There was no association between one-carbon metabolism related nutrients and disease free survival of breast cancer overall, while some effects were observed when stratifying by breast cancer subtypes. To the best of our knowledge, this study is the first to systematically investigate the association between the combined effects of prediagnostic intake of nutrients related to the one-carbon metabolism pathway and the clinicopathological characteristics of breast cancer.
In our study, the range for the intake of vitamin B2, B6 and folate were 0.1-3.4 mg, 0.1-4.8 mg and 9–970 mg, respectively. These levels of vitamin B6 and folate were less than the tolerable upper intake level of Dietary Reference Intakes for Koreans (KDRIs). The tolerable upper intake of vitamin B2 level was not determinable by the KDRIs. In the KDRIs, the tolerable upper intake level of vitamin B6 and folate were 100 mg and 1000 mg. The levels of dietary intake of vitamin B2, B6, and folate in breast cancer patients were hardly reported. Even though there were many previous studies on the association between vitamin B2, B6 and folate and breast cancer risk, they reported the tertiles or quartile levels in both the cases and the controls. Thus, it is hard to compare the nutrients intake level of patients’ with other studies that used different designs.
In observational studies, the results for the relationship between micronutrient intakes and all-cause mortality were inconsistent among breast cancer patients
. Only one study investigated one-carbon metabolism related nutrients intake and all-cause of mortality in women with breast cancer, and showed null results for vitamin B2, B6 and folate
. Few studies have investigated the association between folate intake and breast cancer survival. McEligot et al. studied 516 postmenopausal women diagnosed with breast cancer for 6.6 years (median follow-up) and showed that women in the highest tertile for dietary folate intake had an HR of 0.34 (95% CI, 0.18-0.67) regarding all-cause mortality
. In addition, in the Swedish mammography cohort, dietary folate intake was inversely associated with overall mortality (HR = 0.79; 95% CI, 0.66-0.96)
. However, in the Iowa Women’s Health Study, Sellers et al. reported that among 177 breast cancer patients, folate intake had no association with breast cancer prognosis
. Moreover, in the Nurses’ Health Study, Holmes et al. provided additional support for no association of breast cancer prognosis with vitamin B2, B6 and folate
. In addition, Rossi et al. measured the folate levels in plasma from 1024 breast cancer patients in Australia and reported that plasma folate was not significantly associated with breast cancer survival
. No other prior studies have reported the relationship between one-carbon metabolism related factors and their combined intake effects on the prognosis of breast cancer. The lack of consensus in the results of previous studies could be explained by the variation in study methodologies, micronutrient source, and total micronutrient level. Thus, it is difficult to determine how the micronutrient intake distribution reported in one study compares to other studies
We observed that the combined intake effects of vitamin B2, B6, and folate were associated with breast cancer progression in patients depending on their ER/PR status. No previous studies examining the combined intake effects of one-carbon metabolism related nutrients intake and hormone specific breast cancer have been identified. In the Swedish Mammography Cohort (SMC), only folate intake, which is one of the one-carbon metabolism related nutrients studies, was assessed for association with breast cancer progression
. Although Harris et al. have reported that dietary folate intake has shown protective effects on breast cancer-specific mortality in ER-negative tumors, our results do not support this effect. It is difficult directly compare our study’s results to theirs since the distribution of the hormone receptors in the study subjects was different (ER-negative breast cancer, less than 20% in SMC; 39.2% in the present study). For breast cancer risk, few studies have evaluated the relationship between hormone status and folate intake. A higher folate intake was associated with a lower risk of ER-negative breast cancer in the Nurses’ Health Study
, and in the VITamins And Lifestyle (VITAL) cohort
. In SMC, a high folate intake was related to a decreased risk of ER+/PR– breast cancer
. Otherwise, few cohort studies have reported largely null results, with no findings for associations between folate intake and ER+, ER–, PR + or PR– breast cancers
[26, 27, 29, 30]. From various laboratory studies, their results were inconsistent with our study, which examined whether DNA methylation of the ER CpG island may play a role in suppressing ER gene expression in ER-negative breast cancer cells
[31, 32]. A greater supply of methyl through a high intake of one-carbon metabolism related nutrients may induce the suppression of gene expression in patients with ER–/PR– breast cancers. In addition, a high intake of one-carbon metabolism related nutrients may have a stronger effect on ER–/PR– breast cancer progression than the other types of breast cancers since ER–/PR– breast cancers are less responsive to hormone therapies. Further studies are needed to elucidate the possible association between one-carbon metabolism related nutrients and the hormone receptors in breast cancer patients.
The results of our study were contrary to the hypothesis based on previous studies that a higher intake of B vitamins would have a protective effect on breast cancer survival in population based studies. One prospective cohort study suggested the association of major energy sources with breast cancer survival may be U-shaped rather than linear
. As far as this idea, the association has not yet been proven; however, a midrange intake of vitamins is associated with the most favorable outcomes, and extremes are associated with less favorable outcomes.
This study has some limitations. First, there were likely errors in our estimate of dietary habits. Patients were asked about their dietary intake for the year preceding the diagnosis using the FFQ. Due to this, measurement errors likely occurred because of poor recall despite the validity and reproducibility evidence of the questionnaire. The FFQ correlations were lower than that reported in western countries which were between 0.5-0.7
. In Asia, the median of the correlation coefficients for the FFQ has ranged from 0.3-0.5 in Japan
[35, 36] and Korea
[37, 38], and a lower FFQ correlation may have been caused by the dining etiquette and cultural foods of Korea
. Though the correlation coefficients were low, to date, FFQ is the only method in which long-term usual dietary intake of an individual can be easily obtained with a single measurement
. Second, intake of supplements was not available for the calculations. However, the intake of supplements use can improve the dietary quality for certain micronutrients
. Lastly, we could not evaluate the association between one-carbon metabolism related nutrients and breast cancer specific mortality because the data for the cause of death were not available. Thus, the results must be interpreted cautiously and need to be confirmed by a study that investigates the association of one-carbon metabolism related nutrients with breast cancer specific survival.
Nevertheless, our study has strengths. It is the first study to evaluate the association between the combined intake effects of vitamin B2, B6 and folate and hormone specific breast cancer survival.