Lai, Stephen Y.

Background: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a functional imaging modality that can quantify tissue permeability and blood flow. Due to vasculature changes resulting from radiation therapy (RT), DCE-MRI quantitative parameters should be significantly different in regions receiving a high radiation dose compared to regions receiving a low radiation dose. This study sought to determine whether a significant difference exists in post-head-and-neck-cancer (HNC)-RT DCE-MRI quantitative parameters (Ktrans and ve) between regions of the mandible receiving a high radiation dose and regions of the mandible receiving a low radiation dose. Methods: DCE-MRI was acquired from HNC subjects post-RT. The DCE-MRI quantitative parameters Ktrans and ve were obtained through Tofts model fitting. Four mandible sections (left ramus, left body, right ramus, and right body) were delineated on subject mandible contours. Two Friedman tests comparing the mean Ktrans and ve in low-dose (≤60 Gy) areas of the four mandible regions were computed. If the Friedman test determined that a significant difference for a parameter between mandible regions exists, post hoc Wilcoxon signed-rank tests were completed comparing the four mandible regions. If the Friedman test determined that there was no significant difference between mandible regions, a Wilcoxon signed-rank test was used to determine whether a significant difference exists in the parameter between high-dose (>60 Gy) and low-dose (≤60 Gy) mandible regions. Results: 48 HNC subjects were included in the analysis. The Friedman tests showed no significant difference in ve means between mandible regions (χ(3)2 = 1.63, p = 0.44) and a significant difference in Ktrans means between mandible regions (χ(3)2 = 10.29, p = 0.005). Post hoc testing between Ktrans mandible regions found that the left body and right body differed significantly from the left ramus and right ramus. The Wilcoxon signed-rank test comparing the mean ve between high- and low-dose mandible regions found a significant difference (W = 214, p = 0.00013). Conclusions: no inherent difference in the DCE-MRI quantitative parameter ve was observed within subject mandibles, but a significant difference was observed between ve means in high- and low-radiation-dose mandible regions. These results provide evidence of the utility of DCE-MRI to monitor mandible vasculature changes resulting from head and neck cancer radiation therapy. Monitoring post-HNC-RT mandible vasculature changes is important to initiate earlier toxicity management and ultimately improve HNC survivors’ quality of life.

6008 Background: ATC patients present with advanced, often surgically unresectable disease with historically dismal prognosis. Median PFS and OS of DT without pembrolizumab were 6.7 and 13.5 months, respectively, in the ROAR trial. Neoadjuvant DTP achieved locoregional control without radical surgery in a retrospective series of BRAF m-ATC patients, providing rationale to evaluate efficacy and safety in a phase 2 prospective trial. Methods: In this single-arm multicenter phase 2 trial, patients with BRAF m-ATC stage IVB/IVC were enrolled in 5 US centers. Following a 3-6 week run-in with D (150 mg BID) and T (2 mg daily), P (200 mg Q3W) was added, with restaging every three (21-day) cycles. Post-operatively, patients continued P (or DTP) with radiotherapy or transitioned directly to adjuvant DTP (up to 26 cycles). Primary endpoints included R0/R1 resection rate (historically 5%) and overall survival (OS). Secondary endpoints included RECIST 1.1 response after DTP and progression-free survival (PFS). Results: Between 9/2021-1/2025, 42 patients were enrolled; 36 are included in the current analysis (3 not evaluable, 3 pending surgery) (Table). Patients received median 4 (range: 2-7) neoadjuvant DTP cycles, with 26 (72%) achieving radiographic PR/CR. 30 patients (83%) had surgery after neoadjuvant DTP, achieving R0/R1 resection in 29/30 (97%). Mean surgical morbidity score (0-4 scale, 4=unresectable) improved from 3.3 to 1.6 after DTP (p<0.01). Complete ATC pathologic response occurred in 20/30 patients (67%), while 10/30 (33%) had residual ATC in the surgical specimen. Postoperatively, 11/30 (37%) received adjuvant neck radiation, and 28/36 (78%) completed a median of 11 (range: 1-26) adjuvant DTP cycles. With median follow up 18 months, 15/36 (42%) patients died. Median OS was 20 months (95% CI: 12.6-NR); 1- and 2-year OS were 71% and 48%. Complete pathologic responders had better 2-year OS than those with residual ATC (69% vs. 22%, p=0.02). Median PFS was 13.9 months (95% CI, 7.5-NR); 1- and 2-year PFS were 57% and 36%. Grade 5 adverse events occurred in 8 patients (22%), including one possible (duodenal perforation), one probable (kidney injury with sepsis), and 6 unlikely/unrelated treatment-related deaths. Conclusions: Neoadjuvant DTP enables surgical resection in BRAF m-ATC compared with historical controls, and leads to improved PFS and OS. This approach should now be considered a standard of care for BRAF m-ATC. Clinical trial information: NCT04675710 . Total N=36 Age (y), median (range) 67 (46-86) Stage IVB/IVC, n (%) 15 (42%)/21 (58%) Best RECIST response neoadjuvant phase, n (%) CR 2 (6%) PR 24 (67%) SD 6 (17%) PD 4 (11%) Percent change target lesion diameter, mean (95% CI) -44% (-54%, -34%) Surgical morbidity score change, mean (95% CI) -1.7 (-2.1, -1.3)

TPS6093 Background: Since patients with early-stage oral cavity cancer (OCC; T1-2N0M0; AJCC 8th ed) have a 20-30% rate of occult nodal metastases despite clinical and radiographic assessment, standard of care treatment includes elective neck dissection (END). Many patients have comprehensive surgical management of the regional cervical nodal basin even though the majority of those necks (70-80%) will not contain disease. Assessment of draining first echelon lymph nodes by sentinel lymph node (SLN) biopsy (Bx), a less invasive surgical procedure, may provide an alternative to END, while potentially reducing morbidity and cost. A decisive clinical trial comparing SLN Bx versus END can focus the HNC clinical and research community and resources on establishing the standard of care for management of the neck in early-stage OCC. Methods: In order to address the efficacy of SLN Bx in this population, we recently activated an international multi-institutional phase II/III prospective trial randomizing patients to two surgical arms: SLN Bx and END. PET/CT is an integral imaging biomarker in this trial. A node-negative PET/CT study with central read is required before randomization. Patients with a positive PET/CT central result will remain in a registry to compare imaging findings with final neck pathology. Given the current evidence available regarding morbidity for SLN Bx versus END, the phase II will determine if patient-reported neck and shoulder function and related QOL at 6 months after surgery using the Neck Dissection Impairment Index (NDII) shows a signal of superiority of SLN Bx compared to END. A total of 228 randomized patients with negative PET/CT for potential evaluation of shoulder-related morbidity with difference in 6-month NDII scores (minimum important difference ³7.5; one-sided a = 0.10; 90% power) will serve as the “Go/No-Go” decision to move forward into phase III. The phase III portion is a non-inferiority (NI) trial with disease-free survival (DFS) as the primary endpoint (NI margin hazard ratio 1.34 based on a 5% absolute difference in 2-year DFS; one-sided alpha 0.05; 80% power, and an interim look for efficacy at 67% of the events based on an O’Brien-Fleming boundary). The NDII at 6 months after surgery is a hierarchical co-primary endpoint for the phase III. Target accrual of phase III is 618 PET/CT negative patients, including those randomized in phase II (297 DFS events required for the final analysis). In addition to radiotherapy and imaging credentialing, quality assurance will include central pathology review of all negative SLN Bx cases and surgeon credentialing through an education course and SLN Bx and END case review by the surgical co-chairs. A surgical quality assurance working group will review all trial SLN Bx and END outcomes. As of 02/15/21, 7 patients have been screened and 6 of the planned 228 randomized patients in phase II have been enrolled. Clinical trial information: NCT04333537.

Abstract Purpose: Thyroid cancer cell lines are valuable models but have been neglected in pancancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers. Experimental Design: We performed next-generation sequencing (NGS) and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers. Results: Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g., BRAF, RAS, or gene fusions). Mutations in the TERT promoter (83%) and TP53 (71%) were highly prevalent. There were frequent alterations in PTEN, PIK3CA, and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell-cycle checkpoint, and histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced versus differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAFV600E versus RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in TP53 heterozygous tumors was the most prominent event selected during in vitro immortalization. Conclusions: This cell line resource will help inform future preclinical studies exploring tumor-specific dependencies.