	Pancreatic adenocarcinoma may occur in association with several hereditary cancer predisposition syndromes. Recently, germline mutations in PALB2 have been shown to increase lifetime risk of pancreatic cancer and breast cancer, among other types. Here we review the evidence supporting PALB2, a pancreatic cancer susceptibility gene, and discuss potential implications for therapy exploiting a defective DNA damage response.

Pancreatic adenocarcinoma (PAC) is predicted to become the second-leading cause of cancer death in the United States by the year 2020, due to a rising incidence of the disease, stable-to-increasing mortality rates, and lack of progress in the development of curative therapies.

 While there are several established risk factors for development of PAC, including smoking and obesity,

in the majority of cases the etiology remains unclear. In approximately 10% to 15% of patients, however, a significant family history of pancreatic cancer in two or more close relatives is apparent. Some of these cases are due to known hereditary cancer syndromes that predispose to PAC, the most common of which are germline mutations in 

mutation carrier is estimated at between 2 to 3.5 times that of the general population.

 Less commonly known mutations including, the Li Fraumeni, Peutz Jegher, hereditary non-polyposis colon cancer (HNPCC), and familial atypical mole and melanoma syndrome (FAMMM), are known to carry an increased risk of PAC, along with the inherited conditions such as cystic fibrosis and hereditary pancreatitis 

In an additional group of patients with familial PAC however, a significant family history of PAC is noted, but no identifiable genetic predisposition is found. Registry studies have shown that individuals having three or more affected first-degree relatives (FDR) have a 32-fold increased risk of developing PAC, those with two affected FDRs with pancreatic cancer have a 6.4-fold increased risk, and those with a single affected FDR have a 4.5-fold increased risk. These cases are likely due to as yet unidentified genetic alterations, and family members of affected patients are optimally included in prospective registry studies.

		Table 1. Hereditary Conditions Associated With Increased Risk of Pancreatic Ductal Adenocarcinoma

mutations were first associated with PAC in 2009, when whole exome sequencing of tumor DNA from a patient with familial PAC identified a truncating mutation in 

. This prompted evaluation of a further 96 patients with familial PAC and confirmed an additional 3 patients also with truncating 

 A subsequent study of 81 European patients with familial PAC identified a truncating germline 

 mutation in 3 patients, all of whom had a personal history of breast and pancreatic cancer, and who had tested negative for germline mutations in 

 mutations in patients with familial PAC from these studies of approximately 3% to 4%, however, has not been confirmed in several more recent studies of less highly selected patients.

 are also associated with increased susceptibility to breast cancer

 so a family history of breast or ovarian cancer is frequently noted in carriers. Biallelic germline mutation in 

 results in a typical Fanconi anemia phenotype, but with an additional severe predisposition to pediatric malignancies.

 mutations include individuals with strong family history of breast, ovarian, and pancreatic cancers who have tested negative for mutations in 

, as well as patients with a Fanconi anemia (FA) phenotype who tested negative for other FA genes and blood relatives of individuals with a mutation in 

The potential therapeutic implications of identifying a germline 

 mutation relates to the protein’s critical role in homologous recombination, the process by which cells accurately repair double stranded DNA breaks. PALB2 protein physically links 

to form a “BRCA complex,” and cells deficient in PALB2 have been shown to have an impaired DNA damage response. DNA double-strand breaks (DSBs) may be induced during cell replication by stalled replication forks, and are optimally repaired by homologous recombination; in the absence of functional 

however, these DSBs are repaired by the error prone non-homologous end joining pathway (NHEJ) thus leading to genetic instability.

 therefore may represent a population whereby the identification of an inherited cancer predisposition syndrome may be potentially exploited for therapeutic benefit. Platinum chemotherapy drugs exert their cytotoxic effect by binding directly to DNA, causing crosslinking of DNA strands and thereby inducing double-stranded DNA breaks, which are ineffectively repaired in cells lacking a functional homologous repair pathway. Poly ADP ribose polymerase (PARP) 1 and 2 are key components of the cellular DNA repair mechanism for single-strand breaks and nucleoside base damage; inhibition of PARP in tumor cells leads to transformation of background single-strand breaks into double-strand breaks (DSB),

 which again are inefficiently repaired in cells lacking key components of the DNA damage response pathway. PARP inhibitors and DNA damaging chemotherapy agents therefore represent therapeutic strategies that may have a synthetically lethal effect in 

mutation-associated cancers. Several retrospective series have described significant response to platinum agents and / or PARP inhibitors in patients with known 

 Golen et al reported a median overall survival of 22 months in 

 mutation carriers with stage 3 or 4 PAC who received treatment with a platinum agent, compared with 9 months for those who received non-platinum chemotherapy (N = 43 patients, 

 = .039). The Food and Drug Administration recently approved olaparib for treatment of advanced 

-mutated ovarian cancer under its accelerated approval program. This decision was based on results of an open label phase ll trial in which 137 patients with measurable, germline BRCA-mutated advanced ovarian cancer who had received three or more prior lines of chemotherapy were treated with single-agent olaparib 400 mg orally twice daily. The overall response rate was 34% (95% CI: 26%, 42%) with median response duration of 7.9 months (95% CI: 5.6, 9.6 months).

 This study also included 23 patients with 

 mutant PAC, of whom 22% showed either complete or partial response to treatment with single agent olaparib.

There is, however, much less published experience with treatment of 

mutant PAC. Fortuitously, a murine xenograft tumor model encompassing PAC cells extracted from a patient with advanced 

 mutation associated PAC was generated at one center, which facilitated preclinical study of DNA damaging agents in a mouse model.

 The patient had recurrent PAC following surgical resection, and had progression of disease on first-line gemcitabine chemotherapy. When sensitivity of PAC to mitomycin C was noted in the murine model, the patient received 5 cycles of mitomycin C with both clinical and radiographic response, sustained for 22 months. Two further cycles of mitomycin were given following eventual disease progression. Radiographic response to treatment was demonstrated, as well as toxicity. The patient subsequently responded to platinum-based chemotherapy and remained alive and well at the three-year follow up. Biallelic inactivation of 

These data led to the development of an ongoing randomized phase 2 study at Memorial Sloan Kettering Cancer Center in collaboration with the National Cancer Institute and other sites in the United States, Israel, and Canada, evaluating the addition of the PARP inhibitor, veliparib, to a cytotoxic backbone of cisplatin and gemcitabine in this subpopulation of 

 Results of an associated phase 1b trial conducted at MSKCC were presented in 2014 and identified the phase ll dose of veliparib in combination with gemcitabine and cisplatin (80 mg by mouth twice daily, days 1-12 of a 3-week cycle).

 This study included 17 patients, 9 of whom had known 

 mutations. High activity of the combination was noted in known mutation carriers. In the 

-mutated subgroup, 6 patients responded, for an objective response rate of 66%, and 3 patients achieved stable disease, yielding a disease control rate exceeding 88%. In contrast, no significant activity was observed in non-

-mutated patients. An additional phase 2 protocol evaluated the use of single-agent veliparib, at a dose of 400 mg daily, as second- or third-line therapy in patients with previously treated 

 Veliparib was well â€¨tolerated in this population, with most common side effects being fatigue and hematologic toxicity. While no confirmed partial response was observed, single agent activity of â€¨veliparib was observed, with 25% of patients having stable disease ≥ 4 months.

 mutations account for a small number of familial PAC cases; in patients with a significant family history of breast and pancreas cancer who are not carriers of deleterious 

 mutation may be considered. Anecdotal reports indicated significant activity of DNA-damaging chemotherapy in patients with PAC associated with a deleterious mutation in 

. For now, we await results of prospective studies evaluating the addition of PARP inhibition to platinum-based chemotherapy in this genetically selected population.

 Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center (MAL, EMO).

 Maeve Lowery, MD, Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065. E-mail: lowerym@mskcc.org.

			â€¨Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer Incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. 

			â€¨Iodice S, Gandini S, Maisonneuve P, et al. Tobacco and the risk of pancreatic â€¨cancer: a review and meta-analysis. 

			â€¨Larsson SC, Orsini N, Wolk A: Body mass index and pancreatic cancer risk: a meta-analysis of prospective studies. 

			â€¨Iqbal J, Ragone A, Lubinski J, et al. The incidence of pancreatic cancer in 

			â€¨â€¨Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers Syndrome. 

			â€¨Lowenfels A, Maisonneuve P, DiMagno E, et al. Hereditary pancreatitis and the risk of pancreatic cancer. International hereditary pancreatitis study group. 

			â€¨â€¨Lynch H, Fusaro R, Lynch J, et al. Pancreatic cancer and the FAMMM syndrome. 

			â€¨â€¨Jones S, Hruban RH, Kamiyama M, et al. Exomic sequencing identifies 

 as a pancreatic cancer susceptibility gene. 

			â€¨Slater EP, Langer P, Niemczyk E, et al. 

 mutations in European familial pancreatic cancer families. 

			â€¨â€¨Stadler ZK, Salo-Mullen E, Sabbaghian N, et al. Germline 

mutation analysis in breast—pancreas cancer families. 

			â€¨Grant RC, Selander I, Connor AA, et al. Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. 

			â€¨â€¨Rahman N, Seal S, Thompson D, et al. PALB2, which encodes a 

-interacting protein, is a breast cancer susceptibility gene. 

			â€¨â€¨Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. P

			â€¨â€¨Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. 

			â€¨Jasin M, Rothstein R: Repair of strand breaks by homologous recombination. 

			â€¨â€¨Sandhu SK, Yap TA, de Bono JS. Poly(ADP-ribose) polymerase inhibitors in cancer treatment: A clinical perspective. 

			â€¨Golan T, Kanji ZS, Epelbaum R, et al. Overall survival and clinical character-â€¨istics of pancreatic cancer in BRCA mutation carriers. 

			â€¨â€¨Lowery MA, Kelsen DP, Stadler ZK, et al. An emerging entity: pancreatic adenocarcinoma associated with a known 

 mutation: clinical descriptors, treatment implications, and future directions. 

			â€¨â€¨Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline 

			â€¨â€¨Bella Kaufman RS-F, Rita K. Schmutzler: Olaparib monotherapy in patients with advanced cancer and a germ-line 

 mutation: An open-label phase II study. 

			â€¨Villarroel MC, Rajeshkumar NV, Garrido-Laguna I, et al. Personalizing cancer treatment in the age of global genomic analyses: 

 gene mutations and the response to DNA damaging agents in pancreatic cancer. 

			â€¨â€¨Gemcitabine hydrochloride and cisplatin with or without veliparib or veliparib alone in patients with locally advanced or metastatic pancreatic cancer. ClinicalTrials.gov Identifier [NCT01585805]. http://clinicaltrials.gov/show/NCT01585805NLM Identifier:NCI01585805.

			â€¨â€¨O’Reilly EM, Segal MF. Phase IB trial of cisplatin (C), gemcitabine (G), and veliparib (V) in patients with known or potential 

			â€¨â€¨Lowery MA, Kelson DP, Smith SC, et al. Phase II trial of veliparib (V) in patients (pts) with previously treated 

mutated (mut) pancreas adenocarcinoma (PC). 

Articles

Germline mutations in PALB2 have recently been shown to increase lifetime risk of pancreatic cancer and breast cancer, among other types.

Maeve A. Lowery, MD

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PALB2 Mutations Confer Susceptibility to Familial Pancreatic Cancer and May Provide a Novel Targeted Therapeutic Approach to Cancer