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Purpose Anaplastic thyroid cancer (ATC) is a deadly form of thyroid cancer. BRAF V600E is the only actionable mutation for which there is a Food and Drug Administration–approved drug combination. Rapid detection of BRAF V600E and initiation of therapy is critical. We explored the ability of droplet digital polymerase chain reaction (ddPCR) to identify this mutation in circulating cell-free DNA (cfDNA) in plasma. Materials and Methods The ddPCR assay was evaluated for its sensitivity, specificity for detection of BRAF V600E cfDNA, and concordance with tumor tissue. The assay also was used to evaluate its potential role as a biomarker of response. Results Forty-four patients with ATC who were tested for the BRAF mutation by tumor tissue DNA sequencing or immunohistochemistry were included. Sixteen BRAF V600E–positive patients had treatment samples to evaluate cfDNA levels as a biomarker of response in correlation with restaging scans. Concordance of ddPCR with tumor tissue was 93%, with a sensitivity of 85% and specificity of 100%. Area under the curve by Wilcoxon rank sum test was 0.9 (95% CI, 0.80 to 0.99; P < .001). As a biomarker of response to treatment, 94% of ddPCR samples were concordant with tumor shrinkage in restaging scans, and 47% were concordant with tumor growth (Fisher’s exact test P = .0061). In addition, cfDNA levels by ddPCR were predictive of treatment response in 71% of samples. Conclusion cfDNA detection by ddPCR is highly sensitive, specific, and concordant with mutation status on ATC tumors. ddPCR also can be used for monitoring cfDNA levels in conjunction with imaging scans in patients with ATC.

6514 Background: ATC is a rare/aggressive cancer with dismal outcome. Dabrafenib/trametinib is approved for BRAF-mutated ATC but pts eventually develop resistance. There are no approved drugs for pts with BRAF-wild type ATC. Better treatments (tx) are needed. Methods: ATC pts with PS < 3 enrolled on a prospective trial at a single center, and tx was assigned by driver mutation: BRAF (cohort 1), RAS, NF1, or NF2 (cohort 2), or none of these (cohort 3). Cohort 4 with paclitaxel was exploratory for pts who did not qualify for 1-3. All pts received atezolizumab (A) IV + targeted therapy. Cohort 1 had run-in with vemurafenib (V) 960mg BID/cobimetinib (C) 60mg QD po for 28 days, followed by A 840mg Q2 weeks, at which time V dose was decreased to 720mg BID. Cohort 2: A + C (same doses as cohort 1); cohort 3: A 1200 mg Q3 weeks + bevacizumab 15 mg/kg q3 weeks. Pts unable to swallow used alternative drug preparation (ADP; crushed vemurafenib, suspension cobimetinib). Primary objective is to determine whether the tx in cohorts 1-3 leads to improved overall survival (OS). The trial was designed to enroll 36 pts but we are reporting early due to positive findings. Response rate (RR) was measured by RECISTv1.1. Median OS was estimated by Kaplan-Meier method. cfDNA and biopsy were obtained at baseline, course 2 and progression. Pts were allowed to undergo surgery and radiation while on trial. Results: From August 2017-January 2020, 34 ATC pts were enrolled in cohorts 1-3 and 9 in cohort 4. Cohort 3 closed early for futility. 3 pts had ADP. Median follow-up time was 7.51 mos (range: 0.43 – 27.37). Median OS in cohorts 1-3 was 18.23 mos (CI 10.45-NE) and 1-year OS was 67% (95%CI: 45%, 82%). See table. Response rate (RR) in cohort 1 was 71%: CR 1/17 (6%), PR 11/17 (65%), SD 4/17 (23%), 1 never restaged; in cohort 2 RR was 7%: PR 1/14 (7%), SD 7/14 (50%), PD 4/14 (29%), 2 died early. 8 (24% of cohort 1-3) pts had complete tumor resection after tx with VCA (n = 7) or CA (n = 1); all but 1 of these pts are alive. AEs as expected. cfDNA data will be reported at meeting. Conclusions: Atezolizumab + vemurafenib/cobimetinib for BRAF-mutated or + cobimetinib for NF1/2 or RAS-mutated ATC is effective, as evidenced by the long OS in these pts (13 mos > historical control). A significant number of patients, particularly in cohort 1, were able to undergo complete tumor resection due to a favorable response to tx. Clinical trial information: NCT03181100 . [Table: see text]

6023Background: Anaplastic thyroid cancer (ATC) is a rare malignancy characterized by rapid progression and median overall survival (OS) of less than 6 months. With the goal of improving ATC outcom...

Purpose [18F]Fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) imaging may improve assessment of radiation response in patients with head and neck cancer, but it is not yet known for which patients this is most useful. We conducted a prospective trial to identify patient populations likely to benefit from the addition of functional imaging to the assessment of radiotherapy response. Patients and Methods Ninety-eight patients with locally advanced cancer of the oropharynx, larynx, or hypopharynx were prospectively enrolled and treated with primary radiotherapy, with or without chemotherapy. Patients underwent FDG-PET/CT and contrast-enhanced CT imaging 8 weeks after completion of treatment. Functional and anatomic imaging response was correlated with clinical and pathologic response. Imaging accuracy was then compared between imaging modalities. Results Although postradiation maximum standard uptake values were significantly higher in nonresponders compared with responders, the positive and negative predictive values of FDG-PET/CT scanning were similar to those for CT alone in the unselected study population. Subset analyses revealed that FDG-PET/CT outperformed CT alone in response assessment for patients at high risk for treatment failure (those with human papillomavirus [HPV] –negative disease, nonoropharyngeal primaries, or history of tobacco use). No benefit to FDG-PET/CT was seen for low-risk patients lacking these features. Conclusion These data do not support the broad application of FDG-PET/CT for radiation response assessment in unselected head and neck cancer patients. However, FDG-PET/CT may be the imaging modality of choice for patients with highest risk disease, particularly those with HPV-negative tumors. Optimal timing of FDG-PET/CT imaging after radiotherapy merits further investigation.

6042Background: With the exception of human papilloma virus (HPV), there are no effective biomarkers in Head and Neck Cancer (HNSCC). To identify novel biomarkers in HPV-negative HNSCC we utilized ...

6085Background: ATC is an aggressive disease requiring rapid diagnosis. Targeted therapeutics provide ATC patients (pts) with previously unavailable treatment options. Development of high throughpu...

6001 Background: We designed a randomized phase II trial to determine the efficacy of two induction chemotherapy (ICT) cetuximab (C) containing regimens with demonstrated efficacy and acceptable to...

e17012 Background: Parathyroid carcinoma (PC) is rare, has high morbidity and poor overall survival. Surgery is the mainstay of treatment but recurrence is common. There are no known therapeutic op...

6011 Background: Epithelial-mesenchymal transition (EMT) has been associated with EGFR inhibitor resistance in preclinical studies of head and neck squamous cell carcinoma (HNSCC). Recently, we developed an EMT signature that predicts EGFR inhibitor resistance in lung cancer. Using this signature, we explored the association between EMT and drug response in HNSCC, focusing on the tyrosine kinase Axl as a potential therapeutic target. Methods: We conducted an integrated molecular and drug response analysis in HNSCC. A 76-gene EMT signature previously developed and validated in lung cancer was tested in HNSCC cell lines (n>50) and patient tumors from The Cancer Genome Atlas (TCGA) (n=113) and a MDACC cohort (n=105). Reverse phase protein array (RPPA) and proliferation assays were used to measure protein expression and sensitivity to erlotinib and the Axl inhibitors SGI-7079 and TP-0930. Results: The EMT signature identified distinct epithelial and mesenchymal subsets of HNSCC among cell lines and patient tumors. RPPA experiments revealed higher protein levels of the receptor tyrosine kinase Axl, vimentin, and N-cadherin and lower expression of E-cadherin and beta-catenin in mesenchymal HNSCC (p-values 10μM); however, we discovered that mesenchymal HNSCC were highly sensitive to two Axl inhibitors, SGI-7079 and TP-0930 (IC50s ≤1.2μM and 0.2uM, respectively). Conclusions: Our EMT gene expression signature identified discrete epithelial and mesenchymal subgroups of HNSCC. Mesenchymal HNSCC cells expressed higher levels of Axl protein and exhibited sensitivity to Axl inhibition, but resistance to erlotinib. These results highlight differences in drug response between epithelial and mesenchymal cancers and support Axl as a potential therapeutic target and predictive marker of EGFR inhibitor resistance in HNSCC. (Funded in part by 5 P50 CA097007-10)

6067 Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression but treatments targeting EGFR have met with limited clinical success. We hypothesized that everolimus (EV), an mTOR inhibitor, potentiates the activity of erlotinib (ER), an EGFR tyrosine kinase inhibitor, in platinum-resistant recurrent and/or metastatic HNSCC. Methods: This single-arm two-stage phase II clinical trial evaluated EV 5 mg and ER 150 mg orally daily in patients (pts) with platinum-resistant recurrent and/or metastatic HNSCC. Primary endpoints were response rate and 12-week progression-free survival (PFS). Plasma biomarkers by multianalyte profiling (Luminex Corp) and ELISA at baseline (20 pts), 4 weeks (18 pts) and 12 weeks (16 pts) as well as p16 expression in baseline tumor tissue (29 pts) were assessed in correlation with clinical results. Results: Of the 36 evaluable pts (median age 61 years, 29 males, 19 with oropharynx primaries, 15 with ≥2 lines of chemotherapy, 17 with prior cetuximab), 3 (8%) achieved partial response at 4 weeks, one of which was confirmed at 12 weeks, while 27 (75%) pts achieved disease stabilization at 4 weeks, 11 of which were confirmed at 12 weeks. The 12-week PFS was 49%, median PFS was 11.9 weeks and median overall survival (OS) was 10.25 months. Grade 3 toxicities included mucositis (17%), fatigue (14%), skin (8%), diarrhea (8%), and 5 pts withdrew from trial secondary to toxicity. High neutrophil gelatinase-associated lipocalin(NGAL) levels at baseline were associated with worse OS (HR 4.59; 95%CI 1.36, 15.46; p=0.014) and at 4 weeks with worse PFS (HR=12.29; 95% CI 1.26, 119.87; p=0.03) and OS (HR=6.21; 95% CI 0.95, 40.62; p=0.057). High carbonic anhydrase-9 (CA-9) levels at 4 weeks were associated with worse OS (HR=1.18; 95% CI 1.001, 1.41; p=0.049), while decreased CA-9 levels at 4 weeks were associated with better PFS (p=0.77). Conclusions: Efficacy for the combination ofEV and ER is reasonable however plasma markers of tumor invasion and hypoxia are associated with worse outcomes, and further biomarker analysis may define subsets of pts with significant therapeutic benefit. Clinical trial information: NCT00942734.

6026 Background: The role of the epithelial-mesenchymal transition (EMT) is crucial to invasive and progression of several epithelial malignancies. The role of this process in head and neck squamous cell carcinoma (HNSCC) remains poorly defined. Methods: Eleven head and neck squamous cancer cell lines and 50 primary tumor specimens formed the materials for this study. We used Western blotting, immunohistochemistry, RT-PCR cell motility assay to determine the expression and the functional implications of several cell adhesions and singling molecular associated with EMT in these tumors. Results: Our results showed Src and E-Cadherin to be paradoxically overexpressed in the majority of cell lines and in primary tumor tissues relative to normal squamous mucosa. In both cell lines and tumor tissues elevation of activated Src was accompanied by down-regulation of E-Cadherin and vimentin detection. In-vitro inhibition of Src led to the increased E-Cadherin of expression and cell proliferation in squamous carcinoma cell lines. Immunophenotypic analysis of the protein products of these genes in primary tumor tissues demonstrated a spectrum of changes that correlated significantly with the differentiation, invasive patterns, sarcomatoid transformation and lymph node status. Our results show that high activated Src and low E-Cadherin expression were correlated with finger-like invasive pattern, poor differentiation, sarcomatoid transformation and lymph node metastasis in HNSC. Conclusions: Our study indicates that Src and E-Cadherin play a major role in EMT invasion and progression of head and neck squamous carcinoma. These proteins may be targeted in the therapeutic intervention of patients with HNSCC. No significant financial relationships to disclose.