ORIGINAL ARTICLE Analysis of KRAS, BRAF, PTEN, IGF1R, EGFR intron 1 CA status in both primary tumors and paired metastases in determining benefit from cetuximab therapy in colon cancer Jin Hyun Park • Sae-Won Han • Do-Youn Oh • Seock-Ah Im • Seung-Yong Jeong • Kyu Joo Park • Tae-You Kim • Yung-Jue Bang • Jae-Gahb Park Received: 2 November 2010 / Accepted: 3 February 2011 / Published online: 22 February 2011 Ó Springer-Verlag 2011 Abstract Purpose The aim of this study was to determine the expression of molecular markers in metastatic colorectal cancer (mCRC) and the concordance between primary tumor and metastasis. We also aimed to determine the relationship between molecular markers and clinical out- comes of cetuximab-containing chemotherapy. Methods Seventy-five mCRC patients who received cetuximab-containing chemotherapy between 2000 and 2008 were consecutively enrolled. EGFR, p-EGFR, PTEN, and IGF-1R expression by immunohistochemistry, DNA sequencing for EGFR, KRAS, BRAF, and PI3 KCA, and EGFR amplification by FISH were done. Results The positive expression of EGFR, p-EGFR, PTEN, and IGF-1R was determined in 45 (64.3%), 9 (14.8%), 35 (50.7%), and 10 patients (16.1%), respectively. EGFR gene amplification or high polysomy was detected in 10 patients (17.6%). KRAS mutation and BRAF mutation were detected in 19 patients (27.5%) and five patients (7.0%), respectively. Among tested biomarkers, only the EGFR intron 1 CA repeat polymorphism and BRAF mutation showed concordance (kappa = 0.600, P = 0.003; and kappa = 0.692, P = 0.001, respectively) between pri- mary tumor and paired metastasis. Skin rash was a strong predictive marker for response rate, PFS, and OS. In KRAS mutant tumors, PTEN expression was associated with a longer PFS. BRAF mutation was related to poor outcome in KRAS wild-type tumors. Conclusions BRAF mutations and EGFR intron 1 CA repeat polymorphisms were concordant between primary tumors and paired metastases. In KRAS mutant tumors, PTEN expression was a predictive marker for favorable outcomes. In KRAS wild type, BRAF mutation was strong predictive markers for poor outcomes. Keywords Colon cancer Á Cetuximab Á KRAS Á BRAF Á PTEN Á EGFR intron 1 CA Introduction Since cetuximab was introduced for the treatment of mCRC, there have been many studies aimed at identifying the predictive markers for chemotherapeutic responsive- ness. Several studies have shown, by immunohistochemis- try (IHC), that EGFR protein expression in cancer tissues does not predict the response to cetuximab treatment [1]. In contrast, a gain in the EGFR gene copy number due to polysomy or gene amplification, which has been evaluated by fluorescent in situ hybridization (FISH), seems to be a better predictive marker for response to anti-EGFR therapy [2, 3]. KRAS mutation and PTEN loss by IHC are well known as predictive markers for poor outcome to cetuximab treatment [4]. BRAF and PIK3CA mutations are considered to predict a poor response to cetuximab treatment [5, 6]. IGF1R results in upregulation in the majority of CRCs, most likely contributing to the aggressive growth J. H. Park Á S.-W. Han Á D.-Y. Oh (&) Á S.-A. Im Á T.-Y. Kim Á Y.-J. Bang Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul 110-744, Republic of Korea e-mail: ohdoyoun@snu.ac.kr S.-W. Han Á D.-Y. Oh Á S.-A. Im Á T.-Y. Kim Á Y.-J. Bang Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea S.-Y. Jeong Á K. J. Park Á J.-G. Park Department of Surgery, Seoul National University Hospital, Seoul, Republic of Korea 123 Cancer Chemother Pharmacol (2011) 68:1045–1055 DOI 10.1007/s00280-011-1586-z