and have also been implicated in some familial cancers. ATM mutation was initially identified as a possible cause of non-BRCA familial breast cancer,
      • Apostolou P.
      • Fostira F.
      Hereditary breast cancer: the era of new susceptibility genes.
      and recent studies have found that ATM-associated prostate cancer may respond to PARP inhibition.
      • Mateo J.
      • Carreira S.
      • Sandhu S.
      • et al.
      DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.
      ATM is present in some pancreatic cancer lineages, with uncertain effects on the risk of developing this malignant tumor.
      • Hu C.
      • Hart S.N.
      • Bamlet W.R.
      • et al.
      Prevalence of pathogenic mutations in cancer predisposition genes among pancreatic cancer patients.

      BRCA1, BRCA2, and PALB2 Genes (Hereditary Breast and Ovarian Cancer)

      BRCA1 (17q) and BRCA2 (13q) are widely studied DNA repair genes initially identified because of their association with familial breast and ovarian cancer. In addition, BRCA carriers have a higher than population risk of gastric, prostate, colon, skin (melanoma), and pancreatic cancers, as well as increased risk of hematologic malignant tumors.
      • Mersch J.
      • Jackson M.A.
      • Park M.
      • et al.
      Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian.
      The risk of pancreatic cancer in BRCA1 and BRCA2 carriers has been specifically noted in Ashkenazi Jewish families.
      • Ferrone C.R.
      • Levine D.A.
      • Tang L.H.
      • et al.
      BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma.
      Population studies of BRCA carriers indicate a 2- to 4-fold increased risk of pancreatic cancer among carriers,
      • Brose M.S.
      • Rebbeck T.R.
      • Calzone K.A.
      • et al.
      Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program.
      • Thompson D.
      • Easton D.F.
      Cancer Incidence in BRCA1 mutation carriers.
      with higher risk accorded to BRCA2 mutations versus BRCA1 in most studies.
      • Holter S.
      • Borgida A.
      • Dodd A.
      • et al.
      Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma.
      • van Asperen C.J.
      • Brohet R.M.
      • Meijers-Heijboer E.J.
      • et al.
      Cancer risks in BRCA2 families: estimates for sites other than breast and ovary.
      • Windsor J.A.
      An update on familial pancreatic cancer and the management of asymptomatic relatives.
      PALB2 is found on 16p and also interferes with DNA repair in partnership with BRCA2. The exact role of PALB2 in pancreatic cancer development has not been elucidated; however, PALB2-deficient patients are sensitive to PARP inhibitor therapy.
      • Bhalla A.
      • Saif M.W.
      PARP-inhibitors in BRCA-associated pancreatic cancer.
      The ACG recommends screening only for patients with a proven mutation and a first- or second-degree relative with pancreatic cancer but notes a low quality of evidence.
      • Syngal S.
      • Brand R.E.
      • Church J.M.
      • et al.
      ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.

      CDKN2A Gene (p16, Familial Atypical Multiple Mole Melanoma)

      Mutations in the CDKN2A gene on 9p cause FAMMM syndrome. In 2002, Lynch et al
      • Lynch H.T.
      • Brand R.E.
      • Hogg D.
      • et al.
      Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome.
      identified a cohort of 8 families with FAMMM and CDKN2A mutations who also had increased risk of pancreatic cancer. Germline mutations have been found in multiple studies to cause a significant increase in pancreatic cancer risk, ranging from 10- to 15-fold.
      • Vasen H.F.
      • Gruis N.A.
      • Frants R.R.
      • et al.
      Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden).
      • Bartsch D.K.
      • Gress T.M.
      • Langer P.
      Familial pancreatic cancer: current knowledge.
      • Windsor J.A.
      An update on familial pancreatic cancer and the management of asymptomatic relatives.
      • McWilliams R.R.
      • Wieben E.D.
      • Rabe K.G.
      • et al.
      Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling.
      • de Snoo F.A.
      • Bishop D.T.
      • Bergman W.
      • et al.
      Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families.
      • Lynch H.T.
      • Fusaro R.M.
      • Lynch J.F.
      • et al.
      Pancreatic cancer and the FAMMM syndrome.
      • Aspinwall L.G.
      • Taber J.M.
      • Leaf S.L.
      • et al.
      Genetic testing for hereditary melanoma and pancreatic cancer: a longitudinal study of psychological outcome.
      However, as noted in several of these studies, there is wide variance in PDAC incidence across families.

      MLH1, MSH2, MSH6, PMS2, and EPCAM Genes (Lynch syndrome)

      Germline mutations in this family of DNA mismatch repair genes led to Lynch syndrome, one of the earliest identified gastrointestinal cancer syndromes and one of the first genetic cancer predisposition syndromes to be linked to pancreatic cancer. Germline mutations in this family of DNA mismatch repair genes can lead to predisposition to multiple tumors: colon, endometrial, ovarian, small bowel, gastric, breast, prostate, and genitourinary tract. This leads to a 20% to 70% lifetime risk of colon cancer, 15% to 45% lifetime risk of endometrial cancer, and 2% to 10% lifetime risk of ovarian cancer.
      • Cohen S.A.
      • Leininger A.
      The genetic basis of Lynch syndrome and its implications for clinical practice and risk management.
      The increased risk of pancreatic cancer in patients with Lynch syndrome is estimated at a 3- to 10-fold population risk.
      • Kastrinos F.
      • Mukherjee B.
      • Tayob N.
      • et al.
      Risk of pancreatic cancer in families with Lynch syndrome.
      However, the most recent ACG guidelines do not recommend enhanced screening for pancreatic, prostate, or breast cancer in patients with Lynch syndrome.
      • Syngal S.
      • Brand R.E.
      • Church J.M.
      • et al.
      ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.

      SPINK1 Gene (Hereditary pancreatitis)

      The SPINK genes encode inhibitors that protect the pancreas from inappropriate activation of trypsin. Mutation in SPINK1 on 5p can lead to both acute and chronic pancreatitis, particularly in the presence of alcohol consumption. Because chronic pancreatitis has been put forward as a risk factor for pancreatic cancer, SPINK1 has been investigated as a possible oncogene.
      • Shimosegawa T.
      • Kume K.
      • Satoh K.
      Chronic pancreatitis and pancreatic cancer: prediction and mechanism.
      However, the population prevalence of SPINK1 is not well characterized, and one recent study did not find a correlation between pancreatic cancer and SPINK1 mutation.
      • Schubert S.
      • Traub F.
      • Brakensiek K.
      • et al.
      CFTR, SPINK1, PRSS1, and CTRC mutations are not associated with pancreatic cancer in German patients.

      STK11 Gene (Peutz-Jeghers syndrome)

      STK11 on chromosome 19 is a tumor suppressor gene that, when mutated, leads to an autosomal dominant hamartomatous polyposis of the intestine (Peutz-Jeghers syndrome). The lifetime cancer risk for patients with Peutz-Jeghers syndrome is high for colon, breast, cervical, lung, liver, endometrial, and pancreatic cancers. The relative risk of PDAC is 10- to 20-fold, and patients with Peutz-Jeghers syndrome tend to have the condition diagnosed at a much younger mean age.
      • Windsor J.A.
      An update on familial pancreatic cancer and the management of asymptomatic relatives.
      • Giardiello F.M.
      • Brensinger J.D.
      • Tersmette A.C.
      • et al.
      Very high risk of cancer in familial Peutz-Jeghers syndrome.
      • Grover S.
      • Syngal S.
      Hereditary pancreatic cancer.
      Thus, the ACG recommends surveillance with EUS or MRI starting at the age of 35 years but notes a low quality of evidence.
      • Syngal S.
      • Brand R.E.
      • Church J.M.
      • et al.
      ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.

      p53 Gene (Li Fraumeni syndrome)

      The p53 tumor suppressor gene on 17p is a common somatic mutation in many different malignant tumors. As a germline mutation, it leads to the Li Fraumeni syndrome, a rare but devastating condition. Patients with germline p53 mutations are susceptible to multiple, early, aggressive cancers, including sarcomas, adrenal carcinomas, leukemias, and lung cancer. Many other malignant tumors have been found in Li Fraumeni kindreds, including pancreatic cancer.
      • Ruijs M.W.
      • Verhoef S.
      • Rookus M.A.
      • et al.
      TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes.

      Somatic Mutations

      The number of somatic mutations observed in each type of malignant tumors ranges broadly. Pancreatic ductal adenocarcinoma sits in the middle of this spectrum, with roughly 100 to 150 somatic mutations found in each tested specimen.
      • Martincorena I.
      • Campbell P.J.
      Somatic mutation in cancer and normal cells.
      Of these, almost all PDAC specimens have mutation in the KRAS oncogene. Other common findings are p53, CDKN2A (35%), and SMAD4 (31%-55%). In some cases, p53 and SMAD4 mutations were found in later-stage tumors and metastatic sites rather than in the initial primary.
      • Yachida S.
      • Iacobuzio-Donahue C.A.
      The pathology and genetics of metastatic pancreatic cancer.
      Many other somatic mutations were identified in 5% to 10% of tested tumors, including ARID1A, ROBO2, KDM6A, PREX2, RNF43, EphA2, SHH, and INK4A/ARF.
      • Yachida S.
      • Iacobuzio-Donahue C.A.
      The pathology and genetics of metastatic pancreatic cancer.
      • Waddell N.
      • Pajic M.
      • Patch A.M.
      • et al.
      Whole genomes redefine the mutational landscape of pancreatic cancer.
      • Goggins M.
      Molecular markers of early pancreatic cancer.
      • Harsha H.C.
      • Kandasamy K.
      • Ranganathan P.
      • et al.
      A compendium of potential biomarkers of pancreatic cancer.
      SMAD4 is unique because this tumor suppressor is not often mutated in other tumor types.
      • Maitra A.
      • Kern S.E.
      • Hruban R.H.
      Molecular pathogenesis of pancreatic cancer. Best practice & research.
      A recent genome-wide association study of unselected pancreatic adenocarcinomas from patients with no family history or other known high-risk features found a low rate of common targetable mutations. ERBB2, MET, FGFR1, CKD6, PIK3CA, and BRAF were all identified in only 1% to 2% of tested tumors. Somatic BRCA1 mutations were noted in 3% of tested tumors and BRCA2 in 2%.
      • Waddell N.
      • Pajic M.
      • Patch A.M.
      • et al.
      Whole genomes redefine the mutational landscape of pancreatic cancer.
      Although a moderate number of somatic mutations are found in pancreatic adenocarcinomas, most are not currently actionable with targeted therapy such as tyrosine kinase inhibitors.

      KRAS Gene

      Almost all PDAC specimens have mutations in the KRAS oncogene. In colorectal cancer, mutations in KRAS have been associated with a significant reduction in overall survival and have a lower response to EGFR-targeted therapy.
      • Brudvik K.W.
      • Kopetz S.E.
      • Li L.
      • et al.
      Meta-analysis of KRAS mutations and survival after resection of colorectal liver metastases.
      • Douillard J.Y.
      • Oliner K.S.
      • Siena S.
      • et al.
      Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer.
      • Fakih M.G.
      Metastatic colorectal cancer: current state and future directions.
      • Hecht J.R.
      • Douillard J.Y.
      • Schwartzberg L.
      • et al.
      Extended RAS analysis for anti-epidermal growth factor therapy in patients with metastatic colorectal cancer.
      In PDAC samples, KRAS positivity has also been associated with poor prognosis.
      • Bournet B.
      • Buscail C.
      • Muscari F.
      • et al.
      Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities.
      National Comprehensive Cancer Network© (NCCN©) guidelines now include a recommendation for KRAS and NRAS testing for stage IV colorectal cancers, which has therapeutic implications.
      Clinical Practice Guidelines in Oncology (NCCN Guidelines), Colon Cancer, version 2.2016, www.nccn.org. Accessed February 1, 2016.
      Similar testing recommendations may in the future be recommended for PDAC. Unfortunately, KRAS is not currently directly targetable by drug therapy.

      BRCA Gene

      Somatic mutations in BRCA1 and BRCA2 are common in ovarian cancer, and BRCA-deficient ovarian tumors, whether due to germline or somatic mutation, respond equally well to platinum-based chemotherapy.
      • Hennessy B.T.
      • Timms K.M.
      • Carey M.S.
      • et al.
      Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer.
      A recent review concludes that BRCA mutation is a marker for genetic instability in PDAC and that PARP inhibitors and platinum-based chemotherapy can be effective in this setting as in other tumor types.
      • Sahin I.H.
      • Lowery M.A.
      • Stadler Z.K.
      • et al.
      Genomic instability in pancreatic adenocarcinoma: a new step towards precision medicine and novel therapeutic approaches.

      MSI

      MSI is due to poor DNA mismatch repair and is a critical factor in the treatment of colorectal cancers in particular.
      • Boland C.R.
      • Goel A.
      Microsatellite instability in colorectal cancer.
      MSI-high patients with colon cancer have a favorable prognosis relative to those with intact mismatch repair.
      • Hutchins G.
      • Southward K.
      • Handley K.
      • et al.
      Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer.
      Some studies have found reduced efficacy of fluoropyrimidine-based therapy in MSI-high colorectal cancers.
      • Hutchins G.
      • Southward K.
      • Handley K.
      • et al.
      Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer.
      • Sinicrope F.A.
      • Foster N.R.
      • Thibodeau S.N.
      • et al.
      DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy.
      Recently, MSI has emerged as a potential marker for the efficacy of PD-1 blockade in gastrointestinal malignant tumors. A recent Phase II study found a substantially higher response rate to PD-1 inhibition among MSI-high colorectal cancers.
      • Le D.T.
      • Uram J.N.
      • Wang H.
      • et al.
      PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.
      The same group has expanded their work into noncolorectal gastrointestinal tumors, and preliminary results presented at the recent American Society of Clinical Oncology Gastrointestinal Cancers Symposium revealed similarly promising results.
      • Dung T.
      • Le J.N.U.
      • Hao
      • et al.
      PD-1 blockade in mismatch repair deficient non-colorectal gastrointestinal cancers.
      Although MSI testing is not currently standard in pancreatic cancer, it is emerging in research settings.

      Implications for Treatment

      Germline Mutations

      BRCA1, BRCA2, and PALB2

      Emerging evidence suggests BRCA1- and BRCA2-associated PDACs may respond more briskly to platinum-based therapy. In a recent retrospective review of patients with stage III or IV disease, those treated with platinum-based chemotherapy (n = 22) had a significantly longer overall survival (22 vs 9 months, p < 0.039) than those treated without platinum chemotherapy (n = 21).
      • Golan T.
      • Kanji Z.S.
      • Epelbaum R.
      • et al.
      Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers.
      The results of similar studies in breast and ovarian cancers have been inconsistent but have revealed an overall trend toward improved survival with platinum use.
      • Isakoff S.J.
      • Mayer E.L.
      • He L.
      • et al.
      TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer.
      • Gorodnova T.V.
      • Sokolenko A.P.
      • Ivantsov A.O.
      • et al.
      High response rates to neoadjuvant platinum-based therapy in ovarian cancer patients carrying germ-line BRCA mutation.
      In patients with deficiencies in double-strand repair (due to BRCA1, BRCA2, or PALB2 mutations), PARP inhibitors have substantial efficacy.
      • Bhalla A.
      • Saif M.W.
      PARP-inhibitors in BRCA-associated pancreatic cancer.
      PARP is responsible for the repair of single-strand DNA breaks, and PARP inhibitors block single-strand repair in rapidly dividing tumor cells. In late 2014, olaparib was approved for use in advanced ovarian cancer in patients with germline BRCA mutations.
      • Kim G.
      • Ison G.
      • McKee A.E.
      • et al.
      FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy.
      Currently, multiple PARP inhibitors are in development in a variety of BRCA-associated tumors, and several Phase II and III studies are currently recruiting in pancreatic cancer specifically (NCT02184195, NCT01989546, NCT02286687, NCT01489865, NCT01585805).

      Pharmacogenomics

      Currently, 2 clinical trials are under way on the use of UGT1A1 gene polymorphism testing to dose adjust irinotecan in the FOLFIRINOX regimen used to treat PDAC (NCT02143219, NCT01643499). Similar studies have evaluated this approach for FOLFIRI regimens used in colorectal cancer. Irinotecan can cause neutropenia and delayed diarrhea in some patients. One proposed mechanism for this toxic effect is polymorphisms of the UGT1A1 gene, which is part of the glucoronidation pathway of metabolism. Polymorphisms in UGT1A1, such as the *28 allele, are associated with Gilbert syndrome, and absence of the enzyme leads to Crigler-Najjar syndrome, both disorders of bilirubin glucoronidation.
      • Kadakol A.
      • Ghosh S.S.
      • Sappal B.S.
      • et al.
      Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype.
      The association of irinotecan toxicity with UGT1A1 polymorphisms was first noted in a Japanese population, and further studies in Asian populations have found a correlation between UGT1A1 polymorphisms and these adverse effects.
      • Ando Y.
      • Saka H.
      • Ando M.
      • et al.
      Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis.
      • Cheng L.
      • Li M.
      • Hu J.
      • et al.
      UGT1A1*6 polymorphisms are correlated with irinotecan-induced toxicity: a system review and meta-analysis in Asians.
      • Li M.
      • Wang Z.
      • Guo J.
      • et al.
      Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer.
      • Liu X.
      • Cheng D.
      • Kuang Q.
      • et al.
      Association of UGT1A1*28 polymorphisms with irinotecan-induced toxicities in colorectal cancer: a meta-analysis in Caucasians.
      However, these polymorphisms are present in all ethnic groups. Pharmacogenomic studies have found a correlation between irinotecan-associated neutropenia and the same *28 allele implicated in Gilbert syndrome.
      • Crona D.J.
      • Ramirez J.
      • Qiao W.
      • et al.
      Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study.
      This allele is present in all ethnic groups and is in fact more common in white than in Asian populations.
      A case series of 48 patients receiving gemcitabine monotherapy revealed that a single-nucleotide polymorphism in the MDR1 gene correlated with increased adverse effects but also with longer disease-free survival. This finding was thought to indicate higher drug levels in this population with MDR1 2677 mutation. This MDR polymorphism has not been further investigated for clinical use.
      • Kasuya K.
      • Tsuchida A.
      • Nagakawa Y.
      • et al.
      Prediction of a side effect and efficacy of adjuvant chemotherapy with gemcitabine for post operative patient of pancreatic cancer by a genetic polymorphism analysis.

      Somatic Mutations

      Similar to other gastrointestinal malignant tumors, most of the somatic mutations found in PDAC are not currently targetable. Future treatment approaches that target common mutations, such as CDKN2A or SMAD4, could have significant application.

      KRAS Gene

      KRAS is present almost universally in PDAC but is not a currently targetable mutation. KRAS mutation is associated with poor prognosis in both resected and advanced tumor samples.
      • Bournet B.
      • Buscail C.
      • Muscari F.
      • et al.
      Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities.
      Investigation of the KRAS oncogenic pathway reveals several downstream targets that may prove more amenable to intervention, particularly the RAF/MEK/ERK and PI3K/PDK1/AKT pathways.
      • Eser S.
      • Schnieke A.
      • Schneider G.
      • et al.
      Oncogenic KRAS signalling in pancreatic cancer.
      • Fitzgerald T.L.
      • Lertpiriyapong K.
      • Cocco L.
      • et al.
      Roles of EGFR and KRAS and their downstream signaling pathways in pancreatic cancer and pancreatic cancer stem cells.
      RAF/MEK inhibition is being tested in colorectal cancer among KRAS mutated tumors as an approach for treating EGFR-insensitive metastatic disease (NCT02450656, NCT02278133, NCT02230553). In pancreatic cancer, there are currently open Phase I/II studies of several targeted therapies, with evidence largely drawn from the colorectal cancer experience. RAF/MEK inhibitors are being studied in pancreatic cancer, also with the assumption of KRAS mutation presence (NCT02039336, NCT02230553, NCT02243917, NCT01449058).
      The EGFR inhibitor erlotinib has a small survival benefit in combination with gemcitabine in pancreatic cancer. In a Phase III study, patients had increased overall survival of 2 weeks in the erlotinib group (6.24 vs 5.91 months) and an increased rate of survival at 1 year (23% vs 17%).7 Similar studies with cetuximab did not find any increased survival, and only erlotinib is approved for use in pancreatic cancer in combination with gemcitabine. However, these studies did not stratify patients by serologic or tumor markers.

      MSI

      Colorectal cancers with impaired mismatch repair leading to MSI-high status have better prognosis than those with preserved mismatch repair. Recent studies in PD-1 inhibition reveal particular promise in the MSI-high subset of colorectal tumors. A Phase II study is under way in noncolorectal gastrointestinal tumors, including pancreatic cancer. Early results from the first 17 patients, 4 of them with pancreatic cancer, indicate an overall response rate of 50%.
      • Dung T.
      • Le J.N.U.
      • Hao
      • et al.
      PD-1 blockade in mismatch repair deficient non-colorectal gastrointestinal cancers.
      This study continues enrollment with a goal of an additional 50 patients (NCT 01876511).

      Others

      There are open studies for BRAF, CDK4/6, NTRK1, NTRK2, NTRK3, ROS1, and ALK mutated tumors, many of these in “basket” studies that recruit across multiple solid tumors (NCT01351103, NCT02187783, NCT02568267, NCT02097810). Both lapatinib and the investigational agent AVX901 are being tested in the rare HER2 overexpressed pancreatic tumors as part of larger solid tumor studies. Finally, the investigational antibody-drug conjugate MLN0264 that targets high guanylyl cyclase C–expressing tumor cells is being developed specifically for PDAC (NCT02202785). Given the relatively low prevalence of some of these driver mutations among pancreatic tumors tested to date, it is not clear how broadly applicable these approaches may be in future. A summary of open clinical studies can be found in Figure 5.
      Figure 5.
      Figure 5Investigational treatments for pancreatic adenocarcinoma (PDAC). GCC = guanylyl cyclase C.

      Implications For Prevention

      Germline Mutations

      Screening

      The Cancer of the Pancreas Screening Consortium was formed in 2010 to address the question of who should be screened for pancreatic cancer and how this screening should be performed. The goal of these studies is to identify carcinoma in situ and early-stage invasive cancers that can be resected with a reasonable chance of cure. The 2013 Cancer of the Pancreas Screening guidelines recommend screening via EUS or MRI starting at the age of 50 years for high-risk individuals. High risk is defined as patients with an identified germline BRCA2, CDKN2A, APC, or STK11 mutation and a first-degree family member with PDAC. Individuals without a known germline mutation are recommended for screening if they have ≥2 relatives, with at least 1 a first-degree relative, affected by pancreatic cancer.

      Canto MI, Harinck F, Hruban RH, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013;62:339–347.

      A German national cancer registry applied a similar screening program for 76 high-risk individuals with familial cancer syndromes. These individuals underwent annual EUS and MRI screening for 5 years. Twenty-eight patients had some abnormality by noninvasive imaging, for which 7 fine-needle aspirations were performed and 7 laparoscopies were completed, 6 with limited resections. Pathologic examination revealed 3 adenomas, 1 intraductal papillary mucinous neoplasm (IPMN), and 4 low-intermediate PanINs. PanINs are generally thought to have a low risk of progressing to cancer. Only the individual with IPMN had a lesion with a clear high risk of future pancreatic adenocarcinoma. The authors concluded that the yield of this extensive screening program was low and that it did not justify the significant cost and patient distress incurred.
      • Langer P.
      • Kann P.H.
      • Fendrich V.
      • et al.
      Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer.
      A similar screening program was recently tested in Sweden, in which 40 individuals with increased risk of pancreatic cancer were identified based on family history (≥2 relatives with PDAC). All patients underwent genetic testing for BRCA and CDKN2A, identifying 1 with a BRCA1 mutation, 2 with a BRCA2 mutation, and 4 with a CDKN2A mutation. The patients underwent MRI or magnetic resonance cholangiopancreatography, followed by EUS with biopsy or computed tomography if any suspicious lesions were noted on initial imaging. Sixteen patients had a positive finding, of which 14 were IPMNs and 2 were PDACs. Five patients underwent resection, 3 of whom were found to have early-stage PDAC. In 1 of these 3 patients, the PDAC was found in the surgical specimen but not noted on imaging. This study concluded that in this high-risk population MRI screening could identify early lesions with good accuracy and with lower risk to the patient than strategies that include regular EUS use.
      • Del Chiaro M.
      • Verbeke C.S.
      • Kartalis N.
      • et al.
      Short-term Results of a Magnetic Resonance Imaging-Based Swedish Screening Program for Individuals at Risk for Pancreatic Cancer.
      For individuals with BRCA mutations, NCCN guidelines recommend annual breast MRI and mammography, possible prophylactic mastectomy and salpingo-oophorectomy, prostate cancer screening for men, and symptom-based screening for other malignant tumors. There is no specific NCCN guideline for skin examination, pancreatic cancer screening, or other malignant tumors, although some institutions may have more specific recommendations. The NCCN recommends that individuals with identified p53 mutations undergo annual whole-body MRI, skin examination, mammography, and symptom-targeted surveillance, as well as colonoscopy every 2 to 5 years. Although pancreatic cancer screening is not specified, the whole-body MRI may be adequate to assess for PDAC.

      Clinical Practice Guidelines in Oncology (NCCN Guidelines), Genetic/Familial High Risk Assessment: Breast and Ovarian, version 2.2016, www.nccn.org. Accessed February 1, 2016.

      A summary of screening guidelines can be found in Figure 6.
      Figure 6.
      Figure 6Comparative summary of selected screening strategy recommendations.

      Canto MI, Harinck F, Hruban RH, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013;62:339–347.

      • Syngal S.
      • Brand R.E.
      • Church J.M.
      • et al.
      ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
      Clinical Practice Guidelines in Oncology (NCCN Guidelines), Colon Cancer, version 2.2016, www.nccn.org. Accessed February 1, 2016.

      Clinical Practice Guidelines in Oncology (NCCN Guidelines), Genetic/Familial High Risk Assessment: Breast and Ovarian, version 2.2016, www.nccn.org. Accessed February 1, 2016.

      Clinical Practice Guidelines in Oncology (NCCN Guidelines), Genetic/Familial High Risk Assessment: Colorectal, version 2.2015, www.nccn.org. Accessed October 27, 2015.

      EUS = endoscopic ultrasonography; FAMMM = familial atypical multiple mole melanoma; MRCP = magnetic resonance cholangiopancreatography; MRI = magnetic resonance imaging; NCCN © = National Comprehensive Cancer Network ©; PDAC = pancreatic adenocarcinoma.

      Chemoprevention

      There are no proven interventions to reduce the risk of developing PDAC other than standard healthy lifestyle choices recommend for general cancer prevention. However, there are several medications that have preclinical and in vitro data indicative of potential application in risk reduction, and future research may identify those germline mutations most likely to benefit from these measures.

      Metformin

      For patients with pancreatic cancer, there are dozens of active clinical trials testing metformin in combination with traditional chemotherapy. A recent meta-analysis found that metformin use reduced the risk of pancreatic cancer among diabetic patients (relative risk, 0.63).
      • Wang Z.
      • Lai S.T.
      • Xie L.
      • et al.
      Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.
      Metformin is being tested as a possible means to reduce the risk of breast cancer and hepatocellular carcinoma among patients with obesity or impaired glucose tolerance (NCT02028221, NCT02319200).

      Angiotensin Receptor Blockers

      Similarly, angiotensin II receptor blockers have a beneficial effect in combination with traditional chemotherapy.
      • Nakai Y.
      • Isayama H.
      • Ijichi H.
      • et al.
      Inhibition of renin-angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine.
      • Nakai Y.
      • Isayama H.
      • Ijichi H.
      • et al.
      Phase I trial of gemcitabine and candesartan combination therapy in normotensive patients with advanced pancreatic cancer: GECA1.
      In vitro models have revealed that blocking the renin-angiotensin system reduces the proliferation of pancreatic cancer cells.
      • Kim S.
      • Toyokawa H.
      • Yamao J.
      • et al.
      Antitumor effect of angiotensin II type 1 receptor blocker losartan for orthotopic rat pancreatic adenocarcinoma.
      Losartan is being studied in combination with FOLFIRINOX (NCT01821729), but there are no active prevention studies at this time.

      COX-2 inhibitors

      COX-2 inhibition has also been mooted as a potential mechanism for in vitro suppression of tumor growth.
      • Cheng G.
      • Zielonka J.
      • McAllister D.
      • et al.
      Profiling and targeting of cellular bioenergetics: inhibition of pancreatic cancer cell proliferation.
      Although celecoxib has been tested in combination with chemotherapeutics in early-stage clinical trials, concern about long-term toxic effects has limited its use.

      Aspirin

      Aspirin reduces the development of adenomatous polyps and colon cancer.
      • Flossmann E.
      • Rothwell P.M.
      Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies.
      This reduction may be due to irreversible COX-2 inhibition or to anti-inflammatory effects. It is not currently recommended for regular use for this purpose because of the risk of gastrointestinal bleeding in particular, although a recent Agency for Healthcare Research and Quality decision analysis found benefit in younger adults with limited bleeding risk.
      Routine aspirin or nonsteroidal anti-inflammatory drugs for the primary prevention of colorectal cancer: recommendation statement.
      • Dehmer S.P.
      • Maciosek M.V.
      • Flottemesch T.J.
      Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: A Decision Analysis: Technical Report.
      Retrospective analysis has also found a benefit for aspirin in the prevention of PDAC, although given the lower prevalence of PDAC relative to colorectal cancer, the overall risk-benefit for its use in this setting is likely to be lower as well.
      • Cui X.J.
      • He Q.
      • Zhang J.M.
      • et al.
      High-dose aspirin consumption contributes to decreased risk for pancreatic cancer in a systematic review and meta-analysis.

      Somatic Mutations

      For patients with newly diagnosed PDAC, it would be ideal to identify adjunct treatments that could reduce metastatic potential. Despite the therapeutic potential of small molecule tyrosine kinase inhibitors, patients with PDAC treated with these therapies all eventually have disease progression. In addition, the substantial overall survival and disease-free survival benefit of targeted therapies and immunotherapies seen for many cancers has not yet been found in PDAC. Erlotinib, an EGFR inhibitor approved for use in pancreatic cancer in combination with standard chemotherapy, provides only a small benefit and is not targeted to any particular subpopulation based on tumor or serologic markers. This remains an area of investigation.

      Conclusions

      Genetic testing has become a key component of oncology care for multiple tumor types. Pancreatic cancer has been slower to move toward genomic testing, partially because of a lower prevalence of mutations and partially because of the limited effect on treatment choices outside a clinical trial. A consensus on screening strategies for individuals at high risk for PDAC is still evolving because of the relatively low prevalence of the disease, the relative invasiveness of endoscopic procedures often used as part of screening, and the lack of a clear survival benefit. Although somatic driver mutations have been identified for PDAC, particularly KRAS, effective targeted treatments are not currently available. However, we anticipate that in the near future there will be therapeutic implications of some genetic mutations, particularly PARP inhibitors for patients with BRCA and PALB. We also anticipate that the growth of targeted therapies will yield treatments for PDAC driver mutations in the next 5 to 10 years. With these changes, the value of genetic testing in pancreatic adenocarcinoma will increase. Investigation of PDAC mutations and their implications for management of patients and high-risk individuals will be a key strategy to improve detection and treatment of this aggressive malignant tumor.

      Conflicts of Interest

      The authors received no funding or other financial support directly related to the content of this article.
      Dr Peters and Dr Tseng report no monetary support from other sources.

      Acknowledgments

      No one other than the authors participated in the preparation of this article.
      M.L.B. Peters were responsible in literature search, data collection, data interpretation, figure creation, writing. J.F. Tseng were responsilble in data interpretation, revision. R.A. Miksad were responsible in study design, figure creation, data interpretation, revision.

      References

      1. Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD, 2015. http://seer.cancer.gov/csr/1975_2012/. Accessed October 25, 2015.
      2. Canto MI, Harinck F, Hruban RH, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013;62:339–347.

        • Alexandrov L.B.
        • Nik-Zainal S.
        • Wedge D.C.
        • et al.
        Signatures of mutational processes in human cancer.
        Nature. 2013; 500: 415-421
      3. Ferlay J SI, Ervik M, Dikshit R, et al. Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer.

        • Conroy T.
        • Desseigne F.
        • Ychou M.
        • et al.
        FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
        N Engl J Med. 2011; 364: 1817-1825
        • Von Hoff D.D.
        • Ervin T.
        • Arena F.P.
        • et al.
        Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
        N Engl J Med. 2013; 369: 1691-1703
        • Moore M.J.
        • Goldstein D.
        • Hamm J.
        • et al.
        Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group.
        J Clin Oncol. 2007; 25: 1960-1966
        • Miksad R.A.
        • Schnipper L.
        • Goldstein M.
        Does a statistically significant survival benefit of erlotinib plus gemcitabine for advanced pancreatic cancer translate into clinical significance and value?.
        J Clin Oncol. 2007; 25 (author reply 4508): 4506-4507
        • Wang J.P.
        • Wu C.-Y.
        • Yeh Y.-C.
        • et al.
        Erlotinib is effective in pancreatic cancer with epidermal growth factor receptor mutations: a randomized, open-label, prospective trial.
        Oncotarget. 2015; 6: 18162-18173
        • DiMasi J.A.
        • Feldman L.
        • Seckler A.
        • et al.
        Trends in risks associated with new drug development: success rates for investigational drugs.
        Clin Pharmacol Ther. 2010; 87: 272-277
        • Whitcomb D.C.
        • Shelton C.A.
        • Brand R.E.
        Genetics and Genetic Testing in Pancreatic Cancer.
        Gastroenterology. 2015; 149: e1254
        • Lohr M.
        • Kloppel G.
        • Maisonneuve P.
        • et al.
        Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis.
        Neoplasia (New York, N.Y.). 2005; 7: 17-23
        • Schutte M.
        • Hruban R.H.
        • Geradts J.
        • et al.
        Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas.
        Cancer Res. 1997; 57: 3126-3130
        • Maitra A.
        • Kern S.E.
        • Hruban R.H.
        Molecular pathogenesis of pancreatic cancer. Best practice & research.
        Clin Gastroenterol. 2006; 20: 211-226
        • Ranganathan P.
        • Harsha H.C.
        • Pandey A.
        Molecular alterations in exocrine neoplasms of the pancreas.
        Arch Pathol Lab Med. 2009; 133: 405-412
        • Fukushige S.
        • Horii A.
        Road to early detection of pancreatic cancer: Attempts to utilize epigenetic biomarkers.
        Cancer Lett. 2014; 342: 231-237
        • Vasen H.F.
        • Watson P.
        • Mecklin J.P.
        • et al.
        New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC.
        Gastroenterology. 1999; 116: 1453-1456
        • Umar A.
        • Boland C.R.
        • Terdiman J.P.
        • et al.
        Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.
        J Nat Cancer Inst. 2004; 96: 261-268
        • Brose M.S.
        • Rebbeck T.R.
        • Calzone K.A.
        • et al.
        Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program.
        J Nat Cancer Inst. 2002; 94: 1365-1372
        • Lynch H.T.
        • Fitzsimmons M.L.
        • Smyrk T.C.
        • et al.
        Familial pancreatic cancer: clinicopathologic study of 18 nuclear families.
        Am J gastroenterol. 1990; 85: 54-60
        • Lynch H.T.
        • Fusaro R.M.
        Pancreatic cancer and the familial atypical multiple mole melanoma (FAMMM) syndrome.
        Pancreas. 1991; 6: 127-131
        • Klein A.P.
        • Brune K.A.
        • Petersen G.M.
        • et al.
        Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds.
        Cancer Res. 2004; 64: 2634-2638
        • Thompson D.
        • Easton D.F.
        Cancer Incidence in BRCA1 mutation carriers.
        J Nat Cancer Inst. 2002; 94: 1358-1365
        • Lynch H.T.
        • Smyrk T.
        • Kern S.E.
        • et al.
        Familial pancreatic cancer: a review.
        Semin Onco. 1996; 23: 251-275
        • Vasen H.F.
        • Gruis N.A.
        • Frants R.R.
        • et al.
        Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden).
        Int J Cancer. 2000; 87: 809-811
        • Hampel H.
        • Bennett R.L.
        • Buchanan A.
        • et al.
        A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
        Genet Med. 2015; 17: 70-87
        • Salo-Mullen E.E.
        • O’Reilly E.M.
        • Kelsen D.P.
        • et al.
        Identification of germline genetic mutations in patients with pancreatic cancer.
        Cancer. 2015; 121: 4382-4388
        • Bartsch D.K.
        • Gress T.M.
        • Langer P.
        Familial pancreatic cancer: current knowledge.
        Nat Rev. Gastroenterol Hepatol. 2012; 9: 445-453
        • Zhen D.B.
        • Rabe K.G.
        • Gallinger S.
        • et al.
        BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study.
        Genet Med. 2015; 17: 569-577
        • Harinck F.
        • Kluijt I.
        • van der Stoep N.
        • et al.
        Indication for CDKN2A-mutation analysis in familial pancreatic cancer families without melanomas.
        J Med Gen. 2012; 49: 362-365
        • Holter S.
        • Borgida A.
        • Dodd A.
        • et al.
        Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma.
        J Clin Oncol. 2015; 33: 3124-3129
        • Syngal S.
        • Brand R.E.
        • Church J.M.
        • et al.
        ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
        Am J Gastroenterol. 2015; 110 (quiz 263): 223-262
        • Giardiello F.M.
        • Offerhaus G.J.
        • Lee D.H.
        • et al.
        Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis.
        Gut. 1993; 34: 1394-1396
        • Apostolou P.
        • Fostira F.
        Hereditary breast cancer: the era of new susceptibility genes.
        BioMed Res Int. 2013; 2013: 747318
        • Mateo J.
        • Carreira S.
        • Sandhu S.
        • et al.
        DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.
        N Engl J Med. 2015; 373: 1697-1708
        • Hu C.
        • Hart S.N.
        • Bamlet W.R.
        • et al.
        Prevalence of pathogenic mutations in cancer predisposition genes among pancreatic cancer patients.
        Cancer Epidemiol Biomarkers Prev. 2016; 25: 207-211
        • Mersch J.
        • Jackson M.A.
        • Park M.
        • et al.
        Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian.
        Cancer. 2015; 121: 269-275
        • Ferrone C.R.
        • Levine D.A.
        • Tang L.H.
        • et al.
        BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma.
        J Clin Oncol. 2009; 27: 433-438
        • van Asperen C.J.
        • Brohet R.M.
        • Meijers-Heijboer E.J.
        • et al.
        Cancer risks in BRCA2 families: estimates for sites other than breast and ovary.
        J Med Gen. 2005; 42: 711-719
        • Windsor J.A.
        An update on familial pancreatic cancer and the management of asymptomatic relatives.
        HPB: off j Int Hepato Pancreato Biliary Association. 2007; 9: 4-7
        • Bhalla A.
        • Saif M.W.
        PARP-inhibitors in BRCA-associated pancreatic cancer.
        JOP: Journal Pancreas. 2014; 15: 340-343
        • Lynch H.T.
        • Brand R.E.
        • Hogg D.
        • et al.
        Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome.
        Cancer. 2002; 94: 84-96
        • McWilliams R.R.
        • Wieben E.D.
        • Rabe K.G.
        • et al.
        Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling.
        Eur J Hum Genet. 2011; 19: 472-478
        • de Snoo F.A.
        • Bishop D.T.
        • Bergman W.
        • et al.
        Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families.
        Clin Cancer Res. 2008; 14: 7151-7157
        • Lynch H.T.
        • Fusaro R.M.
        • Lynch J.F.
        • et al.
        Pancreatic cancer and the FAMMM syndrome.
        Familial cancer. 2008; 7: 103-112
        • Aspinwall L.G.
        • Taber J.M.
        • Leaf S.L.
        • et al.
        Genetic testing for hereditary melanoma and pancreatic cancer: a longitudinal study of psychological outcome.
        Psychooncology. 2013; 22: 276-289
        • Kastrinos F.
        • Mukherjee B.
        • Tayob N.
        • et al.
        Risk of pancreatic cancer in families with Lynch syndrome.
        JAMA. 2009; 302: 1790-1795
        • Shimosegawa T.
        • Kume K.
        • Satoh K.
        Chronic pancreatitis and pancreatic cancer: prediction and mechanism.
        Clin Gastroenterol Hepatol. 2009; 7: S23-28
        • Schubert S.
        • Traub F.
        • Brakensiek K.
        • et al.
        CFTR, SPINK1, PRSS1, and CTRC mutations are not associated with pancreatic cancer in German patients.
        Pancreas. 2014; 43: 1078-1082
        • Giardiello F.M.
        • Brensinger J.D.
        • Tersmette A.C.
        • et al.
        Very high risk of cancer in familial Peutz-Jeghers syndrome.
        Gastroenterol. 2000; 119: 1447-1453
        • Grover S.
        • Syngal S.
        Hereditary pancreatic cancer.
        Gastroenterol. 2010; 139 (1080 e1071-1072): 1076-1080
        • Ruijs M.W.
        • Verhoef S.
        • Rookus M.A.
        • et al.
        TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes.
        J med gen. 2010; 47: 421-428
        • Grant R.C.
        • Selander I.
        • Connor A.A.
        • et al.
        Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer.
        Gastroenterology. 2015; 148: 556-564
        • Morin P.J.
        • Sparks A.B.
        • Korinek V.
        • et al.
        Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC.
        Science (New York, N.Y). 1997; 275: 1787-1790
        • Cohen S.A.
        • Leininger A.
        The genetic basis of Lynch syndrome and its implications for clinical practice and risk management.
        App clin gen. 2014; 7: 147-158
        • Martincorena I.
        • Campbell P.J.
        Somatic mutation in cancer and normal cells.
        Science. 2015; 349: 1483-1489
        • Yachida S.
        • Iacobuzio-Donahue C.A.
        The pathology and genetics of metastatic pancreatic cancer.
        Arch Pathol Lab Med. 2009; 133: 413-422
        • Waddell N.
        • Pajic M.
        • Patch A.M.
        • et al.
        Whole genomes redefine the mutational landscape of pancreatic cancer.
        Nature. 2015; 518: 495-501
        • Goggins M.
        Molecular markers of early pancreatic cancer.
        J Clin Oncol. 2005; 23: 4524-4531
        • Harsha H.C.
        • Kandasamy K.
        • Ranganathan P.
        • et al.
        A compendium of potential biomarkers of pancreatic cancer.
        PLoS medicine. 2009; 6: e1000046
        • Brudvik K.W.
        • Kopetz S.E.
        • Li L.
        • et al.
        Meta-analysis of KRAS mutations and survival after resection of colorectal liver metastases.
        British j surg. 2015; 102: 1175-1183
        • Douillard J.Y.
        • Oliner K.S.
        • Siena S.
        • et al.
        Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer.
        N Engl J Med. 2013; 369: 1023-1034
        • Fakih M.G.
        Metastatic colorectal cancer: current state and future directions.
        J Clin Oncol. 2015; 33: 1809-1824
        • Hecht J.R.
        • Douillard J.Y.
        • Schwartzberg L.
        • et al.
        Extended RAS analysis for anti-epidermal growth factor therapy in patients with metastatic colorectal cancer.
        Cancer treat rev. 2015; 41: 653-659
        • Bournet B.
        • Buscail C.
        • Muscari F.
        • et al.
        Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities.
        Eur j cancer (Oxford, England: 1990). 2015; 54: 7583
      4. Clinical Practice Guidelines in Oncology (NCCN Guidelines), Colon Cancer, version 2.2016, www.nccn.org. Accessed February 1, 2016.
        • Hennessy B.T.
        • Timms K.M.
        • Carey M.S.
        • et al.
        Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer.
        J Clin Oncol. 2010; 28: 3570-3576
        • Sahin I.H.
        • Lowery M.A.
        • Stadler Z.K.
        • et al.
        Genomic instability in pancreatic adenocarcinoma: a new step towards precision medicine and novel therapeutic approaches.
        Exp rev gastroenterol hepatol. 2016; : 1-13
        • Boland C.R.
        • Goel A.
        Microsatellite instability in colorectal cancer.
        Gastroenterol. 2010; 138: e2073
        • Hutchins G.
        • Southward K.
        • Handley K.
        • et al.
        Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer.
        J Clin Oncol. 2011; 29: 1261-1270
        • Sinicrope F.A.
        • Foster N.R.
        • Thibodeau S.N.
        • et al.
        DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy.
        J Nat Cancer Inst. 2011; 103: 863-875
        • Le D.T.
        • Uram J.N.
        • Wang H.
        • et al.
        PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.
        N Engl J Med. 2015; 372: 2509-2520
        • Dung T.
        • Le J.N.U.
        • Hao
        • et al.
        PD-1 blockade in mismatch repair deficient non-colorectal gastrointestinal cancers.
        J Clin Oncol. 2016; (abstr 195): 34
        • Golan T.
        • Kanji Z.S.
        • Epelbaum R.
        • et al.
        Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers.
        British J Cancer. 2014; 111: 1132-1138
        • Isakoff S.J.
        • Mayer E.L.
        • He L.
        • et al.
        TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer.
        J Clin Oncol. 2015; 33: 1902-1909
        • Gorodnova T.V.
        • Sokolenko A.P.
        • Ivantsov A.O.
        • et al.
        High response rates to neoadjuvant platinum-based therapy in ovarian cancer patients carrying germ-line BRCA mutation.
        Cancer Letters. 2015; 369: 363-367
        • Kim G.
        • Ison G.
        • McKee A.E.
        • et al.
        FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy.
        Clin Cancer Res. 2015; 21: 4257-4261
        • Kadakol A.
        • Ghosh S.S.
        • Sappal B.S.
        • et al.
        Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype.
        Human Mutation. 2000; 16: 297-306
        • Ando Y.
        • Saka H.
        • Ando M.
        • et al.
        Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis.
        Cancer Res. 2000; 60: 6921-6926
        • Cheng L.
        • Li M.
        • Hu J.
        • et al.
        UGT1A1*6 polymorphisms are correlated with irinotecan-induced toxicity: a system review and meta-analysis in Asians.
        Cancer Chem Pharm. 2014; 73: 551-560
        • Li M.
        • Wang Z.
        • Guo J.
        • et al.
        Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer.
        OncoTargets and Therapy. 2014; 7: 1653-1661
        • Liu X.
        • Cheng D.
        • Kuang Q.
        • et al.
        Association of UGT1A1*28 polymorphisms with irinotecan-induced toxicities in colorectal cancer: a meta-analysis in Caucasians.
        Pharmacogenomics J. 2014; 14: 120-129
        • Crona D.J.
        • Ramirez J.
        • Qiao W.
        • et al.
        Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study.
        Pharmacogenomics J. 2016; 16: 54-59
        • Kasuya K.
        • Tsuchida A.
        • Nagakawa Y.
        • et al.
        Prediction of a side effect and efficacy of adjuvant chemotherapy with gemcitabine for post operative patient of pancreatic cancer by a genetic polymorphism analysis.
        Hepatogastroenterology. 2012; 59: 1609-1613
        • Eser S.
        • Schnieke A.
        • Schneider G.
        • et al.
        Oncogenic KRAS signalling in pancreatic cancer.
        British J Cancer. 2014; 111: 817-822
        • Fitzgerald T.L.
        • Lertpiriyapong K.
        • Cocco L.
        • et al.
        Roles of EGFR and KRAS and their downstream signaling pathways in pancreatic cancer and pancreatic cancer stem cells.
        Adv In Biol Reg. 2015; 59: 65-81
        • Langer P.
        • Kann P.H.
        • Fendrich V.
        • et al.
        Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer.
        Gut. 2009; 58: 1410-1418
        • Del Chiaro M.
        • Verbeke C.S.
        • Kartalis N.
        • et al.
        Short-term Results of a Magnetic Resonance Imaging-Based Swedish Screening Program for Individuals at Risk for Pancreatic Cancer.
        JAMA Surgery. 2015; 150: 512-518
      5. Clinical Practice Guidelines in Oncology (NCCN Guidelines), Genetic/Familial High Risk Assessment: Breast and Ovarian, version 2.2016, www.nccn.org. Accessed February 1, 2016.

      6. Clinical Practice Guidelines in Oncology (NCCN Guidelines), Genetic/Familial High Risk Assessment: Colorectal, version 2.2015, www.nccn.org. Accessed October 27, 2015.

        • Wang Z.
        • Lai S.T.
        • Xie L.
        • et al.
        Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.
        Diabetes Res Clin Pract. 2014; 106: 19-26
        • Nakai Y.
        • Isayama H.
        • Ijichi H.
        • et al.
        Inhibition of renin-angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine.
        British J Cancer. 2010; 103: 1644-1648
        • Nakai Y.
        • Isayama H.
        • Ijichi H.
        • et al.
        Phase I trial of gemcitabine and candesartan combination therapy in normotensive patients with advanced pancreatic cancer: GECA1.
        Cancer Science. 2012; 103: 1489-1492
        • Kim S.
        • Toyokawa H.
        • Yamao J.
        • et al.
        Antitumor effect of angiotensin II type 1 receptor blocker losartan for orthotopic rat pancreatic adenocarcinoma.
        Pancreas. 2014; 43: 886-890
        • Cheng G.
        • Zielonka J.
        • McAllister D.
        • et al.
        Profiling and targeting of cellular bioenergetics: inhibition of pancreatic cancer cell proliferation.
        British J Cancer. 2014; 111: 85-93
        • Flossmann E.
        • Rothwell P.M.
        Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies.
        Lancet (London, England). 2007; 369: 1603-1613
      7. Routine aspirin or nonsteroidal anti-inflammatory drugs for the primary prevention of colorectal cancer: recommendation statement.
        Am Fam Physician. 2007; 76: 109-113
        • Dehmer S.P.
        • Maciosek M.V.
        • Flottemesch T.J.
        Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: A Decision Analysis: Technical Report.
        Agency for Healthcare Research and Quality (US), Rockville, MD2015
        • Cui X.J.
        • He Q.
        • Zhang J.M.
        • et al.
        High-dose aspirin consumption contributes to decreased risk for pancreatic cancer in a systematic review and meta-analysis.
        Pancreas. 2014; 43: 135-140