Clinical and prognostic significance of parathyroid hormone-related protein in breast cancer: a systematic review and meta-analyses of observational studies in women

Parathyroid hormone-related protein (PTHrP) is produced by normal breast epithelial cells and is a cause of hypercalcemia in breast and other cancers. However, there are conflicting data regarding its role(s) in breast cancer biology. This study aimed to clarify PTHrP's potential function(s) in breast cancer by systematically examining its association with tumor characteristics, patient outcomes and hypercalcemia in women. We designed a predetermined strategy based on PRISMA 2020 guidelines. Seven databases were interrogated to identify studies of women with breast cancer reporting associations between tumor or circulating PTHrP levels and prognostic factors, calcium levels, relapse and survival. The ROBINS-E tool was used to examine the risk of bias. Quantitative syntheses of outcomes were performed by drawing forest plots of individual studies and pooling estimates. Forty-five studies met our eligibility criteria. We found that PTHrP is likely associated with positive progesterone receptor status, the presence of microcalcifications and lymph node invasion, but not with tumor type or grade. Most studies interrogating the association between PTHrP expression and breast cancer prognosis or hypercalcemia were at a very high risk of bias. Despite this, our results suggest associations between PTHrP and patient survival, the presence of bone metastases and the diagnosis of hypercalcemia of malignancy. These meta-analyses underscore the need for robust multivariate analyses in women to rigorously re-evaluate the role of PTHrP in breast cancer. This is important since the gene coding for PTHrP (PTHLH) has been consistently identified as a breast cancer susceptibility locus.