Fc-gamma receptor polymorphisms, cetuximab therapy, and overall survival in the CCTG CO.20 trial of metastatic colorectal cancer

Daniel Shepshelovich, Amanda R. Townsend, Osvaldo Espin-Garcia, Lidija Latifovic, Chris J. O’Callaghan, Derek J. Jonker, Dongsheng Tu, Eric Chen, Eric Morgen, Timothy J. Price, Jeremy Shapiro, Lillian L. Siu, Michiaki Kubo, Alexander Dobrovic, Mark J. Ratain, Wei Xu, Taisei Mushiroda, Geoffrey Liu

Research output: Contribution to journalArticle

Abstract

Background: Two germ line Fc-γ receptor (FCGR) polymorphisms, rs1801274 [FCGR2A; His(H)131Arg(R)] and rs396991 [FCGR3A; Phe(F)158Val(V)], produce altered proteins through amino acid substitutions. We previously reported that the FCGR2A H/H genotype was associated with longer overall survival (OS) in cetuximab-treated chemotherapy-refractory patients with metastatic colorectal cancer. Here, we aimed to replicate and extend this finding in the Canadian Clinical Trials Group CO.20 trial. Methods: After germ line DNA genotyping, polymorphic relationships with survival were assessed using log-rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. The dominant genetic inheritance model was used for the main analysis. Results: Of 592 wild-type KRAS patients treated with cetuximab, those with the FCGR2A H/H genotype (n = 165, 28%) had improved OS (HR: 0.66, P < 0.001; median absolute benefit, 1.3 months) compared to those with R/- genotype (n = 427, 72%). Patients with H/R had intermediate results under a codominant genetic inheritance model (HR: 0.72, P = 0.003). No significant associations were found between FCGR3A genotype and OS. In an exploratory analysis, patients with the combination of FCGR2A H/H + FCGR3A F/F genotype had significantly better OS (HR: 0.33, P = 0.003; median absolute benefit, 12.5 months) than patients with the combination of double-variant R/R + V/V genotype. Progression-free survival results were similar to OS. Toxicity rates were not associated with either polymorphism. Conclusions: The FCGR2A genotype was associated with efficacy but not with toxicity in wild-type KRAS, cetuximab-treated colorectal cancer patients. FCGR3A genotype may modulate the relationship between FCGR2A polymorphism and outcome. FCGR2A is a promising biomarker for clinical management for these patients.

Original languageEnglish
Pages (from-to)5478-5487
Number of pages10
JournalCancer Medicine
Volume7
Issue number11
DOIs
Publication statusPublished - 01-11-2018

Fingerprint

IgG Receptors
Colorectal Neoplasms
Genotype
Survival
Genetic Models
Therapeutics
Germ Cells
Fc Receptors
Cetuximab
Amino Acid Substitution
Proportional Hazards Models
Disease-Free Survival
Biomarkers
Clinical Trials
Drug Therapy
DNA

All Science Journal Classification (ASJC) codes

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Shepshelovich, D., Townsend, A. R., Espin-Garcia, O., Latifovic, L., O’Callaghan, C. J., Jonker, D. J., ... Liu, G. (2018). Fc-gamma receptor polymorphisms, cetuximab therapy, and overall survival in the CCTG CO.20 trial of metastatic colorectal cancer. Cancer Medicine, 7(11), 5478-5487. https://doi.org/10.1002/cam4.1819
Shepshelovich, Daniel ; Townsend, Amanda R. ; Espin-Garcia, Osvaldo ; Latifovic, Lidija ; O’Callaghan, Chris J. ; Jonker, Derek J. ; Tu, Dongsheng ; Chen, Eric ; Morgen, Eric ; Price, Timothy J. ; Shapiro, Jeremy ; Siu, Lillian L. ; Kubo, Michiaki ; Dobrovic, Alexander ; Ratain, Mark J. ; Xu, Wei ; Mushiroda, Taisei ; Liu, Geoffrey. / Fc-gamma receptor polymorphisms, cetuximab therapy, and overall survival in the CCTG CO.20 trial of metastatic colorectal cancer. In: Cancer Medicine. 2018 ; Vol. 7, No. 11. pp. 5478-5487.
@article{33f9c55697e44b6cac2bf9c38c982a6b,
title = "Fc-gamma receptor polymorphisms, cetuximab therapy, and overall survival in the CCTG CO.20 trial of metastatic colorectal cancer",
abstract = "Background: Two germ line Fc-γ receptor (FCGR) polymorphisms, rs1801274 [FCGR2A; His(H)131Arg(R)] and rs396991 [FCGR3A; Phe(F)158Val(V)], produce altered proteins through amino acid substitutions. We previously reported that the FCGR2A H/H genotype was associated with longer overall survival (OS) in cetuximab-treated chemotherapy-refractory patients with metastatic colorectal cancer. Here, we aimed to replicate and extend this finding in the Canadian Clinical Trials Group CO.20 trial. Methods: After germ line DNA genotyping, polymorphic relationships with survival were assessed using log-rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. The dominant genetic inheritance model was used for the main analysis. Results: Of 592 wild-type KRAS patients treated with cetuximab, those with the FCGR2A H/H genotype (n = 165, 28{\%}) had improved OS (HR: 0.66, P < 0.001; median absolute benefit, 1.3 months) compared to those with R/- genotype (n = 427, 72{\%}). Patients with H/R had intermediate results under a codominant genetic inheritance model (HR: 0.72, P = 0.003). No significant associations were found between FCGR3A genotype and OS. In an exploratory analysis, patients with the combination of FCGR2A H/H + FCGR3A F/F genotype had significantly better OS (HR: 0.33, P = 0.003; median absolute benefit, 12.5 months) than patients with the combination of double-variant R/R + V/V genotype. Progression-free survival results were similar to OS. Toxicity rates were not associated with either polymorphism. Conclusions: The FCGR2A genotype was associated with efficacy but not with toxicity in wild-type KRAS, cetuximab-treated colorectal cancer patients. FCGR3A genotype may modulate the relationship between FCGR2A polymorphism and outcome. FCGR2A is a promising biomarker for clinical management for these patients.",
author = "Daniel Shepshelovich and Townsend, {Amanda R.} and Osvaldo Espin-Garcia and Lidija Latifovic and O’Callaghan, {Chris J.} and Jonker, {Derek J.} and Dongsheng Tu and Eric Chen and Eric Morgen and Price, {Timothy J.} and Jeremy Shapiro and Siu, {Lillian L.} and Michiaki Kubo and Alexander Dobrovic and Ratain, {Mark J.} and Wei Xu and Taisei Mushiroda and Geoffrey Liu",
year = "2018",
month = "11",
day = "1",
doi = "10.1002/cam4.1819",
language = "English",
volume = "7",
pages = "5478--5487",
journal = "Cancer Medicine",
issn = "2045-7634",
publisher = "John Wiley and Sons Ltd",
number = "11",

}

Shepshelovich, D, Townsend, AR, Espin-Garcia, O, Latifovic, L, O’Callaghan, CJ, Jonker, DJ, Tu, D, Chen, E, Morgen, E, Price, TJ, Shapiro, J, Siu, LL, Kubo, M, Dobrovic, A, Ratain, MJ, Xu, W, Mushiroda, T & Liu, G 2018, 'Fc-gamma receptor polymorphisms, cetuximab therapy, and overall survival in the CCTG CO.20 trial of metastatic colorectal cancer', Cancer Medicine, vol. 7, no. 11, pp. 5478-5487. https://doi.org/10.1002/cam4.1819

Fc-gamma receptor polymorphisms, cetuximab therapy, and overall survival in the CCTG CO.20 trial of metastatic colorectal cancer. / Shepshelovich, Daniel; Townsend, Amanda R.; Espin-Garcia, Osvaldo; Latifovic, Lidija; O’Callaghan, Chris J.; Jonker, Derek J.; Tu, Dongsheng; Chen, Eric; Morgen, Eric; Price, Timothy J.; Shapiro, Jeremy; Siu, Lillian L.; Kubo, Michiaki; Dobrovic, Alexander; Ratain, Mark J.; Xu, Wei; Mushiroda, Taisei; Liu, Geoffrey.

In: Cancer Medicine, Vol. 7, No. 11, 01.11.2018, p. 5478-5487.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Fc-gamma receptor polymorphisms, cetuximab therapy, and overall survival in the CCTG CO.20 trial of metastatic colorectal cancer

AU - Shepshelovich, Daniel

AU - Townsend, Amanda R.

AU - Espin-Garcia, Osvaldo

AU - Latifovic, Lidija

AU - O’Callaghan, Chris J.

AU - Jonker, Derek J.

AU - Tu, Dongsheng

AU - Chen, Eric

AU - Morgen, Eric

AU - Price, Timothy J.

AU - Shapiro, Jeremy

AU - Siu, Lillian L.

AU - Kubo, Michiaki

AU - Dobrovic, Alexander

AU - Ratain, Mark J.

AU - Xu, Wei

AU - Mushiroda, Taisei

AU - Liu, Geoffrey

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Background: Two germ line Fc-γ receptor (FCGR) polymorphisms, rs1801274 [FCGR2A; His(H)131Arg(R)] and rs396991 [FCGR3A; Phe(F)158Val(V)], produce altered proteins through amino acid substitutions. We previously reported that the FCGR2A H/H genotype was associated with longer overall survival (OS) in cetuximab-treated chemotherapy-refractory patients with metastatic colorectal cancer. Here, we aimed to replicate and extend this finding in the Canadian Clinical Trials Group CO.20 trial. Methods: After germ line DNA genotyping, polymorphic relationships with survival were assessed using log-rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. The dominant genetic inheritance model was used for the main analysis. Results: Of 592 wild-type KRAS patients treated with cetuximab, those with the FCGR2A H/H genotype (n = 165, 28%) had improved OS (HR: 0.66, P < 0.001; median absolute benefit, 1.3 months) compared to those with R/- genotype (n = 427, 72%). Patients with H/R had intermediate results under a codominant genetic inheritance model (HR: 0.72, P = 0.003). No significant associations were found between FCGR3A genotype and OS. In an exploratory analysis, patients with the combination of FCGR2A H/H + FCGR3A F/F genotype had significantly better OS (HR: 0.33, P = 0.003; median absolute benefit, 12.5 months) than patients with the combination of double-variant R/R + V/V genotype. Progression-free survival results were similar to OS. Toxicity rates were not associated with either polymorphism. Conclusions: The FCGR2A genotype was associated with efficacy but not with toxicity in wild-type KRAS, cetuximab-treated colorectal cancer patients. FCGR3A genotype may modulate the relationship between FCGR2A polymorphism and outcome. FCGR2A is a promising biomarker for clinical management for these patients.

AB - Background: Two germ line Fc-γ receptor (FCGR) polymorphisms, rs1801274 [FCGR2A; His(H)131Arg(R)] and rs396991 [FCGR3A; Phe(F)158Val(V)], produce altered proteins through amino acid substitutions. We previously reported that the FCGR2A H/H genotype was associated with longer overall survival (OS) in cetuximab-treated chemotherapy-refractory patients with metastatic colorectal cancer. Here, we aimed to replicate and extend this finding in the Canadian Clinical Trials Group CO.20 trial. Methods: After germ line DNA genotyping, polymorphic relationships with survival were assessed using log-rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. The dominant genetic inheritance model was used for the main analysis. Results: Of 592 wild-type KRAS patients treated with cetuximab, those with the FCGR2A H/H genotype (n = 165, 28%) had improved OS (HR: 0.66, P < 0.001; median absolute benefit, 1.3 months) compared to those with R/- genotype (n = 427, 72%). Patients with H/R had intermediate results under a codominant genetic inheritance model (HR: 0.72, P = 0.003). No significant associations were found between FCGR3A genotype and OS. In an exploratory analysis, patients with the combination of FCGR2A H/H + FCGR3A F/F genotype had significantly better OS (HR: 0.33, P = 0.003; median absolute benefit, 12.5 months) than patients with the combination of double-variant R/R + V/V genotype. Progression-free survival results were similar to OS. Toxicity rates were not associated with either polymorphism. Conclusions: The FCGR2A genotype was associated with efficacy but not with toxicity in wild-type KRAS, cetuximab-treated colorectal cancer patients. FCGR3A genotype may modulate the relationship between FCGR2A polymorphism and outcome. FCGR2A is a promising biomarker for clinical management for these patients.

UR - http://www.scopus.com/inward/record.url?scp=85054904820&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054904820&partnerID=8YFLogxK

U2 - 10.1002/cam4.1819

DO - 10.1002/cam4.1819

M3 - Article

VL - 7

SP - 5478

EP - 5487

JO - Cancer Medicine

JF - Cancer Medicine

SN - 2045-7634

IS - 11

ER -

Shepshelovich D, Townsend AR, Espin-Garcia O, Latifovic L, O’Callaghan CJ, Jonker DJ et al. Fc-gamma receptor polymorphisms, cetuximab therapy, and overall survival in the CCTG CO.20 trial of metastatic colorectal cancer. Cancer Medicine. 2018 Nov 1;7(11):5478-5487. https://doi.org/10.1002/cam4.1819