Parathyroid Tumor Clonal Status

A Phase 2 Biomarker Study of Parathyroid Tumor Clonal Status in Hyperparathyroid Disorders (Primary, Secondary, and Tertiary)

To define the frequency of monoclonal-X and polyclonal-X tumors in hyperparathyroid disorders patients having PTX and to define the relationship between parathyroid tumor clonal status and multiple gland neoplasia (MGN), we will compare surgical and pathologic outcomes to tumor clonal status in a multicenter cohort of patients having bilateral neck exploration (BNE) and PTX (primary objectives).

Study Overview

• Status: Recruiting
• Conditions: Primary Hyperparathyroidism; Secondary Hyperparathyroidism (SHPT); Parathyroid Tumor; Tertiary Hyperparathyroidism

Detailed Description

To define the frequency of monoclonal-X and polyclonal-X tumors in PHPT patients having PTX and to define the relationship between parathyroid tumor clonal status and MGN, we will compare surgical and pathologic outcomes to tumor clonal status in a multicenter cohort of patients having bilateral neck exploration (BNE) and PTX.

Study participants will be recruited from four high-volume centers at Washington University in St. Louis (WU. Eligible patients will receive standard of care treatment (parathyroidectomy) and de-identified FFPE tumor samples (1 slide H&E stained, 6 x 10 um sections unstained from each abnormal gland) will be sent to WU for study. DNA will be extracted from FFPE samples and the HUMARA assay will be performed according to our established protocol. (3) Our two published studies show >90% concordance between replicate HUMARA assays of the same tumor. For additional rigor, two regions of each tumor will be assayed independently to ensure concordance of clonal status. Tumors where the clonality call from the two within-tumor samples are discordant will be recorded as such, and we will perform sensitivity analyses, for aims where this is relevant, of assigning one or the other clonal state to these samples.

Further, we will employ a secondary assay (Cytoscan HD array, ThermoFisher) to assess DNA copy number variation (CNV) in a random set of samples from 58 polyclonal-X cases and 49 monoclonal-X cases (estimated 107 total assays). Published and unpublished data have shown that CNV occurs with considerable frequency in parathyroid tumors, including adenomas. CNV assessment can provide independent verification of an X-inactivation-based finding of polyclonality by identifying heterogeneous CNV within a tumor sample indicating polyclonality, or more uniform CNV reflecting monoclonality. Cases with discordant results (estimated <10%) from HUMARA and CNV assays will be comprehensively studied in the exploratory objectives.

De-identified pathologic data including the number and weight of abnormal glands removed from patients will be recorded and entered in a REDCap database maintained at WU. We then will review operative and pathologic reports for correlation of tumor clonality and the presence of SGN or MGN. In cases of MGN we will perform ms-PCR of HUMARA alleles on all resected tumors to assess for concordance of clonality. We will also determine the impact of two common surgical approaches on outcomes in tumors of different clonal status. Participating surgeons in the trial estimate that between 40% and 50% of their cases have unilateral neck exploration (UNE), and all use intraoperative PTH (ioPTH) during UNE. The frequency of MGN stratified by tumor clonality will be examined in patients who undergo UNE with ioPTH monitoring and compared BNE. Operative and pathology reports will be reviewed as well as ioPTH levels drawn before and both 5 and 10 minutes (PTH T1/2 = 5 min.) after tumor removal. Underlying tumor clonality will be determined as described above and will be compared to pathologic results (MGN versus SGN), as well as ioPTH kinetics (% decline from pre-op PTH levels at 5 and 10 minutes after final tumor removal).

To define the relationship between parathyroid tumor clonal status and biochemical outcomes following PTX for PHPT, we will compare baseline clinical features, surgical/pathologic findings and postoperative biochemical outcomes following PTX to tumor clonal status in a large, multicenter cohort of patients having PTX. A total of 645 patients with known tumor clonal status will have standard clinical and biochemical data (serum calcium, albumin, intact PTH, 25(OH)D, and creatinine) recorded at baseline (before PTX), and at 2 weeks, 3 months, and 6 months post-PTX (not all labs are recorded at each follow-up time point). We will compare the frequency of elevated PTH (ePTH) at each time point in patients with monoclonal-X and polyclonal-X tumors. We have previously shown that vitamin D status impacts ePTH following PTX. To investigate abnormal vitamin D metabolism, the most common mechanism of secondary hyperparathyroidism as a cause of polyclonal-X disease, we also will perform a comprehensive analysis of vitamin D status in a subset of 111 WUSM patients with monoclonal-X and polyclonal-X tumors. Our analysis will include biochemical indices of vitamin D metabolism (25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and vitamin D binding protein levels).

Genomic approaches, e.g. whole genome sequencing plus RNA sequencing, will be performed at Wash U, using fresh frozen tissue collected following PTX or from FFPE tissue.

• Study Type: Observational
• Enrollment (Estimated): 839

Contacts and Locations

• Study Contact: Name: John A Olson, MD; Phone Number: (314) 362-8020; Email: jaolsol@wustl.edu
• Study Contact Backup: Name: Kathleen Harris; Phone Number: (314) 273-1433; Email: harrisk@wustl.edu

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Contact: Bryan Bear; Phone Number: 314-651-9717; Email: bearb@wustl.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Females and males scheduled to have surgery for hyperparathyroidism.

Description

Inclusion Criteria:

• 1. Diagnosed with hyperparathyroidism (primary, secondary, or tertiary), biochemically confirmed (e.g., serum calcium and/or intact PTH consistent with the underlying etiology), and undergoing clinically indicated management
• Female and male patients
• Age ≥ 18 years
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• Patients with a history of cervicofacial irradiation.
• Patients currently taking lithium or with a history of lithium use.
• Pregnant patients

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Endpoint 3	Perform a prospective study of biochemical outcomes of PTX in PHPT patients with monoclonal-X and polyclonal-X tumors.	24 months
Primary Endpoint 1	1. Frequency of monoclonal-X versus polyclonal-X parathyroid tumors in patients with hyperparathyroid disorders.	24 months
Primary Endpoint 2	2. To determine the clinicopathologic features of monoclonal-X versus polyclonal-X parathyroid tumors in a prospective multi-center cohort of patients with HPT (PHPT/SHPT/THPT) referred for PTX.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary Endpoint	To investigate mechanism(s) of monoclonal-X and polyclonal-X parathyroid tumorigenesis using functional and genomic approaches (e.g. calcium sensing capacity determined by EC50 and single nucleotide variants / copy number variation).	24 months

Collaborators and Investigators

• Sponsor: Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): July 28, 2023
• Primary Completion (Estimated): January 31, 2031
• Study Completion (Estimated): January 31, 2032

Study Registration Dates

• First Submitted: August 4, 2023
• First Submitted That Met QC Criteria: August 11, 2023
• First Posted (Actual): August 18, 2023

Study Record Updates

• Last Update Posted (Actual): May 12, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Parathyroid Diseases; Hyperparathyroidism; Hyperparathyroidism, Primary; Hyperparathyroidism, Secondary; Parathyroid Neoplasms
• Other Study ID Numbers: 202212100

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: This will be determined at a future date.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No