PTHrP, A biomarker for CNS metastasis in triple-negative breast cancer and selection for adjuvant chemotherapy in node-negative disease

Abstract

Background: Triple-negative breast cancer (TNBC) is characterized by poor prognosis and lack of targeted therapies and biomarkers to guide decisions on adjuvant chemotherapy. Parathyroid hormone-related protein (PTHrP) is frequently overex-pressed in breast cancer and involved in proliferation and metastasis, two hallmarks of poor prognosis for node-negative breast cancer. We investigated the prognostic value of PTHrP with respect to organ-specific metastasis and nodal status in TNBC. Methods: We assessed PTHrP expression using immunohistochemistry in a clinically annotated tissue microarray for a population-based study of 314 patients newly diagnosed with TNBC, then analyzed its correlation to progression and survival using Kaplan-Meier and Cox regression analyses. The Cancer Genome Atlas (TCGA) validation analysis was performed through Bioconductor. All statistical tests were two-sided. Results: PTHrP overexpression (160 of 290 scorable cases, 55.2%) was statistically significantly associated in univariate analysis with decreased overall survival (OS) in our cohort (P =.0055) and The Cancer Genome Atlas (P =.0018) and decreased central nervous system (CNS)-progression-free survival (P =.0029). In multivariate analysis, PTHrP was a statistically significant independent prognostic factor for CNS-progression-free survival in TNBC (hazard ratio [HR] = 5.014, 95% confidence interval [CI] = 1.421 to 17.692, P =.0122) and for OS selectively in node-negative TNBC (HR = 2.423, 95% CI = 1.129 to 5.197, P =.0231). Strikingly, PTHrP emerged as the only statistically significant prognostic factor (HR = 2.576, 95% CI = 1.019 to 6.513, P =.0456) for OS of low-clinical risk node-negative patients who did not receive adjuvant chemotherapy. Conclusions: PTHrP is a novel independent prognostic factor for CNS metastasis and adjuvant chemotherapy selection of low-clinical risk node-negative TNBC. Its predictive value needs to be prospectively assessed in clinical trials.