Genomic screening for early detection and treatment of medullary thyroid carcinoma
Medullary thyroid carcinoma (MTC) is a rare but potentially fatal thyroid cancer originating from the parafollicular C cells of the thyroid gland. Patients with MTC typically undergo more aggressive preoperative evaluation and more extensive surgical treatment than those with other thyroid cancer histologies. Medullary thyroid carcinoma arises sporadically (75%) or via familial inheritance (25%). Those with hereditary MTC have germline gain-of function pathogenic variants in the rearranged during transfection (RET) proto-oncogene. Testing for germline RET variants provides an opportunity for early diagnosis of MTC.
The goal of the current investigation was to describe clinical treatment and patient outcomes following identification of P/LP RET variants via a population genomic screening program in order to further understand the degree to which genomic screening programs can facilitate early detection of MTC in these patients.
This retrospective cross-sectional study was completed between June 1, 2016, and May 31, 2022, for a mean follow-up period of 22.4 months (range, 2-76 months). The study included patients who were identified as having P/LP RET variants through a population genomic screening program at a rural tertiary care center and who underwent thyroidectomy after results disclosure. The outcomes of interest were preoperative evaluation and treatment-related outcomes. Measures included imaging and laboratory findings, extent of surgery, pathologic diagnosis, and staging.
Seventy-five patients were identified as having P/LP RET variants exclusively through genomic screening. Twenty of these patients(27%) underwent total thyroidectomy; 13 of these patients (65%) also had a central neck dissection. No patients had clinically apparent disease at the time of surgery. Pathologic findings indicated MTC for 12 patients and papillary thyroid carcinoma in 2. Of patients with MTC, 10 had stage I disease, 1 had stage II disease, 1 had stage III disease, and none had stage IV disease. Based on postoperative surveillance imaging and laboratory results, no patient had evidence of recalcitrant disease.
This cross-sectional study describes initial experience with a population-based genomic screening program that identified germline P/LP RET proto-oncogene variants in adult patients for whom clinical signs of, and risks for, MTC were unknown.
- Authors explored the capability of such a program to direct management schema aimed at early diagnosis and treatment of MTC in individuals with P/LP RET variants.
- Among the 20 patients identified exclusively via MyCode who subsequently underwent surgery, 14 (70%) were found to have an active malignant neoplasm on histopathology (12 [60%] with MTC and 2 [10%] with papillary thyroid carcinoma).
- Furthermore, 2 (10%) without an active thyroid malignant neoplasm were noted to have C-cell hyperplasia, a known precursor to MTC. Eighty-three percent of the patients with MTC (10 of 12) had stage I disease, and no patients were noted to have advanced disease (stage IV).
- Importantly, no patients had clinical evidence of disease and, therefore, did not have indications for the workup of a thyroid nodule outside of identification of a P/LPRET variant. Therefore, MyCode led to the detection of occult MTC in 60% of our study population, suggesting that genomic screening may lead to early diagnoses of MTC in patients with P/LP RET variants. These findings reinforce the potential for early treatment of MTC and its precursor lesion by Geisinger’s MyCode program.
This initial cross-sectional investigation found benefit of identifying P/LP RET variants via population genomic screening, namely, the ability to enable relevant, early MTC diagnoses. While additional data are needed to shape recommendations in individuals identified via population screening, given the high rate of occult MTC in this cohort, early surgical intervention should be considered in all patients found to have a P/LP RETvariant.
“Our group will continue to identify patients at risk for MTC through genomic screening and offer surgical treatment in appropriate patients. We hope that this process will lead to the identification of a broad range of RET variants associated with MTC in patients who are otherwise asymptomatic and do not have knowledge of their risk for malignancy. With population genomic screening, we hope to reaffirm our initial findings, develop protocols that will support appropriate, interventive measures for patients, and ultimately improve treatment of patients with and at risk for MTC.”
Source: Pichardo PFA, Hellums RN, Hao J, et al. Thyroidectomy Outcomes in Patients Identified With RET Pathogenic Variants Through a Population Genomic Screening Program. JAMA Otolaryngol Head Neck Surg. Published online January 05, 2023. doi:10.1001/jamaoto.2022.4195
