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Korean Journal of Clinical Oncology > Volume 9(2); 2013 > Article
Kwon, Lee, Kim, Koh, Yu, Lee, Son, and Ahn: Impact of seasonal and geographical differences on breast cancer survival

ABSTRACT

Purpose:

Seasonal and geographic variations in ultraviolet B intensities (UVB) impact the vitamin D status, and these differences might significantly affect cancer prognosis. This study evaluates the association between seasonal and geographic differences in UVB exposure and breast cancer survival.

Methods:

We divided Korea into two regions according to erythemally weighted annual UVB exposure as follows: Seoul and the southern region. Recurrence and death were also grouped into two seasons: spring/summer and autumn/winter.

Results:

The survival and relapse rates, when stratified by season of diagnosis, demonstrated no significant differences between spring/summer and autumn/winter. Among the 1,488 breast cancer patients in our cohort who demonstrated recurrence, 775 cases (52.1%) relapsed during the spring/summer and 594 patients (52.6%) died during the autumn/winter. In total, 6,178 patients (89.1%) and 3,909 patients (91.3%) in Seoul and the southern region survived (P=0.005). The relapse rate in the Seoul group (13.7%) was higher than the southern group (11.9%). By Kaplan-Meier analysis, there were no statistical differences between the Seoul and southern groups in terms of disease-free (P=0.43) and cancer-specific survival (P=0.18). In the Cox analysis, after the adjustment of all the other factors, season of diagnosis and residential area have no statistical significance.

Conclusion:

We conclude from our findings that death from breast cancer occurs more frequently in the autumn/winter, and that patients in the southern area of Korea demonstrate better survival. However, we find no significant relationship between geographic and seasonal variations in breast cancer survival.

INTRODUCTION

Vitamin D refers to a group of fat-soluble prohormones that are mainly synthesized following exposure to ultraviolet B (UVB) light (280-315 nm in wavelength). The two major forms of vitamin D are D2 (calciferol) and D3 (cholecalciferol). The photochemical synthesis of vitamin D3 occurs cutaneously, whereas provitamin D3 (7-dehydrocholesterol) is converted to previtamin D3 (pre-D3). Vitamin D3 is hydroxylated by liver 25-hydroxylases (25-OHase) to form 25-hydroxycholecalciferol (25(OH)D3), which is subsequently 1α-hydroxylated in the kidneys by 25-hydroxyvitamin D3-1α-hydroxylase (1α-OHase). This yields the active secosteroid 1,25-dihydroxyvitamin D3 (1,25[OH]2D3; calcitriol), the hormonal form of vitamin D [1-3].
1,25[OH]2D3 exerts various biological effects in cells that possess the vitamin D3 receptor (VDR), including the enhancement of cell differentiation and the inhibition of cell proliferation and angiogenesis [4]. Some preclinical studies have established that calcitriol induces growth arrest, differentiation, and apoptosis in vitro in transformed cell lines derived from breast, prostate, colon, and other tissues, and that these effects are mediated by VDR. VDR is also expressed in 80% of human breast cancers. These results have provided background evidence for use in epidemiologic studies [5,6].
The protective role of sunlight against cancer incidence was first hypothesized by Garland and Grand [7] in 1980 and published in their ecological study on colon cancer mortality rates and annual sunlight levels. Support for this theory has also been published in ecological, case control, and cohort studies [8-11]. In a study from the United Kingdom, Lim et al. [12] reported that patients diagnosed in the summer and autumn demonstrate increased survival compared with patients diagnosed in the winter, especially among breast and lung cancer patients. In a Norwegian study, Porojnicu et al. [13] also reported that male lung cancer patients diagnosed in the summer or autumn and also reside in high-UV regions demonstrate a 15% reduced risk of mortality. Freedman et al. [14] have reported that residential exposure to sunlight is associated with reduced mortality from breast, ovarian, prostate, and colon cancers.
Although vitamin D can be obtained by consuming vitamin D-rich foods or vitamin supplements, vitamin D levels are most heavily influenced by solar radiation. Korea occupies a wide latitudinal area (33˚-39˚N) and thus experiences four very distinct seasons. Geographic and seasonal variations in UVB impact the vitamin D status, and these differences might be of prognostic significance to breast cancer. Our group has previously reported that vitamin D deficiency is correlated with poor clinical outcomes in breast cancer patients [15]. In our present study, we explored whether geographic and seasonal variations in Korea are correlated with breast cancer survival.

METHODS

Patients

Data collected between 1989 and 2010 in the Asan Medical Center Breast Cancer Database were analyzed. A total of 11,698 breast cancer patients listed on this database were included in this study. Patient age (<50 years vs. ≥50 years), tumor size (<2 cm vs. ≥2 cm), lymph node involvement, hormone receptor and HER2-neu status, and adjuvant treatment status were analyzed. Pathological staging was based on the staging criteria of the seventh edition of the American Joint Committee on Cancer. Immunohistochemical staining was performed for the biomarkers of estrogen receptor (ER), progesteron receptor (PR), and human epidermal growth factor receptor 2 (HER2). ER and PR were scored according to the modified allred score. Tumor were considered ER or PR positive when the score was over 5. Tumor were considered HER2 positive only if they were either scored 3+ by immunohistochemistry (IHC) or if they were 2+ by IHC and also HER2 amplified (ratio>2.0) on the basis of fluorescence in situ hybridization (FISH). In the absence of positive FISH data, tumors scored 2+ by IHC were excluded in this study. Using data from the Korea Meteorological Administration collected over the last 22 years, we divided Korea into two residential regions according to erythemally weighted annual UVB exposure (MJ/m2) (Fig. 1): Seoul (Seoul and surround areas) and the southern region (all other areas). We chose 4,550 MJ/m2 as the cut-off value for the amount of daily solar radiation. Recurrence and death were classified as occurring in the spring/summer (March-August) or in autumn/ winter (September-February).

Statistical analysis

The demographic and clinical characteristics of the patients stratified by two residential regions (Table 1) and the season of diagnosis (Table 2) were analyzed using the chi-square test. The frequencies of death and relapse were estimated during each season. Survival and relapse rates according to the area of residence and the season were estimated using the chi-square test. Disease-free survival (DFS; until recurrence or death) and cancer-specific survival (CSS; until death from breast cancer) were calculated using the Kaplan-Meier product- limit method (Figs. 2, 3). Hazard ratio of DFS and CSS for patients with each residential region and season of diagnosis evaluated considering the potential confounding factors: age, tumor size, hormone receptor status, HER2-neu status (Table 3). All other statistical analyses were performed using SPSS ver. 18.0 (SPSS Inc., Chicago, IL, USA). In this study, P<0.05 were considered statistically significant.

RESULTS

This study included 7,077 and 4,348 patients residing in Seoul or the southern region, respectively. The two groups, according to season of diagnosis, were similar in terms of patient characteristics, except for age (P<0.01), HER2 status (P=0.02) (Table 1). The demographic and clinical characteristics of the study patients stratified by residential groups are summarized in Table 2. Patients in Seoul were statistically older than patients in the southern area (P<0.001), and the ER expression level was statistically higher in the southern group (P=0.005). HER2 expression was lower in patients in Seoul (P<0.001). There were no differences in terms of tumor size or lymph node metastasis between the two groups.

Relationship between season, recurrence, and death

The survival and relapse rates, when stratified by season of diagnosis, demonstrated no significant differences between spring/summer and autumn/winter. Kaplan-Meier estimates of DFS and CSS also demonstrated no differences based on the season of diagnosis (Fig. 2). Among the 1,488 breast cancer patients in our cohort who demonstrated recurrence, 775 cases (52.1%) relapsed during the spring/ summer and 594 patients (52.6%) died during the autumn/winter. In the Cox analysis, after the adjustment of all the other factors (age, tumor size, lymph node metastasis, ER, PR, and HER2 status), there were no significant differences with season of diagnosis (Table 3).

Relationship between geography, recurrence, and death

In total, 6,178 patients (89.1%) and 3,909 patients (91.3%) in Seoul and the southern region survived (P=0.005). The relapse rate in the Seoul group (13.7%) was higher than the southern group (11.9%). By Kaplan-Meier analysis, the southern group demonstrated a better overall prognosis, but there were no statistical differences between the Seoul and southern groups in terms of DFS (P=0.43) and CSS (P=0.18) (Fig. 3). In the Cox analysis, we also could not find significant differences with regard to the risk of DFS and CSS between Seoul and Southern group (Table 3).

DISCUSSION

Our present findings shows that breast cancer patients in Seoul, who receive less sunlight exposure, demonstrate a higher risk of recurrence and death compared with patients in the southern region. After adjustment for potential confounders, however, both season of diagnosis and residential area have no statistical significance. Kaplan-Meier estimates also demonstrated no significant differences between our two study groups stratified by region. Moreover, we found no relationship between season of diagnosis and breast cancer recurrence or death in our analysis. This is the first study to report an association between seasonal and geographic variation, recurrence, and death in Korean breast cancer patients. Because race and skin pigmentation also play considerable roles in vitamin D synthesis [16], we compared our study results with those reported from neighboring nations. Fukuda et al. [17] reported the preventive effects of solar radiation on several types of cancer in Japan, most notably gastrointestinal cancer, but found no relationship with female breast cancer and socioeconomic variables were considered to be potential confounders. Cancer mortality rates in China have been inversely associated with UVB exposure for most types of cancer, including breast cancer [18].
Our current hypothesis was based on the fact that sun-induced vitamin D levels are affected by geographic and seasonal variation. As reported previously, this difference in vitamin D levels impacts the risk of breast cancer. Freedman et al. [14] reported that residential exposure to sunlight is negatively and significantly associated with breast cancer mortality. However, many factors must be considered when associating geographic location with vitamin D synthesis. Lifestyle, latitude, seasonal variation, cloud and ozone coverage, and socioeconomic status all influence solar exposure [19]. Millen et al. [20] reported that the region of residence and solar radiation are not significantly related to breast cancer risk, but that time spent outside is associated with this risk.
Several ecological studies have reported significant variation in clinical prognosis according to season of diagnosis [12,21]. In a previous Norwegian study, diagnoses during the summer and fall (the seasons with the highest levels of vitamin D3) demonstrated the lowest risk of cancer death [22]. Lim et al. [12] suggested in their study that female breast cancer patients diagnosed in the summer and autumn demonstrate prolonged survival compared with patients diagnosed in the winter and that sunlight exposure in the months preceding diagnosis is a predictor of survival. Both human and animal studies support this finding [23]. In our present study, we found that more Korean breast cancer patients died in the autumn/ winter than in the spring/summer, but we could not determine any prognostic variations that depended on the season of diagnosis.
Old age has been suggested as a risk factor for vitamin D insufficiency because the cutaneous synthesis of vitamin D3 declines with age. One of the possible causes for increased cancer risk is that aging decreases the capacity of the skin to produce vitamin D. MacLaughlin et al. [24] suggested that epidermal concentrations of 7-dehydrcholesterol demonstrate age-dependent decreases. In addition, age-related decreases in VDR and the renal production of 1,25(OH)2D have been reported in aging kidneys [25]. It must be considered also that older generations may tend to stay indoors more prevalently, especially in the winter. Interestingly in this regard, the Korea National Health and Nutrition Examination Survey (KNHANES) has reported that a vitamin D insufficiency is a greater threat to younger generations in Korea because they have settled in urban areas in increasing proportions and thus spend more time indoors [26].
This study has several limitations to note. First, we were unable to investigate confounding factors such as dietary vitamin D intake, socioeconomic status, and lifestyle. Geography may also be closely related with socioeconomic status. However, we do report for the first time that a relationship exists between sunlight exposure and breast cancer recurrence and mortality. In conclusion, our present retrospective analyses of a Korean cohort indicate that breast cancer deaths occur more often in the winter and less frequently in patients who live in the southern region of Korea. However, geographic and seasonal variations do not appear to affect breast cancer survival. To determine if this relationship is caused by differences in UVB exposure, future prospective studies that examine the associations between individual levels of sunlight exposure and breast cancer survival need to be performed.

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

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Fig. 1.
Annual erythemally-weighted ultraviolet-B exposure (MJ/m2) Obtained from http://minwon.kma.go.kr.
kjco-9-2-168-19f1.gif
Fig. 2.
Kaplan-Meier estimates of (A) disease-free survival and (B) cancer-specific survival are shown stratified by season of diagnosis.
kjco-9-2-168-19f2.gif
Fig. 3.
Kaplan-Meier estimates of (A) disease-free survival and (B) cancer-specific survival are shown stratified by residential groups.
kjco-9-2-168-19f3.gif
Table 1.
Patient demographics and clinical characteristics stratified by the season of diagnosis
Variable Spring, summer (n = 5,575) Autumn, winter (n = 5,554) P-value
Age at operation (yr), mean 55.9 55.2 < 0.01
 < 50 1,402 (24.5) 1,528 (26.8)
 ≥ 50 4,328 (75.5) 4,167 (73.2)
Tumor size (cm) 0.50
 <2 3,261 (58.5) 3,214 (57.9)
 ≥ 2 2,314 (41.5) 2,340 (42.1)
Lymph node metastasis 0.82
 Negative 3,436 (60.0) 3,427 (60.2)
 Positive 2,294 (40.0) 2,268 (39.8)
ER status 0.32
 Negative 2,560 (44.7) 2,492 (34.8)
 Positive 3,170 (55.3) 3,203 (56.2)
PR status 0.40
 Negative 2,927 (21.1) 2,864 (50.3)
 Positive 2,803 (48.9) 2,831 (49.7)
HER2 0.02
 Negative 4,543 (79.3) 4,414 (77.5)
 Positive 1,187 (20.7) 1,281 (22.5)

Values are presented as number (%).

ER, estrogen receptor; PR, progesteron receptor; HER2, human epidermal growth factor receptor 2.

Table 2.
Patient demographics and clinical characteristics stratified by residential groups
Variable Seoul (n = 7,077) Southern (n = 4,348) P-value
Age at operation (yr), mean 56.9 55.3 < 0.01
 < 50 1,720 (24.3) 1,210 (27.8)
 ≥ 50 5,357 (75.7) 3,138 (72.2)
Tumor size (cm) 0.45
 < 2 3,938 (57.9) 2,492 (58.6)
 ≥ 2 2,896 (42.1) 1,758 (41.4)
Lymph node metastasis 0.81
 Negative 4,245 (60.0) 2,618 (60.2)
 Positive 2,832 (40.0) 1,730 (39.8)
ER status < 0.01
 Negative 3,201 (45.2) 1,851 (42.6)
 Positive 3,876 (54.8) 2,497 (57.4)
PR status 0.02
 Negative 3,649 (51.6) 2,142 (49.3)
 Positive 3,428 (48.4) 2,206 (50.7)
HER2 < 0.01
 Negative 5,624 (79.5) 3,333 (76.7)
 Positive 1,453 (20.5) 1,015 (23.3)

Values are presented as number (%).

ER, estrogen receptor; PR, progesteron receptor; HER2, human epidermal growth factor receptor 2.

Table 3.
Multivariate cox proportional hazards model for cancer-specific survival and disease-free survival
Variable Cancer-specific survival
Disease-free survival
95% CI HR P-value 95% CI HR P-value
Tumor size (cm) 1.58-2.10 < 0.01 1.55-1.95 < 0.01
 <2 1.00 1.00
 ≥2 1.82 1.74
Lymph node metastasis 3.91-5.32 < 0.01 2.40-3.02 < 0.01
 Negative 1.00 1.00
 Positive 4.56 2.67
ER status 0.47-0.65 < 0.01 0.71-0.93 < 0.01
 Negative 1.00 1.00
 Positive 0.55 0.81
PR status 0.51-0.73 < 0.01 0.61-0.81 < 0.01
 Negative 1.00 1.00
 Positive 0.61 0.70
HER2 0.68-0.94 < 0.01 0.94-1.21 0.35
 Negative 1.00 1.00
 Positive 0.80 1.06
Residential region 0.08-1.26 0.12 0.87-1.08 0.62
 Seoul 1.00 1.00
 Southern 1.11 0.96
Season of diagnosis 0.84-1.09 0.51 0.90-1.10 0.98
 Spring, summer 1.00 1.00
 Autumn, winter 0.96 1.00

HR, hazard ratio; CI, confidernce interval; ER, estrogen receptor; PR, progesteron receptor; HER2, human epidermal growth factor receptor 2.

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