Tamoxifen response in primary breast cancer with special reference to tumour-specific VEGF-A and VEGFR2

Sammanfattning: Background: Treatment of primary breast cancer is individualised and adjuvant systemic treatment is delivered to most patients after surgery. Oestrogen receptor (ER) status and progesterone receptor status (PR) can define patients who would benefit from adjuvant endocrine therapy with tamoxifen (TAM) alone or as chemo-endocrine therapy. In spite of adjuvant treatment with TAM, some patients with hormone-responsive tumours relapse and eventually die from recurrent disease and new predictive markers are therefore continously being assessed . Purpose: To relate response to adjuvant TAM to established predictive markers (hormone receptor status) and investigational predictive markers such as HER2 status, HER2 gene amplification, vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2). Furthermore, microvessel density (MVD) and VEGF-A in core biopsy specimens were assessed. Patients: Two randomised trials of two years of adjuvant TAM versus no adjuvant treatments containing postmenopausal patients (n=251) and premenopausal patients (n=564) with long-term follow-up were included. Additionally, 102 non-randomised patients were included in a feasibility study of the investigational markersand 54 consecutive patients were analysed, assessing the accuracy in core biopsy specimens. Methods: In the premenopausal trial, hormone receptor status was determined prospectively by cytosol-based methods and retrospectively by immunohistochemistry (IHC)in a tissue microarray (TMA). In the postmenopausal trial, hormone receptor status was determined by IHC in TMA. Investigational predictive markers were evaluated in TMA by IHC including HER2 status, VEGF-A and VEGFR2 and by FISH for HER2 gene amplification.HER2 status and HER2 amplification were restricted to premenopausal patients. Microvessel density and VEGF-A by IHC were evaluated in pairs of whole tumour sections and core biopsy specimens. Results: Two years of adjuvant TAM significantly increased reccurence-free survival (RFS) in all subgroups of premenopausal patients with hormone receptor positive tumours (Paper II). Progesterone receptor status was superior to ER as a predictive marker in this group of patients. The beneficial effect of two years of adjuvant TAM was extended to patients at high risk of recurrence (Paper II). Expression of VEGF-A and HER2 status in tumour cells and HER2 amplification were not significant predictors of response to adjuvant TAM in premenopausal patients with hormone receptor positive tumours, whereas tumour-cell specific expression of VEGFR2 was a significant predictor of response (Paper IV). In postmenopausal node-positive patients with ER positive disease adjuvant TAM increased both disease-free (DFS) and overall survival (OS) (Paper III). Tumour-cell specific expression of VEGF-A and VEGFR2 were predictors of response to adjuvant TAM in ER positive disease (Paper III). Angiogenic markers assessed in core biopsy specimens had in general low accuracy (Paper V). Conclusion: Two years of adjuvant TAM increases RFS in premenopausal patients with hormone-responsive tumours and the beneficial effect is extended to patients at high risk of recurrence. Progesterone receptor is a strong predictive marker for response to adjuvant TAM in premenopausal patients and tumour-cell specific VEGFR2 is a predicitve marker in addition to hormone receptor status. For postmenopausal patients tumour-cell specific VEGF-A and VEGFR2 were predictors of response to adjuvant TAM in ER positive disease.