TY - JOUR
T1 - BRAF-mutant transcriptional subtypes predict outcome of combined BRAF, MEK, and EGFR blockade with dabrafenib, trametinib, and panitumumab in patients with colorectal cancer
AU - Middleton, Gary
AU - Yang, Yiqun
AU - Campbell, Catarina D
AU - André, Thierry
AU - Atreya, Chloe E
AU - Schellens, Jan H M
AU - Yoshino, Takayuki
AU - Bendell, Johanna C
AU - Hollebecque, Antoine
AU - McRee, Autumn J
AU - Siena, Salvatore
AU - Gordon, Michael S
AU - Tabernero, Josep
AU - Yaeger, Rona
AU - O'Dwyer, Peter J
AU - De Vos, Filip
AU - Van Cutsem, Eric
AU - Millholland, John M
AU - Brase, Jan C
AU - Rangwala, Fatima
AU - Gasal, Eduard
AU - Corcoran, Ryan B
N1 - ©2020 American Association for Cancer Research.
PY - 2020/6
Y1 - 2020/6
N2 - Purpose: The influence of the transcriptional and immunologic context of mutations on therapeutic outcomes with targeted therapy in cancer has not been well defined. BRAF V600E–mutant (BM) colorectal cancer comprises two main transcriptional subtypes, BM1 and BM2. We sought to determine the impact of BM subtype, as well as distinct biological features of those subtypes, on response to BRAF/MEK/EGFR inhibition in patients with colorectal cancer. Patients and Methods: Paired fresh tumor biopsies were acquired at baseline and on day 15 of treatment from all consenting patients with BM colorectal cancer enrolled in a phase II clinical trial of dabrafenib, trametinib, and panitumumab. For each sample, BM subtype, cell cycle, and immune gene signature expression were determined using RNA-sequencing (RNA-seq), and a Cox proportional hazards model was applied to determine association with progression-free survival (PFS). Results: Confirmed response rates, median PFS, and median overall survival (OS) were higher in BM1 subtype patients compared with BM2 subtype patients. Evaluation of immune contexture identified greater immune reactivity in BM1, whereas cell-cycle signatures were more highly expressed in BM2. A multivariate model of PFS incorporating BM subtype plus immune and cell-cycle signatures revealed that BM subtype encompasses the majority of the effect. Conclusions: BM subtype is significantly associated with the outcome of combination dabrafenib, trametinib, and panitumumab therapy and may serve as a standalone predictive biomarker beyond mutational status. Our findings support a more nuanced approach to targeted therapeutic decisions that incorporates assessment of transcriptional context.
AB - Purpose: The influence of the transcriptional and immunologic context of mutations on therapeutic outcomes with targeted therapy in cancer has not been well defined. BRAF V600E–mutant (BM) colorectal cancer comprises two main transcriptional subtypes, BM1 and BM2. We sought to determine the impact of BM subtype, as well as distinct biological features of those subtypes, on response to BRAF/MEK/EGFR inhibition in patients with colorectal cancer. Patients and Methods: Paired fresh tumor biopsies were acquired at baseline and on day 15 of treatment from all consenting patients with BM colorectal cancer enrolled in a phase II clinical trial of dabrafenib, trametinib, and panitumumab. For each sample, BM subtype, cell cycle, and immune gene signature expression were determined using RNA-sequencing (RNA-seq), and a Cox proportional hazards model was applied to determine association with progression-free survival (PFS). Results: Confirmed response rates, median PFS, and median overall survival (OS) were higher in BM1 subtype patients compared with BM2 subtype patients. Evaluation of immune contexture identified greater immune reactivity in BM1, whereas cell-cycle signatures were more highly expressed in BM2. A multivariate model of PFS incorporating BM subtype plus immune and cell-cycle signatures revealed that BM subtype encompasses the majority of the effect. Conclusions: BM subtype is significantly associated with the outcome of combination dabrafenib, trametinib, and panitumumab therapy and may serve as a standalone predictive biomarker beyond mutational status. Our findings support a more nuanced approach to targeted therapeutic decisions that incorporates assessment of transcriptional context.
UR - http://www.scopus.com/inward/record.url?scp=85085904962&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-19-3579
DO - 10.1158/1078-0432.CCR-19-3579
M3 - Article
C2 - 32047001
SN - 1078-0432
VL - 26
SP - 2466
EP - 2476
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 11
ER -