Cancer is a major global public health problem and is also the second primary cause of death in the United States [1]. There are many differences between males and females in morbidity, mortality, prognosis, and biological behaviour for most cancers. The sex differences in cancer survival have attracted great attention because they may be a signal of basic biological differences between males and females in cancer pathogenesis and treatment response, which can be incorporated into management strategies. Therefore, sex differences are an essential research direction in tumour research. Interestingly, females seem to have better outcomes in most tumours, such as low morbidity, low mortality, and better prognosis. Moreover, a systematic review indicated that female patients also often have a survival advantage over male patients in many cancers [19]. Among the sex differences in some cancer manifestations, researchers have found that some may be related to male occupational and environmental exposures [20]. Nevertheless, in many circumstances, despite the control of environmental and genetic factors, the sex differences found in many cancers remain unexplained [21–22]. Our study focussed on the prognostic impact of sex on early local CRC. CRC is one of the most common malignant tumours in the U.S. It is the third most common tumour in both male and female patients. The estimated new cases in 2020 will be 78,300 in males and 69,650 in females. Among all tumours, the mortality rate of CRC ranks third among males and females. The data for 2020 projected deaths are 28,630 male patients and 24,570 female patients. Although the morbidity and mortality of CRC rank third in both male and female patients, there are some differences in their morbidity, mortality and prognosis.
The influence of sex on CRC has also been a hot topic in recent years. In 2001, a German study surveyed nearly 900 patients and concluded that being female was related to improved long-term survival in rectal cancer [6]. In 2003, a similar study evaluated 3,200 cases and found that females had a survival benefit in CRC [5]. More studies have indicated that sex is an independent prognostic factor in CRC, and females usually live longer than males [2–8]. Other studies indicated that females improved OS compared with males [3, 5, 23–24]. Compared to males of all ages, females are less likely to have CRC [9–10]. In fact, their risk is equivalent to that of males 4 to 8 years younger [11]. Thus, the effect of sex on CRC is well recognized. Although a large number of studies have shown that the female prognosis is better than male prognosis in many cases, there were many confounding factors that resulted in the better outcomes of women than men in these studies.
Therefore, the purpose of our research is to see whether the female superiority over males remains after controlling for confounding factors. There are several explanations for the sex differences in CRC, including environmental influence, tumour biology, and therapeutic response. First, hormones may be one reason. Postmenopausal hormone use has been linked to a 40% reduction in CRC in the Women's Health Initiative trial [13]. This link between hormone replacement therapy and colon cancer prevention is in line with former reports [14–15]. Therefore, we believe that oestrogen may be a confounding factor, so our study cohort included only menopausal women. Menopause is usually defined as 12 months of amenorrhea in females over 45 years of age. It usually starts between 45 and 55 years of age, with an average age of 50.5 years [25]. However, there are women who go into menopause after age 55 [26]. Based on the above, we only selected patients aged 60 years and older to form our study cohort to ensure that all female patients were postmenopausal. Next, the biological features of tumours may be different between males and females. There is evidence that females are more likely to develop microsatellite-unstable phenotypes of right-sided tumours [7, 27]. Furthermore, some reports suggest that females present at a more advanced stage of cancer [18]. Consequently, we selected early local CRC of stage T1-4N0M0 for analysis after stratification of the primary tumour site. Some studies have shown that sex, age, and ethnicity play an important role in the OS of CRC patients. A review of the literature showed that we analysed the largest cohort of colorectal cancer patients, and sex and age had an important impact on the OS of CRC patients. Therefore, we also conducted a detailed analysis stratified by both race and age.
In that analysis, we still found that females had better survival than males with T1-3N0M0 colon cancer and T1-2N0M0 rectal cancer after taking away the effects all known confounding factors. However, there was no difference in survival between sexes among T3N0M0 rectum cancer patients. For rectum tumours with a postoperative pathological stage of T3N0M0, the preoperative clinical stage is often more advanced and may generally be a locally advanced stage. These patients are often treated with preoperative neoadjuvant treatment. For rectum cancer of the pT3N0M0 stage, the recommendation of the NCCN guidelines [28] is adjuvant therapy or observation. Adjuvant therapy is often recommended for T3rectal cancer with prognostic risk factors. Therefore, we also performed a subgroup analysis of patients with and without preoperative radiotherapy. As a result, we found the benefits of female sex among T3N0M0 rectum cancer patients who underwent postoperative chemotherapy, regardless of whether preoperative radiotherapy was performed. Moreover, the results indicate that the T3N0M0 rectum cancer patients who underwent postoperative chemotherapy had a survival benefit over individuals without postoperative chemotherapy, regardless of sex. Females more often have tumours with microsatellite instability. This reason, as suggested in many studies, could be that females benefit more from chemotherapy [17, 29].However, all of these studies were confined to more advanced CRC, and there are few studies about the influence of sex on chemotherapy in early-stage tumours (T3N0M0). Although it is generally accepted that females have a better survival than males, we did not find a survival benefit of females with T3colorectal cancer. A significant survival benefit was obtained in rectum cancer patients with postoperative chemotherapy, which also confirmed that women can benefit more from postoperative chemotherapy in early rectal cancer (T3N0M0).Therefore, in addition to the existence of risk factors, female sex can also be considered an indicator for postoperative chemotherapy in T3N0M0 rectum cancer.
Although this research is based on a large number of samples, our research should be interpreted on the background of some limitations, some of which are intrinsic in the design of retrospective studies. Our results may not be representative of young patients with colorectal cancer. To exclude the effects of oestrogen on the results, we included only colorectal cancer patients aged 60 years and older. Information on radiotherapy and chemotherapy was ‘None/Unknown’, so we cannot rule out that some of these people had undergone radiotherapy or chemotherapy. Many significant clinical factors, predictive and prognostic biomarkers (e.g., microsatellite instability status), and behavioural differences (e.g., smoking, alcohol, diet, exercise and physical activity) were not available. In addition, there was no information in the SEER database about menopausal status or use of hormone therapy. Thus, there may have been some postmenopausal patients who were still taking oestrogen. Despite these limitations, our large-scale population-based research may make our conclusions more persuasive.
In conclusion, we found that females have a survival benefit over males among patients with T1-3N0M0 colon cancer and T1-2N0M0 rectal cancer. Sex was also proven to be an independent prognostic factor in T1-3N0M0 colon cancer and T1-2N0M0 rectal cancer. Females are more likely to benefit from postoperative adjuvant chemotherapy than males with T3N0M0 rectal cancer. Our research suggests that sex could be considered a factor in practical clinical treatment and prognosis evaluation for stage T1-3N0M0 rectal cancer. Especially in clinical decision-making on postoperative adjuvant therapy for T3N0M0 rectal cancer, female sex can also be considered an indicator for postoperative adjuvant therapy.