Nicole G. Chau

The association between EGFR variant III, HPV, p16, c-MET, EGFR gene copy number and response to EGFR inhibitors in patients with recurrent or metastatic squamous cell carcinoma of the head and neck

BackgroundWe examine the potential prognostic and predictive roles of EGFR variant III mutation, EGFR gene copy number (GCN), human papillomavirus (HPV) infection, c-MET and p16INK4Aprotein expression in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).MethodsWe analyzed the archival tumor specimens of 53 patients who were treated in 4 phase II trials for R/M SCCHN. Two trials involved the EGFR inhibitor erlotinib, and 2 trials involved non-EGFR targeted agents. EGFRvIII mutation was determined by quantitative RT-PCR, HPV DNA by Linear Array Genotyping, p16 and c-MET protein expression by immunohistochemistry, and EGFR GCN by FISH.ResultsEGFRvIII mutation, detected in 22 patients (42%), was associated with better disease control, but no difference was seen between erlotinib-treated versus non-erlotinib treated patients. EGFRvIII was not associated with TTP or OS. The presence of HPV DNA (38%), p16 immunostaining (32%), c-MET high expression (58%) and EGFR amplification (27%), were not associated with response, TTP or OS.ConclusionEGFRvIII mutation, present in about 40% of SCCHN, appears to be an unexpected prognostic biomarker associated with better disease control in R/M SCCHN regardless of treatment with erlotinib. Larger prospective studies are required to validate its significance.

A phase II study of sunitinib in recurrent and/or metastatic adenoid cystic carcinoma (ACC) of the salivary glands: current progress and challenges in evaluating molecularly targeted agents in ACC

BACKGROUND Vascular endothelial growth factor (VEGF) and c-kit are highly expressed in adenoid cystic carcinoma (ACC) and associated with biologic aggressiveness. This study aimed to assess the antitumor activity of sunitinib, a multi-targeted inhibitor of vascular endothelial growth factor receptor, c-kit, platelet-derived growth factor receptor, ret proto-oncogene (RET) and FMS-like tyrosine kinase 3 (FLT3), in ACC of the salivary gland. PATIENTS AND METHODS Patients with progressive, recurrent and/or metastatic ACC were treated with sunitinib 37.5 mg daily in this single-arm, two-stage phase II trial. Response was assessed every 8 weeks. RESULTS Fourteen patients were enrolled on to the study. Among 13 assessable patients, there were no objective responses, 11 patients had stable disease (SD), 8 patients had SD ≥ 6 months and 2 patients had progressive disease as best response. Median time to progression was 7.2 months. Median overall survival was 18.7 months. Toxic effects occurring in at least 50% of patients included fatigue, oral mucositis and hypophosphatemia usually of mild to moderate severity. CONCLUSIONS Although no responses were observed, sunitinib was well tolerated, with prolonged tumor stabilization of ≥ 6 months in 62% of assessable patients. The lack of responses is comparable with other trials of molecularly targeted agents in ACC and highlights the need for novel strategies in phase II clinical trial design.

Marital status and head and neck cancer outcomes

The objective of this study was to examine the effects of marital status on stage at presentation, receipt of treatment, and survival in patients with head and neck cancer (HNC).

Vandetanib for the Treatment of Medullary Thyroid Cancer

Vandetanib (ZD6474, Caprelsa, AstraZeneca), an oral small-molecule tyrosine kinase inhibitor (TKI) that targets the rearranged during transfection receptor (RET), VEGF receptor (VEGFR2-3), and EGF receptor (EGFR), is the first systemic therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of symptomatic or progressive advanced medullary thyroid cancer (MTC). In a randomized phase III trial of patients with unresectable, locally advanced, or metastatic MTC, vandetanib improved progression-free survival compared with placebo [HR, 0.46; 95% confidence interval (CI), 0.31–0.69; P < 0.001]. However, the benefits in delaying disease progression need to be balanced against the associated and potentially serious toxicities, including diarrhea, hypertension, and QTc prolongation. Here, we review the clinical development of vandetanib leading to its integration into the current treatment paradigm and highlight the ongoing and future challenges in TKI use in MTC. Clin Cancer Res; 19(3); 524–9. ©2012 AACR.

Definitive chemoradiation alters the immunologic landscape and immune checkpoints in head and neck cancer

Background:Preclinical and clinical studies suggest potential synergy between high dose per fraction focal radiation and immunotherapy. However, conventionally fractionated radiation regimens in combination with concurrent chemotherapy are more commonly administered to patients as definitive treatment and may have both immune-stimulating and -suppressive effects.Methods:We prospectively collected longitudinal samples from head and neck squamous cell carcinoma patients receiving definitive radiation therapy. We quantified changes in populations of circulating immune cells and chemokines CXCL9, 10, and 16. Analyses of humoral and cellular immune responses were conducted in select patients via proteomic analysis and T-cell receptor sequencing.Results:Treatment not only increased circulating CD-8+ T-effector cells, but also myeloid-derived suppressor cells, regulatory T cells, and checkpoint receptor-expressing T cells, particularly PD-1+ T cells. Significant decreases in CXCL10 and increases in CXLC16 were noted. Treatment also increased the percentage of unique and dominant TCR clones, and increased humoral responses as measured by proteomic array.Conclusions:Our results suggest that fractionated chemoradiation leads to quantifiable effects in circulating immune mediators, including a balance of stimulatory and suppressive mechanisms. These results suggest future combinations with immune checkpoint blockade.

Intensive treatment and survival outcomes in NUT midline carcinoma of the head and neck

NUT midline carcinoma is a rare and aggressive genetically characterized subtype of squamous cell carcinoma frequently arising from the head and neck. The characteristics and optimal management of head and neck NUT midline carcinoma (HNNMC) are unclear.

Incorporation of next-generation sequencing into routine clinical care to direct treatment of head and neck squamous cell carcinoma

Purpose: The clinical impact of next-generation sequencing (NGS) in patients with head and neck squamous cell carcinoma (HNSCC) has not been described. We aimed to evaluate the clinical impact of NGS in the routine care of patients with HNSCC and to correlate genomic alterations with clinical outcomes. Experimental Design: Single-center study examining targeted NGS platform used to sequence tumor DNA obtained from 213 HNSCC patients evaluated in outpatient head and neck oncology clinic between August 2011 and December 2014. We correlated tumor genomic profiling results with clinical outcomes. Results: PI3K/RTK pathway activation occurred frequently [activating PIK3CA mutation or amplification (13%), PTEN inactivation (3%), RAS activation (6%), EGFR or ERBB2 activation (9%)]. Alterations in pathways affecting cell-cycle regulation [CCND1 amplification (9%), CDKN2A inactivation (17%), BRCA2 inactivation (2%)] and squamous differentiation [NOTCH1 inactivation (8%) andEP300 inactivation (6%)] were identified. PIK3CA amplification (n = 43), not PIK3CA mutation, was associated with significantly poorer progression-free survival (P = 0.0006). Oncogenic RAS mutations (n = 13) were associated with significantly poorer progression-free survival (P = 0.0001) and lower overall survival (P = 0.003). Eight patients with advanced, treatment-refractory HNSCC enrolled on clinical trials matched to tumor profiling results, and 50% achieved a partial response. Conclusions: Incorporation of NGS clinical assays into the routine care of patients with HNSCC is feasible and may readily facilitate enrollment into clinical trials of targeted therapy with a higher likelihood of success. Data can be utilized for discovery of genomic biomarkers of outcome. PIK3CA amplification and RAS mutations were frequently identified and associated with poorer prognosis in this cohort. Clin Cancer Res; 22(12); 2939–49. ©2016 AACR.

Pylephlebitis and pyogenic liver abscesses: a complication of hemorrhoidal banding.

Hemorrhoidal banding is a well-established and safe outpatient procedure. Septic complications of hemorrhoidal banding are rare but can be fatal. The first case of pylephlebitis (septic portal vein thrombosis) and pyogenic liver abscess following hemorrhoidal banding in a 49-year-old man with diabetes is reported in the present study. Risk factors, management and the role of prophylaxis in immunocompromised patients are discussed. Caution against hemorrhoidal banding in immunosuppressed patients, including patients with diabetes, is warranted.

Recurrent IDH2 R172X mutations in sinonasal undifferentiated carcinoma

Sinonasal undifferentiated carcinoma is a rare and aggressive malignancy. Sinonasal undifferentiated carcinoma has long been considered a diagnosis of exclusion; to date, the molecular pathogenetic basis for sinonasal undifferentiated carcinoma is unknown. To identify potential oncogenic drivers in sinonasal undifferentiated carcinoma, targeted next-generation sequencing of 300 cancer-related genes was performed on 11 cases of sinonasal undifferentiated carcinoma. We identified IDH2 R172X mutations in 55% of sinonasal undifferentiated carcinomas including R172S, R172T, and R172M. Multispecific mutant IDH1/2 immunohistochemistry was performed and identified mutant-specific protein expression in all cases with available tissue: 3/3 sinonasal undifferentiated carcinomas with R172 mutations were positive and 4/4 wild-type cases were negative. Review of sequencing data for our institutional head and neck cohorts (n=412) confirmed the absence of IDH-activating mutations in other tumor types. Alterations in the IDH2-wild-type sinonasal undifferentiated carcinomas included SMARCA4 loss-of-function with confirmed loss of immunohistochemical expression, NOTCH1 gain-of-function, and TET2 loss-of-function. We demonstrate that the majority of histologically defined sinonasal undifferentiated carcinomas are characterized by IDH2 R172X mutations and overexpression of mutant protein. IDH2 R172X mutations are specific to sinonasal undifferentiated carcinoma among carcinomas of the head and neck, confirming this tumor type as a distinct clinicopathologic entity. These findings have significant implications for diagnosis and therapy with IDH inhibitors for patients with this rare and poorly understood tumor.

Human Papillomavirus-Associated Oropharynx Cancer (HPV-OPC): Treatment Options

Opinion statementHuman papillomavirus-associated oropharynx cancer (HPV-OPC) is growing in incidence and has distinct clinical, pathologic, molecular, and epidemiologic features. However, the management of HPV-OPC does not presently differ from HPV-negative OPC based on the current evidence and requires complex multidisciplinary approaches. The superior prognosis of HPV-OPC and the toxicities of current multimodality treatment in a young population serve as the impetus to evaluate de-intensification treatment regimens aimed at reducing toxicity while maintaining therapeutic efficacy. Clinical trials are underway to evaluate reduced doses of radiation or less toxic systemic therapy regimens in HPV-OPC. Minimally invasive surgical approaches in the HPV-OPC population with early tumor stage also are being investigated. De-intensification strategies should only be employed in the context of clinical trials, and HPV-OPC patients should be offered clinical trials’ participation. Appropriate patient selection is critical to the development of de-intensification regimens, and this requires greater understanding of risk factors within the HPV-OPC population, HPV-OPC biology, and how HPV modulates response to specific therapies. Smoking history and bulky nodal disease have been shown to impact negatively the favorable prognosis of HPV association. Validated biomarkers within the HPV-OPC population are lacking, although alterations in the PI3K pathway and markers of immune response may emerge as important considerations in the future. Novel therapeutic strategies are desperately needed particularly for HPV-OPC patients who fail definitive therapy, and select patients with recurrent or metastatic disease may benefit from aggressive approaches.