HER3 expression and prognosis in colon and rectal cancer

Abstract

In Sweden, about 6000 patients get a colorectal cancer diagnosis annually. Advances in management of both colon and rectal cancer have reduced mortality even though the incidences are increasing. To improve outcome further, it is important to identify prognostic and predictive factors for personalized, optimal surgery and to guide adjuvant treatment decisions. By selecting the right therapy combined with selection of the right patients, one can obtain individualization. Potential drug targets prevalent in primary tumors and metastases are of interest as well. HER3 is a transmembranous, epidermal growth factor receptor that is over expressed in colon and rectal cancer. It affects cellular proliferation, differentiation and migration in embryogenesis and in oncogenesis through activation of intracellular signal pathways.

This thesis investigates HER expression and prognosis in colon and rectal cancer, as well as in correlated lymph node and liver metastases. HER3´s association to a combination of biomarkers, MMR expression and HLA-A*02 genotype, is examined related to prognosis.

Two cohorts of patients have been available for our investigation. Immunohistochemical (IHC) detection of HER3 and MMR expression was performed in a group of Swedish patients with primary colon and rectal cancer of stage II and III. The patients derived from a randomized Nordic trial aiming to evaluate additive effect of adjuvant chemotherapy to surgery. HER3 expression was also detected by IHC in a different group of patients, resected for both colorectal cancer (CRC) and corresponding liver metastases. FISH analysis was done to examine if gene amplification occurred associated to HER3 expression and HLA-A*02 genotype was assessed by PCR.

In the initial study of patients with primary CRC of stage II and III, a high HER3 expression was seen in 70% of tumors and in 75% of lymph node metastases. Tumor and lymph node metastases correlated according to HER3 expression. HER3 did turn out to be an independent prognostic factor and high expression was associated to decreased survival. FISH analysis of CRC tumors did not show gene amplification with respect to HER3 expression.

A high expression of HER3 was seen in about 80% of primary CRC as well as in corresponding lymph node and liver metastases. There was a correlation between HER3 expression in primary tumor and metastases.

In the third study, high HER3 expression in colon cancer was associated to distal colon location and low-grade tumor. In distal colon cancer, high HER3 expression was of negative prognostic value according to disease free survival (DFS).

The results in our last study indicate that a combined analysis of HER3, MMR expression and HLA-A*02 genotype can have a prognostic value and can, to some extent, predict response to adjuvant 5-fluorouracil (5-FU) based chemotherapy in subgroups of primary colon cancer.

A single molecular biomarker or a combination of markers may play a relevant prognostic and predictive role though CRC is a complex and heterogeneous disease. Subtyping of CRC based on molecular, clinical and morphological features includes biomarkers and is difficult however, necessary when planning optimal treatment for each individual patient.