Jarrod J Homer

Relation of a Hypoxia Metagene Derived from Head and Neck Cancer to Prognosis of Multiple Cancers

Affymetrix U133plus2 GeneChips were used to profile 59 head and neck squamous cell cancers. A hypoxia metagene was obtained by analysis of genes whose in vivo expression clustered with the expression of 10 well-known hypoxia-regulated genes (e.g., CA9, GLUT1, and VEGF). To minimize random aggregation, strongly correlated up-regulated genes appearing in >50% of clusters defined a signature comprising 99 genes, of which 27% were previously known to be hypoxia associated. The median RNA expression of the 99 genes in the signature was an independent prognostic factor for recurrence-free survival in a publicly available head and neck cancer data set, outdoing the original intrinsic classifier. In a published breast cancer series, the hypoxia signature was a significant prognostic factor for overall survival independent of clinicopathologic risk factors and a trained profile. The work highlights the validity and potential of using data from analysis of in vitro stress pathways for deriving a biological metagene/gene signature in vivo.

hsa-mir-210 Is a Marker of Tumor Hypoxia and a Prognostic Factor in Head and Neck Cancer

Hypoxia is an important mechanism of treatment resistance in head and neck squamous cell carcinoma (HNSCC). MicroRNAs are short noncoding RNAs that regulate multiple mRNAs and are frequently dysregulated in cancer. The authors have investigated the role of 3 microRNAs, including the hypoxia‐induced hsa‐miR‐210, as potential markers of hypoxia or prognosis.

The small-nucleolar RNAs commonly used for microRNA normalisation correlate with tumour pathology and prognosis.

Background:To investigate small-nucleolar RNAs (snoRNAs) as reference genes when measuring miRNA expression in tumour samples, given emerging evidence for their role in cancer.Methods:Four snoRNAs, commonly used for normalisation, RNU44, RNU48, RNU43 and RNU6B, and miRNA known to be associated with pathological factors, were measured by real-time polymerase chain reaction in two patient series: 219 breast cancer and 46 head and neck squamous cell carcinoma (HNSCC). SnoRNA and miRNA were then correlated with clinicopathological features and prognosis.Results:Small-nucleolar RNA expression was as variable as miRNA expression (miR-21, miR-210, miR-10b). Normalising miRNA PCR expression data to these recommended snoRNAs introduced bias in associations between miRNA and pathology or outcome. Low snoRNA expression correlated with markers of aggressive pathology. Low levels of RNU44 were associated with a poor prognosis. RNU44 is an intronic gene in a cluster of highly conserved snoRNAs in the growth arrest specific 5 (GAS5) transcript, which is normally upregulated to arrest cell growth under stress. Low-tumour GAS5 expression was associated with a poor prognosis. RNU48 and RNU43 were also identified as intronic snoRNAs within genes that are dysregulated in cancer.Conclusion:Small-nucleolar RNAs are important in cancer prognosis, and their use as reference genes can introduce bias when determining miRNA expression.

The role of HPV type in Recurrent Respiratory Papillomatosis

OBJECTIVE Human Papillomavirus (HPV) 6 and 11 are the aetiological agents responsible for Recurrent Respiratory Papillomatosis (RRP). There is general consensus that HPV11 results in more aggressive disease compared to HPV6. METHOD Pubmed was searched using the terms respiratory papillomatosis, HPV 6 and HPV11. Comparisons were made in the outcomes of HPV6 versus HPV11 positive RRP disease. RESULTS There are numerous sub-types or variants of both HPV6 and HPV11. These sub-types have different activities at least in-vitro. The numbers of different HPV types within RRP tissue may be more extensive than initially appeared. This depends specifically upon the HPV types tested for. CONCLUSION The clinical differences between HPV6 and HPV11 disease may not be accurately predictable as these viruses exist in numerous sub-types. Also, RRP tissue may contain more than one subtype or even be co-infected with other viruses that may influence outcome. In-vitro studies upon cell lines are a reasonable starting point for evaluation of these differences.

A 26-Gene Hypoxia Signature Predicts Benefit from Hypoxia-Modifying Therapy in Laryngeal Cancer but Not Bladder Cancer

Purpose: Tumor hypoxia is associated with a poor prognosis, hypoxia modification improves outcome, and hypoxic status predicts benefit from treatment. Yet, there is no universal measure of clinical hypoxia. The aim of this study was to investigate whether a 26-gene hypoxia signature predicted benefit from hypoxia-modifying treatment in both cancer types. Experimental Design: Samples were available from 157 T2–T4 laryngeal cancer and 185 T1–T4a bladder cancer patients enrolled on the accelerated radiotherapy with carbogen and nicotinamide (ARCON) and bladder carbogen nicotinamide (BCON) phase III randomized trials of radiotherapy alone or with carbogen and nicotinamide (CON) respectively. Customized TaqMan low density arrays (TLDA) were used to assess expression of the 26-gene signature using quantitative real-time PCR. The median expression of the 26 genes was used to derive a hypoxia score (HS). Patients were categorized as TLDA-HS low (≤median) or TLDA-HS high (>median). The primary outcome measures were regional control (RC; ARCON) and overall survival (BCON). Results: Laryngeal tumors categorized as TLDA-HS high showed greater benefit from ARCON than TLDA-HS low tumors. Five-year RC was 81% (radiotherapy alone) versus 100% (CON) for TLDA-HS high (P = 0.009). For TLDA-HS low, 5-year RC was 91% (radiotherapy alone) versus 90% (CON; P = 0.90). TLDA-HS did not predict benefit from CON in bladder cancer. Conclusion: The 26-gene hypoxia signature predicts benefit from hypoxia-modifying treatment in laryngeal cancer. These findings will be evaluated in a prospective clinical trial. Clin Cancer Res; 19(17); 4879–88. ©2013 AACR.

Prognostic Significance of Tumor Hypoxia Inducible Factor–1α Expression for Outcome After Radiotherapy in Oropharyngeal Cancer

PURPOSE Head-and-neck squamous cell carcinoma (HNSCC) represents a heterogeneous group of patients in terms of subsite, treatment, and biology. Currently most management decisions are based on clinical parameters with little appreciation of patient differences in underlying tumor biology. We investigated the prognostic significance of clinicopathologic features and tumor hypoxia-inducible factor-1alpha (HIF-1alpha) expression in a homogeneous series of patients who underwent radiotherapy. METHODS AND MATERIALS An audit identified 133 consecutive patients with histologically proven squamous cell carcinoma of the tonsil or tongue base. All patients received primary radiotherapy between 1996 and 2001. Tumor HIF-1alpha expression was examined in 79 patients. RESULTS Features associated with poor locoregional control were low Hb level (p = 0.05) and advancing T (p = 0.008), N (p = 0.03), and disease (p = 0.008) stage. HIF-1alpha expression was a more significant adverse prognostic factor in the tonsil (hazard ratio [HR], 23.1; 95% confidence interval [CI]. 3.04-176.7) than the tongue-base tumor (HR, 2.86; 95% CI, 1.14-7.19) group (p = 0.03, test for interaction). High tumor HIF-1alpha expression was associated with low blood Hb levels (p = 0.03). In a multivariate analysis HIF-1alpha expression retained prognostic significance for locoregional control (HR, 7.10; 95% CI, 3.07-16.43) and cancer-specific survival (HR, 9.19; 95% CI, 3.90-21.6). CONCLUSIONS There are significant differences in radiation therapy outcome within a homogeneous subsite of the oropharynx related to molecular marker expression. The work highlights the importance of studying homogeneous groups of patients in HNSCC, and the complex interrelationships between tumor biology and clinicopathologic factors. The establishment of tumor-type specific markers would represent a major advance in this area.

Phase II study of cisplatin and imatinib in advanced salivary adenoid cystic carcinoma

Patients with adenoid cystic carcinoma of the salivary glands show over-expression of KIT in a high proportion of cases. Options for systemic treatment are limited in locally advanced and metastatic disease. We explored the efficacy of imatinib and cisplatin combined in this group of patients. A Gehans two-stage, phase II trial was conducted on 28 patients. Those with progressive, locally advanced, and metastatic disease with an over-expression of KIT were treated with single agent imatinib 800 mg daily for two months, followed by a combination of imatinib 400mg daily and cisplatin 80 mg/m(2) at four-weekly intervals for six cycles. This was followed by maintenance single agent imatinib 400mg daily until the disease progressed. Response was monitored using fluorodeoxyglucose positron emission tomography (FDG-PET) and morphological imaging using computed tomography, magnetic resonance, and chest radiographs (CT/MRI/CXR). Morphological imaging showed partial response in three of 28 patients, and five patients showed a response on FDG-PET. In addition, 19 patients had useful stabilisation of disease. The median time to progression and overall survival was 15 months (range 1-43) and 35 months (range 1-75), respectively. The combination of imatinib and cisplatin was reasonably well tolerated. This combination may provide stabilisation in locally advanced and metastatic adenoid cystic carcinoma of the salivary glands.

Development and validation of a nomogram for prediction of survival and local control in laryngeal carcinoma patients treated with radiotherapy alone: a cohort study based on 994 patients.

INTRODUCTION To advise laryngeal carcinoma patients on the most appropriate form of treatment, a tool to predict survival and local control is needed. MATERIALS AND METHODS We performed a population-based cohort study on 994 laryngeal carcinoma patients, treated with RT from 1977 until 2008. Two nomograms were developed and validated. Performance of the models is expressed as the Area Under the Curve (AUC). RESULTS Unfavorable prognostic factors for overall survival were low hemoglobin level, male sex, high T-status, nodal involvement, older age, lower EQD(2T) (total radiation dose corrected for fraction dose and overall treatment time), and non-glottic tumor. All factors except tumor location were prognostic for local control. The AUCs were 0.73 for overall survival and 0.67 for local control. External validation of the survival model yielded AUCs of 0.68, 0.74, 0.76 and 0.71 for the Leuven (n=109), the VU Amsterdam (n=178), the Manchester (n=403) and the NKI cohort (n=205), respectively, while the validation procedure for the local control model resulted in AUCs of 0.70, 0.71, 0.72 and 0.62. The resulting nomograms were made available on the website www.predictcancer.org. CONCLUSIONS For patients with a laryngeal carcinoma treated with RT alone, we have developed visual, easy-to-use nomograms for the prediction of overall survival and primary local control. These models have been successfully validated in four external centers.

Clinical and biological factors affecting response to radiotherapy in patients with head and neck cancer: a review.

Objective:  The main aim of this article was to review the clinical and biological factors that have been shown to influence the response of the head and neck squamous cell carcinoma (HNSCC) to primary radiotherapy and briefly discuss how some of these factors could be exploited to improve outcome.

Molecular and cellular processes underlying the hallmarks of head and neck cancer

The hallmarks of cancer were updated by Hanahan and Weinberg in 2011. Here we discuss the updated hallmarks in relation to what is known of the molecular and cellular processes underlying the development of head and neck squamous cell carcinoma (HNSCC). Several mechanisms are described, and recent surveys of HNSCC suggest a limited number of mutations, from which more mechanisms may emerge. There are also epigenetic changes to the control of normal processes. More than one mechanism underlies each hallmark. Processes essential to the development of HNSCC need not be essential to the proliferation of the fully developed tumour. Attention is paid to the emerging hallmarks, deregulation of cellular energy metabolism and evasion of immune destruction, and enabling characteristics, genome instability and mutation and tumour-promoting inflammation. HNSCC may adapt to hypoxia, suppress HLA expression, and express Toll-like receptors to facilitate inflammation, which support the proliferation of the tumour.