An Analysis of Patients with DNA Repair Pathway Mutations Treated with a PARP Inhibitor

Abstract

Background Molecular analysis has revealed four subtypes of pancreatic ductal adenocarcinoma (PDAC). One subtype identified for the presence of DNA damage repair deficiency can be targeted therapeutically with the poly (ADP‐ribose) polymerase (PARP) inhibitor olaparib. We performed a single institution retrospective analysis of treatment response in patients with PDAC treated with olaparib who have DNA damage repair deficiency mutations. Subjects, Materials, and Methods Patients with germline or somatic mutations involving the DNA repair pathway were identified and treated with olaparib. The primary objective was to examine the objective response rate (ORR). The secondary objectives were assessing tolerability, overall survival, and change in cancer antigen 19‐9. Quantitative texture analysis (QTA) was evaluated from CT scans to explore imaging biomarkers. Results Thirteen individuals with metastatic PDAC were treated with Olaparib. The ORR to Olaparib was 23%. Median overall survival (OS) was 16.47 months. Four of seven patients with BRCA mutations had an effect on RAD51 binding, with a median OS of 24.60 months. Exploratory analysis of index lesions using QTA revealed correlations between lesion texture and OS (hepatic lesion tumor texture correlation coefficient [CC], 0.683, p = .042) and time on olaparib (primary pancreatic lesion tumor texture CC, 0.778, p = .023). Conclusion In individuals with metastatic PDAC who have mutations involved in DNA repair, Olaparib may provide clinical benefit. BRCA mutations affecting RAD51 binding domains translated to improved median OS. QTA of individual tumors may allow for additional information that predicts outcomes to treatment with PARP inhibitors. Implications for Practice Pursuing germline and somatic DNA sequencing in individuals with pancreatic ductal adenocarcinoma may yield abnormalities in DNA repair pathways. These individuals may receive benefit with poly (ADP‐ribose) polymerase (PARP) inhibition. Radiomics and deep sequencing analysis may yet uncover additional information that may predict outcome to treatment with PARP inhibitors.

Integrated genomic and transcriptomic analysis reveals unique characteristics of hepatic metastases and pro-metastatic role of complement C1q in pancreatic ductal adenocarcinoma

“…Genes located at 13q12.13 contain BRCA2 which plays an important role in homologous DNA repair pathway. It has been recently reported that PDAC patients with deficient homologous DNA repair system resulted from germline or somatic mutations on BRCA1 or BRCA2 are susceptible to Poly (ADP-ribose) polymerase (PARP) inhibitor therapy [ 24 , 25 ]. However, cases harboring targetable mutations occur at quite low frequency (4–7%) [ 25 ].…”

Methylation Analyses Reveal Promoter Hypermethylation as a Rare Cause of “Second Hit” in Germline BRCA1-Associated Pancreatic Ductal Adenocarcinoma

“…In patients with gBRCA1 -PDAC, prior studies have found a high prevalence of somatic BRCA1 mutations, albeit their findings were limited in the sample size. Yurgelun et al described concomitant sBRCA1 mutations in one (33%) out of three patients [ 23 ], whereas Borazanci et al observed the same finding in one of two PDAC tumors [ 24 ]. Our results indicate that second sBRCA1 mutations are infrequently associated with gBRCA1 P/LPVs and occurred in only two (10.5%) of 19 patients in our cohort.…”

Personalizing Medicine With Germline and Somatic Sequencing in Advanced Pancreatic Cancer: Current Treatments and Novel Opportunities

“…24,25 However, case reports of ATM-mutated pancreatic cancers have not shown disease control with PARP inhibitor maintenance therapy. 26,27 Indeed, PARP inhibitor monotherapy was only cytostatic but did not induce cell killing in ATM-deficient preclinical pancreatic cancer cell models. 28 There are preclinical data suggesting efficacy of ATM inhibitors, ATR inhibitors, and CHK1 inhibitors 29 or of combination therapies of multiple DNA damage repairtargeting therapies, 24 and there are ongoing early-phase clinical trials at this time.…”