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

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          Abstract

          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.

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          Author and article information

          Journal
          The Oncologist
          The Oncologist
          Alphamed Press
          1083-7159
          1549-490X
          April 05 2019
          : theoncologist.2018-0785
          Article
          10.1634/theoncologist.2018-0785
          6795149
          30952821
          6894b508-4e4d-4349-97dd-d497895df732
          © 2019
          History

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