Tissue-Free Liquid Biopsies Combining Genomic and Methylation Signals for Minimal Residual Disease Detection in Patients with Early Colorectal Cancer from the UK TRACC Part B Study.

Purpose: The absence of postoperative circulating tumor DNA (ctDNA) identifies patients with resected colorectal cancer (CRC) with low recurrence risk for adjuvant chemotherapy (ACT) de-escalation. Our study presents the largest resected CRC cohort to date with tissue-free minimal residual disease (MRD) detection.

Experimental Design: TRACC (tracking mutations in cell-free tumor DNA to predict relapse in early colorectal cancer) included patients with stage I to III resectable CRC.

Minimal Residual Disease using a Plasma-Only Circulating Tumor DNA Assay to Predict Recurrence of Metastatic Colorectal Cancer Following Curative Intent Treatment.

Purpose: Minimal residual disease (MRD) detection can identify the recurrence in patients with colorectal cancer (CRC) following definitive treatment. We evaluated a plasma-only MRD assay to predict recurrence and survival in patients with metastatic CRC who underwent curative intent procedures (surgery and/or radiotherapy), with or without (neo)adjuvant chemotherapy. The primary objective of this study was to assess the correlation of postprocedure tumor cell-free DNA detection status with radiographic disease recurrence.

Identification of Somatic Gene Signatures in Circulating Cell-Free DNA Associated with Disease Progression in Metastatic Prostate Cancer by a Novel Machine Learning Platform.

Purpose: Progression from metastatic castration-sensitive prostate cancer (mCSPC) to a castration-resistant (mCRPC) state heralds the lethal phenotype of prostate cancer. Identifying genomic alterations associated with mCRPC may help find new targets for drug development. In the majority of patients, obtaining a tumor biopsy is challenging because of the predominance of bone-only metastasis.

Mutation profile differences in younger and older patients with advanced breast cancer using circulating tumor DNA (ctDNA).

Purpose: Little is known regarding the mutation profiles of ctDNA in the older adult breast cancer population. The objective of this study is to assess differences in mutation profiles in the older adult breast cancer population using a ctDNA assay as well as assess utilization of testing results.

Methods: Patients with advanced breast cancer underwent molecular profiling using a plasma-based ctDNA NGS assay (Guardant360) between 5/2015 and 10/2019 at Siteman Cancer Center.

Identification of Actionable Fusions as an Anti-EGFR Resistance Mechanism Using a Circulating Tumor DNA Assay.

Purpose: Gene fusions are established oncogenic drivers and emerging therapeutic targets in advanced colorectal cancer. This study aimed to detail the frequencies and clinicopathological features of gene fusions in colorectal cancer using a circulating tumor DNA assay.

Methods: Circulating tumor DNA samples in patients with advanced colorectal cancer were analyzed at 4,581 unique time points using a validated plasma-based multigene assay that includes assessment of fusions in , , , , , and Associations between fusions and clinicopathological features were measured using Fisher's exact test.

Duration of Targeted Therapy in Patients With Advanced Non-small-cell Lung Cancer Identified by Circulating Tumor DNA Analysis.

Background: Outcomes of therapy targeting molecular driver alterations detected in advanced non-small-cell lung (NSCLC) using circulating tumor DNA (ctDNA) have not been widely reported in patients who are targeted therapy-naive.

Patients And Methods: We performed a multicenter retrospective review of patients with unresectable stage IIIB to IV NSCLC who received matched therapy after a targetable driver alteration was identified using a commercial ctDNA assay through usual clinical care. Eligible patients must not have received targeted therapy prior to ctDNA testing (prior chemotherapy or immunotherapy was permitted).

Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion Mutations among Patients with Advanced Solid Tumors.

Purpose: PARP inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic) mutations. Acquired reversions can restore function, causing resistance to PARPi and/or platinum-based chemotherapy. The optimal method of identifying patients with germline, somatic, and/or reversion mutations in has not been established.

Analysis of Cell-Free DNA from 32,989 Advanced Cancers Reveals Novel Co-occurring Activating Alterations and Oncogenic Signaling Pathway Aberrations.

Purpose: is an emerging oncogenic target showing promise in phase I/II clinical trials. An understudied aspect of -driven cancers is the extent to which co-occurring genomic alterations exist and how they may impact prognosis or therapeutic response.

Experimental Design: Somatic activating alterations were identified among 32,989 consecutive patients with metastatic solid tumors tested with a clinical cell-free circulating tumor DNA (cfDNA) assay.

Recontacting Patients with Updated Genetic Testing Recommendations for Medullary Thyroid Carcinoma and Pheochromocytoma or Paraganglioma.

Background: No guidelines exist regarding physicians' duty to inform former patients about novel genetic tests that may be medically beneficial. Research on the feasibility and efficacy of disseminating information and patient opinions on this topic is limited.

Methods: Adult patients treated at our institution from 1950 to 2010 for medullary thyroid cancer, pheochromocytoma, or paraganglioma were included if their history suggested being at-risk for a hereditary syndrome but genetic risk assessment would be incomplete by current standards.

All in the family? Analyzing the impact of family history in addition to genotype on medullary thyroid carcinoma aggressiveness in MEN2A patients.

Several guidelines for patients with multiple endocrine neoplasia 2A (MEN2A) take into account genotype and family history of medullary thyroid carcinoma (MTC) disease aggressiveness. We sought to determine if an association exists independent of genotype, which could provide important information for counseling MEN2A patients in management of their MTC. Pedigrees of patients with ≥5 family members with MEN2A were retrospectively reviewed.

Medullary Thyroid Carcinoma Associated with Germline RET Mutation.

Background: Multiple endocrine neoplasia type 2 is an autosomal dominant inherited syndrome caused by activating mutations in the RET proto-oncogene. The RET DNA variant was previously reported in two isolated medullary thyroid carcinoma (MTC) cases, but no family studies are available, and its oncogenic significance remains unknown.

Methods: The clinical features, genetic data, and family information of eight index MTC patients with a germline RET variant were assessed.

Metastatic sympathetic paraganglioma in a patient with loss of the SDHC gene.

Mutation of the genes encoding the succinate dehydrogenase (SDH) subunits A, B, C, or D, or the SDHAF2 protein, cause the SDHx-hereditary paraganglioma syndromes. Hereditary susceptibility to metastatic sympathetic pheochromocytomas and paragangliomas is most commonly due to germline mutations in the SDHB gene. Individuals with SDHD mutations occasionally present with metastatic disease, while conversely malignant paragangliomas are rarely observed in SDHC carriers.

Paragangliomas Arising in the Head and Neck: A Morphologic Review and Genetic Update.

Seventy percent of parasympathetic paragangliomas arise in the head and neck and are nonsecretory. Awareness of the differential diagnosis based on location, overlapping morphology, and immunohistochemical profiles aids in the correct diagnosis, particularly on limited tissue samples. Moreover, 30% to 40% of head and neck paragangliomas are known to be associated with hereditary syndromes, with the succinate dehydrogenase enzyme family comprising the most frequent association.

Hereditary breast cancer syndromes and genetic testing.

Only 5% of breast cancers are explained by highly penetrant multisystem autosomal dominant hereditary disorders. Though another 20-30% has a familial presentation, the genetic and other etiologies are still not well understood. Genetic testing is now widely available and multiple professional societies have published guidelines for testing and management.

Preoperative multiple endocrine neoplasia type 1 diagnosis improves the surgical outcomes of pediatric patients with primary hyperparathyroidism.

Background: Primary hyperparathyroidism (PHPT) is uncommon in children. The surgical management of PHPT in children has evolved over the past two decades.

Methods: A retrospective study of patients who underwent parathyroidectomy for PHPT diagnosed at age < 18 years and managed at a tertiary referral center for endocrine and familial disorders.

Prevalence by age and predictors of medullary thyroid cancer in patients with lower risk germline RET proto-oncogene mutations.

Background: Age-related risk of medullary thyroid carcinoma (MTC) development in presymptomatic carriers of lower risk germline RET mutations is uncertain; such data may aid counseling patients regarding timing of thyroidectomy.

Methods: From an institutional database and an exhaustive literature review, we identified 679 patients with American Thyroid Association (ATA) level A or B mutations who were identified because of family screening (index cases of MTC were excluded to minimize selection bias). We evaluated age at thyroidectomy or last evaluation if no thyroidectomy, preoperative calcitonin level (elevated or not), the mutated codon, and outcome (MTC vs.

Genetic testing in head and neck paraganglioma: who, what, and why?

Background Genetic testing in head and neck paragangliomas (HNPG) can have profound implications in patient and family counseling. Methods Retrospective review was performed of patients with HNPG at a cancer care center from 1970 to present. Patient demographics, disease patterns, outcomes, and genetic mutations were analyzed.

Impact of surgical resection for subdiaphragmatic paragangliomas.

Background: Subdiaphragmatic paraganglioma is a rare neuroendocrine tumor for which scarce data exist regarding long-term patient outcome following resection. The aim of this study was to determine the association of surgical resection with survival.

Methods: A retrospective study at a tertiary care center was performed.

Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases.

The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma. However, the frequency of the syndrome in patients with UM and the association with other cancers are still not clear. In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1.

Comparison of attitudes regarding preimplantation genetic diagnosis among patients with hereditary cancer syndromes.

Preimplantation genetic diagnosis (PGD) allows couples to avoid having a child with an inherited condition, potentially reducing cancer burden in families with a hereditary cancer predisposition. This study investigated and compared awareness and acceptance of PGD among patients with different hereditary cancer syndromes. Questionnaires were mailed to 984 adults with hereditary breast and ovarian cancer, Lynch syndrome, familial adenomatous polyposis, or multiple endocrine neoplasia type 1 or 2.

The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2.

Context: Pheochromocytoma (PHEO) occurs in 50% of patients with multiple endocrine neoplasia type 2 (MEN2). It is unknown if the presence of PHEO is associated with more aggressive medullary thyroid cancer (MTC).

Objective: To present our experience with MEN2 PHEO and evaluate whether PHEO impacts MTC overall survival in patients with RET codon 634 mutations.

Current and future treatments for malignant pheochromocytoma and sympathetic paraganglioma.

Pheochromocytomas (PHs) and sympathetic paragangliomas (SPGs) are rare neuroendocrine tumors. Approximately 17 % of these tumors are malignant, but because no molecular or histologic markers for malignancy exist, patients are often diagnosed with malignant PHs or SPGs after unresectable disease has formed. Patients with progressive metastatic tumors and overwhelming symptoms are currently treated with systemic chemotherapy and radiopharmaceutical agents such as metaiodobenzylguanidine.

Long-term outcomes of surgical treatment for hereditary pheochromocytoma.

Background: The ideal surgical management of hereditary pheochromocytomas includes planning for a potential metachronous bilateral presentation and the possibility of lifelong steroid dependence if bilateral adrenalectomy is needed. An intact and viable cortical remnant after bilateral pheochromocytoma resection can eliminate the necessity for steroid dependency, but can increase the risk of pheochromocytoma recurrence.

Study Design: We retrospectively reviewed outcomes of all patients with a diagnosis of hereditary pheochromocytomas treated at our tertiary cancer institution from 1962-2011, with subset analysis of patients undergoing a cortical-sparing procedure in the setting of bilateral adrenalectomy.