FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study

Ravit Geva; Loredana Vecchione; Konstantinos T Kalogeras; Benny Vittrup Jensen; Heinz-Josef Lenz; Takayuki Yoshino; David Paez; Clara Montagut; John Souglakos; Federico Cappuzzo; Andrés Cervantes; Milo Frattini; George Fountzilas; Julia S Johansen; Estrid Vilma Høgdall; Wu Zhang; Dongyun Yang; Kentaro Yamazaki; Tomohiro Nishina; Demetris Papamichael; Bruno Vincenzi; Teresa Macarulla; Fotios Loupakis; Jef De Schutter; Karen Lise Garm Spindler; Per Pfeiffer; Fortunato Ciardiello; Hubert Piessevaux; Sabine Tejpar

doi:10.1136/gutjnl-2014-307234

FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study

Ravit Geva, Loredana Vecchione, Konstantinos T Kalogeras, Benny Vittrup Jensen, Heinz-Josef Lenz, Takayuki Yoshino, David Paez, Clara Montagut, John Souglakos, Federico Cappuzzo, Andrés Cervantes, Milo Frattini, George Fountzilas, Julia S Johansen, Estrid Vilma Høgdall, Wu Zhang, Dongyun Yang, Kentaro Yamazaki, Tomohiro Nishina, Demetris PapamichaelBruno Vincenzi, Teresa Macarulla, Fotios Loupakis, Jef De Schutter, Karen Lise Garm Spindler, Per Pfeiffer, Fortunato Ciardiello, Hubert Piessevaux, Sabine Tejpar

Department of Clinical Medicine

14 Citations (Scopus)

Abstract

OBJECTIVE: We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled.

DESIGN: To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included.

RESULTS: Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95% CI18.8 to 25.2) versus non-HH (22.0 weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95% CI 13.0 to 19.8) versus non-VV (23 weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV.

CONCLUSIONS: No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab.

Original language	English
Journal	Gut
Volume	64
Issue number	6
Pages (from-to)	921-8
Number of pages	8
ISSN	0017-5749
DOIs	https://doi.org/10.1136/gutjnl-2014-307234
Publication status	Published - 1 Jun 2015

Keywords

Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized
Antineoplastic Agents
Cetuximab
Colorectal Neoplasms
Disease-Free Survival
Female
Genotyping Techniques
Germ-Line Mutation
Humans
Male
Middle Aged
Neoplasm Metastasis
Polymorphism, Genetic
Receptor, Epidermal Growth Factor
Receptors, IgG
Survival Rate
Young Adult

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/gutjnl-2014-307234

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Geva, R., Vecchione, L., Kalogeras, K. T., Jensen, B. V., Lenz, H-J., Yoshino, T., Paez, D., Montagut, C., Souglakos, J., Cappuzzo, F., Cervantes, A., Frattini, M., Fountzilas, G., Johansen, J. S., Høgdall, E. V., Zhang, W., Yang, D., Yamazaki, K., Nishina, T., ... Tejpar, S. (2015). FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study. Gut, 64(6), 921-8. https://doi.org/10.1136/gutjnl-2014-307234

Geva, R, Vecchione, L, Kalogeras, KT, Jensen, BV, Lenz, H-J, Yoshino, T, Paez, D, Montagut, C, Souglakos, J, Cappuzzo, F, Cervantes, A, Frattini, M, Fountzilas, G, Johansen, JS , Høgdall, EV, Zhang, W, Yang, D, Yamazaki, K, Nishina, T, Papamichael, D, Vincenzi, B, Macarulla, T, Loupakis, F, De Schutter, J, Spindler, KLG, Pfeiffer, P, Ciardiello, F, Piessevaux, H & Tejpar, S 2015, 'FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study', Gut, vol. 64, no. 6, pp. 921-8. https://doi.org/10.1136/gutjnl-2014-307234

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title = "FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study",

abstract = "OBJECTIVE: We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled.DESIGN: To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included.RESULTS: Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95% CI18.8 to 25.2) versus non-HH (22.0 weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95% CI 13.0 to 19.8) versus non-VV (23 weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV.CONCLUSIONS: No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab.",

keywords = "Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Cetuximab, Colorectal Neoplasms, Disease-Free Survival, Female, Genotyping Techniques, Germ-Line Mutation, Humans, Male, Middle Aged, Neoplasm Metastasis, Polymorphism, Genetic, Receptor, Epidermal Growth Factor, Receptors, IgG, Survival Rate, Young Adult",

author = "Ravit Geva and Loredana Vecchione and Kalogeras, {Konstantinos T} and Jensen, {Benny Vittrup} and Heinz-Josef Lenz and Takayuki Yoshino and David Paez and Clara Montagut and John Souglakos and Federico Cappuzzo and Andr{\'e}s Cervantes and Milo Frattini and George Fountzilas and Johansen, {Julia S} and H{\o}gdall, {Estrid Vilma} and Wu Zhang and Dongyun Yang and Kentaro Yamazaki and Tomohiro Nishina and Demetris Papamichael and Bruno Vincenzi and Teresa Macarulla and Fotios Loupakis and {De Schutter}, Jef and Spindler, {Karen Lise Garm} and Per Pfeiffer and Fortunato Ciardiello and Hubert Piessevaux and Sabine Tejpar",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.",

year = "2015",

month = jun,

day = "1",

doi = "10.1136/gutjnl-2014-307234",

language = "English",

volume = "64",

pages = "921--8",

journal = "Gut",

issn = "0017-5749",

publisher = "B M J Group",

number = "6",

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TY - JOUR

T1 - FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer

T2 - an international consortium study

AU - Geva, Ravit

AU - Vecchione, Loredana

AU - Kalogeras, Konstantinos T

AU - Jensen, Benny Vittrup

AU - Lenz, Heinz-Josef

AU - Yoshino, Takayuki

AU - Paez, David

AU - Montagut, Clara

AU - Souglakos, John

AU - Cappuzzo, Federico

AU - Cervantes, Andrés

AU - Frattini, Milo

AU - Fountzilas, George

AU - Johansen, Julia S

AU - Høgdall, Estrid Vilma

AU - Zhang, Wu

AU - Yang, Dongyun

AU - Yamazaki, Kentaro

AU - Nishina, Tomohiro

AU - Papamichael, Demetris

AU - Vincenzi, Bruno

AU - Macarulla, Teresa

AU - Loupakis, Fotios

AU - De Schutter, Jef

AU - Spindler, Karen Lise Garm

AU - Pfeiffer, Per

AU - Ciardiello, Fortunato

AU - Piessevaux, Hubert

AU - Tejpar, Sabine

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - OBJECTIVE: We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled.DESIGN: To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included.RESULTS: Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95% CI18.8 to 25.2) versus non-HH (22.0 weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95% CI 13.0 to 19.8) versus non-VV (23 weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV.CONCLUSIONS: No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab.

AB - OBJECTIVE: We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled.DESIGN: To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included.RESULTS: Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95% CI18.8 to 25.2) versus non-HH (22.0 weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95% CI 13.0 to 19.8) versus non-VV (23 weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV.CONCLUSIONS: No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antibodies, Monoclonal, Humanized

KW - Antineoplastic Agents

KW - Cetuximab

KW - Colorectal Neoplasms

KW - Disease-Free Survival

KW - Female

KW - Genotyping Techniques

KW - Germ-Line Mutation

KW - Humans

KW - Male

KW - Middle Aged

KW - Neoplasm Metastasis

KW - Polymorphism, Genetic

KW - Receptor, Epidermal Growth Factor

KW - Receptors, IgG

KW - Survival Rate

KW - Young Adult

U2 - 10.1136/gutjnl-2014-307234

DO - 10.1136/gutjnl-2014-307234

M3 - Journal article

C2 - 25011934

SN - 0017-5749

VL - 64

SP - 921

EP - 928

JO - Gut

JF - Gut

IS - 6

ER -

FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study

Abstract

Keywords

UN SDGs

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