journal contribution
posted on 2023-03-31, 22:02 authored by Yifan Wang, Jin Yong Patrick Park, Alain Pacis, Robert E. Denroche, Gun Ho Jang, Amy Zhang, Adeline Cuggia, Celine Domecq, Jean Monlong, Maria Raitses-Gurevich, Robert C. Grant, Ayelet Borgida, Spring Holter, Chani Stossel, Simeng Bu, Mehdi Masoomian, Ilinca M. Lungu, John M.S. Bartlett, Julie M. Wilson, Zu-Hua Gao, Yasser Riazalhosseini, Jamil Asselah, Nathaniel Bouganim, Tatiana Cabrera, Louis-Martin Boucher, David Valenti, James Biagi, Celia M.T. Greenwood, Paz Polak, William D. Foulkes, Talia Golan, Grainne M. O'Kane, Sandra E. Fischer, Jennifer J. Knox, Steven Gallinger, George Zogopoulos Supplementary Figure 9 shows the Cox proportional hazards model, integrating Moffitt transcriptomic subtype, tumour ploidy, stage and age
Funding
Cancer Research Society
Ganotec-Marc-André Pigeon Memorial Fund
Terry Fox Research Institute
Princess Margaret Cancer Foundation
Canadian Cancer Society Research Institute
Ontario Institute for Cancer Research
McGill University Health Centre
History
ARTICLE ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) arising in patients with a germline BRCA1 or BRCA2 (gBRCA) mutation may be sensitive to platinum and PARP inhibitors (PARPi). However, treatment stratification based on gBRCA mutational status alone is associated with heterogeneous responses.
We performed a seven-arm preclinical trial consisting of 471 mice, representing 12 unique PDAC patient-derived xenografts, of which nine were gBRCA mutated. From 179 patients whose PDAC was whole-genome and transcriptome sequenced, we identified 21 cases with homologous recombination deficiency (HRD), and investigated prognostic biomarkers.
We found that biallelic inactivation of BRCA1/BRCA2 is associated with genomic hallmarks of HRD and required for cisplatin and talazoparib (PARPi) sensitivity. However, HRD genomic hallmarks persisted in xenografts despite the emergence of therapy resistance, indicating the presence of a genomic scar. We identified tumor polyploidy and a low Ki67 index as predictors of poor cisplatin and talazoparib response. In patients with HRD PDAC, tumor polyploidy and a basal-like transcriptomic subtype were independent predictors of shorter survival. To facilitate clinical assignment of transcriptomic subtype, we developed a novel pragmatic two-marker assay (GATA6:KRT17).
In summary, we propose a predictive and prognostic model of gBRCA-mutated PDAC on the basis of HRD genomic hallmarks, Ki67 index, tumor ploidy, and transcriptomic subtype.
