Sex‐specific differences in colorectal cancer: A multicenter retrospective cohort study

Abstract Background Due to sex‐specific differences in the incidence and clinical and histopathological characteristics of colorectal cancer (CRC), understanding the impact of sex on CRC may suggest sex‐targeted strategies for screening, treatment, and prevention, leading to improved prognosis of CRC. However, there have been few studies investigating the sex‐specific differences in CRC in the Republic of Korea. We aimed to assess sex differences in CRC in the Republic of Korea. Methods This was a retrospective, multicenter, cohort study of patients diagnosed with CRC between January 2012 and December 2013 at nine hospitals. Patients who had an uncertain CRC stage, were diagnosed with other cancers within 5 years, had carcinoma in situ, non‐epithelial cancer, or primary cancer other than CRC, were excluded. Factors associated with overall survival or progression‐free survival were investigated using Cox regression analysis. Cumulative probability of metachronous lesions was compared using the Kaplan–Meier estimator survival analysis and we compared the survival curves of each group using a log‐rank test. Outcomes were compared using the chi‐square, Fisher's exact, or Student's t‐test, as appropriate. Results Three thousand one hundred and forteen patients (1999 men, 1315 women) were included. There was no significant difference in the age at onset between men and women. The proportion of patients diagnosed through regular health check‐ups, and asymptomatic at time of diagnosis, was higher in men (48.9% men vs. 42.0% women, p < .001). Rectal cancers were more common in men (38.8% men vs. 31.8% women, p < .001). Right colon cancers were more common in women (31.4% women vs. 22.7% men, p < .001). KRAS mutations were found in 109/317 (34.4%) women and 112/480 (23.3%) men. Overall CRC survival and progression‐free survival were similar in both sexes. Conclusion Sex differences in CRC may be due to the biological and social‐behavioral differences between the sexes. They should be considered during screening, diagnosis, and treatment of CRC for better outcomes.


| Study design and patients
This was a retrospective, multicenter, cohort study that analyzed information from electronic records of nine hospitals. Of nine hospitals, two are located in Seoul and two in Gyeonggi-do. Except for the four hospitals located in the metropolitan area, five hospitals are located in the cities of Gyeongsang-do, Jeolla-do, and Chungcheongdo. The study was reviewed and approved by the National Cancer Center Institutional Review Board (NCC2021-0363).
The patient enrollment flow diagram is shown in Figure 1. Initially, a total of 4228 patients with CRC were recruited between January 2012 and December 2013 from nine hospitals. Only patients who were followed up for more than 6 months were enrolled. Exceptionally, patients whose follow-up was terminated within 6 months of diagnosis of CRC due to death were enrolled in the study. Participants who met at least one of the following criteria

| Definition
Family history of CRC was defined as the diagnosis of CRC in at least one first-degree relative. Tumor staging was performed according to the American Joint Commission on Cancer standards contemporaneous with the treatment period. Obesity was defined as body mass index ≥25 kg/m 2 according to the cut-off value for Asians. 5 Patients who quit smoking for more than 1 year and those who did not smoke were referred to as ex-and never-smokers, respectively.
All current smokers and ex-smokers smoked for more than 10 packyears.
Tumor location was categorized as the right colon (cecum, ascending colon, transverse colon), left colon (descending colon, sigmoid colon), or rectum.

| Treatment according to the sex
Overall, 88.1% of men and 88.2% of women with CRC underwent curative treatment. Surgery was the most common initial treatment in both sexes. However, more men received concurrent chemoradiotherapy before resection than women (8.8% men vs. 5.9% women, p = .033) (

| DISCUSSION
This retrospective cohort study conducted a sex focused analysis of multicenter data on CRC in the Republic of Korea. Several differences were revealed between men and women with CRC, potentially related to screening, diagnosis, and treatment.
According to national cancer statistics, the incidence of CRC among men was significantly higher than that among women in the Republic of Korea. 1 This sex difference in the overall CRC incidence was observed with a similar sex ratio in our data.
Male sex has been proposed to be a risk factor for CRC because of many biological and behavioral factors. [6][7][8] For example, men have higher alcohol consumption and smoking rates 9,10 along with a greater propensity to deposit visceral fat, 11 leading to an increased risk of CRC, compared to women. [12][13][14] Moreover, Several previous studies have suggested that testosterone may promote colorectal neoplasm formation. 15,16 And estrogen has been reported to play a protective role against incidence of CRC, which may be a reason for the relatively low CRC incidence in women. 17 Up to now, there have been many studies showing that the microbiome plays a profound role in development, progression and treatment response of colon cancer. 18,19 Also, it is well known that the distribution of gut microbiota differs according to sex. 20 Therefore, the microbiome is a possible key cause of differences between men and women in CRC.
The proportion of patients who were diagnosed through regular health check-ups, and were asymptomatic at the time of diagnosis, was higher among men compared to women. However, there was no difference between the sexes in the time taken to receive medical treatment after the onset of symptoms. It is known that men are generally less aware of cancer signs and symptoms, such as recognizing changes in the bowel habit. [21][22][23][24][25] However, even if women are more sensitive to CRC symptoms, they usually face a greater barrier to consulting a doctor. Therefore, this does not mean that they have a shorter delay from the onset of symptoms until the first medical consultation. [26][27][28] Our study reported that there were no significant differences by sex in the initial treatment methods for CRC. A Swiss study about sex differences in CRC treatment revealed that there was no sex difference in treatment decisions, and that the probability of receiving initial treatment other than surgery was higher in patients with comorbidities than in patients without comorbidities, and this effect was stronger in women than in men. 29 KRAS mutations were found in 109 (34.4%) of 317 women and 112 (23.3%) of 480 men with CRC. Women were also found to have KRAS mutations in codon 12 more frequently than men, which are associated with more advanced adenomas. 30 Several studies reported that a higher proportion of women presented with right-sided CRC than men, which is consistent with our findings. 24,31 In a study about colorectal cancer risk of type 2 diabetes patients, the risk of developing distal colon cancer was higher in men, and the risk of developing proximal colon cancer was higher in female. 32 Colon cancer has different molecular and pathological characteristics according to the tumor location. Right-sided colon cancer is more advanced and less differentiated than left-sided colon cancer. 26 Endoscopic exams have also clearly revealed the morphological differences between right and left colon cancers. A higher proportion of women showed flat and depressed-type CRC lesions, while a higher proportion of men demonstrated polypoid-type lesions, which are more easily detected. 4 Patients with right colon cancer exhibited more ambiguous symptoms. 26 Furthermore, women were found to have a longer transverse colon and higher redundancy compared to men.
These sex-specific anatomical and physiological characteristics may result in incomplete colonoscopy in women, making it challenging to detect tumors in endoscopies. 27 These findings suggest that more attention needs to be given to colon cancer screening in women in terms of sensitivity. Additionally, sex-specific screening guidelines for CRC are required.
Overall survival and progression-free survival were similar in both sexes in our cohort although women with stage I CRC showed better overall survival than men with stage I CRC. This finding may be partly explained by the better survival of women in the general population because non-cancer deaths have a significant impact on the survival rates of patients with stage I cancer.
A few studies have reported that women have worse survival than men. 28,29 These differences were particularly significant among older patients. According to previous studies, economic difficulties were associated with a reluctance to undergo colon cancer screening, 28 and older women with advanced-stage cancer were found to behave passively while undergoing aggressive medical therapy. 30 These patients are also less likely to undergo regular medical check-ups, and may have fewer opportunities for early diagnosis. Therefore, the poor survival rate in older women may be associated with socioeconomic factors. Perhaps, if women and men had equal opportunities for screening and treatment, there would be no sex differences in the survival rate of patients with CRC.
The major strength of this study is that our multicenter data could represent the population of most regions in the republic of Korea.
However, there are several limitations. First, this is a retrospective study, which is subject to potential bias. Second, there is lack of gene mutation data. Although we have large study population, the results of genetic mutation were not obtained from all subjects, and the sample size was small in some variables. However, the incompleteness is unlikely to vary by sex. Further study with sufficient sample sized is needed to understand sex differences in CRC that focus on gene mutation.

| CONCLUSION
In conclusion, this study shows that there are sex-specific differences such as location of cancer, frequency of gene mutation, and survival rate of stage I cancer in patients with CRC. Biological and socialbehavioral differences between men and women seem to be the reason for the differences in the characteristics of CRC. The results of this study imply that there may be sex-specific differences in optimal colon cancer diagnosis and treatment. Further studies on sexspecific differences in comprehensive molecular analysis and treatment response are required.