Tamoxifen response in primary breast cancer with special reference to tumour-specific VEGF-A and VEGFR2
Research output: Thesis › Doctoral Thesis (compilation)
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.
|Research areas and keywords||
Subject classification (UKÄ) – MANDATORY
|Award date||2004 Nov 19|
|Publication status||Published - 2004|
Defence details Date: 2004-11-19 Time: 10:00 Place: Stora föreläsningssalen, Patologen ing 78 Malmö Universitetssjukhus. External reviewer(s) Name: Bergh, Jonas Title: Professor Affiliation: Radiumhemmet, Stockholm, Sweden --- Article: I. Lisa Rydén, Barbro Linderholm, Nils-Hilmer Nielsen, Stefan Emdin, Per-Ebbe Jönsson and Göran Landberg. Tumor specific VEGF-A and VEGFR2/KDR protein are co-expressed in breast cancer. Breast Cancer Res Treat 2003, 82(3), 147-154 Article: II. Lisa Rydén, Per-Ebbe Jönsson, Gunilla Chebil, Mårten Fernö, Monika Dufmats, Göran Landberg, Ann-Christin Källström, 0lle Stål, Sten Thorstenson and Bo Nordenskjöld on behalf of South Sweden Breast Cancer Group and South-East Sweden Breast Cancer Group. Two years of adjuvant tamoxifen in premenopausal patients with breast cancer: report from a controlled, randomised trial with long-term follow-up. Eur J Cancer 2004, in press Article: III. Lisa Rydén, Maria Stendahl, Stefan Emdin, Nils-Olof Bengtsson and Göran Landberg. Tumor specific VEGF-A and VEGFR2 in postmenopausal breast cancer patients with long-term follow-up. Implication of a link between VEGF-A pathway and tamoxifen response. Breast Cancer Res Treat 2004, in press Article: IV. Lisa Rydén, Karin Jirström, Pär-Ola Bendahl, Per-Ebbe Jönsson, Mårten Fernö, Bo Nordenskjöld, Olle Stål, Sten Thorstenson and Göran Landberg. Tumor specific expression of VEGFR2 is associated with impaired tamoxifen response in premenopausal breast cancer. Submitted manuscript, 2004 Article: V. Lisa Rydén, Poul Boiesen and Per-Ebbe Jönsson. Assessment of microvessel density in core biopsy specimen in breast cancer. Anticancer Res 2004, 24, 371-376.