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GATA6 Expression Distinguishes Classical and Basal-like Subtypes in Advanced Pancreatic Cancer
Open accessPublished version of a preprint
Abstract
Purpose: To determine the impact of basal-like and classical subtypes in advanced pancreatic ductal adenocarcinoma (PDAC) and to explore GATA6 expression as a surrogate biomarker. Experimental Design: Within the COMPASS trial, patients proceeding to chemotherapy for advanced PDAC undergo tumor biopsy for RNA-sequencing (RNA-seq). Overall response rate (ORR) and overall survival (OS) were stratified by subtypes and according to chemotherapy received. Correlation of GATA6 with the subtypes using gene expression profiling, in situ hybridization (ISH) was explored. Results: Between December 2015 and May 2019, 195 patients (95%) had enough tissue for RNA-seq; 39 (20%) were classified as basal-like and 156 (80%) as classical. RECIST response data were available for 157 patients; 29 basal-like and 128 classical where the ORR was 10% versus 33%, respectively (P = 0.02). In patients with basal-like tumors treated with modified FOLFIRINOX (n = 22), the progression rate was 60% compared with 15% in classical PDAC (P = 0.0002). Median OS in the intention-to-treat population (n = 195) was 9.3 months for classical versus 5.9 months for basal-like PDAC (HR, 0.47; 95% confidence interval, 0.32–0.69; P = 0.0001). GATA6 expression by RNA-seq highly correlated with the classifier (P < 0.001) and ISH predicted the subtypes with sensitivity of 89% and specificity of 83%. In a multivariate analysis, GATA6 expression was prognostic (P = 0.02). In exploratory analyses, basal-like tumors, could be identified by keratin 5, were more hypoxic and enriched for a T-cell–inflamed gene expression signature. Conclusions: The basal-like subtype is chemoresistant and can be distinguished from classical PDAC by GATA6 expression. See related commentary by Collisson, p. 4715
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“Patient data suggest that the classical subtype of PDAC responds better to chemotherapy than the poorly prognostic basal-like PDAC subtype (44, 58, 59).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [59]
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Metadata
- Authors
- O’Kane, G. M., Grünwald, B. T., Jang, G.-H., Masoomian, M., Picardo, S., Grant, R. C., Denroche, R. E., Zhang, A., Wang, Y., Miller, J. K., Lam, B., Krzyzanowski, P. M., Lungu, I. M., Bartlett, J. M. S., Peralta, M., Vyas, F., Khokha, R., Biagi, J., Chadwick, D., Ramotar, S., Hutchinson, S., Dodd, A., Wilson, J. M., Notta, F., Zogopoulos, G., Gallinger, S., Knox, J. J., & Fischer, S. E.
- Affiliations
- 1Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
- Ontario Institute for Cancer Research (CA)
- University Health Network (CA)
- Research Institute of the McGill University Health Centre (CA)
- Kingston General Hospital (CA)
- ORCID
- Grünwald, Barbara T.
- Jang, Gun-Ho
- Grant, Robert C.
- Denroche, Robert E.
- Zhang, Amy
- Wang, Yifan
- Miller, Jessica K.
- Lam, Bernard
- Krzyzanowski, Paul M.
- Lungu, Ilinca M.
- Bartlett, John M.S.
- Peralta, Melanie
- Vyas, Foram
- Khokha, Rama
- Biagi, James
- Ramotar, Stephanie
- Hutchinson, Shawn
- Dodd, Anna
- Wilson, Julie M.
- Notta, Faiyaz
- Zogopoulos, George
- Knox, Jennifer J.
- Fischer, Sandra E.
- Venue
- Clinical Cancer Research
- Published
- 2020-03-10
- Volume
- 26
- Issue
- 18
- Pages
- 4901-4910
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W3011562658
- Semantic Scholar
- d72ef3593540c2afcd56ffaaa1ecbdf174cca98b
- Cited by
- 352
- References
- 39
- Citations by year
- 2026: 54 · 2025: 58 · 2024: 58 · 2023: 60 · 2022: 48 · 2021: 56 · 2020: 16
- FWCI
- 16.25
- Type
- journal article
- Language
- en
- Update notices
- correction (2022-06-13)
- Open access
- Licence
- other-oa
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Princess Margaret Cancer Foundation (ALTF 116-2018, DEU 1199182 FLF-P)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Keywords
- GATA6, pancreatic ductal adenocarcinoma, basal-like subtype, classical subtype, cancer subtyping, chemoresistance, modified FOLFIRINOX, overall survival, prognostic factors, keratin 5, tumor hypoxia, COMPASS trial
- MeSH terms
- Irinotecan, Oxaliplatin, RNA-Seq, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Leucovorin, Female, Fluorouracil, Humans, Male, Middle Aged, Pancreatic Neoplasms, Prognosis, Prospective Studies, Multicenter Studies as Topic, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Carcinoma, Pancreatic Ductal, GATA6 Transcription Factor, Response Evaluation Criteria in Solid Tumors
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