EGFR Amplification in Metastatic Colorectal Cancer

Abstract

Background: EGFR amplification occurs in about 1% of metastatic colorectal cancers (mCRCs) but is not routinely tested as a prognostic or predictive biomarker for patients treated with anti-EGFR monoclonal antibodies. Herein, we aimed to characterize the clinical and molecular landscape of EGFR-amplified mCRC.

Methods: In this multinational cohort study, we compared clinical data of 62 patients with EGFR-amplified vs 1459 EGFR nonamplified mCRC, as well as comprehensive genomic data of 35 EGFR-amplified vs 439 EGFR nonamplified RAS/BRAF wild-type and microsatellite stable (MSS) tumor samples. All statistical tests were 2-sided.

Results: EGFR amplification was statistically significantly associated with left primary tumor sidedness and RAS/BRAF wild-type status. All EGFR-amplified tumors were MSS and HER2 nonamplified. Overall, EGFR-amplified samples had higher median fraction of genome altered compared with EGFR-nonamplified, RAS/BRAF wild-type MSS cohort. Patients with EGFR-amplified tumors reported longer overall survival (OS) (median OS = 71.3 months, 95% confidence interval [CI] = 50.7 to not available [NA]) vs EGFR-nonamplified ones (24.0 months; 95% CI = 22.8 to 25.6; hazard ratio [HR] = 0.30, 95% CI = 0.20 to 0.44; P < .001; adjusted HR = 0.46, 95% CI = 0.30 to 0.69; P < .001). In the subgroup of patients with RAS/BRAF wild-type mCRC exposed to anti-EGFR-based therapy, EGFR amplification was again associated with better OS (median OS = 54.0 months, 95% CI = 35.2 to NA, vs 29.1 months, 95% CI = 27.0 to 31.9, respectively; HR = 0.46, 95% CI = 0.28 to 0.76; P = .002).

Conclusion: Patients with EGFR-amplified mCRC represent a biologically defined subgroup and merit dedicated clinical trials with novel and more potent EGFR-targeting strategies beyond single-agent monoclonal antibodies.

Figure 1.

Study flow diagram. mCRC = metastatic colorectal cancer; NGS = next-generation sequencing.

Figure 2.

EGFR-amplified samples alterations profile. A) Heatmap showing the genomic profiles of patients with EGFR amplification. B) Copy number variation frequency for chromosome 7 of EGFR-amplified samples (EGFR is located in the p arm of chromosome 7). Gains are shown in red and losses are shown in blue; the threshold for both gains and losses is set at 0.5. C) and (D) show copy number variation frequencies for, respectively, patients with and without EGFR amplification. amp = amplification; CNV = copy number variation; del = deletion; dup = duplication; IG = intragenic; rear = rearrangement; splicevar = splice variant.

Figure 3.

Kaplan-Meier estimates of overall survival according to the presence of EGFR amplification in the entire study population (N = 1521). Blue lines indicate patients with EGFR nonamplified mCRC (n = 1459), whereas violet lines indicate patients with EGFR-amplified mCRC (n = 62). Patients with EGFR-amplified mCRC showed a better overall survival compared with patients with EGFR-nonamplified mCRC. CI = confidence interval; HR = hazard ratio; mCRC = metastatic colorectal cancer; OS = overall survival.

Figure 4.

Kaplan-Meier estimates of overall survival according to the presence of EGFR amplification in the subgroup of patients with RAS/BRAF wild-type mCRC treated with anti-EGFR agents (n = 465). Blue lines indicate patients with EGFR-nonamplified mCRC (n = 431), whereas violet lines indicate patients with EGFR-amplified mCRC (n = 34). Patients with EGFR-amplified mCRC showed a better overall survival compared with patients with EGFR nonamplified mCRC. P values were calculated by means of the likelihood ratio test, 2-sided, in a Cox univariable regression model. CI = confidence interval; HR = hazard ratio; mCRC = metastatic colorectal cancer; OS = overall survival.