Co-Expression And Predictive Value Of Her Family Members For The Response To Therapy With Cetuximab In Patients With Metastatic Colorectal Cancer.

Abstract Background: Overexpression of the EGFR is common in patients with a wide range of cancers and the EGFR is an important target for therapy with monoclonal antibodies (mAbs) based drugs. Of these, cetuximab and panitumumab have been approved for the treatment of patients with metastatic colorectal cancer (mCRC). However, therapeutic benefits are seen in a subset of such patients and the duration of response can also be short. Indeed, there is currently no reliable predictive biomarkers for the selection of patients who benefit from therapy with the anti-EGFR antibodies. While KRAS mutation is currently used as an important negative predictive biomarker for the response to therapy with anti-EGFR mAbs, not all patients with wild type KRAS gain benefit from therapy with anti-EGFR mAbs and objective responses have been reported in mCRC patients with KRAS mutations. Aim: The aim of this study was to investigate the predictive value of EGFR and its dimerization partner (i.e. all other members of the HER family) for the response to treatment with cetuximab in patients with wild-type KRAS status mCRC. Methods: Using immunohistochemistry (IHC) we investigated the co-expression and predictive value of all four members of the HER family, for the response to cetuximab in 144 mCRC patients and in 21 paired primary tumours and their metastatic sites. Results: Co-expression of all four members of the HER family were found in 10% of the cases examined. The expression of wtEGFR was an indicator of poorer overall survival and the membranous expression of HER2 and HER3 3+ intensity was associated with a shorter progression free survival (PFS). In contrast, the cytoplasmic expression of HER2 was associated with better PFS. In 48% and 71% of the cases examined, there were discordance in the expression of EGFR or one or more HER family members in paired primary and related metastatic tumours, respectively. Conclusion: Our results implicate the importance of large prospective investigation of the expression level and predictive value of not only the therapeutic target (i.e. EGFR protein) but also its dimerization partners for the response to therapy with anti-EGFR mAbs and other forms of HER inhibitors in both the primary tumours and metastatic sites in colorectal cancer. Citation Format: Said A. Khelwatty, Soozana Puvanenthiran, Sharadah Essapen, Izhar Bagwan, Alan M. Seddon, Helmout Modjtahedi. Co-expression and predictive value of HER family members for the response to therapy with cetuximab in patients with metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 350.