06/14/2025
In the search for better breast cancer outcomes, one of the most exciting breakthroughs isn’t a cutting-edge drug—it’s a familiar, affordable supplement: vitamin D. Known for supporting bone health, vitamin D is now gaining recognition for something far more surprising—its potential to significantly enhance the effect of chemotherapy, especially in women with estrogen receptor–negative (ER-negative) tumors.
Two newly published 2025 studies—one from Brazil and another from Turkey—add to growing evidence that higher blood levels of vitamin D may meaningfully increase the odds of completely eliminating the cancer before surgery, a treatment milestone known as a pathologic complete response (pCR).
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ER-Negative Tumors: More Responsive to Chemotherapy
ER-negative tumors, which do not respond to hormone-blocking therapies, are often more aggressive—but also more responsive to chemotherapy. As a result, achieving a pCR is especially important in this group. Studies consistently show that patients who reach pCR have much better long-term survival and lower recurrence rates.
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New Brazilian Study: A Daily Dose with Big Impact
In a randomized controlled trial from São Paulo State University, 80 women undergoing neoadjuvant chemotherapy were randomized to receive either 2,000 IU of vitamin D daily or a placebo for six months.
📍Pathologic complete response occurred in 43% of women receiving vitamin D versus 24% in the placebo group.
📍Women with vitamin D levels over 20 ng/mL had a 73% greater chance of achieving a pCR than those with lower levels.
📍Those with vitamin D above 30 ng/mL had an over 88% greater chance of pCR.
📍ER-negative patients had a more than 83% greater likelihood of achieving a pCR compared to ER-positive patients.
Both vitamin D sufficiency and ER-negative status remained independently associated with better outcomes—even when other tumor characteristics were controlled.
https://www.tandfonline.com/doi/full/10.1080/01635581.2025.2480854
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Turkish Study Confirms: High-Dose Weekly Vitamin D Also Helps
In a separate trial conducted in Istanbul, 227 women undergoing the same type of pre-surgical chemotherapy were randomized to either receive no supplement or 50,000 IU of vitamin D weekly.
📌The group receiving vitamin D had a more than 100% increase in the likelihood of achieving a pCR (in other words, their odds were more than double).
📌Again, ER-negative tumors responded more robustly, and vitamin D’s effect remained statistically significant after adjusting for other variables.
https://onlinelibrary.wiley.com/doi/10.1002/wjs.12587
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🔬 Scientific Explanation
Mechanism of Action: Why Vitamin D May Be More Effective in ER-Negative Breast Cancer
Vitamin D exerts its biological activity through the vitamin D receptor (VDR), a nuclear hormone receptor that regulates the transcription of genes involved in key cellular processes, including cell proliferation, differentiation, apoptosis, immune surveillance, and inflammatory modulation.
In estrogen receptor–positive (ER+) breast cancer, tumor growth is primarily driven by estrogen signaling through ERα, which controls many of these same pathways. However, in ER-negative (ER–) tumors—especially triple-negative breast cancer (TNBC)—this hormonal axis is absent. As a result, tumor progression becomes more reliant on non-hormonal signaling pathways, potentially making them more susceptible to modulation via vitamin D–VDR signaling.
Within this context, vitamin D may assume a compensatory regulatory role by influencing several cancer-relevant mechanisms:
—Inhibition of cyclin D1 and c-MYC → leading to cell cycle arrest at the G1/S checkpoint
—Promotion of apoptosis → by increasing pro-apoptotic gene expression (e.g., BAX) and suppressing anti-apoptotic genes (e.g., BCL-2)
—Suppression of NF-κB signaling → reducing inflammation and pro-survival signaling within the tumor microenvironment
—Enhancement of antigen presentation and T cell recruitment → via upregulation of MHC class II molecules
—Inhibition of epithelial-to-mesenchymal transition (EMT) → which may reduce metastatic spread
ER– tumors are also known to have a more immunogenic microenvironment, with greater presence of tumor-infiltrating lymphocytes (TILs). Vitamin D has been shown to enhance immune cell activation and tumor recognition, thereby promoting immune-mediated tumor clearance.
Taken together, these effects suggest that vitamin D’s role in modulating cell death, immune response, and inflammation is particularly impactful in ER– breast cancer, where the absence of estrogen signaling leaves tumors more vulnerable to alternative control mechanisms—like those regulated by vitamin D.
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🧠 Non-Medical Explanation (In Plain English)
Vitamin D isn’t just important for bones—it also acts like a hormone and helps regulate how cells grow, repair, and interact with the immune system. It does this by attaching to a special receptor inside your cells called the vitamin D receptor (VDR). Once active, it can turn genes on or off, helping the body control things like inflammation, cell growth, and even when damaged cells should die.
In estrogen receptor–positive (ER+) breast cancer, tumors grow with the help of the hormone estrogen. These cancers can be treated with hormone-blocking drugs. But in ER-negative breast cancer, that estrogen pathway doesn’t exist—so doctors rely more on chemotherapy. This also means other growth signals in the cancer become more important—and that’s where vitamin D may step in.
Here’s what vitamin D may do in ER-negative breast cancer:
—Helps stop cancer cells from multiplying
—Encourages damaged or dangerous cells to die (instead of keep dividing)
—Lowers inflammation, which cancer uses to survive and grow
—Makes cancer more visible to the immune system, helping immune cells attack
—Prevents cancer cells from spreading to other parts of the body
Also, ER-negative cancers—especially triple-negative ones—tend to have more immune cells nearby, which means vitamin D might be even more helpful in boosting the immune attack against the tumor.
In short, because ER-negative cancers don’t use estrogen to grow, they’re more vulnerable to other types of control—and vitamin D may be especially good at taking advantage of that weakness, making chemotherapy more effective and possibly improving outcomes.
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Is 20 ng/mL Enough? Probably Not
While many guidelines define vitamin D “sufficiency” as 20 ng/mL, the breast cancer research community increasingly supports 30 ng/mL as the minimum for therapeutic benefit.
The São Paulo study demonstrated a dramatic increase in pCR for women above the 30 ng/mL threshold—more than 88% improvement over lower levels. Other observational data support the idea that risks of recurrence and death continue to decline with higher vitamin D concentrations, at least until around 40–60 ng/mL.
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Safe, Affordable, and Underused
Vitamin D is widely available, extremely low-cost, and well-tolerated at standard dosages. In the studies above:
—The daily dose (2,000 IU) used in Brazil is within safe long-term limits.
—The weekly dose (50,000 IU) used in Turkey is a common short-term correction for deficiency.
Unlike targeted drugs that may cost tens of thousands of dollars and come with intense side effects, vitamin D is low-risk and easy to integrate into treatment plans.
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What Patients Should Do
If you’re receiving neoadjuvant chemotherapy—especially if you have ER-negative or triple-negative breast cancer—it’s worth having a conversation with your oncology team about vitamin D.
—Ask to have your serum 25-hydroxyvitamin D level checked.
—If it’s below 30 ng/mL, discuss whether supplementation might help.
—Avoid high doses without medical supervision, but daily or weekly regimens are safe and may boost your chances of full response.
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A Smarter, Simpler Path Forward
Personalized medicine isn’t always about high-tech genetics or cutting-edge biologics. Sometimes, it’s about identifying simple, evidence-based interventions that can shift the odds. Vitamin D appears to be one of those interventions—especially for women with ER-negative tumors, who already tend to respond better to chemotherapy and may see that response amplified by ensuring their vitamin D levels are optimized.
As larger trials get underway, vitamin D supplementation may soon be more than an optional wellness step—it could become a standard, science-backed component of breast cancer treatment.
