Andrew C. Birkeland

Postoperative clinical radiosensitivity in patients with fanconi anemia and head and neck squamous cell carcinoma.

OBJECTIVE To describe the complications and adverse effects of postoperative radiotherapy in patients with Fanconi anemia (FA). DESIGN Cohort study. SETTING Patients with FA treated at community and tertiary care hospitals throughout the United States. PATIENTS The study included patients with FA who were enrolled in the International FA Registry (IFAR) and who developed head and neck squamous cell carcinoma and received postoperative radiotherapy. MAIN OUTCOME MEASURES Demographics of patients with FA and adverse effects and dosages of radiotherapy. RESULTS Twelve patients with FA (7 men and 5 women) were identified. They developed cancers at a mean age of 35.5 years (age range, 20-48 years). The sites of primary cancer were the oral cavity (n = 8), larynx (n = 2), pharynx (n = 1), and unknown (n = 1). The median radiation dose was 5590 cGy (range, 2500-7020 cGy). The most common adverse effects were mucositis (n = 9), dysphagia (n = 8), and pancytopenia (n = 6). Other complications included esophageal stenosis, laryngeal edema, and wound breakdown. Radiotherapy could not be completed in 5 cases. Overall, 8 patients died, 4 during the course of radiotherapy. The postoperative disease-free survival time ranged from 0 to 55 months. CONCLUSIONS Patients with FA have a high rate of complications from radiotherapy. Common adverse effects, particularly mucositis, are especially prevalent and difficult to manage in this population. Pancytopenia is common and may lead to further complications, particularly bleeding and infection. Overall survival is poor. Further study of the response to radiotherapy in patients with FA should be attempted to establish appropriate dosages to balance treating disease while limiting adverse effects.

Identification of Targetable ERBB2 Aberrations in Head and Neck Squamous Cell Carcinoma

IMPORTANCE ERBB2 (formerly HER2) is an important drug target in breast cancer, where anti-ERBB2 therapy has been shown to lead to improvements in disease recurrence and overall survival. ERBB2 status in head and neck squamous cell carcinoma (HNSCC) has not been well studied. Identification of ERBB2-positive tumors and characterization of response to ERBB2 therapy could lead to targeted treatment options in HNSCC. OBJECTIVE To identify ERBB2 aberrations in HNSCCs and investigate the potential for ERBB2-targeted therapy in HNSCCs. DESIGN, SETTING, AND PARTICIPANTS A retrospective case series of patients with laryngeal (42 tumor specimens) and oral cavity (94 tumor specimens) SCC enrolled in the University of Michigan Head and Neck Specialized Program of Research Excellence was conducted. Publicly available sequencing data (The Cancer Genome Atlas), as well as data from other studies, were reviewed to identify additional mutations and overexpression in ERBB2 in HNSCC. Established HNSCC cell lines were used for follow-up in vitro analysis. The study was conducted from October 1, 2014, to August 30, 2015. INTERVENTIONS With the use of targeted, amplicon-based sequencing with the Oncomine Cancer Panel, the copy number and mutation status of commonly altered genes in HNSCCs were assessed. Immunohistochemical staining was performed on tissue microarrays of HNSCCs to assess the expression of ERBB2. Western blotting for HNSCC cell line ERBB2 expression and cell survival assays after treatment with ERBB2 inhibitors were performed. MAIN OUTCOMES AND MEASURES The prevalence of ERBB2 genetic aberrations and ERBB2 overexpression in laryngeal and oral cavity SCCs, prevalence of ERBB2 aberrations in HNSCC in The Cancer Genome Atlas, ERBB2 protein expression in HNSCC cell lines, and response of HNSCC cell lines to targeted ERBB2 inhibitors. RESULTS Of the 42 laryngeal SCC samples screened by targeted sequencing, 4 (10%) were positive for ERBB2 amplification. Two of these samples showed ERBB2 overexpression on immunohistochemistry. Two of the 94 oral cavity SCC samples (2%) were positive for ERBB2 on immunohistochemistry. Analysis of 288 patients from publicly available HNSCC sequencing data revealed 9 amplifications (3%) in ERBB2. Protein expression was variable across HNSCC cell lines, and a subset of these cell lines showed responsiveness to anti-ERBB2 therapy. CONCLUSIONS AND RELEVANCE ERBB2 aberrations were identified in a subset of HNSCCs. These tumors may be responsive to targeted therapy against ERBB2. Screening for ERBB2 aberrations and applying targeted therapy in ERBB2-positive patients may be useful in personalized therapy trials, particularly in patients who are refractory to current treatment paradigms.

The Tip of the Iceberg: Clinical Implications of Genomic Sequencing Projects in Head and Neck Cancer.

Recent genomic sequencing studies have provided valuable insight into genetic aberrations in head and neck squamous cell carcinoma. Despite these great advances, certain hurdles exist in translating genomic findings to clinical care. Further correlation of genetic findings to clinical outcomes, additional analyses of subgroups of head and neck cancers and follow-up investigation into genetic heterogeneity are needed. While the development of targeted therapy trials is of key importance, numerous challenges exist in establishing and optimizing such programs. This review discusses potential upcoming steps for further genetic evaluation of head and neck cancers and implementation of genetic findings into precision medicine trials.

Getting personal: Head and neck cancer management in the era of genomic medicine

Genetic testing is rapidly becoming an important tool in the management of patients with head and neck cancer. As we enter the era of genomics and personalized medicine, providers should be aware of testing options, counseling resources, and the benefits, limitations, and future of personalized therapy.

Correlation of Crtc1/3-Maml2 fusion status, grade and survival in mucoepidermoid carcinoma

OBJECTIVE Mucoepidermoid carcinoma (MEC) is the most common malignant tumor of the salivary glands. Tumor stage and grade have historically been important predictors of survival. An oncogenic CRTC1- or CRTC3-MAML2 gene fusion has been identified in a number of MECs. Historically, these gene fusions have been associated with lower grade tumors and better survival. However, reported gene fusion rates and prognosis varies widely across studies, and have not controlled for tumor grade. We sought to identify gene fusion rates and outcomes in our cohort of MEC patients. MATERIALS AND METHODS An IRB-approved retrospective cohort of patients with MEC was identified at the University of Michigan. Clinical, histologic, and outcome data was collected from medical records. RNA was isolated from formalin fixed paraffin-embedded tumor sections, and qRT-PCR was performed to identify CRTC1/3-MAML2 gene fusions. Sanger sequencing of qRT-PCR products was used to confirm gene fusions. RESULTS Overall, 90 patient MEC tumors were collected (58 low-grade, 25 intermediate-grade, and 7 high-grade). Gene fusions were identified in 59% (53/90) of tumors. On univariate and bivariate analysis, fusion status did not significantly associate with grade or survival. CONCLUSION We have identified a high rate of CRTC1/3-MAML2 gene fusions in a large cohort of MEC. We do not identify any correlation between fusion status with tumor grade or survival. These findings suggest further characterization of MECs is needed before considering the CRTC1/3-MAML2 gene fusion as a prognostic biomarker. Additional genetic drivers may account for survival and grade in MECs.

Immortal Life of the Common Rule: Ethics, Consent, and the Future of Cancer Research

The advent of the first immortal human cancer cell line in 1951 (HeLa) had profound implications for cancer research.1 Historically, the list of translational cancer research discoveries generated from human-derived cancer cell lines such as HeLa cannot be overstated.2-4 In addition, the future of the research enterprise undoubtedly depends on continued access to the biospecimens that generate such lines. However, it was the 2010 book, The Immortal Life of Henrietta Lacks, and its compelling story of the woman behind HeLa, that initiated an impassioned debate on the ethics and limits of research with such tissue.5 Applied laboratory scientists have a moral and ethical obligation to respect and honor the person from whom biospecimens were derived, but how that respect should be demonstrated is a matter of debate. The Common Rule, initially adopted in 1991, created an overarching guideline for federally funded human subjects research to provide oversight both in response to prior ethical transgressions and to present a unified ethical and regulatory framework for the future. But, in the ensuing years, the research landscape has dramatically changed in ways that could not be anticipated two decades past. Thus, a contemporary update to the Common Rule has been long overdue. After almost 6 years of careful analysis and vetting, along with public commentaries and spirited debate, 16 federal departments and agencies, including the US Department of Health and Human Services, published the eagerly anticipated final rule for the Federal Policy for the Protection of Human Research Subjects (Common Rule) on January 18, 2017, with a plan for implementation in 2018.6-8 The field of cancer research is currently in a watershed, further stimulated by the Cancer Moonshot and Precision Medicine Initiative. The pace of discoveries with immediate translational potential, particularly with regard to tumor biology/immunology and genomics, is frenetic. The translation of new laboratory data to applications at the bedside has never been more dynamic or fluid. Much of this research falls under the purview of the Common Rule and is accordingly dependent on and accountable to its stipulations and revisions. The goals of the Common Rule revisions include to “enhance respect and safeguards for research participants and to increase research efficiency by reducing unnecessary burdens and calibrating oversight to the level of risk.”9(p2293) However, many stakeholders were concerned that several proposed changes would hinder the research enterprise unnecessarily, particularly in the field of oncology. For example, the proposed Common Rule changes in the notice of proposed rulemaking (NPRM), which preceded the final rulemaking, included efforts to require broad consent for all research with biospecimens. Under the previous version, biospecimen informed consent was only required if identifying information accompanied the sample.6 The intent of the proposal—which considers any human tissue to be a human subject triggering informed consent protections—was to respect participant autonomy, but it raised the possibility of serious unintended consequences. A lively discussion ensued regarding how best to balance the need to protect and respect current participants who provide their tissue to advance scientific knowledge while ensuring scientists have the ability to advance science for future patients using invaluable biologic specimens.9-11 Ultimately, the final Common Rule was receptive to such criticisms (Table 1).13 Table 1. Summary of Major Changes to the Final Common Rule

E6 and E7 antibody levels are potential biomarkers of recurrence in patients with advanced stage human papillomavirus positive oropharyngeal squamous cell carcinoma

Purpose: There is a paucity of biomarkers to predict failure in human papillomavirus–positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) following curative therapy. E6/E7 viral oncoproteins are constitutively expressed in HPV+ tumors and highly immunogenic, resulting in readily detected serum antibodies. The purpose of this study is to determine whether serum E6 and E7 antibody levels can potentially serve as a biomarker of recurrence in patients with HPV+OPSCC. Experimental Design: We evaluated E6/E7 antibody levels in patients with previously untreated, advanced stage (III, IVa-b), HPV+OPSCC receiving definitive chemoradiation under a uniform protocol from 2003 to 2010. Baseline and longitudinal serum samples were obtained from our archived repository. E6/E7 serum levels were measured using a glutathione-S-transferase capture ELISA and quantified by approximating the area under the dilution curve, and were analyzed using ANOVA and linear mixed model for longitudinal analysis. Results: We compared 22 HPV+OPSCC patients who developed recurrence with 30 patients who remained disease-free. There were no differences in T classification, N classification, disease subsite, or smoking status between the groups. In a longitudinal analysis, recurrent patients had significantly higher E6 and E7 serum antibody levels than the nonrecurrent patients over the follow-up period (P = 0.02 and P = 0.002, respectively). Patients who recurred had a lower clearance of E7 antibody than patients who remained disease-free (P = 0.0016). Conclusions: Patients with HPV+OPSCC whose disease recurs have a lower clearance of E6 and E7 antibodies than patients who do not have recurrence. The ratio of E7 antibody at disease recurrence compared with baseline is potentially a clinically significant measurement of disease status in HPV+OPSCC. Clin Cancer Res; 23(11); 2723–9. ©2016 AACR.

Occult Nodal Disease Prevalence and Distribution in Recurrent Laryngeal Cancer Requiring Salvage Laryngectomy

Objectives The indications for neck dissection concurrent with salvage laryngectomy in the clinically N0 setting remain unclear. Our goals were to determine the prevalence of occult nodal disease, analyze nodal disease distribution patterns, and identify predictors of occult nodal disease in a salvage laryngectomy cohort. Study Design Case series with planned data collection. Setting Tertiary academic center. Subjects Patients with persistent or recurrent laryngeal squamous cell carcinoma (LSCC) after radiation/chemoradiation failure undergoing salvage laryngectomy with neck dissection. Methods We analyzed a single-institution retrospective case series of patients between 1997 and 2014 and identified those who had clinically N0 (cN0) necks (n = 203). Clinical and pathologic data, including nodal prevalence and distribution, were collected and statistical analyses performed. Results Overall, cN0 necks had histologically positive occult nodes in 17% (n = 35) of cases. Univariate predictors of occult nodal positivity included recurrent T4 stage (34% T4 vs 12% non-T4; P = .0003) and supraglottic subsite (28% supraglottic vs 10% nonsupraglottic; P = .0006). Histologically positive nodes associated with supraglottic primaries were most frequently positive in ipsilateral levels II and III (17% and 16%). Positive nodes for glottic LSCC were most frequently positive in the ipsilateral and contralateral paratracheal nodes (11% and 9%). Conclusion Histologically positive occult nodes are identified in 17% of cN0 patients undergoing salvage laryngectomy with neck dissection. Occult nodal disease varies in frequency and distribution based on tumor subsite. Predictors of high (>20%) occult nodal positivity include T4 tumors and supraglottic subsite. In glottic LSCC, the most frequent sites of occult nodal disease are the paratracheal nodal basins.

Prevalence and Outcomes of Head and Neck versus Non-Head and Neck Second Primary Malignancies in Head and Neck Squamous Cell Carcinoma: An Analysis of the Surveillance, Epidemiology, and End Results Database

Background/Aims: Patients with head and neck squamous cell carcinoma (HNSCC) are at risk for second primary malignancies (SPMs). The prevalence, distribution, and patient survival in head and neck versus non-head and neck SPMs are not fully elucidated. The objective of this study was to quantify the rate of SPMs in patients with HNSCC. Methods: This is a population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. Prevalence and location of SPMs, and survival data were analyzed. Results: There were 58,363 HNSCC patients, and the prevalence of HNSCC and non-HNSCC SPMs was 3.0% (1,746) and 8.8% (5,109), respectively. Overall survival (OS) was higher in patients with HNSCC SPMs compared to non-HNSCC SPMs (p < 0.001), with no difference in disease-specific survival. Patients with SPMs in the lung and esophagus had a worse OS (p < 0.001), and patients with SPMs in the prostate and breast had a better OS (p < 0.001). Conclusion: In HNSCC patients who develop SPMs, nearly 75% are non-HNSCC SPMs. Patients with non-HNSCC SPMs have a lower OS. Future clinical practice guidelines should take the risks and locations of SPM development into consideration for screening.

Fibroblast growth factor family aberrations as a putative driver of head and neck squamous cell carcinoma in an epidemiologically low-risk patient as defined by targeted sequencing

Targeted sequencing of patients with epidemiologically low‐risk (ELR) head and neck squamous cell carcinoma (HNSCC) could help identify novel drivers or lost suppressors leading to precision medicine protocols and improved survival rates.