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1.  Unilateral Neck Therapy in the Human Papillomavirus-Era: Virus Association does not Alter Accepted Regional Spread Patterns 
Head & neck  2012;35(2):160-164.
Background
To determine whether the incidence of bilateral neck disease tonsil cancer is rising.
Methods
We reviewed tonsil cancer incidence data from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute.
Results
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).
Conclusions
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.
doi:10.1002/hed.22929
PMCID: PMC4037756  PMID: 22302641
Tonsil; SEER; HPV; Unilateral Therapy; Stage Migration
2.  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.
Purpose
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.
Results
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.
Conclusion
The addition of gefitinib to docetaxel was well tolerated but did not improve outcomes in poor prognosis but otherwise unselected patients with SCCHN.
doi:10.1200/JCO.2012.45.4272
PMCID: PMC3612594  PMID: 23460714
3.  Markers of Epithelial to Mesenchymal Transition in Association with Survival in Head and Neck Squamous Cell Carcinoma (HNSCC) 
PLoS ONE  2014;9(4):e94273.
Background
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.
Methods
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.
Results
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.
Conclusions
The putative markers of EMT defined within a panel of HNSCC using AQUA are associated with tumors of poor prognosis.
doi:10.1371/journal.pone.0094273
PMCID: PMC3983114  PMID: 24722213
4.  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.
doi:10.1158/2159-8290.CD-12-0031
PMCID: PMC3546138  PMID: 23125191
5.  Nuclear epidermal growth factor receptor and p16 expression in head and neck squamous cell carcinoma 
The Laryngoscope  2012;122(12):2762-2768.
Objective
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1002/lary.23647
PMCID: PMC3574977  PMID: 23086695
HNSCC; nuclear EGFR; p16
6.  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 
Objectives
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.
Methods
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.
Results
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.
Conclusions
Although terminated early, the study supports the detrimental effect of combining VEGF and EGFR inhibition in metastatic colorectal cancer.
doi:10.1007/s12029-012-9368-3
PMCID: PMC3400721  PMID: 22294255
Metastatic colon cancer; Vascular endothelial growth factor (VEGF); Epidermal growth factor receptor (EGFR)
7.  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.
doi:10.1007/s12553-012-0020-9
PMCID: PMC3327509  PMID: 22518350
Head and neck cancer; informational needs; Treatment side effects; Internet
8.  Psychological functioning of caregivers for head and neck cancer patients 
Oral Oncology  2011;48(1):18-25.
SUMMARY
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.
doi:10.1016/j.oraloncology.2011.11.012
PMCID: PMC3357183  PMID: 22154127
Caregiving; Psychological health; Emotional distress; Anxiety; Depression; Head and neck cancer
9.  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.
doi:10.1016/j.drup.2011.08.002
PMCID: PMC3195944  PMID: 21920801
PLC-γ; PI3K; PTEN; SHC; GRB2; RAS; STAT; IGFR; c-MET
10.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1002/cncr.25852
PMCID: PMC3135694  PMID: 21246525
head and neck cancer; adenoid cystic carcinoma; bortezomib; doxorubicin
11.  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 
Purpose
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.
Results
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).
Conclusions
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.
doi:10.1016/j.ijrobp.2009.10.034
PMCID: PMC3339153  PMID: 20385457
IMRT; Head and Neck cancer; Low neck field; RT toxicities; PEG tube
12.  Phase II and Coagulation Cascade Biomarker Study of Bevacizumab with or without Docetaxel in Patients with Previously Treated Metastatic Pancreatic Adenocarcinoma 
Purpose
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.
Design
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.
Results
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.
Conclusion
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.
doi:10.1097/COC.0b013e3181d2734a
PMCID: PMC3030655  PMID: 20458210
13.  Nuclear Localization of Signal Transducer and Activator of Transcription 3 (STAT3) in Head and Neck Squamous Cell Carcinoma Is Associated with a Better Prognosis 
Purpose
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.
Results
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).
Conclusions
Our results indicate that high nuclear STAT3 expression levels by AQUA are associated with favorable outcome in HNSCC.
doi:10.1158/1078-0432.CCR-09-2658
PMCID: PMC3030188  PMID: 20371693
14.  Detection of Tumor Epidermal Growth Factor Receptor Pathway Dependence by Serum Mass Spectrometry in Cancer Patients 
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.1158/1055-9965.EPI-09-0937
PMCID: PMC2846615  PMID: 20086114
15.  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.
doi:10.1016/j.cellsig.2009.02.021
PMCID: PMC2770888  PMID: 19258037
EGFR; epidermal growth factor receptor; head and neck cancer; signaling; resistance pathways; SCCHN
16.  Head and Neck Cancer 
Journal of Oncology  2010;2009:358098.
doi:10.1155/2009/358098
PMCID: PMC2821645  PMID: 20169126
17.  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
18.  Treatment of pancreatic cancer with epidermal growth factor receptor-targeted therapy 
Pancreatic adenocarcinoma is a common malignancy that remains refractory to available therapies. Gemcitabine has long been the standard, first-line agent in advanced disease. The epidermal growth factor receptor (EGFR) is a commonly expressed target in pancreatic cancer that is involved in tumor proliferation, metastasis, and induction of angiogenesis. The addition of the EGFR inhibitor erlotinib to gemcitabine has recently been demonstrated to provide a small, yet statistically significant, survival benefit in advanced disease. This has prompted further research into the applications of EGFR-targeted therapy in pancreatic cancer, albeit with disappointing results. Resistance to these therapies seems highly prevalent and has been implicated in their limited efficacy. The development of rash is associated with treatment efficacy and suggests that predictive factors may one day be identified to guide appropriate patient selection for these agents. Preclinical research has shown promise that resistance to EGFR-targeted therapies can be overcome through a variety of approaches. Application of this research in clinical trials may ultimately yield an unquestioned role for EGFR-targeted therapy in the management of this disease.
PMCID: PMC2747340  PMID: 19774209
cetuximab; drug resistance; epidermal growth factor receptor; erlotinib; gemcitabine; pancreatic cancer

Results 1-19 (19)