cd-22-0412_supplementary_table_2_suppst2.xlsx (63.3 kB)

Supplementary table 2 from Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA–Associated Pancreatic Cancer in the Clinical and Preclinical Setting

Name: Supplementary table 2 from Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA–Associated Pancreatic Cancer in the Clinical and Preclinical Setting
Published: 2023-07-17T13:20:05+00:00
License: https://creativecommons.org/licenses/by/4.0/
Keywords: cancer

dataset

posted on 2023-07-17, 13:20 authored by Chani Stossel, Maria Raitses-Gurevich, Dikla Atias, Tamar Beller, Yulia Glick Gorman, Sharon Halperin, Eyal Peer, Robert E. Denroche, Amy Zhang, Faiyaz Notta, Julie M. Wilson, Grainne M. O'Kane, Elina Haimov Talmoud, Nora Amison, Michael Schvimer, Seth J. Salpeter, Vered Bar, Adi Zundelevich, Itay Tirosh, Rotem Tal, Gal Dinstag, Yaron Kinar, Yonatan Eliezer, Uri Ben-David, Nancy S. Gavert, Ravid Straussman, Steven J. Gallinger, Raanan Berger, Talia Golan

Clinical data of analyzed BRCA PDAC patients

History

ARTICLE 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. 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.