Repurposing PARP inhibitors in molecularly defined subgroups of peritoneal metastatic colorectal cancer (pmCRC): Preclinical analysis of patient-derived xenograft (PDX) models

Peritoneal metastatic colorectal cancer (pmCRC) has the worst outcome compared to metastatic CRC patients with metastases in other organs, such as liver or lung. More importantly, despite of the improvement of both systemic and peritoneal specific treatment, 50% to 90% of patients experience relapse and progression of the disease, leading to premature death. Precision oncology has successfully improved the overall survival of several solid and non-solid malignancies. For CRC, large volumes of information have been acquired regarding the molecular aberrations, characterizing both lung and liver metastases from CRC, thus leading to a more personalized treatment approach. On the contrary, this has not yet been done for pmCRC. In a comprehensive effort to close this gap and to identify new predictive signatures to drug responses in pmCRC, we previously established a novel platform of matched preclinical pmCRC models, including 14 patient-derived xenografts (PDX) of peritoneal metastases from a total of 10 pmCRC patients and showed that tumors intrinsically resistant to 5‑Fluorouracil (5‑FU) were enriched in alterations of the DNA damage response and repair (DDR) machinery. We therefore hypothesize, that those tumors are responsive to DDR inhibitors such as olaparib. In order to prove our hypothesis, we generated a new cohort of 48 pmCRC PDX, characterized by RNA sequencing. Based on both transcriptomic and mutational profiles, we classified 14 PDX as homologous recombination deficient (HRD) and 34 PDX as proficient. The most common alteration identified in the HRD positive group were loss-of-function frameshift insertions/deletions in BRCA1/2, in addition to other homologous recombination repair genes (HRRmut). Clinical data, in particular treatment response data, were combined with the genomic profiles of the respective PDX models, supporting the prediction of 5‑FU resistance. Subsequently, a total of 12 pmCRC models predicted to be resistant to 5‑FU-based treatment regimens, but sensitive to PARP due to HRD, were treated with 5‑FU or olaparib alone, as well as in combination. Response data will be presented. Our study highlights the importance of molecular profiling for better personalized treatment.