Accelerating Progress to Reduce the Cancer Burden through Prevention and Control in the US.

Improvements in cancer prevention and control are poised to be main contributors in reducing the burden of cancer in the US. We quantify top opportunities to accelerate progress using projected life years gained (LYG) and deaths averted as measures. We project that over the next 25 years, realistic gains from tobacco control can contribute 0.4 to 17 million additional LYG per intervention and 8.4 million additional LYG from improving uptake of screening programs over the lifetime of 25 annual cohorts. Additional opportunities include addressing modifiable risk factors (excess weight, alcohol consumption), improving methods to prevent or treat oncogenic infections, and reducing cancer health disparities. Investment is needed in the pipeline of new preventive agents and technologies for early detection to continue progress. There is also a need for additional research to improve the access to and uptake of existing and emerging interventions for cancer prevention and control and to address health disparities. These gains are undeniably within our power to realize for the US population.

Implementing evidence-based assertions of clinical actionability in the context of secondary findings: Updates from the ClinGen Actionability Working Group.

PURPOSE: The ClinGen Actionability Working Group (AWG) developed an evidence-based framework to generate actionability reports and scores of gene-condition pairs in the context of secondary findings from genome sequencing. Here we describe the expansion of the framework to include actionability assertions. METHODS: Initial development of the actionability rubric was based on previously scored adult gene-condition pairs and individual expert evaluation. Rubric refinement was iterative and based on evaluation, feedback, and discussion. The final rubric was pragmatically evaluated via integration into actionability assessments for 27 gene-condition pairs. RESULTS: The resulting rubric has a 4-point scale (limited, moderate, strong, and definitive) and uses the highest-scoring outcome-intervention pair of each gene-condition pair to generate a preliminary assertion. During AWG discussions, predefined criteria and factors guide discussion to produce a consensus assertion for a gene-condition pair, which may differ from the preliminary assertion. The AWG has retrospectively generated assertions for all previously scored gene-condition pairs and are prospectively asserting on gene-condition pairs under assessment, having completed over 170 adult and 188 pediatric gene-condition pairs. CONCLUSION: The AWG expanded its framework to provide actionability assertions to enhance the clinical value of their resources and increase their utility as decision aids regarding return of secondary findings.

Measuring health-related quality of life in children with suspected genetic conditions: validation of the PedsQL proxy-report versions.

PURPOSE: Measuring health-related quality of life (HRQoL) of children with suspected genetic conditions is important for understanding the effect of interventions such as genomic sequencing (GS). The Pediatric Quality of Life Inventory (PedsQL) is a widely used generic measure of HRQoL in pediatric patients, but its psychometric properties have not yet been evaluated in children undergoing diagnostic GS. METHODS: In this cross-sectional study, we surveyed caregivers at the time of their child's enrollment into GS research studies as part of the Clinical Sequencing Evidence Generating Research (CSER) consortium. To evaluate structural validity of the PedsQL 4.0 Generic Core Scales and PedsQL Infant Scales parent proxy-report versions, we performed a confirmatory factor analysis of the hypothesized factor structure. To evaluate convergent validity, we examined correlations between caregivers' reports of their child's health, assessed using the EQ VAS, and PedsQL scores by child age. We conducted linear regression analyses to examine whether age moderated the association between caregiver-reported child health and PedsQL scores. We assessed reliability using Cronbach's alpha. RESULTS: We analyzed data for 766 patients across all PedsQL age group versions (1-12 months through 13-18 years). Model fit failed to meet criteria for good fit, even after modification. Neither age group (categorical) nor age (continuous) significantly moderated associations between PedsQL scores and caregiver-reported child health. Cronbach's alphas indicated satisfactory internal consistency for most PedsQL scales. CONCLUSION: The PedsQL Generic Core Scales and Infant Scales may be appropriate to measure HRQoL in pediatric patients with suspected genetic conditions across a wide age range. While we found evidence of acceptable internal consistency and preliminary convergent validity in this sample, there were some potential problems with structural validity and reliability that require further attention.

Evaluation of mailed results versus telephone disclosure of normal cancer genetic test results in a low-risk underserved population.

Scalable models for result disclosure are needed to ensure large-scale access to genomics services. Research evaluating alternatives to genetic counseling suggests effectiveness; however, it is unknown whether these findings are generalizable across populations. We assessed whether a letter is non-inferior to telephone genetic counseling to inform participants with no personal or family history of cancer of their normal results. Data were collected via self-report surveys before and after result disclosure (at 1 and 6 months) in a study sample enriched for individuals from underserved populations. Primary outcomes were subjective understanding of results (global and aggregated) and test-related feelings, ascertained via three subscales (uncertainty, negative emotions, and positive feelings) of the Feelings About genomiC Testing Results (FACToR) measure. Secondary outcomes related to satisfaction with communication. Non-inferiority tests compared outcomes among disclosure methods. Communication by letter was inferior in terms of global subjective understanding of results (at 1 month) and non-inferior to telephoned results (at 6 months). Letter was non-inferior to telephone for aggregated understanding (at 6 months). Letter was superior (at 1 month) to telephone on the uncertainty FACToR subscale. Letter was non-inferior to telephone on the positive-feelings FACToR subscale (at 6 months). Letter was non-inferior to telephone for satisfaction with mode of result delivery and genetic test results. Communication via letter was inferior to telephone in communicating the "right amount of information." The use of written communication to relay normal results to low-risk individuals is a promising strategy that may improve the efficiency of care delivery.

Genetic counseling services delivered in the usual way­during clinic visits­can take up a lot of time for patients and genetic counselors. Alternatives to this practice have been studied among genetic counseling patients to spare genetic counselors' time and expand access and flexibility for patients. Yet, in these studies, the participants have lacked diversity. So, it is not known how these research findings pertain to all populations. In this study, we looked at the use of an alternative care model, a mailed letter, for sharing normal genetic test results with study participants from underserved populations. We tested whether patients viewed the mailed letter as no worse than a telephone conversation with a genetic counselor, which has been shown to be well received by patients. We learned that study participants felt they understood their results, were not distressed to receive the results, and were satisfied with how their results were delivered. Lastly, we found that participants were more satisfied with the amount of information provided about their test results during the telephone conversation compared with the mailed letter. This study provides new information about different ways to deliver test results to individuals receiving genetic services.

The Long Behavioral Tail of the COVID-19 Pandemic-A Cancer Control Perspective.

This Viewpoint discusses the impact of the COVID-19 public health emergency on the trajectory of cancer deaths.

Risk management actions following genetic testing in the Cancer Health Assessments Reaching Many (CHARM) Study: A prospective cohort study.

BACKGROUND: Genetic testing can identify cancer risk early, enabling prevention and early detection. We describe use of risk management interventions following genetic testing in the Cancer Health Assessment Reaching Many (CHARM) study. CHARM assessed risk and provided genetic testing to low income, low literacy, and other underserved populations that historically face barriers to accessing cancer genetic services. METHODS: CHARM was implemented in Kaiser Permanente Northwest (KPNW) and Denver Health (DH) between 2018 and 2020. We identified post-testing screening (mammography, breast MRI, colonoscopy) and surgical (mastectomy, oophorectomy) procedures using electronic health records. We examined utilization in participants who did and did not receive actionable risk management recommendations from study genetic counselors following national guidelines. RESULTS: CHARM participants were followed for an average of 15.4 months (range: 0.4-27.8 months) after results disclosure. Less than 2% (11/680) received actionable risk management recommendations (i.e., could be completed in the initial years following testing) based on their test result. Among those who received actionable recommendations, risk management utilization was moderate (54.5%, 6/11 completed any procedure) and varied by procedure (mammogram: 0/3; MRI: 2/4; colonoscopy: 4/5; mastectomy: 1/5; oophorectomy: 0/3). Cancer screening and surgery procedures were rare in participants without actionable recommendations. CONCLUSION: Though the number of participants who received actionable risk management recommendations was small, our results suggest that implementing CHARM's risk assessment and testing model increased access to evidence-based genetic services and provided opportunities for patients to engage in recommended preventive care, without encouraging risk management overuse.

Longitudinal adherence to breast cancer surveillance following cancer genetic testing in an integrated health care system.

PURPOSE: Screening with mammography and breast magnetic resonance imaging (MRI) is an important risk management strategy for individuals with inherited pathogenic variants (PVs) in genes associated with increased breast cancer risk. We describe longitudinal screening adherence in individuals who underwent cancer genetic testing as part of usual care in a vertically integrated health system. METHODS: We determined the proportion time covered (PTC) by annual mammography and breast MRI for individuals with PVs in TP53, BRCA1, BRCA2, PALB2, NF1, CHEK2, and ATM. We determined time covered by biennial mammography beginning at age 50 years for individuals who received negative results, uncertain results, or with PVs in genes without specific breast cancer screening recommendations. RESULTS: One hundred and forty individuals had PVs in TP53, BRCA1, BRCA2, PALB2, NF1, CHEK2, or ATM. Among these individuals, average PTC was 48% (range 0-99%) for annual screening mammography and 34% (range 0-100%) for annual breast MRI. Average PTC was highest for individuals with PVs in CHEK2 (N = 14) and lowest for individuals with PVs in TP53 (N = 3). Average PTC for biennial mammography (N = 1,027) was 49% (0-100%). CONCLUSION: Longitudinal screening adherence in individuals with PVs in breast cancer associated genes, as measured by the proportion of time covered, is low; adherence to annual breast MRI falls below that of annual mammography. Additional research should examine screening behavior in individuals with PVs in breast cancer associated genes with a goal of developing interventions to improve adherence to recommended risk management.

Most people share genetic test results with relatives even if the findings are normal: Family communication in a diverse population.

PURPOSE: With increasing utilization of genetic testing, sharing genetic information can become part of general family health communication while providing biological relatives with important information about their own genetic risk. Importantly, little is known about motivations for and barriers to family communication of genetic information in historically underserved populations. METHODS: Using mixed methods, we explored patient experiences with family communication in a study population of English- and Spanish-speaking adults aged 18 to 49 years, enriched for participants from historically underserved backgrounds. Risk screening for hereditary cancer guided genetic testing for cancer risk genes and other medically actionable findings. RESULTS: Most participants overall (91%), including most with normal findings (89%), shared or planned to share their results with relatives. Common motivations for sharing results were to give relatives information about their genetic risk and because the participant thought the results were interesting. Reasons for not sharing were limited contact with relatives, perceptions of limited clinical utility for relatives, and concern that discussion of genetic information was stigmatized or taboo. CONCLUSION: Results demonstrate high rates of sharing genetic information, indicate motivations for sharing go beyond facilitating genetic testing for relatives, and suggest general willingness to share genetic information as part of family health communication.

Evaluating cancer genetic services in a safety net system: overcoming barriers for a lasting impact beyond the CHARM research project.

Underserved patients face substantial barriers to receiving cancer genetic services. The Cancer Health Assessments Reaching Many (CHARM) study evaluated ways to increase access to genetic testing for individuals in underserved populations at risk for hereditary cancer syndromes (HCS). Here, we report the successful implementation of CHARM in a low-resource environment and the development of sustainable processes to continue genetic risk assessment in this setting. The research team involved key clinical personnel and patient advisors at Denver Health to provide input on study methods and materials. Through iterative and collaborative stakeholder engagement, the team identified barriers and developed solutions that would both facilitate participation in CHARM and be feasible to implement and sustain long term in clinical care. With a focus on infrastructure building, educational modules were developed to increase awareness among referring providers, and standard methods of identifying and managing HCS patients were implemented in the electronic medical record. Three hundred sixty-four DH patients successfully completed the risk assessment tool within the study, and we observed a sustained increase in referrals to genetics for HCS (from 179 in 2017 to 427 in 2021 post-intervention). Implementation of the CHARM study at a low-resourced safety net health system resulted in sustainable improvements in access to cancer genetic risk assessment and services that continue even after the study ended.Trial registration NCT03426878.

The PrU: Development and validation of a measure to assess personal utility of genomic results.

PURPOSE: People report experiencing value from learning genomic results even in the absence of clinically actionable information. Such personal utility has emerged as a key concept in genomic medicine. The lack of a validated patient-reported outcome measure of personal utility has impeded the ability to assess this concept among those receiving genomic results and evaluate the patient-perceived value of genomics. We aimed to construct and psychometrically evaluate a scale to measure personal utility of genomic results-the Personal Utility (PrU) scale. METHODS: We used an evidence-based, operational definition of personal utility, with data from a systematic literature review and Delphi survey to build a novel scale. After piloting with 24 adults, the PrU was administered to healthy adults in a Clinical Sequencing Evidence-Generating Research Consortium study after receiving results. We investigated the responses using exploratory factor analysis. RESULTS: The exploratory factor analysis (N = 841 participants) resulted in a 3-factor solution, accounting for 74% of the variance in items: (1) self-knowledge (α = 0.92), (2) reproductive planning (α = 0.89), and (3) practical benefits (α = 0.91). CONCLUSION: Our findings support the use of the 3-factor PrU to assess personal utility of genomic results. Validation of the PrU in other samples will be important for more wide-spread application.

Promoting equity, inclusion, and efficiency: A team science approach to the development of authorship guidelines for a multi-disciplinary research team.

Large research teams and consortia present challenges for authorship. The number of disciplines involved in the research can further complicate approaches to manuscript development and leadership. The CHARM team, representing a multi-disciplinary, multi-institutional genomics implementation study, participated in facilitated discussions inspired by team science methodologies. The discussions were centered on team members' past experiences with authorship and perspectives on authorship in a large research team context. Team members identified challenges and opportunities that were used to create guidelines and administrative tools to support manuscript development. The guidelines were organized by the three values of equity, inclusion, and efficiency and included eight principles. A visual dashboard was created to allow all team members to see who was leading or involved in each paper. Additional tools to promote equity, inclusion, and efficiency included providing standardized project management for each manuscript and making "concept sheets" for each manuscript accessible to all team members. The process used in CHARM can be used by other large research teams and consortia to equitably distribute lead authorship opportunities, foster coauthor inclusion, and efficiently work with large authorship groups.

An accessible, relational, inclusive, and actionable (ARIA) model of genetic counseling compared with usual care: Results of a randomized controlled trial.

PURPOSE: Effective approaches to communicate genomic information are needed to ensure equitable care. In a randomized controlled superiority trial, we tested a novel practice model that aims to make genetic counseling inclusive, by making the communication accessible, relational, and actionable (ARIA). METHODS: In total, 696 English- and Spanish-speaking patients aged 18 to 49 years, enriched for individuals from historically underserved backgrounds, were randomized in 1:1 ratio to ARIA or usual care. Primary outcomes were accuracy of recall, communication satisfaction, and perceived understanding. In total, 33 participants completed qualitative interviews. RESULTS: Recall and understanding were high for all participants. ARIA participants scored higher on the relationship scale of communication satisfaction (mean difference = 0.09, 95% CI = <0.01 to 0.17). Moderator analyses of communication satisfaction showed that those with lower health literacy reported less communication difficulty in ARIA and those using medical interpreters reported greater communication ease in ARIA. No significant difference was found on other primary and secondary outcomes. Qualitative data enhanced understanding of how and why ARIA can be effective. CONCLUSION: This study provides evidence that a genetic counseling intervention that focuses on specific communication skills to enhance relationship-building, patient engagement, and comprehension can be effective with all patients and may be especially valuable for patients of lower health literacy and Spanish-speakers who use a medical interpreter.

Engaging Patient Advisory Committees to Inform a Genomic Cancer Risk Study: Lessons for Future Efforts.

Introduction The Cancer Health Assessments Reaching Many study seeks to reduce disparities in genomic care. Two patient advisory committees (PACs) were formed, 1 of English speakers and 1 of Spanish speakers, to vet study processes and materials. Stakeholder engagement in research is relatively new, and we know little about how stakeholders view their engagement. We wanted to learn how patient stakeholders viewed the process, to inform future patient engagement efforts. Methods Patients at 2 study sites were invited to serve on 2 PACs. We used an iterative engagement process to solicit and incorporate patient feedback. Much of the PAC feedback on study materials and processes was incorporated. Using surveys and exit interviews, we evaluated stakeholders' experiences as PAC members. Results Nearly all PAC members felt satisfied and included in the study decisions, but surveys and exit interviews suggested the need to improve communications. Discussion Although most believed their feedback was used, and most felt included in study decisions, some said they did not know whether their opinions were used to modify materials or approaches. This suggests the need to explain to patient stakeholders the extent to which their feedback was used and to inform them about the impact that other stakeholders, such as institutional review boards, have on decisions. Conclusion Our evaluation highlights the value of dedicating resources to stakeholder engagement. Although gathering patient feedback on study materials and processes introduced time constraints and complexity to our study, adaptations to materials and processes furthered study goals.

Literacy-adapted, electronic family history assessment for genetics referral in primary care: patient user insights from qualitative interviews.

BACKGROUND: Risk assessment for hereditary cancer syndromes is recommended in primary care, but family history is rarely collected in enough detail to facilitate risk assessment and referral - a roadblock that disproportionately impacts individuals with healthcare access barriers. We sought to qualitatively assess a literacy-adapted, electronic patient-facing family history tool developed for use in diverse, underserved patient populations recruited in the Cancer Health Assessments Reaching Many (CHARM) Study. METHODS: Interview participants were recruited from a subpopulation of CHARM participants who experienced barriers to tool use in terms of spending a longer time to complete the tool, having incomplete attempts, and/or providing inaccurate family history in comparison to a genetic counselor-collected standard. We conducted semi-structured interviews with participants about barriers and facilitators to tool use and overall tool acceptability; interviews were recorded and professionally transcribed. Transcripts were coded based on a codebook developed using inductive techniques, and coded excerpts were reviewed to identify overarching themes related to barriers and facilitators to family history self-assessment and acceptability of the study tool. RESULTS: Interviewees endorsed the tool as easy to navigate and understand. However, they described barriers related to family history information, literacy and language, and certain tool functions. Participants offered concrete, easy-to-implement solutions to each barrier. Despite experience barriers to use of the tool, most participants indicated that electronic family history self-assessment was acceptable or preferable in comparison to clinician-collected family history. CONCLUSIONS: Even for participants who experienced barriers to tool use, family history self-assessment was considered an acceptable alternative to clinician-collected family history. Barriers experienced could be overcome with minor adaptations to the current family history tool. TRIAL REGISTRATION: This study is a sub-study of the Cancer Health Assessments Reaching Many (CHARM) trial, ClinicalTrials.gov, NCT03426878. Registered 8 February 2018.

Risk-reducing surgery in unaffected individuals receiving cancer genetic testing in an integrated health care system.

BACKGROUND: Germline genetic testing enables primary cancer prevention, including through prophylactic surgery. We examined risk-reducing surgeries in unaffected individuals tested for hereditary cancer susceptibly between 2010 and 2018 in the Kaiser Permanente Northwest health system. METHODS: We used an internal genetic testing database to create a cohort of individuals who received tests including one or more high-penetrance hereditary cancer susceptibility gene. We then identified, after testing, bilateral mastectomy, bilateral salpingo-oophorectomy (BSO), and total hysterectomy procedures in electronic health record and claims data through 2019. We describe surgery utilization by genetic test results and National Comprehensive Cancer Network (NCCN) guidelines. RESULTS: The cohort included 1020 individuals, 16% with pathogenic/likely pathogenic (P/LP) variants in one or more of the following genes: BRCA1, BRCA2, CHEK2, APC, MUTYH, ATM, MSH2, PALB2, BRIP1, MLH1, MSH6, EPCAM, FLCN, RAD51C, RAD51D, or TP53. Among individuals with P/LP variants making them candidates for mastectomy, BSO, or hysterectomy per NCCN guidelines, 34% (33/97), 24% (23/94), and 8% (1/12), respectively, underwent surgery during follow-up. Fifty-three percent (18/37) of hysterectomies were among APC, BRCA1, and BRCA2 P/LP variant heterozygotes, typically concurrent with BSO. Three individuals with variants of uncertain significance (only) and 22 with negative results had prophylactic surgery after genetic testing. CONCLUSIONS: Uptake of risk-reducing surgery following usual care genetic testing appears to be lower than in studies that actively recruit high-risk patients and provide testing and follow-up care in specialized settings. Factors in addition to genetic test results and NCCN guidelines motivate prophylactic surgery use and deserve further study.

ORCA, a values-based decision aid for selecting additional findings from genomic sequencing in adults: Efficacy results from a randomized trial.

PURPOSE: Individuals having genomic sequencing can choose to be notified about pathogenic variants in genes unrelated to the testing indication. A decision aid can facilitate weighing one's values before making a choice about these additional results. METHODS: We conducted a randomized trial (N = 231) comparing informed values-choice congruence among adults at risk for a hereditary cancer syndrome who viewed either the Optional Results Choice Aid (ORCA) or web-based additional findings information alone. ORCA is values-focused with a low-literacy design. RESULTS: Individuals in both arms had informed values-choice congruence (75% and 73% in the decision aid and web-based groups, respectively; odds ratio [OR] = 1.10, 95% CI = 0.58-2.08). Most participants had adequate knowledge (79% and 76% in the decision aid and web-based groups, respectively; OR = 1.20, 95% CI = 0.61-2.34), with no significant difference between groups. Most had information-seeking values (97% and 98% in the decision aid and web-based groups, respectively; OR = 0.59, 95% CI = 0.10-3.61) and chose to receive additional findings. CONCLUSION: The ORCA decision aid did not significantly improve informed values-choice congruence over web-based information in this cohort of adults deciding about genomic results. Both web-based approaches may be effective for adults to decide about receiving medically actionable additional results.

Identifying patients with Lynch syndrome using a universal tumor screening program in an integrated healthcare system.

INTRODUCTION: Lynch syndrome (LS) is associated with an increased risk of colorectal (CRC) and endometrial (EC) cancers. Universal tumor screening (UTS) of all individuals diagnosed with CRC and EC is recommended to increase identification of LS. Kaiser Permanente Northwest (KPNW) implemented a UTS program for LS among individuals newly diagnosed with CRC in January 2016 and EC in November 2016. UTS at KPNW begins with immunohistochemistry (IHC) of tumor tissue to determine loss of mismatch repair proteins associated with LS (MLH1, MSH2, MSH6, and PMS2)., IHC showing loss of MLH1 is followed by reflex testing (automatic testing) to detect the presence of the BRAF V600E variant (in cases of CRC) and MLH1 promoter hypermethylation to rule out likely sporadic cases. MATERIALS AND METHODS: Individuals newly diagnosed with CRC and EC were identified between the initiation of the respective UTS programs and July 2018. Electronic medical records were reviewed to extract patient data related to UTS, including IHC and reflex testing results, date of referrals to the genetics department, and results of germline genetic testing for LS. RESULTS: 313 out of 362 individuals diagnosed with CRC and 61 out of 64 individuals diagnosed with EC who were eligible were screened by IHC for LS. Most (47/52 or 90%, including 46/49 CRC and 1/3 EC) individuals that were not screened by IHC only had a biopsy sample available. Fourteen individuals (3.7% overall, including 13/313 CRC and 1/61 EC) received an abnormal result after reflex testing and were referred for genetic counseling. Of these, 10 individuals (71% overall, including 9/13 CRC and 1/1 EC) underwent germline genetic testing for LS. Five individuals diagnosed with CRC were found to have pathogenic variants. in PMS2 (n = 3), MLH1 (n = 1), and MSH6 (n = 1). No pathogenic variants were identified in individuals diagnosed with EC. CONCLUSIONS: UTS identified individuals at risk for LS. Most individuals who screened positive for LS had follow-up germline genetic testing for LS. The consistent use of biopsy samples is an opportunity to improve UTS.

Establishing the Medical Actionability of Genomic Variants.

Actionability is an important concept in medicine that does not have a well-accepted standard definition, nor is there a general consensus on how to establish it. Medical actionability is often conflated with clinical utility, a related but distinct concept. This lack of clarity contributes to practice variation and inconsistent coverage decisions in genomic medicine, leading to the potential for systematic bias in the use of evidence-based interventions. We clarify how medical actionability and clinical utility are distinct and then discuss the spectrum of actionability, including benefits for the person, the family, and society. We also describe applications across the life course, including prediction, diagnosis, and treatment. Current challenges in assessing the medical actionability of identified genomic variants include gaps in the evidence, limited contexts with practice guidelines, and subjective aspects of medical actionability. A standardized and authoritative assessment of medical actionability is critical to implementing genomic medicine in a fashion that improves population health outcomes and reduces health disparities.