HER2 Positivity Predicts Unresponsiveness to EGFR-Targeted Treatment in Metastatic Colorectal Cancer

Abstract

Background 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. Subjects and Methods 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. Results 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). Conclusion 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. Implications for Practice 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.

Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer

“…According to the blood CEA values and CT scan, the tumor acquired resistance to anti-EGFR treatment within 9 months and plasma-Seq revealed a novel focal amplification on 17q12, including ERBB2, which represents an established mechanism of resistance to anti-EGFR therapy ( Fig. 5; Additional file 3: Table S2; Additional file 2: Figure S6) [36,[60][61][62]. After switching to anti-VEGF treatment for 5 months, the amplification in 13q12.2 appeared again, along with an increase in CEA level and the size of the lung metastasis region ( Fig.…”

Precision Treatment and Prevention of Colorectal Cancer—Hope or Hype?

“…For RAS/BRAF wild-type CRC, a growing array of potential therapeutic targets in other oncogenic pathways are being identified. For example, CRC with ERBB2 (HER2/neu) amplification demonstrates resistance to anti-EGFR therapy, 14 yet may greatly benefit from anti-HER2 therapies (eg, trastuzumab, pertuzumab, and lapatinib) classically used to treat ERBB2-amplified breast cancers. 15,16 Somatic oncogenic fusions in the NTRK genes are rare in CRC (<1%), yet confer marked susceptibility (75% response rate) to TRK inhibitors such as larotrectinib, for which tumor siteagnostic US Food and Drug Administration approval has been granted.…”

BRAF mutant colorectal cancer: ErbB2 expression levels as predictive factor for the response to combined BRAF/ErbB inhibitors

“…Mutations or amplifications in one of the four ERBB family genes are present in 22 out of 165 (13%) non-hypermutated and 16 out of 30 (53%) hyper-mutated cases [2]. Interestingly, activating mutations and amplifications of ErbB2 account for 7% of cases (Cancer Genome Atlas Network) and patients with HER2-amplified metastatic CRC are less likely to respond to anti-EGFR therapy [25].…”