TY - JOUR
T1 - Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA–Associated Pancreatic Cancer in the Clinical and Preclinical Setting
AU - Stossel, Chani
AU - Raitses-Gurevich, Maria
AU - Atias, Dikla
AU - Beller, Tamar
AU - Gorman, Yulia Glick
AU - Halperin, Sharon
AU - Peer, Eyal
AU - Denroche, Robert E.
AU - Zhang, Amy
AU - Notta, Faiyaz
AU - Wilson, Julie M.
AU - O’kane, Grainne M.
AU - Talmoud, Elina Haimov
AU - Amison, Nora
AU - Schvimer, Michael
AU - Salpeter, Seth J.
AU - Bar, Vered
AU - Zundelevich, Adi
AU - Tirosh, Itay
AU - Tal, Rotem
AU - Dinstag, Gal
AU - Kinar, Yaron
AU - Eliezer, Yonatan
AU - Ben-David, Uri
AU - Gavert, Nancy S.
AU - Straussman, Ravid
AU - Gallinger, Steven J.
AU - Berger, Raanan
AU - Golan, Talia
N1 - Publisher Copyright:
© 2023 The Authors; Published by the American Association for Cancer Research.
PY - 2023/8/1
Y1 - 2023/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85166465253&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-22-0412
DO - 10.1158/2159-8290.CD-22-0412
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 37449843
AN - SCOPUS:85166465253
SN - 2159-8274
VL - 13
SP - 1826
EP - 1843
JO - Cancer Discovery
JF - Cancer Discovery
IS - 8
ER -
