Abstract
BackgroundReceptor activator of nuclear factor kappa-B (RANK)-signaling is involved in tumor growth and spread in experimental models. Binding of RANK ligand (RANKL) to RANK activates signaling, which is inhibited by osteoprotegerin (OPG). We have previously shown that circulating soluble RANKL (sRANKL) and OPG are associated with breast cancer risk. Here we extend these findings to provide the first data on pre-diagnosis concentrations of sRANKL and OPG and risk of breast cancer-specific and overall mortality after a breast cancer diagnosis.MethodsTwo thousand six pre- and postmenopausal women with incident invasive breast cancer (1620 (81%) with ER+ disease) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were followed-up for mortality. Pre-diagnosis concentrations of sRANKL and OPG were quantified in baseline serum samples using an enzyme-linked immunosorbent assay and electrochemiluminescent assay, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer-specific and overall mortality were calculated using Cox proportional hazards regression models.ResultsEspecially in women with ER+ disease, higher circulating OPG concentrations were associated with higher risk of breast cancer-specific (quintile 5 vs 1 HR 1.77 [CI 1.03, 3.04]; ptrend 0.10) and overall mortality (q5 vs 1 HR 1.39 [CI 0.94, 2.05]; ptrend 0.02). sRANKL and the sRANKL/OPG ratio were not associated with mortality following a breast cancer diagnosis.ConclusionsHigh pre-diagnosis endogenous concentrations of OPG, the decoy receptor for RANKL, were associated with increased risk of death after a breast cancer diagnosis, especially in those with ER+ disease. These results need to be confirmed in well-characterized patient cohorts.
Highlights
Receptor activator of nuclear factor kappa-B (RANK)-signaling is involved in tumor growth and spread in experimental models
The majority (86%) of cases had at least one full term pregnancy, with a median age at first full term pregnancy of 25 (16.0, 44.0) years. soluble RANKL (sRANKL) and OPG concentrations were measured in blood samples collected a median of 4.7 (0.02, 11.7) years before breast cancer diagnosis
A total of 421 deaths, including 250 breast cancer deaths, occurred over 21,253 person years of follow-up (Table 1). Compared to those diagnosed with estrogen receptor (ER)- breast cancer, those diagnosed with ER+ disease where slightly older at blood collection and diagnosis, more likely to have progesterone receptor (PR)+ disease, and had a longer survival time
Summary
Receptor activator of nuclear factor kappa-B (RANK)-signaling is involved in tumor growth and spread in experimental models. We have previously shown that circulating soluble RANKL (sRANKL) and OPG are associated with breast cancer risk. We extend these findings to provide the first data on pre-diagnosis concentrations of sRANKL and OPG and risk of breast cancer-specific and overall mortality after a breast cancer diagnosis. The RANK-axis consists of three tumor necrosis superfamily (TNF) members; receptor activator of nuclear factor kappa-B (RANK), its ligand (RANKL), and osteoprotegerin (OPG). There has been increasing interest in the RANK-axis with respect to breast cancer risk and prognosis given the availability of a RANKL inhibitor, denosumab, which has been shown to reduce skeletal-related events in breast cancer patients with bone metastases [7] and may improve disease-free survival in postmenopausal breast cancer patients with ER and progesterone receptor (PR) positive disease [8]. Given the results reported to date, we hypothesized (1) higher sRANKL and lower OPG would be associated with higher risk of breast cancer-associated death among women with ER+ breast cancer; and, (2) a positive association between OPG and risk of breast cancer-associated death among women with ER- disease
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