Key Points:

• Several studies show family history alone is insufficient for determining the population with germline alterations associated with increased risk of pancreatic adenocarcinoma (PDAC).
• Therefore, based on growing evidence, National Comprehensive Cancer Network guidelines adopted universal germline BRCA testing for patients with PDAC regardless of disease stage at diagnosis.
• Germline BRCA testing will not only define screening recommendations but also guide therapeutic approaches for patients with all-stages of PDAC given platinum-based treatments associated with improved survival outcomes.

Question: What is your recommendation for germline BRCA testing before starting first-line treatment for PDAC?

Answer: Historically, germline genetic testing for deleterious alterations was offered based on a personal and family history of cancer, which defines the population at risk for testing. Similarly, BRCA testing was offered to patients based on their personal and family history of cancer. However, emerging data have shown that even reliably good family history is insufficient to capture patients with germline alterations associated with increased risk of PDAC.^1,2 One landmark study investigated deleterious germline alterations, including BRCA mutations, among patients with “sporadic” PDAC.¹ In this study, 33 out of 854 (3.9%) patients were found to carry germline alterations linked to PDAC, including BRCA1/2 mutations (15), and only 3 out of 33 patients had a family history of PDAC indicating several presumed instances of “sporadic PDAC” were driven by a germline alteration. A case-controlled study identified that 5.2% of patients with PDAC without a family history of cancer carry pathogenic germline alterations, including BRCA mutations.² These data indicate that family history is not reliable for determining whether germline testing of BRCA alterations is needed. Therefore, all patients with PDAC, regardless of stage of disease, should undergo germline BRCA testing at the time of diagnosis.

[Based on the data], all patients with PDAC, regardless of stage of disease, should undergo germline BRCA testing at the time of diagnosis.

Increasing next-generation sequencing–based molecular profiling has uncovered potentially pathogenic BRCA variants that were not otherwise recognized as pathogenic in germline testing. This resulted in the expansion of recognized germline BRCA alterations that may directly impact screening recommendations for unaffected family members of affected individuals. It is important to note that germline testing with variant of uncertain significance results should prompt genetic counseling, given conflicting reports of the pathogenicity of these alterations and dynamic change in the classification of variant of uncertain significance alterations. Genetic counseling can also provide further insights for specific risk assessment for pancreatic cancer associated with each BRCA alteration, given that pancreatic cancer risk is higher with pathogenic germline BRCA2 alteration compared with germline BRCA1 alterations.

Why Is Germline Genetic Testing Important?

Currently, National Comprehensive Cancer Network guidelines recommend germline genetic testing for all patients with PDAC, preferably with the use of a comprehensive panel of genes that are associated with pancreatic cancer, including but not limited to BRCA1/2, PALB2, ATM, CDKN2A, STK11, P53, MLH1, PMS2, MSH2, and MSH6.³ If germline testing reveals any pathogenic alteration, patients should be referred for genetic counseling for further recommendations for the implication of the individual germline alteration detected. It is important to note that germline BRCA alterations would not only impact testing the rest of the family but also may define therapeutic approaches for patients with PDAC. For example, platinum-based chemotherapy has been shown to induce deeper and more durable responses in the setting of pathogenic germline BRCA alterations.^4,5 Several studies suggest that the earlier use of platinum-based therapy is also associated with prolonged survival among patients with PDAC with germline BRCA alterations.^6,7 Moreover, PARP inhibitors induce synthetic lethality in cancer cells carrying pathogenic BRCA and PALB2 mutations, resulting in the death of cancer cells. This mechanism created a novel therapeutic opportunity for the use of PARP inhibitors for patients with PDAC. Olaparib has been approved as maintenance therapy for patients with germline BRCA-mutant metastatic PDAC who did not experience progression on platinum-based front-line therapy based on the POLO trial.^8,9

Concluding Remarks

Advances in next-generation sequencing may uncover previously unknown germline BRCA alterations, prompting an expansion of available platforms for comprehensive germline testing. This evolving landscape emphasizes the role of genetic counseling and informs not only family screening but also therapeutic choices. Platinum-based chemotherapy and PARP inhibitors show promise in improving responses and prolonging survival in patients with PDAC with germline alterations, highlighting the growing impact of genetic testing on precision medicine in pancreatic cancer.