The challenge of clinical investigations and “The best laid plans of mice and men...”: great science, great team, great execution, disappointing results

© Digestive Medicine Research. All rights reserved. Dig Med Res 2020;3:90 | http://dx.doi. org/10.21037/dmr-2020-17 The role of BRCA gene mutations as risk factors for breast and ovarian cancer and in surgical decision management for their cancer risk mitigation has been well known for many years (1,2). In addition, the association of BRCA mutations with other malignancies including pancreas, prostate, melanoma, and cholangiocarcinoma is now clear (3-5). Functionally, BRCA genes are involved in the repair of DNA double stranded breaks (DNA DSBs) and in the activation of DNA damage repair checkpoints (6). Specifically, BRCA 1 and BRCA 2 mutations interfere with homologous recombination repair (HR), creating a specific therapeutic opportunity; namely, the creation of synthetic lethality by treating patients carrying these mutations with agents that further compromise DNA DSB repair. The term “synthetic lethality” is defined as a “type of genetic interaction where the co-occurrence of two genetic events results in organismal or cellular death. ” In this context the word “synthetic” is used for its ancient Greek meaning: the combination of two entities to form something new (7). While synthetic lethality was originally observed with naturally occurring mutations in separate genes, it can also be pharmacologically induced by blocking (inhibiting) a relevant gene target in a patient or organism with a naturally occurring mutation in a single (different) functional gene. One such opportunity involves the pharmacologic inhibition of the poly (ADP-ribose) polymerase (PARP) gene. In the presence of BRCA 1 and BRCA 2 mutations, an opportunity for synthetic lethality exists by inhibiting PARP enzymes that are involved in the repair of DNA single and double stranded breaks (8). In fact, this strategy has already been used successfully for some time in breast cancer including patients with triple negative breast cancer with BRCA mutations and in patients with BRCA related ovarian cancer (9,10). Given this growing success in breast and ovarian cancer, the desire to try this approach in other BRCA related malignancies was inevitable and, given the challenges of finding effective therapies for pancreatic cancer, a rapidly lethal malignancy when overtly metastatic, this was both a logical and scientifically reasonable choice, since a small, but measurable fraction of pancreatic cancer appears to be BRCA related (11). Following success with the PARP inhibitor, Olaparib, as maintenance therapy for patients with newly diagnosed BRCA related ovarian cancer (12) a decision was taken to apply a maintenance therapy approach with BRCA related pancreatic cancer, leading in 2018 to the results of the POLO (Pancreas Cancer Olaparib Ongoing) trial (13). This international trial, involving many sites from western Europe, Israel, South Korea and the USA, showed a significant 3.8 months (P=0.004) increase in disease free survival (DFS) among 154 randomized patients (culled from 3,315 screened) with BRCA related pancreatic cancer who remained in remission following 6 months of FOLFIRINOX chemotherapy. Success as maintenance therapy, suggested the possibility of enhanced effect with concurrent platinum based chemotherapy and PARP inhibition and on January 24, Editorial Commentary