The role of molecular diagnostics and targeted therapy in the management of radioiodine-refractory differentiated thyroid carcinoma with aggressive clinical course

Introduction. Despite favorable prognosis for differentiated thyroid cancer, 5–10 % of the cases are radioiodine-refractory form of this pathology characterized by aggressive course. Molecular and genetic causes of the resistance are genetic mutations, primarily in the BRAF (V600E mutations), TP53, TERT, RAS, NTRK and RET genes, oligoclonality, and somatic tumor heterogeneity. These cell events can affect response to targeted therapy, promote the «evasion» effect, development of radioiodine resistance, and underlie the possibility of tumor re-differentiation when treatment affects these targets.

Clinical case. The article describes a clinical case of combination treatment of differentiated thyroid cancer with lung metastases. In 2016–2022, the female patient received 3 courses of radioiodine therapy which did not achieve any significant effect. Due to this, targeted therapy with sorafenib at the place of residence was initiated. Considering development of medication intolerance and disease progression (local metastasis of BRAF-positive tumor and laryngeal stenosis), targeted therapy was switched to BRAF / MEK-specific with subsequent course of radioiodine therapy and achievement of stable disease for 1 year. Genetic examination of the primary tumor and metastasis showed presence of the BRAF^V600E mutation. Variant allele frequencies (VAF) in metastasis and recurrent tumor were 12 and 6 %, respectively. In the recurrent tumor, H1047L mutation in the PIK3CA gene was found (VAF 8 %). Previous examinations in two other laboratories did not show BRAF gene mutation in this tumor which did not correspond to primary partial response to targeted therapy with BRAF / MEK inhibitors. That said, our analysis identified this mutation.

Conclusion. The obtained data highlight significant diagnostic difficulties of analysis of formalin-fixed and paraffin-embedded samples: preanalytical degradation of nucleic acids, fixation artefacts, low VAF, non-representative biopsy sampling increase the risk of false negative results. The presented clinical case demonstrates the necessity of routing of patients with aggressive tumors into specialized centers, and that treatment and diagnostic tactics should be determined by a qualified multidisciplinary team.