In a prospective study of 526 consecutive patients with operable
breast cancer, the significance of positive
parathyroid hormone-related protein (
PTHrP) staining by immunohistology has been evaluated for a median of 10-year follow-up. Improved survival was observed for the 79% of
tumors which stained positively for
PTHrP [estimated univariate hazard ratio, 0.43; 95% confidence interval (95% CI), 0.30-0.62; P < 0.001]. Adjustments for N stage,
progesterone receptor status, and log
tumor size changed this estimate only slightly to 0.47 (95% CI, 0.63-0.69; P = 0.001). Patients with
PTHrP-positive primary
tumors were less likely to develop bone
metastases (hazard ratio, 0.63; 95% CI, 0.41-0.98; P = 0.04).
PTHrP status was associated with
estrogen receptor (P = 0.01),
progesterone receptor (P = 0.03), and menopausal status (P = 0.006) but was not significantly associated with
tumor size, vascular invasion,
tumor grade, or patient age. Of 19 patients requiring surgery for bone
metastases, the primary
cancers were
PTHrP negative in seven, all but one of whom had
PTHrP-positive bone
metastases. All 12 patients with
PTHrP-positive primary
cancers also had positive bone
metastases. We conclude that increased production of
PTHrP by breast
cancers confers on them a less invasive phenotype, an effect distinct from the
bone resorption-stimulating action that favors bone
metastasis. It is likely that the latter property is influenced by factors in the bone microenvironment.