Natural History Study of Children and Adults With Medullary Thyroid Cancer

Background:

- Medullary Thyroid Carcinoma (MTC) is a calcitonin producing tumor arising from the
parafollicular C cells of thyroid. In children and adults, MTC is usually seen in
association with Multiple Endocrine Neoplasia (MEN) 2A and 2B, which are rare cancer
syndromes resulting from germline mutations of Rearranged during Transfection (RET)
proto-oncogene. MTC develops in virtually all patients with MEN 2, and is the leading
cause of death in these patients. Patients with MEN 2 may have other characteristic
manifestations such as pheochromocytoma and hyperparathyroidism in MEN 2A and
pheochromocytoma, ganglioneuromatosis, and skeletal deformities in MEN 2B.

- Complete surgical resection is the only current curative treatment for MTC, and the
tumor is unresponsive to standard chemotherapy and conventional doses of radiation
therapy. However, more than half the patients present with advanced or metastatic
disease and cannot be cured surgically. Novel agents are currently under investigation
for treatment of MTC, and vandetanib, an oral RET and receptor tyrosine kinase (RTK)
inhibitor was recently approved by the FDA for adults with advanced or metastatic MTC.
Vandetanib also has activity in children with hereditary MTC.

- However, complete responses to RTKs have not been observed, and some patients develop
resistance to the treatment with RET and RTK inhibitors or have primary refractory
disease. The natural history of MTC, particularly in patients with MEN 2, the molecular
pathways involved in tumorigenesis, and the development of resistance to targeted
therapies are not well understood.

Objectives:

-The overall objective of this longitudinal study is to develop a better understanding of the
biology and natural history of MEN2 with or without MTC, particularly in children and adults
with MEN 2A and 2B, as well as study non-tumor manifestations of MEN 2. This will hopefully
allow for developing more effective treatment interventions for tumor and non-tumor related
manifestations, and more sensitive endpoints in clinical trials.

Eligibility:

- Patients, must have histologically or cytologically confirmed MTC, confirmed by the
Laboratory of Pathology, NCI or who have MEN2 (regardless of MTC status).

- Parent or primary caregiver of patient participant (< 21)

- Participants may be undergoing standard care or receiving treatment on a clinical trial
while participating in this study.

Design:

This study will allow for longitudinal evaluations of MTC and MEN2 and non-tumor related
manifestations of MEN 2A and 2B in children and adults. Evaluations will consist of the
following (summarized):

1. Clinical and radiological evaluations

2. Detailed pathologic and molecular analysis of tumor specimens will be performed,
including immunohistochemistry (IHC), comparative genomic hybridization (CGH), and
genome sequencing. CGH and genome sequencing will be performd with co-enrollment on
protocol 10-C-0086 Comprehensive Omics Analysis of Pediatric Solid Tumors and
Establishment of a Repository for Related Biological Studies.

- INCLUSION CRITERIA FOR PATIENTS:

- Patients must have histologically or cytologically confirmed MTC, confirmed by the
Laboratory of Pathology, NCI OR Confirmation of MEN2A or MEN2B diagnosis, regardless
of presence of MTC.

- Performance Status: Ability to travel to the NIH and to undergo evaluations to be
performed on this protocol.

- Informed Consent: Ability of patient or their legal guardian (if the patient is <18
years old) to understand and willing to sign a written informed consent document.

- Prior and current therapy: For the purpose of this study subjects who have not
previously received medical or surgical treatment, patients, who have previously
received medical or surgical treatment, and subjects who are currently receiving
medical treatment and/or radiation for MEN 2 related manifestation(s) will be
eligible. Prior and current treatment for MEN 2 related manifestations will be
recorded at trial entry and throughout the study.

- Patients must have a primary care provider (for example a primary oncologist or
endocrinologist) who can provide and coordinate the medical care for the patient.

EXCLUSION CRITERIA FOR PATIENTS:

-In the opinion of the investigator the patient is not able to return for follow-up visits
or obtain required follow-up studies.

Inclusion Criteria for Parents or Primary Caregivers

- Must be a parent or primary caregiver of a patient (< 21) who has a histologically or
cytologically confirmed MTC or who have MEN2 (regardless of MTC status).

- Ability to understand and be willing to sign a written informed consent document.

EXCLUSION CRITERIA FOR PARENTS OR PRIMARY CAREGIVERS: None