Molecular predictive biomarker testing in advanced thyroid cancer - a European consensus

Abstract

As new precision oncology therapies become available in the thyroid cancer (TC) treatment landscape, appropriate and timely biomarker testing is crucial for treatment selection and requires a multidisciplinary approach. Recently published European guidelines on advanced/metastatic TC management include a special focus on biomarker testing. However, to date, there remains a need for comprehensive European guidance for standardized molecular testing strategies in TC that encompass a broad set of targetable or potentially targetable alterations, timing of testing, and patients to be tested. This expert opinion article outlines consensus testing algorithms for differentiated TC, medullary TC, and anaplastic TC from a team of endocrinologists, oncologists, molecular biologists, and pathologists to provide standardized recommendations for physicians involved in treating patients with advanced TC. In the differentiated TC algorithm, patients recommended for comprehensive testing by DNA and RNA next-generation sequencing (NGS) include those whose disease has progressed on or is resistant to radioactive iodine treatment. The medullary TC algorithm recommends RET germline testing for all patients at diagnosis. For patients exhibiting high-risk clinical or pathological features and those whose disease progresses, somatic RET testing with NGS should be discussed and conducted before considering systemic treatment. As anaplastic TC is a highly aggressive disease, molecular reflex testing for BRAF mutations is recommended for all patients at diagnosis, followed by DNA and RNA NGS for those who test BRAF negative. The article also provides consensus recommendations on the use of tumor tissue for testing and on centralization of molecular testing involving multidisciplinary tumor boards.

Keywords: biomarkers; consensus; molecular testing; multidisciplinary; thyroid cancer.

Figure 1

Expert consensus testing algorithm for (A) differentiated thyroid cancer (DTC), (B) medullary thyroid cancer (MTC), and (C) anaplastic thyroid cancer (ATC). *If next-generation sequencing (NGS) testing and referral are not feasible, single-gene analysis of druggable genetic alterations is recommended; **Examples of high-risk clinical or pathologic features: high calcitonin levels both before and after surgery, short calcitonin doubling time, early distant metastases, histologically high-grade disease, tumor burden, and disease stage. IHC, immunohistochemistry; LENVAT/PEM, lenvatinib plus pembrolizumab; MDT, multidisciplinary teams; MKI, multikinase inhibitor; PCR, polymerase chain reaction; RAI, radioactive iodine; SoC, standard of care. Boxes in light red outline an algorithm path that involves testing and treatment with driver mutations. Boxes in light blue indicate steps in the algorithm that do not require testing.