Gene Expression Markers of Efficacy and Resistance to Cetuximab Treatment in Metastatic Colorectal Cancer: Results from CALGB 80203 (Alliance)

被引：75

作者：

Cushman, Stephanie M. ^{[1
]}

Jiang, Chen ^{[2
]}

Hatch, Ace J. ^{[1
]}

Shterev, Ivo ^{[2
]}

Sibley, Alexander B. ^{[2
]}

Niedzwiecki, Donna ^{[2
]}

Venook, Alan P. ^{[3
]}

Owzar, Kouros ^{[2
]}

Hurwitz, Herbert I. ^{[1
]}

Nixon, Andrew B. ^{[1
]}

机构：

[1] Duke Univ, Med Ctr, Durham, NC 27710 USA

[2] Alliance Stat & Data Ctr, Durham, NC USA

[3] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

来源：

CLINICAL CANCER RESEARCH | 2015年 / 21卷 / 05期

关键词：

EPIDERMAL-GROWTH-FACTOR; ADENOSINE GENERATION; TARGETED THERAPIES; RAS MUTATIONS; FACTOR-I; T-CELL; KRAS; CD73; INHIBITION; EPIREGULIN;

D O I：

10.1158/1078-0432.CCR-14-2313

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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 FOL-FOX 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; P-interaction = 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; P-interaction = 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. (C)2014 AACR.

引用

页码：1078 / 1086

页数：9

共 45 条

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