How does vitamin D status at diagnosis influence outcomes in metastatic versus early‑stage breast cancer?
Executive summary
At diagnosis, low circulating vitamin D (25[OH]D) is repeatedly associated with more advanced stage, higher-grade tumors and worse survival in cohorts of early-stage breast cancer patients, though randomized trials have not confirmed causation and results are mixed [1] [2]. For metastatic disease the evidence is sparser but preclinical work shows loss of vitamin D receptor (VDR) signaling promotes metastasis and observational studies report lower 25(OH)D in advanced or metastatic cases, suggesting vitamin D status may correlate with — and potentially influence — metastatic biology and treatment response, but causality remains unproven [3] [4] [5].
1. Early-stage signal: consistent observational links but not proof of benefit
Multiple observational cohorts and meta-analyses report that lower 25(OH)D measured around diagnosis correlates with worse distant disease‑free survival and overall survival in women with early-stage breast cancer, including a large study showing deficient levels (<20 ng/mL) predicted roughly doubled risk of distant recurrence and worse overall survival on multivariate analysis [1] [6]. Systematic reviews and meta-analyses identify an inverse association between vitamin D and several adverse prognostic features (tumor size, lymph node positivity, higher grade), yet the literature is heterogeneous and investigators caution that these associations do not prove that correcting vitamin D will change outcomes [4] [7] [2].
2. Biological plausibility: VDR, calcitriol and anti‑metastatic mechanisms
Mechanistic and preclinical data give biological plausibility for an effect: vitamin D is converted to the active hormone calcitriol in breast tissue, binds VDR and regulates genes controlling differentiation, proliferation, apoptosis, angiogenesis and metastatic behavior; in animal and cell models loss of VDR or vitamin D deficiency increased metastatic spread and markers of epithelial‑to‑mesenchymal transition (EMT) [3] [7] [8]. Experiments showed tumors with low VDR expression metastasized to liver in mice while tumors with normal VDR did not, and vitamin D deficiency sped tumor growth in other mouse models — mechanistic signals that low vitamin D/VDR signaling can enable metastatic phenotypes [3] [8].
3. Metastatic disease: correlation, emerging clinical signals, and big unknowns
Clinical data specifically in metastatic breast cancer are limited but consistent with a pattern: studies report lower 25(OH)D levels in locally advanced or metastatic disease versus early-stage cases and one hospital cohort linked low baseline vitamin D to higher risk of bone metastases [4] [9]. Translational work indicates an “autophagic transcriptional signature” tied to VDR activation is progressively lost in metastatic models, implying metastatic cells may be less susceptible to vitamin D’s effects [5]. Recent clinical hypotheses propose that suboptimal vitamin D might blunt efficacy of modern targeted therapies (e.g., CDK4/6 inhibitors) in HR‑positive metastatic disease, but that remains to be tested in prospective trials [10].
4. Trials, supplementation and the gap between association and intervention
Randomized trials of vitamin D supplementation for cancer outcomes are sparse and inconclusive: while supplementation prevents fractures and is widely used by breast cancer survivors, trials have not produced compelling evidence that vitamin D replacement changes recurrence or survival, and most authors call for well‑designed randomized studies stratified by stage and molecular subtype [2] [11]. Observational associations could reflect reverse causation (sicker or more advanced patients have lower vitamin D because of illness, less sun exposure, or other confounders) or unmeasured factors, so supplementation cannot yet be presented as a proven oncologic therapy [2] [11].
5. Practical interpretation and the research agenda ahead
Taken together, the balance of epidemiology and laboratory science supports the claim that low vitamin D at diagnosis is a marker of worse prognosis in early-stage breast cancer and correlates with metastatic disease, and mechanisms exist that could make vitamin D biologically relevant to metastasis and possibly to response to therapies; however, causation is unproven and randomized interventional data are lacking, particularly in metastatic settings [1] [3] [2]. The field needs prospective trials that (a) test whether normalization of 25(OH)D alters recurrence or progression by stage and subtype, (b) probe interactions with specific therapies (for example CDK4/6 inhibitors in HR+ MBC), and (c) incorporate tumor VDR expression and mechanistic biomarkers to distinguish marker from mediator [10] [3] [7].