Clinical cancer research : an official journal of the American Association for Cancer Research · 2020
GATA6 Expression Distinguishes Classical and Basal-like Subtypes in Advanced Pancreatic Cancer.
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O'Kane Grainne M, Grünwald Barbara T, Jang Gun-Ho, Masoomian Mehdi, Picardo Sarah, Grant Robert C, Denroche Robert E, Zhang Amy, Wang Yifan, Lam Bernard, Krzyzanowski Paul M, Lungu Illinca M, Bartlett John M S, Peralta Melanie, Vyas Foram, Khokha Rama, Biagi James, Chadwick Dianne, Ramotar Stephanie, Hutchinson Shawn, Dodd Anna, Wilson Julie M, Notta Faiyaz, Zogopoulos George, Gallinger Steven, Knox Jennifer J, Fischer Sandra E
Аннотация
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.
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.
Предметные рубрики MeSH
AdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsCarcinoma, Pancreatic DuctalDrug Resistance, NeoplasmFemaleFluorouracilGATA6 Transcription FactorGene Expression Regulation, NeoplasticHumansIrinotecanLeucovorinMaleMiddle AgedMulticenter Studies as TopicOxaliplatinPancreatic NeoplasmsPrognosisProspective StudiesRNA-SeqResponse Evaluation Criteria in Solid Tumors