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Journal of Clinical Oncology, Vol 26, No 6 (February 20), 2008: pp. 948-954 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.0575 Perceptions of Cancer Risks and Predictors of Colon and Endometrial Cancer Screening in Women Undergoing Genetic Testing for Lynch Syndrome
From the Social & Behavioral Research Branch; Office of the Director, National Human Genome Research Institute; Biostatistics and Data Management Section and the Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Uniformed Services University of the Health Sciences, Bethesda, MD; and the Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI Corresponding author: Donald W. Hadley, MS, National Institutes of Health, 31 Center Drive, MSC 2073, Building 31, Room B1B37F, Bethesda, MD 20892-2073; e-mail: dhadley{at}mail.nih.gov
Purpose Lynch syndrome poses multiple cancer risks, yet attention has focused on screening for colorectal cancer. Estimated risks for endometrial cancer equal risks for colorectal cancer. This study (1) evaluated women's perceived risks for cancers, (2) compared endometrial cancer screening and colonoscopy, and (3) identified predictors of screening before and after genetic testing. Patients and Methods Sixty-five adult women at 50% risk for carrying a cancer-predisposing mutation, without a history of endometrial cancer or hysterectomy, participated in genetic counseling and received unequivocal genetic test results for Lynch syndrome. Participants completed questionnaires before and after receipt of genetic results. Results Pretest, perceived risks for colon cancer were significantly higher than for extracolonic cancers (P < .0001). Use of colonoscopy was significantly higher (P = .006) than endometrial cancer screening. Post-test, carriers demonstrated a significant (P < .0001) increase in their perceived risk for extracolonic cancers and increased both colonoscopy (P = .79) and endometrial cancer screening (P = .11). Mutation status, age, perceived likelihood of carrying a mutation, and communication of test results to their physician independently predicted cancer screening at follow-up. Conclusion Women in families with Lynch syndrome are less aware of their risks for extracolonic cancers and undergo endometrial cancer screening significantly less often than colonoscopy before genetic counseling. Given the significantly increased risks for endometrial and ovarian cancers and the mortality associated with ovarian cancer, additional efforts to inform families of cancer risks and screening recommendations seem prudent. Physicians play a critical role in ensuring appropriate cancer screening in women with Lynch syndrome.
Lynch syndrome is an autosomal dominant cancer susceptibility syndrome predisposing carriers to the early onset of multiple cancers including colon, endometrial, small intestine, ovary, hepatobiliary, kidney, ureter, and brain.1,2 Four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS23 have been conclusively associated with Lynch syndrome. Individuals carrying a mutation in one of these genes have a lifetime risk approaching 90%1,4 for developing one of these cancers. The term hereditary nonpolyposis colorectal cancer (HNPCC) was coined in 1985 by Henry Lynch, MD, to differentiate this from familial adenomatous polyposis (FAP)5; however "Lynch syndrome" more accurately designates those with an MMR mutation. Considerable attention has been focused on the risks for colon cancer in Lynch syndrome,3 colorectal cancer screening and prevention strategies,6-8 practices,9-11 and adherence to colonoscopy (COL) recommendations.10 But little attention has been given to screening for other associated cancers.9,11-13 The colorectal emphasis in the literature and in the name HNPCC may limit awareness of other cancer risks, thus reducing comprehensive cancer screening.13 Male and female carriers may have different lifetime risks for colorectal cancer. Two studies4,14 reported colon cancer risks for men of 74% and 82% versus 30% and 54% for women. These same studies reported the lifetime risk for endometrial carcinoma to be 42% to 60%, which meets or exceeds risks for colorectal cancer, and a 12% lifetime risk for ovarian cancer. Given these risks and the mortality associated with ovarian cancer, gynecologic screening seems prudent in women with a known or suspected MMR mutation.8 Consideration of prophylactic surgery (hysterectomy and oophorectomy) has been suggested for carriers who have completed their families and are interested in prevention.8,13 There is no proven satisfactory screening modality for either endometrial or ovarian cancer. Nevertheless, various groups have put forth recommendations for families with Lynch syndrome, based on expert opinion, including endometrial cancer screening (ECS).8,15 The purpose of this study was to compare perceptions of cancer risks and use of COL and ECS before and after the provision of genetic counseling and the receipt of unequivocal genetic test results (GCT). We hypothesized that the participants' perceived risks for colon cancer before GCT would be significantly higher than for extracolonic cancers and, accordingly, ECS before GCT would be significantly less frequent than COL. We also analyzed predictors of screening pre- and post-GCT.
Study Population Participants were identified from a cohort of families16 with an identified deleterious MMR mutation. Inclusion criteria were as follows: female sex, age 18 years or older, at 50% risk of inheriting a mutation, no history of endometrial cancer or hysterectomy, and participation in GCT and receipt of results. Potential participants included 96 women from 27 families; 65 met inclusion criteria. Thirty-one were excluded, 13 for a history of endometrial cancer and 18 for prior hysterectomy for other causes.
Procedures Genetic testing was offered without cost. Individuals choosing testing had blood collected and processed in a Clinical Laboratory Improvement Amendment (CLIA)-approved laboratory. Results were disclosed in person 1 to 2 months after sample collection. Oral and written screening recommendations following published guidelines7 were provided, and a clinical summary was mailed to each participant. Screening recommendations for Lynch syndrome families continue to evolve.8,15 In this study, we used the recommendations of the Cancer Genetics Studies Consortium (Table 1).7 Data on variables of interest were collected at baseline before GCT and at 6 and 12 months post-GCT. Predictor and outcome variables are listed in Table 2.
Statistical Considerations McNemar's test was used to test for differences between paired dichotomous data, whereas for ordered, paired multinomial data, we used the marginal homogeneity test. Fisher's exact test was used to compare two independent proportions. Comparisons of ordered categoric data between two groups were performed with the Cochran-Armitage trend test. For doubly ordered categoric data, we used the Jonckheere-Terpstra trend test to evaluate the association between the parameters. Continuous data were compared between two groups using the Wilcoxon rank sum test; continuous data were tested among three or more groups using the Kruskal-Wallis test. Paired continuous data were tested for equality to zero using the Wilcoxon signed rank test. Multiple logistic regression analyses were performed on variables for which univariate-analysis P values were less than .10; both stepwise and backward selection procedures were used. All P values are two tailed, and those P values less than .005 were interpreted as indicating statistical significance because of the large number of exploratory analyses performed.
Characteristics of Study Sample Participant characteristics are summarized in Table 3. Of the 65 women analyzed, 10 (15%) had a history of nonendometrial cancer, (five colon, one colon and breast, one colon and cervical, one kidney, and one cervical), 92% were white, 58% were married, 68% were employed, 95% reported having health insurance, and 49% reported having an annual household income of $50,000 or less. The median age was 37 years (range, 19 to 70 years). Testing identified 28 women (43%) as carriers and 37 women (57%) as truly negative for their family's mutation.
Pre-GCT Perceived risks of developing cancer. At baseline, 86% of participants (55 of 64) estimated their risk to develop colon cancer as higher than average for a person their age. In contrast, 5% (three of 58) perceived their risks to develop an extracolonic cancer as higher than average. The difference in perceived risk for colon versus extracolonic cancers is highly significant (P < .0001). Use of COL. In the absence of information about mutation status, COL is recommended for persons at risk for inheriting an MMR mutation beginning between the ages of 20 and 25 years. In this sample, 36 (55%) of 65 had undergone COL (Fig 1). There was no significant difference in use of COL between carriers and noncarriers (odds ratio [OR] = 1.14; 95% CI, 0.38 to 3.41; P = .99).
Univariate analyses identified age more than 25 years (P = .0006), income (P = .001), and being married (v single/divorced; P = .008) as significantly associated with COL before GCT (Table 4).
Multiple logistic regression analyses identified both age (P = .011) and higher income (P = .029) as predictors of COL (Table 4). After adjusting for income, women more than 25 years old were almost nine times more likely to undergo COL compared with women younger than 25. Likewise, after adjusting for age, women with incomes between $35,000 and $75,000 were almost six times more likely to undergo COL compared with women with lower incomes; women with incomes more than $75,000 were six times more likely to undergo COL compared with women with income less than $35,000 (OR = 5.99; 95% CI, 1.05 to 42.08; P = .043). Use of ECS. In the absence of information about mutation status, ECS is recommended for women at risk for inheriting a MMR mutation beginning no later than 35 years of age. In this sample, 18 (31%) of 58 women reported having had ECS (nine transvaginal ultrasound, two endometrial biopsy, and seven both) before GCT; 16 of these women were at least 35 years of age (Fig 2). There was no significant difference in use of ECS between carriers and noncarriers (OR = 1.13; 95% CI, 0.32 to 4.05; P = 1.0). Univariate analyses identified having a family history of endometrial cancer (P = .006) and being more than 34 years of age (P = .005) as significantly associated with ECS before GCT. Multiple logistic regression analyses identified being more than 34 years of age (P = .007) as significantly associated with ECS before GCT (Table 4).
Comparison of COL and ECS use pre-GCT. At baseline, our analyses demonstrated that there was a significant difference between the use of COL and ECS. Fifty-seven percent of participants (33 of 58; missing data on seven women) underwent COL before GCT, whereas only 31% (18 of 58) had undergone ECS (P = .006) despite their similar risks for developing both cancers. Sixty-seven percent (34 of 51) of the women more than age 24, reported ever undergoing COL. In contrast, only 47% (15 of 32) women more than 34 years of age had undergone ECS.
Post-GCT The difference in perceived risk for colon verses extracolonic cancers remained significant (P = .008) for mutation carriers post-GCT. At 12 months post–receipt of genetic test results, 92% of carriers (24 of 26) perceived their risk for colon cancer as higher than average. In contrast, 62% (16 of 26) perceived their risk for extracolonic cancers as higher than average. Perceived risks of developing cancer: Noncarriers. Noncarriers demonstrated a significant reduction in their perceived risk for colon cancer from pre- to post-GCT (P < .0001). Specifically, 86% (32 of 37) perceived their risk for colon cancer as higher than average before GCT compared with 22% (eight of 37) post-GCT. Ironically, there was a significant increase in perceived risk for extracolonic cancer from pre- to post-GCT (P = .0004). Specifically, 3% (one of 37) perceived their risk for an extracolonic cancer as higher than average pre-GCT compared with 27% (10 of 37) post-GCT. The difference in perceived risk for colon verses extracolonic cancers was not significant (P = .73) for noncarriers post-GCT. Colonoscopy. Sixty-one percent of carriers (17 of 28) and 11% of noncarriers (four of 37) had a COL post-GCT (OR = 0.08; 95% CI, 0.02 to 0.32; P < .0001; Fig 1). The carriers reflected an increase from 54% (15 of 28) before to 61% (17 of 28) post-GCT (P = .79). There was a highly significant decrease in use of COL by noncarriers from 57% (21 of 37) before to 11% (four of 37) after GCT (P < .0001). Univariate analyses identified COL use to be significantly associated with mutation status (P < .0001), perceived risk for colon cancer at 1 year post-GCT (P = .002), and perceived likelihood of being a mutation carrier (P < .0001). Multiple logistic regression analyses identified that the use of COL post-GCT was simultaneously predicted by mutation status (P < .0001) and age (P = .002; Table 4). After adjusting for age, women who were noncarriers were far less likely to undergo COL post-GCT compared with women who were carriers. Furthermore, after adjusting for mutation status, each incremental increase in age was associated with a 10% increase in probability of undergoing COL post-GCT. ECS. Fifty-four percent of carriers (15 of 28) and 14% of noncarriers (five of 37) underwent ECS post-GCT (OR = 7.13; 95% CI, 1.96 to 30.57; P = .0009; Fig 2). The carriers reflected an increase (P = .11) in their use of ECS from the 30% (eight of 27) use rate before GCT to 54% (15 of 28) post-GCT. There was a decrease in use of ECS by noncarriers from 32% (10 of 31) before to 14% (five of 37) after GCT (P < .070). Univariate analysis identified that ECS post-GCT was significantly associated with mutation status (P = .0009), having a personal history of cancer (P = .007), perceived risk for colon cancer 1 year post-GCT (P = .005), perceived likelihood of being a carrier 1 year post-GCT (P < .0003), and communication of their genetic test results with their physician (P = .0008). Multiple logistic regression analyses identified that ECS after GCT was simultaneously predicted by the participant's perceived likelihood of being a carrier 1 year post-GCT (P = .0004) and communication of their genetic test results with their physician (P = .002; Table 4). After adjusting for the variable of communicating genetic test results with their physician, women who perceived themselves to carry a mutation were nearly 12 times as likely to undergo ECS post-GCT than women who did not. After adjusting for their perceived likelihood of being a carrier, women who did not communicate their results to their physician were 92% less likely to undergo ECS post-GCT than those who did share their test results with their physicians.
Comparison of COL and ECS Use Post-GCT
Prophylactic Surgery Post-GCT
Communication of Results With Physicians
These findings support our concerns about (1) an insufficient awareness of risks for extracolonic cancers among women in families with Lynch syndrome and (2) their relative decreased use of ECS compared with COL before GCT. Given the significantly increased risks for endometrial and ovarian cancers in Lynch syndrome and the mortality associated with ovarian cancer, additional efforts to inform families and physicians of cancer risks and screening recommendations for Lynch syndrome seem prudent. To our knowledge, this is the first study to report predictors of endometrial cancer screening on the basis of logistic regression analyses. The participants' perceived likelihood of being a carrier and communication of their genetic test results to their physician within the first year post-GCT were independent predictors of ECS at follow-up. Mood, worry about cancer, and cancer-specific distress were not found to be significantly associated with either COL or ECS. Although an increase in perceived risks for extracolonic cancers is deemed appropriate in carriers, the significant increase in perceived risks in noncarriers bears consideration. Research with women in families with breast cancer report that they have significantly higher perceived lifetime risks for breast cancer and significantly lower perceived risks for heart disease, colon cancer and possibly other diseases.17 The authors of these studies suggest that although the higher perceived risks for breast cancer is appropriate, the focus on breast cancer may serve to obscure women's recognition of risks for other health threats. In the case of Lynch syndrome, the historical focus on colon cancer may serve to obscure the risks for extracolonic cancers. We posit that the provision of comprehensive genetic counseling and unequivocal genetic test results for Lynch syndrome and the sharing of the results with their physicians facilitate the participants' objectivity of their risks for (1) colon cancer in carriers and noncarriers and (2) endometrial cancer in carriers. However, the post-GCT increase in perceived risks for extracolonic cancers in noncarriers warrants additional studies to evaluate whether the increase is maintained over time. Furthermore, despite the significant change in perceived risk for extracolonic cancers in mutation carriers from pre- to post-GCT, a significant difference remains between perceived risks for colon and extracolonic cancers post-GCT. It is important to note that, despite the significant difference in perceived risks for colon and extracolonic cancers that persists in mutation carriers, there was no significant difference detected between post-GCT use of COL and ECS. Additional research efforts are warranted to determine whether this difference persists and to identify variables that influence this perception. Finally, our findings that the provision of genetic counseling and unequivocal test results improve the use of screening supports previous research.9-12,18 Generally speaking, carriers increase their use of cancer screening and noncarriers decrease their use of cancer screening as recommended. The limitations of this study include the fact that the population is relatively small and homogeneous. It is, however, the largest prospective report of women who have undergone genetic counseling and unequivocal testing for Lynch syndrome to date to our knowledge. Our interpretation of the results pertaining to perceived risks for cancer may be limited by the fact that the question assessing the women's perceived risks for extracolonic cancers was not specific to endometrial cancer. The results clearly show that perceived risks for colon cancer are significantly higher than for extracolonic cancers; however, future studies would benefit from separating endometrial cancer from other extracolonic cancers. And finally, participants' responses to the question assessing communication of their genetic test results to their physician should be considered broadly since the identification of their physician likely varies (eg, general internist, gastroenterologist, obstetrician/gynecologist, oncologist, and so on). We emphasize the finding that our participants' use of ECS post-GCT was significantly associated with sharing results with their physician. This finding supports the need for physicians to be fully aware of the cancer risks associated with Lynch syndrome and recommendations for cancer screening. Although the initial consultation with specialists in the field of cancer genetics remains vital to the test result interpretation, cognitive and emotional processes of decision making and patients' initial adaptation to their cancer risks, ongoing education, counseling, and medical management provided by the patient's physician remain critical in assisting these women in actually undergoing the recommended cancer screening.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Ilan R. Kirsch, Amgen Inc (C) Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None
Conception and design: Donald W. Hadley, Ilan R. Kirsch Financial support: Donald W. Hadley, Peter W. Soballe, Ilan R. Kirsch Administrative support: Donald W. Hadley, Jean F. Jenkins, Stephanie Moller, Jean C. Martin, Kathleen A. Calzone, Peter W. Soballe Provision of study materials or patients: Donald W. Hadley, Jean F. Jenkins, Kathleen A. Calzone, Peter W. Soballe, Ilan R. Kirsch Collection and assembly of data: Donald W. Hadley, Jean F. Jenkins, Stephanie Moller, Jean C. Martin, Ilan R. Kirsch Data analysis and interpretation: Donald W. Hadley, Seth M. Steinberg, David Liewehr Manuscript writing: Donald W. Hadley, Jean F. Jenkins, Seth M. Steinberg, David Liewehr, Stephanie Moller, Jean C. Martin, Kathleen A. Calzone, Peter W. Soballe, Ilan R. Kirsch Final approval of manuscript: Donald W. Hadley, Jean F. Jenkins, Seth M. Steinberg, David Liewehr, Stephanie Moller, Jean C. Martin, Kathleen A. Calzone, Peter W. Soballe, Ilan R. Kirsch
We thank our participants for the willingness to share their lives with us; without their efforts this work would not be possible.
Supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Cancer Institute at the National Institutes of Health in Bethesda, MD. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, Department of Health and Human Services, or the US Government. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Aarnio M, Mecklin JP, Aaltonen LA, et al: Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 64:430-433, 1995[Medline] 2. Watson P, Riley B: The tumor spectrum in the Lynch syndrome. Fam Cancer 4:245-248, 2005[CrossRef][Medline] 3. Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 348:919-932, 2003 4. Dunlop MG, Farrington SM, Carothers AD, et al: Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 6:105-110, 1997 5. Boland CR: Evolution of the nomenclature for the hereditary colorectal cancer syndromes. Fam Cancer 4:211-218, 2005[CrossRef][Medline] 6. Järvinen HJ, Aarnio M, Mustonen H, et al: Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 118:829-834, 2000[CrossRef][Medline] 7. Burke W, Petersen G, Lynch P, et al: Recommendations for follow-up care of individuals with an inherited predisposition to cancer: I, Hereditary nonpolyposis colon cancer Cancer Genetics Studies Consortium. JAMA 277:915-919, 1997 8. Lindor NM, Petersen GM, Hadley DW, et al: Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: A systematic review. JAMA 296:1507-1517, 2006 9. Claes E, Denayer L, Evers-Kiebooms G, et al: Predictive testing for hereditary nonpolyposis colorectal cancer: Subjective perception regarding colorectal and endometrial cancer, distress, and health-related behavior at one year post-test. Genet Test 9:54-65, 2005[CrossRef][Medline] 10. Hadley DW, Jenkins JF, Dimond E, et al: Colon cancer screening practices after genetic counseling and testing for hereditary nonpolyposis colorectal cancer. J Clin Oncol 22:39-44, 2004 11. Wagner A, van Kessel I, Kriege MG, et al: Long term follow-up of HNPCC gene mutation carriers: Compliance with screening and satisfaction with counseling and screening procedures. Fam Cancer 4:295-300, 2005[CrossRef][Medline] 12. Collins V, Meiser B, Gaff C, et al: Screening and preventive behaviors one year after predictive genetic testing for hereditary nonpolyposis colorectal carcinoma. Cancer 104:273-281, 2005[CrossRef][Medline] 13. Lu KH, Dinh M, Kohlmann W, et al: Gynecologic cancer as a "sentinel cancer" for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol 105:569-574, 2005[Medline] 14. Aarnio M, Sankila R, Pukkala E, et al: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81:214-218, 1999[CrossRef][Medline] 15. Engstrom P: Update: NCCN colon cancer Clinical Practice Guidelines. J Natl Compr Canc Netw 3:S25-S28, 2005 (suppl)[Medline] 16. Hadley DW, Jenkins J, Dimond E, et al: Genetic counseling and testing in families with hereditary nonpolyposis colorectal cancer. Arch Intern Med 163:573-582, 2003 17. Erblich J, Bovbjerg DH, Norman C, et al: It won't happen to me: Lower perception of heart disease risk among women with family histories of breast cancer. Prev Med 31:714-721, 2000[CrossRef][Medline] 18. Halbert CH, Lynch H, Lynch J, et al: Colon cancer screening practices following genetic testing for hereditary nonpolyposis colon cancer (HNPCC) mutations. Arch Intern Med 164:1881-1887, 2004 Submitted June 13, 2007; accepted November 1, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
