Inherited Cancer Susceptibility Research Articles

Implementation of hereditary cancer risk assessment in primary care: Intervention strategies and proximal outcomes.

279 Background: Family history-based risk assessment for hereditary breast and ovarian cancer and Lynch syndrome is guideline recommended and has strong evidence supporting its implementation into clinical practice, especially primary care. Yet, adoption has been impeded by limited awareness of genetic evaluation guidelines among primary care providers (PCPs), time constraints in screening during appointments, and limited resources for follow-up within primary care. To close this gap, we implemented a hereditary cancer risk assessment program that addresses these barriers and evaluated proximal implementation outcomes. Methods: We used intervention mapping for adaptation (IM-Adapt), a modified version of Intervention Mapping to guide the adaptation and implementation of the evidence-based 7-question family history screening (FHS-7) at a primary care clinic within an academic medical center. FHS-7 was adapted for administration via electronic patient portal prior to PCP visit or in-person at PCP visit. All clinic patients were offered screening and follow-up genetic counseling and testing per guidelines. Administrative, programmatic, and electronic medical record data were analyzed for program evaluation. Results: Between February 2023 and March 2024, 4,540 primary care patients were offered hereditary cancer risk assessment and 3,497 (77%) completed screening. Patient portals were used to complete screening more frequently than in-person at the clinic (86.6% vs 13.4%). Among patients with qualifying family history of cancer (n=1,267, 36%), 1,117 (88%) were eligible for navigation as they completed their primary care appointment and did not undergo genetic counseling within the last 5 years. Of the eligible patients, 62% were successfully contacted by a navigator and offered genetic counseling. Program implementation was facilitated by key personnel (clinical champion, informatics staff, genetic patient navigator) and adaptations to fit the implementation setting (adapting FHS7 for patient self-report rather than administration by PCP, patient population with high patient-portal adoption rate and in-house genetic service resources). Conclusions: We demonstrate the feasibility of hereditary cancer risk assessment within primary care and describe actionable aspects of the implementation context that influence screening uptake that can be incorporated into the design of future implementation for maximum impact. Findings advance the state of science in identification of unaffected individuals with inherited cancer susceptibility and genetic service delivery.

Uptake of Cancer Genetic Services for Chatbot vs Standard-of-Care Delivery Models: The BRIDGE Randomized Clinical Trial.

Increasing numbers of unaffected individuals could benefit from genetic evaluation for inherited cancer susceptibility. Automated conversational agents (ie, chatbots) are being developed for cancer genetics contexts; however, randomized comparisons with standard of care (SOC) are needed. To examine whether chatbot and SOC approaches are equivalent in completion of pretest cancer genetic services and genetic testing. This equivalence trial (Broadening the Reach, Impact, and Delivery of Genetic Services [BRIDGE] randomized clinical trial) was conducted between August 15, 2020, and August 31, 2023, at 2 US health care systems (University of Utah Health and NYU Langone Health). Participants were aged 25 to 60 years, had had a primary care visit in the previous 3 years, were eligible for cancer genetic evaluation, were English or Spanish speaking, had no prior cancer diagnosis other than nonmelanoma skin cancer, had no prior cancer genetic counseling or testing, and had an electronic patient portal account. Participants were randomized 1:1 at the patient level to the study groups at each site. In the chatbot intervention group, patients were invited in a patient portal outreach message to complete a pretest genetics education chat. In the enhanced SOC control group, patients were invited to complete an SOC pretest appointment with a certified genetic counselor. Primary outcomes were completion of pretest cancer genetic services (ie, pretest genetics education chat or pretest genetic counseling appointment) and completion of genetic testing. Equivalence hypothesis testing was used to compare the study groups. This study included 3073 patients (1554 in the chatbot group and 1519 in the enhanced SOC control group). Their mean (SD) age at outreach was 43.8 (9.9) years, and most (2233 of 3063 [72.9%]) were women. A total of 204 patients (7.3%) were Black, 317 (11.4%) were Latinx, and 2094 (75.0%) were White. The estimated percentage point difference for completion of pretest cancer genetic services between groups was 2.0 (95% CI, -1.1 to 5.0). The estimated percentage point difference for completion of genetic testing was -1.3 (95% CI, -3.7 to 1.1). Analyses suggested equivalence in the primary outcomes. The findings of the BRIDGE equivalence trial support the use of chatbot approaches to offer cancer genetic services. Chatbot tools can be a key component of sustainable and scalable population health management strategies to enhance access to cancer genetic services. ClinicalTrials.gov Identifier: NCT03985852.

Distribution and mutational landscape of inherited cancer susceptibility syndromes in central nervous system tumors.

Distribution and mutational landscape of inherited cancer susceptibility syndromes in central nervous system tumors.

Abstract PO2-09-03: Twenty-one gene recurrence scores in individuals with breast cancer associated with PALB2 germline pathogenic variants

Abstract Background: The 21-gene recurrence score assay (Oncotype DX, Genomic Health Inc., CA) is prognostic, quantifies predicted benefit of adjuvant chemotherapy, and informs clinical decisions for patients with early-stage, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC). Differences in Oncotype recurrence scores (RS) in individuals with and without BRCA1 and BRCA2 (BRCA1/2) pathogenic variants (PV) have been demonstrated, but the results of this assay in patients with BC and germline PALB2 PV have not previously been described. This is of particular relevance as PALB2 BC has demonstrated biologic features similar to BRCA1/2 BC such as poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) sensitivity. Methods: Patients with early-stage, HR+, HER2-, invasive breast cancer and a germline PALB2 PV were ascertained from academic cancer center databases and the Prospective Registry of MultiPlex Testing (PROMPT), an online research registry for individuals who have had multigene panel testing for inherited cancer susceptibility. Study participants (pts) were categorized by age < 50 and ≥50. Oncotype DX RS were retrospectively reviewed and categorized as those that would and would not warrant consideration of chemotherapy (≥16 and < 16, respectively, for pts < 50; ≥26 and < 26, respectively, for pts ≥50). Yates corrected Chi-square tests were used to compare RS distributions between carriers and a previously published genetically unselected reference population. Results: Oncotype DX reports were reviewed for 20 pts with BC and germline PALB2 PV. Median RS was 19 (range 6-41) overall. Four patients were diagnosed under the age of 50 (range 33-48); median RS for these individuals was 19 (range 12-41). Sixteen patients were diagnosed at age 50 or greater (median 59, range 50-70); median RS for these individuals was also 19 (range 6-31). Compared to the genetically unselected reference population, Oncotype DX RS in pts with PALB2-associated BC demonstrated a numerical but not statistically significant shift in distribution towards categories in which chemotherapy would be considered. Among pts under the age of 50, 75% had Oncotype DX RS for which chemotherapy would be considered and 25% had Oncotype DX RS for which endocrine therapy alone would likely be recommended (p=0.726 compared to reference). Among pts aged 50 and older, 25% had Oncotype DX RS for which chemotherapy would be considered and 75% had Oncotype DX RS for which endocrine therapy alone would likely be recommended (p=0.579 compared to reference). Conclusions: Compared to data from the published genetically unselected commercial database, BC associated with PALB2 PV may have higher Oncotype DX RS reflective of intrinsically less favorable biology and greater therapeutic sensitivity. Larger datasets are forthcoming to confirm presence of significant differences in Oncotype DX RS distributions between BC with and without PALB2 PV. Table 1. Oncotype DX RS distribution by age among pts with gPALB2 PV and genetically unselected reference *Jakubowski et al., J Surg Oncol 2020. PMID 3249731 Citation Format: Payal Shah, Siddhartha Yadav, Jamie Brower, Jada Hamilton, Erica Simmons, Judy Garber, Kenneth Offit, Mark Robson, Fergus Couch, Susan Domchek. Twenty-one gene recurrence scores in individuals with breast cancer associated with 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 PO2-09-03.

Germline Pathogenic Variants in Patients With Pancreatic and Periampullary Cancers.

Inherited cancer susceptibility is often not suspected in the absence of a significant cancer family history. Pathogenic germline variants in pancreatic cancer are well-studied, and routine genetic testing is recommended in the guidelines. However, data on rare periampullary cancers other than pancreatic cancer are insufficient. We compared the prevalence of germline susceptibility variants in patients with pancreatic cancer and nonpancreatic periampullary cancers. Six hundred and eight patients who had undergone pancreaticoduodenal resection at a tertiary referral hospital were studied, including 213 with pancreatic ductal adenocarcinoma, 172 with ampullary cancer, 154 with distal common bile duct cancer, and 69 with duodenal adenocarcinoma. Twenty cancer susceptibility and candidate susceptibility genes were sequenced, and variant interpretation was assessed by interrogating ClinVar and PubMed. Pathogenic or likely pathogenic, moderate- to high-penetrant germline variants were identified in 46 patients (7.7%), including a similar percentage of patients with pancreatic (8.5%) and nonpancreatic periampullary cancer (7.1%). Low-penetrant variants were identified in an additional 11 patients (1.8%). Eighty-nine percent of the moderate- to high-penetrant variants involved the major cancer susceptibility genes BRCA2, ATM, BRCA1, CDKN2A, MSH2/MLH1, and PALB2; the remaining 11% involved other cancer susceptibility genes such as BRIP1, BAP1, and MSH6. Almost all pathogenic variant carriers had a family history of cancer. Patients with pancreatic and nonpancreatic periampullary cancer have a similar prevalence of pathogenic cancer susceptibility variants. Germline susceptibility testing should be considered for patients with any periampullary cancer.

Germline mutations of 4567 patients with hereditary breast-ovarian cancer spectrum in Thailand

Multi-gene panel testing has led to the detection of pathogenic/likely pathogenic (P/LP) variants in many cancer susceptibility genes in patients with breast-ovarian cancer spectrum. However, the clinical and genomic data of Asian populations, including Thai cancer patients, was underrepresented, and the clinical significance of multi-gene panel testing in Thailand remains undetermined. In this study, we collected the clinical and genetic data from 4567 Thai patients with cancer in the hereditary breast-ovarian cancer (HBOC) spectrum who underwent multi-gene panel testing. Six hundred and ten individuals (13.4%) had germline P/LP variants. Detection rates of germline P/LP variants in breast, ovarian, pancreatic, and prostate cancer were 11.8%, 19.8%, 14.0%, and 7.1%, respectively. Non-BRCA gene mutations accounted for 35% of patients with germline P/LP variants. ATM was the most common non-BRCA gene mutation. Four hundred and thirty-two breast cancer patients with germline P/LP variants (80.4%) met the current NCCN genetic testing criteria. The most common indication was early-onset breast cancer. Ten patients harbored double pathogenic variants in this cohort. Our result showed that a significant proportion of non-BRCA P/LP variants were identified in patients with HBOC-related cancers. These findings support the benefit of multi-gene panel testing for inherited cancer susceptibility among Thai HBOC patients. Some modifications of the testing policy may be appropriate for implementation in diverse populations.

Acute Myeloid Leukemia Post Cytotoxic Therapy in Breast Cancer Survivors-Over 23 Years of Single Center Analysis.

Background: Acute myeloid leukemia post cytotoxic therapy (AML-pCT) among breast cancer (BC) survivors represents a life-threatening complication. This study aims to assess the clinical outcomes of AML-pCT post BC. Methods: An analysis of all AML patients treated at a single hematology center (2000-2023) was performed to select patients with AML-pCT post BC. We applied the 2022 ELN criteria to define the genetic risk. Results: Among 847 AML patients, 28 were diagnosed with AML-pCT following BC. Complex karyotype (CK) occurred in 23.8% of patients. The median overall survival (OS) was 40 months. The survival outcomes were better after allogenic hematopoietic stem cell transplantation (alloHCT) treatment compared to chemotherapy alone (median OS: 47 versus 7 months, p = 0.008). Patients demonstrating CK showed lower survival compared to those without CK (2-year OS: 25.0% versus 66.2%, p = 0.0048). The multivariable Cox proportional hazards regression model indicated that treatment with alloHCT emerged as a significant factor associated with improved OS. The treatment was associated with superior OS (HR = 0.07, 95% CI = 0.01-0.86, p = 0.04). Conclusions: Patients with AML-pCT following BC were characterized with the highest frequency of adverse genetic risk profiles and demonstrated worse survival rates. AlloHCT should be performed as early as possible in such patients. The growing need for studies on inherited cancer susceptibility underscores the importance of close AML-pCT development monitoring in BC survivors.

Epithelioid angiomyolipoma of the liver in a patient with Li-Fraumeni syndrome: a case report

BackgroundEpithelioid angiomyolipoma (EAML) is a rare variant of angiomyolipoma that predominantly consists of epithelioid cells and belongs to the perivascular epithelioid cell neoplasm (PEComa) family. The majority of EAMLs arise in the kidneys, and primary hepatic EAML appears to be much less common than renal EAML. Most PEComas arise sporadically, but may be associated with tuberous sclerosis complex (TSC), an autosomal dominant genetic disorder characterized by germline mutations in the TSC1 or TSC2 genes. However, PEComas have previously been reported in five patients with Li-Fraumeni syndrome (LFS), which is an inherited cancer susceptibility disorder resulting from germline mutations in the TP53 tumor suppressor gene.Case presentationWe report a 49-year-old female patient with hepatic EAML and pancreatic cancer. Because she had previously been diagnosed with bilateral breast cancer at the age of 30, we performed a comprehensive genetic analysis to identify genetic alterations associated with any cancer predisposition syndrome. Whole-exome sequencing of a blood sample identified a heterozygous germline variant of TP53 (NM_000546.5):c.708C>A, and targeted next-generation sequencing of liver EAML and pancreatic cancer tissue samples demonstrated the same TP53 (NM_000546.5):c.708C>A variant in both. This, plus the patient’s history of early-onset breast cancer, met the 2015 version of the Chompret criteria for diagnosis of LFS.ConclusionsThere have been very few case reports regarding the presence of PEComa in LFS, and to the best of our knowledge, this is the first report of EAML of the liver in a patient with LFS.

Pharmaceutical Agents as Potential Drivers in the Development of Early-Onset Colorectal Cancer: Case-Control Study.

The incidence of early-onset colorectal cancer (EOCRC) rose abruptly in the mid 1990s, is continuing to increase, and has now been noted in many countries. By 2030, 25% of American patients diagnosed with rectal cancer will be 49 years or younger. The large majority of EOCRC cases are not found in patients with germline cancer susceptibility mutations (eg, Lynch syndrome) or inflammatory bowel disease. Thus, environmental or lifestyle factors are suspected drivers. Obesity, sedentary lifestyle, diabetes mellitus, smoking, alcohol, or antibiotics affecting the gut microbiome have been proposed. However, these factors, which have been present since the 1950s, have not yet been conclusively linked to the abrupt increase in EOCRC. The sharp increase suggests the introduction of a new risk factor for young people. We hypothesized that the driver may be an off-target effect of a pharmaceutical agent (ie, one requiring regulatory approval before its use in the general population or an off-label use of a previously approved agent) in a genetically susceptible subgroup of young adults. If a pharmaceutical agent is an EOCRC driving factor, regulatory risk mitigation strategies could be used. We aimed to evaluate the possibility that pharmaceutical agents serve as risk factors for EOCRC. We conducted a case-control study. Data including demographics, comorbidities, and complete medication dispensing history were obtained from the electronic medical records database of Maccabi Healthcare Services, a state-mandated health provider covering 26% of the Israeli population. The participants included 941 patients with EOCRC (≤50 years of age) diagnosed during 2001-2019 who were density matched at a ratio of 1:10 with 9410 control patients. Patients with inflammatory bowel disease and those with a known inherited cancer susceptibility syndrome were excluded. An advanced machine learning algorithm based on gradient boosted decision trees coupled with Bayesian model optimization and repeated data sampling was used to sort through the very high-dimensional drug dispensing data to identify specific medication groups that were consistently linked with EOCRC while allowing for synergistic or antagonistic interactions between medications. Odds ratios for the identified medication classes were obtained from a conditional logistic regression model. Out of more than 800 medication classes, we identified several classes that were consistently associated with EOCRC risk across independently trained models. Interactions between medication groups did not seem to substantially affect the risk. In our analysis, drug groups that were consistently positively associated with EOCRC included beta blockers and valerian (Valeriana officinalis). Antibiotics were not consistently associated with EOCRC risk. Our analysis suggests that the development of EOCRC may be correlated with prior use of specific medications. Additional analyses should be used to validate the results. The mechanism of action inducing EOCRC by candidate pharmaceutical agents will then need to be determined.

Tumor Testing and Genetic Analysis to Identify Lynch Syndrome Patients in an Italian Colorectal Cancer Cohort.

Lynch syndrome (LS) is an inherited cancer susceptibility syndrome caused by germline mutations in a DNA mismatch repair (MMR) gene or in the EPCAM gene. LS is associated with an increased lifetime risk of colorectal cancer (CRC) and other malignancies. The screening algorithm for LS patient selection is based on the identification of CRC specimens that have MMR loss/high microsatellite instability (MSI-H) and are wild-type for BRAFV600. Here, we sought to clinically and molecularly characterize patients with these features. From 2017 to 2023, 841 CRC patients were evaluated for MSI and BRAFV600E mutation status, 100 of which showed MSI-H. Of these, 70 were wild-type for BRAFV600. Among these 70 patients, 30 were genetically tested for germline variants in hereditary cancer predisposition syndrome genes. This analysis showed that 19 of these 30 patients (63.3%) harbored a germline pathogenic or likely pathogenic variant in MMR genes, 2 (6.7%) harbored a variant of unknown significance (VUS) in MMR genes, 3 (10%) harbored a VUS in other cancer-related genes, and 6 (20%) were negative to genetic testing. These findings highlight the importance of personalized medicine for tailored genetic counseling, management, and surveillance of families with LS and other hereditary cancer syndromes.

S318 Implementation of a Digital Cancer Risk Assessment Tool and Genetic Testing Program in Gastroenterology Practices Throughout the US Identifies Inherited Cancer Susceptibility Syndromes in 15.6% of Patients Tested

S318 Implementation of a Digital Cancer Risk Assessment Tool and Genetic Testing Program in Gastroenterology Practices Throughout the US Identifies Inherited Cancer Susceptibility Syndromes in 15.6% of Patients Tested

Evaluation of two Massive Open Online Courses (MOOCs) in genomic variant interpretation for the NHS workforce

BackgroundThe implementation of the National Genomic Medicine Service in the UK has increased patient access to germline genomic testing. Increased testing leads to more genetic diagnoses but does result in the identification of genomic variants of uncertain significance (VUS). The rigorous process of interpreting these variants requires multi-disciplinary, highly trained healthcare professionals (HCPs). To meet this training need, we designed two Massive Open Online Courses (MOOCs) for HCPs involved in germline genomic testing pathways: Fundamental Principles (FP) and Inherited Cancer Susceptibility (ICS).MethodsAn evaluation cohort of HCPs involved in genomic testing were recruited, with additional data also available from anonymous self-registered learners to both MOOCs. Pre- and post-course surveys and in-course quizzes were used to assess learner satisfaction, confidence and knowledge gained in variant interpretation. In addition, granular feedback was collected on the complexity of the MOOCs to iteratively improve the resources.ResultsA cohort of 92 genomics HCPs, including clinical scientists, and non-genomics clinicians (clinicians working in specialties outside of genomics) participated in the evaluation cohort. Between baseline and follow-up, total confidence scores improved by 38% (15.2/40.0) (95% confidence interval [CI] 12.4–18.0) for the FP MOOC and 54% (18.9/34.9) (95%CI 15.5–22.5) for the ICS MOOC (p < 0.0001 for both). Of those who completed the knowledge assessment through six summative variant classification quizzes (V1–6), a mean of 79% of respondents classified the variants such that correct clinical management would be undertaken (FP: V1 (73/90) 81% Likely Pathogenic/Pathogenic [LP/P]; V2 (55/78) 70% VUS; V3 (59/75) 79% LP/P; V4 (62/72) 86% LP/LP. ICS: V5 (66/91) 73% VUS; V6 (76/88) 86% LP/P). A non-statistically significant higher attrition rate was seen amongst the non-genomics workforce when compared to genomics specialists for both courses. More participants from the non-genomics workforce rated the material as “Too Complex” (FP n = 2/7 [29%], ICS n = 1/5 [20%]) when compared to the specialist genomics workforce (FP n = 1/43 [2%], ICS n = 0/35 [0%]).ConclusionsAfter completing one or both MOOCs, self-reported confidence in genomic variant interpretation significantly increased, and most respondents could correctly classify variants such that appropriate clinical management would be instigated. Genomics HCPs reported higher satisfaction with the level of content than the non-genomics clinicians. The MOOCs provided foundational knowledge and improved learner confidence, but should be adapted for different workforces to maximise the benefit for clinicians working in specialties outside of genetics.

Twenty-one gene recurrence scores in individuals with breast cancer associated with CHEK2 and ATM germline pathogenic variants.

10585 Background: The 21-gene recurrence score assay (Oncotype DX, Genomic Health Inc., CA) is prognostic, quantifies predicted benefit of adjuvant chemotherapy, and informs clinical decisions for patients with early-stage, hormone receptor-positive (HR+) breast cancer (BC). Differences in Oncotype recurrence scores (RS) in individuals with and without BRCA1 and BRCA2 pathogenic variants (PV) have been demonstrated, but the results of this assay in patients with BC and germline CHEK2 or ATM PV have not previously been described. This is of particular relevance as CHEK2 BC have been associated with a worse prognosis. Methods: Prospective Registry of MultiPlex Testing (PROMPT) is an online research registry for individuals who have had multigene panel testing for inherited cancer susceptibility. We retrospectively evaluated Oncotype DX recurrence scores from PROMPT participants (pts) with PV or likely PV in CHEK2 or ATM. Mood’s median tests were used to compare median RS, and Yates corrected Chi-square tests were used to compare RS distributions between carriers and a genetically unselected reference population. Results: Oncotype DX reports were reviewed for 75 pts with 77 BC (n = 50 pts with CHEK2 PV with 51 BC; n = 24 with ATM PV; n = 1 with CHEK2 and ATM PV with 2 BC). Among CHEK2 carriers, median RS was 17 (range 2-43) overall, 17 (2-36) for pts &lt; age 50, and 18.5 (8-43) for pts ≥age 50 (p-value 0.47), with distributions not significantly different than reference ( &lt; 50, p = 0.70; ≥50, p = 0.93). Ten pts had low penetrance CHEK2 alleles (p.S428F or p.I157T) with median RS 16 (9-28) compared to 18 (2-43) in those with other CHEK2 alleles (p = 0.35). Among ATM carriers, median RS was 17 (1-35) overall, 17 (1-35) for pts &lt; age 50, and 16 (11-32) for pts ≥age 50 (p = 0.51), with distributions also not significantly different ( &lt; 50, p = 0.78; ≥50, p = 0.79). Conclusions: Unlike data seen in BC associated with BRCA1 and BRCA2, Oncotype DX RS in individuals with CHEK2 and ATM-associated BC are similar to the published genetically unselected commercial database median RS of 16, with no clear difference based on penetrance of CHEK2 allele. Proportions of patients &lt; 50 and ≥50 with CHEK2 and ATM PV with RS within the range for chemoendocrine therapy consideration are also similar to the historical reference. The inferior prognosis that has been suggested in CHEK2 BC is not reflected in Oncotype DX RS. [Table: see text]

Multigene germline testing usefulness instead of BRCA1/2 single screening in triple negative breast cancer cases

Triple negative breast cancer is considered as the worst aggressive subtype with poor prognosis. Recent studies suggest a hereditary component is involved in TNBC development, especially in young patients. However, genetic spectrum remains unclear. Our purpose was to evaluate the usefulness of multigene panel testing in triple negative patients compared to overall breast cancer cases as well as contributing to elucidate which genes are most implicated in triple negative subtype development. Two breast cancer cohorts, comprising 100 triple negative breast cancer patients and 100 patients with other breast cancer subtypes, were analyzed by Next-Generation Sequencing using an On-Demand panel which included 35 predisposition cancer genes associated with inherited cancer susceptibility. The percentage of germline pathogenic variant carriers was higher in the triple negative cohort. ATM, PALB2, BRIP1 and TP53 were the most non-BRCA mutated genes. Moreover, triple negative breast cancer patients without family history related who were identified as carriers were diagnosed at significantly earlier age. As conclusion, our study reinforces the usefulness of multigene panel testing in breast cancer cases but specifically in those with triple negative subtype regardless family history.

Melanoma and Glioblastoma-Not a Serendipitous Association.

Recently, we came across a patient with malignant melanoma and primary glioblastoma. Given this, we parsed the literature to ascertain the relationship, if any, between these 2 malignancies. We begin with a brief overview of melanoma and glioma in isolation followed by a chronologic overview of case reports and epidemiologic studies documenting both neoplasms. This is followed by studies detailing genetic abnormalities common to both malignancies with a view to identifying unifying genetic targets for therapeutic strategies as well as to explore the possibility of a putative association and an inherited cancer susceptibility trait. From a scientific perspective, we believe we have provided evidence favoring an association between melanoma and glioma. Future studies that include documentation of additional cases, as well as a detailed molecular analyses, will lend credence to our hypothesis that the co-occurrence of these 2 conditions is likely not serendipitous.

Examining interprofessional collaboration in oncogenetic service delivery models for hereditary cancers: a scoping review protocol

IntroductionIn a context of limited genetic specialists, collaborative models have been proposed to ensure timely access to high quality oncogenetic services for individuals with inherited cancer susceptibility. Yet, extensive variability...

Abstract IA004: Moving the needle: It is time for universal germline and somatic genetic testing in all colorectal cancer patients

Abstract The rapid evolution and commercialization of new techniques for analyzing DNA have extended our knowledge of inherited genetic abnormalities that can predispose a person to develop colorectal and other cancers. Concomitantly, the genetic fingerprinting of individual tumors has fueled the development of targeted therapies and informed their appropriate deployment for the management of individual patients. Recently, Cercek and colleagues at Memorial Sloan Kettering Cancer Center reported that all 14 patients with MSI-H rectal cancers treated in a clinical trial in the neoadjuvant setting with the PD-L1 inhibitor dostarlimab had complete remissions of their disease without chemotherapy, radiation, or surgery and those individuals are being followed to determine if, as hoped and expected, those remissions are durable (PMID:35660797). These insights have led and will continue to lead us to develop specific strategies to manage and minimize risk for affected individuals and their family members with inherited cancer susceptibility syndromes. They are also enabling us to decipher the practical value of the heterogeneity of colorectal cancers based upon the identification of inherited or acquired genetic abnormalities that drive the development and progression of an individual patient’s cancer. Now it is time to deploy germline and somatic genetic testing as a standard of care in the clinic, universally and equitably, for individualizing the assessment of inherited colorectal cancer susceptibility and for individualizing care in patients with colorectal cancer. Implementing this strategy will require resource allocation to ensure that health care teams and the patients that they care for both understand and derive the maximum possible benefit from implementing this new approach. Citation Format: Richard M. Goldberg. Moving the needle: It is time for universal germline and somatic genetic testing in all colorectal cancer patients [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA004.

Inherited Cancer Susceptibility Gene Sequence Variations Among Patients With Appendix Cancer

Germline sequence variations in APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53 genes are associated with susceptibility to gastrointestinal cancers. As a rare cancer, the evaluation of appendiceal cancer (AC) predisposition has been limited. To assess the prevalence and spectrum of inherited cancer susceptibility gene sequence variations in patients with AC and the utility of germline genetic testing for this population. This cohort study included patients with AC who underwent germline genetic testing of 14 cancer susceptibility genes performed by a clinical testing laboratory between March 1, 2012, and December 31, 2016. Data were analyzed from March to August 2022. Clinical, individual, and family histories were obtained from clinician-completed test requisition forms. Multigene panel testing was performed by targeted custom capture and sequencing and chromosome rearrangement analysis. The main outcomes were germline sequence variation prevalence and spectrum in patients with AC. Among the 131 patients with AC in the cohort (90 female [68.7%]), a total of 16 deleterious sequence variations were identified in 15 patients (11.5%). Similarly, when limited to the 74 patients with AC as the first and only primary tumor, a total of 8 patients (10.8%) had at least 1 deleterious sequence variation in a cancer susceptibility gene. Overall, 6 patients (4.6%) had a deleterious sequence variation observed in MUTYH (5 with monoallelic MUTYH and 1 with biallelic MUTYH). All 4 patients with Lynch syndrome (3.1%) had a sequence variation in the MLH1 gene, of whom 3 were aged 50 years or older at AC diagnosis. Five patients (3.8%) had deleterious sequence variations in other cancer predisposition genes (1 with APC [c.3920T>A, p.I1307K], 2 with CHEK2 [c.470T>C, p.I157T], 1 with SMAD4 [c.263 287dup, p.L98IFS*14], and 1 with TP53 [c.524G>A, p.R175H]). In this cohort study, 1 in every 10 patients with AC who underwent testing for hereditary cancer predisposition carried an inherited gene sequence variation associated with cancer susceptibility. Given the high frequency and broad spectrum of germline gene sequence variations, these data suggest that genetic evaluation might be warranted for all patients diagnosed with this rare malignant tumor. A systemic sequencing effort for all patients with AC may also identify cancer vulnerabilities to exploit for therapeutic development in a cancer type for which clinical trials are limited.

43. Association between Clonal Hematopoiesis and Inherited Cancer Susceptibility Genes

<h3>Background</h3> Understanding how germline mutations affect Clonal Hematopoiesis (CH) will provide insights into germline predisposition to MN. <h3>Methods</h3> We leveraged blood whole-exome sequencing data from 200,643 individuals in the UK Biobank (UKBB). The association between CH and germline mutations in 211 cancer susceptibility genes were tested among participants without hematologic malignancies at baseline using logistic regression adjusted for known confounders. Genes suggestive of association with CH were validated in 17,037 solid tumor patients with blood sequenced using Memorial Sloan Kettering (MSK) IMPACT panel. <h3>Results</h3> Germline pathogenic/likely pathogenic mutations were detected in 8,967 UKBB participants (4.5%). Germline mutations in TP53, ATR, ATM, and MPL were associated with increased risk of CH with odds ratios (ORs) and confidence intervals (CIs) of 4.33(1.31-14.32), 2.53(1.11-5.76), 2.21(1.23-3.97) and 1.44(1.00-2.08), correspondingly. Among 37 subjects with Li Fraumeni in the MSK-IMPACT cohort, TP53 was also associated with CH (OR: 3.75, 95% CI: 1.40-8.94) and this association was independent of cancer therapy (ORuntreated: 13.52, 95% CI: 2.94-57.48). The significant positive associations between germline TP53 mutations and CH were driven by somatic mutations in TP53 (OR:18.5, 95% CI: 2.8-72.8) and DNMT3A (OR: 5.1, 95% CI: 1.8-12.4). The rate of MN in TP53 mutation carriers was significantly increased (incidence rate ratio: 23.3; 95% CI: 6.0-65.4). The transition to MN was demarcated by a second TP53 loss of function mutation or deletion and by complex karyotype. <h3>Conclusions</h3> Germline mutations in cancer susceptibility genes, particularly those in the DNA damage response pathway are independent risk factors for CH and MN development.

Frequent Abnormal Pancreas Imaging in Patients With Pathogenic ATM, BRCA1, BRCA2, and PALB2 Breast Cancer Susceptibility Variants

Germline genetic testing guides gastroenterologists’ recommendations for prevention of gastrointestinal malignancies. This is well-appreciated for individuals at highest risk for colorectal cancer, including Lynch syndrome or polyposis syndromes.1 In the case of pancreatic cancer (PC), several inherited cancer susceptibility genes are associated with increased PC and breast cancer risk, including BRCA1 and BRCA2, ATM, and PALB2.1-3 With increased multigene panel testing performed for personal and family history (FH) of cancer, and recent National Comprehensive Cancer Network guidelines that recommend genetic testing for those with first-degree relatives diagnosed with PC, newly identified carriers of pathogenic variants will seek recommendations from gastroenterologists on PC screening and outcomes.