Management and follow-up strategies for patients with head and neck paraganglioma.

OBJECTIVE: Head-neck paragangliomas (HNPGLs) are rare tumors with approximately half arising due to germline pathogenic variants (PVs) in succinate dehydrogenase genes (SDHx). Patients with HNPGL have heterogeneous propensity to recur and metastasize. Thus, we aim to assess prevalence and predictors of recurrent (RD) and/or metastatic disease in patients with and without SDHx-related HNPGLs. DESIGN AND METHODS: This cross-sectional study used retrospective data of 214 patients enrolled in six referral centers. Data included sex, age, primary tumor treatment, location, and size, biochemical phenotype, germline PVs, presence of RD (locoregional or new tumor), and/or metastasis. RESULTS: Patients with and without SDHx-related HNPGLs showed 74% and 40% prevalence of RD, respectively. Patients without SDHx-related HNPGLs presented with recurrent tumors only in head-neck regions. The only independent predictor for RD in the entire cohort was presence of SDHx PVs. Metastatic prevalence reached 9%-13%. For patients with SDHx-related HNPGLs, large tumor size (>2.3 cm, OR:50.0, CI:2.6-977.6), young age at initial diagnosis (<42years, OR:27.3, CI:1.8-407.2), and presence of SDHB PV (OR:15.6; CI:1.5-164.8) were independent predictors of metastasis. For patients without SDHx-related HNPGLs, only carotid-body location was an independent predictor of metastasis (OR:18.9, CI:2.0-182.5). CONCLUSIONS: Patients without SDHx-related HNPGLs require long-term follow-up due to high prevalence of RD with imaging largely restricted to head-neck regions. As carotid-body HNPGLs have the highest metastatic risk among sporadic tumors, radical treatment with frequent follow-up is suggested until population-based data are available. Importantly, patients with SDHx-related HNPGLs might benefit from early radical treatment when tumors are still small to reduce metastatic risk.

Hereditary and Familial Traits in Urological Cancers and Their Underlying Genes.

Early recognition of hereditary urological cancers may influence diagnostic and therapeutic decision-making, and potentially alter the fate of patients and family members. Here, we introduce readers to the current knowledge on germline genetic testing and clinical practice in prostate, bladder, renal, and testicular carcinoma. Considering all urological cancer patients, routine inquiries about familial cancer history should become a standard practice in clinical settings. If suspicion arises, patients can opt for two avenues: referral to genetic counseling or undergoing genetic tests after consultation with the treating urologist. Patient summary: Tumors of the urogenital tract (prostate, kidney, bladder, and testes) can sometimes be related to genetic mutations that are present in all the cells of the body. Such mutations can be inherited and run in families. Therefore, it is relevant to obtain information on the incidence of all cancers in the family history. The information obtained may initiate genetic testing, leading to the identification of mutations that are related to cancer in the current or next generation. In addition, these mutations may offer alternative treatment options for patients.

Patterns and Frequency of Pathogenic Germline Variants Among Prostate Cancer Patients Utilizing Multi-Gene Panel Genetic Testing.

Background: Germline genetic testing (GGT) has significant implications in the management of patients with prostate cancer (PCa). Herein, we report on patterns and frequency of pathogenic/likely pathogenic germline variants (P/LPGVs) among newly diagnosed Arab patients with PCa. Methods: Patients meeting the National Comprehensive Cancer Network (NCCN) eligibility criteria for GGT were offered a 19-gene PCa panel or an expanded 84-gene multi-cancer panel. Results: During the study period, 231 patients were enrolled; 107 (46.3%) had metastatic disease at diagnosis. In total, 17 P/LPGVs were detected in 17 patients (7.4%). Among the 113 (48.9%) patients who underwent GGT with the 19-gene panel, eight (7.1%) had P/LPGVs, compared to nine (7.6%) of the 118 (51.1%) who did GGT through the expanded 84-gene panel (P = 0.88). Variant of uncertain significance (VUS) rate was higher (n = 73, 61.9%) among the group who underwent expanded 84-gene panel testing compared to those who underwent the 19-gene PCa panel (n = 35, 30.9%) (P = 0.001). P/LPGVs in DNA damage repair (DDR) genes, most frequently BRCA2, CHEK2 and TP53, were the most common P/LPGVs findings. Conclusion: This study is the first to characterize the germline genetic profile of an Arab population with PCa. All detected P/LPGVs were potentially actionable, with most variants able to be detected with a PCa-specific panel.

Utility of pembrolizumab for metastatic castrate resistant prostate cancer with MMR deficiency.

Molecular tumor profiling has become an important diagnostic for prostate cancer, allowing for personalized treatment regimens based on somatic and germline genetic information. We report a 67-year-old patient with metastatic castrate-resistant prostate cancer which was intermittently responsive to androgen-deprivation therapy, docetaxel, abiraterone, radium-223, Sipuleucel-T, and radiotherapy who ultimately demonstrated a remarkable and durable response to pembrolizumab. Our case report underlines the significance of early tumor molecular profiling in aggressive or atypical prostate cancer patients and exhibits the potential for a remarkable clinical response with immunotherapy in candidates with the appropriate tumor profiles.

Rare pathogenic structural variants show potential to enhance prostate cancer germline testing for African men.

Prostate cancer (PCa) is highly heritable, with men of African ancestry at greatest risk and associated lethality. Lack of representation in genomic data means germline testing guidelines exclude for African men. Established that structural variations (SVs) are major contributors to human disease and prostate tumourigenesis, their role is under-appreciated in familial and therapeutic testing. Utilising a clinico-methodologically matched African (n = 113) versus European (n = 57) deep-sequenced PCa resource, we interrogated 42,966 high-quality germline SVs using a best-fit pathogenicity prediction workflow. We identified 15 potentially pathogenic SVs representing 12.4% African and 7.0% European patients, of which 72% and 86% met germline testing standard-of-care recommendations, respectively. Notable African-specific loss-of-function gene candidates include DNA damage repair MLH1 and BARD1 and tumour suppressors FOXP1, WASF1 and RB1. Representing only a fraction of the vast African diaspora, this study raises considerations with respect to the contribution of kilo-to-mega-base rare variants to PCa pathogenicity and African associated disparity.

Pharmacogenetics in Italy: current landscape and future prospects.

Pharmacogenetics investigates sequence of genes that affect drug response, enabling personalized medication. This approach reduces drug-induced adverse reactions and improves clinical effectiveness, making it a crucial consideration for personalized medical care. Numerous guidelines, drawn by global consortia and scientific organizations, codify genotype-driven administration for over 120 active substances. As the scientific community acknowledges the benefits of genotype-tailored therapy over traditionally agnostic drug administration, the push for its implementation into Italian healthcare system is gaining momentum. This evolution is influenced by several factors, including the improved access to patient genotypes, the sequencing costs decrease, the growing of large-scale genetic studies, the rising popularity of direct-to-consumer pharmacogenetic tests, and the continuous improvement of pharmacogenetic guidelines. Since EMA (European Medicines Agency) and AIFA (Italian Medicines Agency) provide genotype information on drug leaflet without clear and explicit clinical indications for gene testing, the regulation of pharmacogenetic testing is a pressing matter in Italy. In this manuscript, we have reviewed how to overcome the obstacles in implementing pharmacogenetic testing in the clinical practice of the Italian healthcare system. Our particular emphasis has been on germline testing, given the absence of well-defined national directives in contrast to somatic pharmacogenetics.

Personalized Medicine in Pancreatic Cancer: The Promise of Biomarkers and Molecular Targeting with Dr. Michael J. Pishvaian.

Pancreatic cancer, with its alarming rising incidence, is predicted to become the second deadliest type of solid tumor by 2040, highlighting the urgent need for improved diagnostic and treatment strategies. Despite medical advancements, the five-year survival rate for pancreatic cancer remains about 14%, dropping further when metastasized. This review explores the promise of biomarkers for early detection, personalized treatment, and disease monitoring. Molecular classification of pancreatic cancer into subtypes based on genetic mutations, gene expression, and protein markers guides treatment decisions, potentially improving outcomes. A plethora of clinical trials investigating different strategies are currently ongoing. Targeted therapies, among which those against CLAUDIN 18.2 and inhibitors of Claudin 18.1, have shown promise. Next-generation sequencing (NGS) has emerged as a powerful tool for the comprehensive genomic analysis of pancreatic tumors, revealing unique genetic alterations that drive cancer progression. This allows oncologists to tailor therapies to target specific molecular abnormalities. However, challenges remain, including limited awareness and uptake of biomarker-guided therapies. Continued research into the molecular mechanisms of pancreatic cancer is essential for developing more effective treatments and improving patient survival rates.

The Cost-Effectiveness of Germline BReast CAncer Gene Testing in Metastatic Prostate Cancer Followed by Cascade Testing of First-Degree Relatives of Mutation Carriers.

OBJECTIVES: Patients with metastatic prostate cancer (mPCa) with BReast CAncer gene (BRCA) mutations benefit from targeted treatments (eg, olaparib). In addition, family members of affected patients have increased risk of hereditary cancers and benefit from early detection and prevention. International guidelines recommend genetic testing in mPCa; however, the value for money of testing patients with mPCa and cascade testing of blood-related family members has not been assessed. In this context, we evaluated the cost-effectiveness of germline BRCA testing in patients with mPCa followed by cascade testing of first-degree relatives (FDRs) of mutation carriers. METHODS: We conducted a cost-utility analysis of germline BRCA testing using 2 scenarios: (1) testing patients with mPCa only and (2) testing patients with mPCa and FDRs of those who test positive. A semi-Markov multi-health-state transition model was constructed using a lifetime time horizon. The analyses were performed from an Australian payer perspective. Decision uncertainty was characterized using probabilistic analyses. RESULTS: Compared with no testing, BRCA testing in mPCa was associated with an incremental cost of AU$3731 and a gain of 0.014 quality-adjusted life-years (QALYs), resulting in an incremental cost-effectiveness ratio of AU$265 942/QALY. Extending testing to FDRs of variant-positive patients resulted in an incremental cost-effectiveness ratio of AU$16 392/QALY. Probability of cost-effectiveness at a willingness-to-pay of AU$75 000/QALY was 0% in the standalone mPCa analysis and 100% in the cascade testing analysis. CONCLUSION: BRCA testing when performed as a standalone strategy in patients with mPCa may not be cost-effective but demonstrates significant value for money after the inclusion of cascade testing of FDRs of mutation carriers.

Therapeutic applications of germline testing for cancer predisposition genes in Asia in the real world.

BACKGROUND: Germline genetic testing is traditionally carried out in patients suspected with hereditary cancer syndrome for enhanced cancer surveillance and/or preventive strategies, but is increasingly carried out for therapeutic indications. MATERIALS AND METHODS: We conducted a retrospective review of patients who underwent germline genetic testing at our centre to determine the prevalence of actionable pathogenic germline variants (PGV) and their clinical utility. RESULTS: From 2000 to 2022, 1154 cancer patients underwent germline testing, with the majority (945/1154) tested with multi-gene panels. Four hundred and eleven (35.6%) patients harboured a PGV and 334 (81%) were clinically actionable. BRCA1/2 accounted for 62.3% of actionable mutations, followed by mismatch repair (18%), and other homologous recombination repair (HRR) genes (19.7%). One hundred and fifty-two germline-positive patients have advanced cancers, and 79 received germline-directed therapies (poly ADP ribose polymerase inhibitors = 75; immunotherapy = 4). Median duration of immunotherapy and poly ADP ribose polymerase were 20.5 months (range 5-40 months) and 8 months (range 1-76 months), respectively. Among BRCA/HRR mutation carriers who received platinum-based chemotherapy, pathological complete response rate in the neoadjuvant setting was 53% (n = 17 breast cancers) and objective response rate was >80% in the advanced setting (n = 71). CONCLUSIONS: One-third of cancer patients tested carried a PGV and ∼80% were clinically actionable. Three-quarters of germline-positive advanced cancer patients received germline-directed therapies in the real world, underscoring the practical utility of germline testing to guide cancer therapeutics.

Parents' and patients' perspectives, experiences, and preferences for germline genetic or genomic testing of children with cancer: A systematic review.

PURPOSE: Germline testing in pediatric cancer presents opportunities and challenges. Understanding family perspectives, experiences, and preferences will optimize integration into routine care. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched 4 databases for studies exploring perspectives, experiences, and preferences of parents/caregivers and/or patients regarding germline testing of children with cancer. Qualitative and quantitative data were extracted, organized, and summarized by research question and themes. RESULTS: We identified 2286 unique articles, of which 24 were included. Interest in and uptake of testing was high. Families were motivated by altruism and a desire for inheritance/causation information. Testing barriers included psychological concerns, timing of the testing approach if offered at diagnosis or in a high-risk cancer setting and privacy/discrimination. Testing experiences highlighted challenges yet also positive impacts, with results providing psychological relief and informing proactive decision making. Timing preferences varied; however, allowing time to adjust to a new diagnosis was a common theme. Most wanted to receive as many germline sequencing-related results as possible. CONCLUSION: Findings underscore the importance of integrating germline analyses into pediatric cancer care with flexibility and support for families facing challenges. Where possible, consent should be provided at a time that suits each family's situation with access to information aligning with their needs and preferences. PROSPERO: CRD42023444890.

Optimizing the Use of Next-Generation Sequencing Assays in Patients With Urothelial Carcinoma: Recommendations by the 2023 San Raffaele Retreat Panel.

BACKGROUND: The application of precision medicine in clinical practice implies a thorough evaluation of actionable genomic alterations to streamline therapeutic decision making. Comprehensive genomic profiling of tumor via next-generation sequencing (NGS) represents a great opportunity but also several challenges. During the 2023 San Raffaele Retreat, we aimed to provide expert recommendations for the optimal use of NGS in urothelial carcinoma (UC). MATERIALS AND METHODS: A modified Delphi method was utilized, involving a panel of 12 experts in UC from European and United States centers, including oncologists, urologists, pathologists, and translational scientists. An initial survey, conducted before the meeting, delivered 15 statements to the panel. A consensus was defined when ≥70% agreement was reached for each statement. Statements not meeting the consensus threshold were discussed during the meeting. RESULTS: Nine of the 15 statements covering patient selection, cancer characteristics, and type of NGS assay, achieved a consensus during the survey. The remaining six statements addressing the optimal timing of NGS use, the ideal source of tumor biospecimen for NGS testing, and the subsequent need to evaluate the germline nature of certain genomic findings were discussed during the meeting, leading to unanimous agreement at the end of the conference. CONCLUSION: This consensus-building effort addressed multiple unanswered questions regarding the use of NGS in UC. The opinion of experts was in favor of broader use of NGS. In a setting where recommendations/guidelines may be limited, these insights may aid clinicians to provide informed counselling and raise the bar of precision and personalized therapy.

Germline and somatic mutations in prostate cancer: Implications for treatment.

Genetic testing is an integral part of the workup of metastatic prostate cancer, in part, because the results can have a profound impact on the subsequent management of this disease. There are now several Food & Drug Administration (FDA) approved therapeutics available for patients with prostate cancer and certain genetic abnormalities - most notably, mutations in DNA damage repair (DDR) pathways such mismatch repair (MMR) and homologous recombination repair (HRR). In this review of the current literature, we discuss the indications for somatic and germline testing, the genetic changes of particular clinical relevance, the associated therapeutic options, and the clinical data supporting their use. We also highlight select trials-in-progress and future directions for the field.

Predictors of germline genetic testing referral and completion in ovarian cancer patients at a Comprehensive Cancer Center.

OBJECTIVES: To identify predictors of referral and completion of germline genetic testing among newly diagnosed ovarian cancer patients, with a focus on geographic social deprivation, oncologist-level practices, and time between diagnosis and completion of testing. METHODS: Clinical and sociodemographic data were abstracted from medical records of patients newly diagnosed with ovarian cancer between 2014 and 2019 in the University of North Carolina Health System. Factors associated with referral for genetic counseling, completion of germline testing, and time between diagnosis and test results were identified using multivariable regression. RESULTS: 307/459 (67%) patients were referred for genetic counseling and 285/459 (62%) completed testing. The predicted probability of test completion was 0.83 (95% CI: 0.77-0.88) for patients with a referral compared to 0.27 (95% CI: 0.18-0.35) for patients without a referral. The predicted probability of referral was 0.75 (95% CI: 0.69-0.82) for patients at the 25th percentile of ZIP code-level Social Deprivation Index (SDI) and 0.67 (0.60-0.74) for patients at the 75th percentile of SDI. Referral varied by oncologist, with predicted probabilities ranging from 0.47 (95% CI: 0.32-0.62) to 0.93 (95% CI: 0.85-1.00) across oncologists. The median time between diagnosis and test results was 137 days (IQR: 55-248 days). This interval decreased by a predicted 24.46 days per year (95% CI: 37.75-11.16). CONCLUSIONS: We report relatively high germline testing and a promising trend in time from diagnosis to results, with variation by oncologist and patient factors. Automated referral, remote genetic counseling and sample collection, reduced out-of-pocket costs, and educational interventions should be explored.

The cost-effectiveness of germline BRCA testing-guided olaparib treatment in metastatic castration resistant prostate cancer.

BACKGROUND: Olaparib targets the DNA repair pathways and has revolutionized the management of metastatic castration resistant prostate cancer (mCRPC). Treatment with the drug should be guided by genetic testing; however, published economic evaluations did not consider olaparib and genetic testing as codependent technologies. This study aims to assess the cost-effectiveness of BRCA germline testing to inform olaparib treatment in mCRPC. METHODS: We conducted a cost-utility analysis of germline BRCA testing-guided olaparib treatment compared to standard care without testing from an Australian health payer perspective. The analysis applied a decision tree to indicate the germline testing or no testing strategy. A Markov multi-state transition approach was used for patients within each strategy. The model had a time horizon of 5 years. Costs and outcomes were discounted at an annual rate of 5 percent. Decision uncertainty was characterized using probabilistic and scenario analyses. RESULTS: Compared to standard care, BRCA testing-guided olaparib treatment was associated with an incremental cost of AU$7,841 and a gain of 0.06 quality-adjusted life-years (QALYs). The incremental cost-effectiveness ratio (ICER) was AU$143,613 per QALY. The probability of BRCA testing-guided treatment being cost effective at a willingness-to-pay threshold of AU$100,000 per QALY was around 2 percent; however, the likelihood for cost-effectiveness increased to 66 percent if the price of olaparib was reduced by 30 percent. CONCLUSION: This is the first study to evaluate germline genetic testing and olaparib treatment as codependent technologies in mCRPC. Genetic testing-guided olaparib treatment may be cost-effective with significant discounts on olaparib pricing.

Mainstream Model of Genetic Testing for Prostate Cancer at a Large Tertiary Cancer Centre.

BACKGROUND: An estimated 20% to 30% of men with advanced prostate cancer carry a mutation in DNA damage repair genes, of which half are estimated to be germline. Eligibility criteria for germline genetic testing expanded significantly for Ontario patients in May 2021 and many centers adopted a "mainstream" model, defined as oncologist-initiated genetic testing. METHODS: We conducted a retrospective chart review to report on the first-year mainstream experience of a large tertiary oncologic center, the Sunnybrook Odette Cancer Centre. All patients who underwent mainstream at the discretion of their treating physician were included. A subset underwent somatic profiling as part of clinical trial screening. Descriptive statistics were used to report baseline clinicopathologic characteristics and treatments received. RESULTS: Between May 1, 2021, and May 30, 2022, 174 patients with prostate cancer underwent mainstream germline genetic testing with a 19-gene panel. Median age was 75 (IQR 68-80), and 82% of patients were diagnosed with either de novo metastatic or high-risk localized prostate adenocarcinoma. Fourteen patients (8%; 95% CI 4%-12%) were found to have a deleterious germline mutation, including pathogenic or likely pathogenic variants in BRCA1/2, ATM, CHEK2, PMS2, RAD51C, HOXB13, and BRIP1. Forty-nine patients (28%; 95% CI 21%-35%) were found to have a variant of uncertain significance. Thirty-four patients also had next-generation sequencing (NGS) of their somatic tissue. Among this subset, 8 of 34 (23%) had an alteration in homologous recombination repair (HRR) genes. Of the 14 patients with a germline mutation, none had a prior personal history of malignancy and 6 (43%) did not have any first- or second-degree relatives with history of prostate, pancreatic, breast, or ovarian cancer. CONCLUSION: We report on the real-world characteristics of prostate cancer patients who underwent mainstream germline genetic testing. Personal history and family history of cancer cannot reliably stratify patients for the presence of pathogenic germline variants.

Limited Independent Follow-Up with Germline Testing of Variants Detected in BRCA1 and BRCA2 by Tumor-Only Sequencing.

Introduction: Genomic profiling is performed in patients with advanced or metastatic cancer, in order to direct cancer treatment, often sequencing tumor-only, without a matched germline comparator. However, because many of the genes analyzed on tumor profiling overlap with those known to be associated with hereditary cancer predisposition syndromes (HCPS), tumor-only profiling can unknowingly uncover germline pathogenic (P) and likely pathogenic variants (LPV). In this study, we evaluated the number of patients with P/LPVs identified in BRCA1 and BRCA2 (BRCA1/2) via tumor-only profiling, then determined the germline testing outcomes for those patients. Methods: A retrospective chart review was performed to identify patients with BRCA1/2 variants on tumor-only genomic profiling, and whether they had germline testing. Results: This study found that of 2923 patients with 36 tumor types who underwent tumor-only testing, 554 had a variant in BRCA1/2 (19.0%); 119 of the 554 patients (21.5%) had a P/LP BRCA1/2 variant, representing 4.1% of the overall population who underwent genomic profiling. Seventy-three (61.3%) of 119 patients with BRCA1/2 P/LPV on tumor-only testing did not undergo germline testing, 34 (28.6%) had already had germline testing before tumor-only testing, and 12 (10.1%) underwent germline testing after tumor-only testing. Twenty-eight germline BRCA1/2 P/LPVs were detected, 24 in those who had prior germline testing, and 4 among the 12 patients who had germline testing after tumor-only testing. Conclusion: Tumor-only testing is likely to identify P/LPVs in BRCA1/2. Efforts to improve follow-up germline testing is needed to improve identification of germline BRCA1/2 alterations.

Germline and somatic testing for ovarian Cancer: An SGO clinical practice statement.

Germline and somatic genetic testing have become critical components of care for people with ovarian cancer. The identification of germline and somatic pathogenic variants as well as homologous recombination deficiency can contribute to the prediction of treatment response, prognostic outcome, and suitability for targeted agents (e.g. poly (ADP-ribose) polymerase (PARP) inhibitors). Furthermore, identifying germline pathogenic variants can prompt cascade genetic testing for at-risk relatives. Despite the clinical benefits and consensus recommendations from several organizations calling for universal genetic testing in ovarian cancer, only about one third of patients complete germline or somatic genetic testing. The members of the Society of Gynecologic Oncology (SGO) Clinical Practice Committee have composed this statement to provide an overview of germline and somatic genetic testing for patients with epithelial ovarian cancer, focusing on available testing modalities and options for care delivery.

Isolated subependymal giant cell astrocytoma (SEGA) in the absence of clinical tuberous sclerosis: two case reports and literature review.

PURPOSE: Subependymal giant cell astrocytoma (SEGA) is a WHO grade I pediatric glioma arising in 5-15% of patients with tuberous sclerosis (TSC). Rare cases of isolated SEGA without TSC have been described. The etiology, genetic mechanisms, natural history, and response to treatment of these lesions are currently unknown. We describe two such cases of isolated SEGA with follow-up. METHODS: Retrospective review was performed at a single institution to describe the clinical course of pathology-confirmed SEGA in patients with germline testing negative for TSC mutations. RESULTS: Two cases of isolated SEGA were identified. Genetic analysis of the tumor specimen was available for one, which revealed an 18 base pair deletion in TSC1. Both cases were managed with surgical resection, one with preoperative embolization. In spite of a gross total resection, one patient experienced recurrence after three years. Treatment with an mTOR inhibitor led to a significant interval reduction of the mass on follow-up MRI. The patient tolerated the medication well for 6 years and is now off of treatment for 2 years with a stable lesion. CONCLUSION: Cases of SEGA outside of the context of TSC are exceedingly rare, with only 48 cases previously described. The genetic mechanisms and treatment response of these lesions are poorly understood. To date, these lesions appear to respond well to mTOR inhibitors and may behave similarly to SEGAs associated with TSC. However, given that experience is extremely limited, these cases should be followed long term to better understand their natural history and treatment response.