title: Cetuximab treatment for metastatic colorectal cancer with KRAS p.G13D mutations improves progression-free survival.
abstract: A number of previous studies have reported that 30-50% of patients with colorectal cancer (CRC) harbor Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, which is a major predictive biomarker of resistance to epidermal growth factor (EGFR)-targeted therapy. Treatment with an anti-EGFR inhibitor is recommended for patients with KRAS wild-type metastatic colorectal cancer (mCRC). A recent retrospective study of cetuximab reported that patients with KRAS p.G13D mutations had better outcomes compared with those with other mutations. The aim of this retrospective study was to assess the prevalence of KRAS p.G13D mutations and evaluate the effectiveness of cetuximab in mCRC patients with KRAS p.G13D or other KRAS mutations. We reviewed the clinical records of 98 mCRC patients with KRAS mutations who were treated between August, 2004 and January, 2011 in four hospitals located in Tokyo and Kyushu Island. We also investigated KRAS mutation subtypes and patient characteristics. In the patients who received cetuximab, univariate and multivariate analyses were performed to assess the effect of KRAS p.G13D mutations on progression-free survival (PFS) and overall survival (OS). Of the 98 patients, 23 (23.5%) had KRAS p.G13D-mutated tumors, whereas 75 (76.5%) had tumors harboring other mutations. Of the 31 patients who received cetuximab, 9 (29.0%) had KRAS p.G13D mutations and 22 (71.0%) had other mutations. There were no significant differences in age, gender, primary site, pathological type, history of chemotherapy, or the combined use of irinotecan between either of the patient subgroups. The univariate analysis revealed no significant difference in PFS or OS between the patients with KRAS p.G13D mutations and those with other mutations (median PFS, 4.5 vs. 2.8 months, respectively; P=0.65; and median OS, 15.3 vs. 8.9 months, respectively; P=0.51). However, the multivariate analysis revealed a trend toward better PFS among patients harboring p.G13D mutations (PFS: HR=0.29; 95% CI: 0.08-1.10; P=0.07; OS: HR=0.23; 95% CI: 0.04-1.54; P=0.13). In conclusion, treatment with cetuximab may be more clinically beneficial in mCRC patients with a KRAS p.G13D mutation, compared with those harboring other mutations. However, further investigation is required to clearly determine the benefits of cetuximab treatment in patients with KRAS p.G13D mutation-positive mCRC.
authors.affiliation: Department of Gastroenterology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Osumi
authors.affiliation: Department of Gastroenterology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Shinozaki
authors.affiliation: Department of Surgery, Kagoshima Medical Association Hospital, Kagoshima, Kagoshima, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Osako
authors.affiliation: Department of Medical Informatics and Economics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Kawazoe
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Oba
authors.affiliation: Department of Gastroenterology, Kirishima Medical Center, Kirishima, Kagoshima, Japan.
authors.forename: Takaharu
authors.initials: T
authors.lastname: Misaka
authors.affiliation: Department of Surgery, Koga General Hospital, Miyazaki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Goto
authors.affiliation: Department of Surgery, Koga General Hospital, Miyazaki, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Kamo
authors.affiliation: Department of Gastroenterology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Mitsukuni
authors.initials: M
authors.lastname: Suenaga
authors.affiliation: Department of Gastroenterology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kumekawa
authors.affiliation: Department of Gastroenterology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Ogura
authors.affiliation: Department of Gastroenterology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Ozaka
authors.affiliation: Department of Gastroenterology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsusaka
authors.affiliation: Department of Gastroenterology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Keisho
authors.initials: K
authors.lastname: Chin
authors.affiliation: Department of Medical Oncology and Hematology, New Drug Development Center, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Hatake
authors.affiliation: Department of Gastroenterology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Mizunuma
keywords: Kirsten rat sarcoma viral oncogene homolog p.G13D; cetuximab; vertical blockade of Ras pathway