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

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

doi:https://doi.org/10.1158/2159-8290.CD-22-0412

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

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 TalGal Dinstag, Yaron Kinar, Yonatan Eliezer, Uri Ben-David, Nancy S. Gavert, Ravid Straussman, Steven J. Gallinger, Raanan Berger, Talia Golan

Tel Aviv University, Weizmann Institute of Science

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1826-1843
Number of pages	18
Journal	Cancer Discovery
Volume	13
Issue number	8
DOIs	https://doi.org/10.1158/2159-8290.CD-22-0412
State	Published - 1 Aug 2023

All Science Journal Classification (ASJC) codes

Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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https://doi.org/10.1158/2159-8290.CD-22-0412

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Stossel, C., Raitses-Gurevich, M., Atias, D., Beller, T., Gorman, Y. G., Halperin, S., Peer, E., Denroche, R. E., Zhang, A., Notta, F., Wilson, J. M., O’kane, G. M., Talmoud, E. H., Amison, N., Schvimer, M., Salpeter, S. J., Bar, V., Zundelevich, A., Tirosh, I., ... Golan, T. (2023). Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA–Associated Pancreatic Cancer in the Clinical and Preclinical Setting. Cancer Discovery, 13(8), 1826-1843. https://doi.org/10.1158/2159-8290.CD-22-0412

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title = "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.",

author = "Chani Stossel and Maria Raitses-Gurevich and Dikla Atias and Tamar Beller and Gorman, {Yulia Glick} and Sharon Halperin and Eyal Peer and Denroche, {Robert E.} and Amy Zhang and Faiyaz Notta and Wilson, {Julie M.} and O{\textquoteright}kane, {Grainne M.} and Talmoud, {Elina Haimov} and Nora Amison and Michael Schvimer and Salpeter, {Seth J.} and Vered Bar and Adi Zundelevich and Itay Tirosh and Rotem Tal and Gal Dinstag and Yaron Kinar and Yonatan Eliezer and Uri Ben-David and Gavert, {Nancy S.} and Ravid Straussman and Gallinger, {Steven J.} and Raanan Berger and Talia Golan",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors; Published by the American Association for Cancer Research.",

year = "2023",

month = aug,

day = "1",

doi = "https://doi.org/10.1158/2159-8290.CD-22-0412",

language = "الإنجليزيّة",

volume = "13",

pages = "1826--1843",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "John Wiley and Sons Inc.",

number = "8",

}

Stossel, C, Raitses-Gurevich, M, Atias, D, Beller, T, Gorman, YG, Halperin, S, Peer, E, Denroche, RE, Zhang, A, Notta, F, Wilson, JM, O’kane, GM, Talmoud, EH, Amison, N, Schvimer, M, Salpeter, SJ, Bar, V, Zundelevich, A, Tirosh, I, Tal, R, Dinstag, G, Kinar, Y, Eliezer, Y, Ben-David, U, Gavert, NS, Straussman, R, Gallinger, SJ, Berger, R & Golan, T 2023, 'Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA–Associated Pancreatic Cancer in the Clinical and Preclinical Setting', Cancer Discovery, vol. 13, no. 8, pp. 1826-1843. https://doi.org/10.1158/2159-8290.CD-22-0412

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

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.

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U2 - https://doi.org/10.1158/2159-8290.CD-22-0412

DO - https://doi.org/10.1158/2159-8290.CD-22-0412

M3 - مقالة

C2 - 37449843

SN - 2159-8274

VL - 13

SP - 1826

EP - 1843

JO - Cancer Discovery

JF - Cancer Discovery

IS - 8

ER -

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

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