Exploratory biomarker analysis for treatment response in KRAS wild type metastatic colorectal cancer patients who received cetuximab plus irinotecan.
BACKGROUND
More than half of the patients selected based on KRAS mutation status fail to respond to the treatment with cetuximab in metastatic colorectal cancer (mCRC). We designed a study to identify additional biomarkers that could act as indicators for cetuximab treatment in mCRC.


METHODS
We investigated 58 tumor samples from wild type KRAS CRC patients treated with cetuximab plus irinotecan (CI). We conducted the genotyping for mutations in either BRAF or PIK3CA and profiled comprehensively the expression of 522 kinase genes.


RESULTS
BRAF mutation was detected in 5.1 % (3/58) of patients. All 50 patients showed wild type PIK3CA. Gene expression patterns that categorized patients with or without the disease control to CI were compared by supervised classification analysis. PSKH1, TLK2 and PHKG2 were overexpressed significantly in patients with the disease control to IC. The higher expression value of PSKH1 (r = 0.462, p < 0.001) and TLK2 (r = 0.361, p = 0.005) had the significant correlation to prolonged PFS.


CONCLUSIONS
The result of this work demonstrated that expression nature of kinase genes such as PSKH1, TLK2 and PHKG2 may be informative to predict the efficacy of CI in wild type KRAS CRC. Mutations in either BRAF or PIK3CA were rare subsets in wild type KRAS CRC.
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. seungtae1.kim@samsung.com.|Colorectal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. seungtae1.kim@samsung.com.
Seung Tae
ST
Kim
Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. taejin.ahn@samsung.com.|Samsung Genome Institute, Samsung Biological Research Institute, Seoul, Korea. taejin.ahn@samsung.com.
Tae Jin
TJ
Ahn
Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. eunjin_2.lee@samsung.com.|Samsung Genome Institute, Samsung Biological Research Institute, Seoul, Korea. eunjin_2.lee@samsung.com.
Eunjin
E
Lee
Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. ingu.do@samsung.com.
In-Gu
IG
Do
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. ssjj.lee@samsung.com.|Colorectal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. ssjj.lee@samsung.com.
Su Jin
SJ
Lee
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. sh1767.park@samsung.com.|Colorectal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. sh1767.park@samsung.com.
Se Hoon
SH
Park
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. joonoh.park@samsung.com.|Colorectal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. joonoh.park@samsung.com.|Innovative Cancer Medicine Institute, Samsung Medical Center, Seoul, Korea. joonoh.park@samsung.com.
Joon Oh
JO
Park
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. pys27hmo.park@samsung.com.|Colorectal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. pys27hmo.park@samsung.com.
Young Suk
YS
Park
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. hoy.lim@samsung.com.|Colorectal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. hoy.lim@samsung.com.
Ho Yeong
HY
Lim
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. wonki.kang@samsung.com.|Colorectal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. wonki.kang@samsung.com.
Won Ki
WK
Kang
Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. parmenides.kim@samsung.com.|Colorectal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. parmenides.kim@samsung.com.
Suk Hyeong
SH
Kim
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. jyunlee@skku.edu.|Colorectal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. jyunlee@skku.edu.
Jeeyun
J
Lee
Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. hckim@skku.edu.|Colorectal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. hckim@skku.edu.
Hee Cheol
HC
Kim
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab / Q000008:administration & dosage; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; C503859:PI3KCA protein, human; D014157:Transcription Factors; D000077146:Irinotecan; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins; D000068818:Cetuximab; D002166:Camptothecin