Blood‐based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance). (27th July 2016)

• Record Type: Journal Article
• Authors: Hatch, Ace J.; Sibley, Alexander B.; Starr, Mark D.; Brady, J. Chris; Jiang, Chen; Jia, Jingquan; Bowers, Daniel L.; Pang, Herbert; Owzar, Kouros; Niedzwiecki, Donna; Innocenti, Federico; Venook, Alan P.; Hurwitz, Herbert I.; Nixon, Andrew B.
• Is Part Of: Cancer medicine. Volume 5:Number 9(2016:Sep.)
• Page Start: 2249
• Page End: 2260
• Publication Date: 2016-07-27
• Subjects: Biomarker -- cetuximab -- colorectal cancer -- plasma; 616.994005
• DOI: 10.1002/cam4.806
• Languages: English
• ISSNs: 2045-7634

Abstract

Abstract: Circulating protein markers were assessed in patients with colorectal cancer (CRC) treated with cetuximab in CALGB 80203 to identify prognostic and predictive biomarkers. Patients with locally advanced or metastatic CRC received FOLFOX or FOLFIRI chemotherapy (chemo) or chemo in combination with cetuximab. Baseline plasma samples from 152 patients were analyzed for six candidate markers [epidermal growth factor (EGF), heparin‐binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. Analyte levels were associated with survival endpoints using univariate Cox proportional hazards models. Predictive markers were identified using a treatment‐by‐marker interaction term in the Cox model. Plasma levels of EGF, HBEGF, HER3, and CD73 were prognostic for overall survival (OS) across all patients ( KRAS mutant and wild‐type). High levels of EGF predicted for lack of OS benefit from cetuximab in KRAS wild‐type (WT) patients (chemo HR = 0.98, 95% CI = 0.74–1.29; chemo+cetuximab HR = 1.54, 95% CI = 1.05–2.25; interaction P = 0.045) and benefit from cetuximab in KRAS mutant patients (chemo HR = 1.72, 95% CI = 1.02–2.92; chemo+cetuximab HR = 0.90, 95% CI = 0.67–1.21; interaction P = 0.026). Across all patients, higher HER3 levels were associated with significant OS benefit from cetuximab treatment (chemo HR = 4.82, 95% CI = 1.68–13.84; chemo+cetuximab HR = 0.95, 95% CI = 0.31–2.95; interaction P = 0.046). CD73 was also identified as predictive of OS benefit in KRAS WT patients (chemo HR = 1.28, 95% CI = 0.88–1.84; chemo+cetuximab HR = 0.60, 95% CI = 0.32–1.13; interaction P = 0.049). Although these results are preliminary, and confirmatory studies are necessary before clinical application, the data suggest that HER3 and CD73 may play important roles in the biological response to cetuximab. Abstract : Plasma samples collected during the randomized phase II trial CALGB 80203 comparing FOLFOX or FOLFIRI chemotherapy with or without cetuximab in metastatic colorectal cancer (mCRC) were assayed for levels of six candidate biomarker proteins [epidermal growth factor (EGF), heparin‐binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. High EGF was predictive of lack of benefit from cetuximab in KRAS WT patients and predictive of benefit in KRAS Mut patients. High HER3 was predictive of lack of benefit in all patients and CD73 was predictive of benefit in KRAS WT patients. These data implicate HER3 signaling and inflammatory signaling in the biological response to cetuximab.