Aarti Bhatia

Human Papillomavirus–Associated Oropharyngeal Cancer: Defining Risk Groups and Clinical Trials

Human papillomavirus-associated oropharynx cancer (HPVA-OPC) is rapidly increasing in incidence and has unique epidemiologic, molecular, and biologic characteristics. Despite being recognized as having superior prognosis, current evidence does not support less intense therapy compared with HPV-negative OPC. Current combined modality therapies confer a significant risk of morbidity, and patients with HPVA-OPC have a younger median age. These patients, therefore, live longer with the adverse effects of treatment, and this spurs the development of treatment deintensification trials that attempt to decrease treatment-related morbidity without compromising efficacy. Many radiation and chemotherapy de-escalation trials are underway. Minimally invasive surgical techniques are also being evaluated. It is important to identify the ideal patient group for treatment deintensification and to define prognostic risk groups to avoid undertreating the poorer-risk subset in HPVA-OPC, and validated biomarkers are needed to identify patients with the best prognosis. Significant smoking exposure mitigates the favorable prognosis of HPVA-OPC. Currently, less intense treatment is an option only in the setting of clinical trials, and patients with HPVA-OPC should be offered clinical trial options whenever they are available. Finally, recognition of novel therapeutic targets and signaling pathways is critical to the development of new treatment strategies that are desperately needed for patients with poor risk and those with recurrent and metastatic disease.

Demethylation therapy as a targeted treatment for human papilloma virus-associated head and neck cancer

Purpose: DNA methylation in human papillomavirus–associated (HPV+) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation, and survival. Here, we determined activity of a global DNA-demethylating agent, 5-azacytidine (5-aza), against HPV+ HNSCC in preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV+ HNSCC. Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV+ HNSCC. Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV+ HNSCC. 5-aza reduced expression of HPV genes, stabilized p53, and induced p53-dependent apoptosis in HNSCC cells and tumors. 5-aza repressed expression and activity of matrix metalloproteinases (MMP) in HPV+ HNSCC, activated IFN response in some HPV+ head and neck cancer cells, and inhibited the ability of HPV+ xenografted tumors to invade mouse blood vessels. Conclusions: 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy. Clin Cancer Res; 23(23); 7276–87. ©2017 AACR.

Adjuvant therapy in major salivary gland cancers: Analysis of 8580 patients in the National Cancer Database

BACKGROUND Evidence surrounding the effect of adjuvant treatment in salivary gland cancers is limited. The benefit of adding chemotherapy to adjuvant treatment is also of interest. We investigated the association of these treatments with survival and whether this differed by stage or the presence of adverse features. METHODS A retrospective study of adult salivary gland cancer cases diagnosed from 2004 to 2013 in the National Cancer Data Base (NCDB) was conducted. RESULTS Treatment with adjuvant radiotherapy was associated with improved survival for both patients with early-stage (hazard ratio [HR] 0.744; P = .004) and late-stage (HR 0.688; P < .001) disease with adverse features. Further addition of chemotherapy to the adjuvant treatment of patients with late-stage disease with adverse features was not associated with a survival benefit (HR 1.028; P = .705). CONCLUSION Adjuvant radiotherapy is associated with improved survival for patients with adverse features, regardless of stage. The addition of chemotherapy to the adjuvant treatment of patients with late-stage disease with adverse features is not associated with improved outcomes.

Treatment guidelines and patterns of care in oral cavity squamous cell carcinoma: Primary surgical resection vs. nonsurgical treatment

BACKGROUND The 2017 National Comprehensive Cancer Network Clinical Practice Guidelines recommend surgical resection or definitive radiation therapy for early-stage oral cavity malignancies, and surgical resection or multimodality clinical trials for late-stage disease. Few studies have been conducted to identify predictors of choice of treatment modality for oral cavity malignancies. METHODS All patients in the National Cancer Data Base (NCDB) diagnosed with oral cavity squamous cell carcinoma (OCSCC) between 1998 and 2011 were identified. Chi-square and binary logistic regression were used to identify factors predictive of surgical or nonsurgical treatment; multiple imputation was used for missing data. Cox proportional hazards models were generated to identify associations between treatment modality and overall survival (OS). RESULTS Of 23,459 patients, 4139 (17.6%) underwent primary nonsurgical treatment. Among NCDB-registered facilities, there has been a decrease in use of nonsurgical treatment for OCSCC (OR 0.97, p<0.001). Older age, non-white race, Medicaid insurance, low income, low education, and later-stage disease were associated with nonsurgical therapy, while patients at academic/research programs were more likely to undergo surgery (OR 0.38, p<0.001). Nonsurgical treatment was associated with decreased OS (HR=2.02, p<0.001); this was upheld on subgroup analysis of early- and late-stage disease. CONCLUSIONS Use of primary nonsurgical treatment for OCSCC has decreased over time among NCDB-registered facilities and is associated with factors related to access to care. Surgical resection for the primary treatment of oral cavity cancer may be associated with improved OS, though conclusions regarding survival are limited by the non-randomized nature of the data.

Novel Molecular Targets for Chemoprevention in Malignancies of the Head and Neck

Cancers of the head and neck region are among the leading causes of cancer-related mortalities worldwide. Oral leukoplakia and erythroplakia are identified as precursor lesions to malignancy. Patients cured of an initial primary head and neck cancer are also susceptible to developing second primary tumors due to cancerization of their mucosal field. Multi-step acquisition of genetic mutations leading to tumorigenesis and development of invasive cancer has been previously described. Recently, whole exome sequencing of tumor specimens has helped to identify driver mutations in this disease. For these reasons, chemoprevention or the use of systemic or biologic agents to prevent carcinogenesis is an attractive concept in head and neck cancers. Nonetheless, despite extensive clinical research in this field over the past couple decades, no standard of care option has emerged. This review article reports on targeted interventions that have been attempted in clinical trials to date, and focuses on novel molecular pathways and drugs in development that are worthy of being tested for this indication as part of future endeavors.

Double-blind, randomized phase 3 trial of low-dose 13-cis retinoic acid in the prevention of second primaries in head and neck cancer: Long-term follow-up of a trial of the Eastern Cooperative Oncology Group-ACRIN Cancer Research Group (C0590)

13‐Cis retinoic acid (13‐CRA) is a synthetic vitamin A derivative. High‐dose 13‐CRA in patients with squamous cell cancers of the head and neck (SCCHNs) reduces the incidence of second primary tumors (SPTs). The authors report long‐term results from a phase 3 randomized trial that compared treatment with low‐dose 13‐CRA versus placebo for patients who had early stage SCCHN, with a focus on the development of SPTs and overall survival (OS).

Epigenetic Changes and Epigenetic Targets in Head and Neck Cancer

Epigenetic changes are both inheritable and reversible, affecting the spatial conformation of DNA and its transcriptional activity. The most common classes of epigenetic regulation include modification of DNA (typically by methylation), or modification of the histones that form nucleosomes (typically by methylation, acetylation, or phosphorylation). Epigenetic changes can influence gene expression patterns without making permanent changes in DNA. In this article, we discuss characteristic changes in the epigenetic modification of tumor DNA that occurs in squamous cell carcinomas of the head and neck (SCCHN), which controls the selective induction and repression of genes relevant to the disease pathology. We also describe key proteins that mediate epigenetic control of gene expression, and emerging therapeutic approaches to target epigenetic control systems.