Abstract P6-11-07: Quantitative p95HER2 levels in primary breast cancers and in matched brain metastases

Abstract

Abstract Background: Patients with HER2-positive breast cancer are at high risk for brain metastases. A large number of HER2-positive tumors also express p95HER2 (p95), a truncated form of HER2 that lacks the trastuzumab binding site but retains kinase activity. Although p95 expression in primary breast tumors is well studied, the prevalence and significance of p95 expression in brain metastases is unknown. In the current study we examined expression of p95 in brain metastases and in matched primary breast tumors. Methods: Seventy-five pairs of formalin-fixed paraffin-embedded samples from matched primary breast cancers and brain metastases were assayed for quantitative p95 protein expression using the p95 VeraTag® assay (Clin Cancer Res, 16:4226, 2010) specific for the M611 form of p95. Sufficient material to obtain p95 data in both primary and matched brain metastasis samples was available in 52 cases. In the remaining 23 cases, a p95 measurement was obtained in either the primary or brain metastasis sample. Estrogen (ER) and progesterone (PR) receptor status were scored using immunohistochemistry. Hormone receptor positivity was defined as either ER or PR positive. Quantitative HER2 protein expression was measured using the HERmark® assay. Both the p95 VeraTag assay and the HERmark assay measure tumor-averaged protein expression in units of relative fluorescence per mm2 tumor (RF/mm2). Measurements of p95 > 2.8 RF/mm2 and HER2 > 17.8 RF/mm2 were considered as positive results. Results: There was a net increase in p95 expression in brain metastases relative to the matched primary tumor with a median increase of 1.5-fold (p = 0.001, range 0.2-fold to 35-fold). The increase in p95 expression was only weakly correlated with the increase in quantitative HER2 expression (R2 = 0.18; p = 0.0018). Cases with HERmark-positive tumors were more likely to have the largest (≥ 5-fold) increase in p95 expression compared to those with lower HER2 expression (odds ratio = 6.3; p = 0.018). Changes in p95 levels from primary to brain metastasis were unrelated to hormone receptor status (p = 0.59). P95 positivity in the primary tumor correlated with time from breast cancer diagnosis to first progression (HR = 2.2; p = 0.012) when stratified by hormone receptor status and tumor grade. Although there was a trend towards correlation of p95 positivity in the brain metastasis with time from diagnosis to brain metastasis (HR = 1.7; p = 0.058, stratified as above), p95 positivity did not correlate with overall survival from the time of brain metastasis diagnosis (HR = 1.3; p = 0.42, stratified as above). Conclusions: This is the first study of quantitative p95 expression in matched primary tumors and brain metastases. Brain metastases of breast cancer show significant increases in p95 protein expression compared to matched primary tumors. These data provide a rationale for future correlative studies on p95 levels in brain metastases. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-07.