Retrospective review of outcomes in patients with DNA-damage repair related pancreatic cancer

Abstract

Background: Patients with DNA-damage response genes (DDR)-related pancreas cancer (BRCA1/2 or other DNAdamage related genes) may have improved outcomes secondary to increased sensitivity to DNA-damaging drugs (platinum chemotherapy/ poly ADP ribose polymerase (PARP)-inhibitors). However, data is scarce pertaining to outcomes in this subset of patients. Our objective was to retrospectively identify DDR-related pancreas cancer patients and report on clinical outcomes. Methods: Pancreas cancer patients with a germline pathogenic variant in BRCA1/2 or other DDR gene were identified retrospectively through review of medical records (medical genetics/oncology) and genetic testing results at our institution. Data regarding clinical outcomes, therapy received, and survival was subsequently extracted. Results: A total of 11 patients with pancreas cancer were identified to carry a pathogenic DDR-variant: BRCA1 (3), ATM (4), BRCA2 (2), PALB2 (1) and FANCC (1). Five of these individuals had prior history of other cancers. Clinically these tumors were localized (4), locally advanced (3), and metastatic (4) at diagnosis. Four out of 11 patients were still alive at time of data review. Survival in the 7 patients who had died was 13.7, 140.0, 20.5, 22.3, 23.5, 25.8, and 111.5 months. All patients with advanced disease had exposure to platinum chemotherapy. Conclusions: Historical survival in patients with advanced and metastatic pancreas cancer is poor. Results of this DDRsubset of patients do show significantly superior outcomes, likely secondary to exposure to platinum drugs. This data, alongside other similar cohorts, would favor the DDR-genes being a predictive marker with improved survival if exposed to these drugs and the new class of drugs, PARP-inhibitors.

Circulating Tumor DNA-Based Testing and Actionable Findings in Patients with Advanced and Metastatic Pancreatic Adenocarcinoma

“…This was recently shown in a retrospective study of 262 patients with PDAC in which 19% of the patients were found to have HRm (defined as germline or somatic pathogenic alterations of 17 HRm including ATM , BRCA1 , and BRCA2 ); PFS was better in patients with HRm when platinum‐based therapy was used compared with nonplatinum‐based therapy [6]. Additional series are corroborating better outcomes in patients harboring the HRm aberrations, highlighting the value of identifiyin these patients [42]. In our study, we detected HRm in 8.8% of the patients.…”

Impact of comprehensive family history and genetic analysis in the multidisciplinary pancreatic tumor clinic setting

“…Indeed, while PGVs in certain DNA damage repair genes (e.g. BRIP1 , CHEK2 , FANCC , NBN , RAD50 , RAD51C , RAD51D ) are not currently linked to PDAC risk or included in PDAC surveillance guidelines, there is considerable interest in defining their role in PDAC tumorigenesis and treatment response 8,37,38 . As broader multi‐gene panels become more common, documenting all findings in pancreatic cancer families through registries will be important to advancing understanding of the missing heritability for pancreatic cancer, and also offers opportunities to provide couseling for other cancer risks.…”

BRCA-Mutated Pancreatic Cancer: From Discovery to Novel Treatment Paradigms

“…In the case of pancreatic cancers, recent studies reported that germline mutations in genes such as BRCA1, BRCA2, PALB2, and CDKN2A occur in about 10-20% of patients without extra-pancreatic manifestations, and 5-8% of patients with pancreatic cancer without family history are in fact carriers of germline mutations [34,35]. Some studies have reported a near doubling of the risk of pancreatic cancer in BRCA female carriers [36].…”