Pancreatic ductal adenocarcinoma in BRCA2 mutation carriers

Abstract

Germline BRCA2 mutations are the first known cause of inherited (familial) pancreatic ductal adenocarcinoma (PDAC). This tumor is the third most frequent cancer in carriers of germline BRCA2 mutations, as it occurs in around 10% of BRCA2 families. PDAC is known as one of the most highly lethal cancers, mainly because of its chemoresistance and frequently late diagnosis. Based on recent developments in molecular biology, a subgroup of BRCA2-associated PDAC has been created, allowing screening, early surgical treatment and personalized systemic treatment. BRCA2 germline mutation carriers who have ≥1 first-degree relative, or ≥2 blood relatives with PDAC, should undergo screening and regular follow-up based on magnetic resonance imaging and endoscopic ultrasound. The goal of screening is to detect early invasive PDAC and advanced precancerous lesions suitable for a stepwise surgical complete (R0) resection. Increasing evidence on the molecular role of the BRCA2 protein in the homologous recombination of DNA damages suggest that BRCA2-related PDAC are sensitive to agents causing DNA cross-linking damage, such as platinum salts, and treatments targeting rescue DNA repair pathways, such as poly(ADP-ribose) polymerase inhibitors that are currently under investigation.

Long-Term Survivors of Pancreatic Cancer

“…The promise of targeting molecular vulnerabilities has been unfulfilled with the exception of rare patients with deficient mismatch repair (~1%–2%) treated with PD-1 blockade 31 , 32 and BRCA mutations (~4%–5%) treated with platinum agents and experimental PARP inhibitors. 33 , 34 Nevertheless, the impressive responses in these small subgroups offer proof of concept that there remain subgroups susceptible to targeted therapy and that the immune system is potent enough to be effective if there are neoantigens to recognize. The key to these developments is achieving a better understanding of the biology and immunology of the disease, and studying this unique cohort of long-term survivors may bring us a step closer to achieving this goal.…”

BRCA2: a grown-up cancer susceptibility gene

“…In their in-depth look at BRCA2 and BRCA2, de Mestier and coworkers (de Mestier et al 2016) review the state of knowledge with regard to the relationship between BRCA2 and pancreas cancer, and how this might be exploited therapeutically. PARP inhibitors, of course, could play a role (Andrei et al 2015, Kaufman et al 2015, but it is not known whether this class of drug will be as effective in treatment of BRCA-related pancreas cancer, compared with BRCA-related ovarian cancer, where the effect is most pronounced thus far.…”

Procedures and recommended times in the care process of the patient with pancreatic cancer: PAN-TIME consensus between scientific societies

“…However, only 5–10% of PC cases were related to hereditary factors [3, 10]. The most frequent mutation associated with PC is a mutation of breast cancer gene 2 (BRCA2), which is also associated with breast and ovarian cancer [11], although other mutations are also associated with PC [3]. In addition, there are other family syndromes associated with PC such as Peutz–Jeghers syndrome, hereditary pancreatitis, hereditary non-polyposis colorectal cancer (Lynch syndrome), and ataxia-telangiectasia, among others [3].…”