Successful Replacement Therapy After a Confirmed Vitamin D Deficiency Correlates with Improved DFS in the Curative Intent Treatment of HER2+ Breast Cancer

Background. Vitamin D has recognized immunomodulatory, anti-proliferative, and differentiation-regulating effects primarily mediated through its genomic effects via the vitamin D receptor (VDR). Observational studies have suggested associations between vitamin D deficiency and more aggressive breast cancer phenotypes, including estrogen receptor–negative disease and higher-grade tumors. Recent randomized trials have also reported improved pathological complete response (pCR) rates with vitamin D supplementation during neoadjuvant chemotherapy, although these studies included heterogeneous breast cancer subtypes and greater effects were mostly seen in the ER- subtypes. Because HER2-targeted therapies have dramatically improved outcomes in HER2-positive breast cancer, it was hypothesized that successful correction of vitamin D deficiency would be associated with improved disease-free survival (DFS) in patients with early-stage HER2-positive breast cancer treated with curative-intent therapy. Methods. We conducted a retrospective cohort study of patients with HER2-positive breast cancer treated at Cancer Treatment Centers of America Midwestern Regional Medical Center between 2008 and 2014. Eligible patients had early-stage HER2-positive disease, received trastuzumab-based therapy with curative intent (± pertuzumab), continued follow-up at the institution for at least 12 months, and had baseline vitamin D deficiency defined as serum 25-hydroxyvitamin D (D25) < 30 ng/mL. Vitamin D levels were routinely measured at baseline and serially during treatment as part of institutional standard practice. Patients received vitamin D3 supplementation, typically ranging from 2,000–10,000 IU/day, with dose adjustments guided by follow-up D25 levels. Patients were classified as responders if their mean D25 level during the first year of follow-up reached ≥30 ng/mL and non-responders if levels remained < 30 ng/mL. Responders were further stratified into low (30–40 ng/mL), medium (40–50 ng/mL), and high (>50 ng/mL) categories to explore potential dose-response relationships. The primary endpoint was disease-free survival (DFS), defined as time from initiation of neoadjuvant therapy or surgery to recurrence, metastasis, or death. Kaplan–Meier methods and Cox proportional hazards models were used to evaluate associations between vitamin D response and DFS while adjusting for relevant clinical covariates. Results. Among 196 eligible patients, 129 (65.8%) were vitamin D deficient at baseline. Of these, 76 (60.3%) achieved adequate vitamin D repletion and were classified as responders, while 50 (39.7%) remained deficient. Over the follow-up period, 31 DFS events (15.8%) occurred. The mean DFS for the cohort was 10.2 years (95% CI 9.58–10.83), and the estimated 3-year DFS rate was 88%. Responders demonstrated numerically improved outcomes compared with non-responders, with 3-year DFS rates of 90% versus 85%, respectively. Kaplan–Meier curves suggested a potential dose-response relationship, with progressively improved DFS among patients achieving higher mean D25 levels, particularly those exceeding 50 ng/mL. In Cox regression analyses, vitamin D non-responders demonstrated a 1.7-fold higher hazard of recurrence compared with responders, although this did not reach statistical significance. Conclusions. In this retrospective cohort of patients with HER2-positive breast cancer, failure to correct baseline vitamin D deficiency was associated with a numerically higher risk of disease recurrence. The observed separation of Kaplan–Meier curves across increasing vitamin D levels suggests a possible dose-response relationship supporting a biologically meaningful effect. Although the study is limited by retrospective design and modest sample size, the findings are consistent with emerging randomized trial data suggesting improved treatment responses with vitamin D supplementation. Prospective studies specifically targeting correction of vitamin D deficiency in HER2-positive breast cancer are warranted to determine whether optimized vitamin D status can improve oncologic outcomes.