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Laboratory-related outcomes from integrating an accessible delivery model for hereditary cancer risk assessment and genetic testing in populations with barriers to access
Correspondence and requests for materials should be addressed to Laura M. Amendola, University of Washington, Division of Medical Genetics, 1705 NE Pacific St, Box 357720, Seattle, WA 98195-7720.
Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WADepartment of Laboratory Medicine and Pathology, UW Medicine, University of Washington, Seattle, WA
Treuman Katz Center for Pediatric Bioethics, Seattle Children’s Hospital, Seattle, WADivision of Bioethics and Paliative Care, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA
This study aimed to evaluate the laboratory-related outcomes of participants who were offered genomic testing based on cancer family history risk assessment tools.
Methods
Patients from clinics that serve populations with access barriers, who are screened at risk for a hereditary cancer syndrome based on adapted family history collection tools (the Breast Cancer Genetics Referral Screening Tool and PREMM5), were offered exome-based panel testing for cancer risk and medically actionable secondary findings. We used descriptive statistics, electronic health record review, and inferential statistics to explore participant characteristics and results, consultations and actions related to pathogenic/likely pathogenic variants identified, and variables predicting category of findings, respectively.
Results
Of all the participants, 87% successfully returned a saliva kit. Overall, 5% had a pathogenic/likely pathogenic cancer risk variant and 1% had a secondary finding. Almost all (14/15, 93%) participants completed recommended consultations with nongenetics providers after an average of 17 months. The recommended actions (eg, breast magnetic resonance imaging) were completed by 17 of 25 participants. Participant personal history of cancer and PREMM5 score were each associated with the category of findings (history and colon cancer finding, Fisher’s exact P = .02; history and breast cancer finding, Fisher’s exact P = .01; PREMM5TM score; and colon cancer finding, Fisher’s exact P < .001).
Conclusion
This accessible model of hereditary cancer risk assessment and genetic testing yielded results that were often acted upon by patients and physicians.
However, access to genetic evaluation and testing is inequitable and is influenced by geographical, economic, referral-related, and other factors, which limit access.
Patient-provider communication, lack of patient awareness and knowledge, and health literacy barriers are also related to disparities in genetic service delivery for underrepresented populations in clinical genetics.
Specifically, in cancer genetics, patients from historically underserved populations are less likely to have their family history evaluated and be referred to a genetic specialist.
In addition, suboptimal communication between diverse and underserved patients and genetics providers in the setting of cancer risk counseling has been identified.
In 2017, the Clinical Sequencing Evidence-Generating Research consortium was funded by the National Institutes of Health to investigate the integration of exome and genome sequencing into a range of health care settings and disease states in diverse racial/ethnic and medically underserved patient populations.
As part of the Clinical Sequencing Evidence-Generating Research consortium, the Cancer Health Assessments Reaching Many (CHARM) study evaluated a series of interventions to address health care disparities in germline cancer genomic services, with the goal of learning how to better deliver these services equitably in diverse populations.
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; 106 (Published correction appears in Contemp Clin Trials. Published online February 2, 2022.): 106432
The CHARM study enrolled participants at increased risk for hereditary cancer or with limited family history information or structure from 1 of 2 sites: (1) Kaiser Permanente Northwest (KPNW) and (2) Denver Health (DH). Twenty-three percent of KPNW members are from racial/ethnic populations that are underrepresented in genetic studies. In addition, 81% of the patient population at DH is publicly insured or uninsured, 69% is from racial/ethnic populations underrepresented in genetic studies, and 21% of those between the ages of 18 and 49 years primarily or exclusively speak Spanish.
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; 106 (Published correction appears in Contemp Clin Trials. Published online February 2, 2022.): 106432
Here we report the characteristics and exome-based panel testing results for the 967 participants in the CHARM study. We summarize the recommendations made during results disclosure and related follow-up care for participants with a pathogenic or likely pathogenic (P/LP) variant. Finally, we investigate variables associated with the category of findings returned. This study highlights key laboratory-related outcomes from the integration of an alternative service delivery model to increase access to genetic testing and informs expectations for results in diverse and underserved participant populations that include individuals at risk for hereditary cancer syndromes.
Materials and Methods
Enrollment in the CHARM study
Recruitment approaches varied by site and are described in detail elsewhere.
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; 106 (Published correction appears in Contemp Clin Trials. Published online February 2, 2022.): 106432
Briefly, recruitment for the CHARM study took place between August 2018 and August 2020. Primary recruitment at KPNW was carried out via email and follow-up text to patients with upcoming visits at 1 of the 3 KPNW CHARM study clinic sites. At DH, participants were primarily recruited via post card with a follow-up telephone call or by provider referral. Patients from both health systems with an English or Spanish language preference aged between 18 and 49 years were invited to take the risk assessment. Participants who could not speak either English or Spanish, were unable to provide informed consent, or who did not want their results placed in their medical records were not eligible.
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; 106 (Published correction appears in Contemp Clin Trials. Published online February 2, 2022.): 106432
Mittendorf KF, Ukaegbu C, Gilmore MJ, et al. Adaptation and early implementation of the PREdiction model for gene mutations (PREMM5™) for lynch syndrome risk assessment in a diverse population. Fam Cancer. Published online March 23, 2021. https://doi.org/10.1007/s10689-021-00243-3
for hereditary breast and ovarian cancer (HBOC) syndrome. The tool also included a novel algorithm that assessed unknown family history and the number of female family members living beyond age 45 years to screen for limited family history knowledge and limited family structure, respectively. All participants were provided information about their risk assessment results online immediately after completion of the screening tool.
Online consent included custom illustrations of key concepts and audio voiceovers in English and Spanish.
Participants could also request a paper copy or download a PDF copy of the consent if they preferred and/or could complete the risk assessment and consent over the phone. The online consent and risk assessment tools were developed and adapted for limited health literacy in English and were culturally modified and translated into Spanish in an iterative process involving patient stakeholders.
Mittendorf KF, Ukaegbu C, Gilmore MJ, et al. Adaptation and early implementation of the PREdiction model for gene mutations (PREMM5™) for lynch syndrome risk assessment in a diverse population. Fam Cancer. Published online March 23, 2021. https://doi.org/10.1007/s10689-021-00243-3
Participants who were determined to be high risk by the screening tool(s) (high or moderate risk on B-RST 3.0 and/or ≥2.5% risk on PREMM5) or who reported limited family information or structure were provided with information about genetic testing and the options to (1) receive exome-based panel testing through the CHARM study or (2) receive information about access to clinical cancer genetic counseling and testing.
were provided with a saliva sample collection kit by mail or in the clinic, which included literacy-adapted, pictorial, and written instructions congruent with their language selection. The enrollment and consent process for participants in the CHARM study is presented in Figure 1.
Study participants who returned a saliva sample underwent genetic testing at the University of Washington Northwest Clinical Genomics Laboratory via an exome-based panel, which included the clinically relevant portion of the genome (about 5000 of the 20,000 genes in the human genome). DNA was extracted from saliva samples collected via the Oragene Dx OGD-500 kit (DNAGenotek). Sample-specific, dual-indexed libraries were constructed and enriched using an optimized xGen Inherited Diseases Panel (Integrated DNA Technologies). Enriched libraries were pooled and sequenced using an Illumina HiSeq 2500 (Illumina, Inc). Resulting sequences were aligned with the human genome build hg19 reference using the Burrows-Wheeler Aligner.
A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3.
Variants were annotated in 39 genes associated with cancer risk and 77 noncancer, medically actionable secondary finding genes (Supplemental Table 1). Cancer risk genes were identified from the literature and currently available commercial cancer gene panels and were reviewed for inclusion by members of the University of Washington, Northwest Clinical Genomics Laboratory CHARM study team. The medically actionable secondary finding list included the American College of Medical Genetics and Genomics V2.0 secondary finding list genes
Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
All P and LP variants identified in cancer risk genes and medically actionable secondary finding genes were reported. Variants of uncertain significance (VUS) were reported only if the participant reported a personal and/or family history of a cancer associated with the VUS, because this family history information was not collected by a genetics provider, patients were tested for the same cancer genes regardless of their personal and family history, and the majority of VUS will eventually be reclassified as benign.
Pathogenic and likely pathogenic variants were reported in medically actionable secondary finding genes to participants who opted to receive them. Carrier status for autosomal recessive conditions in the cancer or medically actionable secondary finding gene lists was not reported, and only select variants were reported for some genes (Supplemental Table 1).
Annotated variants were prioritized and initially reviewed by a genetic counselor and a molecular geneticist. All variants identified as eligible to be returned or as requiring discussion before classification were reviewed by the Northwest Clinical Genomics Laboratory team, which included a second genetic counselor, a molecular pathologist, and a medical geneticist. Variants were classified on the basis of the American College of Medical Genetics and Genomics recommendations for germline variant classification.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Participant laboratory reports included a section for reporting cancer risk results and a section for reporting medically actionable secondary findings. Cancer risk findings were reported in the same section regardless of whether they were concordant with the participant reported personal and family cancer history.
Participant characteristics and overall results
We explored characteristics of all participants in the CHARM study and of participants who returned a saliva kit using descriptive statistics. Descriptive statistics were also used to summarize the findings reported by the CHARM study in cancer risk and medically actionable secondary findings genes.
Characteristics assessed included age, sex assigned at birth, personal history of cancer, enrollment site, risk assessment result, and whether or not participants had barriers to access. Participants were defined as having barriers to access on the basis of any of the following criteria established by CHARM study investigators: (1) Hispanic ethnicity or a race other than White indicated by participant report or health system electronic medical record data, (2) residing in a Health Resources and Services Administration–defined medically underserved area,
(3) Spanish language preference for the risk assessment or any survey, (4) education attainment less than high school graduate, (5) income <200% of the Federal Poverty Level or Medicaid insurance, (6) uninsured, (7) sexual orientation other than heterosexual, and/or (8) gender identity other than cisgender female/male. The term barriers to access is used throughout this paper as shorthand to describe participants who met 1 or more of these criteria. In addition, given that individuals with Ashkenazi Jewish ancestry are more likely to have P variants in the BRCA1/2 genes, we calculated the proportion of participants who reported this ancestry on the B-RST 3.0 portion of the risk assessment.
To test whether participants who reported a personal history of cancer were more likely to return a saliva kit than participants who qualified on the basis of family history of cancer or limited family history information, we performed Fisher exact tests to evaluate the statistical significance and report Cramér’s V as an estimate of magnitude.
Recommendations and related care activities for participants with a P/LP variant disclosed
We aggregated selected participant characteristics and result details and reviewed disclosure discussions and related activities for participants with a P/LP variant in a cancer risk or medically actionable secondary finding gene disclosed. Participants with other types of results or who did not complete results disclosure were not included in this review. Because changes to colon cancer screening are only recommended on the basis of the finding of a single P/LP variant in the MUTYH gene when there is a family history of colon cancer in a first-degree relative, participants with this finding were also not included.
Three genetic counselors and a medical oncologist on the CHARM study team developed and piloted a data abstraction table over the course of several teleconference calls during which the group iteratively finalized the process and desired content. Results disclosure summary notes that were entered into the participant electronic medical records were reviewed by 1 of the 3 genetic counselors who abstracted relevant personal and family history information and the recommendations made. The other 2 genetic counselors and the medical oncologist then reviewed participant electronic medical records from the time of results disclosure until the present time and abstracted information on the follow-up care completed in relation to the P/LP finding (ie, other provider consultations and/or health care actions).
Results disclosures of P/LP variants took place between December 2018 and July 2020. A subset of normal results was returned via letter. The remainder of the normal results and all VUS and positive results were disclosed via phone by 1 of 4 study genetic counselors. Half of the participants were randomized to receive results disclosure genetic counseling by 1 of the study genetic counselors trained in the Accessible, Relational, Inclusive, and Actionable approach described elsewhere.
The review of participant electronic medical records was conducted between 10 and 27 months post results disclosure with an average elapsed time of 17 months.
Investigation of variables associated with findings reported
We explored participant level characteristics that may be associated with the category of findings returned. For the purpose of this analysis, findings were categorized as either (1) positive: P/LP variants in a high or moderate risk breast, ovarian, and/or colon cancer gene; (2) uncertain: VUS in a high or moderate risk breast, ovarian, and/or colon cancer gene; or (3) negative: all other results, including P/LP variants in medically actionable secondary finding genes. High and moderate risk breast and/or ovarian cancer risk genes from the cancer risk gene list (Supplemental Table 1) included ATM, BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53. High and moderate colon cancer risk genes included APC, BMPR1A, EPCAM, MUTYH (if 2 P/LP variants) MSH6, MLH1, MSH2, POLD1, POLE, PMS2, SMAD4, and STK11. Cancer risk designations for each gene were determined using estimates provided by the Clinical Genome (ClinGen) Resource,
Given that an individual with a history of cancer is more likely to have a hereditary cancer condition, we explored whether a participant’s personal history of breast, ovarian, colon, and/or endometrial cancer was associated with having a positive finding. We also explored if having barriers to access was associated with having a positive finding, hypothesizing that less access to clinical genetic testing among those with barriers would lead to more positive results in this group. In addition, we hypothesized that having limited family information would be more common among those with barriers to access. Thus, we compared the proportion of participants with and without barriers to access who qualified on the basis of limited family information.
Both PREMM5 and B-RST 3.0 have been validated as risk assessment tools to identify patients at risk for LS and HBOC, respectively.
Recent data indicate that PREMM5 risk results ≥2.5% may not be specific to LS but can also indicate the presence of non-LS high penetrance germline P variants.
Comparison of colorectal and endometrial microsatellite instability tumor analysis and Premm5 risk assessment for predicting pathogenic germline variants on multigene panel testing.
Thus, we investigated if having a positive finding in any colon cancer or breast and/or ovarian cancer risk gene returned was associated with screening above the threshold in PREMM5 or with screening high risk in B-RST 3.0, respectively.
Finally, we explored the rates of VUS across race/ethnicity groups from participant reports or health system electronic medical record data, hypothesizing that there would be a higher rate of VUS in Asian, Hispanic, and Black participants based on both previous research
and on historically lower rates of genetic testing and less representation in genomic research in these populations. Participant race/ethnicity groups were deliberately not combined for this analysis. VUS in high-, moderate-, and low-risk cancer genes were included.
To evaluate each of the relationships described above, we performed Fisher’s exact test to evaluate statistical significance and reported Cramér’s V as an estimate of magnitude.
Results
Participant characteristics
A total of 841 of the 967 (87%) participants in the CHARM study who were sent a saliva collection kit returned their sample to the laboratory. Successful DNA extraction and sequencing was completed for 827 of these 841 participants (98.3%). In total, 83 (10%) participants with completed sequencing were identified as Ashkenazi Jewish. Participants with a personal history of a breast, ovarian, colon, and/or endometrial cancer were more likely to return their saliva kit than participants without a personal history (98.3% vs 86.3%; Cramér's V = 0.08; Fisher's exact P = .04). Otherwise, participant characteristics and cancer risk assessment results were similar for all CHARM study participants and participants who returned their sample to the laboratory (Table 1).
Table 1Characteristics of all participants and participants who returned a saliva kit
Cancer risk and medically actionable secondary findings
Overall, 28 participants (3%) had a P/LP variant associated with breast and/or ovarian cancer risk, including 10 participants with a P/LP variant in BRCA1 or BRCA2. In total, 8 participants (1%) had a P/LP variant associated with colon cancer risk, including 7 in the LS associated genes. The overall VUS rate was 9% or 75 out of 827 participants. The number of participants with a P/LP variant and VUS identified in a breast, ovarian, and/or colon cancer risk gene is presented in Table 2.
Table 2Breast, ovarian, and colon cancer-related findings in 827 sequenced participants
In total, 20 participants (2%) were heterozygous for a P/LP variant in the MUTYH gene and 4 participants (0.5%) had a P/LP variant in a cancer risk gene not associated with breast, ovarian, colon, and/or endometrial cancer (1 each in PTCH1, SDHD, SDHB, and TMEM127). Nine (1%) of the 810 participants who opted for return of medically actionable secondary findings had a P/LP variant. Medically actionable secondary findings were identified in APOB, LDLR, MYBPC3 (×2), PAH (compound heterozygote), RYR1, SERPINA1 (SZ alleles), TNNI3, and TSC1.
Recommendations and related care activities for participants with P/LP variants disclosed
Of the 40 participants with a P/LP variant in a cancer risk gene, and 9 participants with a medically actionable secondary finding, 34 (85%) and 8 (89%), respectively, had a results disclosure conversation with a study genetic counselor. The participant characteristics, results, disclosure session details, and care activities related to the P/LP results disclosed are presented in Supplemental Table 2.
Of the 34 participants who were disclosed a cancer risk variant, 6 of 17 (35%) completed a recommended consultation with a genetics provider and 9 of 10 (90%) completed a consultation related to their result with other providers. Eighteen of these 34 participants were recommended to change their current care (eg, breast magnetic resonance imaging, colonoscopy) and 11 (61%) completed at least 1 of the recommended actions. Ten (29%) participants with cancer risk variants received recommendations for health care actions that did not change their care at their current age (eg, recommendation for a 25-year-old female participant with a P/LP CHEK2 variant to consider breast magnetic resonance imaging at age 40 years). Of note, 6 of the 34 (18%) participants disclosed a P/LP cancer risk variant were no longer receiving care at DH or KPNW at the time of electronic health record review.
Of the 8 participants who disclosed a medically actionable secondary finding, 2 of 4 (50%) completed the recommended consultations with a genetics provider and 5 of 5 (100%) completed related follow-up consultations with other providers. Five of 6 (83%) participants completed recommended actions.
None of the 8 participants with a secondary finding disclosed had previous knowledge of the variant in themselves or in their family; however, 11 of the 34 (32%) participants with a cancer risk P/LP variant disclosed reported previous knowledge of the finding in themselves (n = 6) or in 1 or more family members (n = 5) during results disclosure conversations. These findings had been identified by genetic testing conducted in a clinical setting outside of the CHARM study. Four of the 6 participants with a known P/LP cancer risk variant in themselves had a personal history of cancer. Most participants with a cancer risk variant (24/33, 73%) and a secondary finding (6/8, 75%) did not have a related personal history.
Variables associated with results reported
No differences in the VUS rates were found across self-reported race/ethnicity groups (Table 3) (high/moderate/low risk breast/ovarian cancer genes: Cramér’s V = 0.24; Fisher's exact P = .10; high/moderate risk colon cancer genes: Cramér’s V = 0.07; Fisher's exact P = .61).
Table 3VUS in breast/ovarian and colon cancer risk genes across race/ethnicity groups from participant report or health system electronic medical record data
The category of findings returned (positive, uncertain, or negative) was associated with whether or not participants had a personal history of breast, ovarian, colon, and/or endometrial cancer (breast and/or ovarian cancer risk gene, Cramér’s V = 0.11; Fisher's exact P = .02; colon cancer risk gene, Cramér’s V = 0.13; Fisher's exact P = .01). Participants with a personal history of cancer had a positive finding more often in breast and/or ovarian cancer risk genes (7.3% vs 1.6%) and colon cancer risk genes (5.5% vs 0.7%) and had an uncertain finding less often (breast/ovarian cancer risk genes, 1.8% vs 4.8%; colon cancer risk genes 0% vs 2.9%).
There was no association between having barriers to access and the category of findings for breast and ovarian cancer risk genes (Cramér’s V = 0.02; Fisher’s exact P = 1.0); however, there was an association between having barriers to access and the category of findings for colon cancer risk genes (Cramér’s V = 0.09; Fisher’s exact P = .04). Participants had similar rates of uncertain findings in colon cancer risk genes (no barriers 2.58% vs barriers 2.69%); but a higher proportion of participants who did not have barriers to access had a positive colon cancer finding (no barriers 2.58% vs barriers 0.47%). There was no association between having barriers to access and being eligible for enrollment based on limited family information (Fisher’s exact P = .26).
Screening above the threshold on PREMM5 was associated with the category of findings for colon cancer risk genes (Cramér’s V = 0.22; Fisher’s exact P < .001). Those who screened ≥2.5% in PREMM5 had an uncertain or positive colon cancer risk finding more frequently than those who qualified for the study based on limited family information or screening high risk in B-RST 3.0 (uncertain 7.9% vs 1.1%; positive 3.2% vs 0.3%). Screening high risk in B-RST 3.0 was not associated with the category of findings for breast and/or ovarian cancer risk genes (Cramér’s V = 0.08; Fisher’s exact P = .09).
Discussion
The CHARM study evaluated a streamlined approach to increase access to genetic testing for patients from diverse and medically underrepresented groups at risk for hereditary cancer or with limited family information or structure. As part of the CHARM study, multiple intervention components were designed and implemented to reduce barriers to risk assessment, consent, and sample acquisition, including the use of web-based patient-facing tools and saliva collection at home.
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; 106 (Published correction appears in Contemp Clin Trials. Published online February 2, 2022.): 106432
Mittendorf KF, Ukaegbu C, Gilmore MJ, et al. Adaptation and early implementation of the PREdiction model for gene mutations (PREMM5™) for lynch syndrome risk assessment in a diverse population. Fam Cancer. Published online March 23, 2021. https://doi.org/10.1007/s10689-021-00243-3
A high proportion (841/967, 87%) of participants who consented for genetic testing through the study successfully returned a saliva kit, and there was no difference in the rate of return between those who met the CHARM study definition of having barriers to access and those who did not. This suggests that the CHARM study multimodal service delivery approach provided an accessible delivery model for genetic testing. Increasing access to genetic services is essential to providing genomic medicine equitably. Integrating multiple, evidence-based modifications with traditional care delivery approaches will likely be necessary to effectively address the needs and preferences of providers, health systems, and patients.
With the introduction of massively parallel sequencing into clinical genetics, hereditary cancer testing has evolved from targeted, sequential, single-gene testing toward larger panels of genes that predispose to all types of cancers.
Recent research providing cancer gene panel testing for all patients with solid tumors, regardless of age, cancer type, or family history, identified P/LP variants in 13% of patients.
In the CHARM study, 5% of participants had a P/LP variant in a cancer risk gene. This rate reflects the personal and family cancer history characteristics of the sequenced participants. The prior probability of a positive result is highest for an individual diagnosed with cancer, raising suspicion for a hereditary predisposition in a family. Most participants tested in the CHARM study had no personal history of breast, ovarian, colon, and/or endometrial cancer (781/837, 93%). In addition, 20% (170/837) of the sequenced CHARM participants qualified for the study based on limited family information or structure, and 2 (1%) of these individuals had a P/LP cancer risk variant. These estimates of testing yield can inform guidelines and recommendations for hereditary cancer genetic testing that include criteria related to patient reported personal and family history of cancer and limited family history information or structure.
US Preventive Services Task Force Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US Preventive Services Task Force recommendation statement.
JAMA.2019; 322 (Published correction appears in JAMA. 2019;322(18):1830.): 652-665
Although a subset (18%) of participants with a P/LP cancer risk variant had previous knowledge of the variant in themselves, most (73% cancer risk, 75% secondary findings) participants with a P/LP finding had no known related personal history. These participants gained the opportunity to discuss and pursue prevention and surveillance for early detection of disease. Each participant disclosed a P/LP variant met with a genetics provider through the CHARM study to discuss their result and the implications, and almost all completed recommended downstream consultations with nongenetics providers (90% cancer risk, 100% secondary finding) who could facilitate risk management behaviors associated with reduced morbidity and mortality.
The PREMM5 risk assessment has been validated and integrated into clinical practice as a LS evaluation tool.
In the CHARM study, screening above the threshold on the PREMM5 was associated with having a P/LP variant in a colon cancer risk gene. This suggests that the literacy and cultural adaptation of this tool for implementation as a self-completed, patient-facing electronic application in this population was effective at identifying those at increased risk. This finding also suggests that integrating the PREMM5 as a patient-facing tool could identify patients with non-LS hereditary colon cancer conditions, which is consistent with recently published research,
Comparison of colorectal and endometrial microsatellite instability tumor analysis and Premm5 risk assessment for predicting pathogenic germline variants on multigene panel testing.
and provides further support for recommending multigene panel testing for those who screen at increased risk.
Screening high risk on the B-RST 3.0 in the CHARM study was not associated with the category of finding returned (positive, uncertain, negative) in breast and/or ovarian cancer risk genes. Family history of ovarian cancer and bilateral breast cancer are both highly weighted in the B-RST 3.0 algorithm. It is possible that inaccurate reporting of family members with these cancers on the B-RST 3.0 qualified individuals for the CHARM study who did not actually have a family history suggestive of HBOC, underpowering the analysis for this association.
These findings need to be interpreted in the context of several limitations. First, the rate of positive cancer risk findings in the CHARM study may not be generalizable to a clinical setting with testing ordered by a genetic specialist and/or on the basis of a provider-collected family history. Second, although a difference in VUS rate across participant reported race/ethnicity categories was not identified, it is possible that the CHARM study was underpowered to evaluate this question. Research opportunities and dedicated funding that is focused on engagement of diverse participant cohorts are necessary to generate data sets and evidence to support equitable variant classification outcomes. Third, the interpretation of these findings is limited by the absence of a comparison group. A manuscript comparing outcomes of those who declined participation in the CHARM study is forthcoming and will add context for the findings reported here. Finally, there are several limitations related to the review of recommendations and related care activities for participants with P/LP variants disclosed. The time frame during which completion of recommended consultations and care activities was evaluated overlapped with the COVID-19 pandemic and related restrictions on routine medical care, which may have lowered rates of adherence to related recommendations. It is also not possible to identify which and to what extent each of the 12 components in the CHARM multimodal intervention may have influenced participant actions related to follow-up care. In addition, the review was conducted at a single point in time, and information from each chart was abstracted by only 1 reviewer, so interrater reliability and changes over time were not assessed.
The integration of an alternative delivery model incorporating electronic, patient-facing hereditary cancer risk assessment and at-home saliva-based genetic testing enabled successful genetic testing service delivery in diverse and medically underserved patient populations in the CHARM study. The continued development, evaluation, and tailoring of alternative approaches, such as those integrated in the CHARM study, is essential to address barriers and inequities in access to genetic services. Identifying participants at increased cancer risk and with other medically actionable genetic conditions increased opportunities for prevention and early detection. Longer term studies that can evaluate the patient health and economic outcomes related to these changes in recommended care will inform the utility of larger scale, less targeted genomic testing. Finally, additional work to identify and address barriers to adherence to recommended health care, especially in traditionally underrepresented populations, is necessary.
Data Availability
Classifications and evidence details for all variants returned to Cancer Health Assessments Reaching Many participants have been submitted to ClinVar under the submitter name “Division of Medical Genetics, University of Washington” and can be accessed at: https://www.ncbi.nlm.nih.gov/clinvar/submitters/507302/.
Conflict of Interest
S.S. reports being a consultant for Myriad Genetics and reports receiving an inventor share of licensing revenues from the PREMM model. L.M.A. is an employee of Illumina, Inc. All other authors declare no conflicts of interest.
Acknowledgments
This work was part of the Clinical Sequencing Evidence-Generating Research consortium funded by the National Human Genome Research Institute with cofunding from the National Institute on Minority Health and Health Disparities and the National Cancer Institute. This work was supported by a grant from the National Human Genome Research Institute (U01HG007292; multiple principle investigators: Wilfond, Goddard), with additional support from U24HG007307 (Coordinating Center) and National Institutes of Health 5R01CA132829 (S.S. and C.U.).
Patient consent for participation in the Cancer Health Assessments Reaching Many study was received. The Cancer Health Assessments Reaching Many study was approved by the Kaiser Permanente Northwest Institutional Review Board (IRB), and all collaborating IRBs relied on Kaiser Permanente Northwest IRB except for Dana-Farber Cancer Institute and Columbia University, which approved the study separately.
Jake Allen, Laura M. Amendola, Katherine P. Anderson, Frank Angelo, Briana L. Arnold, Cecelia Bellcross, Tiffany Bendelow, Barbara B. Biesecker, Kristin D. Breslin, Joanna E. Bulkley, Kristina F. Booker, Mikaella Caruncho, James V. Davis, Sonia Deutsch, Beth Devine, Michael O. Dorschner, Devan M. Duenas, Donna J. Eubanks, Heather Spencer Feigelson, Amanda S. Freed, Marian J. Gilmore, Katrina A.B. Goddard, Clay Greaney, Inga Gruß, Claudia Guerra, Boya Guo, Joan Holup, Jessica Ezzell Hunter, Chalinya L. Ingphakorn, Paige Jackson, Gail P. Jarvik, Charisma L. Jenkins, Galen Joseph, Leah S. Karliner, Tia L. Kauffman, Erin Keast, Sarah Knerr, Alyssa H. Koomas, Stephanie A. Kraft, Mi H. Lee, Robin Lee, Sandra Soo-Jin Lee, Michael C. Leo, Hannah S. Lewis, Elizabeth G. Liles, Nangel M. Lindberg, Frances Lynch, Carmit K. McMullen, Elizabeth Medina, Kathleen F. Mittendorf, Kristin R. Muessig, Sonia Okuyama, C. Samuel Peterson, Angela R. Paolucci, Rosse Rodriguez Perez, Kathryn M. Porter, Chelese L. Ransom, Ana Reyes, Leslie S. Riddle, Sperry Robinson, Bradley A. Rolf, Alan F. Rope, Emily Schield, Jennifer L. Schneider, Kelly J. Shipman, Brian H Shirts, Elizabeth Shuster, Sapna Syngal, Britta N. Torgrimson-Ojerio, Chinedu Ukaegbu, Meredith L. Vandermeer, Alexandra M. Varga, David L. Veenstra, W. Chris Whitebirch, Larissa Lee White, Benjamin S. Wilfond, Jamilyn M. Zepp.
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NCCN Guidelines Insights: genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 1.2020.
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; 106 (Published correction appears in Contemp Clin Trials. Published online February 2, 2022.): 106432
Mittendorf KF, Ukaegbu C, Gilmore MJ, et al. Adaptation and early implementation of the PREdiction model for gene mutations (PREMM5™) for lynch syndrome risk assessment in a diverse population. Fam Cancer. Published online March 23, 2021. https://doi.org/10.1007/s10689-021-00243-3
A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3.
Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Comparison of colorectal and endometrial microsatellite instability tumor analysis and Premm5 risk assessment for predicting pathogenic germline variants on multigene panel testing.
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