Biological factors with additional treatment predictive value for adjuvant endocrine therapy: receptor tyrosine kinases (c-erbB-2/HER2 and vascular endothelial growth factor receptor 2 (VEGFR2), VEGF and p38 phosphorylated MAP kinase (p38MAPK)
Department of Oncology, Cancer Center Karolinska, Radiumhemmet, Stockholm, Sweden
Background: Expression of estrogen- (ER) and progesterone receptors (PgR) are predictive factors for high efficacy by endocrine therapy. Preclinical data have suggested a cross-talk between c-erbB-2 a receptor tyrosine kinase (RTK) and the MAP kinase pathway, resulting in lost efficacy by tamoxifen. VEGF binds to another RTK, the VEGF receptor 2 (VEGFR2). Whether a cross-talk exist between VEGFR2 and the MAP kinase pathway, is at present unknown. Aims: To investigate the possible additional predictive value of c-erbB-2/HER2, VEGF and VEGFR2 (KDR) in 404 patients subjected to adjuvant endocrine therapy, including 295 patients with a ER and PgR positive breast cancer. To investigate the additional predictive value of p38MAPK in receptor-positive patients with a high expression of VEGF or VEGFR2 or overexpressing c-erbB-2. Methods: Levels of c-erbB-2, VEGF, VEGFR2 and p38 MAPK in primary breast tumors were determined by enzyme-linked immuno-sorbent assays (ELISA´s). The ELISA for p38 MAPK used a detection antibody specific for p38 MAPK phosphorylated at threonine 180 and 182. Results: A wide range of VEGF and VEGFR2 expression was found; the median levels were 2,8 and 0.7 pg/µg DNA respectively and were used as cut-off levels. Overexpression of c-erbB-2 was found in 15% and detectable levels of p38 MAPK were found in 35% of the patients and classified as positive. Overexpression of c-erbB-2, higher expression of VEGF or VEGFR2 were all significantly correlated with shorter relapse-free (RFS) and breast cancer corrected survival (BCCS) both in all patients and in the ER/PgR positive group. In multivariate analyses, factors retaining independent prognostic factors in patients with an ER and PgR positive breast cancer were for RFS: nodal status (p<0.001) and VEGF (p=0.010), for DDFS: nodal status (p<0.001) and VEGF (p=0.024) for BCCS nodal status (p<0.001), and VEGFR2 (p=0.004). Patients with a high expression of VEGF or VEGFR2 with a detectable p38 MAPK had a statistically significantly worse survival compared with patients with high VEGF/VEGFR2 without detectable p38 MAPK (p=0.0154) and (p=0.0467) respectively. A similar correlation was seen regarding c-erbB-2, with no events in patients overexpressing c-erbB-2 without detectable p38 MAPK, compared with 19% in c-erbB-2 positive breast cancers with detectable p38 MAPK. In part due to the small number of patients and events this did not reach statistical significance (p=0.3286). Conclusions: A co-expression of VEGF and the major functional receptor VEGFR2 was found. High expression of VEGF, VEGFR2 or over-expression of c-erbB-2 were statistically significantly correlated with shorter survival-times in ER/PgR positive breast cancer patients treated with adjuvant tamoxifen suggesting an additional predictive value to steroid receptors. Patients with high VEGF/VEGFR2 or with overexpression of c-erbB-2, without detectable levels of p38 MAPK were significantly associated with longer survival times.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 997 (Chemoprevention).