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- Material and Methods
The risk of endometrial cancer (EC) subsequent to a diagnosis of colorectal cancer in women with a germline mutation in a mismatch repair gene [Lynch syndrome or hereditary non-polyposis colon cancer (HNPCC)] is unknown. We estimated the risk of EC following a diagnosis of colorectal carcinoma (CRC) for women with Lynch syndrome. A retrospective cohort study was performed on women diagnosed with CRC with a germline mutation in a mismatch repair (MMR) gene (Lynch syndrome cases), and women with microsatellite stable (MSS) CRC who were not known to carry a germline mutation (non-Lynch cases), identified from the Colon Cancer Family Registry. The incidence of EC following CRC was estimated and compared for women with and without Lynch syndrome, using adjusted hazards ratios calculated for time at risk among each group. A total of 112 women with Lynch syndrome and a previous diagnosis of CRC were compared with 908 women without Lynch and with a MSS CRC diagnosis. The estimated 10-year cumulative risk of EC subsequent to CRC was 23.4% [95% confidence interval (CI): 15–36%] for Lynch syndrome women compared with 1.6% (95% CI: 0.7–3.8%) for non-Lynch women. After adjusting for ascertainment, age at diagnosis and diagnosis of other cancers, risk of subsequent diagnosis with EC was elevated sixfold in women with Lynch syndrome compared with non-Lynch women (HR 6.2; 95% CI 2.2–17.3; p = 0.001). Approximately one quarter of women diagnosed with Lynch syndrome-associated CRC developed EC within 10 years. This supports the sentinel cancer concept and suggests that active and early management is important for these women.
Lynch syndrome [also known as hereditary non-polyposis colon cancer (HNPCC)] is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6 or PMS2. Carriers of MMR gene mutations are at increased risk of cancers of the colon, endometrium, ovary, upper urologic tract, stomach, small bowel, biliary/pancreas, skin and brain.1 In individuals who carry such mutations, inactivation of the remaining normal allele in a cell results in dysfunctional or absent DNA MMR. These unrepaired mismatches typically occur in regions of repetitive nucleotide sequences, commonly referred to as microsatellites. The consequent phenotype, referred to as microsatellite instability (MSI), is the signature change in Lynch syndrome-associated cancers.2, 3 Detection of a deleterious germline mutation in a particular MMR gene in a case of cancer with MSI unequivocally establishes the diagnosis of Lynch syndrome, with MLH1 and MSH2 sequence variants accounting for ∼80% of all MMR gene mutations.4
Early age of cancer diagnosis and multiplicity of cancers are considered hallmarks of Lynch syndrome. A meta-analysis5 of data from three population-based studies,6–8 and previous clinic-based work,9 estimated that the risk of colorectal cancer for MLH1 and MSH2 carriers to age 70 years was 53% for males, 33% for females and for endometrial cancer (EC) was 44%. Although the increased risk of EC in women with Lynch syndrome is well established, the risk of EC after Lynch-associated colorectal cancer is unknown. Possible reasons for a change in EC risk after colorectal cancer diagnosis include, but are not limited to: effects of radio- or chemo-therapy for the colorectal cancer, increased surveillance, weight change and changes in exposures to environmental risk factors. A number of attempts have been made to address this question, but the relationship could not be estimated with sufficient precision due to the limited number of cases analyzed or the design of the original study.10–12 If women with Lynch syndrome-related colorectal cancer have an increased risk for subsequent primary gynecological cancer, they could be advised to undertake interventions such as screening13, 14 and/or risk-reducing surgery to prevent subsequent primary cancers.
Hence, the aim of this study was to estimate the risk of EC subsequent to a diagnosis of colorectal cancer in women with Lynch syndrome. To achieve this aim, we analyzed cancer risk using a large cohort of MMR mutation carriers from the international Colon Cancer Family Registry (Colon CFR).15
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- Material and Methods
Characteristics of the cohort are summarized in Table 2. There were 112 women with a previous diagnosis of colorectal cancer who had Lynch syndrome (Lynch group) and 908 women with a previous diagnosis of colorectal cancer who did not have Lynch syndrome (non-Lynch group). Approximately one-third (32.1%, n = 36) of the women with Lynch syndrome and 1.7% (n = 15) of the non-Lynch women had at least one other relative included in this analysis. The Lynch group were generally younger when first diagnosed with colorectal cancer, with a median age of 39 years compared with 54 years for the non-Lynch cases (p < 0.001). Few participants reported using tamoxifen–only one of the Lynch group (0.9%) and 15 (1.7%) from the non-Lynch group.
After a diagnosis of colorectal cancer, almost half of the cases (44.6%) with Lynch syndrome had a hysterectomy, compared with only 4.1% of the non-Lynch group (p < 0.001). The reasons for those hysterectomies were not stated. None of the 50 cases in the Lynch group who had a hysterectomy died within 5 years of follow-up. Among the 62 Lynch group cases that did not have a hysterectomy, six (9.7%) had died within 5 years.
About 1 in 5 of the women in the Lynch group were subsequently diagnosed with EC (n = 22, 19.6%) compared with 0.9% (n = 8) in the non-Lynch group (p < 0.001). Of the 30 reported EC diagnoses in both groups, we were able to verify 23 (76.7%) by either pathology reports or medical records.
Two of 112 (1.8%) cases of the Lynch group developed ovarian cancer subsequent to colorectal cancer compared with three of 908 (0.3%) in the non-Lynch group. The proportion of cases diagnosed with cancers other than endometrial or ovarian cancer subsequent to colorectal cancer was significantly higher in the Lynch group (17.0 vs. 5.8%; p < 0.001).
There were a total of 1,059 person years at risk among the Lynch group and 5,383 person years at risk among the non-Lynch group. Although differences in the distribution of time at risk for EC between Lynch and non-Lynch CRC cases were statistically significant (p = 0.011), the median time at risk was similar for the two groups (6.3 years and 6.0 years, respectively).
For the Lynch group, there was no significant difference (p = 0.284) in the MMR gene that was mutated for those who were subsequently diagnosed with EC and those who were not (Table 3). The majority of the deleterious mutations occurred in either the MLH1 gene (50.0% for both those with and without EC) or the MSH2 gene (40.9% for those with EC and 47.8% for those without subsequent EC). In the group of mutation carriers who developed EC, two women (9.1%) had a MSH6 mutation compared with two women in the group who did not (2.2%).
Table 3. Subsequent diagnosis of endometrial cancer by type of deleterious mutation for colorectal cancer cases with Lynch syndrome
Crude incidence rates of EC following colorectal cancer were 20.8 cases per 1,000 years at risk for women in the Lynch group and 1.5 cases per 1,000 years at risk for women in the non-Lynch group. Corresponding age standardized rates were significantly higher in the Lynch group with 18.6 cases per 1,000 years at risk (95% confidence interval (CI) = 11.7–28.2) in contrast to 1.1 cases per 1,000 years at risk (95% CI = 0.5–2.1), respectively (p < 0.001).
The 10-year cumulative risk of EC following colorectal cancer in the Lynch group was 23.4% (95% CI = 14.5–36.3%) compared with the corresponding risk of 1.6% (95% CI = 0.7–3.8%; p < 0.001) for the non-Lynch group (see Fig. 1).
Figure 1. Cumulative risk (95%-confidence intervals) of colorectal cancer cases subsequently being diagnosed with endometrial cancer by study group (Lynch Syndrome vs. non-Lynch group).
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After adjusting for age at colorectal cancer diagnosis, presence of cancers other than colorectal or EC and ascertainment type (Table 4), it was estimated that women in the Lynch group were about six times more likely to be diagnosed with EC following colorectal cancer (hazard ratio = 6.2; 95% CI = 2.2–17.7, p = 0.001).
Table 4. Adjusted hazard ratios for endometrial cancer following colorectal cancer
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- Material and Methods
We found that for every 100 women diagnosed with Lynch syndrome-associated colorectal cancer, around 23 (95% CI = 15–36) will be diagnosed with EC within 10 years if they do not have a hysterectomy. This compares with less than two women being diagnosed with EC for every 100 women who are diagnosed with colorectal cancer who have not inherited a mutation in a MMR gene, although the non-Lynch group available for our study were somewhat younger on average than is generally the case.
The concept of a “sentinel” cancer suggests that Lynch carriers are at increased risk of developing subsequent primary cancers following an initial (sentinel) cancer diagnosis compared with non-Lynch carriers. Two other research groups suggested that the risk of a second primary cancer in Lynch carriers is 25 and 50% by 10 and 15 years, respectively, after diagnosis of a first cancer.18, 19 In a series of 117 women with dual primary (endometrial and colon) cancers from 223 Amsterdam families, 16 women had synchronous cancers.20 Of the remaining 101 women, 52 developed an endometrial or ovarian cancer first, whereas 49 cases were diagnosed with colorectal cancer first and had a second primary cancer subsequently. Hence, colorectal cancer can be seen as a sentinel event in approximately half of women with Lynch syndrome affected with multiple malignancies, and EC represents the sentinel cancer in the remainder, a finding consistent with the present report. Our data confirm the sentinel cancer concept; the risk of subsequent EC in cases with Lynch syndrome on the occasion of a colorectal cancer event is a significant increase over what would be expected in unselected cases.
Clinically, the concept of sentinel cancer is potentially very helpful not only for affected individuals but also for their relatives. The proportion of women with EC diagnosed at or before the age of 50 years who carry germline mutations in a MMR gene varies between 9 and 18%.21, 22 Current evidence supports colorectal screening in those cases. In one observational analysis, screened cases had more than a 60% reduction of colorectal cancer incidence compared with unscreened cases.23 Data from the United Kingdom suggested a 72% reduction in mortality attributed to screening colonoscopy for individuals with a strong family history of colorectal cancer,24 and women diagnosed with Lynch syndrome-related EC are advised to have regular colorectal and other screening postoperatively.
Until recently, no population-based data were available regarding the risk of EC following a Lynch syndrome-associated colorectal cancer diagnosis. Current recommendations are based on the extrapolation of evidence from various contexts. This is the first study of sufficient size to quantify the risk of EC following Lynch syndrome-related colorectal cancer, thus supporting early and active management in those young women.
Recent reports have addressed the efficacy of EC screening in Lynch carriers. In a series of 35 premenopausal and six postmenopausal women who were MMR gene mutation carriers or who fulfilled the Amsterdam criteria and mismatch gene mutation status was unknown, three premalignant lesions were detected within a total of 197 patient years at risk.25 In addition, one patient was diagnosed with interval EC based on her symptoms. Generally, it is believed that endometrial sampling/biopsy is superior to transvaginal ultrasound alone for EC surveillance in premenopausal women.13, 14 In postmenopausal women, the threshold for endometrial thickness on transvaginal ultrasound has been analyzed several times and ultrasound might be equivalent to endometrial sampling for that group of patients.26, 27 In a multi-institutional retrospective cohort analysis, Schmeler et al. investigated 315 women with documented germline MMR mutations.28 A total of 61 women had undergone prophylactic risk-reducing hysterectomy and 47 women had undergone prophylactic bilateral salpingo-oophorectomy. These women were matched with mutation-positive women who had not undergone prophylactic surgery. The prophylactic surgery group experienced no occurrences of endometrial or ovarian cancer, comparing favorably with 33% EC and 5% ovarian cancer in the control group. The results from this study suggest that prophylactic hysterectomy with bilateral salpingo-oophorectomy is effective in preventing gynecological cancer in women with Lynch syndrome.
Although 100% of EC could be prevented by prophylactic surgery, this may or may not translate into survival benefits. Given that the incidence of ovarian cancer is consistently low in Lynch syndrome series,29, 30 and given the normally excellent prognosis of clinically diagnosed EC,31 the actual survival benefits may be modest at best. To date, only case reports32–34 but no data from cohort series or clinical trials are available on the use of a levonorgestrel intrauterine device and its potential ability to prevent EC.
Clinically, one of the major research questions is: “Should women diagnosed with Lynch-associated colorectal cancer require specific management addressing this risk?” Several outcome parameters are relevant to this important question. Our study focused on the incidence rates of EC and we demonstrate a high risk of developing EC after Lynch-associated colorectal cancer but only five cases of ovarian cancer were diagnosed. Two of those five women had Lynch syndrome and three were non-Lynch. Unfortunately, we are unable to answer whether screening or prophylactic, risk-reducing hysterectomy will improve survival.
Because the recruitment to the Colon CFR was weighted toward early-onset colorectal cancer,15 the majority of women in this series (96% for Lynch patients and 62% for non-Lynch) were diagnosed with colorectal cancer before the age of 60 years. Inference of these findings to cases diagnosed at a relatively young age is therefore straightforward, but a potential limitation may be the inability to infer our findings to cases diagnosed at an older age.
Another potential limitation of this study relates to the Colon CFR recruitment process. Although no clinic-based families were ascertained because of a case of EC following a colorectal cancer, some families may have been recruited due to EC occurring in a relative; hence, for the estimate of increased risk over non-Lynch women, we adjusted for ascertainment type. However, this recruitment strategy is unlikely to have resulted in biased estimates as women with both CRC and EC were not more likely to be eligible for the study and were not more likely to be tested for MMR mutations than women with CRC only. Less than a third of all cases completed their baseline interview within 1 year of being diagnosed with colorectal cancer, meaning that those who died within the 1st year were less likely to be recruited to the study than those who survived longer. It is unclear what effect excluding these women would have on the calculation of cumulative risk of EC.
In summary, our article suggests that about one quarter of cases who were diagnosed with Lynch syndrome-associated colorectal cancer who do not have a hysterectomy will develop EC within 10 years. Given the extent of that risk, identification of these patients and proactive management is justified to reduce the burden of this cancer. Management options include risk-reducing, prophylactic total hysterectomy and bilateral salpingo-oophorectomy28 or regular screening with endometrial sampling on a yearly basis for premenopausal women or transvaginal ultrasound examinations for postmenopausal women.