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
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.1 While there are several established risk factors for development of PAC, including smoking and obesity,2,3 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 BRCA1/2, whereby the lifetime risk of PAC in a BRCA1/2 mutation carrier is estimated at between 2 to 3.5 times that of the general population.4 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 (Table).5-7 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.
PALB2 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 PALB2. This prompted evaluation of a further 96 patients with familial PAC and confirmed an additional 3 patients also with truncating PALB2 germline mutations.8 A subsequent study of 81 European patients with familial PAC identified a truncating germline PALB2 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 BRCA1/2.9 The estimated prevalence of PALB2 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.10,11 Monoallelic germline mutations in PALB2 are also associated with increased susceptibility to breast cancer12 and ovarian cancer,13 so a family history of breast or ovarian cancer is frequently noted in carriers. Biallelic germline mutation in PALB2 results in a typical Fanconi anemia phenotype, but with an additional severe predisposition to pediatric malignancies.14 Indications for germline testing for PALB2 mutations include individuals with strong family history of breast, ovarian, and pancreatic cancers who have tested negative for mutations in BRCA1/2, 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 PALB2.
The potential therapeutic implications of identifying a germline PALB2 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 BRCA1 and BRCA2 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 BRCA1, BRCA2, or PALB2 however, these DSBs are repaired by the error prone non-homologous end joining pathway (NHEJ) thus leading to genetic instability.15 Patients with germline mutations in BRCA1/2 or PALB2 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),16 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 BRCA1/2 or PALB2 mutation-associated cancers. Several retrospective series have described significant response to platinum agents and / or PARP inhibitors in patients with known BRCA1/2 mutations and pancreatic cancer.17,18 Golen et al reported a median overall survival of 22 months in BRCA1/2 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, P = .039). The Food and Drug Administration recently approved olaparib for treatment of advanced BRCA-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).19 This study also included 23 patients with BRCA mutant PAC, of whom 22% showed either complete or partial response to treatment with single agent olaparib.20
Eileen M. O’Reilly, MD
There is, however, much less published experience with treatment of PALB2 mutant PAC. Fortuitously, a murine xenograft tumor model encompassing PAC cells extracted from a patient with advanced PALB2 mutation associated PAC was generated at one center, which facilitated preclinical study of DNA damaging agents in a mouse model.21 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 PALB2 was confirmed in the PAC tumor sample.
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 BRCA and PALB2 mutated PAC.22 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).23 This study included 17 patients, 9 of whom had known BRCA 1/2 mutations. High activity of the combination was noted in known mutation carriers. In the BRCA-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-BRCA-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 BRCA- or PALB2-mutated pancreas cancer.24 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.
Overall, monoallelic germline PALB2 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 BRCA1 or BRCA 2 mutations, germline testing for a PALB2 mutation may be considered. Anecdotal reports indicated significant activity of DNA-damaging chemotherapy in patients with PAC associated with a deleterious mutation in PALB2. For now, we await results of prospective studies evaluating the addition of PARP inhibition to platinum-based chemotherapy in this genetically selected population.
ABOUT THE AUTHORS
Affiliations: Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center (MAL, EMO).
Corresponding author: Maeve Lowery, MD, Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065. E-mail: firstname.lastname@example.org.