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 - Glick Gorman, Yulia
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 - Haimov Talmoud, Elina
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
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) \lt;6 months], (ii) durable response followed by acquired resistance (OS \lt;36 months), and (iii) long-term responders (OS \gt;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.This article is highlighted in the In This Issue feature, p. 1749
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) \lt;6 months], (ii) durable response followed by acquired resistance (OS \lt;36 months), and (iii) long-term responders (OS \gt;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.This article is highlighted in the In This Issue feature, p. 1749
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 - Article
SN - 2159-8274
VL - 13
SP - 1826
EP - 1843
JO - Cancer Discovery
JF - Cancer Discovery
IS - 8
ER -