Molecular test of indeterminate thyroid nodules

Rationale: Approximately 15 to 30% of thyroid nodules evaluated by means of fine-needle aspirate biopsy (FNAB) are not clearly benign or malignant. Patients with cytological indeterminate nodules (Bethesda III/IV) are often referred for diagnostic surgery, though most of these nodules prove to be benign. A novel diagnostic test that measures the expression of 167 genes (the Afirma gene expression classifier (GEC)) has shown to identify many benign thyroid nodules accurately when FNA results were cytological indeterminate.

Objective: The purpose of this study is to compare the diagnostic surgical rate of a matched control group, derived from a retrospective review of patients without GEC testing, with a prospective GEC tested group.

Study design: We will perform a retrospective study to describe the clinical management of patients undergoing thyroid fine needle aspirate biopsy resulting in an indeterminate cytopathology diagnoses (Bethesda III/IV) in the absence of molecular diagnostic testing. The operative rate within the first year after FNAB will be calculated for this retrospective cohort. Next, prospectively, patients with indeterminate cytopathology will be offered GEC testing in the absence of other reasons to operate. Clinician(s) will receive the test result to incorporate into clinical decision making, and patients will then receive care as decided locally. Primary outcome is the percentage of patients who underwent diagnostic surgery. Prospective cases will be matched against historical controls. Matching will be performed blinded to the management outcome after FNA. The subjects will be matched according to the following characteristics: Age, gender, FNA result and hospital. Factors influencing the decision regarding surgery such as ultrasound characteristics, cytopathology and clinical findings, will be evaluated.
Study population: Patients with cytological indeterminate nodules (Bethesda III/IV) who presented themselves or were referred for further treatment in one of the three university hospital Thyroid Cancer Centers collaborating in the Dutch thyroid Cancer Network.

Intervention (if applicable): Addition of the Afirma gene expression classifier into the clinical management of patients with indeterminate thyroid nodules.

Main study parameters/endpoints: The primary study endpoint is the comparison of diagnostic surgical rates between the historical control group (the retrospective review of patients without GEC testing) and a prospective group in which the GEC test is added to the regular clinical management of patients with cytologically indeterminate nodules enrolled in this study.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: There are no extra risks associated with the GEC test other than the risks of FNA (described later in detail). Considering the major impact of surgery on quality of life, a significant reduction in the number of diagnostic surgeries will benefit a lot of patients. It will also prevent life-long replacement with levothyroxine which is often, not always, required after diagnostic surgery. The GEC test result may be added to the regular clinical management as one of several factors for clinical decision making. A benign GEC result reduces the risk of malignancy to less than 6% justifying a wait and see policy in the majority of patients. This is currently the standard of care for patients with a Bethesda II FNA result, with have the same malignancy risk. All patients with a GEC benign result will be closely monitored with repeat ultrasound after 6 months and then annually for at least 5 years.

Approximately 15 to 30% of thyroid nodules evaluated by means of fine-needle aspirate biopsy (FNAB) are not clearly benign or malignant. Patients with cytological indeterminate nodules (Bethesda III/IV) are often referred for diagnostic surgery, though most of these nodules prove to be benign. A novel diagnostic test that measures the expression of 167 genes (the Afirma gene expression classifier (GEC)) has shown to identify many benign thyroid nodules accurately when FNA results were cytological indeterminate.

The purpose of this study is to compare the diagnostic surgical rate of a matched control group, derived from a retrospective review of patients without GEC testing, with a prospective GEC tested group.

The duration of patient participation will be up to 1 year; the time between the study FNAB and potential surgical procedure. Any patient who has not undergone surgery after a 1 year period will be classified as “clinical and/or sonographic management.” Patients whose GEC classifier reports “benign” are included in a a structured follow-up plan to ensure that these patients are not lost to follow-up, with repeat ultrasound after 6 months, and then annually for at least 5 years.

The intervention is an extra FNA biopsy which will be tested with the molecular GEC test. No intervention will be performed on the control group.