Over the past decades, ecological studies have inspired to the hypothesis that exposure to sunlight and hence difference in serum vitamin D may influence both risk and prognosis for breast cancer.^{1, 2} The hypothesis has been supported by several in vitro and animal studies,^{3, 4} in addition to case–control and cohort studies with measurements of vitamin D as serum 25 hydroxy-vitamin D (25(OH)D),^5–15 although not all studies including two meta-analyses could support these findings.^16–19 Four studies found the prognosis of breast cancer to vary with the season for diagnosis. The three of them found that patients diagnosed in summer–autumn had a better disease outcome than those diagnosed in winter–spring,^20–22 and one study found a higher overall mortality for patients diagnosed in late summer compared with those diagnosed in mid-winter.²³

In Denmark, positioned at 55–58° northern latitude, there is no sufficient sun to synthesise vitamin D in the human skin during 6–8 months of the year. Measurements of vitamin D in healthy Danish volunteers demonstrate a pronounced seasonal variation of vitamin D with a maximum in late summer and a minimum in early spring, which indicates that the content of vitamin D in the average Danish diet could not compensate for the lack of sun-induced vitamin D production during wintertime.²⁴

If the vitamin D status at the time of the operation is important for the overall survival (OS), it should be both easy and inexpensive to adjust preoperatively. The aim of this study is to compare the prognostic outcome for early breast cancer patients diagnosed and operated at different seasons of the year based on a large population-based registration of women with breast cancer in Denmark including detailed information on prognostic factors.

The Danish Breast Cancer Cooperative Group (DBCG) founded in 1977 is a population-based registry, which collects data on almost all cases of invasive breast cancer among residents in Denmark (a population of 5.5 million, emigration and immigration rates <2%) (http://www.dst.dk). Virtually, all involved Danish hospital departments have applied DBCG's guidelines for diagnostic procedures, surgery, radiotherapy, adjuvant systemic therapy and follow-up for early breast cancer. Diagnostic, therapeutic and follow-up data have been accumulated prospectively in the DBCG registry by the use of standardised forms. The DBCG Data Center applied the same procedures for all patients, including monitoring and analysis of data, whether or not the patients participated in randomised trials.²⁵

The person-years of observation were 78 587 for the survival period 0–1 years, 151 980 for the survival period 0–2 years, 327 646 for the survival period 0–5 years and 516 011 for the survival period 0–10 years after surgery. For the latter group, the median observation period for patients without an event was 10.0 year. The basic characteristics of the patient material according to season of surgery are presented in table 1.

HRs of OS up to 10 years with surgery performed in winter as reference are given in table 2. Overall, no statistically significant association between OS and season of surgery are observed in 2-, 5- and 10-year follow-up periods. Only for the 1-year follow-up, a close to significant association is observed (p=0.052, fully adjusted analysis); OS is highest for patients undergoing surgery in autumn (HR: 0.97, 95% CI 0.86 to 1.09) and lowest for patients undergoing surgery in summer (HR: 1.12, 95% CI 1.00 to 1.26). Heterogeneity of seasonal effects according to period of inclusion was not statistical significant irrespective of model adjustment or survival period.

In the present study, we found no evidence of a seasonal variation in the OS among almost 80 000 Danish women with primary breast cancer. The strengths of this study are the sample size, the population-based approach in a limited geographic area,²⁹ the prospectively collected characteristics of tumour and lymph node status and the long follow-up (median 10.0 years). The detailed information's offer the possibility of including season of surgery in a multivariate analysis with the variables year, age at surgery, tumour size, nodal status, hormone receptor status and histopathological type. It should be noted that in our analysis, the ‘adjusted II’ models are stratified by treatment programme and age at surgery only. Thus, the estimates of association between OS and seasonal of surgery are not affected by the variables potentially associated with vitamin D or season of surgery (tumour size, positive axillary nodes, high-grade tumours and oestrogen receptor/progesterone receptor status). Using this approach, the independent prognostic effect of season of surgery seems to disappear. The limitations of the study are the lack of information about serum vitamin D in the individual patient at the time of surgery. Using the estimated UV dose as surrogate for vitamin D status must cause reservation, as it is not known whether vitamin D status of the breast cancer patients follow that of the background population. Lack of seasonal variation in this study does not necessarily mean that vitamin D is not important for the OS for breast cancer patients. The serum vitamin D in Danish women treated for breast cancer could be so low even among patients treated in the summer–autumn so that no difference could be detected. One nested case–control study (N=142) showed lower serum vitamin D among Danish patients at the diagnostic mammography.¹⁴ Cross-sectional studies of the plasma vitamin D in healthy Danish volunteers demonstrate a higher level in summer–autumn than in winter–spring.²⁴

Results from UK and Norway indicate a better prognosis if diagnosis of breast cancer takes place during the summer or autumn.^20–22 This seasonal variation was interpreted as a result of vitamin D deficiency in the dark months of the year, although one author considered the possibility that the seasonal effect might be due to a relative higher rate of diagnoses in summer and the prevalence of infections during wintertime leading to early death.²⁰ In contrast, results from Sweden demonstrate a worse OS for patients diagnosed in the summer probably due to a relative reduction in the number of early stage diagnoses from mammography screening which are closed in the summer months and the healthcare system treating primarily the most sick patients in holiday periods.^{23, 30} Breast cancer is regarded as a relatively slow growing cancer, with a long preclinical course.³¹ If vitamin D level should be of etiologic or prognostic importance, it is supposed that the influence is working over a longer time period and not just reflected by vitamin D status at time of diagnosis. If the level of vitamin D at the time of surgery should influence prognosis, the mechanism must be differences in perioperative resistance to cancer dissemination and the logical precaution would be to ensure a high preoperative vitamin D level. However, limited evidence including the present study supports this statement.

To cite: Teilum D, Bjerre KD, Tjønneland AM, et al. Breast cancer survival and season of surgery: an ecological open cohort study. BMJ Open 2012;2:e000358. doi:10.1136/bmjopen-2011-000358

Funding:This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests: All authors have completed the ICMJE disclosure form (available on request from the corresponding author) and declare: no support from any organisation for the submitted work, no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

Ethics approval: The data are from Danish Breast Cancer Group.

Contributors: DT contributed to conception and interpretation of data, reviewed the literature, drafted the article and finally approved the submitted paper. KDB analysed and interpreted the data, drafted the statistical part and finally approved the submitted paper. AMT and NK contributed to the interpretation of data, revised it critically for important intellectual contents and finally approved the submitted paper.

Provenance and peer review: Not commissioned; externally peer reviewed.