The Comparison of Breast Cancer in Southern China and America: A Multicentre Study in China Versus SEER Database

Background and Objective: There are different characteristics of BC in developing countries and developed countries. We intend to study the factors which inuence the survival and prognosis of BC between southern China and the United States. Methods: To study the two groups BC patients in southern China from 2001 to 2016 and SEER database from 1975 to 2016. To register, collect and analyze the clinicopathological features and treatment information. Results: Our study found that there are signicant differences in tumor size, positive lymph node status and KI-67 between southern China and SEER cohort (P<0.000). Conclusions: The age, tumor size, positive-node and KI-67 may cause the difference of morbidity and mortality of BC patients in southern China and SEER cohort.

with the expression of PR and ER. Wang X et al found that the frequency of BRCA1 mutation in triple negative BC patients is higher than that in non-triple negative BC patients in China [15].
In contrast, there are about 12% of women in the United States are diagnosed with BC in their lifetime, nevertheless, it is estimated that there are about 3.1 million BC survivors each year [16,17]. With the development of treatment strategies, the mortality of BC has been decreased in the United States, which the 5-year survival rate was about 90% after treating [18]. A large number of studies have shown that, BC also has its own characteristics in the United States. DeSantis CE et al reported that BC patients in the United States from 2004 to 2014, young women have higher invasive and speci c genomic characteristics, meanwhile, the incidence of HR positive (ER positive or PR positive) breast cancer increased, while the morbidity of HR negative tumors decreased [19].
There are different researchers in the world comparing BC in China and other regions, and nding that there exist some differences between them. Sung H et al suggested that with the widespread assimilation of western lifestyles, the incidence of BC in China is narrowing gradually [20]. Wu AH et al reported that the incidence of BC in Filipino people is signi cantly higher than that in Japan and China [21]. Zhang G et al found that compared with the white, the expression of TP53 and AKT1 is higher in Chinese, which may be a potential factor affecting the incidence of BC [22]. Yang SY et al found that the morbidity of BC is different between China and other Asian populations, and the mutation frequency of BRCA2 was much higher than that of BRCA1, by comparison, BRCA1 mutations are more common than BRCA2 mutations in Caucasian populations [23]. Chen L et al researched the Asia and African Americans, discovering that there are more than 50% of BC cases in Asia were lumA subtype, and the basal-like subtype only accounts for 5%, however, in African-American populations, this subtype accounts for more than 30% [24].
Additionally, there are different characteristics of BC in different regions of China. A previous study showed that the incidence of BC is the highest in eastern China, followed by central China, and then in western China [25]. Among these, BRCA1 mutations are more frequent than BRCA2 mutations in patients with familial breast cancer in Henan, central China [26]. Co M et al reported that the age of onset of BC in mainland China is younger than in Hong Kong [27]. Moreover, it has been reported that the incidence of BC in Taiwan, China (similar to that in Hong Kong), is even higher than that in the United States in recent years [28]. However, the comparison of BC patients between southern China and the United States has not been reported. This study aims to investigate the differences of BC patients between southern China and the population-based Surveillance, Epidemiology, and End Results (SEER) cohort.
Researches showed that the age of diagnosis, stage and grade of tumor and treatment methods may be the prognostic factors of BC [29][30][31] . Based on these, our study intends to research the age, stage and grade of tumor, ER, PR, HER2, KI-67 and treatment methods, in order to report and analyze the age distribution, clinical characteristics, treatment and prognosis of BC patients in southern China and SEER database, to compare and analyze the two groups.

Patients and ethics
Retrospective analysis and compare the patients who have been diagnosed with primary breast cancer in southern China (2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016) and SEER database . Overall, there was a total of 525 breast cancer patients were diagnosed in southern China, among them, 15 patients were excluded from this study due to lack of age information. In addition, 129 patients were removed, which without tumor stage, ER, PR, HER2, KI-67 and treatment information. Additionally, there are about 95 patients were lost. Finally, a total of 286 patients were included in the study (Fig. 1)

Clinical Data Collection
A retrospective review of medical records and pathology reports was conducted. Staging was performed according to the American Joint Committee on Cancer (AJCC) guidelines [32]. The age of the patients was classi ed to young adult group (< 40), middle aged group  and aged + group (> 70), and then, calculated the median age of each age group (35,48,75), nally, statistical analysis was carried out respectively. A cutoff of 14% for KI-67 was used, which was recommended by 2011 St Gallen consensus panel [33], and then, we divided the group of KI-67 ≥ 14% into two subgroups, according to the median (51.7% in southern China). Patients in southern China were told to have an examination and treatment according to the guidelines of the breast cancer center and were followed up by telephone, and collect the information about survival and treatment, including date of progression metastasis, date of relapse and date cause of death.

Statistical Methods
The IBM SPSS Statistics (Version 21.0; IBM Corp., New York, USA) and GraphPad Prism (Version 6.0; GraphPad software, Inc., LaJolla, CA, USA) were used for statistical analysis. Disease-free survival (DFS) was measured from the beginning of the operation to the rst recurrence / metastasis of the tumor or the death of the subject for any reason (the last follow-up time was the patients who lost the follow-up; the patients who were still alive at the end of the study were the end of the follow-up). Overall Survival (OS) was measured from the beginning of operation to death due to any reason. Univariate analysis and multivariate analysis was performed by Cox regression analysis,according to comparing the age (< 40 and ≥ 40), tumor size (≤ 2cm and > 2cm), node status, ER, PR, HER2, KI-67, surgery and radiation. Kaplan-Meier method was used to estimate DFS and OS, Log-rank test was used to compare the patients with different clinicopathologic characteristics. The count data were tested by χ 2 test, sher exact probability method was used when the cases was less than 6. Statistical signi cance was set at a P < 0.05, P < 0.01 had signi cant difference.  and OS of all included breast cancer patients were compared: in comparing of DFS, there was no signi cant different between southern China and SEER cohort (P = 0.133), but there was signi cant different in OS (P = 0.000), and the OS in SEER cohort was signi cantly higher than southern China ( Fig. 2A-B). Secondly, due to the data of southern China was only included from 2001 to 2016, so layered statistic was used to count the DFS and OS in both southern China and SEER database from 2001 to 2016. Among them, in the rst 70 months of follow-up, DFS in southern China was higher than SEER cohort, and then, DFS in SEER cohort was signi cantly higher than that in southern China (P = 0.035), and OS in this period also has signi cant statistical different (P = 0.000), SEER cohort was signi cantly higher than that in southern China (Fig. 2C-D). Finally, SEER cohort was analyzed in stages, dividing into 1975 to 2000 and 2001 to 2016 two subgroups, furthermore, DFS and OS of each subgroup were counted respectively. The results showed that, in SEER cohort, the DFS and OS of 2001 to 2016 were signi cantly higher than 1975 to 2000 (P = 0.000) (Fig. 2E-F).

Patients
Analyzing and comparing the in uence of different clinicopathological features on survival and prognosis of BC patients in southern China. By analyzing the effects of age, tumor size, lymph node status, ER, PR, HER2, KI-67, surgery and radiotherapy on the prognosis of breast cancer, we found that tumor size, positive lymph node status and KI-67 expression affected OS of BC patients in southern China, which had signi cant statistical different (P = 0.018, P = 0.000, P = 0.034 respectively) ( Supplementary Fig. 1). To further analyze and compare the effect of different tumor size on survival of different BC cohorts. There were statistical different of DFS and OS in SEER cohort and southern China when the tumor size (T) > 2cm (P = 0.01 and P = 0.04), however, DFS and OS were no statistical different of the two groups when T ≤ 2cm (P = 0.188 and P = 0.604) (Fig. 3A-D). Secondly, the effects of different tumor sizes on the survival of BC patients in each cohort were analyzed separately. Among them, tumor size had little effect on DFS in southern China (P = 0.487), but for OS, there was signi cant statistical different, OS in T > 2cm group was signi cantly lower than T ≤ 2cm (P = 0.012) (Fig. 3E-F). However, for SEER cohort, DFS and OS of T > 2cm group were slightly lower than that of T ≤ 2cm group, but there was no statistical different (P = 0.738 and P = 0.299) (Fig. 3G-H). Analyze and compare the effect of different node stage on survival of different BC cohorts. Positive-node affected DFS and OS in both southern China and SEER cohort (P = 0.000 and P = 0.044). Meanwhile, negative-node also affected DFS and OS in the two groups (P = 0.000 and P = 0.000). OS of SEER cohort with different lymph node status was higher than that of southern China (Fig. 4A-D). Analyzing southern China and SEER cohort separately, DFS and OS of positive-node were lower than negative-node, among them, OS of lymph node status has signi cant statistical different (P = 0.000), but DFS of lymph node status has no statistical different (P = 0.448) (Fig. 4. E-F). But for SEER cohort, DFS and OS of positive-node was slightly higher than negativenode, while there was no statistical different (P = 0.226 and P = 0.087) (  (Table 2).    [34] . However, the morbidity of young BC patients in China is signi cantly higher than that in western countries (about 4-6%) [35][36][37][38] , which was similar to the incidence of our study: it was 6.14% of SEER cohort from 1975 to 2016. All of these suggested that the incidence of BC in China is younger than that in western countries, which indicated that age may be a factor affecting the survival and prognosis of BC patients in southern China and the United States.
To further study DFS and OS, we focused on T stage, positive lymph node status, ER, PR, HER2, KI-67 expression of BC patients, and thought that T stage, positive lymph node status and KI-67 expression all could be regarded as factors, which affected the survival and prognosis of BC patients. Other scholars had also studied tumor stage, and found that there were about 60-70% of BC patients were diagnosed with stage 1, which was higher than Asian countries, but there were only about 10% women were stage 4 [39]. This research was similar as our results, our nding showed that most BC patients in southern Besides, we further to explore the effect of ER, PR, HER2, KI-67 expression on survival and prognosis of BC. The proportion of ER (+) BC patients was similar in both southern China and SEER cohort. It was 56.86% in southern China and 65.34% in SEER cohort, which was slightly lower than that had been reported (about 70%) [40] . It may be related to excessive data deletion in SEER cohort, which was about 16.7% of ER data were missing in this study. There were studies have showed that the most important factors affecting the prognosis of BC were tumor grade and ER status [41] . However, in our study, ER was not an indicator of survival and prognosis of BC. Additionally, there were different treatment methods of BC according to the different status of hormone receptor (HR). Endocrine therapy could be used for ER or PR positive patients, but the effect of chemotherapy was not as good as these of negative patients, and the different treatment methods could signi cantly affect the prognosis of BC. Therefore, PR was also an important factor affecting the prognosis of BC. In our study, there was 52.94% of PR positive in southern China, and 55.55% of that in SEER cohort, there was signi cant statistical different between the two groups (P = 0.000). Similarly, the results of Cox regression analysis showed that PR was also not an indicator of survival and prognosis of BC, which may had a relationship between a large data missing. In addition, Ding L et al found that BC with HER2 and KI-67 overexpression had higher lymph node metastasis rate and higher AJCC tumor stage [42,43] , which was the same as our researches. In this study, HER2 positive were 55.49% and 9.46% in southern China and SEER cohort respectively (P = 0.000), which was consistent with the literature that BC cells from young patients are more likely to show HER2 positive expression [34] . Besides, KI-67 positive was 70.01% in southern China, which high expression was also an important factor affecting OS in BC patients. However, DFS was detected by χ 2 test when KI-67 was regarded as an independent factor, P = 0.05, but we thought that this was mainly due to the small sample size, the trend in the conclusion was still valid, with the sample size continues to increase, the value of P may gradually decrease. In summary, our results showed that T stage, positive-node status, KI-67 expression were all important factors affecting the prognosis of BC, which also re ected that BC patients in southern China and the United States have different biological behaviors and pathogenesis.
Additionally, the treatment methods of BC were also important factors affecting its prognosis. At present, the main treatments of BC were surgery, radiotherapy, chemotherapy, targeted therapy and hormone therapy [44,45] . Among them, surgery can signi cantly reduce the mortality rate, which is the most critical step in the treatment of breast cancer, there are ve common surgical methods: Breast conserving surgery (BCS), simple mastectomy (SM), modi ed radical mastectomy (MRM), radical mastectomy (RM) and extensive radical mastectomy (ERM) [46] . Among them, Bartelink H et al reported that BCS has the equivalence with mastectomy [47] . However, the comparison of treatment methods between southern

Availability of data and materials
The raw data required to reproduce these ndings cannot be shared at this time as the data also forms part of an ongoing study.
Ethics approval and consent to participate All procedures implemented in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee, and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Ethics/Institutional Review Board approval of research-Yunnan Cancer Hospital, Cancer Hospital A liated to Guangxi Medical University and Foshan rst people's Hospital. Informed consent was obtained from all individual participants included in the study.

Consent for publication
All patients enrolled in the study signed the consent for publication.

Con ict of interests
The authors have no con icts of interest to declare.       Comparison of different years all patients' age in SEER database.

Supplementary Files
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