Tumor Biomarkers for the Prediction of Distant Metastasis in Head and Neck Squamous Cell Carcinoma.

Distant metastases (DM) in head and neck squamous cell carcinoma (HNSCC) remain a challenge as treatment options are limited. To identify biomarkers predictive of DM in primary tumors (PT), gene expression profiling was performed in PT from patients who did, or did not develop DM (T-with and T-without, n = 25 and 24, respectively), and in matched DM. A total of 185 and 42 differentially expressed genes were identified in the T-with vs. T-without and the T-with vs. DM comparisons, respectively. The intersection between these two comparisons identified COX7A1 and TBX5 as common genes. In three independent datasets, both genes were able to significantly distinguish patients according to their DM-free survival. By functional biological analyses, the T-without group showed enrichment in immune-response pathways, whereas the T-with group showed an enrichment in B-plasma cells and Tregs. Increased enrichment of proliferation-related pathways was observed in the T-with group compared with that in the DM group. Further comparisons with/without DM are needed to confirm these data in order to improve clinical management of HNSCC.

Apparent diffusion coefficient and tumor volume measurements help stratify progression-free survival of bevacizumab-treated patients with recurrent glioblastoma multiforme.

BACKGROUND: The aim of this study was to determine whether apparent diffusion coefficient (ADC) bi-component curve-fitting histogram analysis and volume percentage change (VPC) prior to bevacizumab treatment can stratify progression-free survival (PFS) and overall survival (OS) in patients with glioblastoma multiforme (GBM) on first recurrence. METHODS: We retrospectively evaluated 17 patients with recurrent GBM who received bevacizumab and fotemustine (n = 13) or only bevacizumab (n = 4) on first recurrence at our institution between December 2009 and July 2015. Both T2/FLAIR abnormalities and enhancing tumor on T1 images were mapped to the ADC images. ADC-L and ADC-M values were obtained trough bi-Gaussian curve fitting histogram analysis. Furthermore, the study population was dichotomized into two subgroups: patients displaying a reduction in enhancing tumor volume of either >55% or <55% between the mean value calculated at baseline and first follow-up. Subsequently, a second dichotomization was performed according to a reduction in the T2 / FLAIR volume >41% or <41% at first check after treatment. OS and PFS were assessed using volume parameters in a Cox regression model adjusted for significant clinical parameters. RESULTS: In univariate analysis, contrast-enhanced (CE)-ADC-L was significantly predictive of PFS (p = 0.01) and OS (p = 0.03). When we dichotomized our sample using the 55% cut-off for enhancing tumor volume, CE-VPC was able to predict PFS (p = 0.01) but not OS (p = 0.08). In multivariate analysis, only the CE-ADC-L was predictive of PFS (p = 0.01), albeit not predictive of OS (p = 0.14). CE-ADC-M, T2/FLAIR-ADC-L, T2/FLAIR-ADC, and T2/FLAIR VPC were not significantly predictive of PFS and OS (p > 0.05) in both univariate and multivariate analysis. CONCLUSIONS: CE-ADC and CE-VPC can stratify PFS for patients with recurrent glioblastoma prior to bevacizumab treatment.

Prognostic value of relative cerebral blood volume in patients with recurrent glioblastoma multiforme treated with bevacizumab.

BACKGROUND: The aim of this study was to assess whether the early monitoring of the effects of bevacizumab in patients with recurrent glioblastoma multiforme (GBM) using perfusional dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) before and after the beginning of antiangiogenic therapy is predictive of treatment response. METHODS: Thirteen patients with recurrent GBM underwent perfusion MRI with relative cerebral blood volume (rCBV) mapping before (T0) and after the beginning (T1) of bevacizumab treatment. Recurrence Regions of Interest (RoIs) were positioned on the enhancing component of tumoral tissue revealed by postcontrast T1-weighted images. The rCBV measurements on the corresponding maps were made before and after the start of the antiangiogenic therapy. The Cox proportional hazards model and the Kaplan-Meier method were used with the log-Rank Test to establish whether pre- and postbevacizumab rCBV predicted progression-free survival (PFS). We tried to assess if there was a correlation between rCBV at T0 and rCBV at T1 using the Pearson's correlation coefficient. RESULTS: In the univariable analysis, rCBV was significantly predictive of PFS at T0 (HR=5.3, P=0.003) and at T1 (HR=4.14, P=0.04). Similarly, in the multivariate Cox model analysis, rCBV was predictive of PFS at T0 (HR=4.4, P=0.04) and T1 (HR=4.2, P=0.02). PFS was longer in patients whose rCBV was less than 4.50 mL/100g at T0 and less than 1.83 mL/100g at T1 than in patients with higher rCBV values. There was a moderate positive correlation between rCBV at T0 and rCBV at T1 (P=0.032, R=0.546). CONCLUSIONS: Despite the limited number of enrolled patients, rCBV assessed using DSC-MRI through the parameter rCBV is proved reliable in predicting the effects of antiangiogenic treatment in patients with recurrent GBM.

Are Fusion Transcripts in Relapsed/Metastatic Head and Neck Cancer Patients Predictive of Response to Anti-EGFR Therapies?

Prediction of benefit from combined chemotherapy and the antiepidermal growth factor receptor cetuximab is a not yet solved question in head and neck squamous cell carcinoma (HNSCC). In a selected series of 14 long progression-free survival (PFS) and 26 short PFS patients by whole gene and microRNA expression analysis, we developed a model potentially predictive of cetuximab sensitivity. To better decipher the "omics" profile of our patients, we detected transcript fusions by RNA-seq through a Pan-Cancer panel targeting 1385 cancer genes. Twenty-seven different fusion transcripts, involving mRNA and long noncoding RNA (lncRNA), were identified. The majority of fusions (81%) were intrachromosomal, and 24 patients (60%) harbor at least one of them. The presence/absence of fusions and the presence of more than one fusion were not related to outcome, while the lncRNA-containing fusions resulted enriched in long PFS patients (P = 0.0027). The CD274-PDCD1LG2 fusion was present in 7/14 short PFS patients harboring fusions and was absent in long PFS patients (P = 0.0188). Among the short PFS patients, those harboring this fusion had the worst outcome (P = 0.0172) and increased K-RAS activation (P = 0.00147). The associations between HNSCC patient's outcome following cetuximab treatment and lncRNA-containing fusions or the CD274-PDCD1LG2 fusion deserve validation in prospective clinical trials.

Functional Genomics Uncover the Biology behind the Responsiveness of Head and Neck Squamous Cell Cancer Patients to Cetuximab.

PURPOSE: To identify the tumor portrait of the minority of head and neck squamous cell carcinoma (HNSCC) patients with recurrent-metastatic (RM) disease who upon treatment with platinum-based chemotherapy plus cetuximab present a long-lasting response. EXPERIMENTAL DESIGN: The gene expression of pretreatment samples from 40 HNSCC-RM patients, divided in two groups [14 long-progression-free survival (PFS) and 26 short-PFS (median = 19 and 3 months, respectively)], was associated with PFS and was challenged against a dataset from metastatic colon cancer patients treated with cetuximab. For biologic analysis, we performed functional and subtype association using gene set enrichment analysis, associated biology across all currently available HNSCC signatures, and inferred drug sensitivity using data from the Cancer Genomic Project. RESULTS: The identified genomic profile exhibited a significant predictive value that was essentially confirmed in the single publicly available dataset of cetuximab-treated patients. The main divergence between long- and short-PFS groups was based on developmental/differentiation status. The long-PFS patients are characterized by basal subtype traits such as strong EGFR signaling phenotype and hypoxic differentiation, further validated by the significantly higher association with the hypoxia metagene. The short-PFS patients presented a strong activation of RAS signaling confirmed in an in vitro model of two isogenic HNSCC cell lines sensitive or resistant to cetuximab. The predicted drug sensitivity for all four EGFR inhibitors was higher in long- versus short-PFS patients (P range: <0.0022-1e-07). CONCLUSIONS: Our data uncover the biology behind response to platinum-based chemotherapy plus cetuximab in RM-HNSCC cancer and may have translational implications improving treatment selection. Clin Cancer Res; 22(15); 3961-70. ©2016 AACRSee related commentary by Chau and Hammerman, p. 3710.

Bevacizumab treatment for vestibular schwannoma in a patient with neurofibromatosis type 2: hearing improvement and tumor shrinkage.

PURPOSE: Neurofibromatosis type 2 (NF2) is a dominantly inherited genetic condition that clinically manifests through the appearance of multiple meningiomas, ependymomas and bilateral vestibular schwannomas (acoustic neuromas) which lead to progressive hearing loss. Neovascularization is necessary for tumor growth and is driven by tumor-produced angiogenic factors such as vascular endothelial growth factor (VEGF). Bevacizumab is a humanized monoclonal antibody that neutralizes the activity of VEGF. Recent data have shown that VEGF is produced by schwannoma tumor cells. Bevacizumab treatment in patients with NF2 who were considered poor candidates for surgery and radiation therapy was found to result in clinically meaningful hearing improvement and tumor volume reduction in previous studies. METHODS: We report the case of a 40-year-old woman with sudden right-sided hearing loss. Magnetic resonance imaging (MRI) revealed multiple meningiomas and neurinomas (C2 and L5 lesions) and a right-sided acoustic neurinoma, confirming the diagnosis of NF2. Bevacizumab was given as infusion every 2 weeks at a dose of 5.0 mg/kg body weight with MRI monitoring every 6 months. RESULTS: After 6 months from the start of therapy the patient reported progressive improvement of hearing response in audiometry, word recognition and face-to-face conversation. MRI evidenced reduction of the volume of the right vestibular schwannoma and the multiple meningiomas as well as attenuation of brain stem compression. CONCLUSIONS: At the time of writing the patient is continuing treatment with bevacizumab without adverse events. She has good functional status and quality of life.