Skip to main content
Top
Published in: Surgery Today 8/2014

01-08-2014 | Original Article

Impact of second-line and later cetuximab-containing therapy and KRAS genotypes in patients with metastatic colorectal cancer: a multicenter study in Japan

Authors: Hiroshi Saeki, Yasunori Emi, Ryuichi Kumashiro, Hajime Otsu, Hiroyuki Kawano, Koji Ando, Satoshi Ida, Yasue Kimura, Eriko Tokunaga, Eiji Oki, Masaru Morita, Mototsugu Shimokawa, Yoshihiko Maehara

Published in: Surgery Today | Issue 8/2014

Login to get access

Abstract

Purposes

This retrospective study evaluated the treatment outcomes and clinical relevance of the KRAS mutation status in Japanese metastatic colorectal cancer patients treated with second-line and later cetuximab-containing therapy.

Methods

The subjects comprised 65 patients with metastatic colorectal cancer who received cetuximab-containing therapy. At the start of cetuximab-containing therapy, the KRAS mutation status had been proven to be wild type in 12 patients. Tumors were retrospectively screened for KRAS mutations using direct sequencing.

Results

A detailed analysis revealed the presence of 24 wild-type (57.1 %) and 18 mutant tumors (42.9 %). Grade 3–4 neutropenia and anemia were observed in 21 (32.3 %) and nine (13.8 %) patients, respectively. An acne-like rash was observed in 50 patients (76.9 %), and among them three patients (4.6 %) experienced a Grade 3 rash. A KRAS mutation was associated with resistance to cetuximab-containing treatment (11.1 vs. 41.7 % responders among 18 mutant and 36 wild-type patients, respectively; P = 0.03). A KRAS mutation was also associated with poorer survival (MST: 6.9 vs. 14.1 months in 18 mutant and 36 wild-type patients, respectively; P = 0.018).

Conclusions

The present results indicated the clinical relevance of KRAS mutations in predicting the efficacy of cetuximab-containing therapy for metastatic colorectal patients in the Japanese population.
Literature
1.
go back to reference Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–45.PubMedCrossRef Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–45.PubMedCrossRef
2.
go back to reference Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040–8.PubMedCrossRef Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040–8.PubMedCrossRef
3.
go back to reference Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66:3992–5.PubMedCrossRef Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66:3992–5.PubMedCrossRef
4.
go back to reference Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007;67:2643–8.PubMedCrossRef Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007;67:2643–8.PubMedCrossRef
5.
go back to reference Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–34.PubMedCrossRef Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–34.PubMedCrossRef
6.
go back to reference Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–71.PubMedCrossRef Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–71.PubMedCrossRef
7.
go back to reference Calistri D, Rengucci C, Seymour I, Leonardi E, Truini M, Malacarne D, et al. KRAS, p53 and BRAF gene mutations and aneuploidy in sporadic colorectal cancer progression. Cell Oncol. 2006;28:161–6.PubMed Calistri D, Rengucci C, Seymour I, Leonardi E, Truini M, Malacarne D, et al. KRAS, p53 and BRAF gene mutations and aneuploidy in sporadic colorectal cancer progression. Cell Oncol. 2006;28:161–6.PubMed
8.
go back to reference De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008;19:508–15.PubMedCrossRef De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008;19:508–15.PubMedCrossRef
9.
go back to reference Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer. 2007;96:1166–9.PubMedCentralPubMedCrossRef Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer. 2007;96:1166–9.PubMedCentralPubMedCrossRef
10.
go back to reference Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26:5705–12.PubMedCrossRef Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26:5705–12.PubMedCrossRef
11.
go back to reference Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–65.PubMedCrossRef Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–65.PubMedCrossRef
12.
go back to reference Lee S, Cho NY, Choi M, Yoo EJ, Kim JH, Kang GH. Clinicopathological features of CpG island methylator phenotype-positive colorectal cancer and its adverse prognosis in relation to KRAS/BRAF mutation. Pathol Int. 2008;58:104–13.PubMedCrossRef Lee S, Cho NY, Choi M, Yoo EJ, Kim JH, Kang GH. Clinicopathological features of CpG island methylator phenotype-positive colorectal cancer and its adverse prognosis in relation to KRAS/BRAF mutation. Pathol Int. 2008;58:104–13.PubMedCrossRef
13.
go back to reference Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374–9.PubMedCrossRef Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374–9.PubMedCrossRef
14.
go back to reference Tahara M, Shirao K, Boku N, Yamaguchi K, Komatsu Y, Inaba Y, et al. Multicenter phase II study of cetuximab plus irinotecan in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin and fluoropyrimidines. Jpn J Clin Oncol. 2008;38:762–9.PubMedCrossRef Tahara M, Shirao K, Boku N, Yamaguchi K, Komatsu Y, Inaba Y, et al. Multicenter phase II study of cetuximab plus irinotecan in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin and fluoropyrimidines. Jpn J Clin Oncol. 2008;38:762–9.PubMedCrossRef
15.
go back to reference Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.PubMedCrossRef Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.PubMedCrossRef
16.
go back to reference van Krieken JH, Jung A, Kirchner T, Carneiro F, Seruca R, Bosman FT, et al. KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program. Virchows Arch. 2008;453:417–31.PubMedCrossRef van Krieken JH, Jung A, Kirchner T, Carneiro F, Seruca R, Bosman FT, et al. KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program. Virchows Arch. 2008;453:417–31.PubMedCrossRef
17.
go back to reference Saigusa S, Toiyama Y, Tanaka K, Okugawa Y, Fujikawa H, Matsushita K, et al. Prognostic significance of glucose transporter-1 (GLUT1) gene expression in rectal cancer after preoperative chemoradiotherapy. Surg Today. 2012;42:460–9.PubMedCrossRef Saigusa S, Toiyama Y, Tanaka K, Okugawa Y, Fujikawa H, Matsushita K, et al. Prognostic significance of glucose transporter-1 (GLUT1) gene expression in rectal cancer after preoperative chemoradiotherapy. Surg Today. 2012;42:460–9.PubMedCrossRef
18.
go back to reference Akiyoshi T, Kobunai T, Watanabe T. Predicting the response to preoperative radiation or chemoradiation by a microarray analysis of the gene expression profiles in rectal cancer. Surg Today. 2012;42:713–9.PubMedCrossRef Akiyoshi T, Kobunai T, Watanabe T. Predicting the response to preoperative radiation or chemoradiation by a microarray analysis of the gene expression profiles in rectal cancer. Surg Today. 2012;42:713–9.PubMedCrossRef
19.
go back to reference Ishiguro M, Watanabe T, Yamaguchi K, Satoh T, Ito H, Seriu T, et al. A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. Jpn J Clin Oncol. 2012;42:287–94.PubMedCentralPubMedCrossRef Ishiguro M, Watanabe T, Yamaguchi K, Satoh T, Ito H, Seriu T, et al. A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. Jpn J Clin Oncol. 2012;42:287–94.PubMedCentralPubMedCrossRef
20.
go back to reference De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA. 2010;304:1812–20.PubMedCrossRef De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA. 2010;304:1812–20.PubMedCrossRef
21.
go back to reference Guerrero S, Casanova I, Farré L, Mazo A, Capellà G, Mangues R. K-ras codon 12 mutation induces higher level of resistance to apoptosis and predisposition to anchorage-independent growth than codon 13 mutation or proto-oncogene overexpression. Cancer Res. 2000;1:6750–6. Guerrero S, Casanova I, Farré L, Mazo A, Capellà G, Mangues R. K-ras codon 12 mutation induces higher level of resistance to apoptosis and predisposition to anchorage-independent growth than codon 13 mutation or proto-oncogene overexpression. Cancer Res. 2000;1:6750–6.
Metadata
Title
Impact of second-line and later cetuximab-containing therapy and KRAS genotypes in patients with metastatic colorectal cancer: a multicenter study in Japan
Authors
Hiroshi Saeki
Yasunori Emi
Ryuichi Kumashiro
Hajime Otsu
Hiroyuki Kawano
Koji Ando
Satoshi Ida
Yasue Kimura
Eriko Tokunaga
Eiji Oki
Masaru Morita
Mototsugu Shimokawa
Yoshihiko Maehara
Publication date
01-08-2014
Publisher
Springer Japan
Published in
Surgery Today / Issue 8/2014
Print ISSN: 0941-1291
Electronic ISSN: 1436-2813
DOI
https://doi.org/10.1007/s00595-013-0716-0

Other articles of this Issue 8/2014

Surgery Today 8/2014 Go to the issue