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HER2-HER3 heterodimer quantification by FRET-FILM and patient subclass analysis of the COIN colorectal trial

Barber, Paul R., Weitsman, Gregory, Lawler, Katherine, Barrett, James E., Rowley, Mark, Rodriguez-Justo, Manuel, Fisher, David, Gao, Fangfei, Tullis, Iain D.C., Deng, Jinhai, Brown, Louise, Kaplan, Richard, Hochhauser, Daniel, Adams, Richard, Maughan, Timothy S., Vojnovic, Borivoj, Coolen, Anthony C.C. and Ng, Tony 2019. HER2-HER3 heterodimer quantification by FRET-FILM and patient subclass analysis of the COIN colorectal trial. JNCI: Journal of the National Cancer Institute 10.1093/jnci/djz231

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Abstract

BACKGROUND: The phase 3 MRC COIN trial showed no statistically significant benefit from adding the EGFR-target cetuximab to oxaliplatin-based chemotherapy in first-line treatment of advanced colorectal cancer. This study exploits additional information on HER2-HER3 dimerization to achieve patient stratification and reveal previously hidden subgroups of patients who had differing disease progression and treatment response. METHODS: HER2-HER3 dimerization was quantified by 'FLIM Histology' in primary tumor samples from 550 COIN trial patients receiving oxaliplatin and fluoropyrimidine chemotherapy +/-cetuximab. Bayesian latent class analysis (LCA) and covariate reduction was performed to analyze the effects of HER2-HER3 dimer, RAS mutation and cetuximab on progression-free survival (PFS) and overall survival (OS). All statistical tests were two-sided. RESULTS: LCA on a cohort of 398 patients revealed two patient subclasses with differing prognoses (median OS: 1624 days [95%CI=1466-1816] vs 461 [95%CI=431-504]): Class 1 (15.6%) showed a benefit from cetuximab in OS (HR = 0.43 [95%CI=0.25-0.76]; p = 0.004). Class 2 showed an association of increased HER2-HER3 with better OS (HR = 0.64 [95%CI=0.44-0.94]; p = 0.02). A class prediction signature was formed and tested on an independent validation cohort (N = 152) validating the prognostic utility of the dimer assay. Similar subclasses were also discovered in full trial dataset (N = 1,630) based on 10 baseline clinicopathological and genetic covariates. CONCLUSIONS: Our work suggests that the combined use of HER dimer imaging and conventional mutation analyses will be able to identify a small subclass of patients (>10%) who will have better prognosis following chemotherapy. A larger prospective cohort will be required to confirm its utility in predicting the outcome of anti-EGFR treatment.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Medicine
Centre for Trials Research (CNTRR)
Publisher: Oxford University Press
ISSN: 0027-8874
Date of First Compliant Deposit: 13 December 2019
Date of Acceptance: 5 December 2019
Last Modified: 12 May 2020 14:29
URI: http://orca.cf.ac.uk/id/eprint/127500

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