Germline Aberrations in Pancreatic Cancer: Implications for Clinical Care

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis and represents a major public health issue, as both its incidence and mortality are expecting to increase steeply over the next years. Effective screening strategies are lacking, and most patients are diagnosed with unresectable disease precluding the only chance of cure. Therapeutic options for advanced disease are limited, and the treatment paradigm is still based on chemotherapy, with a few rare exceptions to targeted therapies. Germline variants in cancer susceptibility genes—particularly those involved in mechanisms of DNA repair—are emerging as promising targets for PDAC treatment and prevention. Hereditary PDAC is part of the spectrum of several syndromic disorders, and germline testing of PDAC patients has relevant implications for broad cancer prevention. Germline aberrations in BRCA1 and BRCA2 genes are predictive biomarkers of response to poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor olaparib and platinum-based chemotherapy in PDAC, while mutations in mismatch repair genes identify patients suitable for immune checkpoint inhibitors. This review provides a timely and comprehensive overview of germline aberrations in PDAC and their implications for clinical care. It also discusses the need for optimal approaches to better select patients for PARP inhibitor therapy, novel therapeutic opportunities under clinical investigation, and preclinical models for cancer susceptibility and drug discovery.

Clinical Significance of Germline Pathogenic Variants among 51 Cancer Predisposition Genes in an Unselected Cohort of Italian Pancreatic Cancer Patients

“…Overall, 70 PVs (17%) were found, a relatively high frequency compared to similar studies. However, due to the heterogeneity in cohort selection and dissimilar sequencing approaches across studies, the prevalence of PVs in PC susceptibility genes cannot be easily quantified, ranging from 5% to nearly 20% in different studies and reviews [ 18 , 34 , 37 , 38 , 39 , 40 , 41 , 42 ].…”

Targeted therapy for pancreatic ductal adenocarcinoma: Mechanisms and clinical study

“…Several studies have combined to show that cancer predisposing germline mutations, which are directly passed down from parents to children, are present in 3.8–9.7% of PDAC patients. 273 , 274 These mutations predispose individuals for several hereditary cancers, such as ovarian and breast cancer ( BRCA1, BRCA2, ATM, PALB2 ), atypical multiple mole melanoma ( CDKN2A ), Peutz‐Jeghers ( STK11 ), and so on. 274 , 275 , 276 , 277 The NCCN recommends that all patients diagnosed with PDAC to undergo germline mutation testing regardless of stage and family history.…”

“… 273 , 274 These mutations predispose individuals for several hereditary cancers, such as ovarian and breast cancer ( BRCA1, BRCA2, ATM, PALB2 ), atypical multiple mole melanoma ( CDKN2A ), Peutz‐Jeghers ( STK11 ), and so on. 274 , 275 , 276 , 277 The NCCN recommends that all patients diagnosed with PDAC to undergo germline mutation testing regardless of stage and family history. 197 Additionally, genetic testing for at‐risk individuals with family history of cancers can help enhance screening measures and reach asymptomatic individuals earlier on in the disease.…”

A systematic review and meta-analysis of germline BRCA mutations in pancreatic cancer patients identifies global and racial disparities in access to genetic testing

“…Germline aberrations in BRCA1 and BRCA2 genes are prevalent and clinically relevant for treatment and potential screening for pancreatic cancer (PC). 1 , 2 , 3 They are associated with increased progression-free survival in metastatic PC patients treated with poly-ADP-ribose polymerase inhibitor olaparib in the maintenance setting 4 and confer better response to platinum-based chemotherapy. 5 , 6 , 7 , 8 Germline BRCA1 and/or BRCA2 mutations (gBRCAm) can also inform cancer risk and drive preventative strategies in healthy relatives of patients with PC who are at high risk of BRCA-associated cancers (i.e.…”