SERUM 1,25-DIHYDROXYVITAMIN-D MAY BE RELATED INVERSELY TO DISEASE-ACTIVITY IN BREAST-CANCER PATIENTS WITH BONE METASTASES

1,25-dihydroxyvitamin D (1,25-(OH)(2)D) stimulates differentiation and controls proliferation in breast cancer cells. The role of endogenous 1,25-(OH)(2)D and its relation to PTH related protein (PTHrP) during the progression of breast cancer is not known; we therefore investigat ed these hormones in two studies. In a cross-sectional study of patien ts with breast cancer at different stages of disease, serum 1,25-(OH)( 2)D levels (mean +/- SE) were highest in early disease (102 +/- 3.7 pm ol/L), fell in normocalemic patients with bone metastases (52 +/- 5.3 pmol/L; P < 0.01), and were lowest in hypercalcemic patients (33 +/- 5 .6 pmol/L; P < 0.001). PTHrP was detectable in the serum of only one n ormocalcemic patient with progressive metastases but was present in 11 of the 12 hypercalcemic patients, thus PTHrP did not stimulate 1,25-( OH)(2)D synthesis.In a 6-month longitudinal study of normocalcemic pat ients with bone metastases undergoing hormonal therapy, serum 1,25-(OH )(2)D concentrations fell in patients whose disease progressed (P = 0. 0056), but remained constant in those who were stable or responded to treatment. These changes in 1,25-(OH)(2)D preceded clinical signs of p rogression and predicted disease response. In the progressive group fi ve of whom died during the study, 1,25-(OH)(2)D decreased between the initial and final samples, PTH fell significantly from 24.8 to 13.5 ng /L (P = 0.025), serum calcium rose from 2.27 to 2.39 mmol/L (P = 0.017 ), and the urinary calcium/creatinine ratio rose from 0.37 to 0.68 (P = 0.046). PTH and 1,25-(OH)(2)D were significantly correlated in the f inal samples from this group, Spearman's rank correlation = 0.80, P = 0.022. The results indicate that normocalcemia in these patients is ma intained, at the expense of suppressing PTH and 1,25-(OH)(2)D, in the face of increased calcium released from lytic lesions in bone. Loss of the antiproliferative effects of 1,25-(OH)(2)D may then permit more r apid secondary growth of the tumor.