HER2-HER3 Heterodimer Quantification by FRET-FLIM and Patient Subclass Analysis of the COIN Colorectal Trial

Abstract Background The phase III 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...

Celý popis

Uložené v:
Podrobná bibliografia
Vydané v:JNCI : Journal of the National Cancer Institute Ročník 112; číslo 9; s. 944 - 954
Hlavní autori: 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, Ng, Tony
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Oxford University Press 01.09.2020
Predmet:
Adenocarcinoma - diagnosis
Adenocarcinoma - metabolism
Adenocarcinoma - mortality
Adenocarcinoma - therapy
Aged
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Bayes Theorem
Capecitabine - therapeutic use
Cohort Studies
Colorectal Neoplasms - diagnosis
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - mortality
Colorectal Neoplasms - therapy
Female
Fluorescence Resonance Energy Transfer
Humans
Latent Class Analysis
Male
Microscopy - methods
Middle Aged
Oxaloacetates - therapeutic use
Prognosis
Protein Multimerization
Randomized Controlled Trials as Topic - statistics & numerical data
Receptor, ErbB-2 - analysis
Receptor, ErbB-2 - metabolism
Receptor, ErbB-3 - analysis
Receptor, ErbB-3 - metabolism
Tissue Array Analysis
Treatment Outcome
ISSN:0027-8874, 1460-2105, 1460-2105
On-line prístup:Získať plný text
Tagy: Pridať tag
Žiadne tagy, Buďte prvý, kto otaguje tento záznam!
Popis
Shrnutí:Abstract Background The phase III 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 fluorescence lifetime imaging microscopy in primary tumor samples from 550 COIN trial patients receiving oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab. Bayesian latent class analysis and covariate reduction was performed to analyze the effects of HER2-HER3 dimer, RAS mutation, and cetuximab on progression-free survival and overall survival (OS). All statistical tests were two-sided. Results Latent class analysis on a cohort of 398 patients revealed two patient subclasses with differing prognoses (median OS = 1624 days [95% confidence interval [CI] = 1466 to 1816 days] vs 461 days [95% CI = 431 to 504 days]): Class 1 (15.6%) showed a benefit from cetuximab in OS (hazard ratio = 0.43, 95% CI = 0.25 to 0.76, P = .004). Class 2 showed an association of increased HER2-HER3 with better OS (hazard ratio = 0.64, 95% CI = 0.44 to 0.94, P = .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 = 1630) 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.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ObjectType-Undefined-3
ISSN:0027-8874
1460-2105
1460-2105
DOI:10.1093/jnci/djz231