Head and Neck TRDG: Meetings and Minutes

Dr. Jeffrey Liu spoke about “Examining DNA Damage Response Genes in Head and Neck Cancer Racial Disparity”. Dr. Liu has been a Temple faculty member since 2011; he is a surgeon who operates 50% at FCCC and 50% at Temple. He previously trained at Cornell and Columbia, MSKCC. He is a collaborator with Drs. Camille Ragin and Erica Golemis. Dr. Liu spoke about squamous cancers within the organs in the head and neck region with focus on racial disparities. He presented SEER data from 1975-2013; incidence of H&N higher in blacks and mortality is higher as well. The curves are trending downward with decreased smoking. HPV cases have been on the rise since 2000 which is more common in whites where the rise in incidence is demonstrated. The drivers in the SEER data are smoking and drinking alcohol. African American and poor patients have a dramatically worse prognosis in H&N cancer and access to care is a major issue that matters. There was a higher frequency of advanced disease in African Americans even after controlling for access to care, smoking exposure and socioeconomic status. There is therefore a question as to whether there are biological factors that explain the racial disparities. Dr. Liu has been interested in DNA damage response genes and germ-line genetic factors. He has pursued a hypothesis that inherited differences in genes affecting tobacco metabolism and DNA repair pathways contribute to risk and prognosis in SCCHN. There was discussion about degree of inhaling smoke and menthol as possible but unproven factors. Dr. Liu spoke about translational directions funded by a grant looking at DDR genes, SNPs enriched in African American (AA) populations, sequenom-MassArray panel testing in Philadelphia AA set (control population), and are AIMs (Ancestral Informative Markers) enriched in any AA SCC patients. The study had a bioinformatics component in silico followed by sequencing. Found 196 AIMs in 33 genes from ENCODE data analysis. There is little data on non-white populations in TCGA. There was discussion about announcements of nivolumab approval in metastatic H&N cancer. It was mentioned that very few H&N cancer patients enrolled in the NCI MATCH trial had actionable mutations. Dr. Liu spoke in more detail about specific DNA damage repair genes and markers. There was some discussion that there is no information about epigenetic factors or gene expression.

Dr. Oneida Arosarena spoke about “Osteoactivin promotes migration and invasion of head and neck cancer cells”. She trained at U. Michigan and SUNY Syracuse and is working on bone cell biology and does some work in collaboration with Dr. Fayez Safadi. She is interested in osteoactivin.  Oral Squamous Cell Cancers (OSCC) represent 40% of Head and Neck cancer and the 5 year survival is 50%. Bone invasion is an independent risk factor for poor prognosis. Invasive tumors more common in minority populations and Dr. Arosarena is interested in why that is. OSCC bone invasion is osteoclast-mediated (as opposed to hematogenous spread) and involves osteoclast activation factors. RANKL is induced by PTH, TNF, IL6, IL-1, IL-11. OPG competes with RANK to suppress metastases. RANKL is induced on osteoblasts which binds to RANK on osteoblasts. Dr. Arosarena has examined archived tissues looking for regulation of RANKL by TGF-beta in OSCC samples. She recently published results (https://www.ncbi.nlm.nih.gov/pubmed/26636434). There was discussion of translational research directions including effects of bisphosphonates and potential experiments in mouse models of bone invasion, and further studies of osteoactivin in clinical samples. There was mention of an osteoactivin antibody therapeutic in phase III in melanoma.

Dr. El-Deiry mentioned an R21 RFA on clinical and translational exploratory/developmental studies. http://grants.nih.gov/grants/guide/pa-files/PAR-16-176.html  Dr. Miriam Lango mentioned that there are many patients being seen with larynx cancer at Fox Chase Cancer Center. There was discussion about the need to follow-up with Caris on a submitted LOI and mention of Syapse meeting occurring tomorrow to explore a data aggregation platform for precision medicine studies. Dr. El-Deiry spoke about various opportunities of liquid biopsies. Dr. Thomas Galloway spoke about “TTI and Head and Neck Cancer”. He described a case where delay in diagnosis was significant in a patient with hypopharynx cancer with symptoms. The delay took 6.5 months (192 days). Then the patient came to FCCC and it took 24 days prior to beginning therapy. He mentioned that nationally, treatment delays are being seen regardless of stage or how patients are being treated and these have gotten worse over the last 15 years. Transitions of care are a big driver of delay in therapy. He showed some poor prognostic factors in terms of hazard rations including racial and socioeconomic factors. Patient outcomes correlated with how quickly tumors are growing in oropharynx cancer. There is already some risk stratification into low, intermediate and high risk (RTOG 0129 risk groups). There was discussion about whether Ki67 or other histopathologic parameters correlate with the risk groups. At this time this is not standard practice in head and neck cancer. There was discussion of imaging modalities including 18F-MISO and FLT. The TH4000 study is opening at FCCC; an EGFR inhibitor that is reduced under hypoxic conditions and converted to an active form that has better tumor penetration. The trial is in Head & Neck cancer and uses HX4 for hypoxia imaging. There was discussion about morphologic profiles of HPV-related Head & Neck cancer that have less projections and are more clearly demarcated by imaging. Typically positive margins are dealt with by post-op therapy such as RT, not by intraoperative cautery that may affect tongue function. There was discussion about management of lymph nodes. High risk tumors grow more quickly. Ki67 is low hanging fruit for risk stratification. Bcl2 is routine at MGH per Dr. Bauman. There was discussion about lymphocytic infiltration and PD1 in the context of clinical protocols. There is a Head & Neck cancer month in April and increasing awareness of different forms including those not related to smoking.

Dr. Camille Ragin spoke about genomic risk association studies, genetic ancestry contributions to Head & Neck cancer risk and outcomes. She is interested in Phase I enzymes, phase II enzymes, and DNA repair pathways. SNPs, tobacco metabolites; work supported through an American Cancer Society research grant. Now she has added DNA repair pathways and is interested in validating bioinformatics and SNPs associated with risk of head and neck cancer. She has enrolled 100 cases and 775 controls in the catchment area and collected saliva and urine and is working with the PA State registry in addition to TU-FCCC patients. She is not focusing primarily on smokers. There are 229 tobacco metabolism genes and 33 DNA repair genes; some more polymorphic than others. She has compared SNP allele frequencies between whites and blacks and then did functional analysis. For SNPs in coding sequences did functional modeling and for non-coding sequences, she used TCGA to look at impact on gene expression. Dr. Ragin discussed specific genes, their function, and the potential impact of polymorphisms. She also discussed non-coding SNPs as well as potentially remote effects of SNPs on DNA repair gene expression. She mentioned there are no GWAS studies involving African Americans. There was discussion that the associations that are being uncovered may not only be with disease risk but also treatment response. She gave some possible examples and described some plans for laboratory studies. One goal is to eventually be able to look at multiple SNPs in combination that impact risk of Head & Neck cancer as well as survival differences between blacks and whites. The impact can be part of risk assessment for smokers in the future. Findings may also apply to lung cancer.

Dr. Suraj Peri spoke about TCGA analysis in SCCHN. These tumors are heterogeneous, and important to compare HPV+ vs HPV-. He reviewed a 2004 study by Christine Chung in Cancer Cell where the study looked at 60 tumors found 4 sub-types: Group 1: basal (HIF genes upreg; neuregulin), Group 2: mesenchymal (vimentin, cadherin), Group 3: atypical (keratin 1, keratin 9; mostly HPV+), Group 4: classical (xenobiotic pathways; smokers). He reviewed a Clinical Cancer Res 2015 paper 21:870-881 that involved discovery and validation cohorts; transcriptomic data and reported basal, classical, immunoinflammatory subtype but did not describe an atypical category. The atypical (HPV+) fell into classical and mesenchymal but not the basal category.

Survival curves based on category; HPV+ had better prognosis. Dr. Peri spoke further about TCGA data: currently 528 tumors; 279 published. 172 oral cavity, 33 oropharynx, 72 laryngeal

majority male heavy smokers. RNA-seq if >1000 mapped RNA reads for E6 and E7 these are called HPV+ in addition to p16 reads. He spoke about a 2015 Nature paper 517:576-582 that described a comprehensive genomic characterization of head and neck cancer (http://www.nature.com/nature/journal/v517/n7536/full/nature14129.html). He spoke about EGFR amplification, caspase 8 mutation, p53 mutation, p16 mutation, Notch 1, HRAS mutation tracked with stable copy number and casp 8 mutation. He mentioned that Walter et al from UNC published 138 HNSCC cases from UNC and conformed to the Chung classification. He described methylation data and mentioned a 2013 PNAS paper that included some MSI cases. He described results from Peri et al., submitted manuscript looking at TCGA data for 256 cases for which all 4 molecular datasets are available. There are a number of future directions in terms of prognostication, and therapeutic development.