Association between serum Vitamin D levels and prognostic factors in nonmetastatic breast cancer patients
Mohammad Karim Shahrzad1, Reyhaneh Gharehgozlou2, Sara Fadaei3, Parastoo Hajian2, Hamid Reza Mirzaei2
1 Department of Internal Medicine and Endocrinology, Shohadae Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Department of Radiation Oncology, Cancer Research Center, Shohada Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
3 Shahid Beheshti University of Medical Sciences, Tehran, Iran
|Date of Submission||27-Oct-2021|
|Date of Decision||11-Dec-2021|
|Date of Acceptance||19-Jan-2022|
|Date of Web Publication||29-Jul-2022|
Dr. Hamid Reza Mirzaei
Department of Radiation Oncology, Cancer Research Center, Shohada Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran
Source of Support: None, Conflict of Interest: None
Background: Breast cancer is among the most common malignancies in women around the world. There is evidence of high prevalence of serum/blood Vitamin D deficiency in Iranian women. Considering the multitude of factors that may be involved in the prognosis and lifespan of breast cancer patients, this study investigated the level of Vitamin D in Iranian patients with nonmetastatic breast cancer. Materials and Methods: This cross-sectional study was carried out on 214 women diagnosed with breast cancer, who were referred to the radio-oncology department. Serum Vitamin D level of the patients was measured. Prognostic factors were determined based on demographic and pathological characteristics. The results were analyzed using descriptive statistics tests, Chi-square, one-way analysis of variance, Kaplan–Meier, and Cox regression model in SPSS v22. For all cases, the significance level was considered to be P < 0.05. Results: The total mean of 25-hydroxyvitamin D serum level was 25.15 ± 17.68 ng/ml. There was no significant relationship between levels of Vitamin D with disease stage, tumor size, tumor grade, estrogen receptor, progesterone receptor, and Human epidermal growth factor receptor 2 (P > 0.05). The mean survival time was 5 years and 45 days. Conclusion: No relationship was found between serum Vitamin D levels and the factors affecting the prognosis of nonmetastatic breast cancer. The Cox analysis showed that the survival time was not influenced by Vitamin D as a prognosis factor.
Keywords: Breast cancer, prognosis, Vitamin D
|How to cite this article:|
Shahrzad MK, Gharehgozlou R, Fadaei S, Hajian P, Mirzaei HR. Association between serum Vitamin D levels and prognostic factors in nonmetastatic breast cancer patients. J Res Med Sci 2022;27:56
|How to cite this URL:|
Shahrzad MK, Gharehgozlou R, Fadaei S, Hajian P, Mirzaei HR. Association between serum Vitamin D levels and prognostic factors in nonmetastatic breast cancer patients. J Res Med Sci [serial online] 2022 [cited 2022 Aug 18];27:56. Available from: https://www.jmsjournal.net/text.asp?2022/27/1/56/352947
| Introduction|| |
Breast cancer is one of the most common malignancies in women worldwide.,,, Although the reported incidence of this cancer is higher in developed countries, its mortality rate is higher in less developed countries.,,,, This cancer is one of the important causes of death in women. In recent years, there has been an increase in the incidence of breast cancer among Iranian women and it has become one of the main causes of death in this group.,, This cancer imposes great burdens on patients and their families as well as the healthcare system and the economy.,,
The Vitamin D receptor with ligand 1α, 25 (OH) 2D3 is involved in the moderation of the genome of epithelial cells., In recent studies on cancer, Vitamin D has been considered a factor of interest. Various studies suggest that Vitamin D receptors play a role in cell replication and differentiation. Hypervitaminosis D plays a role in the prognosis of some cancers. There exist some evidence showing a relationship between the level of Vitamin D and the risk of breast cancer.,, However, in another study, no relationship was found between Vitamin D and breast cancer. In addition, a correlation has been reported between the serum level of 25 (OH) D and breast cancer prognosis. Additional evidence suggests that Vitamin D deficiency is highly prevalent among Iranian women., Considering the multitude of factors that may be involved in the prognosis and lifespan of breast cancer patients, as well as the high prevalence of breast cancer in Iranian women, the relationship between Vitamin D and prognosis factors in this population was addressed herein, investigating the level of Vitamin D in Iranian patients with nonmetastatic breast cancer.
| Methods|| |
This cross-sectional study was conducted on 214 women diagnosed with breast cancer. Every eligible breast cancer patient who was referred to the radiology department between January 2013 and January 2017 entered the study. Vitamin D nonsupplemented patients were also included. Eligibility criteria included women with histologically confirmed primary, incident, breast cancer, with no prior cancer history except nonmelanoma skin cancer. A blood specimen taken with a mean of 30.1 days prior to surgery was used to determine the total 25-OH Vitamin D level (the sum of 25-OH Vitamin D2 and 25-OH Vitamin D3). Controls were selected between the ages of 40 and 70 who had their total 25-OH Vitamin D level. Inclusion criteria were: Consent, aged 18–75 years, diagnosis of nonmetastatic breast cancer, and no use of Vitamin D and complementary medications during the 6 months before breast surgery.
The data collection instruments were a demographic inventory, a breast cancer pathology information form, and laboratory investigation of Vitamin D levels. Patients at all serum Vitamin D levels received adjuvant therapy (chemotherapy, radiotherapy, and hormone therapy) as needed. A serum 25-hydroxyvitamin D concentration of <10 ng/ml was classified as deficiency, 10–30 ng/ml as insufficiency, 100–30 ng/ml as sufficiency, and >100 ng/ml was classified as toxic.
The results were analyzed using descriptive statistics, Chi-square test, one-way analysis of variance (ANOVA), Kaplan–Meier analysis (for univariate analysis), and Cox regression (for multivariate analysis) with the SPSS v. 22 software (IBM SPSS Statistics, Developed by IBM, Armonk, New York, USA). In all cases, the significance level was set at <0.05. This study was approved by the vice president for research at Shahid Behshti University of Medical Sciences (Ethical code: IR.SBMU.MSP.REC.1397.812).
| Results|| |
A total of 214 women with nonmetastatic breast cancer who were referred to the radiology department were studied. The mean age of participants was 52.02 ± 11.51 years, and 93.5% of them were married. The total mean of 25-hydroxyvitamin D serum level was 25.15 ± 17.68 ng/ml. The overall prevalence of deficiency is estimated at 24.8%. Among the rest of the patients, 87 cases (40.7%) had insufficiency and 74 (34.6%) had sufficiency. In 81.3% of cases (n = 174) invasive ductal pathology was confirmed. In 86% of patients (n = 184) the breasts were preserved. Demographic characteristics and prognosis factors are listed in [Table 1]. Of all cases with Vitamin D deficiency, 45.3% were observed in tumor sizes of T1 (2≥), 41.5% in T2 (2<−5), and 13.2% in T3 (5<) (P = 0.204). Furthermore, 9.4% of all the Vitamin D deficiency cases were in Grade I tumors, 50.9 in Grade II tumors, and 39.6 in Grade III tumors (P = 0.957). Among the patients, 83% of Vitamin D deficiency cases were in estrogen receptor (ER)-positive patients, and 17% were in ER-negative patients (P = 0.930). In addition, serum Vitamin D deficiency was noted 77.4% in subjects with positive progesterone receptor and 22.6% in subjects with negative progesterone receptor (P = 0.650). Finally, of all cases with serum Vitamin D deficiency, 20.8% had positive human epidermal growth factor receptor 2 (HER2) and 79.2% had negative HER2 (P = 0.874). Chi-square test showed no statistically significant relationship between Vitamin D level and the tumor size, grade, ER, progesterone receptor, or HER2 (P > 0.05). [Table 2] shows the breast-cancer-related information of patients based on their serum Vitamin D levels. The results of ANOVA showed no statistically significant relationship between the mean Vitamin D level and the stage of the disease (P > 0.05) [Table 3]. In the Kaplan–Meier analysis, the overall, 1-year, 2-year, 3-year, and 4-year survival rate of patients was found to be 100%, 99.5%, 98.8%, 97.5%, and 87.5%, respectively. Out of the 214 patients followed up for 4 years, 7 died. The mean survival time was 5 years and 45 days [Figure 1]. The 1-year, 2-year, and 3-year disease-free survival rate for these patients was 99%, 97.3%, and 94.2%, respectively. Of all the cases, only 9 underwent metastasis. The mean time of metastasis for these patients was 5 years and 22 days [Figure 2]. A multivariate analysis (tumor size, tumor grade, posterior nipple line, lymphovascular invasion, ER, progesterone receptors [PR], and HER2) and a Cox regression model were used to determine the factors influencing the survival time. But none of the variables were found to be significant in this model. In patients with positive lymph nodes, those with elevated serum Vitamin D level had 4.34 times higher mortality risk than those with lower Vitamin D levels. Among the patients with negative lymph nodes, those who had elevated serum Vitamin D levels had 0.971 times lower mortality risk than those with lower levels of Vitamin D, although this is not statistically significant. The Cox model was used to study the effect of serum Vitamin D in different levels of lymph node variables. No analysis was conducted for patients with less than three positive lymph nodes, as there was no mortality among them. In the patients who had more than three positive lymph nodes, the mortality risk of those with high serum Vitamin D levels was 1.581 times higher than those with low levels of serum Vitamin D, which is not statistically significant. [Figure 3] shows the survival curve for patients in relation to their serum Vitamin D levels.
|Table 3: Mean and standard deviation of serum Vitamin D in different stages of breast cancer|
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|Figure 3: Survival curve of patients in relation to their serum Vitamin D levels|
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| Discussion|| |
This study investigated the level of serum Vitamin D in Iranian women with nonmetastatic breast cancer. The results showed no relationship between Vitamin D level levels and the stage of the disease or the factors affecting the prognosis of nonmetastatic breast cancer patients.
Vitamin D suppresses the 17-beta-estradiol induced proliferation and regulation of ERs. It affects the estrogen function pathway at multiple stages as well as the ability of these receptors to act as transcriptional activators. Kim et al. showed in 310 Korean breast cancer patients before surgery that serum 25-hydroxyvitamin D concentrations did not significantly correlate with Her2/neu prognosis (P = 0.245). In another study in Korea, in breast cancer patients who received neoadjuvant chemotherapy, the serum levels of 25 (OH) D had no relationship with survival rates. In another study, this relationship was observed only in white women and not those of other races. These results are consistent with the findings of the present study. Herein, the mean serum 25-hydroxyvitamin D level was generally low, and even in the cases that were classified as normal, the serum levels were mostly in the lower half of the normal range. This may explain the insignificant relationship between serum Vitamin D level and the disease stage and the factors affecting the prognosis of nonmetastatic breast cancer patients.
Elsamany et al. showed that Vitamin D deficiency had a significant relationship with negative ER/PR phenotype and lymphatic system invasion. Ismail et al. also reported that Vitamin D deficiency had a significant positive relationship with the increase of tumor size, cancer stage, grade, positive status of lymph node, and HER2/neu expressions. In an analytical cross-sectional study conducted by De-Sousa-Almeida-Filho et al. in 192 Brazilian women, the relationship between Vitamin D deficiency before treatment and prognosis of breast cancer was assessed in postmenopausal women. The results showed a higher prevalence of deficient serum 25 hydroxyvitamin D levels in high-grade tumors, advanced diseases, and local metastasis (greater number of positive lymph nodes) compared to positive PR tumors and Ki-67 (P < 0.05). Janbabai et al. found that low levels of Vitamin D have a statistically significant relationship with advanced stages of breast cancer, especially in postmenopausal women. Another study also reported that the prognosis of breast cancer patients is correlated with blood 25-OH Vitamin D level. These results are not consistent with the findings of the present study. This inconsistency may be due to genetic differences or differences in sample size and study durations.
The results of several of these studies point to the potential role of Vitamin D in breast cancer, with altered Vitamin D signaling may lead to illness. On the other hand, Vitamin D has an anticancer effect that is partly related to sex hormones. The inconsistencies in the results of past studies with the causal relationship or the role of Vitamin D in the risk and prognosis of breast cancer highlight the need for further research in this area.
The limitations of this study included a small sample size and the lack of control for all confounding factors that may affect survival. Therefore, further studies with larger sample size and longer follow-up period on the relation of blood/serum Vitamin D levels with factors affecting the survival and prognosis of breast cancer are warranted.
| Conclusion|| |
No relationship was found between serum Vitamin D levels and factors affecting the prognosis of nonmetastatic breast cancer. Cox analysis showed that the survival time was not influenced by serum Vitamin D as a prognosis factor. This relationship should be assessed more accurately in a randomized prospective study with a large sample size.
The authors appreciate the cooperation and assistance of the officials of Shohadaye Tajrish Educational Hospital. We are greatly thankful for participate and Dr. Khayamzadeh.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Akbari ME, Mirzaei HR, Soori H. year survival of breast cancer in Shohada-e-Tajrish and Jorjani hospitals. Hakim 2006;9:39-44.
Ortiz-Mendoza CM. Impaired fasting glucose in breast cancer survivors of a general hospital at Mexico City: A case series study. J Res Med Sci 2019;24:9.
] [Full text]
Krishnamoorthy Y, Rajaa S, Giriyappa DK, Bharathi A, Velmurugan B, Ganesh K. Worldwide trends in breast cancer incidence from 1993 to 2012: Age-period-cohort analysis and joinpoint regression. J Res Med Sci 2020;25:98. [Full text]
Ahmed S, Mirzaei H, Aschner M, Khan A, Al-Harrasi A, Khan H. Marine peptides in breast cancer: Therapeutic and mechanistic understanding. Biomed Pharmacother 2021;142:112038.
Ghoncheh M, Pournamdar Z, Salehiniya H. Incidence and mortality and epidemiology of breast cancer in the world. Asian Pac J Cancer Prev 2016;17:43-6.
Jafarzadeh A, Paknahad MH, Nemati M, Jafarzadeh S, Mahjoubin-Tehran M, Rajabi A, et al.
Dysregulated expression and functions of microRNA-330 in cancers: A potential therapeutic target. Biomed Pharmacother 2022;146:112600.
Mostafaei S, Vahidi Manesh P, Sadri Nahand J, Nesaei A, Sorayyayi S, Abasabadi F, et al.
The role of Epstein-Barr virus-expressed genes in breast cancer development. Breast J 2020;26:2323-6.
Shahrzad MK, Gharehgozlou R, Fadaei S, Hajian P, Mirzaei HR. Vitamin D and Non-coding RNAs: New insights into the regulation of breast cancer. Curr Mol Med 2021;21:194-210.
Jafari SH, Saadatpour Z, Salmaninejad A, Momeni F, Mokhtari M, Nahand JS, et al.
Breast cancer diagnosis: Imaging techniques and biochemical markers. J Cell Physiol 2018;233:5200-13.
Haq A, Sofi NY. Vitamin D and breast cancer: Indian perspective. Clin Nutr Exp 2017;12:1-10.
Rafiemanesh H, Salehiniya H, Lotfi Z. Breast cancer in Iranian woman: Incidence by age group, morphology and trends. Asian Pac J Cancer Prev 2016;17:1393-7.
Akbari ME, Sayad S, Sayad S, Khayamzadeh M, Shojaee L, Shormeji Z, et al.
Breast cancer status in Iran: Statistical analysis of 3010 cases between 1998 and 2014. Int J Breast Cancer 2017;2017:2481021.
Shamshirian A, Heydari K, Shams Z, Aref AR, Shamshirian D, Tamtaji OR, et al.
Breast cancer risk factors in Iran: A systematic review & meta-analysis. Horm Mol Biol Clin Investig 2020;41. [doi: 10.1515/hmbci-2020-0021].
Ginsburg O, Bray F, Coleman MP, Vanderpuye V, Eniu A, Kotha SR, et al.
The global burden of women's cancers: A grand challenge in global health. Lancet 2017;389:847-60.
Mirzaei H, Mostafaei D, Estebsari F, Sattarzadeh M, Estebsari K. The quality of life of breast cancer patients receiving palliative and supportive care. Iran J Rehabil Res 2017;3:19-26.
Ebadi P, Bahari F, Mirzaei HR. The effectiveness of reality therapy on the hope of breast cancer patients. ijbd 2013;6:26-34.
Narvaez CJ, Matthews D, LaPorta E, Simmons KM, Beaudin S, Welsh J. The impact of vitamin D in breast cancer: Genomics, pathways, metabolism. Front Physiol 2014;5:213.
Rashidi B, Hoseini Z, Sahebkar A, Mirzaei H. Anti-atherosclerotic effects of vitamins D and E in suppression of atherogenesis. J Cell Physiol 2017;232:2968-76.
Imtiaz S, Siddiqui N, Raza SA, Loya A, Muhammad A. Vitamin D deficiency in newly diagnosed breast cancer patients. Indian J Endocrinol Metab 2012;16:409-13.
Bouillon R, Moody T, Sporn M, Barrett JC, Norman AW. NIH deltanoids meeting on Vitamin D and cancer. Conclusion and strategic options. J Steroid Biochem Mol Biol 2005;97:3-5.
Buttigliero C, Monagheddu C, Petroni P, Saini A, Dogliotti L, Ciccone G, et al.
Prognostic role of vitamin d status and efficacy of vitamin D supplementation in cancer patients: A systematic review. Oncologist 2011;16:1215-27.
Wu Y, Sarkissyan M, Clayton S, Chlebowski R, Vadgama JV. Association of vitamin D3 level with breast cancer risk and prognosis in African-American and hispanic women. Cancers (Basel) 2017;9:144.
Atoum M, Alzoughool F. Vitamin D and breast cancer: Latest evidence and future steps. Breast Cancer (Auckl) 2017;11:1178223417749816.
Shaukat N, Jaleel F, Moosa FA, Qureshi NA. Association between Vitamin D deficiency and Breast Cancer. Pak J Med Sci 2017;33:645-9.
Mohr SB, Gorham ED, Alcaraz JE, Kane CI, Macera CA, Parsons JK, et al.
Serum 25-hydroxyvitamin D and breast cancer in the military: A case-control study utilizing pre-diagnostic serum. Cancer Causes Control 2013;24:495-504.
Kermani IA, Kojidi HT, Gharamaleki JV, Sanaat Z, Ziaei JE, Esfahani A, et al.
Association of serum level of 25 hydroxy-vitamin D with prognostic factors for breast cancer. Asian Pac J Cancer Prev 2011;12:1381-4.
Tabrizi R, Moosazadeh M, Akbari M, Dabbaghmanesh MH, Mohamadkhani M, Asemi Z, et al
. High prevalence of vitamin D deficiency among Iranian population: A systematic review and meta-analysis. Iran J Med Sci 2018;43:125-39.
Alipour S, Saberi A, Seifollahi A, Shirzad N, Hosseini L. Risk factors and prevalence of vitamin d deficiency among Iranian women attending two university hospitals. Iran Red Crescent Med J 2014;16:e15461.
Rosen CJ. Clinical practice. Vitamin D insufficiency. N Engl J Med 2011;364:248-54.
Colston KW, Hansen CM. Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer. Endocr Relat Cancer 2002;9:45-59.
Kim HJ, Lee YM, Ko BS, Lee JW, Yu JH, Son BH, et al.
Vitamin D deficiency is correlated with poor outcomes in patients with luminal-type breast cancer. Ann Surg Oncol 2011;18:1830-6.
Kim JS, Haule CC, Kim JH, Lim SM, Yoon KH, Kim JY, et al.
Association between changes in serum 25-hydroxyvitamin D levels and survival in patients with breast cancer receiving neoadjuvant chemotherapy. J Breast Cancer 2018;21:134-41.
Kim Y, Franke AA, Shvetsov YB, Wilkens LR, Cooney RV, Lurie G, et al.
Plasma 25-hydroxyvitamin D3 is associated with decreased risk of postmenopausal breast cancer in whites: A nested case-control study in the multiethnic cohort study. BMC Cancer 2014;14:29.
Elsamany S, Alzahrani A, Elemam O, Elmorsy S, Hashish NA. 90P prognostic value of vitamin-D level in non-metastatic breast cancer patients in Saudi Arabia. Ann Oncol 2016;27:ix26.
Ismail A, El-Awady R, Mohamed G, Hussein M, Ramadan SS. Prognostic significance of serum vitamin D levels in egyptian females with breast cancer. Asian Pac J Cancer Prev 2018;19:571-6.
de Sousa Almeida-Filho B, De Luca Vespoli H, Pessoa EC, Machado M, Nahas-Neto J, Nahas EAP. Vitamin D deficiency is associated with poor breast cancer prognostic features in postmenopausal women. J Steroid Biochem Mol Biol 2017;174:284-9.
Janbabai G, Shekarriz R, Hassanzadeh H, Aarabi M, Borhani SS. A survey on the relationship between serum 25-hydroxy vitamin D level and tumor characteristics in patients with breast cancer. Int J Hematol Oncol Stem Cell Res 2016;10:30-6.
Peppone LJ, Rickles AS, Janelsins MC, Insalaco MR, Skinner KA. The association between breast cancer prognostic indicators and serum 25-OH vitamin D levels. Ann Surg Oncol 2012;19:2590-9.
Lopes N, Paredes J, Costa JL, Ylstra B, Schmitt F. Vitamin D and the mammary gland: A review on its role in normal development and breast cancer. Breast Cancer Res 2012;14:211.
Simpson ER. Sources of estrogen and their importance. J Steroid Biochem Mol Biol 2003;86:225-30.
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[Table 1], [Table 2], [Table 3]