PMID- 25520391 OWN - NLM STAT- MEDLINE DCOM- 20160318 LR - 20220410 IS - 1557-3265 (Electronic) IS - 1078-0432 (Print) IS - 1078-0432 (Linking) VI - 21 IP - 5 DP - 2015 Mar 1 TI - Gene expression markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance). PG - 1078-86 LID - 10.1158/1078-0432.CCR-14-2313 [doi] AB - PURPOSE: Formalin-fixed, paraffin-embedded tumor samples from CALGB 80203 were analyzed for expression of EGFR axis-related genes to identify prognostic or predictive biomarkers for cetuximab treatment. PATIENTS AND METHODS: Patients (238 total) with first-line metastatic colorectal cancer (mCRC) were randomized to FOLFOX or FOLFIRI chemotherapy +/- cetuximab. qRT-PCR analyses were conducted on tissues from 103 patients at baseline to measure gene expression levels of HER-related genes, including amphiregulin (AREG), betacellulin (BTC), NT5E (CD73), DUSP4, EGF, EGFR, epigen (EPGN), epiregulin (EREG), HBEGF, ERBB2 (HER2), ERBB3 (HER3), ERBB4 (HER4), PHLDA1, and TGFA. The interactions between expression levels and treatment with respect to progression-free survival (PFS) and overall survival (OS) were modeled using multiplicative Cox proportional hazards models. RESULTS: High tumor mRNA levels of HER2 [hazard ratio (HR), 0.64; P = 0.002] and EREG (HR, 0.89; P = 0.016) were prognostic markers associated with longer PFS across all patients. HER3 and CD73 expression levels were identified as potential predictive markers of benefit from cetuximab. In KRAS wild-type (WT) tumors, low HER3 expression was associated with longer OS from cetuximab treatment, whereas high HER3 expression was associated with shorter OS from cetuximab treatment (chemo + cetuximab: HR, 1.15; chemo-only: HR, 0.48; Pinteraction = 0.029). High CD73 expression was associated with longer PFS from cetuximab treatment in patients with KRAS-WT (chemo + cetuximab: HR, 0.91; chemo-only: HR, 1.57; Pinteraction = 0.026) and KRAS-mutant (Mut) tumors (chemo + cetuximab: HR, 0.80; chemo-only: HR, 1.29; P = 0.025). CONCLUSIONS: Gene expression of HER3 and CD73 was identified as a potential predictive marker for cetuximab. These data implicate HER axis signaling and immune modulation as potential mechanisms of cetuximab action and sensitivity. CI - (c)2014 American Association for Cancer Research. FAU - Cushman, Stephanie M AU - Cushman SM AD - Duke University Medical Center, Durham, North Carolina. FAU - Jiang, Chen AU - Jiang C AD - Alliance Statistical and Data Center, Durham, North Carolina. FAU - Hatch, Ace J AU - Hatch AJ AD - Duke University Medical Center, Durham, North Carolina. FAU - Shterev, Ivo AU - Shterev I AD - Alliance Statistical and Data Center, Durham, North Carolina. FAU - Sibley, Alexander B AU - Sibley AB AD - Alliance Statistical and Data Center, Durham, North Carolina. FAU - Niedzwiecki, Donna AU - Niedzwiecki D AD - Alliance Statistical and Data Center, Durham, North Carolina. FAU - Venook, Alan P AU - Venook AP AD - University of California, San Francisco-Helen Diller Family Comprehensive Cancer Center, San Francisco, California. FAU - Owzar, Kouros AU - Owzar K AD - Alliance Statistical and Data Center, Durham, North Carolina. FAU - Hurwitz, Herbert I AU - Hurwitz HI AD - Duke University Medical Center, Durham, North Carolina. FAU - Nixon, Andrew B AU - Nixon AB AD - Duke University Medical Center, Durham, North Carolina. anixon@duke.edu. LA - eng GR - U10 CA047577/CA/NCI NIH HHS/United States GR - U10 CA032291/CA/NCI NIH HHS/United States GR - CA33601/CA/NCI NIH HHS/United States GR - CA47577/CA/NCI NIH HHS/United States GR - U10 CA086726/CA/NCI NIH HHS/United States GR - U10 CA045564/CA/NCI NIH HHS/United States GR - P30 DK026743/DK/NIDDK NIH HHS/United States GR - U10 CA045808/CA/NCI NIH HHS/United States GR - U10 CA031946/CA/NCI NIH HHS/United States GR - U10 CA033601/CA/NCI NIH HHS/United States GR - U10 CA045389/CA/NCI NIH HHS/United States GR - CA60138/CA/NCI NIH HHS/United States GR - U10 CA180821/CA/NCI NIH HHS/United States GR - U10 CA077597/CA/NCI NIH HHS/United States GR - U10 CA059518/CA/NCI NIH HHS/United States GR - U10CA180882/CA/NCI NIH HHS/United States GR - U10 CA077440/CA/NCI NIH HHS/United States GR - U10 CA041287/CA/NCI NIH HHS/United States GR - U10 CA047559/CA/NCI NIH HHS/United States GR - U10 CA180882/CA/NCI NIH HHS/United States GR - U10 CA074811/CA/NCI NIH HHS/United States GR - U10CA180821/CA/NCI NIH HHS/United States GR - CA31946/CA/NCI NIH HHS/United States GR - U10 CA003927/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20141217 PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 0 (KRAS protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) RN - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) RN - PQX0D8J21J (Cetuximab) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Agents/pharmacology/*therapeutic use MH - *Biomarkers, Tumor MH - Cetuximab/pharmacology/*therapeutic use MH - Colorectal Neoplasms/drug therapy/*genetics/mortality/pathology MH - Drug Resistance, Neoplasm/*genetics MH - ErbB Receptors/genetics/metabolism MH - Female MH - *Gene Expression MH - Gene Expression Profiling MH - Humans MH - Kaplan-Meier Estimate MH - Male MH - Middle Aged MH - Mutation MH - Neoplasm Metastasis MH - Prognosis MH - Proto-Oncogene Proteins B-raf/genetics/metabolism MH - Proto-Oncogene Proteins p21(ras)/genetics/metabolism MH - Treatment Outcome MH - Young Adult PMC - PMC4772749 MID - NIHMS762803 COIS- Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed by the other authors. EDAT- 2014/12/19 06:00 MHDA- 2016/03/19 06:00 PMCR- 2016/03/01 CRDT- 2014/12/19 06:00 PHST- 2014/12/19 06:00 [entrez] PHST- 2014/12/19 06:00 [pubmed] PHST- 2016/03/19 06:00 [medline] PHST- 2016/03/01 00:00 [pmc-release] AID - 1078-0432.CCR-14-2313 [pii] AID - 10.1158/1078-0432.CCR-14-2313 [doi] PST - ppublish SO - Clin Cancer Res. 2015 Mar 1;21(5):1078-86. doi: 10.1158/1078-0432.CCR-14-2313. Epub 2014 Dec 17.