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Awareness of Endometrial Cancer Risk and Compliance With Screening in Hereditary Nonpolyposis Colorectal Cancer

Ketabi, Zohreh, MD; Mosgaard, Berit J., MD, PhD; Gerdes, Anne-Marie, MD, PhD; Ladelund, Steen; Bernstein, Inge T., MD, PhD

doi: http://10.1097/AOG.0b013e31826ba2aa
Original Research

OBJECTIVE: Women with hereditary nonpolyposis colorectal cancer (HNPCC) have a 40–60% lifetime risk for endometrial cancer. Guidelines in Denmark recommend gynecologic screening for female members of families with HNPCC. We estimated the knowledge of endometrial cancer risk and identified possible predictors of compliance with the screening among women from families with HNPCC.

METHODS: A questionnaire exploring the knowledge of endometrial cancer risk and compliance with screening was sent to 707 women from families with HNPCC who had been recommended endometrial cancer surveillance. The response rate after one reminder was 86% (606 of 707). Data were analyzed by simple and multivariable logistic regression models.

RESULTS: Four hundred seventy-one women were included in the final analyses; 65% reported being aware of the increased risk of endometrial cancer. The awareness was significantly greater among women with high educational level (81%; P<.001), women who had received genetic counseling (75%; P<.001), women with family history of gynecologic cancer (76%; P<.001), and those with high perceived endometrial cancer risk (77%; P<.001). Overall, 67% had participated in gynecologic screening. No significant differences were found in compliance regarding women's educational level or their family risk classification. Analyses of data in a multivariable logistic regression model showed that knowledge of endometrial cancer risk was the most important predictor for positive compliance with the gynecologic screening (odds ratio 4.86, 95% confidence interval 3.05–7.74).

CONCLUSION: Women's awareness of endometrial cancer risk is the most important predictor of their compliance with gynecologic screening in families with HNPCC.


The Danish HNPCC-register, Department of Surgical Gastroenterology and Department of Clinical Research Centre, Copenhagen University Hospital, Hvidovre, the Department of Obstetrics and Gynecology, Copenhagen University Hospital, Herlev, and the Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Denmark.

Corresponding author: Zohreh Ketabi, HNPCC-register, Clinical Research Centre 136, Hvidovre Hospital, Kettegård Allé 30, DK 2650, Hvidovre, Denmark; e-mail:

Supported by a grant from the Danish Cancer Society (grant number: A20-A822–10-S2) and the Aase and Ejnar Danielsen's Foundation.

The authors thank the women who participated in this study and the clinical genetic departments for recruiting families to the national database.

Presented as an oral presentation at the InSiGHT meeting, March 31–April 2, 2011, San Antonio, Texas, and at the Danish Gynecologic Cancer Group's annual meeting, October 11, 2011, Vejle, Denmark.

Financial Disclosure The authors did not report any potential conflicts of interest.

Hereditary nonpolyposis colorectal cancer, including Lynch syndrome, is an autosomal-dominant syndrome, characterized by early occurrence of malignancies. The condition is caused by mutations of DNA mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. Although colorectal cancers traditionally have been the hallmark cancer of the syndrome, women with hereditary nonpolyposis colorectal cancer (HNPCC) have 40–60% cumulative lifetime risk for endometrial cancer, which equals or exceeds that of colorectal cancer.1–3 In approximately 50% of women with both colorectal and endometrial cancers, endometrial cancer is the prime cancer.4 Women with HNPCC also have an increased risk (8–12%) of ovarian cancer.5,6 Considerable attention has been focused on colorectal cancer risk in HNPCC, and consensus colorectal cancer screening guidelines are supported by prospective studies substantiating the benefit of the screening.7–9 However, data on the efficacy of endometrial cancer screening in Lynch syndrome are limited. Nevertheless, current recommendations advise women to undergo annual or biennial transvaginal ultrasonography and endometrial biopsy beginning between the ages of 30 and 35 years, based on expert opinion.10 To date, little is known about the extent of women's knowledge of gynecologic cancer risk and screening in families with HNPCC. Previous studies have shown that women in these families are less aware of their risks for extracolonic cancers and undergo endometrial cancer screening significantly less often than colonoscopy.11–14 We estimated the knowledge of gynecologic cancer risks and identified the possible predictors of compliance with endometrial cancer screening among women from families with HNPCC.

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The Danish HNPCC register was established in 1991 as a national database registering clinical and genetic data in families with HNPCC with the aim of improving the prognosis by identifying at-risk individuals, establishing screening, and evaluating the outcome on a national level.15 The families were counseled and identified at the departments of clinical genetics and at the HNPCC register at Hvidovre Hospital. When data were entered into the database at the HNPCC register, family risk classification was performed according to standardized criteria such as families with a disease-causing mutation in an mismatch repair gene (MLH1, MSH2, MSH6, or PMS2; Lynch families), families fulfilling the Amsterdam I or II criteria, and families with suspected Amsterdam criteria fulfillment. The last-mentioned criterion included families who fulfilled the Amsterdam I or II criteria except: 1) one cancer was not documented by hospital records, histopathology reports, or death certificates; 2) one invasive colorectal cancer was replaced by an adenoma with severe dysplasia: or 3) there was the presence of HNPCC--related cancers not included in the Amsterdam II criteria (ovary, stomach, brain, hepatobiliary system, or pancreas).

Families were offered a clinical surveillance program including colonoscopy, gynecologic examination, and biennial transvaginal ultrasonography from the age of 25 years. All at-risk persons were contacted by letter, informed about HNPCC--related cancer risk and the recommended surveillance program, and offered genetic counseling. Information about phenotypes and genotypes were collected continuously over time. Hence, the family pedigrees and the risk classification could potentially change over time. These changes were registered in the database and new at-risk persons were contacted by letter. The Danish Data Protection Agency and the Scientific Ethics Committee of Copenhagen approved the HNPCC register, including this study ( 2009–41–3565).

The cohort was identified from the database as women at risk for endometrial cancer, age between 25 and 75 years and living in eastern Denmark from families classified as Lynch, Amsterdam I or II, or Amsterdam-suspected, including all mutation carriers, and women with HNPCC--related cancer or first-degree relative of such a person. HNPCC--related cancers included colorectal, endometrial, ovarian, upper urinary tract, small intestine, stomach, pancreatic, hepatobiliary tract, and brain. The exclusion criterion was previous hysterectomy. From May 2009 to February 2010, 707 women from 298 families were included in the survey.

A questionnaire including 27 questions was developed to assess the awareness of gynecologic cancer risk and self-reported compliance with gynecologic screening among women from families with HNPCC. The questions included: date and source of information about the HNPCC diagnosis; knowledge of gynecologic cancer risk; personal or family history and the perceived risk of gynecologic cancers (five questions); participation in gynecologic screening, pattern of participation, and women's attitude about the screening (seven questions); medical and gynecologic history (13 questions); education; and height and weight. The questionnaire was initially tested in a pilot study of 50 women who were informed about the purpose of the study and requested to comment on the questionnaire. In addition, six of the women completed and commented on the questionnaire in the outpatient department in the presence of the first author. The final version was adjusted by a few minor linguistic changes and sent to the participants with an information letter. Participants were asked to return a blank questionnaire as a “do not wish to participate or be contacted” message if they declined to be included in the study. Women who did not return the completed or blank questionnaire after a month were sent a reminder. Because the results of the pilot study and the final questionnaire were comparable and attributable to only minor changes in the final questionnaire, we included the 50 women in the pilot study in our analysis. Compliance with endometrial cancer screening was defined by three questions. Women were defined to be compliant with HNPCC--related endometrial cancer screening if they reported participating in gynecologic screening annually or biennially and the examinations were performed by a specialist (practitioner gynecologist or at a gynecologic department). A summary of the variables of interest including the questions used to define the variables and outcomes are listed in Table 1.

Table 1

Table 1

Discrete data are reported as counts and percentages, and continuous data are reported as means. All P values comparing proportions were calculated using alternating logistic regression16 to account for clustering within families. Multivariable logistic models, also alternating logistic regression, are reported with odds ratios and their 95% confidence limits and type 3 P values; P<.05 was considered to be statistically significant. All analyses were performed in SAS 9.2 for windows.

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Figure 1 illustrates the flow of the study population. Our response rate was 86% (606 of 707). Nonrespondents were significantly younger than respondents (mean age 47 compared with 52, respectively; P<.001). There was no difference in family risk classification between the two groups. A blank questionnaire was returned by 46 (7%) women. These women were significantly older than those who completed the questionnaire (mean age 62 compared with 51, respectively; P<.001). Five-hundred sixty women completed the questionnaire. Of these, 89 reported having undergone hysterectomy and were excluded from the analyses, leaving 471 women in the final analysis. The results of completed questionnaires are shown in Table 2.

Fig. 1

Fig. 1

Table 2

Table 2

In total, 460 women reported that they were informed about HNPCC: 198 women (43%) had received genetic counseling (of whom 53% had received genetic counseling more than 3 years before entry into the study); 108 (23%) had been informed by letter from the HNPCC register; and 154 (33%) had been reformed by their relatives. Overall, 302 women (65%) reported that they were aware of the increased endometrial cancer risk: 212 (47%) had known about their genetic predisposition for more than 6 years; 191 (41%) reported family history of gynecologic cancer; and 269 (60%) reported that they anticipated their risk for endometrial cancer was higher compared with that of the background population.

In univariable analyses, the awareness of endometrial cancer was significantly related to age younger than 65 years (P=.02), high educational level (P<.001), genetic counseling (P<.001), family history of gynecologic cancer (P<.001), and high perceived risk of endometrial cancer (P<.001). The awareness was greater in women from Lynch families compared with women from Amsterdam or Amsterdam-suspected families; however, the difference was not statistically significant (Table 3).

Table 3

Table 3

In the multivariable analyses, after adjusting for the variables of interest, women with university-degree education (P=.01), women who had a close relative with a gynecologic cancer (P=.002), and women with high perceived risk of endometrial cancer (P<.001) were more likely to be aware of endometrial cancer risk. Although women who had received genetic counseling were more likely to be aware of their cancer risk, the difference was not statistically significant in these analyses (P=.07) (Table 3).

Overall, 312 women (67%) reported attendance at gynecologic screening; gynecologic examinations included 267 (86%) transvaginal ultrasound examinations, 80 (26%) endometrial biopsies, and 48 (15%) serum CA 125 tests. Fifty-eight women (19%) reported having had annual screening visits, 205 women (66%) had biennial screening visits, and 39 women (13%) reported that they, so far, had one screening visit. Univariable analyses showed that attendance at endometrial cancer screening was significantly related to age between 45 and 54 years (P=.006), genetic counseling (P=.001), family history of gynecologic cancer (P=.04), high-perceived risk of endometrial cancer (P<.001), and the awareness of gynecologic cancer risk (P<.001). Neither educational level nor family risk classification had any association with the use of endometrial cancer screening. However, in multivariable analyses, only age between 45 and 54 years (odds ratio 2.8; P=.02) and the awareness of endometrial cancer risk (odds ratio 4.86; P<.001) were identified as significantly positively related to use of gynecologic screening (Table 4).

Table 4

Table 4

One-hundred fourteen women reported that they had not attended an endometrial cancer screening. The most frequent reasons were: “I have mainly been concerned about colorectal cancer” (41%) and “I had never heard that it was necessary to have gynecologic screening in my family” (35%).

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We investigated the awareness of endometrial cancer risk and self-reported compliance with gynecologic screening among women with increased risk of gynecologic cancer in HNPCC. The question assessing women's awareness and perceived risk for cancer in our study was specific to endometrial cancer. To our knowledge, this is the first large study that describes women's long-term awareness of endometrial cancer in families with HNPCC and that identifies predictors of compliance with endometrial cancer screening. This is based on a systematic search of the literature in PubMed (latest: June 18, 2012). The search terms used were: “hereditary nonpolyposis colorectal neoplasms” or “lynch syndrome;” AND “endometrial neoplasms” or “endometrial cancer” and “risk;” AND “endometrial cancer screening” or “endometrial cancer surveillance;” AND “knowledge” or “awareness,” and included all languages. Almost two-thirds of the women reported that they were aware of an increased risk of endometrial cancer and attended at endometrial cancer screening. More than half of the participants perceived their risk for development of endometrial cancer as higher than average.

Our rate of compliance with endometrial cancer screening was comparable with, if not better than, those of studies reporting the use of endometrial cancer screening after genetic counseling and testing.11–14 However, this study cohort included both women who had received genetic counseling in a genetics clinic and those who had been informed about the syndrome by letter from the HNPCC register or by their relatives.

The awareness of endometrial cancer risk was the main predictor of adherence to endometrial cancer screening in multivariable regression analyses. In addition, women between 45 and 54 years of age reported attending screening almost three-times more often. One explanation could be that women in this age group approaching menopause are more concerned about their heredity cancer risk. However, once awareness was entered into the logistic regression, the genetic counseling, perceived risk, and gynecologic cancer among close relatives were not significantly associated with the compliance, probably because of the high correlation between these variables and awareness of cancer risk. In other words, a person's awareness of cancer risk is dependent of many factors, such as age, education, family risk classification, experience of cancer (personal or in the family), and genetic counseling. Therefore, “awareness” will be a strong intermediate factor between these variables and the compliance. Hence, after adjusting for these variables in multivariable analyses, “awareness” will obscure the effect of the other factors. Nevertheless, our findings are consistent with a meta-analysis review by Katapodi et al,17 who note that perceived risk is weakly influenced by age and has a small but significant effect on adherence to mammography screening. Family risk classification and educational level did not show any relation to the compliance either in the univariable or in the multivariable analyses. After adjusting for the variables of interest, the awareness of cancer risk was significantly associated with education, genetic counseling, gynecologic cancer in the family, and the high perceived risk of endometrial cancer, in line with other studies.11,13

Hadley et al11 reported that use of endometrial cancer screening was significantly associated with women's perceived likelihood of being a mutation carrier and with sharing results of genetic testing with their physicians, and concluded that sharing the test results with the physicians facilitates the women's objectivity of their cancer risk. Our study demonstrated a higher rate of awareness of cancer risk and compliance with screening. However, 35% of the women were unaware of their elevated risk, despite an organized national systematic attempt to educate these women regarding their increased risk of endometrial cancer. This supports the need for better education of HNPCC family members and the physicians to improve the awareness of endometrial cancer risk related to Lynch syndrome.18

In the only study of awareness of gynecologic surveillance, which included 27 women, the authors concluded that if the gynecologists are the source of information about the gynecologic cancer risk, then these women presumably will be more aware of the gynecologic surveillance.12 Our findings, based on a much larger group, substantiate the importance of personal information of gynecologic cancer risk, thereby improving the awareness of and compliance with gynecologic screening. The participants in our study are derived from families with HNPCC, including Lynch families, Amsterdam-positive families, and Amsterdam-like families; hence, our findings most likely represent all family members with increased risk for Lynch syndrome--related endometrial cancer. The predictors of compliance with screening in our study correspond with findings from other studies of cancer screening practices in healthy women and women from families with hereditary breast and ovarian cancers. Age has been identified as a significant factor in screening behavior after genetic counseling and testing for BRCA 1 or 2.19

Lijovic et al20 reported that women with a first-degree relative with breast cancer had smaller, earlier-stage cancers at diagnosis, and they concluded that it might reflect more diligent use of breast cancer screening among women who considered themselves at increased risk for development of the disease. Another study by Isaacs21 reported a 12-times higher use of ovarian cancer screening among women with at least one relative with ovarian cancer. These findings are consistent with our data, supporting the idea that the correlation between awareness of cancer risk and uptake of recommended screening could be generalized to a variety of hereditary cancer syndromes.

The relatively high response rate is the main strength of this study. Denmark has many national registries with a high validity of personal identities, cancer diagnoses, and demographic data, which in combination with our active strategy to identify and contact persons at risk is the other strength of our study. However, the study design with questionnaires implies a risk of selection bias and recall bias, eg, that women who are aware of their increased risk for cancer are perhaps more likely to complete the study questionnaire and to recall their screening procedures. The frequency of a high level of knowledge therefore might be overestimated. These biases imply an underrepresentation of unaware women in the study group and a higher rate of compliance with the screening.

In conclusion, awareness of cancer risk is the prime predictor of compliance with recommended screening, indicating the importance of improvement of awareness of cancer risk in at-risk persons and their physicians. A substantial number of women at risk for endometrial cancer were not aware of their elevated cancer risk, supporting the need to educate the physicians and the family members about the Lynch syndrome--related endometrial cancer risk.

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