Prognosis Of Head And Neck Squamous Cell Carcinoma Research Articles

MicroRNA-Related Genetic Variants Associated with Survival of Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is commonly diagnosed at an advanced stage, and prognosis for such patients is poor. There remains a gap in our understanding of genetic variants related with HNSCC prognosis. miRNA-related single nucleotide polymorphisms (miR-SNPs) are a class of genetic variants with gene-regulatory potential. We used a genome-scale approach and independent patient populations in a two-stage approach to test 40,286 common miR-SNPs for association with HNSCC survival in the discovery population (n = 847), and selected the strongest associations for replication in validation phase cases (n = 1,236). Furthermore, we leveraged miRNA interaction databases and miRNA expression data from The Cancer Genome Atlas, to provide functional insight for the identified and replicated associations. Joint population analyses identified novel miR-SNPs associated with overall survival in oral and laryngeal cancers. rs1816158, located within long noncoding RNA MIR100HG, was associated with overall survival in oral cavity cancer (HR, 1.56; 95% confidence interval (CI), 1.21-2.00). In addition, expression of MIR100HG-embedded miRNA, miR-100, was significantly associated with overall survival in an independent cohort of HNSCC cases (HR, 1.25; 95% CI, 1.06-1.49). A SNP in the 3'UTR of SH3BP4 (rs56161233) that overlaps predicted miRNA-binding sites and is predicted to disrupt several miRNA-mRNA interactions was associated with overall survival of laryngeal cancer (HR, 2.57; 95% CI, 1.71-3.86). This work reveals novel miR-SNPs associated with HNSCC survival, and utilizes miRNA-mRNA interaction and expression data to provide functional support for these associations. These findings extend our understanding of how genetic variation contributes to HNSCC survival, and may contribute to future prognostic models for improved risk stratification.

Identification of novel methylated DNA marker ZNF569 for head and neck squamous cell carcinoma.

Aberrant DNA methylation pattern plays an indispensable role in the initiation and development of head and neck squamous cell carcinoma (HNSCC). It is well recognized that lymph node metastasis is closely with unfavorable prognosis of HNSCC. Therefore, exploring the methylation events accounting for the lymph node metastasis of HNSCC is very important for improving the clinical outcome of HNSCC. Methylation data, RNA-seq data and clinical data were downloaded from The Cancer Genome Atlas (TCGA) and processed using the R package TCGA-Assembler. MethylMix was use for data analysis by integrating both methylation and gene expression data on HNSCC patients with lymph node metastasis and without lymph node metastasis. Pathway analysis was performed on significantly altered genes using ConsensusPathDB. The role of our interested gene zinc figure protein 569 (ZNF569) in HNSCC was further evaluated. Our results identified many novel hypermethylated/hypomethylated genes that might be closely associated with the lymph node metastasis of HNSCC. Pathway analysis revealed that increase in methylation of genes involved in generic transcription pathway including zinc figure proteins. ZNF569 was hypermethylated in HNSCC tissues especially those with lymph node metastasis. In addition, the expression levels of ZNF569 mRNA and protein were significantly lower in HNSCC tissues and cell lines compared to their respective controls. Moreover, overexpression of ZNF569 inhibited the proliferation, migration and invasion of HNSCC cells. HNSCC patients with lower ZNF569 expression suffered a significantly shorter overall survival than those with higher ZNF569 expression. In conclusion, we have identified many novel differentially methylated genes that might be important for the lymph node metastasis of HNSCC. In addition, ZNF569 might play a tumor suppressive role in carcinogenesis of HNSCC.

Prognostic and clinicopathological significance of CTTN/cortactin alterations in head and neck squamous cell carcinoma: Systematic review and meta-analysis.

To evaluate the prognostic significance of CTTN/cortactin alterations in head and neck squamous cell carcinoma (HNSCC). We searched PubMed, Embase, Web of Science, and Scopus for studies published before May 2018. We conducted a meta-analysis to quantify the impact of CTTN/cortactin alterations on clinicopathological and survival variables. Eighteen studies (1633 patients) met inclusion criteria. Quantitative evaluation revealed a strong association of CTTN/cortactin alterations with N+ status (P < .001), higher T status (P < .001), advanced clinical stage (P < .001), high histological grade (P = .001), and lower overall survival (OS) (P < .001). We found heterogeneity in T status, histological grade, and OS and observed small-study effects on N status and OS. In subgroup analyses, a significant association of CTTN amplification and cortactin overexpression with the above variables was preserved. The strongest association between CTTN/cortactin alterations and a worse outcome was observed in the subgroups of Asian patients and pharyngolaryngeal squamous cell carcinomas. CTTN/cortactin alterations should be evaluated to predict the HNSCC prognosis.

Impact of tumor budding in head and neck squamous cell carcinoma: A meta-analysis.

Tumor budding (TB) has been suggested as an adverse prognostic factor in head and neck squamous cell carcinoma (HNSCC). This meta-analysis evaluated the prognostic role of TB in HNSCC. We systematically reviewed the literatures of electronic databases and performed a meta-analysis to address the impact of TB on prognosis in HNSCC. Published data were extracted and organized. Then, pooled odds ratios for lymph node metastasis (LNM) and hazard ratios for survival were calculated by using the Mantel-Haenszel fixed effect model. The results showed that high TB was significantly associated with LNM and worse survival in patients with HNSCC. Moreover, high TB was also correlated with poor prognosis in patients with cT1-2N0 oral squamous cell carcinoma. TB is a promising prognostic factor associated with LNM and worse survival, which should be included in the routine pathological examination of HNSCC.

High expression of ACTL8 is poor prognosis and accelerates cell progression in head and neck squamous cell carcinoma.

Actin-like protein 8 (ACTL8) is a member of the cancer-testis antigens (CTA) family, which is mainly localized in the cytoplasm and generally expressed in the testis. The association between ACTL8 and various types of cancer, including glioblastoma and breast cancer, has previously been demonstrated. However, whether ACTL8 is involved in the development of head and neck squamous cell carcinoma (HNSCC) remains unknown. In the present study, the expression of ACTL8 in patients with HNSCC was analyzed in The Cancer Genome Atlas (TCGA) dataset, clinical tissues and cell lines. Correlations between the expression levels of ACTL8 and HNSCC clinical outcomes were analyzed with the Kaplan-Meier method and the Cox proportional hazards model. Cell Counting Kit-8, plate colony formation and Transwell assays were used to assess the effects of ACTL8 interference on the proliferation, migration and invasion of HNSCC PCI-13 cells. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to evaluate the expression levels of ACTL8 in PCI-13 cells. Furthermore, alterations in the expression levels of key proteins in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/RAC-α protein kinase B (AKT) signaling pathway were determined by western blotting. Increased expression of ACTL8 in HNSCC was observed in TCGA dataset, cancerous tissue samples and HNSCC cell line. Cox regression analysis indicated that ACTL8 expression could be regarded as an independent prognostic factor for HNSCC, since increased expression of ACTL8 was associated with a poor prognosis. Knocking down ACTL8 markedly inhibited the proliferation, invasion and migration of PCI-13 cells. Additionally, activation of the PI3K/AKT signaling pathway was suppressed by reduced expression levels of certain key proteins in this pathway. The present data indicate that ACTL8 serves a role in the progression and clinical prognosis of HNSCC. Therefore, ACTL8 may be a potential prognostic marker and novel therapeutic target for HNSCC.

A three-lncRNA expression signature predicts survival in head and neck squamous cell carcinoma (HNSCC).

Increasing evidence has shown that long non-coding RNAs (lncRNAs) have important biological functions and can be used as a prognostic biomarker in human cancers. However, investigation of the prognostic value of lncRNAs in head and neck squamous cell carcinoma (HNSCC) is in infancy. In the present study, we analyzed the lncRNA expression data in a large number of HNSCC patients (n=425) derived from The Cancer Genome Atlas (TCGA) to identify an lncRNA expression signature for improving the prognosis of HNSCC. Three lncRNAs are identified to be significantly associated with survival in the training dataset using Cox regression analysis. Three lncRNAs were integrated to construct an lncRNA expression signature that could stratify patients of training dataset into the high-risk group and low-risk group with significantly different survival time (median survival 1.85 years vs. 5.48 years; P=0.0018, log-rank test). The prognostic value of this three-lncRNA signature was confirmed in the testing and entire datasets, respectively. Further analysis revealed that the prognostic power of three-lncRNA signature was independent of clinical features by multivariate Cox regression and stratified analysis. These three lncRNAs were significantly associated with known genetic and epigenetic events by means of functional enrichment analysis. Therefore, our results indicated that the three-lncRNA expression signature can predict HNSCC patients’ survival.

Co-expression of XIAP and CIAP1 Play Synergistic Effect on Patient’s Prognosis in Head and Neck Cancer

To explore the influence of chemotherapy on prognosis of Head and Neck Squamous Cell Carcinoma (HNSCC) and the relationship between XIAP and CIAP1 co-expression and the prognosis in HNSCC. 129 patients were recruited in our study, they were divided into two groups, neoadjuvant group (n = 60) and non-neoadjuvant group (n = 69). Expression level of XIAP and CIAP1 were examed in neoadjuvant group, and was correlated with clinical outcomes of the patients. The unselected patients were not benefit from neoadjuvant chemotherapy. Moreover, the patients whose tumors co-express high level of XIAP and CIAP1 presented poorer overall and disease-free survival rates than those whose tumors co-express low level of XIAP and CIAP1 (overall survival P < 0.001, disease-free survival P < 0.001). Our results validate that individual chemotherapy is important for HNSCC, and co-expression of XIAP and CIAP1 prompted a worse prognosis.

A Prognostic 5-lncRNA Expression Signature for Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a common malignant cancer that accounts for 5–10% of all cancers. This study aimed to identify essential genes associated with the prognosis of HNSCC and construct a powerful prognostic model for the risk assessment of HNSCC. RNAseq expression profile data for the patients with HNSCC were obtained from the TCGA database (GEO). A total of 500 samples with full clinical following-up were randomly divided into a training set and a validation set. The training set was used to screen for differentially expressed lncRNAs. Single-factor survival analysis was performed to obtain lncRNAs that associated with prognosis. A robust likelihood-based survival model was constructed to identify the lncRNAs that are essential for the prognosis of HNSCC. A co-expression network between genes and lncRNAs was also constructed to identify lncRNAs co-expressed with genes to serve as the final signature lncRNAs for prognosis. Finally, the prognostic effect of the signature lncRNAs was tested by multi-factor survival analysis and a scoring model for the prognosis of HNSCC was constructed. Moreover, the results of the validation set and the relative expression levels of the signature lncRNAs in the tumour and the adjacent tissue were consistent with the results of the training set. The 5 lncRNAs were distributed among 3 expression modules. Further KEGG pathway enrichment analysis showed that these 3 co-expressed modules participate in different pathways, and many of these pathways are associated with the development and progression of disease. Therefore, we proposed that the 5 validated lncRNAs can be used to predict the prognosis of HNSCC patients and can be applied in postoperative treatment and follow-up.

Molecular features of head and neck squamous cell carcinoma

Relevance.To identify new markers of early diagnosis and prognosis of head and neck squamous cell carcinoma (HNSCC) it is necessary to study the molecular features of this disease.Purpose.The aim of the study was to analyze blood serum protein spectrum in patients with HNSCC and in healthy volunteers using the methods of mass spectrometry and to evaluate the selected serum protein markers as candidates for early detection of HNSCC.Materials and Methods: The blood serum of HNSCC patients before therapy with metastases, without metastases and healthy volunteers was studied by proteomic methods. Validation of the results of proteomic analysis was carried out by ELISA in serum of 52 patients with HNSCC (T1-4N0-3M0), 10 patients with chronic hyperplastic laryngitis, dysplasia DII-DIII and 10 healthy volunteers. The statistical analysis was carried out using Statistica 6.0. Software package.Results.Blood serum proteome of HNSCC patients with metastases, without metastases and healthy volunteers are different and contain proteins of different classes. Adenylyl cyclase-associated protein 1 (CAP1) and protein phosphatase 1B (PPM1B) were selected to validate the obtained results. It was shown that the serum level of CAP1 and PPM1B differed in control and dysplasia groups and dysplasia and cancer groups (p ≤ 0,05). In patients with HNSCC (T1N0M0) the serum CAP1 and PPM1B levels were higher than in patients with dysplasia and healthy individuals (p ≤ 0,05). It was noted the positive correlation of the CAP1 level in the serum with the presence of metastases and the PPM1B level.Conclusion.Candidates for serum markers of HNSCC prognosis were identified. The difference in serum levels of CAP1 and PPM1B depending on the prevalence of primary tumors and the difference in serum level of CAP1 depending on the presence of regional metastases was shown. Determination of CAP1 level in the serum can be useful for early diagnosis and prognosis of HNSCC.

Predictive Value of the Pretreatment Neutrophil-to-Lymphocyte Ratio in Head and Neck Squamous Cell Carcinoma.

This study assessed the significance of the neutrophil-to-lymphocyte ratio (NLR) in head and neck squamous cell carcinoma (HNSCC), and the relationships of the NLR with the aldehyde dehydrogenase 1 (ALDH1) level in tumors and the proportion of myeloid-derived suppressor cells (MDSCs) in the peripheral circulation. In total, 227 HNSCC patients who had received curative treatment at our hospital were enrolled into the present study. The NLR of each HNSCC patient before treatment was calculated. The associations of NLR with various clinicopathological parameters and prognoses were then examined. In addition, correlations between the proportion of MDSCs and level of ALDH1 with the NLR were assessed. Our data revealed that an elevated NLR was significantly correlated with the risk of developing locoregional recurrence and with a reduced overall survival in HNSCC patients. Multivariate analyses revealed that the NLR pretreatment and surgical resection were significantly correlated with the rate of treatment failure and the overall survival rate in HNSCC patients. Furthermore, the levels of ALDH1 in tumors and MDSCs in the peripheral circulation were significantly correlated with the prognosis of HNSCC, and the NLR was positively correlated with MDSC levels in the circulation and ALDH1 staining intensity in tumor specimens. In conclusion, the NLR has power in predicting the expression of ALDH1 in tumors, the circulating level of MDSCs, and the prognosis in HNSCC. We suggest that the NLR is an important biomarker that can assist the clinician and patient in making informed decisions regarding treatment options for HNSCC patients.

Platelet count and platelet-lymphocyte ratio as prognostic markers for head and neck squamous cell carcinoma: Meta-analysis.

Thrombocytosis is associated with the prognosis of various types of cancer. The purpose of this study was to quantify the prognostic impact of platelet count and platelet-lymphocyte ratio (PLR) in head and neck squamous cell carcinoma (HNSCC). We systematically searched electronic databases and identified articles reporting an association between platelet count or PLR and HNSCC prognosis. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) were extracted, and the pooled HRs were estimated using random effect models. Eight studies that enrolled 4096 patients and 9 studies that enrolled 2327 patients were included in the platelet count and PLR analyses, respectively. A platelet count greater than the cutoff value was associated with poor OS (HR 1.81; 95% CI 1.16-2.82) and any PLR greater than the cutoff value was associated with poor OS (HR 1.64; 95% CI 1.13-2.37). Elevated platelet count and PLR are associated with poor prognosis in patients with HNSCC.

SLC5A12 is a prognostic marker in head and neck squamous cell carcinoma

Background: Solute carrier family 5 (sodium/monocarboxylate cotransporter) member 12 (SLC5A12) is a low-affinity sodium-coupled lactate transporter. Tumor cells are known to selectively upregulate nutrient transporters such as lactate transporters to support their rapid growth. The goal of this study was to measure SLC5A12 levels in head and neck squamous cell carcinoma (HNSCC) and explores the association of SLC5A12 expression and prognosis in HNSCC.

SLC5A12 is a prognostic marker in head and neck squamous cell carcinoma

Background: Solute carrier family 5 (sodium/monocarboxylate cotransporter) member 12 (SLC5A12) is a low-affinity sodium-coupled lactate transporter. Tumor cells are known to selectively upregulate nutrient transporters such as lactate transporters to support their rapid growth. The goal of this study was to measure SLC5A12 levels in head and neck squamous cell carcinoma (HNSCC) and explores the association of SLC5A12 expression and prognosis in HNSCC. Methods: We determined the expression levels of SCL5A12 mRNA in HNSCC tissues and adjacent normal tissues by quantitative reverse transcription PCR and SLC5A12 protein expression by western blot and tissue microarray immunohistochemistry. SLC5A12 expression was analyzed using UALCAN online resources. Results: SCL5A12 mRNA and protein levels were significantly higher in HNSCC tissues than in adjacent normal tissues. High SCL5A12 protein levels were also associated with lymph node metastasis and higher clinical staging. Conclusions: We conclude that SCL5A12 is a potential indicator for HNSCC development and progression, and that detection of its expression could be a useful independent marker of HNSCC prognosis in the Chinese population.

Abstract 4278: Somatic MAPK pathway mutations are associated with high mutational burden and good survival in head and neck squamous cell carcinoma (HNSCC)

Abstract Somatic mutations of the MAPK pathway occur in ~14% of head and neck squamous cell carcinoma (HNSCC; TCGA Provisional; www.cbioportal.org). Notably, mutations found in MAPK signaling components are apparent hotspot or activating mutations, potentially driving activation of the MAPK pathway. These mutations include HRAS p.G12V/D/A/C/S &amp; p.G13V/R, MAPK1 p.E322K/*, BRAF p.D594N &amp; p.V600E mutations. We found that this MAPK pathway mutated subset of HNSCC tumors have a higher mutational burden than MAPK-wildtype (WT) tumors. The average rate of non-synonymous mutations in MAPK pathway mutated tumors is 265.1±42.84 mutation/tumor vs 143.5±5.83 mutation/tumor in WT tumors in the TCGA cohort (P=0.0005). MAPK pathway mutations are not associated with HPV positivity (P=0.5815). Subsequent analysis shows that this subset of MAPK pathway-mutated tumors is unexpectedly associated with TP53 wildtype status (P=0.005584), as well as CASP8 mutations [29.3%; 27/92 cases vs. a 6.5% rate (27/418 cases) in the MAPK pathway WT group; P=9.91 x10-9]. Based on the current survival data of the TCGA Provisional cohort, it appears that patients whose tumors bearing HRAS, BRAF, MAPK1, MAP2K1, and RPS6KA1 mutations have a long median survival of 7.94 years (95.3 months; P=0.0165) vs. patients without these somatic mutations. Though TP53 WT status is a well-recognized biomarker for good prognosis in HNSCC, it only predicts with a median survival of ~45.8 months in this very same cohort. Thus, our findings suggest that MAPK pathway mutations may serve as potential genomic biomarkers for good prognosis in HNSCC. Recently, both HRAS and MAPK1 hotspot mutations have been shown to serve as potential neo-antigens in cervical cancer. Further investigation is needed to determine if these somatic MAPK pathway mutations are capable of mounting an anti-cancer immunity (via hotspot neo-antigens or neo-antigens due to higher mutational burden per se) in these patients, which may contribute to their improved survival. Acknowledgements: VWYL received funding supports from the Research Grant Council, Hong Kong (General Research Fund: #1711484, #17121616; Theme-based Research: T12-401/13-R) and the Hong Kong Cancer Fund, Hong Kong. Citation Format: Hoi-Lam Ngan, Andrew Y. Fong, Sharon Chan, Shing Chun Yu, Laura R. H. Ip, Jennifer R. Grandis, Vivian Lui. Somatic MAPK pathway mutations are associated with high mutational burden and good survival in head and neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4278.

Abstract 5332: Prognostic value of aberrant promoter hypermethylation of tumor-related genes in early-stage head and neck cancer

Abstract Staging and pathological grading are useful, but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). Accordingly, molecular biomarkers that predict the risk of recurrence are necessary to improve clinical outcomes. The ability to distinguish between low- and high-risk HNSCCs at an early stage may reduce follow-up costs. We hypothesized that the quantitative methylation specific PCR (Q-MSP) assay could be used to define patterns of DNA methylation that differentiate low- and high-risk HNSCCs. The methylation statuses of the promoters of 11 tumor-related genes (p16, RASSF1A, E-cadherin, H-cadherin, MGMT, DAPK, DCC, COL1A2, TAC1, SST, and GALR1) were analyzed in 133 HNSCC cases using quantitative methylation-specific PCR. Frequent methylation of p16 (44%), RASSF1A (18%), E-cadherin (53%), H-cadherin (35%), MGMT (35%), DAPK (53%), DCC (42%), COL1A2 (44%), TAC1 (61%), SST (64%), and GALR1 (44%) in HNSCC were detected. Disease-free survival was lower in patients with 6-11 methylated genes than in those with 0-5 methylated genes (log-rank test, P = 0.001). In a multivariate Cox proportional hazards analysis, the methylation of E-cadherin, COL1A2, TAC1, and GALR1 was associated with poor survival, with hazard ratios of 4.474 (95% CI, 1.241-16.124). In a joint analysis of these four genes, patients with 2-4 methylated genes had a significantly lower survival rate than those with 0-1 methylated genes in early-stage HNSCC. Importantly, the methylation of some genes was closely related to poor prognosis in early-stage HNSCC, providing strong evidence that these hypermethylated genes are valuable biomarkers for prognostic evaluation. In conclusion, the methylation profiles of E-cadherin, COL1A2, TAC1, and GALR1 were the most powerful combination for predicting early-stage HNSCC. This demonstrates that molecular stratification may predict cancer progression. These findings can benefit HNSCC screening and surveillance algorithms. Although our study was retrospective, was conducted at a single institution, and the number of patients was small, it serves as a platform to establish optimal therapeutic strategies for early-stage HNSCC. Citation Format: Atsushi Imai, Kiyoshi Misawa, Daiki Mochizuki, Hiroyuki Mineta, Takeharu Kanazawa. Prognostic value of aberrant promoter hypermethylation of tumor-related genes in early-stage head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5332.

Abstract A33: Head and neck squamous cell carcinoma in adolescents and young adults: Survivorship patterns and disparities

Abstract Introduction: Head and neck squamous cell carcinoma (HNSCC) incidence and survivorship has been thoroughly described in the literature. Most of the literature has mainly focused on older adults. However, there are documented cases of early-onset HNSCC, typically in adolescents and young adults (AYA) aged 15-39 years. In fact, 12% of all pediatric cancers are in the head and neck region. As individuals live longer in the general population, it will become more important to track AYA cancer cases due to the potential for treatment effects, late toxicities, and comorbidities after cancer survivorship. Additionally, the emergence of the human papillomavirus (HPV)-associated oropharyngeal cancer as a dominant head and neck cancer means that more HNSCC patients are diagnosed at a younger age than previously known. These patients with HPV-associated oropharyngeal cancer are likely to live longer since HPV-associated HNSCC typically has better prognosis than other HNSCC. While numerous studies have investigated HNSCC survivorship in older adults and the elderly, limited research exists describing the incidence and survivorship in adolescents and young adults. The aim of this study is to characterize survivorship of HNSCC in the AYA population. Methods: In this retrospective study, we utilized a patient cohort of 3,366 first primary HNSCC cases from the Surveillance, Epidemiology, and End Results (SEER) 18 database diagnosed between ages 15-39 and the years 2000-2014. Actuarial survival curves stratified by age group (15-29, 30-34, 35-39) indicated differences in HNSCC survival among groups with a log-rank test. Patient characteristics including age, sex, race/ethnicity, HNSCC site, stage, and treatment modality were utilized in a Fine and Gray competing risk proportional hazard model to examine their impact on HNSCC death in this cohort. Results: The cohort was mostly male (65.1%) with an average age of 33.6. There was no significant HNSCC survival difference between the age-stratified survival curves (log-rank p=0.83). The Fine and Gray model also did not find a significant effect for age. All race/ethnicity groups had a significantly increased hazard of HNSCC death compared with non-Hispanic whites, with non-Hispanic American Indians/Alaska Natives having the highest increased hazard (aHR=4.01, 95% CI: 2.18, 7.38). Each increasing year of diagnosis was associated with a 5% decrease in hazard of death from HNSCC (aHR=0.95, 95% CI: 0.93, 0.97). Regional (aHR=3.90, 95% CI: 3.13, 4.86) and distant (aHR=6.77, 95% CI: 5.27, 8.70) stage had a higher HNSCC death hazard compared with localized stage. Patients who did not receive surgery had a 93% (aHR=1.93, 95% CI: 1.60, 2.33) increased hazard of HNSCC death compared with those who received surgery. Compared with oropharyngeal cancer, hypopharyngeal, oral cavity, and sinonasal cancers were associated with significantly increased hazard of HNSCC death, while nasopharynx was associated with a decreased hazard (aHR=0.68, 95% CI 0.52, 0.90). Conclusions: We found no survival differences between adolescents and young adults based on age at diagnosis; however, minorities, especially American Indians/Alaskan Natives, had the worst survival outcomes. Also, patients who did not have the definite treatment of surgery and had regional or distant stage faced increased death from HNSCC. More research needs to be done to understand the mechanisms underlying the survival disparities noted among minorities, especially American Indians/Alaskan Natives. Efforts should also focus on establishing risk factor awareness and educational interventions, earlier screening measures, and patient navigator programs to improve prognosis of HNSCC in the American Indian/Alaskan Natives and other high-risk populations. Citation Format: Sai D. Challapalli, Eric Adjei Boakye, Matthew C. Simpson, Nosayaba Osazuwa-Peters. Head and neck squamous cell carcinoma in adolescents and young adults: Survivorship patterns and disparities [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A33.

Abstract 4985: M4OC-Prevent: Clinical evaluation of metformin for oral cancer precision prevention

Abstract Despite encouraging recent results from novel treatment options, such as immunotherapy, for head and neck squamous cell carcinoma (HNSCC), limited progress has been made in improving outcomes for most patients. Prevention and early detection are key to improving the prognosis of HNSCC. We have previously shown that persistent activation of the PI3K/mTOR signaling circuitry is the most frequent dysregulated signaling mechanism in HNSCC, and that PI3K/mTOR inhibition exerts potent antitumor activity in a large series of genetically-defined and chemically-induced HNSCC models. However, potential immunosuppression and other dose-dependent side effects raise concerns regarding long term use of PI3K/mTOR inhibitors as chemopreventive agents. The repurposed drug metformin, used for frontline treatment of type 2 diabetes, decreases mTOR signaling in HPV- and HPV+ experimental HNSCC models and displays potent chemopreventive activity in mouse oral-premalignancy models. Furthermore, two recent large retrospective case-control cohort studies involving more than 300,000 diabetic patients demonstrated a decreased HNSCC risk in patients using metformin. Therefore, we conducted a single-arm, open label phase IIa clinical trial (NCT02581137) in individuals with oral premalignant lesions (OPL; oral leukoplakia or erythroplakia) to explore the potential of metformin for HNSCC prevention. Subjects were eligible if they had an OPL at any site with dysplasia or hyperplasia not associated with mechanical factors, and were otherwise healthy, without diabetes. They underwent pre- and post-treatment clinical exam of the oral cavity with lesion measurement and biopsy, along with saliva and blood collection. Eligible participants received metformin for 12 weeks (500 mg per day for the first week, 1,000 mg per day for the second week, and then 2,000 mg per day for the remaining treatment period). 26 participants were accrued and 22 were assessable for response. The toxicity profile was consistent with the known side effect profile of metformin. The clinical response rate was 18%, lower than the 30% spontaneous regression rate documented in several published long term oral leukoplakia trials. The clinical progression rate was also 18%. The significance of the clinical response assessment was limited by the short duration of treatment (only 12 weeks). Of interest, however, the histologic response rate was 59%, including 13% complete responses, and the histologic progression rate was 18%. Most of the responses consisted of a one grade improvement in histology. Circulating and tissue biomarker analyses, the latter focused on the impact of metformin on the AMPK-mTOR signaling network, are being analyzed. The goal of our studies is to provide a mechanistic framework for the selection of patients who may benefit from metformin for precision prevention of oral cancer. Citation Format: J Silvio Gutkind, Frank G. Ondrey, Denise Laronde, Miriam Rosin, Alfredo A. Molinolo, Charles Coffey, Beverly R. Wuertz, Leigha D. Rock, Huyen Huynh, H-H. Sherry Chow, Valerie D. Butler, Scott M. Lippman, Eva Szabo. M4OC-Prevent: Clinical evaluation of metformin for oral cancer precision prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4985.

Correlation between prognosis and IL-33 expression in head and neck squamous cell carcinoma

Objective:To determine the correlation between the expression of IL-33 and significance in cancer biologial and patient's prognosis in head and neck squamous cell carcinoma (HNSCC). Method:Twenty pairs of tumor tissue and adjacent normal tissue were collected. qRT-PCR and immunohistochemistry (IHC) were used to detect the expression of IL-33 mRNA and protein in tissues. Correlation between IL-33 expression with clinicopathologic features of 107 HNSCC patients were analyzed. Result:IL-33 mRNA and protein expression levels in normal tissue were higher than paired tumor tissue. IL-33 level was significantly lower in patients with advanced T stages, lymph node metastases and advanced clinical stages, IL-33 expression was higher in well differentiated tumor than moderate or poor differentiated tumor. Low IL-33 expression predicts poor prognosis. Multivariate analysis indicated that IL-33 expression was an independent predictive factor. Conclusion:IL-33 is related with the clinicopathological features in HNSCC and could be an independent predictor of HNSCC prognosis.

The role of MGMT polymorphisms rs12917 and rs11016879 in head and neck cancer risk and prognosis.

Head and neck squamous cell carcinoma (HNSCC) is one of the leading cancers by incidence worldwide. The risk of these cancers is strictly associated with alkylation factors present in tobacco smoke. The crucial role in preventing DNA alkylation is played by O6-methylguanine-DNA methyltransferase (MGMT). Dysfunction or lack of MGMT is associated with an increased risk of cancer. The aim of the study was to assess the influence of MGMT polymorphisms: rs12917 and rs11016879 on HNSCC risk and course. The study consisted of 69 HNSCC patients and 242 healthy individuals. Case samples were taken from resected tumour tissue. The control group comprised samples of epithelial cells collected from mucous membranes using swabs. DNA samples were genotyped by employing the 5' nuclease assay for allelic discrimination using TaqMan SNP Genotyping Assays. The significance between distributions of genotypes and alleles was tested using Pearson's χ2 test analysis. Our results indicated that the MGMT rs12917 TT genotype increases the risk of HNSCC. The MGMT rs11016879 AG genotype and A allele were associated with increased HNSCC risk. We noted higher risk of nodal metastasis in rs11016879 AA homozygotes. Mechanisms leading to MGMT enzymatic defect are unknown and hence further studies need to be carried out. Our data suggest that the examined polymorphisms may be considered as potential prognostic factors for HNSCC risk and outcome. Further studies are necessary to verify our results.

Decreasing cytokeratin 17 expression in head and neck cancer predicts nodal metastasis and poor prognosis: The first evidence.

Cytokeratins (CKs) are mainly expressed in epithelial carcinomas and are valuable for making diagnoses and identifying metastatic status. Changes in the expression of individual CKs in certain carcinoma may be relevant to establishing a prognosis. However, the prognostic significance of CKs in head and neck squamous cell carcinoma (HNSCC) remains elusive. Herein, we investigated the diverse and unique expression patterns of Cytokeratin 13 (CK13) and Cytokeratin 17 (CK17) and assessed the role of CK17 as a predictor for HNSCC metastasis and prognosis. CK13 and CK17 expressions were evaluated using immunohistochemical tissue microarray (TMA) analysis with 106 patients of HNSCC. To clarify the characterisation of CK17 expression with respect to its ability in predicting metastatic disease, an invitro study of cells migration/invasion assays was conducted. Furthermore, the correlation of CK17 expression to clinicopathologic variables and prognosis was analyzed using a serial statistical method. CK13 was predominately expressed in non-cancerous tissues and was lost in HNSCC. Decreasing expression of CK17 correlated with cancerous cell migration and invasion (P<.0001) in an invitro study. CK17 expression was lower in the N1 and N2 nodal metastases category compared to the N0 stage. Moreover, Kaplan-Meier survival analyses showed that a lower CK17 expression was associated with a poorer survival connotation in HNSCC patients (P<.05) with 10-year follow-up. Our findings provide the first evidence that CK17 under-expression might be a potential predictor of nodal metastasis and adverse prognosis.