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 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.

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.

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.

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.

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.

Ultrasonography should not guide the timing of thyroidectomy in pediatric patients diagnosed with multiple endocrine neoplasia syndrome 2A through genetic screening.

Background: American Thyroid Association (ATA) guidelines suggest that thyroidectomy can be delayed in some children with multiple endocrine neoplasia syndrome 2A (MEN2A) if serum calcitonin (Ct) and neck ultrasonography (US) are normal. We hypothesized that normal US would not exclude a final pathology diagnosis of medullary thyroid cancer (MTC).

Methods: We retrospectively queried a MEN2A database for patients aged<18 years, diagnosed through genetic screening, who underwent preoperative US and thyroidectomy at our institution, comparing preoperative US and Ct results with pathologic findings.

Achieving eugastrinemia in MEN1 patients: both duodenal inspection and formal lymph node dissection are important.

Background: Controversy exists regarding the role and extent of operation for patients with multiple endocrine neoplasia type 1 (MEN1) and hypergastrinemia.

Methods: An institutional MEN1 database was reviewed to identify patients with evidence of hypergastrinemia. The relationship of extent of resection to achievement of eugastrinemia was evaluated.

A novel SDHB mutation associated with hereditary head and neck paraganglioma.

Objectives/hypothesis: To describe a novel germline mutation in the succinate dehydrogenase subunit B (SDHB) gene.

Study Design: Retrospective review.

Methods: The medical records of a patient with bilateral carotid body paragangliomas were reviewed.

Management of medullary thyroid carcinoma and MEN2 syndromes in childhood.

Medullary thyroid carcinoma (MTC) and the multiple endocrine neoplasia (MEN) type 2 syndromes are rare but important endocrine diseases that are increasingly managed by pediatric providers. MTC is generally associated with a favorable prognosis when diagnosed during childhood, where it frequently occurs secondary to activating mutations in the RET proto-oncogene and arises from pre-existing C-cell hyperplasia. MEN2A accounts for 90-95% of childhood MTC cases and is most commonly due to mutations in codon 634 of RET.

Multiple endocrine neoplasia type 2B with a RET proto-oncogene A883F mutation displays a more indolent form of medullary thyroid carcinoma compared with a RET M918T mutation.

Background: Most cases of multiple endocrine neoplasia type 2B (MEN-2B) are attributable to a germline methionine to threonine mutation at codon 918 (M918T) of the RET proto-oncogene; very few cases of a germline alanine to phenylalanine mutation at codon 883 (A883F) are reported without a clear description of the clinical course. Nevertheless, RET-A883F is currently considered to be among the highest risk mutations, and prophylactic thyroidectomy is recommended as early as 6 months of life. Further characterization of the clinical behavior of RET-A883F mutation is warranted.

Do the recent American Thyroid Association (ATA) Guidelines accurately guide the timing of prophylactic thyroidectomy in MEN2A?

Background: In 2009, the American Thyroid Association (ATA) published consensus guidelines for timing of prophylactic thyroidectomy (PrThy) for treatment of hereditary medullary thyroid cancer (MTC). The aim of this study was to assess whether the clinical guidelines outlined in the ATA recommendations added to the specific mutation risk level could predict the presence of MTC on final pathology.

Methods: A retrospective study was performed of patients undergoing PrThy.

Paraganglioma syndrome type 1 in a patient with Carney-Stratakis syndrome.

Background: A 33-year-old man was referred to a specialist center with a left neck mass and hypertension. The patient underwent surgery, which confirmed a malignant neck paraganglioma with metastasis to a cervical lymph node. He had no family history of carotid body tumors or pheochromocytoma.

Genetic risk assessment, counseling and testing.

Hereditary cancer risk assessment, counseling, and testing are becoming ever more complex as the understanding of the genetic components of disease grows. The demand for highly trained professionals with expertise in this field, such as genetic counselors, is also growing. Surgical oncologists are likely to encounter patients with hereditable cancer syndromes in their practice and should be able to identify patients appropriate for genetic assessment and counseling.

Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau disease-related tumors.

Context: von Hippel-Lindau disease is characterized by highly vascularized tumors of multiple organs.

Evidence Acquisition: We present a patient with von Hippel-Lindau disease with multiple renal and pancreatic tumors and a malignant pheochromocytoma infiltrative of the sacrum and associated with lymph nodule metastases. The pheochromocytoma expressed high protein level of vascular endothelial growth factor and platelet-derived growth factor-beta receptor.

Multiple endocrine neoplasia syndromes.

The multiple endocrine neoplasia (MEN) syndromes are rare autosomal-dominant conditions that predispose affected individuals to benign and malignant tumors of the pituitary, thyroid, parathyroids, adrenals, endocrine pancreas, paraganglia, or nonendocrine organs. The classic MEN syndromes include MEN type 1 and MEN type 2. However, several other hereditary conditions should also be considered in the category of MEN: von Hippel-Lindau syndrome, the familial paraganglioma syndromes, Cowden syndrome, Carney complex, and hyperparathyroidism jaw-tumor syndrome.