Is Season a Prognostic Factor in Breast Cancer ?

There have been many epidemiological studies of the relationship between sunlight and cancer. Some of those reported that there were inverse relationship between cancer risk and sunlight exposure (Apperly, 1941; Hanchette et al., 1992; John et al., 2004). Several studies showed that the prognosis of some cancer is related to season of diagnosis and cancer patients diagnosed on summer have a good prognosis (Lim et al., 2006; Porojnicu et al., 2007). Reduced cancer risk and mortality have been reported in prostate, colon, ovarian and non-melanoma skin cancer diagnosed in summer (Hanchette et al., 1992; Freedman et al., 2002; John et al., 2004; 2005; Porojnicu et al., 2005; 2007). The patients with cancer diagnosed in the summer and autumn have better survival when compared to those diagnosed in winter (Robsahm et al., 2004; Moan et al., 2005; Porojnicu et al., 2005). Some studies investigated relationship between prognosis and season in breast cancer patients reported significant differences. A study that evaluated breast cancer patients in two different climate region ssowed that patients with breast cancer living in cold climate had more ostrogen and progesteron receptor expression and more high grade tumour than those living in hot and warm climate (Mutlu et


Introduction
There have been many epidemiological studies of the relationship between sunlight and cancer.Some of those reported that there were inverse relationship between cancer risk and sunlight exposure (Apperly, 1941;Hanchette et al., 1992;John et al., 2004).Several studies showed that the prognosis of some cancer is related to season of diagnosis and cancer patients diagnosed on summer have a good prognosis (Lim et al., 2006;Porojnicu et al., 2007).Reduced cancer risk and mortality have been reported in prostate, colon, ovarian and non-melanoma skin cancer diagnosed in summer (Hanchette et al., 1992;Freedman et al., 2002;John et al., 2004;2005;Porojnicu et al., 2005;2007).The patients with cancer diagnosed in the summer and autumn have better survival when compared to those diagnosed in winter (Robsahm et al., 2004;Moan et al., 2005;Porojnicu et al., 2005).Some studies investigated relationship between prognosis and season in breast cancer patients reported significant differences.A study that evaluated breast cancer patients in two different climate region ssowed that patients with breast cancer living in cold climate had more ostrogen and progesteron receptor expression and more high grade tumour than those living in hot and warm climate (Mutlu et

Is Season a Prognostic Factor in Breast Cancer?
Hasan Mutlu 1 *, Zeki Akca 2 , Yasemin Benderli Cihan 3 , Fatih Kurnaz 4 , Tuncay Aslan 5 , Abdülsamet Erden 5 , Hediye Ugur 5 , Arzu Akşahin 5 , Abdullah Büyükçelik 6 al., 2011).In according to the season of cancer diagnosis, mortality reduction was reported among breast cancer patients that were diagnosed in the autumn in England (Roychoudhuri et al., 2009).In another study reported that breast cancer patients diagnosed in July to September had poorer prognosis however that study found that the season of breast cancer diagnosis was not an independent prognostic factor in multivariate analysis (Joensuu et al., 1991).For cases diagnosed in 1980-1986, with of 12 years follow, it was reported that cumulative probability of death from breast cancer was the highest in cases diagnosed in winter and the lowest in those diagnosed in autumn and spring (Stajner, 2010).Nonetheless, for cases diagnosed other 2 periods (1973-1979 and 1987-1993), it was found that cumulative probability of death from breast cancer was similar in different seasons.
In this study,we aimed whether the season of cancer diagnosis is an independent prognostic factor and effect the disease free or overall survival in patients with breast cancer.

Materials and Methods
Totally 517 patients from Kayseri Training and Research Hospital were analysed retrospectively collected from archieve.The patients were divided into 4 groups according to the season of cancer diagnosis as winter (December, January, February), spring (March, April, May), summer (June, July, August) and autumn (September, October, November).The prognostic factors such as age, menopausal status, stage, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor (HER 2 or cerb B2) receptor 2 status, grade, lymphovascular invasion (LVI) and perineural invasion (PNI), disease free survial (DFS) and overall survival (OS) were investigated using Statistical Package for the Social Sciences 16.0 (SPSS16.0)statistical software.
To determine patients characteristics, descriptive statistics methods was performed.To evaluate prognostic factors between groups, chi-square tests was performed.The DFS and OS were estimated using Kaplan-Meier methods and were compared using the log-rank test.Univariate analysis was performed using Cox proportional hazards regression modeling.The parameters those their p values <0.250 were included in multivariate analysis.P <0.05 was considered to be statistically significant.

Discussion
In our study, the season that cancer diagnosed was evaluated whether it was independent prognostic factor in patients with breast cancer.For the others prognostic factors (age, menopausal status, stage, estrogen receptor status, progesteron receptor status, cerb B2 receptor status, grade, lymphovascular invasion and perineural invasion), there were no significant differences between groups.Despite of knowing prognostic factors were not significant different, the season when breast cancer was diagnosed has affected significantly DFS (p=0.019).But after univariate and multivariate analysis, the DFS has been affected only by ER and LVI in our study.The season when cancer was diagnosed was important for DFS but was not independent prognostic factor.The season can not affect directly DFS but the other factors such as sunlight exposure and vitamin D intake those effecting by season may be resposible for this reason (Garland et al., 1995;Gorham et al., 1989;John et al., 1999;Shin et al., 2002;Grant et al., 2003;Abbas et al., 2008;Mohr et al., 2008).
The 1 α 25 (OH)2D3-vitamin D receptor (VDR) complex may play a role in maintaining genomic integrity and facilitating DNA repair.Similarly some studies have shown that vitamin D3 had a modulatory effects (upregulation of proapoptotic genes or down-regulation of proantiptotic genes) on apoptosis related genes (Narvaez et al., 2001;Pirianov et al., 2001;Kizildağ et al., 2010).In a study, it was mentioned close cooperation between VDR action and p53 tumor suppressor pathway (Patel et al., 2012).Wild type p53 induces apoptosis and mutation rate of p53 in breast cancer is approximetely 30% and it was reported that the median level of 25(OH)D was lower in the P53+ group in a borderline trend (Kermani et al., 2011).Also it was previously reported that vitamin D promotes cell differentiation and 1α 25(OH)2 D3 reduces the invasive potential of cancer cells in experimental studies and it was found that the median level of 25(OH) D was significantly higher in the patients with metastasis (Krishnan et al., 2010;Kermani et al., 2011).As mentioned above, vitamin D3 may play a important role during occurence of cancer.Also vitamin D3 and sunlight exposure may have an effect in determining of prognostic factors in patients with breast cancer.
Unlike the others studies that mentioned in introduction section, we found that cancer patients diagnosed in winter had better disease free survival.When we evaluated the groups as overall survival, although winter groups had longer OS ratio than other groups, the difference did not have a statistical meaning (p=0,637).In this case, we need to answer: ''Which date is important for prognosis?Date of diagnosis or unknowing initial time at the beginning of tumor?''Because especially sunlight exposure are much more in summer than winter.We can speculated that season at the beginning of tumor (not at the diagnosis of tumor) may be an important factor on prognosis of breast cancer via sunlight exposure and vitamin D3 instead of season at the diagnosis of cancer.
We think that the season of cancer diagnosed time is important as cancer prognosis.Duo to the others factors those are occured by season, the season can effect breast cancer prognosis.

Figure
Figure 2. Overall Survival Curves