Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA–Associated Pancreatic Cancer in the Clinical and Preclinical Setting

Abstract

Germline BRCA–associated pancreatic ductal adenocarcinoma (glBRCA PDAC) tumors are susceptible to platinum and PARP inhibition. The clinical outcomes of 125 patients with glBRCA PDAC were stratified based on the spectrum of response to platinum/PARP inhibition: (i) refractory [overall survival (OS) <6 months], (ii) durable response followed by acquired resistance (OS <36 months), and (iii) long-term responders (OS >36 months). Patient-derived xenografts (PDX) were generated from 25 patients with glBRCA PDAC at different clinical time points. Response to platinum/PARP inhibition in vivo and ex vivo culture (EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA PDAC and identified homologous recombination (HR) proficiency and secondary mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient (HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor mutational burden was high in HRD PDAC and significantly higher in tumors with secondary mutations. Anti–PD-1 attenuated tumor growth in a novel humanized glBRCA PDAC PDX model. This work demonstrates the utility of preclinical models, including EVOC, to predict the response of glBRCA PDAC to treatment, which has the potential to inform time-sensitive medical decisions. Significance: glBRCA PDAC has a favorable response to platinum/PARP inhibition. However, most patients develop resistance. Additional treatment options for this unique subpopulation are needed. We generated model systems in PDXs and an ex vivo system (EVOC) that faithfully recapitulate these specific clinical scenarios as a platform to investigate the mechanisms of resistance for further drug development.

NALIRIFOX, FOLFIRINOX, and Gemcitabine With Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Cancer

“…Moreover, biomarker-driven treatment selection should be encouraged in the future. Previous research has shown that a tumor’s homologous recombination deficiency is associated with sensitivity to platinum-based chemotherapy . In this light, testing for germline BRCA1-2 alterations should be routinely performed, as recommended by most guidelines, while there is increasing interest toward the assessment of somatic homologous recombination deficiency, including but not limited to BRCA1-2 or PALB2 alterations.…”

“…Previous research has shown that a tumor’s homologous recombination deficiency is associated with sensitivity to platinum-based chemotherapy. 20 , 21 In this light, testing for germline BRCA1-2 alterations should be routinely performed, as recommended by most guidelines, 22 , 23 while there is increasing interest toward the assessment of somatic homologous recombination deficiency, including but not limited to BRCA1-2 or PALB2 alterations. Ultimately, our data do not suggest a preference between NALIRIFOX and FOLFIRINOX, which can thus be still considered a valid option to be further explored in its modified version in the metastatic disease setting.…”

Clinical homologous recombination repair gene reversion analysis identifies mechanisms of resistance to PARP inhibitors and platinum‐chemotherapy

“…Moreover, a meta‐analysis highlighted that 26% of patients with BRCA1/2 mutations who progressed on these treatments developed reversion mutations 12 . Notably, over 30% of pancreatic cancer patients with germline BRCA1/2 mutations who did not respond favorably to treatment also exhibited secondary reversion mutations 21 . In addition, PALB2 and RAD51C/D reversion mutations have been significantly associated with poor responses to PARPi, further underscoring the clinical importance of understanding these genetic changes 18,22 …”

Establishment and Thorough Characterization of Xenograft (PDX) Models Derived from Patients with Pancreatic Cancer for Molecular Analyses and Chemosensitivity Testing

“…When working with PDX, everyone should keep the limits of these models in mind [66,93]: maintenance of human tumor tissues in mice selects the fast adapting population of cancer cells, altering the clonal heterogeneity of the PDX tumor, while the influential human tumor stroma is replaced by murine analogues and the tumor-intrinsic immune cells are lost. However, no other preclinical model provides this high heterogeneity of tumor cells and similarity of morphologic and genomic features with patient material [29,37]. The combination of molecular profiles, information on the ECM, as well as immune-related data provide a broader basis for the development of novel drugs in a preclinical setup.…”

“…Interfering with the repair of inherent DNA damage by polyADP-ribose polymerase (PARP) inhibitors emerges as a therapeutic concept also for PDAC patients, especially for tumors deficient in homologous recombination [26,27]. In combination with platinum-based therapy, PARP inhibitors already contribute to improved patient survival in metastatic PDAC tumors with inherited BRCA mutations [28,29].…”