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Vitamin D after breast cancer diagnosis - May 2012

How important is Vitamin D before and after breast cancer diagnosis?

From Food For Breast Cancer - unknown date: sometime before May 2012

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Vitamin D regulates the flow of calcium into the bloodstream and is crucial for normal bone development. Vitamin D also has a role in regulating parathyroid, neuromuscular, immune, and insulin functions. Vitamin D has been found to be associated with lower risks of cardiovascular disease and age-related cognitive impairment, as well as Hodgkin’s and non-Hodgkin’s lymphoma and esophageal, lung, pancreatic, renal, colorectal, endometrial, prostate and ovarian cancer.

Vitamin D binds to the vitamin D receptor

Vitamin D influences breast cancer development and progression in important ways, but the relationship is not fully understood. Vitamin D influences the expression of breast cancer-related gene activity, including cell differentiation, cell growth, and angiogenesis, all of which are related to cancer development and progression. Vitamin D binds to the vitamin D receptor (VDR). The impact of vitamin D on breast cancer is influenced by VDR genotype; women can have one of several variants in the VDR gene and these gene polymorphisms influence the potential anticarcinogenic effects of vitamin D. The effect of vitamin D on breast cancer risk is also modified by the level of calcium consumed since various combinations of calcium and vitamin D can have differing effects on cellular proliferation and differentiation. One study found that certain VDR genotypes are associated with lower risk of breast cancer in women consuming high levels of calcium. In addition, vitamin D has been shown to inhibit the growth of tamoxifen-resistant breast cancer cells in the laboratory, possibly through a VDR-related mechanism. However, there is also some preliminary evidence that vitamin D supplementation could reduce the effectiveness of aromatase inhibitors in reducing circulating estrogen.

Measuring vitamin D intake is not straightforward

Intake of vitamin D can be difficult to assess since the vitamin is produced in the skin as well as being a component of some foods. The level of vitamin D in the blood is not necessarily proportionate to the levels in other tissues such as the breast. In addition, it appears that vitamin D may be more influential in protecting against breast cancer when consumed early in life. For these and others reasons, not all population studies have found an association between vitamin D intake or plasma vitamin D and breast cancer.

Forms of vitamin D

Generally speaking, "Vitamin D" refers to a set of fat-soluble prosteroids and their metabolites. Vitamin D3 (cholecalciferol) is the form most useful to human beings. Vitamin D3 is made in the skin when skin is exposed to sunlight (when the UV index is at least 3). Although some vitamin D supplements contain Vitamin D2 (ergocalciferol), it makes more sense to take Vitamin D3 since Vitamin D2 is not produced by vertebrates. Whether obtained from sun exposure to the skin, food, or supplements, vitamin D must undergo chemical reactions to become calcitriol (1,25-Dihydroxycholecalciferol) to be useable in the body. The blood test for vitamin D measures the level of 25-hydroxyvitamin D (25(OH)D, 25-OH-D or 25-OHD), which is the primary metabolic product of vitamin D3 in the blood. In this web page, by "vitamin D," we mean vitamin D3 and its metabolites unless otherwise stated.

Vitamin D and risk of breast cancer diagnosis

Numerous studies have examined the association between vitamin D and risk of breast cancer. Most, but not all, have found that low levels of vitamin D increase risk of breast cancer whereas higher levels are protective:

A Japanese study found a reduced risk of breast cancer among women with the highest quartile of vitamin D intake, however this inverse association was confined to premenopausal women.
A 2011 meta-analysis of 11 case-control studies reported that a serum 25(OH)D level of 47 ng/ml was associated with a 50% lower risk of breast cancer. A 2009 meta-analysis of 36 studies also concluded that there was a significant inverse relationship between vitamin D intake and risk of breast cancer. In addition, the study reported a significant decrease in risk of breast cancer for those with the highest calcium consumption.

A large Swedish prospective study found no significant relationship between risk of breast cancer and sun exposure variables, including annual number of sunburns, skin sun sensitivity, time spent on sunbathing vacations, or solarium use at any age of exposure. There was also no association found between breast cancer incidence and dietary vitamin D intake or supplementary multivitamin use.

A Canadian case-control study found that while vitamin D intake was most strongly associated with lower risk of hormone receptor positive (ER+/PR+) breast cancer, it also appeared to be associated with lower risks of hormone receptor negative (ER-/PR-) and mixed receptor status (ER+/PR-) tumors.
A U.S. study reported that breast cancer patients with suboptimal levels (under 32 ng/mL) of vitamin D were three times more likely to develop triple negative (ER-/PR-/HER2-) breast cancer than patients with optimal levels. In other words, low vitamin D appears to increase the aggressiveness of breast cancer that develops.
An Italian study found that risk of breast cancer was significantly lower for women in the top three tenths of vitamin D intake than those in the bottom three tenths. In fact, no protection was found for vitamin D up to the seventh decile of intake. The inverse association between high intake of vitamin D and breast cancer was consistent regardless of menopausal status.

A Chinese case-control study reported that breast cancer patients were more likely to be severely vitamin D deficient than cancer-free women. A significant dose-response was found, with women in the highest quintile of vitamin D having the lowest risk of breast cancer and those in the lowest quintile having the highest risk.
A study of women with at least one first-degree or second-degree relative with breast or ovarian cancer found that breast density was inversely associated with vitamin D intake. High breast density has been found to be associated with increased risk of breast cancer.

A Canadian case-control study found that increasing sun exposure during ages 10 to 19 was associated with lower subsequent risk of breast cancer. Reduced risk was also found for cod liver oil consumption and increasing milk intake.

Vitamin D during breast cancer treatment

Levels of vitamin D normally drop during chemotherapy. Vitamin D supplementation during chemotherapy can raise circulating vitamin D levels, but it is not known whether this would enhance or interfere with its treatment effects. The long-term impact of taking vitamin D during treatment on prognosis are not clear:

Over two-thirds of breast cancer patients in one study were found to be vitamin D deficient. Generally speaking, deficiency was higher in non-Caucasian patients and patients with later-stage disease. High-dose vitamin D supplementation (at least 50,000 IU weekly) resulted in a greater increase in plasma vitamin D (+28 ng/mL; p<0.01) than low-dose vitamin D (+7 ng/mL; p=0.03) or no supplementation (+2 ng/mL). The authors concluded that conventional low-dose vitamin D was not effective.

In a laboratory study, vitamin D3 was found to increase breast cancer cell death caused by radiation treatment from approximately 30% to 75%.
Vitamin D3 supplementation with 50,000 IU per week was found to be safe, to significantly increases vitamin D levels, and to reduce disability from aromatase inhibitor-induced joint pain in some women in a study of breast cancer patients starting letrozole (Femara).
However, preliminary results of a study presented at the 2011 American Society of Clinical Oncology Meeting indicate that vitamin D supplementation during aromatase inhibitor treatment could reduce the treatment's effectiveness.

A large Norwegian population study found significant variations in long-term prognosis by season of diagnosis of breast, colon and prostate cancer. The lowest risks of cancer death were associated with diagnoses that had been made during the summer and fall, the seasons with the highest levels of vitamin D3. The authors concluded that a relatively high level of vitamin D3 at the time of diagnosis, and therefore, during cancer treatment, may improve prognosis of the three cancer types studied.

A phase 2 trial of daily 10,000 IU vitamin D supplementation in women with bone metastases found that the vitamin D did not influence bone resorption or reduce pain overall. However, a reduction in the number of pain sites was observed and the treatment reduced elevated parathyroid hormone levels, which presumably had been caused by long-term bisphosphonate use.
Vitamin D and risk of breast cancer recurrence or metastasis

Does a vitamin D deficiency at diagnosis predict recurrence? Once a woman has been diagnosed with breast cancer, is there a benefit to increasing the level of circulating vitamin D? And does vitamin D supplementation after treatment affect long-term prognosis? Few studies have attempted to answer these questions:

A prospective study which used stored blood of breast cancer patients to measure Vitamin D levels found that women with deficient vitamin D levels had a significantly increased risk of distant recurrence and death compared with those with sufficient levels. The authors concluded that vitamin D deficiency may be associated with poor outcomes in breast cancer.

A German prospective study found that low levels of circulating vitamin D at diagnosis were associated with increased risk of recurrence during the first five years.
Still another prospective study found no association between circulating levels of vitamin D and risk of recurrence among breast cancer survivors overall. However, the same study found that dietary vitamin D intake was protective against recurrence among premenopausal women.

A study using a mouse model found that vitamin D deficiency increased the growth of bone metastases. The study examined the intraskeletal growth of the human breast cancer cells in nude mice. Mice weaned onto a vitamin D-free diet developed vitamin D deficiency associated with secondary hyperparathyroidism and accelerated bone turnover. Osteolytic lesions appeared earlier and were significantly larger in vitamin D-deficient mice than in vitamin D-sufficient mice.

How much vitamin D is optimal?

The optimal 25(OH)D level for breast cancer prevention appears to be at least 45 ng/mL (45 to 60 ng/mL may be an appropriate target range). How to achieve this level is less certain. Given that most women get little sun exposure and that there are few food sources of vitamin D, supplementation with vitamin D3 are necessary for most. This is especially true for dark-skinned women for whom vitamin D photosynthesis is less efficient and vitamin D insufficiency is very common.

Current recommendations of 1,000 units of vitamin D3 per day may not be enough to achieve a 25(OH)D level of 40 ng/mL and some experts believe that intakes of up to 4,000 IU per day are safe and appropriate. Some studies have used doses of as much as 50,000 IU/week, a dosage that appears not to result in vitamin D toxicity (which manifests as high levels of calcium in the blood, as well as bone and kidney problems) in the short term. However, evidence to date suggests that the toxicity threshold is between 10,000 and 40,000 IU of vitamin D per day for long-term use. Note that the risk that massive vitamin D supplementation could actually promote breast cancer has not been investigated.

A large case-control study found that, compared to participants with vitamin D deficiency (defined as 25-OHD levels below 20 ng/mL), women with levels above 40 ng/mL had a lower risk of breast cancer. The reduction in risk was greater among postmenopausal women but did not vary according to tumor hormone receptor status. The authors concluded that whereas circulating 25-OHD levels of 32 ng/mL or higher have been found to be associated with normal bone mineral metabolism, the optimal level for breast cancer prevention is 40 ng/mL.

A prospective study including 34,321 postmenopausal women in the Iowa Women’s Health Study cohort found that women who consumed at least 800 IU of vitamin D per day in total (from food and supplements) had a lower risk of breast cancer than those who consumed less than 400 IU/day. Relative risks were stronger among women with negative estrogen receptor (ER-) or negative progesterone (PR-) tumors.

A Norwegian prospective study reported that vitamin D levels under 46 nmol/L at diagnosis were associated with reduced survival for cancers of the breast, colon, and lung, as well as lymphoma.
One 2011 study reported that individuals with 25(OH)D levels above 100 ng/mL are at increased risk for atrial fibrillation (a type of irregular heartbeat).
Sources of vitamin D

In addition to exposing the skin to sunlight, the following foods and supplements are sources of vitamin D while also having been found to protect against breast cancer:

Salmon, wild
Vitamin D3 supplements
Vitamin D appears to act synergistically with calcium in the diet to oppose breast cancer.
  Adequate (but not excessive) levels of calcium are required to maximize the beneficial effects of vitamin D.

Bottom line

Low levels of vitamin D are associated with higher risk of breast cancer. Adequate vitamin D levels at diagnosis and after treatment might improve long-term survival. Please partner with your oncologist or primary physician to have your vitamin D level tested and develop a plan to increase the level, if indicated.

Tags: angiogenesis, aromataseInhibitors, boneHealth, breastDensity, calcium, cellDifferentiation, eggs, endometrialCancer, ER+/PR-, Femara, fishOil, foodsArticles, herring, hormoneReceptorNegative, hyperparathyroidism, Japanese, letrozole, mackerel, metastasis, milk, mushrooms, ovarianCancer, salmon, sardines, sunExposure, supplements, tamoxifen, thyroid, tripleNegative, vitaminD

Increased prevalence of vitamin D insufficiency in patients with breast cancer after neoadjuvant chemotherapy
Vitamin D deficiency increases breast cancer risk: A population based case-control study in the Chinese population
Vitamin D threshold to prevent aromatase inhibitor-related bone loss: the B-ABLE prospective cohort study
The Association Between Breast Cancer Prognostic Indicators and Serum 25-OH Vitamin D Levels
20-Hydroxyvitamin D3 Inhibits Proliferation of Cancer Cells with High Efficacy while Being Non-toxic
Dose Response to Vitamin D Supplementation in Postmenopausal Women: A Randomized Trial
Serum levels of 25-hydroxyvitamin D and survival in Norwegian patients with cancer of breast, colon, lung, and lymphoma: a population-based study
Influence of Calcitriol on Prostaglandin- and Vitamin D-metabolising Enzymes in Benign and Malignant Breast Cell Lines
Tolerable Upper Intake Levels: Calcium and Vitamin D
Prospective association of vitamin D concentrations with mortality in postmenopausal women: results from the Women's Health Initiative (WHI)
Serum 25-Hydroxyvitamin D and Prevention of Breast Cancer: Pooled Analysis
Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial
An analysis of vitamin D (Vit D) and serum estrogens in postmenopausal (PM) breast cancer (BC) patients receiving aromatase inhibitors (AIs)
Vitamin D and Sterol Composition of 10 Types of Mushrooms from Retail Suppliers in the United States
Serum 25-hydroxyvitamin D and postmenopausal breast cancer survival: a prospective patient cohort study
Ultraviolet Sunlight Exposure During Adolescence and Adulthood and Breast Cancer Risk: A Population-based Case-Control Study Among Ontario Women
The Association between Prognostic Demographic and Tumor Characteristics of Breast Carcinomas with Serum 25-OH Vitamin D Levels
Vitamin D Supplement Doses and Serum 25-Hydroxyvitamin D in the Range Associated with Cancer Prevention
Vitamin D Deficiency is Correlated with Poor Outcomes in Patients with Luminal-type Breast Cancer
Vitamin D Deficiency in Post-Menopausal Breast Cancer Survivors
Vitamin D and breast cancer recurrence in the Women's Healthy Eating and Living (WHEL) Study
Serum 25(OH) Vitamin D and Risk of Breast Cancer: A Nested Case-Control Study from the French E3N Cohort
Radiosensitization of breast cancer cells by Vitamin D3 and Vitamin D analogs
Vitamin D Deficiency Promotes Human Breast Cancer Growth in a Murine Model of Bone Metastasis
A phase 2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D3 in breast cancer patients with bone metastases
Association between vitamin D and calcium intake and breast cancer risk according to menopausal status and receptor status in Japan
Meta-analysis of vitamin D, calcium and the prevention of breast cancer
The effect of high-dose vitamin D supplementation on 25-OH vitamin D levels in breast cancer patients during treatment
Prospective Study of Solar Exposure, Dietary Vitamin D Intake, and Risk of Breast Cancer among Middle-aged Women
Prognostic Effects of 25-Hydroxyvitamin D Levels in Early Breast Cancer
Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer
Association between Plasma 25-Hydroxyvitamin D and Breast Cancer Risk
High Prevalence of Vitamin D Deficiency Despite Supplementation in Premenopausal Women With Breast Cancer Undergoing Adjuvant Chemotherapy
Vitamin D From Dietary Intake and Sunlight Exposure and the Risk of Hormone-Receptor-Defined Breast Cancer
Vitamin D intake and breast cancer risk: a case-control study in Italy
Dietary intake and breast density in high-risk women: a cross-sectional study
Vitamin D intake and breast cancer risk in postmenopausal women: the Iowa Women’s Health Study
Vitamin D and Reduced Risk of Breast Cancer: A Population-Based Case-Control Study
Vitamin D3 from sunlight may improve the prognosis of breast-, colon- and prostate cancer
Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety

See also VitaminDWiki

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