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Oropharyngeal squamous cell carcinoma (OPSCC) accounts for more than half of all head and neck cancers. Since the 1970s, OPSCC has shifted from an environmentally triggered to virally mediated disease due to a sharp rise in human papillomavirus (HPV)–related squamous cell carcinoma. Although a highly effective prophylactic vaccine is available, its current implementation is far below national targets, and OPSCC incidence is predicted to further increase by 2045. However, we believe that with prompt action now, we can not only defy these predictions but also effectively eradicate HPV-related OPSCC in these next 20 years. We herein provide an overview of the necessary elements to eliminate this disease: improved primary vaccine uptake, a 1-time universal vaccination effort, and implementation of novel therapeutics that have potential to cure existing disease. more...

Background Patients with advanced esophageal cancer carry poor prognoses; limited data exist to guide second-line therapy in the metastatic setting. Paclitaxel has been used yet is associated with limited efficacy. There is preclinical evidence of synergy between paclitaxel and cixutumumab, a monoclonal antibody targeting insulin-like growth factor-1 receptor. We conducted a randomized phase II trial of paclitaxel (arm A) versus paclitaxel plus cixutumumab (arm B) in the second-line for patients with metastatic esophageal or gastroesophageal junction (GEJ) cancers. Methods The primary endpoint was progression-free survival (PFS); 87 patients (43 in arm A, 44 in arm B) were treated. Results Median PFS was 2.6 months in arm A [90% CL 1.8-3.5] and 2.3 months in arm B [90% 2.0-3.5], P = .86. Stable disease was observed in 29 (33%) patients. Objective response rates for Arms A and B were 12% [90% CI, 5-23%] and 14% [90% CI, 6-25%]. Median overall survival was 6.7 months [90% CL 4.9-9.5] in arm A and 7.2 months [90% CL 4.9-8.1] in arm B, P = 56. Conclusion The addition of cixutumumab to paclitaxel in second-line therapy of metastatic esophageal/GEJ cancer was well tolerated but did not improve clinical outcomes relative to standard of care (ClinicalTrials.gov Identifier: NCT01142388). more...

signal to noise ratio plots for tumor, leukocyte and macrophage compartments

b2m expression range, multivariate analysis of pfs and os and association with response and disease control in Yale cohort

b2m expression range, multivariate analysis of pfs and os and association with response and disease control in Athens cohort

association of B2M mRNA expression with OS in the non-immunotherapy treated TCGA HNSCC ccohort

Kaplan-Meier survival curves for T1/2 and T3/4 tumors stratified by the expression of (A) EGFR and (B) HER2. Based on AQUA-expression scores.

Correlation between marker expression intensity and sample collection year. Corr. = correlation coefficient, A.U. = arbitrary unites.

Supplementary Table S1 (Excel file). TCGA datasets; Supplementary Table S2. CART cutoff points for each marker and the number of samples (N) in each category; Supplementary Table S3. Adjusted survival analysis; Supplementary Table S4. TCGA p16 expression data for HPV- and HPV+ HNSCC. more...

Supplementary Figure S1, Supplementary Figure S2 and Supplementary Table 1

(A) Western blots for the indicated protein markers after siRNA depletion, (B) representative high and low staining immunofluorescent microscopy images for each marker. CK = cytokeratin (epithelial tumor stain), DNA = DAPI stain, C = control siRNA (siGL2), IB = immunoblotting, scale bar = 100μm. more...

TCGA datasets.

EGFR signaling confers resistance to radiotherapy and is a validated target in head and neck squamous cell carcinoma (HNSCC). The inhibition of EGFR in combination with radiotherapy improves local control and overall survival in these patients; however, therapeutic resistance limits the efficacy of this approach. We therefore sought to identify cellular mechanisms that cause resistance to EGFR inhibition and radiotherapy in HNSCC. Though clonal isolation of carcinoma cells exposed to increasing concentrations of cetuximab, we found that resistant cells upregulate prosurvival ErbB3 and AKT signaling. Using EFM-19 cells and confirmatory analysis of protein levels, we demonstrate that cetuximab resistance is characterized by enhanced neuregulin expression identifying a novel adaptive mechanism of therapeutic resistance. Inhibition of this autocrine loop with CDX-3379 (an ErbB3 specific antibody) was sufficient to block ErbB3/AKT signaling in cetuximab resistant cells. The combination of CDX-3379 and cetuximab reduced proliferation and survival after radiotherapy in several HNSCC cell lines. These in vitro findings were confirmed in xenograft tumor growth experiments including an approach using growth factor–supplemented Matrigel. In vivo, the delivery of EGFR and ErbB3 antibodies significantly reduced tumor growth in cetuximab-resistant FaDu and CAL27 xenografts. In summary, this work demonstrates that autocrine NRG ligand secretion is a mechanism for therapeutic resistance to cetuximab and radiotherapy. This cross-resistance to both therapeutic modalities identifies NRG as an actionable therapeutic target for improving treatment regimens in HNSCC. more...

(A and B) KM survival curves specimens with (A) high EGFR stratified by wild type (WT) or amplified (AMP) CCND1, or cases with (B) low EGFR stratified by p16 mRNA expression (TCGA cohort), (C) correlation between medium CDK6 (M) or high CDK6 (H) mRNA expression and CCND1 expression. m = slope. mRNA data for 243 HPV- HNSCC samples (6) were downloaded using cBioportal (26, 27). Please also see Figure 4. more...

PDF file - 55K, Kaplan-Meier estimates of (a) overall survival, (b) progression-free survival by NRAS and ERK cluster status.

PDF file - 67K, Odds Ratio and Hazard Ratio (with 95% Confidence Interval) with A Unit Increase in the Form of log10 Transformation in AQUA Scores by Biomarker.

PDF file - 61K, Kaplan-Meier estimates of (a) overall survival, (b) progression-free survival by PIK3CA, NRAS, and PTEN cluster status.

PDF file - 53K, Kaplan-Meier estimates of (a) overall survival, (b) progression-free survival by PIK3CA, PTEN, and Akt cluster status.

Supplemental Table 1. Criteria for Unresectable Disease Supplemental Table 2. Modified RECIST Criteria for Head and Neck Cancer. Supplemental Table 3. Summary of Serum Analyte Levels. Supplemental Figure 1. Study Schematic Supplemental Figure 2. Time to locoregional failure for all eligible and treated patients (a) and by tumor HPV status (b). Log rank test comparing time to failure for HPV+ versus HPV- p value provided. Supplemental Figure 3. Representative tissue cores with high or low expression levels of XPF or ERCC1 as assessed by AQUA. Tumors were stained for cytokeratin (CK) to create a tumor mask and with DAPI to define the nuclear compartment. Supplemental Figure 4. Representative tumor IHC molecular correlates ERCC1, XPF and MET. more...

Background: We hypothesized that a serum proteomic profile predictive of survival benefit in non–small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) reflects tumor EGFR dependency regardless of site of origin or class of therapeutic agent.Methods: Pretreatment serum or plasma from 230 patients treated with cetuximab, EGFR-TKIs, or chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC) were analyzed by mass spectrometry. Each sample was classified into “good” or “poor” groups using VeriStrat, and survival analyses of each cohort were done based on this classification. For the CRC cohort, this classification was correlated with the tumor EGFR ligand levels and KRAS mutation status.Results: In the EGFR inhibitor–treated cohorts, the classification predicted survival (HNSCC: gefitinib, P = 0.007 and erlotinib/bevacizumab, P = 0.02; CRC: cetuximab, P = 0.0065) whereas the chemotherapy cohort showed no survival difference. For CRC patients, tumor EGFR ligand RNA levels were significantly associated with the proteomic classification, and combined KRAS and proteomic classification provided improved survival classification.Conclusions: Serum proteomic profiling can detect clinically significant tumor dependence on the EGFR pathway in non–small cell lung cancer, HNSCC, and CRC patients treated with either EGFR-TKIs or cetuximab. This classification is correlated with tumor EGFR ligand levels and provides a clinically practical way to identify patients with diverse cancer types most likely to benefit from EGFR inhibitors. Prospective studies are necessary to confirm these findings. Cancer Epidemiol Biomarkers Prev; 19(2); 358–65 more...

PDF file - 64K, Summary of Biomarker AQUA Scores at Baseline.

List of Supplemental Materials: Supplemental Table 1. Criteria for Unresectable Disease Supplemental Table 2. Modified RECIST Criteria for Head and Neck Cancer. Supplemental Table 3. Summary of Serum Analyte Levels. Supplemental Figure 1. Study Schematic Supplemental Figure 2. Time to locoregional failure for all eligible and treated patients (a) and by tumor HPV status (b). Log rank test comparing time to failure for HPV+ versus HPV- p value provided. Supplemental Figure 3. Representative tissue cores with high or low expression levels of XPF or ERCC1 as assessed by AQUA. Tumors were stained for cytokeratin (CK) to create a tumor mask and with DAPI to define the nuclear compartment. Supplemental Figure 4. Representative tumor IHC molecular correlates ERCC1, XPF and MET. more...

PDF file - 65K, REMARK Flow Chart of E2303 translational research study.

Purpose: We sought to evaluate the correlation between tissue biomarker expression (using standardized, quantitative immunofluorescence) and clinical outcome in the E2303 trial.Experimental Design: Sixty-three eligible patients with operable stage III/IV head and neck squamous cell cancer (HNSCC) participated in the Eastern Cooperative Oncology Group (ECOG) 2303 phase II trial of induction chemotherapy with weekly cetuximab, paclitaxel, and carboplatin followed by chemoradiation with the same regimen. A tissue microarray (TMA) was constructed and EGF receptor (EGFR), ERK1/2, Met, Akt, STAT3, β-catenin, E-cadherin, EGFR Variant III, insulin-like growth factor-1 receptor, NF-κB, p53, PI3Kp85, PI3Kp110a, PTEN, NRAS, and pRb protein expression levels were assessed using automated quantitative protein analysis (AQUA). For each dichotomized biomarker, overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) were estimated by the Kaplan–Meier method and compared using log-rank tests. Multivariable Cox proportional hazards models were used to estimate HRs and test for significance.Results: Forty-two of 63 patients with TMA data on at least one biomarker were included in the biomarker analysis. Tumor extracellular signal–regulated kinase (ERK)1/2 levels were significantly associated with PFS [HR (low/high), 3.29; P = 0.026] and OS [HR (low/high), 4.34; P = 0.008]. On multivariable Cox regression analysis, ERK1/2 remained significantly associated with OS (P = 0.024) and PFS (P = 0.022) after controlling for primary site (oropharynx vs. non-oropharynx) and disease stage (III vs. IV), respectively. Clustering analysis revealed that clusters indicative of activated RAS/MAPK/ERK and/or PI3K/Akt pathways were associated with inferior OS and/or PFS and maintained significance in multivariable analysis.Conclusions: These results implicate PI3K/Akt and RAS/MAPK/ERK pathways in resistance to cetuximab-containing chemoradiation in HNSCC. Large prospective studies are required to validate these results. Clin Cancer Res; 20(11); 3023–32. ©2014 AACR. more...

Purpose: Treatment with cisplatin or cetuximab combined with radiotherapy each yield superior survival in locally advanced squamous cell head and neck cancer (LA-SCCHN) compared with radiotherapy alone. Eastern Cooperative Oncology Group Trial E3303 evaluated the triple combination.Experimental Design: Patients with stage IV unresectable LA-SCCHN received a loading dose of cetuximab (400 mg/m2) followed by 250 mg/m2/week and cisplatin 75 mg/m2 q 3 weeks ×3 cycles concurrent with standard fractionated radiotherapy. In the absence of disease progression or unacceptable toxicity, patients continued maintenance cetuximab for 6 to 12 months. Primary endpoint was 2-year progression-free survival (PFS). Patient tumor and blood correlates, including tumor human papillomavirus (HPV) status, were evaluated for association with survival.Results: A total of 69 patients were enrolled; 60 proved eligible and received protocol treatment. Oropharyngeal primaries constituted the majority (66.7%), stage T4 48.3% and N2-3 91.7%. Median radiotherapy dose delivered was 70 Gy, 71.6% received all three cycles of cisplatin, and 74.6% received maintenance cetuximab. Median PFS was 19.4 months, 2-year PFS 47% [95% confidence interval (CI), 33%–61%]. Two-year overall survival (OS) was 66% (95% CI, 53%–77%); median OS was not reached. Response rate was 66.7%. Most common grade ≥3 toxicities included mucositis (55%), dysphagia (46%), and neutropenia (26%); one attributable grade 5 toxicity occurred. Only tumor HPV status was significantly associated with survival. HPV was evaluable in 29 tumors; 10 (all oropharyngeal) were HPV positive. HPV+ patients had significantly longer OS and PFS (P = 0.004 and P = 0.036, respectively).Conclusions: Concurrent cetuximab, cisplatin, and radiotherapy were well tolerated and yielded promising 2-year PFS and OS in LA-SCCHN with improved survival for patients with HPV+ tumors. Clin Cancer Res; 20(19); 5041–51. ©2014 AACR. more...

Understanding the prevalence of guideline non-adherence among patients with advanced head and neck cancer (HNC) and its impact on survival may facilitate increased adherence. Our objective was to perform a detailed analysis of overall National Comprehensive Care Network (NCCN) guideline adherence in a national cohort.Using the National Cancer Database, we analyzed site-specific NCCN guideline adherence for treatment of 100,074 overall stage III and IVA HNC patients from 2004 to 2013. Main outcomes were guideline adherence rates and overall survival (OS). Adherence was categorized by treatment: surgery/ radiation. Reasons were categorized as: (1) high risk; (2) refusal; (3) not planned.After exclusion, the care of 25,620 patients was defined as non-adherent (25.6%), yet adherence rates significantly improved across the study's years. After multivariate analysis, non-adherence was associated with age ≥ 65, female gender, black race, comorbidity score ≥ 1, insurance status, clinical staging, primary site, and facility type. Patients not managed according to NCCN guidelines had a significantly reduced OS compared with patients treated on-guideline (hazard ratio (HR) = 1.51 (95 %CI 1.48-1.54), p 0.001). 'Not planned' patients had reduced OS when compared to adherent patients (HR = 1.27 (95 %CI 1.23-1.30), p 0.001). Off-guideline treated patients due to 'risk factors' had a decrease in overall survival (OS) compared with other reasons (p 0.001 for all).Despite improvement over time, non-adherence to NCCN guidelines for advanced stage HNC remains high. Non-adherence is associated with decreased OS, regardless of the reason. Despite concerns from both patient and physician, efforts should be made to increase guideline awareness and adherence. more...

Approximately 3% to 9% of head and neck cancer presents with a metastatic node and no identifiable primary tumor. These cases of head and neck carcinoma of unknown primary (HNCUP) present a therapeutic challenge. Therapy of this disease varies based on factors such as institutional, surgeon, and patient preference. Evidence demonstrating the outcomes associated with these therapies for HNCUP is limited, and among the available series, the tumor human papillomavirus (HPV) status is often ignored. Treatment deintensification has been proposed for a subset of these patients. We aim to evaluate the treatment-related outcomes for HPV-associated and HPV-negative HNCUP.A retrospective study of 978 adult HNCUP diagnosed from 2010 to 2013 in the NCDB was conducted. Multivariate Cox survival regressions as well as univariate Kaplan-Meier analyses were conducted.Patients with HPV-associated disease had superior survival, with a 3-year survival of 94.8% (standard error [SE]: 1.0), compared with 80.3% (SE: 2.9) among those with HPV-negative disease. Among HPV-negative patients with clinical nodal classification (cN)2/cN3 disease, treatment with definitive radiotherapy alone compared to definitive chemoradiotherapy was associated with diminished survival (hazard ratio 5.507, P = 0.005). Among patients with HPV-associated cancer and cN2/cN3 disease, all treatments (surgery alone, surgery with adjuvant radiotherapy, surgery with adjuvant chemoradiotherapy, definitive chemoradiotherapy, definitive radiotherapy) resulted in statistically equivalent survival.Tumor HPV status has a significant prognostic value for HNCUP and should be considered in future studies of treatment deintensification in this group. Treatment deintensification to radiotherapy alone in cN2/cN3 cases may result in poorer patient survival for HPV-negative patients, whereas it may be a promising option for further investigation in HPV-positive patients.4 Laryngoscope, 129:684-691, 2019. more...

Extranodal (or extracapsular) extension (ENE) is an adverse prognostic factor in patients with head and neck cancers who undergo primary surgery. However, the significance of ENE in human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is not well established, and single-institution studies have not established that ENE predicts inferior outcome. The authors investigated the prognostic value of ENE in HPV-positive patients who underwent primary surgery and whether adjuvant chemoradiation improved overall survival (OS) compared with radiation alone in ENE-positive patients.Patients who underwent primary surgery for pathologic T1 (pT1) through pT4 tumors, pathologic N1 (pN1) through pN3 lymph node status, HPV-positive OPSCC were identified in the National Cancer Data Base from 2010 through 2012. Features associated with ENE were analyzed. Univariable and multivariable Cox regression analyses identified predictors of OS. The effect of adjuvant treatment on OS in ENE-positive cohort was also evaluated.In total, 1043 patients met inclusion criteria, among whom 43.5% were ENE-positive. Of the ENE-positive patients who had treatment details available, 72% received concurrent chemoradiotherapy, 16% received radiotherapy, and 12% received no adjuvant treatment. After a median follow-up of 28.4 months, ENE was associated with worse 3-year OS (89.3% vs 93.6%; P = .01). On multivariable analysis that included involved lymph nodes, only ENE, lymphovascular invasion, pT3/pT4 tumors, and Charlson-Deyo score were associated with worse OS. Among ENE-positive patients, there was no difference in 3-year OS between those who received adjuvant concurrent chemoradiotherapy versus radiotherapy alone (89.6% vs 89.3%, respectively; P = .55). Propensity score-matched comparison revealed similar results.ENE is associated with inferior OS in patients with HPV-positive OPSCC. However, OS was not better with adjuvant chemoradiotherapy compared with radiotherapy alone in ENE-positive patients. The current findings support the need for prospective studies of adjuvant chemoradiation in HPV-positive patients with ENE. Cancer 2017;123:2762-72. © 2017 American Cancer Society. more...

Prognostic lymph node yield thresholds have been identified and incorporated into treatment guidelines for multiple cancer sites, but not for oral cancer. The objective of this study was to identify optimal thresholds in elective and therapeutic neck dissection for oral cavity cancers.Patients with oral cavity cancers in the National Cancer Database (NCDB) were stratified into clinically lymph node-negative (cN0) and clinically lymph node-positive (cN+) cohorts to reflect the differing surgical management for these diseases. Univariate and multivariate analyses were performed to assess the relation between lymph node yield and overall survival, adjusting for other prognostic factors. Thresholds derived from the NCDB were validated in the Surveillance, Epidemiology, and End Results database.In patients with cN0 cancers of the oral cavity from the NCDB, those who had16 lymph nodes had significantly decreased survival. The proportion of positive lymph nodes was higher for patients who had ≥16 lymph nodes (27.2% vs 16.3% for 16 lymph nodes; P .001). This threshold was validated in 2715 lymph node-negative cancers from SEER, with a mortality hazard ratio of 0.825 for ≥ 16 lymph nodes (95% confidence interval, 0.764-0.950; P = .004). In patients with cN + oral cavity cancers from the NCDB, groups with26 lymph nodes had significantly decreased survival. This threshold was validated in 1903 lymph node-positive cancers from SEER, with a mortality hazard ratio of 0.791 (95% confidence interval, 0.692-0.903; P = .001). Academic centers, higher volume centers, and geographic location predicted higher lymph node yields.More extensive neck dissection (≥16 lymph nodes in cN0, ≥ 26 lymph nodes in cN+) was associated with better survival. Further evaluation of practice patterns in lymph node yield may represent an opportunity for improved quality of care. Cancer 2016;122:3624-31. © 2016 American Cancer Society. more...

The current study was performed to characterize trends and survival outcomes for chemotherapy in the definitive and adjuvant treatment of hypopharyngeal cancer in the United States.A total of 16,248 adult patients diagnosed with primary hypopharyngeal cancer without distant metastases between 1998 and 2011 were identified in the National Cancer Data Base. The association between treatment modality and overall survival was analyzed using Kaplan-Meier survival curves and 5-year survival rates. A multivariate Cox regression analysis was performed on a subset of 3357 cases to determine the treatment modalities that predict improved survival when controlling for demographic and clinical factors.There was a significant increase in the use of chemotherapy with radiotherapy both as definitive treatment (P.001) and as adjuvant chemoradiotherapy with surgery (P=.001). This was accompanied by a decrease in total laryngectomy/pharyngectomy rates (P.001). Chemoradiotherapy was associated with improved 5-year survival compared with radiotherapy alone in the definitive setting (31.8% vs 25.2%; log rank P.001). Similarly, in multivariateanalysis, definitive radiotherapy was found to be associated with compromised survival compared with definitive chemoradiotherapy (hazard ratio, 1.51; P.001).Survival analysis revealed that overall 5-year survival rates were higher for chemoradiotherapy compared with radiotherapy alone in the definitive setting, but were comparable between surgery with chemoradiotherapy and surgery with radiotherapy. Cancer 2016;122:1853-60. © 2016 American Cancer Society. more...

BACKGROUND Measures of vascular endothelial growth factor (VEGF) expression in pancreatic cancer typically have been qualitative or semiquantitative. The objective of this study was to use a series of algorithms called AQUA that quantitatively assesses protein expression on tissue microarrays (TMAs) to compare in situ expression of VEGF and its primary receptors, VEGF receptor 1 (FLT-1) and VEGF receptor 1 (FLK-1), on a pancreatic cancer TMA. METHODS TMAs were constructed by arraying 1.5-mm cores from 76 samples of pancreatic adenocarcinoma (1996-2002) that were obtained from the archives of the Yale Department of Pathology. The staining for AQUA was similar to standard immunohistochemistry and involved antigen retrieval and the application of primary antibodies, but with epifluorescence detection. Slides were counterstained with 4′,6-diamidino-2-phenylindole for nuclear visualization and cytokeratin for membrane visualization. The primary antibodies used were VEGF, FLT-1, FLK-1, and cytokeratin. RESULTS Disease stage was highly prognostic for outcome, as expected. Total amounts of VEGF and its receptors were assessed within the tumor mask and were divided into quartiles. Kaplan–Meier survival curves showed that VEGF and FLK-1 were not associated clearly with outcome. However, the expression of FLT-1 was correlated significantly, and the patients who had tumors with the lowest expression FLT-1 levels had the worst survival (P = .0038). In multivariate analysis, FLT-1 expression was an independent prognostic factor for overall survival (P = .0044). CONCLUSIONS VEGF and its 2 principal receptors were expressed to varying degrees in tumors of the pancreas. A significant association was found between low expression of FLT-1 and both poor prognosis and advanced stage, suggesting that tumor expression of this VEGF receptor is a marker of less aggressive disease. Cancer 2006. © 2006 American Cancer Society. more...

These NCCN Guidelines Insights focus on nutrition and supportive care for patients with head and neck cancers. This topic was a recent addition to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers. The NCCN Guidelines Insights focus on major updates to the NCCN Guidelines and discuss the new updates in greater detail. The complete version of the NCCN Guidelines for Head and Neck Cancers is available on the NCCN Web site (NCCN.org). more...