title: Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance).
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.
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: Ace J
authors.initials: AJ
authors.lastname: Hatch
authors.affiliation: Duke Cancer Institute Bioinformatics Shared Resource, Duke University, Durham, North Carolina.
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Sibley
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Starr
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: J Chris
authors.initials: JC
authors.lastname: Brady
authors.affiliation: Alliance Statistical and Data Center, Durham, North Carolina.
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.affiliation: East Carolina University, Greenville, North Carolina.
authors.forename: Jingquan
authors.initials: J
authors.lastname: Jia
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Bowers
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.|School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China.
authors.forename: Herbert
authors.initials: H
authors.lastname: Pang
authors.affiliation: Duke Cancer Institute Bioinformatics Shared Resource, Duke University, Durham, North Carolina.|Alliance Statistical and Data Center, Durham, North Carolina.|Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
authors.forename: Kouros
authors.initials: K
authors.lastname: Owzar
authors.affiliation: Alliance Statistical and Data Center, Durham, North Carolina.|Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
authors.forename: Donna
authors.initials: D
authors.lastname: Niedzwiecki
authors.affiliation: University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Federico
authors.initials: F
authors.lastname: Innocenti
authors.affiliation: University of California, San Francisco - Helen Diller Family Comprehensive Cancer Center, San Francisco, California.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Venook
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
authors.affiliation: Duke University Medical Center, Durham, North Carolina. anixon@duke.edu.
authors.forename: Andrew B
authors.identifier: 0000-0003-3971-2964
authors.initials: AB
authors.lastname: Nixon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D000068818:Cetuximab / Q000008:administration & dosage / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018631:ras Proteins; D000068818:Cetuximab
keywords: Biomarker; cetuximab; colorectal cancer; plasma