Abstract
BackgroundTriple-negative breast cancer (TNBC) is a heterogeneous subgroup of breast cancer with poor prognosis and no targeted therapy available. Receptor tyrosine kinases (RTKs) are emerging targets in anticancer therapy and many RTK-inhibiting drugs are currently being developed. The aim of this study was to elucidate if there is a correlation between the protein expression of three RTKs c-KIT, VEGFR2 and PDGFRα, their gene copy number, and prognosis in TNBC compared to non-TNBC.MethodsTumor tissue samples from patients diagnosed with primary breast cancer were stained with immunohistochemistry (IHC) for protein assessment, and with fluorescence in situ hybridization (FISH) for gene copy number determination. Breast cancer mortality (BCM), measured from the date of surgery to death, was used as endpoint.ResultsThe cohort included 464 patients, out of which 34 (7.3%) had a TNBC. High expression of the three RTKs was more common in TNBC compared to non-TNBC: c-KIT 49% vs. 10% (P<0.001), PDGFRα 32% vs. 19% (P = 0.07) and VEGFR2 32% vs. 6% (P<0.001). The odds ratio (OR) of c-KIT, VEGFR2 and PDGFRα positivity, adjusted for tumor characteristics, was 6.8, 3.6 and 1.3 times higher for TNBC than for non-TNBC. 73.5% of the TNBC had high expression of at least one of the three investigated receptors, compared to 30.0% of the non-TNBC (P<0.001). Survival analysis showed no significant difference in BCM for TNBC patients with high vs. low c-KIT, PDGFRα or VEGFR2 protein expression. 193 (42%) tumors were evaluated with FISH. No correlation was seen between increased gene copy number and TNBC, or between increased gene copy number and high protein expression of the RTK.Conclusionc-KIT, VEGFR2 and PDGFRα show higher protein expression in TNBC compared to non-TNBC. Further investigation clarifying the importance of these RTKs in TNBC is encouraged, as they are possible targets for anticancer therapy.
Highlights
Breast cancer is a complex heterogeneous disease and it can be classified into several distinctive subgroups based on gene expression profiles [1,2,3]
Higher expression of c-KIT and vascular endothelial growth factor receptor-2 (VEGFR2) was found in Triple-negative breast cancer (TNBC) compared to nonTNBC tumors (P,0.001) and plateletderived growth factor receptor alpha (PDGFRa) showed the same tendency (P = 0.07)
TNBC is a subgroup of breast cancer with poor prognosis and no targeted therapy available
Summary
Breast cancer is a complex heterogeneous disease and it can be classified into several distinctive subgroups based on gene expression profiles [1,2,3] This classification gives important information about prognosis and cellular molecular aberrations that could serve as targets for novel medical therapy. Guidelines for classification in the clinical setting have been proposed by St Gallen and are based on IHC analysis of the estrogen receptor (ER), the progesterone receptor (PR) and Ki67, and ISH-analysis of the human epidermal growth factor receptor 2 (HER2) By these analyses breast cancers are classified as luminal A (ER+ and/or PR+, Ki67 low and HER22), luminal B HER22 (ER+ and/or PR+, Ki67 high and HER22), luminal B HER2+ (ER+ and/or PR+, any Ki67 and HER2+), HER2-type (ER2, PR2 and HER2+) and triplenegative (ER2, PR2 and HER22) [6]. The aim of this study was to elucidate if there is a correlation between the protein expression of three RTKs c-KIT, VEGFR2 and PDGFRa, their gene copy number, and prognosis in TNBC compared to non-TNBC
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