This article reports results of a study that examined the clinicopathological characteristics
of patients with metastatic colorectal cancer displaying amplification or overexpression
of the HER2 oncogene, focusing on response to anti‐EGFR treatment. HER2 amplification
is detected in 3% of patients with colorectal cancer (CRC), making tumors in the metastatic
setting vulnerable to double pharmacological HER2 blockade. Preclinical findings show
that it also might impair response to anti‐epidermal growth factor receptor (EGFR)
treatment. Patients with KRAS exon 2 wild‐type metastatic CRC underwent molecular
screening of HER2 positivity by HERACLES criteria (immunohistochemistry 3+ or 2+ in
≥50% of cells, confirmed by fluorescence in situ hybridization). A sample of consecutive
HER2‐negative patients was selected as control. A regression modeling strategy was
applied to identify predictors explaining the bulk of HER2 positivity and the association
with response to previous anti‐EGFR treatment. From August 2012 to April 2018, a total
of 100 HER2‐positive metastatic CRC tumors were detected out of 1,485 KRAS exon
2 wild‐type screened patients (6.7%). HER2‐positive patients show more frequently
lung metastases (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.15–3.61;
p = .014) and higher tumor burden (OR, 1.48; 95% CI, 1.10–2.01; p = .011), and
tumors were more likely to be left sided (OR, 0.50; 95% CI, 0.22–1.11; p = .088).
HER2‐positive patients who received treatment with anti‐EGFR agents ( n = 79) showed
poorer outcome (objective response rate, 31.2% vs. 46.9%, p = .031; progression‐free
survival, 5.7 months vs. 7 months, p = .087). Testing for HER2 should be offered
to all patients with metastatic CRC because the occurrence of this biomarker is unlikely
to be predicted based on main clinicopathological features. Patients with HER2‐amplified
metastatic CRC are less likely to respond to anti‐EGFR therapy. Patients with HER2
‐amplified/overexpressed metastatic colorectal cancer (mCRC) harbor a driver actionable
molecular alteration that has been shown in preclinical models to hamper efficacy
of the anti‐epidermal growth factor receptor (EGFR) targeted therapies. The present
study confirmed that this molecular feature was associated with worse objective tumor
response and shorter progression‐free survival in response to previous anti‐EGFR therapies.
Moreover, it was found that the occurrence of this biomarker is unlikely to be predicted
based on main clinicopathological features. Therefore, HER2 status assessment should
be included in the molecular diagnostic workup of all mCRC for speedy referral to
clinical trials encompassing HER2‐targeted double blockade independently of previous
anti‐EGFR treatment.