In this cohort of 585 breast cancer survivors, serum 25(OH)D was associated with reduced overall mortality. Compared to women with lowest values of 25(OH)D (<20 ng/mL), those with “sufficient” 25(OH)D values (≥ 30 ng/mL) had a 42% reduced risk of overall mortality in age-adjusted models which were attenuated and lost statistical significance with adjustment for other potential confounders. These results, including the size of the HRs and the lack of statistical significance on adjustment for confounders, are comparable to reports from previously published studies of women diagnosed with breast cancer. In 2009, Goodwin et al
. reported that 512 non-Hispanic white women with the lowest serum 25(OH)D (<20 ng/mL) had a statistically non-significant 71% increased risk of overall mortality, compared to those with 25(OH)D concentrations ≥32 ng/mL [10
]. In a nested case-control study with 250 matched pairs, Jacobs et al
. reported a non-significant 13% increased odds of overall mortality in breast cancer survivors with 25(OH)D <20 ng/mL, compared to those with serum 25(OH)D >20 ng/mL [13
]. In a cohort of 1,295 postmenopausal women, Vieling et al
. (2011) reported with those with 25(OH)D <14 ng/mL had a 55% increased risk of overall mortality compared to those with 25(OH)D ≥22 ng/mL[15
]. Most recently (2012), in a Norwegian population-based study among 251 breast cancer patients, Tretli et al.
report women with 25(OH)D >33 ng/mL had a decreased risk of overall mortality, compared to women with 25(OH)D <18.4 ng/mL (HR=0.37; 95% CI 0.21 to 0.67) [14
We reported an age-adjusted non-significant 38% decreased risk of breast cancer-specific mortality between survivors with 25(OH)D >30 ng/mL compared to 25(OH)D <20 ng/mL. The magnitude of this association is similar to the results reported by both Goodwin [10
] and Tretli [14
], but these two studies only adjusted for age at diagnosis, tumor characteristics, and/or season of blood draw. Upon adjustment for potential confounders, including race-ethnicity/study site, we reported a non-statistically significant association between serum 25(OH)D and breast cancer-specific mortality. These results are somewhat similar to related results (i.e. disease-free survival) reported by Vrieling [15
] and Jacobs [13
]. The association between serum 25(OH)D and breast cancer-specific mortality was not specifically examined in the cohort of German postmenopausal women or the Women’s Healthy Eating and Living (WHEL) intervention study. However, Vrieling reported no association between serum 25(OH)D, measured after completing chemotherapy, and risk of distant disease (i.e., distant recurrence, death, second primary invasive non-breast cancer) for German women with serum 25(OH)D < 14 ng/mL, compared to those with serum 25(OH)D > 22 ng/mL. In a subset of the WHEL participants, serum 25(OH)D was assessed and examined with breast cancer recurrence or new breast cancer primary and women with 25(OH)D <20 ng/mL had a statistically non-significant increased odds of local recurrence (OR, 1.48; 95% CI 0.47, 4.65) and regional recurrence (OR,1.13; 95% CI 0.20, 6.44) compared to 25(OH)D >20 ng/mL [13
]. Our data, which reveals significant attenuation of the association in multivariate-adjusted model, may be in part due to confounding from race-ethnicity/study site variable.
Vitamin D may influence survival following a diagnosis of breast cancer via several mechanisms. The binding of 1,25(OH)2
D to the vitamin D receptor (VDR) results in the enhancement or suppression of gene transcription to modulate the inhibition of cell proliferation and angiogenesis, promotion of cell differentiation, and induction of apoptosis in both normal and malignant cells [1
]. In vitro
and in vivo
studies report direct effects on breast cancer cell lines, such as growth inhibition, cellular differentiation and apoptosis when both 25(OH)D and 1,25(OH)D are applied directly to MCF-7 cell lines. [32
] Additional data from animal models suggest that vitamin D deficiency may play an important role in cancer progression by promoting metastasis in bone, via vitamin D endocrine pathways [36
]. While it is not possible to test these specific mechanisms in humans, these data from in vitro
and animal model studies provide support for the associations observed here as well as elsewhere [10
The strengths of our study include the prospective design and participation by non-Hispanic White, non-Hispanic African-American and Hispanic women. We used well-annotated tumor-, treatment-, and traditional prognostic-related data to adjust for confounding and have approximately 10 years of mortality outcomes from annual SEER registry updates. We used a reliable biomarker for vitamin D status, serum concentration of 25(OH)D, which was measured after the completion of breast cancer treatment so that measures would not be confounded by concurrent exposure to chemotherapy or radiation treatments.
Limitations include the observational design, which limits the ability to infer cause and effect. While we adjusted our models for clinical and lifestyle-related covariates, as with all observational studies, residual confounding may still exist. Other limitations are that we were unable to adjust for completion of primary or hormone therapy, quantitative UV exposure or serum PTH concentration, the latter is directly linked with vitamin D metabolism and vitamin D activity [35
]. However, following adjustment for hours of outdoor physical activity (a surrogate variable for direct UV exposure), we observed no appreciable change in the HR for vitamin D status. We carefully considered examining the effect of serum 25(OH)D on disease recurrence. The pathological diagnosis to differentiate between recurrence and the new occurrence of a breast cancer is sometimes difficult [37
]. Rather than risk misclassification, we have chosen to report only data with clear outcomes, which is breast-cancer specific and total mortality. In addition, few breast cancer-specific deaths occurred in our cohort, resulting in limited power to examine breast cancer-specific mortality by vitamin D status or examine the effects of confounding or effect modification. Further, there is a possibility that the association of low serum 25(OH)D with high BMI, African-American and Hispanic race-ethnicity, less physical activity, and other known prognostic factors for breast cancer may explain the significant association observed in the unadjusted analysis. Finally, as with all observational studies there may be residual confounding.
In conclusion, in this multi-ethnic cohort of breast cancer survivors, higher vs. lower serum 25(OH)D suggest an association with improved overall survival, but results were not statistically significant and must be interpreted with caution. However, lacking clinical trial evidence, we cannot confirm that supplementation with vitamin D will improve survival, nor can we speculate on the dosage necessary to achieve optimal ranges in this population. We note that there is ongoing debate on these cut-off values with others suggesting lower cut-off levels for vitamin D deficiency (e.g. 12 ng/mL) or believe that levels of 20 ng/mL are sufficient [38
]. Of interest, the Institute of Medicine (2010) and the Endocrine Society (2011) recommend that in order to maintain bone health and normal calcium metabolism, normal weight healthy women aged 19–50 consume 600 IU/day of vitamin D3 and normal weight healthy women older than 50 years consume 800 IU/day [42
]. Additional research is needed to determine whether breast cancer patients should be screened for vitamin D deficiency and to determine the optimal practice guidelines for treatment.