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.

  1. What are the optimal ages and intervals for implementing risk assessment for Lynch syndrome?
  2. 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.