Dan P. Zandberg

The role of human papillomavirus in nongenital cancers.

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Correlation of p16 expression and HPV type with survival in oropharyngeal squamous cell cancer

OBJECTIVES Examine the effect of concordance between p16 overexpression and HR (high risk) HPV DNA status on overall survival in a large series of oropharyngeal squamous cell carcinoma (OPSCC) cases. MATERIALS AND METHODS A total of 185 patients with primary OPSCC had genomic DNA tested by PCR for the HPV16 E6 and E7 oncogenes. 184 of 185 patients had p16 IHC performed. Linear array HPV genotyping was performed in all 21 HPV16/p16 discordant cases (HPV16+/p16- or HPV16-/p16+) as well as in 43 control cases. RESULTS 73 of 185 patients were positive for HR HPV (39%). Six of 73 HPV infections were due to HR HPV types other than HPV16: types 31 (1), 33 (2), 51 (1), 58 (1), and 59 (1); all 6 cases were p16 positive. p16 IHC was concordant with HR HPV testing in 169 of 184 cases (92%), and had a sensitivity and specificity of 92% and 92%. HR HPV+/p16+ and discordant HR HPV/p16 patients had significantly improved overall survival compared to HR HPV-/p16- patients. CONCLUSION p16 IHC is a reliable surrogate marker for HR HPV testing in OPSCC. Prognostically favorable HR HPV genotypes other than HPV16 are reflected in p16 positivity.

The role of antagonists of the PD-1:PD-L1/PD-L2 axis in head and neck cancer treatment

We review the current clinical knowledge surrounding one of the most promising immune checkpoint pathways currently investigated in head and neck squamous cell carcinoma patients, programmed cell death-1 (PD-1) and its ligands (PD-L1 and PD-L2). We review ongoing clinical trials and associated clinical responses observed with targeting the receptor, PD-1, and its ligand, PD-L1. A recent phase III clinical trial (Checkmate 141) demonstrated an improved overall survival in head and neck cancer patients treated with anti-PD-1 monotherapy as compared to standard of care for recurrent and/or metastatic disease, which raises questions on how best to incorporate immunotherapy in the context of standard of care. We discuss biomarkers of response to this class of novel drugs, which is an area of active investigation. Lastly, we project future directions in the field wherein understanding how the Fc portions of the various monoclonal antibodies may impact their clinical efficacy as well as discuss areas where our next advances may take place, such as combination strategies.

Emergence of HPV16-positive oropharyngeal cancer in Black patients over time: University of Maryland 1992-2007.

While we previously reported a striking racial difference in the prevalence of human papilloma virus (HPV)–positive squamous cell carcinoma of the oropharynx (OPSCC), less is known about differences in outcomes and trends over time in OPSCC by HPV status and race. We conducted a retrospective analysis of 467 patients with OPSCC treated at the University of Maryland Greenebaum Cancer Center (Baltimore, MD) between 1992 and 2007, of which 200 had tissue available for HPV16 testing. HPV16-positive patients were significantly more likely to be white, with 45.5% of whites and 15.5% of blacks testing positive for HPV16. There was a significant increase in HPV16-positive OPSCC for all patients over time from 15.6% in 1992 to 1995 to 43.3% in 2004 to 2007 (P = 0.01). From 1992 to 1995, 33% of white patients were HPV16-positive, with no black patients positive. From 2004 to 2007, 17.7% of black patients and 54% of white patients were HPV16-positive. White and black patients with HPV16-positive tumors had an identical and favorable overall survival (OS; median, 8.1 and 8.1 years, respectively). However, among HPV16-negative patients, whites had an improved OS compared with blacks (median, 2.3 vs. 0.9 years, respectively; P = 0.02), including when analyzed in a multivariable Cox regression model. From 1992 to 2007, the percentage of HPV16-positive OPSCC increased for white patients and was seen for the first time in black patients. While survival for HPV-positive black and white patients was similar and favorable, outcomes for HPV-negative patients were poor, with blacks having worse survival even after controlling for baseline characteristics.Cancer Prev Res; 8(1); 12–19. ©2014 AACR. See related article by E. Cohen and C. Fakhry, p. 9

Oropharyngeal cancer as a driver of racial outcome disparities in squamous cell carcinoma of the head and neck: 10‐year experience at the University of Maryland Greenebaum Cancer Center

Racial outcome disparities have been observed in head and neck squamous cell carcinoma (HNSCC) with diminished survival for black patients compared with white patients.

Oropharyngeal cancer (OPC) drives racial outcome disparities in squamous cell carcinoma of the head and neck (HNSCC): Ten year experience at the university of maryland greenebaum cancer center (UMGCC)

Racial outcome disparities have been observed in head and neck squamous cell carcinoma (HNSCC) with diminished survival for black patients compared with white patients.

Effects of Toll-like receptor signals in T-cell neoplasms

T-cell neoplasms have poor prognosis and few effective therapeutic options. Therefore, identification of factors in T-cell leukemia/lymphoma that are associated with cancer progression may represent novel therapeutic targets. Recent studies have highlighted a previously unappreciated role for the expression of Toll-like receptors (TLRs) on T cells and their effects on cell survival and proliferation. TLRs can bind exogenous molecules derived from pathogens as well as endogenous self-ligands released from damaged cells. Recent reports demonstrate that TLR engagement on primary mouse or human T cells enhances proliferation and/or cell survival. The mechanisms by which TLR stimulation on T cells influences these parameters and the different T-cell subsets that are affected by TLR stimulation are currently under investigation. Furthermore, neither the biological importance of stimulating TLRs on neoplastic T cells nor the prevalence of TLR expression in T-cell malignancies have yet to be characterized. Based on published reports and compelling preliminary data, we propose that the activation of the TLR-MyD88 signaling pathway in neoplastic T cells contributes to disease progression by reducing cell death and enhancing cell division. In this article, we present both theoretical arguments and experimental data in support of this hypothesis.

Oropharyngeal cancer as a driver of racial outcome disparities in squamous cell carcinoma of the head and neck: 10-year experience at the University of Maryland Greenebaum Cancer Center: Racial disparities in HNSCC

Racial outcome disparities have been observed in head and neck squamous cell carcinoma (HNSCC) with diminished survival for black patients compared with white patients.