Prognostic value of HER3 and HER2 alterations in colorectal cancer: Relationship with sidedness, KRAS and BRAF mutation status

Research output: Contribution to conferenceAbstract

Abstract

Background Human epidermal growth factors 2 and 3 (HER2 and HER3) are members of the EGFR family that drives oncogenesis mainly through activation of the RAS-RAF-MEK-ERK pathway. While the prognostic value of HER2 and HER3 alterations in colorectal cancer (CRC) remains uncertain, KRAS and BRAF mutations confer resistance to targeted therapies and poor prognosis. Sidedness of the primary tumour has also been shown to be an important prognostic and predictive factor. Herein, we examined the prognostic value of HER2 and HER3 expression in CRC, with reference to sidedness, KRAS and BRAF mutational status. Methods The study cohort encompassed 557 incident CRC cases from the prospective, population-based Malmö Diet and Cancer study. Immunohistochemistry and dual-in situ hybridization were applied on tissue microarrays to assess HER2 and HER3 expression and HER2 gene copy number (GCN) alterations. Kaplan-Meier and Cox regression analyses were applied to determine their impact on 5-year overall survival (OS) in different strata. Results We found a significant, gradual increase in HER2 GCN alterations and HER3 overexpression from the right colon to the rectum (p=0.010 and p<0.001, respectively). In the full cohort, HER3 expression was not prognostic. However, a significant prognostic interaction between HER3 and KRAS status was observed in that high HER3 expression was significantly associated with a reduced OS in KRAS wild-type (wt) and with a prolonged OS in KRAS-mutated tumours (pinteraction = 0.001). HER3 overexpression was also significantly associated with a reduced OS in BRAF-mutated tumours but was not prognostic in BRAF wt tumours (pinteraction =0.014). In addition, HER3 overexpression was significantly associated with a reduced OS in patients with right-sided tumours (HR= 1.64, 95% CI 1.06-2.55). No prognostic significance was found for HER2 overexpression or GCN alterations. Conclusions These novel findings of significant prognostic interactions between HER3 overexpression and mutational status of KRAS and BRAF in CRC are potentially highly relevant in the clinical setting. Speculatively, HER3 overexpression may influence the efficacy of EGFR-inhibitors in metastatic CRC.

Details

Authors
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Publication statusUnpublished - 2017 May 24
Publication categoryResearch
Peer-reviewedNo
EventEuropean Society of Medical Oncologys annual congress - Madrid, Spain
Duration: 2017 Sep 82017 Sep 12

Conference

ConferenceEuropean Society of Medical Oncologys annual congress
Abbreviated titleESMO
CountrySpain
CityMadrid
Period2017/09/082017/09/12