Draft Research Plan
Lynch Syndrome-Related Cancer in Adults: Risk Assessment, Genetic Counseling, and Genetic Testing
February 02, 2023
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
1. In asymptomatic adults, does risk assessment, genetic counseling, and genetic testing for pathogenic variants associated with Lynch syndrome change all-cause mortality, cancer-specific mortality or morbidity, or quality of life?
2a. What is the accuracy of risk assessment tools for predicting pathogenic variants in genes associated with Lynch syndrome when used by a primary care clinician in a clinical setting?
2b. What is the accuracy of targeted next-generation sequencing for detecting pathogenic variants associated with Lynch syndrome?
3a. What are the harms associated with use of risk assessment tools for Lynch syndrome?
3b. What are the harms associated with genetic testing for pathogenic variants associated with Lynch syndrome?
4. For adults with Lynch syndrome, what is the effectiveness of preventive interventions for improving all-cause mortality, cancer-specific mortality or morbidity, or quality of life?
5. For adults with Lynch syndrome, what are the harms associated with preventive interventions?
Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.
- What are the optimal ages and intervals for implementing risk assessment for Lynch syndrome?
- Does genetic counseling (related to genetic testing for Lynch syndrome–related cancer) improve patient knowledge, understanding of benefits and harms of interventions to reduce risk, risk perception, satisfaction, and health and psychological outcomes?
To the extent possible, we plan to describe the population, risk assessment, genetic testing, and intervention characteristics of the included studies. Data on population characteristics will help us explore the degree to which the findings are representative of persons at risk for Lynch syndrome as well as investigate potential differences in benefits and harms by different population groups. These groups include, but are not limited to, categorizations by age; sex; gender; those with a personal history of cancer; and racial, ethnic, and cultural identity.
The Proposed Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the Evidence Review. Criteria are overarching as well as specific to each of the key questions.
| Category | Include | Exclude |
|---|---|---|
| Populations | KQs 1–3: Asymptomatic adults (older than age 18 years); persons with or without a personal or family history of cancer
KQs 4, 5: Adults with Lynch syndrome All KQs: Specific populations of interest include those defined by sex, gender, race, or ethnicity |
KQs 1–3: Children, persons with symptoms; persons with a very recent diagnosis of colorectal cancer undergoing tumor testing (e.g., for microsatellite instability that, if abnormal, would lead to genetic testing for Lynch syndrome)
KQs 4, 5: Children |
| Interventions | KQ 1: Risk assessment initiated by a primary care clinician, pretest genetic counseling, genetic testing, and posttest counseling
KQs 2a, 3a: Risk assessment tools that are applicable to primary care, such as the PREMM5 (and previous iterations of PREMM) or other brief cancer risk assessment tools KQs 2b, 3b: Germline genetic testing with targeted next-generation sequencing of DNA isolated from blood, saliva, or buccal swab to identify variants in MLH1, MSH2, MSH6, PMS2, or EPCAM genes associated with Lynch syndrome KQs 4, 5: Earlier and more frequent cancer screening (e.g., colonoscopy), use of risk-reducing medications (e.g., aspirin), or prophylactic surgery |
All KQs: No assessment; other assessment and testing modalities; and testing of tumors
KQs 4, 5: Chemotherapy, radiation therapy, and natural therapies |
| Comparisons | KQ 1: No screening or usual care
KQs 2a, 3a: Targeted next-generation sequencing or Sanger sequencing KQs 2b, 3b: Sanger sequencing KQs 4, 5: No intervention or usual care |
Studies without a comparison group; comparative effectiveness studies (head-to-head studies comparing interventions) |
| Outcomes | KQ 1: All-cause mortality, cancer-specific mortality and morbidity, and quality of life
KQ 2: Sensitivity and specificity KQ 3: False-positive results, anxiety, psychosocial harms (including any caused by the detection of variants of uncertain significance), irritation, pain, bleeding, overdiagnosis, and additional tests and subsequent harms KQ 4: All-cause mortality, cancer-specific mortality and morbidity, and quality of life KQ 5: Irritation, pain, bleeding, infection, altered bowel functioning, altered urinary functioning, altered sexual functioning, bowel perforation, and surgical morbidity or mortality |
Cost |
| Study designs | Controlled trials are eligible for all KQs
KQ 2: Studies evaluating accuracy are also eligible KQs 3, 5 (harms): Prospective cohort studies and case-control studies are also eligible |
All other designs |
| Study duration | Any length | |
| Settings | Primary care settings or settings referable from primary care | Other settings |
| Countries | Studies conducted in countries categorized as “Very High” on the Human Development Index (as defined by the United Nations Development Program) | Studies conducted in countries that are not categorized as “Very High” on the Human Development Index |
| Language | English | Non-English |
| Study quality | Good or fair | Poor (according to design-specific USPSTF criteria) |
Abbreviations: KQ=key question; USPSTF=U.S. Preventives Services Task Force.