Cancer Health Assessments Reaching Many (CHARM)

National Human Genome Research Institute (NHGRI), University of Washington, Seattle Children's Hospital, University of California, San Francisco, Denver Health and Hospital Authority, Emory University, Dana-Farber Cancer Institute, Columbia University

The CHARM (Cancer Health Assessment Reaching Many) study will assess the utility of clinical exome sequencing and how it affects care in diverse populations. The study population includes adults at risk for hereditary cancer syndromes. The primary objective is to implement a hereditary cancer risk assessment program in healthy 18-49 year-olds in primary care settings within a vertically integrated health delivery system (Kaiser Permanente) and a federal qualified health center (Denver Health). The investigators will assess clinical exome sequencing implementation and interpretation, as well as tailored interactions for low health literacy including a contextualized consent process, and a modified approach to results disclosure and genetic counseling. The investigators will also assess the clinical utility (healthcare utilization and adherence to recommended care) and personal utility of primary and additional results from clinical exome sequencing, and evaluate the ethical and policy implications of considering personal utility of genomic information decisions for health care coverage.

Aim 1. Implement a hereditary cancer risk-assessment program in healthy 18-49-year-old adults in primary care settings, with stakeholder input, and offer exome sequencing to clarify risk. Aim 1A. Identify and recruit 880 adult participants at-risk of a hereditary cancer syndrome. Aim 1B: Generate medical exome sequence data and interpret variants. Aim 1C: Disclose findings from medical exome sequencing, incorporate results into the electronic medical record (EMR), and facilitate downstream patient management and coordination of care with the provider. Aim 1D. Engage stakeholders to tailor and optimize the program in diverse populations. Aim 2. Evaluate and tailor for diverse populations the critical interactions in the program, including the consent process, choices for reporting additional findings, and the response to results disclosure. Aim 2A. Design, implement, and assess a contextualized consent process to support informed decision-making about participation in research about medical exome sequencing. Aim 2B. Design, implement, and compare a novel decision aid in the second half of the study for selecting the optional categories of additional findings with the approach we developed in CSER1 that offered a category checklist. Aim 2C. Design, implement, and compare a modified (communication-focused) approach to results disclosure, genetic counseling, and decision making with a standard (information-focused) approach. Aim 3. Evaluate the clinical utility (including personal utility) of using exome sequencing to diagnose individuals with hereditary cancer syndromes and provide additional findings. Aim 3A: Measure the yield of reportable findings for hereditary cancer syndromes and additional findings. Aim 3B: Evaluate subsequent healthcare utilization for all study participants and adherence to recommended care among individuals who are identified with a hereditary cancer syndrome in diverse settings. Aim 3C. Assess the personal utility of exome sequencing, including primary and additional findings. Aim 4. Address pragmatic and ethical challenges to the integration of genomic medicine into clinical and health systems decision-making. Aim 4A: Develop and pilot a system that integrates genomic, clinical, and healthcare utilization data to inform clinicians and patients acting on genomic information and to reduce care gaps in patient management. Aim 4B: Advance the analysis of the ethical and policy implications of incorporating personal utility of genomic information into the decision framework for healthcare coverage.

All participants will receive exome sequencing. The randomization will be into one of two types of genetic counseling - traditional and modified.

This will be typical genetic counseling that a patient would receive in a traditional genetic counseling setting.

This will be genetic counseling that is modified for a lower literacy patient and will include fewer technical terms and less complicated genetic information.

After participants at high risk for a hereditary cancer syndrome receive exome sequencing, they will receive modified genetic counseling to help them understand the results.

After participants at high risk for a hereditary cancer syndrome receive exome sequencing, they will receive traditional genetic counseling to help them understand the results.

Number of people found to have a pathogenic variant in one of the cancer genes associated with Lynch syndrome or hereditary breast and ovarian cancer

Number of people with pathogenic variants found in genes related to medically actionable hereditary conditions

Downstream healthcare utilization of specific recommended procedures (e.g., colonoscopy, mammography, surgery) will be compared between participants in the traditional genetic counseling arm, the modified genetic counseling arm, and patients at high risk for a hereditary cancer syndrome that do not join the study (usual care)

Measurement of participant's understanding of the recommended care based on their genetic test result will be assessed using a validated survey tool

Measurement of patient's understanding of the genetic test results will be assessed using a validated survey tool

Measurement of the patient's satisfaction of genetic counseling will be assessed using a validated survey tool

Measurement of the degree to which participants shared their genetic test results with various family members will be assessed using a validated survey tool

Measurement of the participant's perceived utility of obtaining genetic testing and counseling will be assessed using validated survey tools that assess lifestyle behaviors and self-reported health/quality of life.

Inclusion Criteria: Kaiser Permanente Northwest or Denver Health patient Screens as high risk for a hereditary cancer syndrome via the risk assessment tool algorithms OR have unknown family history on either their mother or father's side of the family (or both) No known prior testing for familial mutations predisposing them to Lynch syndrome or hereditary breast and ovarian cancer English or Spanish speaker Exclusion Criteria: Participant self-reported prior testing for Lynch syndrome (LS) or Hereditary Breast and Ovarian Cancer (HBOC) syndrome or identified as having previous comprehensive testing via Kaiser Permanente data files Not an English or Spanish speaker Unable to provide informed consent Don't want results placed in their medical record

https://www.genome.gov/Funded-Programs-Projects/Computational-Genomics-and-Data-Science-Program/Genomic-Analysis-Visualization-Informatics-Lab-space-AnVIL

Mittendorf KF, Lewis HS, Duenas DM, Eubanks DJ, Gilmore MJ, Goddard KAB, Joseph G, Kauffman TL, Kraft SA, Lindberg NM, Reyes AA, Shuster E, Syngal S, Ukaegbu C, Zepp JM, Wilfond BS, Porter KM. Literacy-adapted, electronic family history assessment for genetics referral in primary care: patient user insights from qualitative interviews. Hered Cancer Clin Pract. 2022 Jun 10;20(1):22. doi: 10.1186/s13053-022-00231-3.

Mittendorf KF, Kauffman TL, Amendola LM, Anderson KP, Biesecker BB, Dorschner MO, Duenas DM, Eubanks DJ, Feigelson HS, Gilmore MJ, Hunter JE, Joseph G, Kraft SA, Lee SSJ, Leo MC, Liles EG, Lindberg NM, Muessig KR, Okuyama S, Porter KM, Riddle LS, Rolf BA, Rope AF, Zepp JM, Jarvik GP, Wilfond BS, Goddard KAB; CHARM study team. Cancer Health Assessments Reaching Many (CHARM): A clinical trial assessing a multimodal cancer genetics services delivery program and its impact on diverse populations. Contemp Clin Trials. 2021 Jul;106:106432. doi: 10.1016/j.cct.2021.106432. Epub 2021 May 11. Erratum In: Contemp Clin Trials. 2022 Mar;114:106682.