Detection of KRAS Oncogene in Peripheral Blood as a Predictor of
the Response to Cetuximab Plus Chemotherapy in Patients with
Metastatic Colorectal Cancer
Chien-Yu Lu,3,7Yu-Tang Chang,5Koung-Shing Chu,3,8Shiu-Ru Lin,9,11andJaw-YuanWang1,3,4,5
Purpose: Previously we developed membrane-arrays as a promising tool to detect circulating
tumorcells(CTC)withKRAS oncogeneinpatientswithmalignancies.This study wasconducted
to determinate the predictive values of CTCs with KARS mutationby membrane-arrays formeta-
static colorectal cancer patients treated with cetuximab plus chemotherapy.
Experimental Design: Seventy-six metastatic colorectal cancer patients receiving cetuximab
plus FOLFIRI or FOLFOX-4 chemotherapy were enrolled. KRAS mutation status in the peripheral
blood of these patients was analyzed using membrane-arrays, and KRAS mutation status in
tumors was analyzedby DNA sequencing.
Results: Among 76 metastatic colorectal cancer patients, KRAS mutations in tumors andinpe-
ripheralbloodwereidentifiedin 33(43.4%)and 30 (39.5%)patients,respectively.The detection
sensitivity, specificity, and accuracy of membrane-arrays for CTCs with KRAS oncogene were
84.4%, 95.3%, and 90.8%, respectively, and indeed a highly significant correlation to KRAS
imab plus chemotherapy, and 41and 40 were wild-type KRAS in tumors and peripheral blood,
respectively (both P < 0.0001). Patients with tumors that harbor wild-type KRAS are more likely
to have a better progression-free survival and overall survival when treated with cetuximab plus
chemotherapy (P < 0.0001). Likewise, patients with CTCs of wild-type KRAS inperipheralblood
express a better progression-free survival and overall survival when treated with cetuximab plus
chemotherapy (P < 0.0001).
Conclusions: These findings provide evidence that detection of KRAS mutational status in
CTCs, by gene expression array, has potential for clinical applicationin selecting metastatic colo-
rectal cancer patients mostlikely to benefit from cetuximab therapy.
Colorectal cancer is the second leading cause of cancer-related
per year.12In the past decade, significant improvements have
overall survival (OS) of metastatic colorectal cancer patients (1–
4). This prominent improvement is mainly due to the recent
introduction of new combinations of standard chemotherapy,
and to the new therapeutic agents targeting molecular events
involved in colorectal carcinogenesis such as monoclonal anti-
bodies (mAb) against epidermal growth factor receptor (EGFR)
or mAbs against vascular endothelial growth factor. Previous
studies (5–11) showed that the benefits of the anti-EGFR mAb
cetuximab among patients with metastatic colorectal cancer
are limited to those who have colorectal tumor tissues with
wild-type KRAS genes, and KRAS genes with mutations are
12http://www.doh.gov.tw/statistic/index.htm; accessedin November 2008.
Cancer Therapy: Clinical
Authors’Affiliations:1Graduate Institute of Medicine, College of Medicine, and
2Department of Emergency Medicine, Kaohsiung Municipal Hsiao-Kang Hospital,
3Faculty of Medicine and4Graduate Institute of Medical Genetics, College of
Medicine, Departments of5Surgery,6Emergency Medicine,7Internal Medicine, and
and9SchoolofMedicaland Health Sciences,FooyinUniversity, Kaohsiung,Taiwan;
10Division of Colorectal Surgery, Department of Surgery,TaichungVeterans General
Hospital, Taichung, Taiwan; and11Department of Medical Research, Fooyin
University Hospital, Pingtung,Taiwan
Grant support:The National Science Council of the Republic of China, NSC 96-
The costs of publicationof this article were defrayedinpartby thepaymentof page
charges.This article must therefore be hereby marked advertisement in accordance
with18 U.S.C. Section1734 solely toindicate this fact.
Note: S-R. Lin andJ-Y.Wang contributedequally to this article.
Requests for reprints: Jaw-Yuan Wang, Department of Surgery, Kaohsiung
Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1st
Road, Kaohsiung 807,Taiwan. E-mail: email@example.com; and Shiu-Ru Lin,
School of Medical and Health Sciences, Fooyin University, No.151, Jinxue Road,
Daliao Shiang, Kaohsiung County 831,Taiwan. Phone: 886-7-3122805; Fax: 886-
7-3114679; E-mail: firstname.lastname@example.org.
F2009 American Associationfor Cancer Research.
www.aacrjournals.orgClin Cancer Res 2009;15(13) July1, 2009
on September 13, 2015. © 2009 American Association for
2009;15:4508-4513. Clin Cancer Res
Li-Chen Yen, Yung-Sung Yeh, Chao-Wen Chen, et al.
in Patients with Metastatic Colorectal Cancer
Predictor of the Response to Cetuximab Plus Chemotherapy
Oncogene in Peripheral Blood as a
Access the most recent version of this article at:
This article has been cited by 6 HighWire-hosted articles. Access the articles at:
This article cites 26 articles, 9 of which you can access for free at:
related to this article or journal.Sign up to receive free email-alerts
To request permission to re-use all or part of this article, contact the AACR Publications
. email@example.comDepartment at
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
. firstname.lastname@example.orgDepartment at
on September 13, 2015. © 2009 American Association for clincancerres.aacrjournals.org Downloaded from