PMID- 27104867 OWN - NLM STAT- MEDLINE DCOM- 20170911 LR - 20210108 IS - 1555-8576 (Electronic) IS - 1538-4047 (Print) IS - 1538-4047 (Linking) VI - 17 IP - 7 DP - 2016 Jul 2 TI - Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer. PG - 751-9 LID - 10.1080/15384047.2016.1178426 [doi] AB - Several studies have reported that epidermal growth factor receptor (EGFR)-related molecules may serve as predictors of cetuximab treatment for metastatic colorectal cancer (mCRC), such as EGFR gene copy number (GCN), expression of 2 ligands of EGFR, amphiregulin (AREG) and epiregulin (EREG), and EGFR CA simple sequence repeat 1 (CA-SSR1) polymorphism; however, these biomarkers still remain not useful in clinical practice since they have been evaluated using cohorts with patients treated in various settings of chemotherapy. We therefore analyzed associations of mRNA expression of AREG and EREG, EGFR GCN, and CA-SSR1 polymorphism [short (S;/= 20)] with clinical outcomes in 77 Japanese patients with KRAS exon 2 wild-type mCRC enrolled in phase II trials of FOLFOX (n = 28/57, UMIN000004197) or SOX (n = 49/67, UMIN000007022) plus cetuximab as first-line therapy. High AREG expression correlated with significantly better progression-free survival (median 11.6 vs. 66 months, HR 0.52, P = 0.037); moreover, it remained statistically significant in multivariate analysis (HR: 0.48, P = 0.027). S/S genotype of CA-SSR1 predicted severe skin toxicity (P = 0.040). Patients with both AREG-low and EGFR low-GCN had significantly shorter overall survival than the others (median 22.2 vs. 42.8 months, HR 2.34, P = 0.042). The multivariate analysis showed that molecular status with both AREG-low and EGFR low-GCN was a predictor of worse survival (P = 0.006). In conclusion, AREG mRNA expression and EGFR CA-SSR1 polymorphism predict survival and skin toxicity, respectively, of initial chemotherapy with cetuximab. Our results also suggest potential prognostic value of the combined assessment of AREG and EGFR GCN for first-line cetuximab treatment. FAU - Sunakawa, Yu AU - Sunakawa Y AD - a Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles , CA , USA. AD - b Division of Medical Oncology, Department of Internal Medicine, Showa University Northern Yokohama Hospital , Yokohama , Kanagawa , Japan. FAU - Yang, Dongyun AU - Yang D AD - c Department of Preventive Medicine , Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles , CA , USA. FAU - Moran, Miriana AU - Moran M AD - d Response Genetics, Inc. , Los Angeles , CA , USA. FAU - Astrow, Stephanie H AU - Astrow SH AD - d Response Genetics, Inc. , Los Angeles , CA , USA. FAU - Tsuji, Akihito AU - Tsuji A AD - e Department of Clinical Oncology , Kagawa University Faculty of Medicine Cancer Center, Kagawa University Hospital , Kita-gun , Kagawa , Japan. FAU - Stephens, Craig AU - Stephens C AD - d Response Genetics, Inc. , Los Angeles , CA , USA. FAU - Zhang, Wu AU - Zhang W AD - a Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles , CA , USA. FAU - Cao, Shu AU - Cao S AD - c Department of Preventive Medicine , Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles , CA , USA. FAU - Takahashi, Takehiro AU - Takahashi T AD - f Division of Medical Oncology, Showa University Hospital , Shinagawa-ku, Tokyo , Japan. FAU - Denda, Tadamichi AU - Denda T AD - g Division of Gastroenterology, Chiba Cancer Center , Chuo-ku, Chiba , Japan. FAU - Shimada, Ken AU - Shimada K AD - h Division of Medical Oncology, Department of Internal Medicine, Showa University Koto Hospital , Toyosu, Koto-ku, Tokyo , Japan. FAU - Kochi, Mitsugu AU - Kochi M AD - i Department of Digestive Surgery , Nihon University School of Medicine , Itabashi-ku, Tokyo , Japan. FAU - Nakamura, Masato AU - Nakamura M AD - j Aizawa Comprehensive Cancer Center, Aizawa Hospital , Matsumoto , Nagano , Japan. FAU - Kotaka, Masahito AU - Kotaka M AD - k Gastrointestinal Center, Sano Hospital , Kobe , Hyogo , Japan. FAU - Segawa, Yoshihiko AU - Segawa Y AD - l Division of Medical Oncology, Saitama Medical University International Medical Center , Hidaka , Saitama , Japan. FAU - Masuishi, Toshiki AU - Masuishi T AD - m Division of Gastroenterology, Tsuchiura Kyodo General Hospital , Tsuchiura , Ibaraki , Japan. FAU - Takeuchi, Masahiro AU - Takeuchi M AD - n Department of Clinical Medicine (Biostatistics) , Kitasato University School of Pharmacy , Shirokane, Minato-ku, Tokyo , Japan. FAU - Fujii, Masashi AU - Fujii M AD - i Department of Digestive Surgery , Nihon University School of Medicine , Itabashi-ku, Tokyo , Japan. FAU - Nakajima, Toshifusa AU - Nakajima T AD - o Japan Clinical Cancer Research Organization , Chuo-ku, Tokyo , Japan. FAU - Ichikawa, Wataru AU - Ichikawa W AD - p Division of Medical Oncology, Showa University Fujigaoka Hospital , Yokohama , Kanagawa , Japan. FAU - Lenz, Heinz-Josef AU - Lenz HJ AD - a Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles , CA , USA. LA - eng PT - Journal Article DEP - 20160422 PL - United States TA - Cancer Biol Ther JT - Cancer biology & therapy JID - 101137842 RN - 0 (Antineoplastic Agents) RN - EC 2.7.10.1 (ErbB Receptors) RN - PQX0D8J21J (Cetuximab) SB - IM MH - Adult MH - Aged MH - Antineoplastic Agents/administration & dosage/pharmacology/*therapeutic use MH - Cetuximab/administration & dosage/pharmacology/*therapeutic use MH - Colorectal Neoplasms/*drug therapy/pathology MH - ErbB Receptors/metabolism MH - Female MH - Humans MH - Male MH - Middle Aged MH - Neoplasm Metastasis MH - Prognosis MH - Treatment Outcome PMC - PMC4970538 OTO - NOTNLM OT - Amphiregulin OT - EGFR OT - EGFR gene copy number OT - cetuximab OT - colorectal cancer EDAT- 2016/04/23 06:00 MHDA- 2017/09/12 06:00 PMCR- 2017/04/22 CRDT- 2016/04/23 06:00 PHST- 2016/04/23 06:00 [entrez] PHST- 2016/04/23 06:00 [pubmed] PHST- 2017/09/12 06:00 [medline] PHST- 2017/04/22 00:00 [pmc-release] AID - 1178426 [pii] AID - 10.1080/15384047.2016.1178426 [doi] PST - ppublish SO - Cancer Biol Ther. 2016 Jul 2;17(7):751-9. doi: 10.1080/15384047.2016.1178426. Epub 2016 Apr 22.