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1.  A pilot study of psychosocial functioning and vascular endothelial growth factor in head and neck cancer patients 
Head & neck  2013;36(8):1113-1119.
Psychosocial functioning is associated with vascular endothelial growth factor (VEGF) in various patient populations. This study examined whether psychosocial functioning in patients with head and neck squamous cell carcinoma (HNSCC) is associated with tumor VEGF expression, a protein that stimulates angiogenesis and is associated with poor prognosis.
Forty-two newly diagnosed patients completed assessments of psychosocial functioning (i.e. depressive symptoms, perceived stress, anxiety, social support) prior to surgery. Tumor samples were obtained for VEGF analysis and HPV-typing.
Poorer psychosocial functioning was associated with greater VEGF expression controlling for disease stage (OR=4.55, 95% CI = 1.72, 12.0, p < 0.01). When examined by HPV-status, the association between psychosocial functioning and VEGF remained significant among HPV-negative patients (OR=5.50, 95% CI = 1.68, 17.3, p < 0.01), but not among HPV-positive patients.
These findings inform our understanding of the biobehavioral pathways that may contribute to poor outcomes in non-HPV-associated HNSCCs.
PMCID: PMC4099415  PMID: 23804308
depressive symptoms; perceived stress; anxiety; social support; human papillomavirus
2.  Prognostic biomarkers in phase II trial of cetuximab-containing induction and chemoradiation in resectable HNSCC: Eastern Cooperative Oncology Group E2303 
We sought to evaluate correlation between tissue biomarker expression (using standardized, quantitative immunofluorescence) and clinical outcome in E2303 trial.
Experimental Design
Sixty-three eligible patients with operable stage III/IV HNSCC participated in ECOG 2303, phase II trial of induction chemotherapy with weekly cetuximab, paclitaxel and carboplatin followed by chemoradiation with same regimen. A tissue microarray (TMA) was constructed and epidermal growth factor receptor (EGFR), ERK1/2, Met, Akt, STAT3, β-catenin, E-cadherin, EGFR Variant III, insulin-like growth factor-1 receptor, NF-kappa b, p53, PI3Kp85, PI3Kp110a, PTEN, NRAS, and pRb protein expression levels were assessed using automated quantitative protein analysis (AQUA). For each dichotomized biomarker, overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) were estimated by Kaplan-Meier method and compared using log-rank tests. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and test for significance.
Forty-two of 63 patients with TMA data on at least one biomarker were included in the biomarker analysis. Tumor ERK1/2 levels were significantly associated with PFS (HR (low/high)=3.29, p=0.026) and OS (HR (low/high)=4.34, p=0.008). On multivariable Cox regression analysis, ERK1/2 remained significantly associated with OS (p=0.024) and PFS (p=0.022) after controlling for primary site (oropharynx vs. non-oropharynx) and disease stage (III vs. IV), respectively. Clustering analysis revealed that clusters indicative of activated RAS/MAPK/ERK and/or PI3K/Akt pathways were associated with inferior OS and/or PFS and maintained significance in multivariable analysis.
These results implicate PI3K/Akt and RAS/MAPK/ERK pathways in resistance to cetuximab-containing chemoradiation in HNSCC. Large prospective studies are required to validate these results.
PMCID: PMC4049169  PMID: 24700741
3.  Predicting survival in head and neck squamous cell carcinoma from TP53 mutation 
Human genetics  2014;134(5):497-507.
For TP53-mutated head and neck squamous cell carcinomas (HNSCCs), the codon and specific amino acid sequence change resulting from a patient’s mutation can be prognostic. Thus, developing a framework to predict patient survival for specific mutations in TP53 would be valuable. There are many bioinformatics and functional methods for predicting the phenotypic impact of genetic variation, but their overall clinical value remains unclear. Here, we assess the ability of 15 different methods to predict HNSCC patient survival from TP53 mutation, using TP53 mutation and clinical data from patients enrolled in E4393 by the Eastern Cooperative Oncology Group (ECOG), which investigated whether TP53 mutations in surgical margins were predictive of disease recurrence. These methods include: server-based computational tools SIFT, PolyPhen-2, and Align-GVGD; our in-house POSE and VEST algorithms; the rules devised in Poeta et al. with and without considerations for splice-site mutations; location of mutation in the DNA-bound TP53 protein structure; and a functional assay measuring WAF1 transactivation in TP53-mutated yeast. We assessed method performance using overall survival (OS) and progression-free survival (PFS) from 420 HNSCC patients, of whom 224 had TP53 mutations. Each mutation was categorized as “disruptive” or “non-disruptive”. For each method, we compared the outcome between the disruptive group vs. the non-disruptive group. The rules devised by Poeta et al. with or without our splice-site modification were observed to be superior to others. While the differences in OS (disruptive vs. non-disruptive) appear to be marginally significant (Poeta rules + splice rules, P = 0.089; Poeta rules, P = 0.053), both algorithms identified the disruptive group as having significantly worse PFS outcome (Poeta rules + splice rules, P = 0.011; Poeta rules, P = 0.027). In general, prognostic performance was low among assessed methods. Further studies are required to develop and validate methods that can predict functional and clinical significance of TP53 mutations in HNSCC patients.
PMCID: PMC4324386  PMID: 25108461
4.  Baseline health perceptions, dysphagia and survival in head and neck cancer 
Cancer  2013;120(6):840-847.
Baseline dysphagia, more common than abnormalities on formal swallowing testing, is believed to predict survival in untreated head and neck cancer patients. We hypothesized that patient-reported dysphagia impacts multiple domains of quality of life and predicts disease recurrence and disease-related death.
The Swal-QOL, a dysphagia-specific measure, and the EuroQOL were administered to 159 patients prior to treatment with curative intent, in this prospective cross-sectional cohort study. Logistic regression evaluated associations among clinical and subjective measures. Multivariable competing risk regression tested the impact of clinical, tumor and patient-reported measures on survival.
Baseline dysphagia, pain and diminished patient-reported health state (PRHS) were more closely associated with weight loss prior to treatment and advanced T-classification, than any other clinical feature. However, only 56% (23/40) of patients reporting dysphagia had >5% weight loss. Dysphagia was associated with pain and/or diminished PRHS, independent of weight loss. Female patients were more likely to report pain and dysphagia, while males reported dysphagia alone. Dysphagia predicted recurrence and disease related death, adjusting for T and N classification, performance status, smoking and weight loss, and accounting for competing risks of death (RFS: HR 3.8 (95%CI 1.7–8.4), p=.001; DOD HR 4.2 (95%CI 1.04–5), p=.004).
Baseline dysphagia affects multiple domains of quality of life and general health perceptions in untreated head and neck cancer patients. A dysphagia measure captures the effort of maintaining nutrition with cancer, identifying patients with or at risk for weight loss, and predisposed to disease recurrence and disease-related death.
PMCID: PMC3951722  PMID: 24352973
5.  EGFR-directed antibodies increase the risk of severe infection in cancer patients 
BMC Medicine  2015;13:37.
Monoclonal antibodies directed to the epidermal growth factor receptor (EGFR) have a role in the management of several solid tumors, alone or in combination with chemotherapy or radiation therapy. Recognized toxicities have included hypersensitivity reactions, rash, hypomagnesemia, and constitutional symptoms, but the possibility that the agents lead to immunosuppression or increase the risk of infection has only recently been recognized. Two latest meta-analyses, including the recently published article by Qi et al., highlight the increased risk of severe infections with EGFR-directed monoclonal antibodies. Further studies are needed to better identify the association between EGFR-directed monoclonal antibody treatment and infection, as well as to elucidate the mechanism of this toxicity and to develop tools to identify patients at increased risk for these complications. In the meantime, awareness of the role of EGFR-directed antibodies in increased infection risk may have implications for dose modification strategies in both clinical trial design and the practice of oncology.
Please see related article:
PMCID: PMC4336483  PMID: 25857245
EGFR; Infection; Monoclonal antibody
6.  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
7.  Afatinib versus placebo as adjuvant therapy after chemoradiation in a double-blind, phase III study (LUX-Head & Neck 2) in patients with primary unresected, clinically intermediate-to-high-risk head and neck cancer: study protocol for a randomized controlled trial 
Trials  2014;15:469.
Over 50% of patients with head and neck squamous cell carcinoma (HNSCC) present with locoregionally advanced disease. Those at intermediate-to-high risk of recurrence after definitive therapy exhibit advanced disease based on tumour size or lymph node involvement, non-oropharynx primary sites, human papillomavirus (HPV)-negative oropharyngeal cancer, or HPV-positive oropharynx cancer with smoking history (>10-pack-years). Non-surgical approaches include concurrent chemoradiotherapy, induction chemotherapy followed by definitive radiotherapy or chemoradiotherapy, or radiotherapy alone. Following locoregional therapies (including surgical salvage of residual cervical nodes), no standard intervention exists. Overexpression of epidermal growth factor receptor (EGFR), an ErbB family member, is associated with poor prognosis in HNSCC. EGFR-targeted cetuximab is the only targeted therapy that impacts overall survival and is approved for HNSCC in the USA or Europe. However, resistance often occurs, and new approaches, such as targeting multiple ErbB family members, may be required. Afatinib, an irreversible ErbB family blocker, demonstrated antiproliferative activity in preclinical models and comparable clinical efficacy with cetuximab in a randomized phase II trial in recurrent or metastatic HNSCC. LUX-Head & Neck 2, a phase III study, will assess adjuvant afatinib versus placebo following chemoradiotherapy in primary unresected locoregionally advanced intermediate-to-high-risk HNSCC.
Patients with primary unresected locoregionally advanced HNSCC, in good clinical condition with unfavourable risk of recurrence, and no evidence of disease after chemoradiotherapy will be randomized 2:1 to oral once-daily afatinib (40 mg starting dose) or placebo. As HPV status will not be determined for eligibility, unfavourable risk is defined as non-oropharynx primary site or oropharynx cancer in patients with a smoking history (>10 pack-years). Treatment will continue for 18 months or until recurrence or unacceptable adverse events occur. The primary endpoint measure is duration of disease-free survival; secondary endpoint measures are disease-free survival rate at 2 years, overall survival, health-related quality of life and safety.
Given the unmet need in the adjuvant treatment of intermediate-to-high-risk HNSCC patients, it is expected that LUX-Head & Neck 2 will provide new insights into treatment in this setting and might demonstrate the ability of afatinib to significantly improve disease-free survival, compared with placebo.
Trial registration NCT01345669.
Electronic supplementary material
The online version of this article (doi:10.1186/1745-6215-15-469) contains supplementary material, which is available to authorized users.
PMCID: PMC4289298  PMID: 25432788
Adjuvant; Afatinib; Head and neck; Local advanced; Phase III; Unfavourable risk
8.  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
9.  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
10.  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
11.  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
12.  Phase III Randomized, Placebo-Controlled Trial of Docetaxel With or Without Gefitinib in Recurrent or Metastatic Head and Neck Cancer: An Eastern Cooperative Oncology Group Trial 
Journal of Clinical Oncology  2013;31(11):1405-1414.
We hypothesized that the addition of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, to docetaxel would enhance therapeutic efficacy in squamous cell carcinoma of the head and neck (SCCHN).
Patients and Methods
Patients with recurrent or metastatic SCCHN with Eastern Cooperative Oncology Group (ECOG) performance status of 2, or patients with ECOG performance status of 0 to 2 but were previously treated with chemotherapy, were randomly assigned to receive weekly docetaxel plus either placebo (arm A) or gefitinib 250 mg/d, orally (arm B) until disease progression. At the time of progression, patients in the placebo arm could receive single-agent gefitinib. EGFR, c-MET, and KRAS mutations and polymorphisms in drug metabolizing enzymes and transporters were evaluated by pyrosequencing.
Two hundred seventy patients were enrolled before the study was closed early at interim analysis (arm A, n = 136; arm B, n = 134). Median overall survival was 6.0 months in arm A versus 7.3 months in arm B (hazard ratio, 0.93; 95% CI, 0.72 to 1.21; P = .60). An unplanned subset analysis showed that gefitinib improved survival in patients younger than 65 years (median 7.6 v 5.2 months; P = .04). Also, there was a trend for improved survival in patients with c-MET wild-type (5.7 v 3.6 months; P = .09) regardless of treatment. Grade 3/4 toxicities were comparable between the two arms except that grade 3/4 diarrhea was more common with docetaxel/gefitinib. Of 18 eligible patients who received gefitinib after disease progression in arm A, one patient had a partial response.
The addition of gefitinib to docetaxel was well tolerated but did not improve outcomes in poor prognosis but otherwise unselected patients with SCCHN.
PMCID: PMC3612594  PMID: 23460714
13.  Markers of Epithelial to Mesenchymal Transition in Association with Survival in Head and Neck Squamous Cell Carcinoma (HNSCC) 
PLoS ONE  2014;9(4):e94273.
Elucidating the molecular phenotype of cancers with high metastatic potential will facilitate the development of novel therapeutic approaches to the disease. Gene expression profiles link epithelial to mesenchymal transition (EMT) phenotype with high-risk HNSCC. We sought to determine the role of protein biomarkers of EMT in head and neck squamous carcinoma (HNSC) prognosis.
Protein expression analysis of EGFR, β-catenin and E-cadherin was performed on a cohort of 102 patients with HNSCC recruited between 1992 and 2005 using automated quantitative protein analysis (AQUA). We evaluated associations with clinicopathological parameters and prognosis.
There were 67 patients with primary squamous cell carcinoma of the head and neck in this cohort who met inclusion criteria and for whom we had complete E-cadherin, beta-catenin and EGFR expression data. High E-cadherin expressers had longer 5-year progression-free survival (PFS) compared to those with low E-cadherin (59.7% versus 40.6%, p = 0.04) and overall survival (OS) (69.6% versus 44.3%, p  = 0.05). Kaplan-Meier analysis showed that patients with low beta-catenin-expressing tumors trended toward worse 5-year PFS (p = 0.057). High EGFR expressers had inferior OS compared to low EGFR expressers (27.7% vs. 54%, p = 0.029). In the multivariable analysis context, E-cadherin remained an independent predictor of improved OS (HR = 0.204, 95% CI 0.043 to 0.972, p = 0.046) while EGFR trended towards significance for OS.
The putative markers of EMT defined within a panel of HNSCC using AQUA are associated with tumors of poor prognosis.
PMCID: PMC3983114  PMID: 24722213
14.  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
15.  A Phase II Study of Capecitabine, Oxaliplatin, and Cetuximab with or Without Bevacizumab as Frontline Therapy for Metastatic Colorectal Cancer. A Fox Chase Extramural Research Study 
Dual inhibition of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) demonstrated initial promise in clinical trials. This phase II study tested the efficacy and safety of capecitabine, oxaliplatin, and cetuximab with or without bevacizumab as first-line treatment for metastatic colorectal cancer patients.
Patients were randomized to receive capecitabine 850 mg/m2 PO twice daily for 14 days, oxaliplatin 130 mg/m2 IV day 1, and cetuximab 400 mg/m2 IV loading dose followed by 250 mg/m2 IV days 1, 8, and 15 with (Arm A) or without (Arm B) bevacizumab 7.5 mg/kg IV day 1 every 21 days. Tumor samples were collected and retrospectively analyzed for KRAS mutation status. The primary endpoint was response rate, with time to progression (TTP) and overall survival (OS) as secondary objectives.
Twenty-three patients (12 in Arm A, 11 in Arm B) were enrolled onto the study. Median follow-up was 25.9 months. Both treatments were well tolerated, with expected higher rates of grade 1/2 hypertension and bleeding in Arm A. The overall response rate was 54% (36.4% in Arm A and 72.7% in Arm B). Median time to progression was 8.7 months in Arm A and 14.4 months in Arm B. The median survival was 18.0 months in Arm A and 42.5 months in Arm B. The study was prematurely terminated after other studies reported inferior outcomes with dual antibody therapy.
Although terminated early, the study supports the detrimental effect of combining VEGF and EGFR inhibition in metastatic colorectal cancer.
PMCID: PMC3400721  PMID: 22294255
Metastatic colon cancer; Vascular endothelial growth factor (VEGF); Epidermal growth factor receptor (EGFR)
16.  Nuclear epidermal growth factor receptor and p16 expression in head and neck squamous cell carcinoma 
The Laryngoscope  2012;122(12):2762-2768.
Epidermal growth factor receptor (EGFR) and p16 [a surrogate marker of human papillomavirus (HPV) infection] expression are strong prognostic factors in patients with head and neck squamous cell carcinoma (HNSCC).
Study Design
We examined expression levels of total and nuclear EGFR as well as p16 status based on evidence that nuclear EGFR may have a role in DNA damage repair.
A HPV-negative (SQ20B) and a HPV-positive (UMSCC47) HNSCC cell line were examined for EGFR and γH2AX expression. A tissue microarray (TMA) containing 123 cores obtained from 101 HNSCC tumors was analyzed for EGFR expression by automated quantitative analysis and p16 expression by immunohistochemical staining (IHC) and these results were correlated with available clinical data.
SQ20B had higher EGFR expression than UMSCC47. Nuclear localization of EGFR upon activation with transforming growth factor-alpha was observed in SQ20B, but not in UMSCC47. SQ20B also had increased γH2AX foci compared to UMSCC47 suggesting that SQ20B has more DNA damage compared to UMSCC47. Total and nuclear EGFR was reliably obtained from 80 of 101 patients. p16 levels were determined in 87 of 101 patients. p16 levels were strongly associated with the oropharyngeal subsite and poorly differentiated histology. Expression of total and nuclear EGFR was higher in p16-negative tumors compared to p16-positive tumors (Wilcoxon Rank Test, p=0.038 and p=0.014, respectively).
Further studies are required to determine a mechanistic link between these two prognostic factors, and the significance of EGFR localization to nucleus has in DNA damage repair upon pathway activation.
PMCID: PMC3574977  PMID: 23086695
HNSCC; nuclear EGFR; p16
17.  Informational Needs of Head and Neck Cancer Patients 
Health and technology  2012;2(1):57-62.
Treatment for head and neck squamous cell carcinoma (HNSCC) can lead to considerable functional impairment. As a result, HNSCC patients experience significant decrements in quality of life, high levels of emotional distress, deteriorations in interpersonal relations, and increased social isolation. Studies suggest that HNSCC patients may have extensive informational and psychosocial needs that are not being adequately addressed. However, few programs have been developed to address the needs of HNSCC patients. Therefore, we conducted a pilot study of HNSCC patients to: 1) characterize patients' informational needs; and 2) describe preferred formats and time points for receiving such information. The majority of participants desired additional information regarding treatment options, managing changes in swallowing and speaking, and staying healthy after treatment. Overall, patients with early-stage disease reported more informational needs compared to patients with advanced disease. Female patients were more likely to desire information about coping with emotional stress and anxiety than male patients. Younger patients (29–49 years) were more interested in receiving information about sexuality after cancer compared to their older (50+) counterparts. Although information was requested throughout the cancer trajectory, most patients preferred to receive such information at diagnosis or within 1–3 months post-treatment. The majority of patients reported having computer and Internet access, and they were most receptive to receiving information delivered via the Internet, from a DVD, or from pamphlets and booklets. The relatively high percentage of patients with computer and Internet access reflects a growing trend in the United States and supports the feasibility of disseminating health information to this patient population via Internet-based programs.
PMCID: PMC3327509  PMID: 22518350
Head and neck cancer; informational needs; Treatment side effects; Internet
18.  Psychological functioning of caregivers for head and neck cancer patients 
Oral Oncology  2011;48(1):18-25.
Patients with head and neck squamous cell carcinoma (HNSCC) often require assistance from family caregivers during the treatment and post-treatment period. This review article sought to summarize current findings regarding the psychological health of HNSCC caregivers, including factors that may be associated with poorer psychological health. Online databases (PUBMED, MEDLINE and PSYCINFO) were searched for papers published in English through September 2010 reporting on the psychological health of caregivers of HNSCC patients. Eleven papers were identified. Caregivers experience poorer psychological health, including higher levels of anxious symptoms, compared to patients and to the general population. Fear of patient cancer recurrence is evident among caregivers and is associated with poorer psychological health outcomes. The 6-month interval following diagnosis is a significant time of stress for caregivers. Greater perceived social support may yield positive benefits for the psychological health of caregivers. To date, there have been relatively few reports on the psychological health of caregivers of HNSCC patients. Well designed, prospective, longitudinal studies are needed to enhance our understanding of how caregiver psychological health may vary over the cancer trajectory and to identify strategies for improving caregiver outcomes.
PMCID: PMC3357183  PMID: 22154127
Caregiving; Psychological health; Emotional distress; Anxiety; Depression; Head and neck cancer
19.  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
20.  A phase II trial of bortezomib followed by the addition of doxorubicin at progression in patients with recurrent or metastatic adenoid cystic carcinoma of the head and neck: a trial of the Eastern Cooperative Oncology Group (E1303) 
Cancer  2011;117(15):3374-3382.
Bortezomib, an inhibitor of the 26S proteasome and NF-κB, may have antitumor activity in adenoid cystic carcinoma (ACC). Preclinical studies have shown synergy between bortezomib and doxorubicin.
Eligibility criteria included incurable ACC, any number of prior therapies but without an anthracycline, unidimensionally measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, and ejection fraction within normal limits. Patients with stable disease for 9 months or more were excluded. Patients received bortezomib 1.3 mg/m2 IV push on days 1,4,8, and 11, every 21 days, until progression. Doxorubicin 20 mg/m2 IV on days 1 and 8 was added at the time of progression.
25 patients were enrolled of whom 24 were eligible; the most common distant metastatic sites were the lung (n=22) and the liver (n=7). There was no objective response with single-agent bortezomib; best response was stable disease in 15 of 21 evaluable patients (71%). The median progression-free survival and overall survival were 6.4 months and 21 months, respectively. Of 10 evaluable patients who received bortezomib plus doxorubicin, 1 had a partial response and 6 stable disease. The most frequent toxicity with bortezomib was grade 3 sensory neuropathy (16%). With bortezomib plus doxorubicin serious toxicities seen more than once were grade 3–4 neutropenia (n=3) and grade 3 anorexia (n=2).
Bortezomib was well tolerated and resulted in disease stabilization in a high percentage of patients but no objective responses. The combination of bortezomib and doxorubicin was also well tolerated and may warrant further investigation in ACC.
PMCID: PMC3135694  PMID: 21246525
head and neck cancer; adenoid cystic carcinoma; bortezomib; doxorubicin
21.  The Use of a Conventional Low Neck Field (LNF) and Intensity-Modulated Radiation Therapy (IMRT): No Clinical Detriment of IMRT to an Anterior LNF during the Treatment of Head and Neck Cancer 
Appropriate treatment of the lower neck when using IMRT is controversial. Our study tried to determine differences in clinical outcomes using IMRT or a standard LNF to treat low neck.
Methods and Materials
This is a retrospective, single institution study. Ninety-one patients with squamous cell carcinoma of head and neck cancer were treated with curative intent. Based on physician preference, some patients were treated with LNF (PTV3) field using a single anterior photon field matched to the IMRT field. Field junctions were not feathered. The endpoints were time to failure and use of PEG tube (as a surrogate of laryngeal edema causing aspiration) and analysis done with chi-square and the log-rank tests.
Median follow up 21 months (range 2 – 89). The median age 60 years. Thirty seven (41%) were treated with LNF, 84% were stage III or IV. PEG tube was required in 30% as opposed to 33% without the use of LNF. N2 or 3 neck disease was treated more commonly without a LNF (38% vs. 24%, p = 0.009). Failures occurred in 12 patients (13%). Only one patient treated with LNF failed regionally, 4.5 cm above the match line. The 3-year disease-free survival rate was 87%, 79% with LNF and without LNF respectively (p = 0.2) and the 3-year LR failure rate was 4%, 21% respectively, (p = 0.04).
Using LNF to treat the low neck did not increase the risk of regional failure “in early T& early N diseases” or decrease PEG tube requirements.
PMCID: PMC3339153  PMID: 20385457
IMRT; Head and Neck cancer; Low neck field; RT toxicities; PEG tube
22.  Phase II and Coagulation Cascade Biomarker Study of Bevacizumab with or without Docetaxel in Patients with Previously Treated Metastatic Pancreatic Adenocarcinoma 
Treatment options are limited for advanced pancreatic cancer progressive after gemcitabine therapy. The vascular endothelial growth factor (VEGF) pathway is biologically important in pancreatic cancer, and docetaxel has modest anti-tumor activity. We evaluated the role of the anti-VEGF antibody bevacizumab as second-line treatment for patients with metastatic pancreatic cancer.
Patients with metastatic adenocarcinoma of the pancreas who had progressive disease on a gemcitabine-containing regimen were randomized to receive bevacizumab alone or bevacizumab in combination with docetaxel.
Thirty-two patients were enrolled; 16 to bevacizumab alone (Arm A) and 16 to bevacizumab plus docetaxel (Arm B). Toxicities were greater in Arm B with the most common grade 3/4 nonhematologic toxicities including fatigue, diarrhea, dehydration and anorexia. No confirmed objective responses were observed. At 4 months, 2/16 patients in Arm A and 3/16 in Arm B were free from progression. The study was stopped according to the early stopping rule for futility. Median PFS and OS were 43 days and 165 days in Arm A and 48 days and 125 days in Arm B. Elevated D-dimer levels and thrombin-antithrombin complexes were associated with decreased survival and increased toxicity.
Bevacizumab with or without docetaxel does not have antitumor activity in gemcitabine-refractory metastatic pancreatic cancer. Baseline and on-treatment D-dimer and thrombin-antithrombin complex levels are associated with increased toxicity and decreased survival.
PMCID: PMC3030655  PMID: 20458210
23.  Nuclear Localization of Signal Transducer and Activator of Transcription 3 (STAT3) in Head and Neck Squamous Cell Carcinoma Is Associated with a Better Prognosis 
A high frequency of head and neck squamous cell cancers (HNSCC) contain constitutively activated STAT3. To further elucidate the prognostic role of STAT3 in HNSCC, the expression pattern of STAT3 was correlated with outcome in two independent data sets.
Experimental Design
STAT3 protein expression analysis was performed on a test cohort of 102 patients with HNSCC recruited between 1992 and 2005. Automated quantitative analysis (AQUA) was used to assess STAT3 protein expression. We evaluated associations with clinicopathological parameters and survival prognosis. Associations were validated in a second, independent cohort of 58 patients with confirmed HNSCC enrolled in Early Detection Research Network (EDRN) sponsored study who underwent surgical resection with curative intent at the University of Pittsburgh Medical Center between 2000 and 2004.
STAT3 displayed mixed nuclear and cytoplasmic staining. Survival analysis showed that high nuclear STAT3 expression (top tertile versus the rest) was associated with longer progression-free survival (PFS) (n = 70, mean survival 88.9 vs. 46.7 months, p = 0.012 for the first cohort; n = 37; mean survival 60.3 vs. 33.0 months, p = 0.009 for the second cohort). After best model selection in the multivariable analysis context, only STAT3 was significant, revealing a lower risk of progression and death for patients with high nuclear STAT3-expressing tumors (HR = 0.28, 95% CI 0.10 to 0.82, p = 0.019 and HR = 0.23, 95% CI 0.07 to 0.76, p = 0.016 respectively).
Our results indicate that high nuclear STAT3 expression levels by AQUA are associated with favorable outcome in HNSCC.
PMCID: PMC3030188  PMID: 20371693
24.  Detection of Tumor Epidermal Growth Factor Receptor Pathway Dependence by Serum Mass Spectrometry in Cancer Patients 
We hypothesized that a serum proteomic profile predictive of survival benefit in non–small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) reflects tumor EGFR dependency regardless of site of origin or class of therapeutic agent.
Pretreatment serum or plasma from 230 patients treated with cetuximab, EGFR-TKIs, or chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC) were analyzed by mass spectrometry. Each sample was classified into “good” or “poor” groups using VeriStrat, and survival analyses of each cohort were done based on this classification. For the CRC cohort, this classification was correlated with the tumor EGFR ligand levels and KRAS mutation status.
In the EGFR inhibitor–treated cohorts, the classification predicted survival (HNSCC: gefitinib, P = 0.007 and erlotinib/bevacizumab, P = 0.02; CRC: cetuximab, P = 0.0065) whereas the chemotherapy cohort showed no survival difference. For CRC patients, tumor EGFR ligand RNA levels were significantly associated with the proteomic classification, and combined KRAS and proteomic classification provided improved survival classification.
Serum proteomic profiling can detect clinically significant tumor dependence on the EGFR pathway in non–small cell lung cancer, HNSCC, and CRC patients treated with either EGFR-TKIs or cetuximab. This classification is correlated with tumor EGFR ligand levels and provides a clinically practical way to identify patients with diverse cancer types most likely to benefit from EGFR inhibitors. Prospective studies are necessary to confirm these findings.
PMCID: PMC2846615  PMID: 20086114
25.  Targeting EGFR resistance networks in Head and Neck Cancer 
Cellular signalling  2009;21(8):1255-1268.
A core set of oncoproteins is over-expressed or functionally activated in many types of cancer, and members of this group have attracted significant interest as subjects for development of targeted therapeutics. For some oncoproteins such as EGFR/ErbB1, both small molecule and antibody agents have been developed and applied in the clinic for over a decade. Analysis of clinical outcomes has revealed an initially unexpected complexity in the response of patients to these agents. Diverse factors, including developmental lineage of the tumor progenitor cell, co-mutation or epigenetic modulation of genes encoding proteins in an extended EGFR signaling network or regulating core survival responses in individual tumors, and environmental factors including inflammatory agents and viral infection, all have been identified as modulating response to treatment with EGFR-targeted drugs. Second and third generation therapeutic strategies increasingly incorporate knowledge of cancer type-specific signaling environments, in a more personalized treatment approach. This review takes squamous cell carcinoma of the head and neck (SCCHN) as a specific example of an EGFR-involved cancer with idiosyncratic biological features that influence design of treatment modalities, with particular emphasis on commonalities and differences with other cancer types.
PMCID: PMC2770888  PMID: 19258037
EGFR; epidermal growth factor receptor; head and neck cancer; signaling; resistance pathways; SCCHN

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