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Germline testing in pancreatic adenocarcinoma
Background
Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease to treat. Despite advances in medical therapies, the 5-year survival rate remains below 9%. BRCA mutations have emerged as a target for the development of more effective therapies. Alterations in germline BRCA and PALB2 are detected in approximately 5-9% of patients with PDAC and can lead to homologous repair deficiency (HRD). PDAC with HRD is more susceptible to cytotoxic agents, that cause DNA damage and PARP inhibitors have emerged as an effective non-cytotoxic approach. Germline mutations in other genes involved in the homologous DNA repair pathway -such as ATM and RAD51- are potential targets. The aim of our study is to analyse the frequency of germline mutations in patients with PDAC and to evaluate the role of family history as a supportive criterion for genetic testing.
Methods
Descriptive and retrospective study of the germline study of pathogenic variants (PV) and variants of unknown significance (VUS) in patients (p) with PDAC and those with 1st degree family history of pancreatic cancer studied at the Salamanca Genetic Counselling Unit (UCGS) from 2004 to 2022. The determination of BRCA1/2 and other genes in peripheral blood was carried out using Next-Generation Sequencing (NGS) techniques.
Results
We included 30 patients (p) with PDAC, studied as index case. Males (36.7%). Age (median): 68.5 years [28-84]. BRCA1/2 was performed in 26p and multiplex-gene panel (MGP) in 4p. Four PV were finding: 13.3% (2 in BRCA2 and 2 in PALB2) and 2 VUS in BRCA1 and BRCA 2. 1p carrier of the PALB2 mutation suffered pancreatic and gastric cancer. In patients carrying PV, 4 cases of breast cancer, 1 pancreatic cancer, 1 prostate cancer and 1 ovarian cancer were recorded as first-degree antecedents. Other oncological antecedents described in the family (2nd and 3rd degree): 3 breast cancer, 1 gastric cancer and 2 prostate cancer. In patients carrying VUS in BRCA1/2, familial aggregation was also described with 1 case of pancreatic cancer, 1 breast cancer and 1 breast cancer in immediate family. We collected 96p with cancer: breast cancer 64p (66.7%) followed by ovarian cancer 19p (19.8%), with 1st degree family history of pancreatic cancer. Age (median): 61.5 years [30-93]. BRCA1/2 was performed in 89p and MGP in 7p. Seven PV (7.3%) were found: 5 in BRCA1, 1 BRCA2 and 1 CHEK2. 16 VUS (16.7%) were found: 6 BRCA2, 5 BRCA1, 1 ATM, 1 MSH3, 1 POLE, 1 MLH1, 1 PABL2. In 2p, two variants were found in the same patient (1 of them 1PV in CHEK2 and 1 VUS in MSH1, and the other, 1 VUS in ATM and 1VUS in POLE).
Conclusions
PDAC could be an inherited condition in around 10% of cases. Germline testing BRCA and other HRD genes will improve therapeutic strategies and precision medicine in PDAC. In addition, familial involvement due to the identification of a hereditary syndrome should be taken into account.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosures
All authors have declared no conflicts of interest.
