Genetic Referral Research Articles

Revisiting the Threshold for Cancer Genetics Referral in Patients With Wilms Tumor.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in the Journal of Clinical Oncology, to patients seen in their own clinical practice.

AB024. SOH22ABS189. Patients with a family history of colorectal cancer (CRC) within a surveillance programme, a case series review to evaluate the compliance of colonoscopy and frequency of genetics referrals

AB024. SOH22ABS189. Patients with a family history of colorectal cancer (CRC) within a surveillance programme, a case series review to evaluate the compliance of colonoscopy and frequency of genetics referrals

Prenatal genetic counseling practices regarding recommendations for cancer genetic counseling: A retrospective chart review from two academic institutions.

Prenatal and preconception genetic counselors are trained to take patient pedigrees to evaluate for potential risks for genetic conditions, including hereditary cancer syndromes. However, little research has been published on how often prenatal/preconception genetic counselors provide recommendations for cancer genetic counseling solely based on a family history of cancer. Therefore, this study sought to (a) characterize the types of cancers recognized for a cancer genetic counseling recommendation, (b) analyze appointment indications associated with discussion documentation, and (c) investigate how often National Comprehensive Cancer Center (NCCN) genetic testing criteria for Hereditary Breast and Ovarian Cancer syndrome (HBOC) and Lynch syndrome were met and how often a recommendation for cancer genetic counseling was made. A retrospective chart review and pedigree analysis were performed for prenatal/preconception genetic counseling patients with a family history of cancer seen at two academic institutions between August 10, 2019, and December 1, 2019. In the 170 charts included, a recommendation for cancer genetic counseling was documented in 40% of all genetic counseling summaries and in 59.2% of summaries when NCCN genetic testing criteria for HBOC and/or Lynch syndrome was met. Using chi-squared and logistic regression analysis, these data support that individuals were significantly more likely to receive a recommendation when NCCN genetic testing criteria were met (OR=5.01, p<.001) or when the family history contained two or more types of cancer (OR=2.24, p=.02). Overall, this study identified the NCCN genetic testing criteria for HBOC and Lynch syndrome for which recommendations for cancer genetic counseling were commonly missed. This characterization suggests that continuing education for prenatal and preconception genetic counselors on updated NCCN guidelines may be helpful for improving rates of cancer genetic counseling referrals, uptake of genetic testing, and cancer screening recommendations.

Demographic Differences Among US Department of Veterans Affairs Patients Referred for Genetic Consultation to a Centralized VA Telehealth Program, VA Medical Centers, or the Community

Telehealth enables access to genetics clinicians, but impact on care coordination is unknown. To assess care coordination and equity of genetic care delivered by centralized telehealth and traditional genetic care models. This cross-sectional study included patients referred for genetic consultation from 2010 to 2017 with 2 years of follow-up in the US Department of Veterans Affairs (VA) health care system. Patients were excluded if they were referred for research, cytogenetic, or infectious disease testing, or if their care model could not be determined. Genetic care models, which included VA-telehealth (ie, a centralized team of genetic counselors serving VA facilities nationwide), VA-traditional (ie, a regional service by clinical geneticists and genetic counselors), and non-VA care (ie, community care purchased by the VA). Multivariate regression models were used to assess associations between patient and consultation characteristics and the type of genetic care model referral; consultation completion; and having 0, 1, or 2 or more cancer surveillance (eg, colonoscopy) and risk-reducing procedures (eg, bilateral mastectomy) within 2 years following referral. In this study, 24 778 patients with genetics referrals were identified, including 12 671 women (51.1%), 13 193 patients aged 50 years or older (53.2%), 15 639 White patients (63.1%), and 15 438 patients with cancer-related referrals (62.3%). The VA-telehealth model received 14 580 of the 24 778 consultations (58.8%). Asian patients, American Indian or Alaskan Native patients, and Hawaiian or Pacific Islander patients were less likely to be referred to VA-telehealth than White patients (OR, 0.54; 95% CI, 0.35-0.84) compared with the VA-traditional model. Completing consultations was less likely with non-VA care than the VA-traditional model (OR, 0.45; 95% CI, 0.35-0.57); there were no differences in completing consultations between the VA models. Black patients were less likely to complete consultations than White patients (OR, 0.84; 95% CI, 0.76-0.93), but only if referred to the VA-telehealth model. Patients were more likely to have multiple cancer preventive procedures if they completed their consultations (OR, 1.55; 95% CI, 1.40-1.72) but only if their consultations were completed with the VA-traditional model. In this cross-sectional study, the VA-telehealth model was associated with improved access to genetics clinicians but also with exacerbated health care disparities and hindered care coordination. Addressing structural barriers and the needs and preferences of vulnerable subpopulations may complement the centralized telehealth approach, improve care coordination, and help mitigate health care disparities.

Can Automated Alerts in the Electronic Health Record Encourage Referrals for Genetic Counseling and Testing Among Patients at High Risk for Hereditary Cancer Syndromes?

Up to 10% of cancers may be associated with an inherited mutation that increases cancer risk. National guidelines emphasize referral for genetic counseling and testing for patients whose personal and/or family history increases their risk of having a hereditary cancer syndrome. To increase appropriate referrals for cancer genetic counseling and testing, we piloted an automated alert known as a Best Practice Advisory (BPA) in the electronic health record, Epic, to notify oncology providers when a patient had a personal and/or family history that merited referral to cancer genetics. Epic could not gather the complex clinical data needed for the referral decision automatically, necessitating staff completion of a questionnaire. After educating providers, the BPA was implemented with resources to support its use. Initial interaction with the alert was high but rapidly dwindled, resulting in questionnaire completion in 7.2% of more than 32,000 encounters and 14.9% of patients over 9 months. However, cancer genetics referrals increased 95.9% during the pilot (P < .0001), with 18.5% placed through the BPA and the rest from a non-BPA mechanism. Semistructured interviews with key stakeholders revealed not only general acceptance of the BPA concept but also barriers to completion, such as pressure to room patients quickly in the face of competing BPAs and lack of buy-in from some providers. These results suggest that provider engagement and BPA fatigue are significant obstacles to acceptance of a new automated alert. Despite interest in a tool for cancer genetics, the demand on clinical time for this complex BPA was poorly tolerated.

Patient navigation for hereditary colorectal cancer: Design of a randomized controlled trial to determine the effectiveness of pathways to genetic counseling

BackgroundDiagnosis of Lynch and other hereditary colorectal cancer (CRC) syndromes through germline genetic testing has important implications for treatment and risk-management, yet guideline-recommended genetic counseling referral and attendance is suboptimal. MethodsOur team developed an adapted patient navigation program—Pathways to Genetic Counseling—to address multilevel barriers to genetic counseling referral and receipt. This paper describes the methods of a randomized controlled trial (RCT) testing Pathways to Genetic Counseling's effectiveness at increasing genetic counseling attendance in the University of Washington Medicine health system. We will identify CRC patients eligible for genetic counseling (diagnosed before age 50 or at any age with evidence of inherited mismatch repair deficiency) through a combination of structured electronic health record queries and manual chart review. Patients will be randomized 1:1 prior to consent and receive either care as usual (no contact) or be invited to participate in patient navigation. We will use chart review to compare rates of genetic counseling referral and attendance within six months of randomization, regardless of patients' engagement with navigation. We plan to identify and randomize 161 eligible CRC patients over a nine-month period beginning in late 2021. DiscussionOur pragmatic RCT design will provide real-world data on the potential for patient navigation to address longstanding care gaps in preventive genomic medicine. If effective, we hope to pilot Pathways to Genetic Counseling in additional settings with a long-term goal of improving appropriate diagnosis of hereditary CRC syndromes and subsequent cascade screening of eligible family members.

Integrating Medical Genetics Into Precision Oncology Practice in the Veterans Health Administration: The Time Is Now.

Increased access and utilization of tumor profiling of cancers in our veteran population uncovered a modest number of potentially pathogenic germline variants (PPGVs) that require genetics referral for follow-up evaluation and germline sequencing. Challenges identified specific to the veteran population include paucity of genetics providers, either at a veteran's VA facility or nearby non-VA facilities. We sought to investigate the number of veterans who would benefit from having such resources at both local and national levels. Annotated clinical reports of mutations identified by tumor-only profiling and medical records of veterans with solid tumors at the Veterans Administration Ann Arbor Healthcare System (VA AAHS) between 2015 and 2020 were reviewed. PPGVs were identified according to society recommendations (such as ESMO and American Board of Medical Genetics and Genomics), expert review, and/or previously published criteria. After the analysis of our local VA population, these same criteria were then applied to veterans in the National Precision Oncology Program (NPOP). Two hundred eight veterans underwent tumor profiling at the VA AAHS over the defined time period. This included 20 different primary tumor sites with over half (n = 130) being advanced cancer at diagnosis. Of these, 18 veterans (8.5%) had mutations suggestive of a PPGV. Applying these criteria to the larger NPOP database (n = 20,014), a similar percentage (6%) of PPGVs were identified. These results indicate a PPGV frequency (6%-9% of veterans) consistent with the prevalence of inherited cancer predisposition syndromes in the general population, underscoring the need for medical genetics as part of standard oncologic care for veterans. We explore current and future care delivery models to optimize incorporation of medical genetics and genetic counseling to best serve veterans needing such services.

EP479: Primary care providers’ use of genetic services in the Southeast United States: Barriers, facilitators, and strategies

eP479: Primary care providers’ use of genetic services in the Southeast United States: Barriers, facilitators, and strategies

EP507: Patients’ reasons for genetic testing refusal in cancer evaluations: An analysis of the literature and opportunities to educate

eP507: Patients’ reasons for genetic testing refusal in cancer evaluations: An analysis of the literature and opportunities to educate

Impact of provider education on prostate cancer genetic counseling referrals.

59 Background: Guidelines recommend germline genetic not only for men with advanced and metastatic prostate cancer but also those with NCCN-high risk disease. Many men harboring germline DNA repair defects would not have met criteria for testing under previous guidelines (Nicolosi et al, JAMA Oncol 2019). Knowledge of germline mutations is pertinent due to recent regulatory approval of PARP inhibitors olaparib and rucaparib and guides screening for first-degree relatives who are at increased risk for other cancers (Pritchard et al, NEJM 2016). Knowledge gaps for germline genetic testing have been previously described (Loeb et al, Cancer Treat Res Commun 2020). Through a series of educational sessions, we sought to increase utilization of appropriate genetic services for men with prostate cancer. Methods: Starting March 2021, virtual educational presentations were held for nurse navigators, urologists, and medical oncologists throughout our large community-based healthcare system. Surveys were distributed following each presentation to measure clinicians’ perception of their knowledge regarding prostate cancer genetics referrals on a five-step scale. Prostate cancer patient referral data was measured from September 2020 to August 2021, six months prior to and after the presentations. Results: Self-reported understanding of prostate cancer genetics referral practices following the educational presentations increased by an average of 1.7/5 steps (2.5 to 4.2/5) for physicians and 1.4/5 steps (2.9 to 4.1/5) for nurse navigators. From March to August 2021, there were 107 genetic referrals for prostate cancer (average 17.8 referrals/month) compared to 49 referrals from September 2020 to February 2021 (8.2 referrals/month). Conclusions: Prostate cancer genetics referrals increased 118% following educational presentations to urologists, medical oncologists, and nurse navigators. This correlates with an improvement in self-reported knowledge gaps. Provider education interventions may improve access to genetic services for men with prostate cancer. The increase in referrals likely does not account for all patients meeting criteria for germline testing. Work is ongoing to calculate the number of referrals as a proportion of the eligible population.[Table: see text]

Putative germline findings in tumor-only and liquid biopsy sequencing in veterans with aggressive prostate cancer.

179 Background: Tumor-only and/or liquid-biopsy based Next Generation Sequencing (NGS)-based tests, which are routinely performed in metastatic prostate cancer patients, may identify putative germline mutations. The European Society of Medical Oncology (ESMO) made recommendations on findings which should be referred for germline genetic testing; however, it is unknown the burden of genetic testing referrals that may result from implementation of these recommendations. We therefore determined the frequency of putative germline findings in Veterans with metastatic prostate cancer who have undergone NGS-based sequencing of tumor and/or cell-free DNA (cfDNA) on the Foundation Medicine (FMI) platform. Methods: This is a retrospective analysis of Veterans with FMI NGS testing results reported from January 2019-February 2021 who had prostate cancer as the submitted diagnosis and metastatic diagnosis according to a VINCI natural language processing tool. Raw variant data were extracted from FMI reports and harmonized for variant annotation. Variants were annotated using ANNOVAR. Putative germline mutations were defined as 1) likely pathogenic or pathogenic (LP/P) by Clinvar annotation and VAF&gt; 30%. Mutation rates are reported in genes recommended by ESMO to trigger referral for germline testing in all tumor types and all ages of diagnosis and proposed prostate cancer susceptibility genes ( ATM, BARD1, CHEK2). Results: 1,597 Veterans with metastatic prostate cancer underwent FMI NGS testing (63% White, 33% African American, 4% other). Median age was 66 years, with 78.6% of cases from men &gt;60 years. Of 1,597 prostate cancer patients who underwent blood or tumor testing, n=85 (5.3%) had an LP/P mutation in an ESMO-guideline gene. When mutations in ATM, BARD1 and CHEK2 were added, n=133 (8.3%) of patients had an LP/P mutation. The most commonly identified putative germline findings were in BRCA2 (n=49 patients, 3.1%). 18 patients (1.1%) had mutations in other prostate cancer risk genes on the ESMO list ( BRCA1, MLH1, MSH2, MSH6, PMS2). 18 (1.1%) of patients had putative incidental germline findings, which included mutations in PALB2, BRIP1, RAD51C, RAD51D, SDHC. No putative incidental germline mutations were identified in RET, SDHA, SDHB, SDHD, TSC2, VHL. Comparing self-identified White versus self-identified Black patients, putative germline mutation rates were nearly the same in all ESMO-referral genes combined (8.2% vs 8.5%), BRCA2 (2.9% vs 3.0%), and ATM (2.4% vs 2.1%). Conclusions: While guidelines recommend that all veterans with metastatic prostate cancer undergo germline genetic testing, significant patient and system-level barriers continue to limit access to germline genetic testing for many Veterans. Tumor-only NGS testing, with a low rate of putative incidental findings, can help to prioritize which Veterans should be referred for germline genetic testing.

Analysis of Molecular Genetic Testing Referrals for Inherited Retinal Dystrophies in a Quebec Tertiary Care Center Over a Decade.

Analysis of Molecular Genetic Testing Referrals for Inherited Retinal Dystrophies in a Quebec Tertiary Care Center Over a Decade.

A1106 - The risk of Von Hippel-Lindau disease according to individual sporadic cancer in a multidisciplinary program: External validation of the VHL Alliance guidelines for genetic referral

A1106 - The risk of Von Hippel-Lindau disease according to individual sporadic cancer in a multidisciplinary program: External validation of the VHL Alliance guidelines for genetic referral

Incidental germline findings during molecular profiling of tumor tissues for precision oncology: molecular survey and methodological obstacles

BackgroundA fraction of patients referred for complex molecular profiling of biopsied tumors may harbor germline variants in genes associated with the development of hereditary cancer syndromes (HCS). Neither the bioinformatic analysis nor the reporting of such incidental germline findings are standardized.MethodsData from Next-Generation Sequencing (NGS) of biopsied tumor samples referred for complex molecular profiling were analyzed for germline variants in HCS-associated genes. Analysis of variant origin was performed employing bioinformatic algorithms followed by manual curation. When possible, the origin of the variant was validated by Sanger sequencing of the sample of normal tissue. The variants’ pathogenicity was assessed according to ACMG/AMP.ResultsTumors were sampled from 183 patients (Males: 75 [41.0%]; Females: 108 [59.0%]; mean [SD] age, 57.7 [13.3] years) and analysed by targeted NGS. The most common tumor types were colorectal (19%), pancreatic (13%), and lung cancer (10%). A total of 56 sequence variants in genes associated with HCS were detected in 40 patients. Of them, 17 variants found in 14 patients were predicted to be of germline origin, with 6 variants interpreted as pathogenic (PV) or likely pathogenic (LPV), and 9 as variants of uncertain significance (VUS). For the 41 out of 42 (97%) missense variants in HCS-associated genes, the results of computational prediction of variant origin were concordant with that of experimental examination. We estimate that Sanger sequencing of a sample of normal tissue would be required for ~ 1–7% of the total assessed cases with PV or LPV, when necessity to follow with genetic counselling referral in ~ 2–15% of total assessed cases (PV, LPV or VUS found in HCS genes).ConclusionIncidental findings of pathogenic germline variants are common in data from cancer patients referred for complex molecular profiling. We propose an algorithm for the management of patients with newly detected variants in genes associated with HCS.

Abstract PO-050: Characterizing access to genetics referrals for prostate cancer in a safety net hospital

Abstract Genetic testing, as a key component of precision medicine, may reduce prostate cancer treatment-related disparities, but only if widely disseminated outside of tertiary cancer care settings. This study sought to characterize predictors of germline genetic testing referrals and use among patients diagnosed with prostate cancer at a safety-net hospital using electronic medical record data. Men who had a confirmed diagnosis of prostate cancer between January 1, 2011 and March 10, 2020 were identified via the tumor registry. Using a centralized clinical data warehouse, we collected data on age, race, ethnicity, primary language, marital status, clinical stage, and insurance. The primary outcome was receipt of a referral to genetic counseling. We hypothesized that men who were foreign-born, non-English speaking, identified as Black race or Hispanic ethnicity, and were older would be less likely to be referred for genetic testing. A secondary outcome was the completion of genetic testing. Descriptive statistics (means, standard deviations, frequencies) described the cohort. In multivariable analyses, logistic regression estimated odds ratios (OR) and 95% confidence intervals (95% CI) for factors hypothesized to influence referral to genetic testing: age, race (Black, White, Asian, Other), ethnicity (Hispanic vs. non-Hispanic), language (English vs. non-English), country of origin (US vs. Other), insurance (Medicare, Medicaid, Private, Other), and clinical cancer stage (Local, Regional, Metastatic). Overall, 1,877 patients were diagnosed with prostate cancer in the study period. The mean age was 65 years (SD=9). 44% identified as Black race, 32% White. Ethnic composition was 17% Hispanic, 80% Non-Hispanic. Almost half (49%) were married, 46% were foreign born, and 34% had Medicaid insurance at diagnosis. Two-thirds (67%) spoke English, and 33% were non-English speakers. The majority (65%) had local-only disease at diagnosis, 3% had regional disease, 9% metastatic, and 22% had missing clinical stage data. For the primary outcome, 163 (9%) of all patients received at least one genetics referral. In multivariate models, we found that those who were older (OR=0.95, 95% CI: 0.93, 0.98) and identified as White race (OR=0.60, 95% CI: 0.38, 0.96) had lower odds of receiving a referral. Those with regional or metastatic disease at diagnosis were significantly more likely to receive referral, as expected (OR= 4.45 and 4.78, respectively). No other demographics significantly predicted referral. Of the 163 men referred to genetics, 136 (83%) had at least one genetics encounter and 19 (14%) had genetic testing. In sum, few patients received referrals for genetic counseling and testing from 2010-2021, with 80% occurring post-guideline changes in 2018. When referrals were made, our sample had high rates of genetics encounters, although lower rates of testing completion. Low rates of referral and testing indicate opportunities to improve both identification of eligible patients and resolve barriers to completing genetic testing post-encounter. Citation Format: Christine M. Gunn, Gretchen Gignac, Magdalena Pankowska, Kimberly Zayhowski, Catharine Wang. Characterizing access to genetics referrals for prostate cancer in a safety net hospital [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-050.

An Electronic Health Record Tool Increases Genetic Counseling Referral of Individuals at Hereditary Cancer Risk: An Intervention Study

Introduction: There is widespread under-identification of individuals at hereditary cancer risk despite national guidelines calling for screening. We evaluated the utilization of a tool embedded in the electronic health record (EHR) to assist primary care providers in screening patients for cancer genetic counseling referral. Methods: We designed BestPractice Advisories linked to a Genetic Cancer Screening Tool (GCST) in EpicCare Ambulatory. The GCST identifies individuals for evaluation for BRCA1/2, Lynch syndrome, and other risk mutations due to personal and family history. We tested the tool in a 7-week intervention in adult wellness visits at two clinics, one urban and one rural. Results: Out of 687 eligible patients, the screening survey was completed for 469 (67%), and of these, 150 (32%) screened positive for a personal and/or family history meeting genetic counseling referral criteria. Of individuals screening positive, a referral order was placed for 20 (13%). GCST screen-positive rate varied by patient gender but not race or age. Referral rate varied by provider and clinic but was not significantly affected by patient demographics. In the previous year over an equivalent date range, 0.1% of wellness visits (1 of 1,086) led to a referral, and this rate increased to 2.1% (22 of 1,062) during the intervention. The proportion of providers referring patients also increased, from 3.8% (1 of 26) to 42.3% (11 of 26). Discussion/Conclusion: Genetic counseling referral of individuals at hereditary cancer risk was increased by use of an EHR-integrated tool. These findings add evidence for the benefit of clinical decision support for cancer genetic risk screening in primary care.

Factors influencing genetic counseling and testing for hereditary breast and ovarian cancer syndrome in a large US health care system.

Investigate whether disparities and other factors influence referral to genetic counseling and testing for hereditary breast and ovarian cancer syndrome (HBOC) in a large health care system. Examination of clinical, demographic, and socioeconomic factors from electronic health records associated with genetic referral and testing within 12months after a new cancer diagnosed between August 1, 2013 and December 31, 2018. For patients meeting institutional criteria for HBOC testing, 60.6% were referred for genetic counseling, 88% of whom underwent germline testing; at least one pathogenic variant was found in 15.3%. Referral rates for patients with breast (69%) or ovarian cancer (65.7%) were much higher than for metastatic prostate (11.1%, p< 0.0001) or pancreatic cancer (22.3%, p< 0.0001); referral criteria were implemented more recently for the latter two cancers. Younger age, family history, and chemotherapy were associated with referral. Higher Elixhauser comorbidity score and prior cancer were associated with non-referral. No other factors were associated with genetic referral for all eligible cancers combined, although differences were seen in specific cancers. Race was a significant factor only for breast cancer, with fewer Asians than Whites referred. Health disparities in referral to genetics for HBOC cancers are mitigated in a comprehensive integrated health care system.

Psychosocial impact of proactive rapid genetic counseling following breast cancer diagnosis.

As germline genetic referral becomes increasingly routine as part of the care of newly diagnosed breast cancer patients, it is important to understand the psychosocial impact of genetic counseling at the time of diagnosis. We examined the psychosocial and quality of life (QOL) impact of providing proactive rapid genetic counseling and testing (RGCT) in the immediate aftermath of a breast cancer diagnosis. We randomized 330 patients in a 2:1 ratio to proactive rapid genetic counseling (RGCT; N=222) versus usual care (UC; N=108). Participants completed a baseline telephone survey before randomization and definitive surgery and a follow-up survey at 1-month post-randomization. We evaluated the impact of RGCT versus UC on breast cancer genetic knowledge, distress, QOL, and decisional conflict. Given that 43% of UC participants and 86% of RGCT participants completed genetic counseling prior to the 1-month assessment, we also evaluated the impact of genetic counseling participation over and above group assignment. The RGCT intervention led to increased breast cancer genetic knowledge relative to UC but did not differentially impact other study outcomes. Across groups patients who participated in genetic counseling had significantly increased knowledge and improved QOL compared to those who did not participate in genetic counseling. While prior research has documented the impact of genetic counseling and testing on surgical decisions, these results confirm that participation in genetic counseling at the time of diagnosis can yield improvements in knowledge and QOL in the short-term.

Impact of molecular tumour board discussion on targeted therapy allocation in advanced prostate cancer

BackgroundMolecular tumour boards (MTB) optimally match oncological therapies to patients with genetic aberrations. Prostate cancer (PCa) is underrepresented in these MTB discussions. This study describes the impact of routine genetic profiling and MTB referral on the outcome of PCa patients in a tertiary referral centre.MethodsAll PCa patients that received next-generation sequencing results and/or were discussed at an MTB between Jan 1, 2017 and Jan 1, 2020 were included. Genetically matched therapies (GMT) in clinical trials or compassionate use were linked to actionable alterations. Response to these agents was retrospectively evaluated.ResultsOut of the 277 genetically profiled PCa patients, 215 (78%) were discussed in at least one MTB meeting. A GMT was recommended to 102 patients (47%), of which 63 patients (62%) initiated the GMT. The most recommended therapies were PARP inhibitors (n = 74), programmed death-(ligand) 1 inhibitors (n = 21) and tyrosine kinase inhibitors (n = 19). Once started, 41.3% had a PFS of ≥6 months, 43.5% a PSA decline ≥50% and 38.5% an objective radiographic response.ConclusionRecommendation for a GMT is achieved in almost half of the patients with advanced prostate cancer, with GMT initiation leading to durable responses in over 40% of patients. These data justify routine referral of selected PCa patients to MTB’s.

ARMC5-associated Bilateral Macronodular Adrenocortical Hyperplasia: A Novel Germline Variant Associated with Concomitant Papillary Thyroid Carcinoma and Meningioma

Abstract Introduction/Objective Germline mutations in the tumor suppressor gene Armadillo-containing repeat protein 5 gene (ARMC5) have been very recently recognized as a cause for a familial form of bilateral macronodular adrenocortical hyperplasia (BMAH), itself a rare cause of Cushing syndrome. In patients with ARMC5 mutations, scattered case reports have also shown an association with meningiomas and cancers of the pancreas, breast, colon, and thyroid. Methods/Case Report We present the case of BMAH, arising in a 61-year-old female with a history of metastatic papillary thyroid carcinoma and meningioma. The patient presented with bilateral but asymmetric adrenal enlargement (right greater than left) and Cushing syndrome. Given history of thyroid cancer and meningioma, genetics referral was ordered. Counseling revealed a pedigree without a strongly evident familial pattern of hereditary endocrine neoplasia characteristic of any of the more common inherited dispositions to endocrine neoplasia. Additionally, a targeted capture-based NGS germline genetic sequencing study for variants in 12 genes associated with associated with hereditary thyroid cancer was performed and negative. However, based on recent scholarship regarding ARMC5, follow-up germline NGS and Sanger sequencing studies encompassing the entire coding sequences of ARMC5 were ordered. These identified a germline, heterozygous, novel (not in ClinVar) but likely pathogenic variant in (c.802C&amp;gt;T, p.Arg268*), providing a likely explanation for the patient’s BMAH. In attempt to control the patient’s Cushing symptoms, right-sided adrenalectomy was performed, revealing a 220g adrenal gland with marked multinodular hyperplasia with solid, nested, and tubular architecture. Results (if a Case Study enter NA) NA Conclusion While case reports exist describing an association between other ARMC5 mutations and BMAH with concomitant meningiomas and/or malignancies, greater study is needed in order to better characterize the phenotypic spectrum of this disease. Our experience with this case not only reports a novel, apparently pathogenic mutation, but it documents its association with BMAH and, additionally, papillary thyroid carcinoma and meningioma.