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

HAU, SOFIE LU ; Larsson, Anna H LU ; Nodin, Björn LU and Jirström, Karin LU (2017) European Society of Medical Oncologys annual congress
Abstract (Swedish)
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to conference
publication status
unpublished
subject
conference name
European Society of Medical Oncologys annual congress
language
English
LU publication?
yes
id
92c1b560-efe6-453e-bfbe-7576d93d2209
date added to LUP
2017-05-24 22:26:24
date last changed
2017-11-21 08:19:12
@misc{92c1b560-efe6-453e-bfbe-7576d93d2209,
  abstract     = {Background <br>
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. <br>
Methods <br>
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. <br>
<br>
Results <br>
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&lt;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.<br>
<br>
Conclusions <br>
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.},
  author       = {HAU, SOFIE and Larsson, Anna H and Nodin, Björn and Jirström, Karin},
  language     = {eng},
  month        = {05},
  title        = {Prognostic value of HER3 and HER2 alterations in colorectal cancer: Relationship with sidedness, KRAS and BRAF mutation status},
  year         = {2017},
}