Clinical Cancer Genetics Research Articles

Establishment of a clinical cancer genetics program for breast cancer in a resource-limited country; challenges and opportunities.

Breast cancer is the most common cancer among women worldwide, and its incidence rate is still increasing, especially among younger women. Nationally, it constitutes one-fifth of all cancer cases and almost 40% of all female cancers. With a median age of 51 years, breast cancer is diagnosed at least a decade earlier, and at more advanced stages compared to Western societies. Hereditary cancers account for 10% or more of all cancer burden worldwide. With expanded indications, increased number of genes tested, and significant decline in cost of testing, such proportion will probably increase. Individuals with pathogenic variants of BRCA1 and BRCA2 are at higher risk of breast, ovarian, pancreatic and many other cancers. Over the past two decades, several highly penetrant cancer-susceptibility genes were identified across almost all tumor sites, thus increasing the need for comprehensive cancer genetic programs that address the testing process, counselling patients and at-risk family members, and then deal with all testing results and its consequences. In addition to its important role in preventing more cancers in index patients themselves and among their close relatives, identification of pathogenic or likely pathogenic variants, mostly in BRCA1 or BRCA2, may inform therapeutic decisions in common cancers including breast, ovarian, prostate and pancreatic cancers. In this manuscript, we describe the experience of a comprehensive cancer center, in a resource-limited country in establishing a comprehensive clinical cancer genetics program that can serve as an example for others who share similar demographic and financial restrains.

Feasibility of an environmental scan-based approach to collecting information about factors impacting cancer genetics services in Latin American countries.

Clinical cancer genetics services are expanding globally, but national policy and health care systems influence availability and implementation. Understanding the environmental factors within a country is required to appropriately implement, adapt, and evaluate cancer genetics service delivery models. An environmental scan (ES) is an approach used in business, public health, health care and other sectors to collect information about an environment or system for strategic decision making and program planning. An ES has been previously used to assess cancer genetics clinic-level factors to inform quality improvement efforts in the United States. We assessed the feasibility of using an ES to collect information about factors that may influence cancer genetics service delivery in the outer-most socio-ecological model environmental levels (policy, national agencies, healthcare systems, cultural considerations) in three Latin American countries. Oncology and Genetics care team members at three participating sites used publicly available sources and personal experiences to complete a data collection form (DCF) that included questions about subtopics: laws and policies, relevant agencies and regulations, health care systems and insurance, and cultural considerations. Time to complete the DCF and DCF completeness were used to measure ES feasibility. Participating sites completed the DCF in 3 months, and most questions (average, 87.0%) were answered. Questions in the cultural considerations subtopic had the fewest answers (average, 77.8%). Overall, the ES was feasible and identified a lack of published literature related to cultural considerations impacting health care and genetics services uptake in Latin America. Environmental factors impact cancer genetics services, and identification of these factors will facilitate future collaborative research and genetics service delivery dissemination efforts.

Randomized control trial comparing genetic counseling service delivery models in an underserved population.

This randomized controlled trial compares outcomes of telephone versus in-person genetic counseling service models in underserved, bilingual patient populations referred for cancer genetic counseling. Between 2022 and 2023, a two-arm (telephone vs. in-person genetic counseling) prospective, randomized controlled study with 201 participants was conducted at two county hospital cancer genetics clinics. Primary outcomes included comparison of pre- and post-genetic counseling genetics knowledge (Multi-dimensional Model of Informed Choice, MMIC), genetic counseling visit satisfaction (Genetic Counseling Satisfaction Scale, GCSS), and genetic counseling visit completion rates. Secondary outcomes included comparison of genetic testing attitudes and informed choice (MMIC), genetic counseling-specific empowerment (Genomic Outcomes Scale, GOS), and genetic testing completion and cancellation/failure rates, using linear regression models (significance ≤0.05). There were no statistically significant differences between arms in pre/post-genetic counseling MMIC knowledge and attitude, GOS or GCSS scores or genetic counseling completion. While more participants in the telephone versus in-person arm made an informed choice about testing (52.5% v. 39.0%, p = 0.0552), test completion was lower (74% v. 100%, p < 0.05) for this group. Genetic counseling completion rates and MMICknowledge and attitude, GOS, and GCSS scores suggest telephone genetic counseling is comparable to in-person genetic counseling for underserved populations. Higher informed choice scores and significantly lower testing completion rates for telephone visits require further study.

Hereditary and clinical insights into paraganglioma and pheochromocytoma.

Approximately 30-40% of paragangliomas (PGLs) and pheochromocytomas (PCCs) harbor an underlying hereditary cause. Early identification of at-risk individuals is imperative given the early onset, aggressiveness of tumors, and other tumor/cancer risks associated with hereditary PGLs/PCCs. This study analyzes the clinical presentations and genetic histories of patients with PGL/PCC and/or hereditary risk to contribute to the expanding knowledge in this rare population. A retrospective chart review identified two cohorts of patients seen in cancer genetics clinics at an academic medical center and a safety-net hospital between August 2016 and December 2022. Cohort 1 consisted of patients with likely pathogenic variants (LPVs)/pathogenic variants (PVs) in hereditary PGL/PCC predisposition genes. Cohort 2 consisted of patients with a personal history of a PGL/PCC. Demographics, personal/family history, and genetic testing outcomes were analyzed. A total of 560 patients met the study criteria (Cohort 1, n = 364; Cohort 2, n = 269). In Cohort 1, 77 (21.1%) patients had an incidental LPV/PV in a PGL/PCC gene. Nearly half (n = 36, 46.8%) were in SDHx genes, with a majority in SDHA (n = 21). In Cohort 2, 86 patients tested positive for 87 LPV/PV in a hereditary cancer predisposition gene. The SDHx genes were most likely to have an LPV/PV identified (SDHB n = 24, SDHD n = 23). Multigene panels identify patients at risk for hereditary PGL/PCC, many of whom are incidentally found. While SDHA LPV/PVs were the most frequent incidental finding, they were less common in patients with PGL/PCC, indicating the need for longitudinal studies to better understand the prevalence and penetrance of these tumors.

Abstract C125: Improving access to genetic counseling and testing for underserved populations through telehealth

Abstract Introduction: A lack of access to genetic counseling for hereditary cancer risk in rural and underserved areas is well-documented and can exacerbate disparities in cancer risk reduction and early detection. Telehealth has the potential to bridge this gap, providing remote access to specialized care. The COVID-19 pandemic accelerated telehealth availability, allowing estimation of the causal effects of shifting to a model of virtual care delivery for genetic counseling services. Methods: The Stanford Cancer Genetic Counseling Clinic provided solely in-person care at two clinical sites (Palo Alto and San Jose, CA) until March 2020, and solely virtual care from April 2020 onward. We performed a regression discontinuity design, allowing outcomes comparison before and after the threshold of early 2020, to evaluate the impact of telehealth genetic counseling on access to care for patients living in areas of higher deprivation. The assignment variable (the exposure measured before versus after the threshold) was the three-month period during which the patients were seen, with the March-May 2020 quarter excluded because of disruption of care during the early COVID-19 pandemic. The primary endpoint was proportion of patients whose primary residence zip code had a state area deprivation index of at least 4. Secondary endpoints included driving distance to the primary clinic location in Palo Alto, CA, insurance type, race/ethnicity, and primary language. Results: The study included N=5,957 patients seen in the Stanford Cancer Genetics Program between January 2017 and February 2020, and N=9,469 patients seen between June 2020 and April 2024. The regression discontinuity analysis revealed a significant discontinuity at the threshold for telehealth in access for patients living in areas of higher deprivation, who accounted for 22% of patients seen just prior to telehealth implementation and 27% just after telehealth implementation, a proportional increase of 21% (p=0.006). Mean driving distance to Palo Alto, CA also increased, from 49 minutes just prior to the threshold to 56 minutes just after (p=0.003). There were no significant differences in insurance type, race/ethnicity, or primary language across the threshold. Conclusion: The implementation of telehealth services at the Stanford Cancer Genetic Counseling Clinic significantly improved access to genetic counseling for patients from areas with higher deprivation, as evidenced by a 21% increase in the proportion of such patients among those seen. These results quantify the effectiveness of telehealth in reducing geographical and socioeconomic barriers to specialized genetic counseling and testing services. Citation Format: Jennifer L. Caswell-Jin, Hao Tang, Mina Satoyoshi, Kerry Kingham, Allison W. Kurian. Improving access to genetic counseling and testing for underserved populations through telehealth [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C125.

Abstract B115: Intensive Course in genetic cancer risk assessment: Empowering clinicians, expanding clinical knowledge, and elevating care in underserved populations

Abstract Background: Despite efforts to integrate genetic cancer risk assessment (GCRA) services into mainstream medicine, the dearth of healthcare providers adequately trained in clinical cancer genetics remains a significant barrier to care, particularly in underserved communities. Since 2001, City of Hope has helped address this need through a distance mediated lntensive Course (IC) and Clinical Cancer Genomics Community of Practice (CCGCoP), with a focus on training and supporting clinicians who deliver care to underserved patient populations. Here we report on the reach, education, and practice outcomes from the past five annual cohorts of the IC in its pursuit to expand GCRA care to underserved areas and minority populations. Methods: Practice catchment area and patient population data were collected on the course application. Cancer genetics knowledge was assessed at baseline and immediate post-course; professional self-efficacy and practice changes were measured at baseline, immediate, and 12 months post-course. Results: Of 762 participants from five IC cohorts (2020-2024), 566 (74%) indicated they provide all or part of their care in an underserved area and/or to minority populations; 55 (10%) practice outside the U.S. Of these 566 clinicians, mean pre-to-post course knowledge scores increased 59%, and mean pre-to-post self-efficacy scores increased by 38%. Of 195 participants who completed a one-year post-course practice survey, 68 (35%) did not practice GCRA at baseline, of whom 61 (88%) reported implementing GCRA into their practice one-year post-course. Of 126 participants who were practicing GCRA at baseline, 55 (44%) reported an increase in their GCRA patient volume at one-year post-course. Open-ended feedback revealed that participants highly valued IC training and ongoing CCGCoP support for building and sustaining their GCRA skills, resources, and practices. Conclusions:Results demonstrate the efficacy of distance-mediated training and ongoing practice support in enhancing clinician competencies and knowledge of practicing GCRA therefore increasing access to GCRA services for underserved and minority patient populations. Efforts are underway to leverage the resources of the IC and CCGCoP to develop a more flexible, cost-effective course model and collaborate with champions to increase access to best practices in GCRA in diverse underserved settings across the US and internationally. Citation Format: Dev Tanna, John Luna, Alex Capasso, Kathleen Blazer. Intensive Course in genetic cancer risk assessment: Empowering clinicians, expanding clinical knowledge, and elevating care in underserved populations [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B115.

Cancer Care in Resource-Limited Countries: Jordan as an Example.

Jordan, a lower- to middle-income country, is relatively small, but with rapidly growing population and a challenged economy. Cancer is a growing health care problem and currently ranked second, after cardiovascular diseases, as a cause of death. Jordan's national cancer registry continues to suffer from problems mostly related to long lag time in reporting, absence of outcome data, and accurate staging. The number of new patients with cancer diagnosed in Jordan is increasing at an expected, none disturbing rate, fueled by population growth, improving life expectancy, changing population structure that hosts more older population, high rate of obesity, smoking, and lack of adequate exercise. However, age-standardized rate for cancer incidence is significantly lower than Western societies, yet, mortality rate is higher. Despite efforts, cancer is still diagnosed at more advanced stages and at younger age. The Jordan breast cancer program represents a great example of opportunistic screening that led to significant downstaging of breast cancer. Efforts to evaluate the feasibility of screening programs for colorectal and lung cancers are underway. Tremendous efforts resulted in the execution of the largest clinical cancer genetics program in the region that helps identify patients and at-risk relatives for hereditary cancers. Low-resourced countries, including Jordan, will not be able to keep up with the rapidly increasing cost of cancer care. A better access to clinical trials and moving cancer care to ambulatory settings should offset some of this cost. A cancer control program that addresses all issues of cancer care from screening and early detection, through active cost-effective treatment that assures wider access to palliative care, hospice, and survivorship programs under an expanded universal health coverage, is an urgent national health priority.

Translating potential germline findings from tumour profiling into routine clinical care.

105 Background: Tumor molecular profiling (TMP) provides an opportunity to identify heritable cancer predisposition. Molecular Screening and Therapeutics Study (MoST) (8000 patients, 2016-23) and Cancer Screening Program (CaSP) (23000 patients, 2023-25) are Australian research programs providing TMP for therapy matching in advanced cancer. Matched germline testing is resource-inefficient and is not performed . An integrated approach between TMP and cancer genetics is needed to improve familial cancer outcomes through prevention and early detection. Methods: In MoST, potential germline variants (PGV) in actionable cancer genes were investigated in blood DNA in a research setting. Positive cases were informed, and a genetics review for clinical testing recommended. In CaSP, germline follow-up recommendations are included in the Molecular Oncology Board (MOB) Report based on decision algorithms to inform clinicians of PGV needing clinical assessment. Cancer genetics clinics in Australia were surveyed regarding preferences for the return of genetic information from tumor profiling. A centralised precision care clinic was launched in March 2024 to investigate the implementation of returning PGV information from tumor-only profiling. Results: In MoST, 38% (140/367) of PGVs tested were positive in blood DNA. Of these, 44% were identified in the highest actionability genes: BRCA1, BRCA2, PALB2, Lynch Syndrome. The validation and return of results process was unsatisfactory; it was resource-heavy, timeframes were extended, DNA was sometimes unavailable, and communicating information to non-participating relatives of deceased participants was challenging due to a lack of established pathways. The systems design in CaSP has allowed the study to manage higher volume without a net increase in germline workforce. To date, 2372 patients have completed profiling with 173 MOB recommendations for PGV validations. Fifty-four cancer genetics staff nationally responded to the survey. Many (61%) were concerned about the increased uptake of TMP without a workforce to match germline testing demand (97%) and lack of funding assigned in a universal healthcare system (70%) being main concerns. Most (82%) supported a centralised service anticipating improved efficiency gain (71%), equity of access (77%) and streamlining of processes (71%). The stakeholders voiced a consistently high (&gt;50%) demand for information regarding PGV in lower actionability genes. MOB recommendations were adapted to reflect 3 tiers of actionability The centralised clinic has reviewed 21 patients nationally to test 23 highest actionability variants. The average referral to review time is 2 weeks. Conclusions: Precision oncology can play a role in familial cancer prevention. Deliberate collaboration and integration between precision research and relevant specialised care can lead to resource-optimised, equitable delivery of quality care.

Barriers to implementing clinical cancer genetics in sub-Saharan Africa: Perspectives of participants of a virtual cancer genetics course.

10597 Background: While clinical cancer genetics remains underutilized in sub-Saharan Africa (SSA) and many low-middle income countries, there are few empiric studies assessing knowledge gaps and perspectives of healthcare providers. We conducted a survey of participants of a virtual short course ( https://www.africanoncogenetics.org/home ). Methods: The comprehensive survey, partly adapted from other published instruments, included multiple-choice knowledge and practice questions on cancer genetics, Likert-scale questions on perspectives, and open-ended questions on barriers. Cancer genetics experts reviewed the survey to ensure face-content validity. The online course was given between October and November 2021; participants were invited through snowball circulation on global oncology listservs. Data were summarized with descriptive analysis. Results: There were 370 participant responses included in this analysis. Participants represented 40 countries, with largest representation from Nigeria (n=106, 29%), South Africa (n=50, 14%), and Uganda (n=39, 13%). Participants represented various medical specialties and research domains: laboratory medicine (15%), medical genetics (14%), biomedical science (10%), general practice (9%), and oncology (8%) were the most common. Participants also represented a spectrum of practice settings, with the highest proportions from national hospitals (29%) and private hospitals (8%). Most of the participants 223 (71%) had some genetics lectures during medical/nursing school or other training, but only 116 (37%) had attended any continuing medical education (CME) activities in cancer genetics since starting practice. Moreover, the overwhelming majority 95% expressed interest and willingness to attend a future CME course. Many participants, 148 (47.2%) rated their knowledge of cancer genetics as poor or very poor, 150 (48%) as fair, while only 15 (5%) rated as good or very good. Most participants 196 (62%) considered themselves not qualified to interpret results of clinical cancer genetics testing, 100 (32%) were somewhat qualified, and 19 (6%) very qualified. Many participants 93 (30%) noted cancer genetics testing was not available to their patients; another 67 (22%) noted testing was only available outside the country; and only 47 (15%) had testing available within their primary institutions. In aggregate, the most common listed perceived barriers to implementing cancer genetics testing were costs (18%), lack of testing infrastructure (17%), lack of personnel (17%), and lack of provider knowledge (16%). Conclusions: Our survey demonstrates several perceived gaps limiting clinical cancer genetics testing implementation in SSA. A multi-pronged approach that addresses testing costs, testing infrastructure, and patient and provider education is urgently needed.

Large cohort analysis of incidental CDH1 PVs among patients undergoing MGPT.

10618 Background: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant condition caused by a heterozygous pathogenic variant (PV) in CDH1.HDGC is associated with an increased risk for DGC (33-70%) and invasive lobular breast cancer (LBC) (~64%) [1]. The National Cancer Center Network (NCCN) and International Gastric Cancer Linkage Consortium (IGCLC) recommend consideration of CDH1 germline testing based on personal and family history of DGC and LBC. However, with the advent of next generation sequencing and the inclusion of CDH1 in multigene panels (MGP), several cohort studies have identified CDH1+ patients who do not meet criteria [2,3,4,5]. Our group previously analyzed a cohort of patients with a personal or family history of BC who had CDH1 testing through MGPT and did not observe a significant association between CDH1 PVs and suspicion for HDGC (p-value=0.2066) [6]. In this expanded study, we aim to evaluate a larger cohort of patients of all cancer histories to gain a more comprehensive picture of the prevalence of incidental CDH1 PV among patients undergoing MGPT. Methods: 14,891 individuals who underwent CDH1 testing within MGPT were seen at MD Anderson’s Clinical Cancer Genetics (CCG) program between August 2013 and January 2024. This cohort was obtained from a prospectively maintained patient database within MD Anderson’s CCG program. Individuals were stratified based on CDH1 germline status (PV vs. negative or variant of uncertain significance) and meeting modified criteria for HDGC. Results: Within our expanded cohort, 1,716 individuals (11.5%) met criteria for suspicion for HDGC, while 13,715 did not meet criteria. Of the 70 individuals who tested positive for CDH1 (0.47%), 39 (0.28%) met criteria while 31 (0.23%) did not. We observed a statistically significant relationship between meeting our modified criteria for suspicion for HDGC and testing positive for a pathogenic variant in CDH1 (p-value &lt;0.0001). Conclusions: Among patients who underwent CDH1 testing within MGPT, we observed a correlationbetween having a CDH1PV and meeting criteria for suspicion for HDGC. This contrasts with prior findings from our breast cancer cohort, potentially due to the limited number of CDH1 positive patients (n=3). These results suggest that while perhaps not robustly capturing HDGC families within a sub-population of patients undergoing MGPT, overall, NCCN and IGCLC guidelines closely reflect the clinical picture of a significant number of HDGC families. Meanwhile, the presence of incidental CDH1 PVs in this cohort portrays the variable expressivity and incomplete penetrance among patients with HDGC, including the detection of occult signet ring cell carcinomas during endoscopies or total gastrectomies [7]. We seek to expand this analysis by comparing these findings to rates of incidental CDH1 PVs in a subset of patients who meet NCCN guidelines for CDH1 testing based on suspicion for hereditary breast cancer syndromes.

Hematologic malignancies in Li-Fraumeni syndrome.

10613 Background: Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome caused by mutations in the tumor suppressor gene TP53. Since its discovery, a growing list of cancers have been described in association with LFS, predominantly solid tumors. However, hematologic malignancies (HMs) cumulatively account for 4-10% of cancer diagnoses in LFS. In this study, we present the largest series of HMs in families with LFS with detailed clinical courses. Methods: This was a two-center retrospective observational cohort study conducted at the University of Utah and the University of Wisconsin-Madison with IRB approval. Cancer genetics clinic registries were reviewed to identify all families with LFS who also had a confirmed diagnosis of a HM. To meet criteria for LFS, the patient had to have a confirmed germline pathologic or likely pathologic TP53 variant. Patients with a TP53 variant of unknown significance (VUS) were also included if they met classical LFS testing criteria. Data was gathered by manual chart review of both the families’ histories and electronic health records. Results: Among the 121 families identified with LFS, 35 (29%) families had one or more HM. Of these, 17 individuals from 16 families (13%) had confirmed germline TP53 mutations. The most frequent HMs found were acute lymphoblastic leukemia (ALL) (n=6), non-Hodgkin lymphoma (NHL) (n=5), myelodysplastic syndromes (MDS) (n=3), and chronic lymphocytic leukemia (CLL) (n=2). Acute myeloid leukemia (AML), Langerhans cell histiocytosis (LCH), and chronic myeloid leukemia (CML) were each diagnosed once. Most cases were identified in adulthood (n=12, 71%). Of the 19 total HMs, the minority (n=5, 26%) were diagnosed post-cytotoxic therapy and only six (35%) individuals had received a diagnosis of LFS prior to HM diagnosis. The MDS/AML cohort (n=4) all exhibited bi-allelic inactivation of TP53. Two of these four patients achieved long term survival after matched-unrelated donor (MUD) hematopoietic stem cell transplant (HSCT). All three patients who underwent MUD donor HSCT had immune-mediated adverse events. Conclusions: In this study we found a significantly higher incidence of HMs in LFS than previously described, with a predominance of lymphoid over myeloid malignancies. The majority of patients had excellent outcomes after standard of care therapy pointing towards more favorable outcomes for patients with LFS and HMs than previously reported. We also report several unusual immune-mediated adverse events in our patients indicating possible immunogenicity of some TP53 variants. Most patients did not have prior exposure to cytotoxic treatments and were diagnosed with the HM prior to their LFS diagnosis. We also show that 38% of individuals with an HM have multiple family members with an HM, consistent with a familial HM pattern. This underscores the importance of detailed family and personal histories in HM patients found to carry a somatic TP53 variant.

Lessons learned in migrating from one commercial genetics decision-support tool to another: Assessment of data integrity and utilization readiness.

e23232 Background: Rapid advancements in health information technology have greatly influenced how clinicians engage with patient health data. In the context of clinical genetics, the electronic health record (EHR) often contains a wide array of data to identify patients at elevated risk for hereditary cancer syndromes. However, these data often exist in multiple forms and disparate locations, which in the presence of numerous commercial EHR solutions, results in significant variations in how institutions codify genetic data. Furthermore, within an institution, there is often internal pressure to migrate from one support tool to another, necessitating a focus on data integrity during such a transition. Methods: Fred Hutchinson Cancer Center (Fred Hutch) is a large academic cancer care center associated with the University of Washington. Between July and December 2023, the Fred Hutch Clinical Cancer Genetics and Genetic Counseling Service migrated their family history database from commercial pedigree software, Progeny, to another commercial pedigree and decision-support tool, CancerIQ. Following completion of the data migration on more than 13,000 patient records, study team planned to review a total of 500 randomly selected patient charts in both support tools. Each chart was reviewed to determine: (1) the presence of genetic intake information, (2) the presence and results of genetic testing, if available, and (3) whether the patient met National Comprehensive Cancer Network (NCCN) criteria for testing. A chart was noted to be concordant between the two support tools if there was agreement in all three of the above. Results: So far, a total of 240 patient charts were reviewed between the two support tools. Of these, 226 (94.2%) were noted to be fully concordant. Of the 14 charts that were noted to be discordant, the distribution of the discordant data was: 5 charts differed on whether genetic testing had been ordered, 5 charts differed on the results of the testing (often omitting one or more variants), and 4 differed on whether the patient met NCCN criteria for testing. Conclusions: At our institution, there was high data integrity following migration from one commercial and pedigree-generating software solution to another. While these results can ease clinician concerns following such support tools transitions, it also highlights areas for improvement in how family and patient genetic data is recorded.

Downstream Revenue Generated by Patients With Hereditary Cancer in the Multigene Panel Testing Era.

Patients with hereditary cancer syndromes face increased medical management recommendations to address their cancer risks. As multigene panels are the standard of testing today, more patients needing clinical intervention are being identified. This study calculates the downstream revenue (DSR) generated by patients ascertained by a genetic counselor (GC) with a hereditary cancer likely pathogenic/pathogenic variant (LPV/PV). Retrospective chart review was performed for patients seen in a high-volume cancer genetics clinic between October 1, 2009, and December 31, 2021, with LPV/PVs in hereditary cancer predisposition genes. DSR and work relative value units (wRVUs) were calculated for each patient before and after they met with a GC. Subgroup analyses calculated DSR/wRVUs from patients affected and unaffected with cancer and those whose genetic counseling visit was the first at the institution (naїve). A total of 978 patients were available for analysis after exclusions were applied. Patients generated $73.06 million (M) in US dollars (USD) in DSR and 54,814 wRVUs after their initial genetic counseling visit. Unaffected patients (n = 370, 37.8%) generated $11.38M (USD) and 13,879 wRVUs; affected patients (n = 608, 62.2%) generated $61.68M (USD) and 40,935 wRVUs. Naïve patients (n = 367, 37.5%) generated $15.39M (USD) and 11,811 wRVUs; established patients (n = 611, 62.5%) generated $57.67M (USD) and 43,003 wRVUs. Unaffected, naïve patients (n = 204, 20.9%) generated $5.48M (USD) and 5,186 wRVUs. By identifying patients with hereditary cancer, GCs can bring in substantial DSR for their institution. Naïve and unaffected patients provide the greatest GC value-add as these patients represent new business and revenue sources to the institution. As multigene panels continue to expand, the number of patients needing downstream services will increase. Recognizing patients at increased cancer risk will improve patient outcomes while simultaneously providing DSR for institutions.

How hereditary cancer risk disclosure to relatives is handled in practice – Patient perspectives from a Swedish cancer genetics clinic

ObjectivesHereditary cancer risks can be effectively managed if at-risk relatives enroll in surveillance and preventive care. Family-mediated risk disclosure has internationally been shown to be incomplete, selective and leave over a third of eligible at-risk individuals without access to genetic counseling. We explored patients handling of cancer risk information in practice. MethodsWe conducted twelve semi-structured interviews with patients who had completed their genetic counseling and been asked to disclose risk information to relatives. Questions were designed to investigate lived experiences of communicating hereditary risk and focused on disclosure strategies, intrafamilial interactions and emotional responses. ResultsQualitative content analysis yielded five categories. These span personal fears, shared responsibilities, feeling of empowerment, innovative solutions and unmet needs. Patients put high value on collaboration with their genetic healthcare professionals but also solicited better overview of the counseling process and more personalized, case-tailored information. ConclusionsOur results add novel insights about the practical strategies employed by genetic counselees and their motivations behind disclosing hereditary risk information to relatives. Practice implicationsA patient-centered cancer genetics care would clarify roles and responsibilities around risk disclosure, inform counselees about the process upfront and tailor information to offer case-specific data with the family’s inheritance pattern explained.

Abstract PO5-09-04: Oncotype DX Breast Recurrence Score® analysis in early-stage breast cancer associated with CHEK2, ATM and PALB2 germline pathogenic variants

Abstract Background: The 21-gene assay (Oncotype DX Recurrence Score, RS) is the only clinically validated assay to determine the prognosis in hormone-positive, HER2-negative breast cancer (BC) patients treated with endocrine therapy alone by predicting locoregional and distant recurrence. Outcomes of Oncotype RS in BRCA-associated BC has been studied previously, but the results of RS analysis in BC patients with the other BC susceptibility genes have not been documented. This study evaluates the clinical and pathological characteristics of BC patients with ATM, CHEK2 and PALB2 germline pathogenic variants (PV). Methods: Patients with invasive hormone-positive, HER2-negative BC who have had Oncotype DX Breast Recurrence Score® testing and who underwent genetic testing in the Breast Medical Oncology and the Breast Clinical Cancer Genetics Clinic at the University of Texas MD Anderson Cancer Center (MDACC) were identified from the prospectively maintained research database. Clinical and tumor characteristics were analyzed using descriptive statistics. Results: Between 1996 and June 2023, 5652 patients with Oncotype RS were included in this analysis. Amongst those 828 BC patients had genetic testing and 81 patients were found to have a pathogenic variant: 17 patients with a CHEK2 mutation, 10 patients with an ATM mutation, and 18 patients with a PALB2 mutation. Among patients with CHEK2 PV, median Oncotype RS was 17 (5–32) overall, 21 (13–32) for patients age &amp;lt; 50, and 14.5 (5–28) for patients age ≥50 (p= 0.2). Among patients with ATM PV, median RS was 16.5 (3–54) overall, 25 (10–54) for patients age &amp;lt; 50, and 14.5 (3–29) for patients age ≥50 (p= 0.19). Among patients with PALB2 PV, median RS was 26.5 (15–40) overall, 20 (15–40) for patients age &amp;lt; 50, and 31 (26–37) for patients age ≥50 (p= 0.012). Further patient and tumor characteristics are shown in Table 1. Conclusion: This is a single-institutional cohort of hormone-positive, HER2-negative BC patients who had Oncotype RS and who underwent genetic testing. Further analysis on clinical and tumor pathological characteristics and long-term outcome is ongoing. Table1. Patient and tumor characteristics Citation Format: Fatma Akkoc Mustafayev, Angelica Gutierrez Barrera, Diane Liu, Banu Arun. Oncotype DX Breast Recurrence Score® analysis in early-stage breast cancer associated with CHEK2, ATM and PALB2 germline pathogenic variants [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-09-04.

Assessment of BRCA1 and BRCA2 Germline Variant Data From Patients With Breast Cancer in a Real-World Data Registry.

The emergence of large real-world clinical databases and tools to mine electronic medical records has allowed for an unprecedented look at large data sets with clinical and epidemiologic correlates. In clinical cancer genetics, real-world databases allow for the investigation of prevalence and effectiveness of prevention strategies and targeted treatments and for the identification of barriers to better outcomes. However, real-world data sets have inherent biases and problems (eg, selection bias, incomplete data, measurement error) that may hamper adequate analysis and affect statistical power. Here, we leverage a real-world clinical data set from a large health network for patients with breast cancer tested for variants in BRCA1 and BRCA2 (N = 12,423). We conducted data cleaning and harmonization, cross-referenced with publicly available databases, performed variant reassessment and functional assays, and used functional data to inform a variant's clinical significance applying American College of Medical Geneticists and the Association of Molecular Pathology guidelines. In the cohort, White and Black patients were over-represented, whereas non-White Hispanic and Asian patients were under-represented. Incorrect or missing variant designations were the most significant contributor to data loss. While manual curation corrected many incorrect designations, a sizable fraction of patient carriers remained with incorrect or missing variant designations. Despite the large number of patients with clinical significance not reported, original reported clinical significance assessments were accurate. Reassessment of variants in which clinical significance was not reported led to a marked improvement in data quality. We identify the most common issues with BRCA1 and BRCA2 testing data entry and suggest approaches to minimize data loss and keep interpretation of clinical significance of variants up to date.

Clinical features of prostate cancer by polygenic risk score.

Genome-wide association studies have identified more than 290 single nucleotide variants (SNVs) associated with prostate cancer. These SNVs can be combined to generate a Polygenic Risk Score (PRS), which estimates an individual's risk to develop prostate cancer. Identifying individuals at higher risk for prostate cancer using PRS could allow for personalized screening recommendations, improve current screening tools, and potentially result in improved survival rates, but more research is needed before incorporating them into clinical use. Our study aimed to investigate associations between PRS and clinical factors in affected individuals, including age of diagnosis, metastases, histology, International Society of Urological Pathology (ISUP) Grade Group (GG) and family history of prostate cancer, while taking into account germline genetic testing in known prostate cancer related genes. To evaluate the relationship between these clinical factors and PRS, a quantitative retrospective chart review of 250 individuals of European ancestry diagnosed with prostate cancer who received genetic counseling services at The Ohio State University's Genitourinary Cancer Genetics Clinic and a 72-SNV PRS through Ambry Genetics, was performed. We found significant associations between higher PRS and younger age of diagnosis (p = 0.002), lower frequency of metastases (p = 0.006), and having a first-degree relative diagnosed with prostate cancer (p = 0.024). We did not observe significant associations between PRS and ISUP GG, histology or a having a second-degree relative with prostate cancer. These findings provide insights into features associated with higher PRS, but larger multi-ancestral studies using PRS that are informative across populations are needed to understand its clinical utility.

Uptake of screening and risk-reducing recommendations among women with hereditary breast and ovarian cancer syndrome due to pathogenic BRCA1/2 variants evaluated at a large urban comprehensive cancer center.

Carriers of pathogenic variants in BRCA1/2 have an elevated lifetime cancer risk warranting high-risk screening and risk-reducing procedures for early detection and prevention. We report on prevention practices among women with pathogenic BRCA variants in order to document follow through with NCCN recommendations and to identify barriers to guideline-recommended care. Our cohort included women who had genetic testing through a cancer genetic clinic and completed a 54-item questionnaire to measure socio-demographics, medical history, rates of cancer screening and risk-reducing surgery, disclosure of test results, and cancer worry. Outcomes included rates of completion of risk-reducing salpingo-oophorectomy (RRSO), risk-reducing mastectomy (RRM), and NCCN risk-reducing and age-dependent screening guidelines (version 3.2019). Multivariable logistic regression analyses were used to evaluate potential predictors of these outcomes. Of 129 evaluable women with pathogenic BRCA1/2 variants, 95 (74%) underwent RRSO and 77 (60%) had RRM, respectively, and 107 (83%) were considered adherent to NCCN guidelines. Women with a history of breast or ovarian cancer were more likely to have RRM (OR = 4.38; 95% CI 1.80-11.51; p = 0.002). Increasing age was associated with an increased likelihood of RRSO (OR = 1.05; 95% CI 1.01-1.09; p = 0.019) and decreased likelihood for RRM (OR = 0.95; 95% CI 0.92-0.99; p = 0.013). Women who had RRM were 3 times more likely to undergo RRSO (OR = 2.81; 95% CI 1.10-7.44; p = 0.025). Women who had genetic testing after June 2013 were less likely to have RRM than those tested before June 2013 (OR = 0.42; 95% CI 0.18-0.95; p = 0.040. None of the other measured factors were associated with rates of RRSO, RRM or follow through with NCCN recommendations. There was near universal (127/129) reported disclosure of genetic test results to family members, resulting in the discovery of a median of 1 relative with a pathogenic variant (range = 0-8). An evaluation of follow up practice in a cohort of women with pathogenic variants in BRCA1/2 revealed high rates of reported completion of screening and surgical risk-reducing recommendations. Educational efforts should continue to reinforce the importance of follow-through with guideline recommended care among this high-risk group.

Abstract 6201: Early-onset CRC, vitamin A deficiency, and stem cell origin of cancer

Abstract The recent surge in early-onset CRC (EOCRC) has been attributed to a Westernized lifestyle, but the underlying molecular mechanism is largely unknown. In our cancer genetics clinic, we provide care for 10-20 young (&amp;lt;50 age) CRC patients per year. But, only a fraction (~15%) of these young CRC patients are found to have CRC-predisposing germline mutations which doesn’t provide a hereditary factor that can explain EOCRC. Other genetic studies have found that the spectrum of somatic alterations was largely comparable between EOCRC and adult-onset CRC, particularly common are mutations occurring in APC and other members of the WNT pathway. Since a genetic etiology has not turned-up, we are exploring possible lifestyle factors. We hypothesize that vitamin A (retinol) deficiency is a likely etiologic factor because vitamin A is an essential nutrient that is not made by the human body. Thus, young individuals might be prone to any cancer-initiating effects of a vitamin A deficient diet. Indeed, many population-based studies (including ones on well-nourished populations) have reported a high prevalence of vitamin A deficiency in pre-school-aged children. Since APC mutation commonly occurs in early-onset CRCs, we conjecture that vitamin A (retinol) metabolism and APC mutation-induced activation of WNT signaling may be co-factors in promoting EOCRC. Accordingly, we have been investigating whether there is a functional connection between WNT and vitamin A/retinoic acid (RA) signaling, and if APC mutation generates an imbalance in a WNT:RA-linked mechanism that contributes to CRC development by impeding retinoid-induced colonic stem cell (SC) differentiation. We previously reported that RA signaling mainly occurs in aldehyde dehydrogenase-positive (ALDH+) SCs and that APC mutation leads to overpopulation of ALDH+ SCs and incomplete differentiation during CRC development. Thus, our findings suggest that APC mutation attenuates RA signaling in ALDH+ SCs, which might explain how vitamin A deficiency contributes to EOCRC development. Citation Format: Bruce M. Boman, Victoria O. Hunsu, Caroline O. Facey. Early-onset CRC, vitamin A deficiency, and stem cell origin of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6201.

The dynamic buffering of social support on depressive symptoms and cancer worries in patients seeking cancer genetic counseling.

Social support is a crucial protective factor against psychological concerns in patients with cancer. However, there is limited knowledge regarding the differential impacts of social support on cancer worries and depressive symptoms in patients undergoing genetic counseling for hereditary cancer. The current study utilized a high-volume database from a multi-site cancer genetics clinic to assess the impact of perceived social support on depressive symptoms and cancer worries among patients of different age groups (young versus older patients) and diagnosis status (diagnosed survivors versus undiagnosed). 6,666 patients completed brief assessments of depressive symptoms, cancer worries, social support, and demographic questionnaires as part of routine clinical care between October 2016 and October 2020. Logistics and moderated regression were used to analyze the relationships between social support, depressive symptoms, and cancer worries. Increased social support was associated with fewer depressive symptoms and fewer cancer worries across all patients. Social support mitigated depressive symptoms most significantly for young adult patients with and without cancer. Social support mitigated cancer worries most significantly for young adults with cancer and older adults without cancer. While results were mixed, general findings upheld original hypotheses. Social support buffered depressive symptoms and cancer worries differentially for patients of different ages and different disease status. Social support groups are beneficial for all patients and should be emphasized by cancer clinics. However, increasing patient-tailored and age-appropriate support networks will be crucial for managing depression and cancer worries for high-risk survivors: young adults with cancer.