Surgery After BRAF-Directed Therapy Is Associated with Improved Survival in BRAFV600E Mutant Anaplastic Thyroid Cancer: A Single-Center Retrospective Cohort Study

Abstract

Background: The aim of this study was to describe the oncologic outcomes of patients with BRAF^V600E-mutated anaplastic thyroid cancer (ATC) who had neoadjuvant BRAF-directed therapy with subsequent surgery. For context, we also reviewed patients who received BRAF-directed therapy after surgery, and those who did not have surgery after BRAF-directed therapy. Methods: This was a single-center retrospective cohort study conducted at a tertiary care cancer center in Texas from 2017 to 2021. Fifty-seven consecutive patients with BRAF^V600E-mutated ATC and at least 1 month of BRAF-directed therapy were included. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Results: All patients had stage IVB (35%) or IVC (65%) ATC. Approximately 70% of patients treated with BRAF-directed therapy ultimately had surgical resection of residual disease. Patients who had neoadjuvant BRAF-directed therapy followed by surgery (n = 32) had 12-month OS of 93.6% [confidence interval (CI) 84.9-100] and PFS of 84.4% [CI 71.8-96.7]. Patients who had surgery before BRAF-directed therapy (n = 12) had 12-month OS of 74.1% [CI 48.7-99.5] and PFS of 50% [CI 21.7-78.3]. Finally, patients who did not receive surgery after BRAF-directed therapy (n = 13) had 12-month OS of 38.5% [CI 12.1-64.9] and PFS of 15.4% [CI 0-35.0]. Neoadjuvant BRAF-directed therapy reduced tumor size, extent of surgery, and surgical morbidity score. Subgroup analysis suggested that any residual ATC in the surgical specimen was associated with significantly worse 12-month OS and PFS (OS = 83.3% [CI 62.6-100], PFS = 61.5% [CI 35.1-88]) compared with patients with pathologic ATC complete response (OS = 100%, PFS = 100%). Conclusions: We observed that neoadjuvant BRAF-directed therapy reduced extent of surgery and surgical morbidity. While acknowledging potential selection bias, the 12-month OS rate appeared higher in patients who had BRAF-directed therapy followed by surgery as compared with BRAF-directed therapy without surgery; yet, it was not significantly different from surgery followed by BRAF-directed therapy. PFS appeared higher in patients treated with neoadjuvant BRAF-directed therapy relative to patients in the other groups. These promising results of neoadjuvant BRAF-directed therapy followed by surgery for BRAF-mutated ATC should be confirmed in prospective clinical trials.

Keywords: BRAF therapy; BRAFV600E; anaplastic thyroid cancer; neoadjuvant; surgery; thyroid cancer.

FIG. 1.

Flow diagram for study cohorts. ATC, anaplastic thyroid cancer; MDACC, MD Anderson Cancer Center.

FIG. 2.

Response to BRAF-directed therapy by CT imaging. (A) Percent change in tumor by longest axis by CT imaging after BRAF-directed therapy. (B) Absolute size change in tumor size as measured by longest axis. (n = 30).

FIG. 3.

Change in surgical morbidity after BRAF-directed therapy. (A) Sankey graph demonstrating changes in surgical morbidity before BRAF-directed therapy (left) and after BRAF-directed therapy (right) as measured using the TNMC scoring system. (B) Example of patient presenting as initially inoperable owing to common carotid encasement and regression of tumor from carotid after BRAF therapy. TNMC, Thyroid Neck Morbidity and Complexity.

FIG. 4.

OS and PFS for patients in relation to surgery after BRAF-directed therapy. Red neoadjuvant + surgery group: Patients who had surgery after BRAF-directed therapy, Green: upfront surgery group: Patients who had surgery before BRAF-directed therapy, Blue: No surgery group: Patients who received BRAF-directed therapy but did not receive surgery. (A) OS. (B) PFS. OS, overall survival; PFS, progression-free survival.

FIG. 5.

OS and PFS based on surgical pathology. (A) Pathology of surgical specimens separated based on PTC and ATC. (B) OS and (C) PFS based for pathologic residual ATC or ATC CR after definitive surgery. CR, complete response; PTC, papillary thyroid cancer.