Risk of Breast/Gynecological Cancer Development in Patients With CRC
Table 2 lists the HRs for breast/gynecological cancers during the follow-up period after treatment for CRC. Patients were followed for a total of 330,442 person-years (mean: 5.83 years/person) in the CRC group and 1,691,937 person-years (mean: 5.87 years/person) in the general population. Overall, 949 of 56,682 patients with CRC (1.67%) and 1675 of 288,119 in the general population (0.58%) developed breast/gynecological cancer (HR, 2.91; 95% CI, 2.69–3.15; p < 0.001; incidence ratio, 2.87 vs 0.99 per 100,000 person-years).
The HRs for the development of site-specific breast/gynecological cancers were higher among CRC survivors than among control subjects. This increased risk was most prominent for ovarian cancer, followed by uterine corpus cancer, cervical cancer, and breast cancer (ovarian cancer: HR, 6.72; 95% CI, 5.72–7.91; p < 0.001; uterine corpus cancer: HR, 3.99; 95% CI, 3.21–4.96; p < 0.001; cervical cancer: HR, 2.82; 95% CI, 2.34–3.40; p <0.001; breast cancer: HR, 1.85; 95% CI, 1.64–2.08; p < 0.001).
The risk of female cancer was higher among CRC patients younger than 55 years (HR, 3.51; 95% CI, 3.09–3.98; p < 0.001) than among those older than 55 years (HR, 2.59; 95% CI, 2.34–2.87; p < 0.001).
Figure 2 shows the cumulative incidence of breast/gynecological cancer in each group over time. The incidence of these cancers was concentrated within the first 5 years after the diagnosis of CRC. However, the risk of all breast/gynecological cancers remained higher among patients with CRC relative to the general population, even after 5 years, with annual averages of 0.99 and 2.87 breast/gynecological cancer diagnoses per 1000 women in the control group and the CRC patient group.
Subgroup Analysis Using BMI and Health Behavior Data
A total of 14,190 women with CRC and 71,933 women without CRC who had undergone a health checkup within 1 year of CRC diagnosis were included in an additional subgroup analysis (Supplementary Table 1, http://links.lww.com/DCR/A732). Patients with diabetes mellitus, hypertension, or dyslipidemia were significantly more common in the CRC group than in the control group. However, smoking, alcohol consumption, and BMI did not significantly differ between the 2 groups.
In this subgroup analysis, 210 of 14,190 patients with CRC (1.48%) and 372 of 71,933 subjects in the general population (0.52%) were diagnosed with breast/gynecological cancer (adjusted HR, 2.88; 95% CI, 2.43–3.41; p < 0.001) (Supplementary Table 2, http://links.lww.com/DCR/A733). Even after adjusting for BMI and health behavior data in addition to demographic differences and comorbidities, the risks of breast, ovarian, and uterine cancer were higher in the CRC group than in the general population.
We next conducted a multivariable analysis of CRC survivors to evaluate potential risk factors for secondary breast/gynecological cancer development (Table 3). In this analysis, BMI, alcohol consumption, physical exercise, income, and the status of hypertension or diabetes mellitus were not associated with the risk of secondary breast/gynecological cancer among CRC survivors. However, current smoking was associated with an increased risk of developing ovarian and uterine cervical cancers (HR, 1.62; 95% CI, 1.05–2.5 and HR, 1.54; 95% CI, 1.07–2.22), whereas dyslipidemia was associated with an increased risk of breast cancer (HR, 1.40; 95% CI, 1.10–1.79).
We additionally evaluated the possible combined effect of CRC and dyslipidemia on the development of secondary breast/gynecological cancers (Table 4). Among non-CRC subjects, dyslipidemia was associated with an increased risk of breast cancer (HR, 1.45; 95% CI, 1.09–1.92 in dyslipidemic subjects). Among CRC patients, the incidence of breast/gynecological cancer was significantly higher among those with dyslipidemia (HR, 2.66; 95% CI, 1.78–3.98; p < 0.001) than among those without dyslipidemia (HR, 2.06; 95% CI, 1.52–2.78; p < 0.001) (Table 4). In other words, dyslipidemia is an additional contributor to the development of secondary breast cancer.
In this nationwide population-based cohort study of CRC survivors, we have identified an increased risk of breast and gynecological (ovarian, uterine cervix, and uterine corpus) cancers in comparison to age- and sex-matched non-CRC controls. Several studies have addressed the risk of second primary malignancies as the life expectancies of patients with CRC continue to increase.14–19 However, few studies have focused on breast and gynecological cancers among CRC survivors. Lee et al19 reported 2-fold and 3.2-fold increases in the risks of ovarian and uterine cancers among patients with CRC relative to the general population. Hemminki et al17 reported higher risks of breast, ovarian, and uterine cancer among patients with CRC than among the general population, in particular, within 1 year after the diagnosis of CRC. Although the present study showed an increased risk of all site-specific breast/gynecological cancers in the CRC group, Yang et al14 reported a higher incidence of uterine corpus cancer, but not of ovarian and breast cancers, among survivors of CRC than in the general population. Furthermore, Yang and colleagues14,15 observed an increased risk of second primary malignancies within 5 years after the diagnosis of CRC. Although the reasons underlying the variable risks of breast and gynecological cancers among studies remain unclear, ethnic variation is likely a major contributor. In previous studies, the incidence of malignancy was found to vary according to differences in racial background and accessibility to medical services.20,21
In the present study, the risk of breast/gynecological cancer was higher among patients who were younger than 55 years at the first CRC diagnosis (HR, 3.51), compared with those aged 55 years or older (HR, 2.59). Other studies have similarly reported a higher risk of secondary malignancy in patients initially diagnosed with CRC at a younger age.10,11,16 In summary, a lower age at CRC diagnosis corresponds to a higher probability of early breast/gynecological cancer detection during surveillance tests.
The occurrence of a second primary malignancy may be associated with genetic susceptibility, cancer-related treatment, environmental exposures, or hormonal effects. Currently, the most common and well-known syndromes are hereditary breast and ovarian cancer and hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Mutations in mismatch repair genes (MLH1, MSH2, PMS1, and MSH6) can cause both CRC and gynecological (ovarian, breast, and endometrial) cancers at a young age.22 However, HNPCC is a very rare disease, accounting for <1% of all CRC cases.23 Evans et al16 reported that patients with HNPCC had a 0.2% to 2% risk of developing primary carcinomas, with the exception of ovarian cancer. Women harboring a deleterious mutation in BRCA1 or BRCA2, which encodes tumor suppressors, have an elevated risk of developing breast or ovarian cancer, as well as an elevated risk of CRC.24 However, women harboring a BRCA mutation have only a slight overall increased risk of non-breast or -ovarian malignancies.24 HNPCC and BRCA mutations are rare, and therefore cannot account for most of the secondary breast/gynecological cancers in patients with CRC. Genetic susceptibility to therapeutic agents is thought to correlate with the development of secondary cancers. Because individuals harbor genetic differences (ie polymorphisms) related to drug metabolism (eg, glutathione transferase), patients who are more sensitive to drugs have a higher risk of developing secondary cancers.25
Environmental and lifestyle factors such as smoking, excess alcohol intake, and dietary patterns also affect secondary cancer development.26 Until recently, smoking was not considered a risk factor for breast/gynecological cancers, and studies of this issue were very limited. In 2009, the International Association for Cancer Research added ovarian cancer to the list of cancers caused by smoking.27 Although smoking may not directly cause uterine cervical cancer, it appears to accelerate the damage to cervical tissues caused by the human papillomavirus or an otherwise unhealthy lifestyle.28 In this study, we showed that current smoking is associated with an increased risk of secondary ovarian and cervical cancer development. However, whether a history of CRC might increase susceptibility to tobacco-related breast/gynecological carcinogenesis remains to be determined.
The other factor that may contribute to the association between CRC and uterine corpus cancer is the influence of hormones. Notably, nulliparous women have a higher risk of uterine corpus cancer.29 In addition, nulliparous women with a family history of CRC had a risk ratio of 2.38 for CRC, compared with a risk ratio of 1.21 among women who bore more than 4 children.30
Interestingly, the present study found an increased risk of secondary breast cancer development among CRC survivors with that dyslipidemia. An elevated cholesterol level is a risk factor for breast cancer, although the mechanism by which this occurs is not well understood.31 It is possible that dyslipidemia increases the cholesterol contents of cell membranes, which affects membrane fluidity and subsequent signaling. Moreover, the metabolite 27-hydroxycholesterol can function as an estrogen, thus increasing the proliferation of estrogen receptor-positive breast cancer cells.31 In the present study, the CRC survivors with dyslipidemia had a synergistically elevated risk for developing breast cancers in comparison with CRC survivors without dyslipidemia. Further studies are needed to determine the mechanism of increased risk of breast cancer in patients with CRC who have dyslipidemia.
This study had several limitations. First, because this study was based on claims data, disease stage data were not available; in addition, we could not discern locally advanced and recurrent CRCs affecting female organs from true second primary cancers. Second, information related to other confounding factors, including parity, age of first menstruation and menopause, history of breastfeeding, and hormone therapy, was not available. Third, although hereditary CRC is rare, it could not be excluded because information about family histories or genetic testing was not available. Despite these limitations, this population-based study sourced data from a nationwide database compiled by the NHIC program, in which more than 97% of Koreans are obliged to participate. Because a biopsy confirmation is required for all patients registered for cancer, the cancer diagnoses were exhaustive and reliable. Moreover, studies evaluating the association between CRC and cancers of female organs are limited.
The risk of developing breast, ovarian, and uterine (including cervix and corpus) cancers is higher among patients with CRC than in the non-CRC population. Further causal and mechanistic studies are warranted.
The authors thank Jin Hyeong Jung.
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Breast cancer; Colorectal cancer; Ovarian cancer; Second primary malignancy; Uterine cancer
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