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

Forskningsoutput: KonferensbidragKonferensabstract

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.

Detaljer

Författare
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
Originalspråkengelska
StatusUnpublished - 2017 maj 24
PublikationskategoriForskning
Peer review utfördNej
EvenemangEuropean Society of Medical Oncologys annual congress - Madrid, Spanien
Varaktighet: 2017 sep 82017 sep 12

Konferens

KonferensEuropean Society of Medical Oncologys annual congress
Förkortad titelESMO
LandSpanien
OrtMadrid
Period2017/09/082017/09/12