Germline Genetic Testing Research Articles

Influence of preoperative Lynch syndrome diagnosis on surgery in patients with colorectal cancer.

94 Background: Lynch Syndrome (LS) can guide surgery for colorectal cancer (CRC), particularly for MLH1/MSH2 carriers, who may benefit from extended procedures: total colectomy (TC) or total proctocolectomy (TP). We investigated timing of germline genetic testing (GGT) and surgical approach in patients (pts) with LS and CRC. Methods: Integrated GGT (Labcorp, formerly Invitae Corp.) and insurance claims (Komodo Healthcare Map) data for adult pts with non-metastatic colon (CC) or rectal (RC) cancer and CRC surgery from 2015-23, ≥ 6 months of claims pre-CRC diagnosis, and GGT for EPCAM, MLH1, MSH2, MSH6, and PMS2 . Χ 2 and t tests and multivariable logistic regression compared GGT results and surgical approach. Results: Of 1616 CRC pts (1553 CC, 63 RC), 15% were LS positive (15% CC, 11% RC). Compared to pts with negative GGT, pts with LS were more likely male, Black, younger at diagnosis and GGT, to have family history of GI/any cancer and to have GGT pre-CRC surgery. Of 129 LS pts with CC and MLH1/MSH2/EPCAM, 41 (32%) had GGT pre-surgery and 20/41 (49%) had TC/TP (Table). 5/6 (83%) of the corresponding RC pts had GGT pre-surgery and 3/5 (60%) had TP. 88 CC MLH1 / MSH2 / EPCAM pts had GGT post-surgery and 17/88 (19%) had TC/TP. 1 MLH1 / MSH2 / EPCAM RC patient had GGT post-surgery and 0 had TP. More CC pts had TC/TP than RC pts (p<0.001). Compared to pts with negative GGT, pts with LS and CRC were more likely to have TC/TP (21% vs. 6%, p<0.001), particularly with GGT pre-surgery (43% vs. 13%, p<0.001). RC LS pts with GGT pre-surgery had shorter mean months from GGT to surgery than pts with negative GGT (6 vs 14, p=0.026). CC pts with MLH1 or MSH2/EPCAM and GGT pre-surgery had higher odds of undergoing TC/TP (odds ratio (OR): 6, confidence interval (CI): 3-10; OR: 7, CI: 4-14; OR: 4, CI: 2-6) than pts with negative or post-surgery GGT. Conclusions: GGT performed pre-surgery for a new diagnosis of CRC was more likely to result in extended procedures, especially in MLH1/MSH2/EPCAM carriers. More data in RC is needed to better understand the influence of GGT on surgical approach. CC surgery type and timing in relation to GGT. Pts w/ CC surgery GGT pre-surgery (N=295) GGT post-surgery (N=1258) Total Partial Colectomy (N=245)N (% total) TC/TP (N=50) N (% total) P-value: partial vs TC/TP^ Total Partial Colectomy (N=1203)N (% total) TC/TP (N=55)N (% total) P-value: partial vs TC/TP^ MLH1 (N=75) 24 (32) 13 (54) 11 (46) 0.001 51 (68) 42 (82) 9 (18) <0.001 MSH2/ EPCAM (N=54) 17 (32) 8 (47) 9 (53) 0.006 37 (69) 29 (78) 8 (22) <0.001 MSH6 (N=49) 13 (27) 11 (85) 2 (15) 1 36 (74) 35 (97) 1 (3) 1 PMS2 (N=51) 6 (12) 3 (50) 3 (50) 0.252 45 (88) 43 (96) 2 (4) 1 LS positive (N=229) 60 (26) 35 (58) 25 (42) <0.001 169 (74) 149 (88) 20 (12) <0.001 LS VUS (N=61) 6 (10) 6 (100) 0 (0) 1 55 (90) 55 (100) 0 (0) 0.526 LS Negative (N=1263) 229 (18) 204 (89) 25 (11) <0.001 1034 (82) 995 (96) 39 (4) 0.006 Note: Excludes pts with RC due to small N. ^Adjusted for multiple testing.

Germline pathogenic variants in a cohort of individuals with biliary tract cancer.

559 Background: Biliary tract cancers (BTC) are rare but have been implicated in hereditary cancer conditions such as Lynch syndrome (LS) and BRCA1 and BRCA2. Data from paired somatic and germline genetic testing on BTC have shown that ~5% may be related to germline pathogenic variants in BRCA1 and BRCA2. Identification of these germline pathogenic variants (PV) often provide patients with an opportunity for personalized treatment including platinum-based chemotherapies, PARP inhibitors and/or immunotherapy. Germline testing also provides crucial data to relatives regarding cancer risk and access to increased cancer surveillance and risk-reducing surgeries. Current guidelines recommend germline genetic testing when the likelihood of identifying a PV is >5%. The contribution of germline PV in BTC has not been described in a diverse patient population. Methods: In this prospective clinic-based study, individuals with BTC were referred by their oncologist for genetic counselling and testing. The majority of individuals were enrolled based on participation in the Legresley Biliary Registry, which recruits all individuals with BTC. Blood was sent for germline multi-gene panel testing. Results: Germline genetic testing was performed for 139 individuals. Average age of diagnosis was 57.8 years (range 28-84). The majority of individuals were diagnosed with intrahepatic cholangiocarcinoma (CCA) (54.7%), followed by extrahepatic CCA (20.9%) and gallbladder cancer (10.1%). The majority of individuals were male (56.1%). The population was ethnically diverse with 55% European, 24% Asian, 9% Middle Eastern/North African and 6% African. A minority of individuals had a previous cancer (18%) and 24.5% met current provincial eligibility criteria. Germline testing was complete on 136 individuals. 25/136 (14.7%) PV were identified in 20 individuals. 8/136 (5.9%) of the cohort carried PV in genes known to increase the risk for BTC ( BRCA1, BRCA2 and LS genes), 9/136 (6.6%) carried PV in other genes with clinically actionability (e.g. PALB2, ATM ), and 8/136 (5.9%) carried heterozygous PV in genes for recessive diseases. Variants of uncertain significance were identified in 42/136 (30.9%) and negative results were identified in 74/136 (54.4%). Personal and/or family history was not suggestive of the associated cancer condition in 9/16 (56%) of the PV cohort. Tumor profiling by whole genome sequencing on some individuals with PV found corresponding somatic mutational signatures, consistent with variant pathogenicity. Conclusions: Detection rates for PV in a diverse BTC cohort was up to 14.7%, including 5.9% among genes known to increase the risk for BTC. The majority of PV were found in individuals lacking personal and/or family history suggestive of the associated hereditary cancer condition. These results suggest that guidelines should be updated to recommend universal germline genetic testing for individuals with BTC.

Randomized phase II trial of olaparib + pembrolizumab vs olaparib alone as maintenance therapy in patients with metastatic pancreatic cancer with germline BRCA1 or BRCA2 mutations: SWOG S2001 NCT04548752.

TPS793 Background: Olaparib was approved in 2019 as maintenance therapy for gBRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression-free survival (mPFS) with olaparib compared to placebo (7.4 vs 3.8 months) for platinum sensitive gBRCA1/2+ mPDA pts. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Results of the phase 2 pembrolizumab and olaparib (POLAR) maintenance trial in patients with germline or somatic BRCA1/2 or PALB2 mutations responding to platinum-based chemotherapy for at least 4 months was presented at ESMO 2024. In 33 patients, a 35% overall response rate with 90% disease control rate at 6 months was observed. S2001 is an important randomized study to better define the impact of the combination. Methods: S2001 was developed in collaboration with the Alliance and was activated in SWOG in October 2020. Key eligibility criteria include: mPDA pts with gBRCA1/2 mutations identified with standard of care germline genetic testing and progression-free after receiving at least 4 months of platinum-based chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin +/- nab-paclitaxel). One cycle of gemcitabine and nab-paclitaxel is allowed while waiting for germline testing. Zubrod performance status (PS) 0 or 1 pts are eligible. Pts are stratified according to first line chemotherapy, PS 0 vs 1, and disease status after 1st line treatment. The primary objective of this study is to evaluate the PFS of mPDA pts treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha = 0.10, this design requires 78 evaluable pts with a total sample size of 88 pts. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Support: NIH/NCI grants U10CA180888 and U10CA180819, U10CA180821 and U10CA180868. Clinical trial information: NCT04548752 .

Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: ASCO Guideline Update.

To provide updated guidance regarding neoadjuvant chemotherapy (NACT) and primary cytoreductive surgery (PCS) among patients with stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer (epithelial ovarian cancer [EOC]). A multidisciplinary Expert Panel convened and updated the systematic review. Sixty-one studies form the evidence base. Patients with suspected stage III-IV EOC should be evaluated by a gynecologic oncologist, with cancer antigen 125, computed tomography of the abdomen and pelvis, and chest imaging included. All patients with EOC should be offered germline genetic and somatic testing at diagnosis. For patients with newly diagnosed advanced EOC who are fit for surgery and have a high likelihood of achieving complete cytoreduction, PCS is recommended. For patients fit for PCS but deemed unlikely to have complete cytoreduction, NACT is recommended. Patients with newly diagnosed advanced EOC and a high perioperative risk profile should receive NACT. Before NACT, patients should have histologic confirmation of invasive ovarian cancer. For NACT, a platinum-taxane doublet is recommended. Interval cytoreductive surgery (ICS) should be performed after ≤four cycles of NACT for patients with a response to chemotherapy or stable disease. For patients with stage III disease, good performance status, and adequate renal function treated with NACT, hyperthermic intraperitoneal chemotherapy may be offered during ICS. After ICS, chemotherapy should continue to complete a six-cycle treatment plan with the optional addition of bevacizumab. Patients with EOC should be offered US Food and Drug Administration-approved maintenance treatments. Patients with progressive disease on NACT should have diagnosis reconfirmed via tissue biopsy. Patients without previous comprehensive genetic or molecular profiling should be offered testing. Treatment options include alternative chemotherapy regimens, clinical trials, and/or initiation of end-of-life care.Additional information is available at www.asco.org/gynecologic-cancer-guidelines.This guideline has been endorsed by the Society of Gynecologic Oncology.

MLH1 promoter hypermethylation and Lynch Syndrome: When to test for constitutional epimutations of MLH1 gene?

Lynch syndrome is a genetic condition predisposing to cancer, particularly colorectal cancer and endometrial cancer, due to germline mutations in MisMatch Repair genes. More rarely, Lynch syndrome is the result of a constitutional MLH1 promoter methylation. This review summarizes the current knowledge about the role of this epigenetic mechanism in the Lynch syndrome. Universal Tumor Screening, performed on tumoral specimens to identify features suggestive of Lynch syndrome, shows the same features both in the case of sporadic cancers and Lynch syndrome-cancers due to a constitutional MLH1 methylation: microsatellite instability, deficiency of MisMatch Repair proteins, and methylation of MLH1 gene. Over the last few years, identifying methylation of MLH1 promoter on tumors was used to discern sporadic tumors from Lynch syndrome tumors: the methylation of the MLH1 promoter was usually explained as a somatic event and this could lead to a missed diagnosis of some Lynch syndrome cases. Therefore, establishing criteria to decide when to test patients for constitutional MLH1 methylation is urgent. In the case of microsatellite instability/deficiency of MisMatch Repair tumors with MLH1 methylation, a germline genetic test could be requested for all colorectal cancer patients aged 55 years or younger and all endometrial cancer patients younger than 50 years old, independently from family history. The prevalence of germline MLH1 epimutations is not precisely known and possibly underestimated. The associated cancer risk could be similar to that due to a MLH1 sequence variant. MLH1 epimutations could be secondary to other genetic defects and follow an autosomal dominant inheritance. On the contrary, primary epimutations are often "de novo" events, and their transmission does not follow Mendelian rules.

Developing and Assessing a Scalable Digital Health Tool for Pretest Genetic Education in Patients With Early-Onset Colorectal Cancer: Mixed Methods Design.

National guidelines recommend germline genetic testing (GT) for all patients with early-onset colorectal cancer. With recent advances in targeted therapies and GT, these guidelines are expected to expand to include broader groups of patients with colorectal cancer. However, there is a shortage of genetic professionals to provide the necessary education and support for informed consent. As such, there is a pressing need to identify alternative approaches to facilitate and expedite access to GT. This study describes the development of a pretest education intervention, Nest-CRC, to facilitate the uptake of germline GT among patients with early-onset colorectal cancer. Patients with early-onset colorectal cancer and health care providers reviewed Nest-CRC, and their reactions and recommendations were captured using a nested mixed methods approach. Using the learner verification approach, we conducted 2 sequential phases of surveys and interviews with English- and Spanish-speaking patients with early-onset colorectal cancer and health care providers. The surveys assessed participants' experiences with genetic services and provided immediate feedback on the Nest-CRC genetic education modules. Semistructured interviews evaluated participants' perceptions of self-efficacy, attraction, comprehension, cultural acceptability, and usability of Nest-CRC. Survey data were analyzed using descriptive statistics (mean, median, and proportions), while interview data were analyzed through line-by-line coding of the transcribed interviews. After each phase, Nest-CRC was refined based on participants' recommendations. A total of 52 participants, including 39 patients with early-onset colorectal cancer and 13 providers, participated in the study. Of these, 19 patients and 6 providers participated in phase 1 (N=25), and 20 patients and 7 providers participated in phase 2 (N=27). Most participants (phase 1: 23/25, 92%, to 25/25, 100%; phase 2: 24/27, 89%, to 27/27, 100%) agreed that each of the 5 education modules was easy to understand and helpful; 13 patients reported no history of GT, with 11 (85%) expressing interest in GT and 2 (15%) remaining unsure after completing Nest-CRC. Participants reported that Nest-CRC provided sufficient information to help them decide about GT. The tool was deemed acceptable by individuals from diverse backgrounds, and participants found it visually attractive, easy to comprehend, and user-friendly. The findings revealed that Nest-CRC is a promising strategy for facilitating pretest education and promoting GT. Nest-CRC has been refined based on participant recommendations and will be re-evaluated.

Genomic Profiling of Cardiac Angiosarcoma Reveals Novel Targetable KDR Variants, Recurrent MED12 Mutations and a High Burden of Germline POT1Alterations.

Cardiac angiosarcoma (CAS) is a rare, aggressive malignancy with limited treatment options. Both sporadic and familial cases occur, with recent links to germline POT1 mutations. The genomic landscape of this disease is poorly understood. We conducted comprehensive genomic profiling of CAS to assess the burden of germline predisposition and identify other recurrent genomic alterations of clinical significance. Six patients were female and four were male. The median age at presentation was 40 years (range 21- 69 years). All cases with available follow up exhibited an aggressive clinical course (6/8 patients died of disease). KDR alterations, including novel structural variants, were found in 9/11 cases, at a rate significantly higher than in non-cardiac angiosarcomas. POT1 mutations were present in 45.5% of CAS cases. In three of five POT1-mutant cases, the germline status was confirmed through testing of normal tissue and in one additional case, the germline status was inferred with high probability through allele frequency analysis. Additionally, we identified novel recurrent MED12 exon 2 mutations in POT1-wild type CAS, suggesting an alternative path to CAS oncogenesis. CAS demonstrate unique genetic profile, distinct from non-cardiac angiosarcoma. This study highlights the role of germline POT1 burden on CAS development and demonstrates recurrent MED12 alterations for the first time. The reported KDR variants provide a potential avenue for treatment of this aggressive disease. Given the prevalence of germline POT1 mutations reported herein, germline genetic testing should be considered in patients diagnosed with CAS.

Yield of Multigene Panel Germline Genetic Testing Among those with Advanced Colorectal Adenomas.

Yield of Multigene Panel Germline Genetic Testing Among those with Advanced Colorectal Adenomas.

Clinicopathological features and prognostic analysis of synchronous mucinous metaplasia and neoplasia of the female genital tract

Objective: Synchronous mucinous metaplasia and neoplasia of the female genital tract (SMMN-FGT) occurring at multiple sites during the same period of time is extremely rare, and the aim of this study was to investigate the clinicopathologic features of SMMN-FGT and its relationship with prognosis. Methods: We retrospectively analyzed the clinicopathological features and follow-up records of 25 cases of SMMN-FGT diagnosed from January 2012 to October 2022 in the case database of Obstetrics and Gynecology Hospital of Fudan University. Results: The median age at onset was 46 years old, respectively. Clinical manifestations included irregular vaginal bleeding or drainage, pelvic pain, and ovarian cysts, etc. Germline genetic test confirmed Peutz-Jeghers syndrome (P-J syndrome) in two patients. All patients underwent surgery, and 13 patients had postoperative adjuvant radiotherapy and/or chemotherapy. The most frequent site of lesion was the cervix (21 cases), with 11, 10 and 16 cases occurring in the endometrium, fallopian tubes and ovaries, respectively. Six cases involved three sites simultaneously, and only one case had all four sites involved at the same time. Among the 9 cases with P53 mutation phenotype, 6 cases had gastric-type mucinous adenocarcinoma, 2 cases had lobular endocervical glandular hyperplasia, and 1 case had mucinous adenocarcinoma, whereas all the minimally deviated adenocarcinomas had wild phenotype of P53. The median follow-up time was 59 months, during which 3 cases died and 6 cases developed local recurrence or distant metastasis. According to our analysis, postoperative recurrence or metastasis was correlated with the FIGO stage of the disease, the number of lesion sites and the severe degree of the uterine lesions (P＜0.05). Conclusions: SMMN-FGT has a relatively good clinical prognosis, and even advanced patients can benefit from surgery and adjuvant therapy. In young patients, the ovaries may be preserved if no evidence of lesions are seen after adequate evaluation. In SMMN-FGT, gastric-type mucinous adenocarcinoma occurring in the cervix may have a better prognosis than gastric-type mucinous adenocarcinoma of the cervix alone, so the accurate diagnosis of SMMN-FGT is critical for clinical management.

Implementation of Universal Germline Genetic Testing Into Standard of Care for Patients With Prostate Cancer: The Time Is Now.

Indications for and implications of germline genetic testing (GGT) in patients with prostate cancer have expanded over the past decade, particularly related to precision therapies and management. GGT has become the standard of care for many cancers such as breast, ovarian, colorectal, pancreatic, and metastatic prostate cancer, and it is imperative that patients be offered timely and equitable access to testing as it can inform patient-physician shared decision making for management of the current cancer as well as anticipatory guidance for disease progression. Additionally, GGT guides screening for and prevention of secondary malignancies for the patient and cascade testing for at-risk family members. Here, we present data supporting the notion that clinicians should offer all patients with prostate cancer the opportunity to undergo comprehensive GGT for pathogenic germline variants known to be associated with familial cancer and/or known to have implications for treatment and management.

Experience of urologists, oncologists and nurse practitioners with mainstream genetic testing in metastatic prostate cancer.

International guidelines recommend germline genetic testing for men with metastatic prostate cancer. If offered to all patients by genetic healthcare professionals, there will be insufficient capacity to cope with the high patient numbers. In a mainstreaming pathway, non-genetic healthcare professionals (ngHCPs) discuss and order germline genetic testing instead of referring patients to genetic healthcare professionals. We aimed to evaluate the experience of ngHCPs with pre-test genetic counselling and to explore the feasibility from the ngHCPs' perspective. We carried out a prospective cohort study in 15 hospitals in the Netherlands. All participating ngHCPs (i.e. urologists, medical oncologists, specialist nurses and nurse practitioners) completed an online training module of 45 min. The ngHCPs completed a questionnaire both before the training and at three and nine months after it. Paired analyses were used to compare the first with the last questionnaires on attitude, confidence in the ability to discuss and order germline genetic testing, and perceived and actual knowledge of genetics and genetic testing. 167 ngHCPs were invited to participate of whom 69 completed the first questionnaire and started or completed the last one. They had a positive attitude towards offering genetic testing themselves. After nine months of providing pre-test genetic counselling, significantly more ngHCPs considered mainstreaming helpful (94% after versus 81% before, p = 0.01). Both perceived and actual knowledge increased significantly. Pre-test genetic counselling took less than 10 minutes for 82% of ngHCPs and the majority (88%) were in favour of continuing the mainstream pathway. Only six participating ngHCPs considered mainstreaming possible without completing a training module beforehand. After completing a short online training module, ngHCPs feel well-prepared to discuss germline genetic testing with metastatic prostate cancer patients.

ASO Visual Abstract:Impact of Mainstream Germline Genetic Testing with Expanded Eligibility for Early Stage Breast Cancer Patients in a Large Integrated Health System.

ASO Visual Abstract:Impact of Mainstream Germline Genetic Testing with Expanded Eligibility for Early Stage Breast Cancer Patients in a Large Integrated Health System.

Prevalence of the major thyroid cancer-associated syndromes in the United States.

A subset of thyroid cancers develops in a setting of a known hereditary cancer-associated syndrome. Understanding the population prevalence of thyroid cancer-associated syndromes is important to guide germline genetic testing and clinical management. To estimate the prevalence of the major thyroid cancer-associated syndromes in the United States using the All of Us Research Program (AoU) data. In this cohort study, we identified pathogenic and likely pathogenic (P/LP) variants from the ClinVar database in 245,394 AoU biobank participants. We performed a logistic regression analysis of the association of ClinVar P/LP variants with thyroid cancer. P/LP variants in the genes of interest were manually curated to ensure match and pathogenicity status. We calculated the prevalence of thyroid cancer-associated syndromes defined by the presence of P/LP variants. Using logistic regression, we found that three hereditary syndromes, multiple endocrine neoplasia type 2 (MEN2, RET gene, p = 3.23e-20), PTEN hamartoma syndrome (PHPS, PTEN gene, p = 2.59e-15), and familial adenomatous polyposis type 1 (FAP, APC gene, p = 2.73e-10) were significantly associated with thyroid cancer. All these syndromes were previously reported to increase the risk of thyroid cancer. The prevalence of thyroid cancer-associated syndromes in the AoU was 1:2,172 (113 cases), 1:8,764 (28 cases), and 1:8,461 (29 cases) for MEN2, PHPS, and FAP, respectively. Most carriers of P/LP variants were not diagnosed with the features of the syndromes, including thyroid cancer, pheochromocytoma, or primary hyperparathyroidism. Three pathogenic RET variants that cause two amino acid substitutions, V804M and V804L, constitute 65% of all MEN2 variants in the AoU, and none of these carriers were diagnosed with thyroid cancer. The prevalence of MEN2 and PHPS is ~10-20 times higher than it is currently estimated for the general population (1:35,000 - 1,50,000 for MEN2 and 1:200,000-1:250,000 for PHTS). Most affected individuals are not diagnosed with thyroid cancer. These results further refine our understanding of the prevalence of hereditary syndromic thyroid cancers and may change the clinical approach to patients with moderate-risk RET mutations (such as V804M and V804L), potentially emphasizing active surveillance over prophylactic thyroidectomy.

Optimizing Mainstreaming of Genetic Testing in Parallel With Ovarian and Endometrial Cancer Tumor Testing: How Do We Maximize Our Impact?

PURPOSE Although germline genetic testing (GT) is recommended for all patients with ovarian cancer (OC) and some patients with endometrial cancer (EC), uptake remains low with multiple barriers. Our center performs GT in parallel with somatic testing via a targeted sequencing assay (MSK-IMPACT) and initiates testing in oncology clinics (mainstreaming). We sought to optimize our GT processes for OC/EC. METHODS We performed a quality improvement study to evaluate our GT processes within gynecologic surgery/medical oncology clinics. All eligible patients with newly diagnosed OC/EC were identified for GT and tracked in a REDCap database. Clinical data and GT rates were collected by the study team, who reviewed data for qualitative themes. RESULTS From February 2023 to April 2023, we identified 116 patients with newly diagnosed OC (n = 57) and EC (n = 59). Patients were mostly White (62%); English was the preferred language for 90%. GT was performed in 52 (91%) patients with OC (seven external, 45 MSK-IMPACT) and in 44 (75%) patients with EC (three external, 41 MSK-IMPACT). GT results were available within 3 months for 100% and 95% of patients with OC and EC, respectively. Reasons for not undergoing GT included being missed by the clinical team where there was no record that GT was recommended, feeling overwhelmed, financial and privacy concerns, and language barriers. In qualitative review, we found that resources were concentrated in the initial visit with little follow-up to encourage GT at subsequent points of care. CONCLUSION A mainstreaming approach that couples somatic and germline GT resulted in high testing rates in OC/EC; however, barriers were identified. Processes that encourage GT at multiple care points and allow self-directed, multilingual digital consenting should be piloted.

A qualitative study of the experiences of patients with prostate cancer when receiving negative genetic results: "I still don't have a grasp of what it all means".

Germline genetic testing has been increasingly conducted for treatment implications in patients with prostate cancer due to the expansion of testing eligibility. Understanding patients' comprehension of genetic results is crucial for establishing effective result disclosure practices. This importance has grown due to the increasing prevalence of negative genetic results being conveyed via electronic communication and by providers without a genetics specialization. This study explores patients with prostate cancer's perceptions of genetic results communication. We analyzed 24 qualitative, semi-structured interviews with patients with prostate cancer at an urban safety-net hospital who had genetic results documented in their medical records. Interview questions focused on patient experiences with genetic referrals, genetic counseling, and genetic result disclosure. Audio recordings were professionally transcribed and analyzed by the study team utilizing an inductive thematic approach to generate themes from recurring codes. Of those who participated, 18 were interviewed in English, 5 in Spanish, and 1 in Haitian Creole. No participants reported having a pathogenic variant identified with genetic testing. Study participants identified a number of gaps in results communication which led to misconceptions regarding hereditary cancer risk. Three themes were generated: (1) Patients desired clear communication about the next steps after genetic testing, (2) Patients commonly experienced cognitive dissonance with negative genetic results given personal and family history of cancer, and (3) Patients felt reassurance from negative genetic results. This research suggests that maintaining conversations between patients and healthcare providers alongside the delivery of negative results assists in patient comprehension. Additionally, it is essential to evaluate the accessibility and appropriateness of notes and results sent to patients. Ultimately, understanding communication barriers in genetic results return is imperative in order to provide high-quality genetic care.

Germline sequence variation in cancer genes in Rwandan breast and prostate cancer cases

Cancer genetic data from Sub-Saharan African (SSA) are limited. Patients with female breast (fBC), male breast (mBC), and prostate cancer (PC) in Rwanda underwent germline genetic testing and counseling. Demographic and disease-specific information was collected. A multi-cancer gene panel was used to identify germline Pathogenic Variants (PV) and Variants of Uncertain Significance (VUS). 400 patients (201 with BC and 199 with PC) were consented and recruited to the study. Data was available for 342 patients: 180 with BC (175 women and 5 men) and 162 men with PC. PV were observed in 18.3% fBC, 4.3% PC, and 20% mBC. BRCA2 was the most common PV. Among non-PV carriers, 65% had ≥1 VUS: 31.8% in PC and 33.6% in BC (female and male). Our findings highlight the need for germline genetic testing and counseling in cancer management in SSA.

EPCO-56. INHERITED PREDISPOSITION TO ADULT GLIOMAS: OVERVIEW OF THE CURRENT CLINICAL PRACTICE AND FUTURE RECOMMENDATIONS

Abstract Gliomas are the most common adult primary malignant brain tumor and occur in ages 45-65 years old. While most gliomas are sporadic in nature, a small portion is related to cancer predisposition syndromes (CPS), such as Li Fraumeni or Lynch syndromes. Given that 5–10% of patients will have a family history of glioma, there is currently an effort in identifying germline variants associated with gliomas. Additionally, with the advent of somatic tumor testing, it is possible to pick up suspected germline mutations in genes that cause CPS. Our experience includes a 32-year-old patient diagnosed with astrocytoma IDH mutant, Grade 2 who was found to have a BRAC1 mutation on somatic brain tumor testing. 10 years later, the patient was found with metastatic ovarian cancer and a germline BRAC1 mutation. Early identification of CPS can lead to early detection or prevention of malignancies in affected patients and relatives. However, gliomas are rarely the primary or presenting tumor of CPS, and guidance of CPS screening for these individuals is still lacking. Due to the increasing interest and importance of CPS testing in patients with glioma we have developed a collaborative protocol between our neuro-oncologists and genetic counselors aso that patients have access to germline testing. We propose that all patients with glioma at age of 50 or under, patients with strong family history of cancer including gliomas, and patients with suspected germline mutations based on tumoral somatic mutational profile should be referred to the genetic counselors. Our preliminary findings include 8 patients who completed germline genetic testing. Of these, one patient tested positive for a BRCA1 pathogenic variant. We are planning to continue to collect this data to better inform clinical practice.

Should We Offer Universal Germline Genetic Testing to All Patients with Pancreatic Cancer? A Multicenter Study.

Pancreatic ductal adenocarcinoma (PDAC) is associated with a significant percentage of germline pathogenic variants (GPVs). Unlike in the United States, routine universal genetic testing is not performed in Europe. The aim of the study is to evaluate the diagnostic yield of germline genetic testing in all patients with PDAC. Individuals with newly diagnosed PDAC from three Spanish hospitals were enrolled, regardless of family history. Thirteen known susceptibility genes for PDAC were studied using a multigene panel or whole-exome sequencing. One hundred seventy-nine PDAC patients underwent genetic testing. Fourteen (7.8%) had a GPV or likely pathogenic variant In the genes studied: six in ATM, six in BRCA2, one in PALB2, and one in TP53. Of these, seven (50%) did not meet the clinical criteria for genetic study and would have been classified as sporadic PDAC. Presenting with a personal history of any other neoplasm was associated with some GPV, with an odds ratio (OR) of 3.5 (1.1-11.5). A family history of PDAC and breast cancer was also associated with some GPV, with oRs of 3.7 (1.08-13.6) and 8.5 (2.6-26.6), respectively. None of the patients over 60 years without a relevant family history of malignancies presented a GPV associated with PDAC. In our PDAC cohort, a noteworthy number of GPVs were identified, and half of these patients would have been classified as sporadic based solely on clinical criteria. Genetic testing should always be considered, particularly in patients under 60 years or those with a history of other malignancies, especially where economic resources need optimization.

Validation of a guidelines-based digital tool to assess the need for germline cancer genetic testing

BackgroundEfficient and scalable solutions are needed to identify patients who qualify for germline cancer genetic testing. We evaluated the clinical validity of a brief, patient-administered hereditary cancer risk assessment digital tool programmed to assess if patients meet criteria for germline genetic testing, based on personal and family history, and in line with national guidelines.MethodsWe applied the tool to cases seen in a nationwide telehealth genetic counseling practice. Validity of the tool was evaluated by comparing the tool’s assessment to that of the genetic counselor who saw the patient. Patients’ histories were extracted from genetic counselor-collected pedigrees and input into the tool by the research team to model how a patient would complete the tool. We also validated the tool’s assessment of which specific aspects of the personal and family history met criteria for genetic testing. Descriptive statistics were used.ResultsOf the 152 cases (80% female, mean age 52.3), 56% had a personal history of cancer and 66% met genetic testing criteria. The tool and genetic counselor agreed in 96% of cases. Most disagreements (4/6; 67%) occurred because the genetic counselor’s assessment relied on details the tool was not programmed to collect since patients typically don’t have access to the relevant information (pathology details, risk models). We also found complete agreement between the tool and research team on which specific aspects of the patient’s history met criteria for genetic testing.ConclusionWe observed a high level of agreement with genetic counselor assessments, affirming the tool’s clinical validity in identifying individuals for hereditary cancer predisposition testing and its potential for increasing access to hereditary cancer risk assessment.

Clinical Variant Reclassification in Hereditary Disease Genetic Testing

Because accurate and consistent classification of DNA sequence variants is fundamental to germline genetic testing, understanding patterns of initial variant classification (VC) and subsequent reclassification from large-scale, empirical data can help improve VC methods, promote equity among race, ethnicity, and ancestry (REA) groups, and provide insights to inform clinical practice. To measure the degree to which initial VCs met certainty thresholds set by professional guidelines and quantify the rates of, the factors associated with, and the impact of reclassification among more than 2 million variants. This cohort study used clinical multigene panel and exome sequencing data from diagnostic testing for hereditary disorders, carrier screening, or preventive genetic screening from individuals for whom genetic testing was performed between January 1, 2015, and June 30, 2023. DNA variants were classified into 1 of 5 categories: benign, likely benign, variant of uncertain significance (VUS), likely pathogenic, or pathogenic. The main outcomes were accuracy of classifications, rates and directions of reclassifications, evidence contributing to reclassifications, and their impact across different clinical areas and REA groups. One-way analysis of variance followed by post hoc pairwise Tukey honest significant difference tests were used to analyze differences among means, and pairwise Pearson χ2 tests with Bonferroni corrections were used to compare categorical variables among groups. The cohort comprised 3 272 035 individuals (median [range] age, 44 [0-89] years; 2 240 506 female [68.47%] and 1 030 729 male [31.50%]; 216 752 Black [6.62%]; 336 414 Hispanic [10.28%]; 1 804 273 White [55.14%]). Among 2 051 736 variants observed over 8 years in this cohort, 94 453 (4.60%) were reclassified. Some variants were reclassified more than once, resulting in 105 172 total reclassification events. The majority (64 752 events [61.65%]) were changes from VUS to either likely benign, benign, likely pathogenic, or pathogenic categories. An additional 37.66% of reclassifications (39 608 events) were gains in classification certainty to terminal categories (ie, likely benign to benign and likely pathogenic to pathogenic). Only a small fraction (663 events [0.63%]) moved toward less certainty, or very rarely (61 events [0.06%]) were classification reversals. When normalized by the number of individuals tested, VUS reclassification rates were higher among specific underrepresented REA populations (Ashkenazi Jewish, Asian, Black, Hispanic, Pacific Islander, and Sephardic Jewish). Approximately one-half of VUS reclassifications (37 074 of 64 840 events [57.18%]) resulted from improved use of data from computational modeling. In this cohort study of individuals undergoing genetic testing, the empirically estimated accuracy of pathogenic, likely pathogenic, benign, and likely benign classifications exceeded the certainty thresholds set by current VC guidelines, suggesting the need to reevaluate definitions of these classifications. The relative contribution of various strategies to resolve VUS, including emerging machine learning-based computational methods, RNA analysis, and cascade family testing, provides useful insights that can be applied toward further improving VC methods, reducing the rate of VUS, and generating more definitive results for patients.