A Retrospective Interventional Study Examining Whether Successful Replacement Therapy After a Confirmed Vitamin D Deficiency Correlates with Improved Disease-Free Survival in the Curative Intent Treatment of HER2+ Breast Cancer

BACKGROUND: Vitamin D is a secosteroid that exerts immunomodulatory and anti-proliferative effects through the vitamin D receptor (VDR). Because HER2-targeted therapies substantially improve prognosis in HER2-positive breast cancer and introduces a new mechanism of immunotherapy, we hypothesized that successful correction of vitamin D deficiency would be associated with improved disease-free survival (DFS) in patients treated with curative intent. METHODS: We performed a retrospective interventional cohort study of patients with early-stage HER2-positive breast cancer treated at Cancer Treatment Centers of America Midwestern Regional Medical Center from 2008 to 2014. Eligible patients had baseline vitamin D deficiency (25-hydroxyvitamin D or D25 < 30 ng/mL), received trastuzumab-based therapy, and had ≥12 months follow-up. Patients received vitamin D3 supplementation (typically 2000-10,000 IU/day) with doses adjusted based on D25 level follow-up. Responders were defined as having achieved a mean D25 ≥ 30 ng/mL during the first year; non-responders remained <30 ng/mL DFS was analyzed using Kaplan-Meier and Cox models. RESULTS: Of 196 patients, 129 (65.8%) were vitamin D-deficient at baseline. Among these, 76 (60.3%) achieved repletion while 50 (39.7%) remained deficient. Three did not have D25 follow-up obtained. Thirty-one DFS events occurred but no deaths. Responders demonstrated numerically improved outcomes (3-year DFS 90% vs. 85%). Non-responders had a 1.7-fold higher hazard of recurrence, and those who achieved the highest D25 levels (>50 ng/mL) had the most favorable DFS trends, suggesting a dose response. CONCLUSIONS: Failure to correct a vitamin D deficiency was associated with a 1.7-fold higher recurrence risk, although the relationship did not achieve statistical significance. A similar effect size was reported in another retrospective cohort of HER2-positive breast cancer that did achieve statistical significance, and a doubling of pCR rates was seen in two recently completed RCTs in 2025, with benefits particularly seen in the triple-negative and HER2-positive subtypes. Prospective trials evaluating optimized vitamin D repletion in HER2-positive breast cancer are warranted.