Surgery After BRAF-Directed Therapy Is Associated with Improved Survival in BRAF^V600E 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.

Recent advances in anaplastic thyroid cancer management

“…Zhao et al [17 ▪ ] recently published a retrospective cohort study of 32 patients with BRAFm-ATC treated with neoadjuvant BRAF-directed therapy followed by surgery, where this treatment approach allowed significant reduction in tumor size, extent of surgery, and surgical morbidity. Notably, eight of nine patients who had unresectable disease at initial presentation were recategorized as having only moderate or mild surgical morbidity.…”

“…For instance, the ROAR trial excluded patients with an Eastern Cooperative Oncology Group performance status > 2, and those unable to swallow the trial medication. In the past year, multiple real-world studies have been published confirming the efficacy and safety of DT outside the setting of a clinical trial [12 ▪▪ ,17 ▪ ,21 ▪ –23 ▪ ], although they reported shorter OS and PFS durations compared to the phase II trial. These differences are likely due to greater patient heterogeneity and potential delays in access to drugs.…”

“…ATCs are richly infiltrated by macrophages and T cells, have a high tumor mutational burden (TMB) and express PDL-1 in up to 90% of cases, making them favorable targets for immune checkpoint inhibitors (ICIs) [30]. After minimal efficacy of single agent anti-PD-1 in locally advanced or metastatic ATC [31], its combination with DT led to more promising results in retrospective cohorts of BRAFm-ATC [12 ▪▪ ,17 ▪ ]. This is due to synergistic effect between BRAF/MEK inhibitors and ICIs, as well as higher expression of PDL-1 in presence of the BRAFV600E mutation [32].…”

The role of surgery for anaplastic thyroid carcinoma in the era of targeted therapeutics: A scoping review

“…Twenty-one studies met criteria for inclusion in the final review. 5,12,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] However, six further studies were subsequently excluded due to overlapping patient data 5,12,28,[32][33][34] leaving 15 studies to be included in the final review [16][17][18][19][20][21][22][23][24][25][26][27][29][30][31] (Figure 1).…”

“…Eight out of the 15 included studies (53.3%) provided details pertaining to postoperative surgical morbidity 16,17,20,21,24,[29][30][31] (Table 4). or restricted radical surgery (14.3%).…”