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author:("Mehra, range")
1.  Quantification of excision repair cross complementing group 1 (ERCC1) and survival in p16-negative squamous cell head and neck cancers 
Multimodality treatment for squamous cell carcinoma of the head and neck (SCCHN) often involves radiation (RT) and cisplatin-based therapy. Elevated activity of DNA repair mechanisms, such as the nucleotide excision repair (NER) pathway, of which ERCC1 is a rate-limiting element, are associated with cisplatin and possibly RT resistance. We have determined ERCC1 expression in HPV-negative SCCHN treated with surgery (+/− adjuvant RT/chemoradiation (CRT)).
Experimental Design
We assessed ERCC1 protein expression in archival tumors using automated, quantitative analysis (AQUA) immunohistochemistry (IHC) and three antibodies to ERCC1 (8F1 (2009, Lab Vision), FL297 (Santa Cruz) and HPA029773 (Sigma)). Analysis with Classification and Regression Tree Methods (CART) ascertained the cut-points between high/low ERCC1 expression. Multivariable analysis adjusted for age, T and N stage. Kaplan-Meier curves determined median survival. ERCC1 expression at initial tumor presentation and in recurrent disease were compared. Performance characteristics of antibodies were assessed.
ERCC1 low/high groups were defined based on AQUA analysis with 8F1/2009, FL297 and HPA029773. Among patients treated with surgery plus adjuvant RT/CRT, longer median survival was observed in ERCC1 low tumors versus ERCC1 high (64 vs. 29 months, p=0.02 (HPA029773)). Data obtained with HPA029773 indicated no survival difference among patients treated only with surgery. Recurrent cancers had lower ERCC1 AQUA scores than tumors from initial presentation. Extensive characterization indicated optimal specificity and performance by the HPA029773 antibody.
Using AQUA, with the specific ERCC1 antibody HPA029773, we found a statistical difference in survival among high/low ERCC1 tumors from patients treated with surgery and adjuvant RT.
PMCID: PMC4045641  PMID: 24088734
ERCC1; radiation; head and neck cancer; immunohistochemistry
2.  Dysplasia at the Margin? Investigating the Case for Subsequent Therapy in ‘Low-Risk’ Squamous Cell Carcinoma of the Oral Tongue 
Oral oncology  2013;49(11):1083-1087.
This is a retrospective analysis of the impact of moderate dysplasia at the resection margin for early stage cancer of the oral tongue.
Materials and Methods
Patients with T1-2N0 oral tongue cancer treated with surgery alone at Fox Chase Cancer Center (FCCC) from 1990 – 2010 were reviewed. Tumor and margin characteristics were abstracted from the pathology report.
Overall survival (OS), disease-free survival (DFS) and local control (LC) were calculated using the Kaplan Meier method. Predictors of LC, OS and DFS were analyzed.
126 patients met the inclusion criteria. Dysplasia was present at the final margin in 36% of the cases (severe: 9%, moderate: 15%, mild: 12%).
Median follow-up was 52 months. 3 and 5-year actuarial LC for the entire cohort was 77 and 73%, respectively. Actuarial 5-year LC and DFS were significantly worse for patients with moderate or severe dysplasia at the margin vs. none or mild dysplasia at the margin (49 v 82%, p = 0.005 and 49 v 80%, p = 0.008, respectively); 3-year comparisons were not significant. When analyzed separately, the detrimental local effect of moderate dysplasia at the margin persisted (p = 0.02) and the effect of severe dysplasia at the margin was approaching significance (p = 0.1). Mild dysplasia at the margin did not significantly impair LC or DFS.
Multivariate analysis demonstrated worse LC (HR: 2.99, p=0.006) and DFS (HR: 2.84, p=0.008) associated with severe or moderate dysplasia at the margin.
Both severe and moderate dysplasia at the margin appear to be correlated with inferior LC and DFS. Additional therapy may be justified, despite added morbidity.
PMCID: PMC4037753  PMID: 24054332
Oral tongue cancer; dysplasia; margin
3.  Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer 
The New England journal of medicine  2014;370(13):1189-1197.
Non–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.
In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib.
A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5).
Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; number, NCT01283516.)
PMCID: PMC4079055  PMID: 24670165
4.  The role and targeting of Aurora kinases in head and neck cancer 
The Lancet. Oncology  2013;14(10):e425-e435.
Controlled activation of the Aurora kinases regulates mitotic progression in normal cells. Overexpression and hyperactivation of the Aurora-A and -B kinases play a leading role in tumorigenesis, inducing aneuploidy and genomic instability. In squamous cell carcinomas of the head and neck (SCCHN), overexpression of Aurora-A is associated with decreased survival, and reduction of Aurora-A and -B expression inhibits SCCHN cell growth and increases apoptosis. In this article, we provide a basic overview of the biological functions of Aurora kinases in normal cells and in cancer, and review both small studies and high throughput datasets that implicate Aurora-A, particularly, in the pathogenesis of SCCHN. Early phase clinical trials are beginning to evaluate the activity of small molecule inhibitors of the Aurora kinases. We summarize the state of current trials evaluating Aurora inhibitors in SCCHN, and discuss rational directions for future drug combination trials and biomarkers for use with Aurora-inhibiting agents.
PMCID: PMC4139969  PMID: 23993387
5.  Extranodal Extension of Metastatic Papillary Thyroid Carcinoma: Correlation with Biochemical Endpoints, Nodal Persistence, and Systemic Disease Progression 
Thyroid  2013;23(9):1099-1105.
The impact of extranodal extension (ENE) of metastatic papillary thyroid carcinoma (PTC) on short- and long-term clinical outcomes, including biochemical testing, has not been reported.
This single-institution National Cancer Institute-designated Comprehensive Cancer Center cohort study included patients with macroscopic metastases and excluded patients with gross residual disease after surgery, distant disease, or poorly differentiated papillary carcinoma. A suppressed or stimulated thyroglobulin (Tg) <1 ng/mL, without suspicious imaging or anti-thyroglobulin antibodies, after radioactive iodine (RAI) treatment was termed an excellent or “complete biochemical response” (CR).
Of 89 subjects included, 60 previously untreated patients underwent total thyroidectomy and therapeutic neck dissection; 29 additional patients underwent a neck dissection for persistence or recurrence after prior surgery and RAI administration. ENE, identified in 29 patients (33%), was associated with T4 classification (p=0.02) and involvement of a greater number of nodes (median 11 vs. 5, p=0.03). ENE was associated with a 20% increased risk of nodal persistence necessitating additional surgery (p=0.02). In a multivariable analysis, ENE, T4 classification, and recurrence/persistence proved to be independent predictors of systemic disease progression (ENE: hazard ratio [HR] 4.3 [95% confidence interval (CI) 1.2–15], p=0.02; T4 classification: HR 4.2 [CI 1.3–14], p=0.01; recurrent/persistent status: HR 3.6 [CI 1.1–12], p=0.035). Nodal or systemic disease progression was rare after a biochemical CR; in contrast, in previously untreated patients, stimulated Tg levels (sTg) >50 ng/mL prior to initial RAI administration, heralded the progression of nodal disease, and also predicted the eventual development of systemic disease (p=0.0001). Of those with a sTg >50 ng/mL, over 70% underwent surgery for nodal persistence within five years. The presence of ENE diminished the odds of a biochemical CR (odds ratio 3.5% [CI 1.3–10], p=0.02), and increased the probability that the sTg levels after surgery will exceed 50 ng/mL (odds ratio 5 [CI 1.2–21], p=0.03). Following surgery for tumor persistence, 25% of those with ENE were rendered biochemically free of disease.
ENE diminishes the probability of a biochemical CR after treatment for regional metastatic PTC, and increases the probability of tumor persistence after initial resection, likely from abundant metastasis. ENE and nodal persistence independently predict eventual systemic disease progression.
PMCID: PMC3770240  PMID: 23421588
6.  Unilateral Neck Therapy in the Human Papillomavirus-Era: Virus Association does not Alter Accepted Regional Spread Patterns 
Head & neck  2012;35(2):160-164.
To determine whether the incidence of bilateral neck disease tonsil cancer is rising.
We reviewed tonsil cancer incidence data from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute.
The annual incidence of advanced neck disease (≥N2) with small primary tonsil cancer is increasing (annual percent change (APC), p < 0.05) during two evaluable time frames (1988–2003 and 2004–2008). The increase for small primary tonsil cancer from 2004–2008 is associated with increased ipsilateral disease (ie, T1-2N2ab, APC 10.6%, p < 0.05) rather than bilateral neck disease (T1-2N2c, APC 5.9%, APC = NS). The increase in bilateral neck disease is less than the overall rise in T1-2 tonsil cancer (APC 7.2%, p < 0.05).
In the HPV era bilateral neck disease is increasingly common. This appears to be a consequence of increasing incidence of tonsil cancer rather than a new biologic behavior.
PMCID: PMC4037756  PMID: 22302641
Tonsil; SEER; HPV; Unilateral Therapy; Stage Migration
7.  Targeting C4-demethylating genes in the cholesterol pathway sensitizes cancer cells to EGFR inhibitors via increased EGFR degradation 
Cancer discovery  2012;3(1):96-111.
Persistent signaling by the oncogenic epidermal growth factor receptor (EGFR) is a major source of cancer resistance to EGFR targeting. We established that inactivation of two sterol biosynthesis pathway genes, SC4MOL (sterol C4-methyl oxidase-like) and its partner NSDHL (NADP-dependent steroid dehydrogenase-like), sensitized tumor cells to EGFR inhibitors. Bioinformatics modeling of interactions for the sterol pathway genes in eukaryotes allowed us to hypothesize, and then extensively validate an unexpected role for SC4MOL and NSDHL in controlling the signaling, vesicular trafficking and degradation of EGFR and its dimerization partners, ERBB2 and ERBB3. Metabolic block upstream of SC4MOL with ketoconazole or CYP51A1 siRNA rescued cancer cell viability and EGFR degradation. Inactivation of SC4MOL markedly sensitized A431 xenografts to cetuximab, a therapeutic anti-EGFR antibody. Analysis of Nsdhl-deficient Bpa1H/+ mice confirmed dramatic and selective loss of internalized PDGFR in fibroblasts, and reduced activation of EGFR and its effectors in regions of skin lacking NSDHL.
PMCID: PMC3546138  PMID: 23125191
8.  Protein-intrinsic and signaling network-based sources of resistance to EGFR- and ErbB family-targeted therapies in head and neck cancer 
Agents targeting EGFR and related ErbB family proteins are valuable therapies for the treatment of many cancers. For some tumor types, including squamous cell carcinomas of the head and neck (SCCHN), antibodies targeting EGFR were the first protein-directed agents to show clinical benefit, and remain a standard component of clinical strategies for management of the disease. Nevertheless, many patients display either intrinsic or acquired resistance to these drugs; hence, major research goals are to better understand the underlying causes of resistance, and to develop new therapeutic strategies that boost the impact of EGFR/ErbB inhibitors. In this review, we first summarize current standard use of EGFR inhibitors in the context of SCCHN, and described new agents targeting EGFR currently moving through pre-clinical and clinical development. We then discuss how changes in other transmembrane receptors, including IGF1R, c-Met, and TGF-β, can confer resistance to EGFR-targeted inhibitors, and discuss new agents targeting these proteins. Moving downstream, we discuss critical EGFR-dependent effectors, including PLC-γ; PI3K and PTEN; SHC, GRB2, and RAS and the STAT proteins, as factors in resistance to EGFR-directed inhibitors and as alternative targets of therapeutic inhibition. We summarize alternative sources of resistance among cellular changes that target EGFR itself, through regulation of ligand availability, post-translational modification of EGFR, availability of EGFR partners for hetero-dimerization and control of EGFR intracellular trafficking for recycling versus degradation. Finally, we discuss new strategies to identify effective therapeutic combinations involving EGFR-targeted inhibitors, in the context of new system level data becoming available for analysis of individual tumors.
PMCID: PMC3195944  PMID: 21920801
9.  Activity of XL184 (Cabozantinib), an Oral Tyrosine Kinase Inhibitor, in Patients With Medullary Thyroid Cancer 
Journal of Clinical Oncology  2011;29(19):2660-2666.
XL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical models. Early observations of clinical benefit in a phase I study of cabozantinib, which included patients with medullary thyroid cancer (MTC), led to expansion of an MTC-enriched cohort, which is the focus of this article.
Patients and Methods
A phase I dose-escalation study of oral cabozantinib was conducted in patients with advanced solid tumors. Primary end points included evaluation of safety, pharmacokinetics, and maximum-tolerated dose (MTD) determination. Additional end points included RECIST (Response Evaluation Criteria in Solid Tumors) response, pharmacodynamics, RET mutational status, and biomarker analyses.
Eighty-five patients were enrolled, including 37 with MTC. The MTD was 175 mg daily. Dose-limiting toxicities were grade 3 palmar plantar erythrodysesthesia (PPE), mucositis, and AST, ALT, and lipase elevations and grade 2 mucositis that resulted in dose interruption and reduction. Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response. Overall, 18 patients experienced tumor shrinkage of 30% or more, including 17 (49%) of 35 patients with MTC with measurable disease. Additionally, 15 (41%) of 37 patients with MTC had stable disease (SD) for at least 6 months, resulting in SD for 6 months or longer or confirmed partial response in 68% of patients with MTC.
Cabozantinib has an acceptable safety profile and is active in MTC. Cabozantinib may provide clinical benefit by simultaneously targeting multiple pathways of importance in MTC, including MET, VEGFR2, and RET. A global phase III pivotal study in MTC is ongoing ( number NCT00215605).
PMCID: PMC3646303  PMID: 21606412
10.  The contribution of cetuximab in the treatment of recurrent and/or metastatic head and neck cancer 
Recurrent and/or metastatic squamous cell carcinoma of the head and neck (HNSCC) continues to be a source of significant morbidity and mortality worldwide. Agents that target the epidermal growth factor receptor (EGFR) have demonstrated beneficial effects in this setting. Cetuximab, a monoclonal antibody against the EGFR, improves locoregional control and overall survival when used as a radiation sensitizer in patients with locoregionally advanced HNSCC undergoing definitive radiation therapy with curative intent. Cetuximab is also active as monotherapy in patients whose cancer has progressed on platinum-containing therapy. In the first-line setting for incurable HNSCC, cetuximab added to platinum-based chemotherapy significantly improves overall survival compared with standard chemotherapy alone. These positive results have had a significant impact on the standard of care for advanced HNSCC. In this review, we will discuss the mechanism of action, clinical data and common toxicities that pertain to the use of cetuximab in the treatment of advanced incurable HNSCC.
PMCID: PMC2921255  PMID: 20714355
cetuximab; squamous cell carcinoma of the head and neck; epidermal growth factor receptor
11.  New agents in the Treatment for Malignancies of the Salivary and Thyroid Glands 
PMCID: PMC2659655  PMID: 19010274
malignant salivary gland tumors; thyroid cancer; tyrosine kinase inhibitors
12.  The Role of Cetuximab for the Treatment of Squamous Cell Carcinoma of the Head and Neck 
Squamous cell carcinoma of the head and neck (HNSCC) while curable in many cases with surgery, radiation, and chemotherapy, remains a disease that is associated with significant morbidity and mortality. Agents that target the epidermal growth factor receptor (EGFR) have demonstrated activity in this disease. Cetuximab, a monoclonal antibody, is FDA-approved in conjunction with radiation for locally advanced, potentially curable disease, and as a single agent for incurable recurrent/metastatic disease. In addition, there are more recent data showing a survival benefit for patients with recurrent/metastatic disease who were treated with a 1st-line regimen of platinum, fluorouracil and cetuximab. These promising results have had a significant impact on the standard of care for HNSCC, and have prompted further research on the role of EGFR inhibitors in the treatment of HNSCC. In the following review, we will discuss the history, mechanism, and clinical trials that pertain to the role of cetuximab in the treatment of HNSCC.
PMCID: PMC2745918  PMID: 18997665
5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome.
Twenty-three patients were tested for DPD deficiency after excessive toxicities from 5-FU and/or capecitabine. DPD activity was evaluated by Peripheral Blood Mononuclear Cell (PBMC) radioassay, genotyping of DPYD gene by Denaturing High Performance Liquid Chromatography (DHPLC), or 2-13C uracil breath test (UraBT).
Of 23 patients with excessive toxicities from 5-FU and/or capecitabine, 7 (30%) were DPD deficient with a median age of 66 years, M:F ratio = 1.3:1 and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). DPD activity ranged from 0.064 – 0.18nmol/min/mg. Three patients were treated with bolus 5-FU/LV, two with capecitabine, and two with high dose bolus 5-FU with 2′, 3′, 5′-tri-O-acetyluridine. Toxicities included mucositis (71%), diarrhea (43%), skin rash (43%), memory loss/altered mental status (43%), cytopenias (43%), nausea (29%), hypotension (14%), respiratory distress (14%) and acute renal failure (14%) Re-challenge with capecitabine in one patient after the Mayo regimen caused grade 3 hand-foot syndrome. Genotypic analysis of the DPYD gene in one patient with severe leucopenia demonstrated a heterozygous mutation (IVS14+1 G>A, DPYD). The UraBT in two patients of 112.8; PDR of 49.4%) and borderline normal values revealed 1 to be DPD-deficient (DOB50 of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths among (DOB50 DPD-deficient patients (28%).
DPD deficiency was observed in several ethnicities. Akin to 5-FU, capecitabine can also lead to severe toxicities in DPD-deficient patients. Screening patients for DPD deficiency prior to administration of 5-FU or capecitabine using UraBT could potentially lower risk of toxicity. Future studies should validate this technique.
PMCID: PMC2563423  PMID: 18846242
5-Fluorouracil; Fluoropyrimidines; Capecitabine; Uridine; DPD; DPYD gene; Neutropenia; HFS; Mucositis

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