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1.  Impact of Precision Medicine in Diverse Cancers: A Meta-Analysis of Phase II Clinical Trials 
Journal of Clinical Oncology  2015;33(32):3817-3825.
Purpose
The impact of a personalized cancer treatment strategy (ie, matching patients with drugs based on specific biomarkers) is still a matter of debate.
Methods
We reviewed phase II single-agent studies (570 studies; 32,149 patients) published between January 1, 2010, and December 31, 2012 (PubMed search). Response rate (RR), progression-free survival (PFS), and overall survival (OS) were compared for arms that used a personalized strategy versus those that did not.
Results
Multivariable analysis (both weighted multiple linear regression and random effects meta-regression) demonstrated that the personalized approach, compared with a nonpersonalized approach, consistently and independently correlated with higher median RR (31% v 10.5%, respectively; P < .001) and prolonged median PFS (5.9 v 2.7 months, respectively; P < .001) and OS (13.7 v 8.9 months, respectively; P < .001). Nonpersonalized targeted arms had poorer outcomes compared with either personalized targeted therapy or cytotoxics, with median RR of 4%, 30%, and 11.9%, respectively; median PFS of 2.6, 6.9, and 3.3 months, respectively (all P < .001); and median OS of 8.7, 15.9, and 9.4 months, respectively (all P < .05). Personalized arms using a genomic biomarker had higher median RR and prolonged median PFS and OS (all P ≤ .05) compared with personalized arms using a protein biomarker. A personalized strategy was associated with a lower treatment-related death rate than a nonpersonalized strategy (median, 1.5% v 2.3%, respectively; P < .001).
Conclusion
Comprehensive analysis of phase II, single-agent arms revealed that, across malignancies, a personalized strategy was an independent predictor of better outcomes and fewer toxic deaths. In addition, nonpersonalized targeted therapies were associated with significantly poorer outcomes than cytotoxic agents, which in turn were worse than personalized targeted therapy.
doi:10.1200/JCO.2015.61.5997
PMCID: PMC4737863  PMID: 26304871
2.  Phase Ib Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Patients with Barrett’s Esophagus 
This study was conducted to determine the safety and efficacy of the green-tea derived Polyphenon E (Poly E) in patients with Barrett’s Esophagus (BE). Subjects were randomized to a 6-month, twice daily (BID) oral treatment of placebo or Poly E (200 mg, 400 mg, or 600 mg). Endoscopic evaluation, including biopsies, was performed before and after treatment. The primary objective was to demonstrate safety; secondary objectives investigated catechin accumulation and effects in clinical specimens. Of the 44 enrolled subjects, 11 received placebo, and 33 received Poly E. No dose-limiting toxicities were encountered, and a maximum tolerated dose (MTD) was not reached. The recommended phase 2 dose was 600 mg BID. The most common treatment-related adverse events (AEs) in Poly E-treated subjects were grade 1–2 nausea, grade 1 belching, and grade 1 LDH elevation. No treatment-related AEs were reported in placebo-treated subjects, aside from grade 1 laboratory abnormalities. Pill counts and subject diaries were not consistently collected, and compliance was difficult to determine. However, based on an intention-to-treat analysis there was a significant relationship between Poly E dose and esophageal EGCG level – mean changes (pmol/g) of 0.79 (placebo), 6.06 (200 mg), 35.67 (400 mg), and 34.95 (600 mg); p=0.005. There was a possible relationship between Poly E dose and urine PGE-M concentration. In conclusion, Poly E was well-tolerated, and treatment with Poly E (400 mg and 600 mg) but not Poly E (200 mg) or placebo resulted in clinically relevant and detectable EGCG accumulation in the target organ, esophageal mucosa.
doi:10.1158/1940-6207.CAPR-14-0274-T
PMCID: PMC4670789  PMID: 26471236
Barrett’s Esophagus; Polyphenon E; Chemoprevention; Green tea; Esophageal cancer
3.  Phase I Trial of Weekly Topotecan and Gemcitabine in Patients With Solid Tumors 
Objective
This phase I trial was designed to determine the maximal tolerated dose (MTD) of the combination of topotecan and gemcitabine given in a weekly schedule.
Materials and Methods
In this single-arm, open label, dose-escalation study, we administered topotecan (0.75–1.5 mg/m2) and gemcitabine (1000 mg/m2) on days 1, 8, and 15 every 4 weeks to 25 patients with advanced solid tumors.
Results
The topotecan MTD, when combined with gemcitabine, was 1.25 mg/m2/wk. Dose-limiting toxicities consisted of febrile granulocytopenia in 2 patients at the highest dose level. At the MTD, no episodes of granulocytopenia were observed, whereas 2/9 patients exhibited grade 3 thrombocytopenia. Other common grades 3–4 adverse events across all cohorts included non-neutropenic infections, fatigue, skin reactions, vomiting, and fever. One partial response and 2 stable diseases were observed in patients with nasopharyngeal carcinoma. Disease stabilization was also observed in patients with squamous cell carcinoma of the head and neck (3), nonsmall cell lung cancer (1), and thymoma (1).
Conclusions
Topotecan and gemcitabine combined in a weekly schedule exhibit a favorable toxicity profile. Efficacy results support the further evaluation of this regimen in patients with head and neck cancer (particularly nasopharyngeal carcinoma).
doi:10.1097/COC.0b013e318178e513
PMCID: PMC5120668  PMID: 19194117
gemcitabine; topotecan; weekly
4.  Clinical and Biomarker Outcomes of the Phase II Vandetanib Study from the BATTLE Trial 
Background
The Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination trial1 prospectively obtained serum and tumor core biopsies and randomized 255 chemorefractory non–small-cell lung cancer (NSCLC) patients into four phase II trials: erlotinib, erlotinib-bexarotene, vandetanib, or sorafenib. Herein, we report the clinical and biomarker results of the phase II vandetanib trial.
Results
Fifty-four patients received vandetanib. The 8-week disease control rate was 33%, median progression-free survival (PFS) 1.81 months, and median overall survival (OS) 6.5 months. No demographic subgroups had PFS or OS benefit. Eight patients with EGFR mutations had a trend for higher 8-week disease control rate (63% versus 31%; p = 0.12) but worse OS (5.9 months versus 9 months; p = 0.8). Patients with EGFR gene amplification (n = 6) had a worse OS (3.9 months versus 9.5 months; p = 0.04). KRAS mutation patients (3.9 months versus 9.5 months; p = 0.23) also had a worse OS. For the serum biomarker analysis, patients with below the median serum expression of interleukin 9c (p = 0.019) and eotaxin (p = 0.007) had a shorter PFS. A trend toward a shorter PFS was also seen in patients with higher than the median neutrophil gelatinase-associated lipocalin (p = 0.079) and lower than the median TNF-related apoptosis-inducing ligand (p = 0.087).
Conclusion
Our trial results are largely consistent with the literature in unselected pretreated NSCLC patients. Although vandetanib improved median PFS in EGFR mutation patients with epidermal growth factor receptor tyrosine kinase inhibitor–resistance compared with EGFR wild-type, there was no OS advantage. Although vandetanib is no longer in development in NSCLC, identification of a molecular phenotype that responds to dual epidermal growth factor receptor and vascular endothelial growth factor receptor inhibition would contribute to the field.
doi:10.1097/JTO.0b013e31828d08ae
PMCID: PMC5118909  PMID: 23584298
Vandetanib; Non–small-cell lung cancer; EGFR mutation; EGFR gene amplification
5.  Phase II Study of Vinorelbine and Docetaxel in the Treatment of Advanced Non–Small-Cell Lung Cancer as Frontline and Second-Line Therapy 
Objectives
Combination chemotherapy with third-generation, nonplatinum agents (ie, gemcitabine, vinorelbine, taxanes, or camptothecins) represents a well-tolerated frontline treatment option for metastatic non–small-cell lung cancer and might play a role as salvage therapy as well. The aim of this phase 2 study was to investigate the use of docetaxel and vinorelbine in the frontline and second-line setting in patients with incurable non–small-cell lung cancer.
Patients and Methods
Seventy-eight patients (42 untreated, 36 previously treated) were administered vinorelbine (20 mg/m2) on days 1 and 8 and docetaxel (75 mg/m2 for untreated patients; 60 mg/m2 for previously treated patients for cycle 1, increased to 75 mg/m2 for the subsequent cycles in the absence of grade 3 fever/neutropenia) on day 8, repeated every 21 days, with routine filgrastim support.
Results
The most common grade 3 to 4 nonhematologic toxicities were diarrhea, dyspnea, fatigue, and nausea/vomiting (5% each). Grade 3 to 4 granulocytopenia occurred in 55% of the patients, however only 5% experienced febrile neutropenia. Response rates were 13% in the chemotherapy-naive cohort and 9% in previously treated patients. Median time to progression was 2.9 and 3.0 months and median overall survival was 15.0 and 6.2 months, for the frontline and second-line patients, respectively.
Conclusions
Compared with historical controls, in the first-line setting, the combination of docetaxel and vinorelbine did not demonstrate increased efficacy advantages over platinum- or other nonplatinum-based doublets. In the second-line setting, single agent chemotherapy is as effective as, and less toxic than the docetaxel-vinorelbine combination, and the former remains the cytotoxic treatment of choice.
doi:10.1097/COC.0b013e318199fb99
PMCID: PMC5118944  PMID: 19687727
non–small-cell lung cancer; docetaxel; vinorelbine; frontline; second-line
6.  Immunohistochemical Expression of Basic Fibroblast Growth Factor and Fibroblast Growth Factor Receptors 1 and 2 in the Pathogenesis of Lung Cancer 
Purpose
To identify the patterns of protein expression of bFGF, FGFR1, and FGFR2 in non–small cell lung carcinoma (NSCLC) and their role in the early pathogenesis of squamous cell carcinoma of the lung.
Experimental Design
Archived tissue from NSCLC (adenocarcinoma and squamous cell carcinoma; n = 321) and adjacent bronchial epithelial specimens (n = 426) were analyzed for the immunohistochemical expression of bFGF, FGFR1, and FGFR2, and the findings were correlated with clinicopathologic features of the patients.
Results
High expression of bFGF, FGFR1, and FGFR2 was demonstrated in most NSCLC tumors. The pattern of expression for all markers varied according to tumor histologic type and cellular localization. Cytoplasmic expression scores were significantly higher in tumors than in normal epithelia. Nuclear bFGF (P = 0.03) and FGFR1 (P = 0.02) levels were significantly higher in women than in men. Although cytoplasmic FGFR1 expression was significantly higher (P = 0.002) in ever smokers than in never smokers, nuclear FGFR1 (P = 0.0001) and FGFR2 (P = 0.003) expression was significantly higher in never smokers. Different prognostic patterns for the expression of these markers were detected for both NSCLC histologic types. Dysplastic changes showed significantly higher expression of all markers compared to squamous metaplasia.
Conclusions
bFGF, FGFR1, and FGFR2 are frequently overexpressed in squamous cell carcinoma and adenocarcinoma of the lung. bFGF signaling pathway activation may be an early phenomenon in the pathogenesis of squamous cell carcinoma and thus an attractive novel target for lung cancer chemopreventive and therapeutic strategies.
doi:10.1158/1078-0432.CCR-08-0167
PMCID: PMC5108626  PMID: 18829480
bFGF; FGFR; NSCLC; lung preneoplasia
7.  New DNA methylation markers and global DNA hypomethylation are associated with oral cancer development 
DNA promoter methylation of tumor suppressor genes and global DNA hypomethylation are common features of head and neck cancers. Our goal was to identify early DNA methylation changes in oral premalignant lesions (OPLs) that may serve as predictive markers of developing oral squamous cell carcinoma (OSCC). Using high-throughput DNA methylation profiles of 24 OPLs, we found that the top 86 genes differentially methylated between patients who did or did not develop OSCC were simultaneously hypermethylated, suggesting that a CpG island methylation phenotype may occur early during OSCC development. The vast majority of the 86 genes were non-methylated in normal tissues and hypermethylated in OSCC versus normal mucosa. We used pyrosequencing in a validation cohort of 44 patients to evaluate the degree of methylation of AGTR1, FOXI2, and PENK promoters CpG sites that were included in the top 86 genes, and of LINE1 repetitive element methylation, a surrogate of global DNA methylation. A Methylation Index (MI) was developed by averaging the percent methylation of AGTR1, FOXI2, and PENK promoters; patients with a high MI had a worse OCFS (P=0.0030). On the other hand, patients with low levels of LINE1 methylation had a significantly worse OCFS (P=0.0153). In conclusion, AGTR1, FOXI2 and PENK promoter methylation and LINE1 hypomethylation may be associated with an increased risk of OSCC development in patients with OPLs.
doi:10.1158/1940-6207.CAPR-14-0179
PMCID: PMC4777304  PMID: 26342026
oral leukoplakia; oral cancer; squamous cell carcinoma; DNA promoter methylation; DNA global hypomethylation; risk biomarker
8.  Impact of a Biomarker-Based Strategy on Oncology Drug Development: A Meta-Analysis of Clinical Trials Leading to FDA Approval 
Background:
In order to ascertain the impact of a biomarker-based (personalized) strategy, we compared outcomes between US Food and Drug Administration (FDA)–approved cancer treatments that were studied with and without such a selection rationale.
Methods:
Anticancer agents newly approved (September 1998 to June 2013) were identified at the Drugs@FDA website. Efficacy, treatment-related mortality, and hazard ratios (HRs) for time-to-event endpoints were analyzed and compared in registration trials for these agents. All statistical tests were two-sided.
Results:
Fifty-eight drugs were included (leading to 57 randomized [32% personalized] and 55 nonrandomized trials [47% personalized], n = 38 104 patients). Trials adopting a personalized strategy more often included targeted (100% vs 65%, P < .001), oral (68% vs 35%, P = .001), and single agents (89% vs 71%, P = .04) and more frequently permitted crossover to experimental treatment (67% vs 28%, P = .009). In randomized registration trials (using a random-effects meta-analysis), personalized therapy arms were associated with higher relative response rate ratios (RRRs, compared with their corresponding control arms) (RRRs = 3.82, 95% confidence interval [CI] = 2.51 to 5.82, vs RRRs = 2.08, 95% CI = 1.76 to 2.47, adjusted P = .03), longer PFS (hazard ratio [HR] = 0.41, 95% CI = 0.33 to 0.51, vs HR = 0.59, 95% CI = 0.53 to 0.65, adjusted P < .001) and a non-statistically significantly longer OS (HR = 0.71, 95% CI = 0.61 to 0.83, vs HR = 0.81, 95% CI = 0.77 to 0.85, adjusted P = .07) compared with nonpersonalized trials. Analysis of experimental arms in all 112 registration trials (randomized and nonrandomized) demonstrated that personalized therapy was associated with higher response rate (48%, 95% CI = 42% to 55%, vs 23%, 95% CI = 20% to 27%, P < .001) and longer PFS (median = 8.3, interquartile range [IQR] = 5 vs 5.5 months, IQR = 5, adjusted P = .002) and OS (median = 19.3, IQR = 17 vs 13.5 months, IQR = 8, Adjusted P = .04). A personalized strategy was an independent predictor of better RR, PFS, and OS, as demonstrated by multilinear regression analysis. Treatment-related mortality rate was similar for personalized and nonpersonalized trials.
Conclusions:
A biomarker-based approach was safe and associated with improved efficacy outcomes in FDA-approved anticancer agents.
doi:10.1093/jnci/djv253
PMCID: PMC4857149  PMID: 26378224
9.  Genomic heterogeneity of multiple synchronous lung cancer 
Nature Communications  2016;7:13200.
Multiple synchronous lung cancers (MSLCs) present a clinical dilemma as to whether individual tumours represent intrapulmonary metastases or independent tumours. In this study we analyse genomic profiles of 15 lung adenocarcinomas and one regional lymph node metastasis from 6 patients with MSLC. All 15 lung tumours demonstrate distinct genomic profiles, suggesting all are independent primary tumours, which are consistent with comprehensive histopathological assessment in 5 of the 6 patients. Lung tumours of the same individuals are no more similar to each other than are lung adenocarcinomas of different patients from TCGA cohort matched for tumour size and smoking status. Several known cancer-associated genes have different mutations in different tumours from the same patients. These findings suggest that in the context of identical constitutional genetic background and environmental exposure, different lung cancers in the same individual may have distinct genomic profiles and can be driven by distinct molecular events.
Some patients present with multiple lung tumours but it is unclear whether these are metastases or individual lesions. Here, the authors use genomics techniques to demonstrate in six patients that multiple tumours have individual genetic profiles and represent separate tumours.
doi:10.1038/ncomms13200
PMCID: PMC5078731  PMID: 27767028
10.  The tobacco-specific carcinogen-operated calcium channel promotes lung tumorigenesis via IGF2 exocytosis in lung epithelial cells 
Nature Communications  2016;7:12961.
Nicotinic acetylcholine receptors (nAChRs) binding to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces Ca2+ signalling, a mechanism that is implicated in various human cancers. In this study, we investigated the role of NNK-mediated Ca2+ signalling in lung cancer formation. We show significant overexpression of insulin-like growth factors (IGFs) in association with IGF-1R activation in human preneoplastic lung lesions in smokers. NNK induces voltage-dependent calcium channel (VDCC)-intervened calcium influx in airway epithelial cells, resulting in a rapid IGF2 secretion via the regulated pathway and thus IGF-1R activation. Silencing nAChR, α1 subunit of L-type VDCC, or various vesicular trafficking curators, including synaptotagmins and Rabs, or blockade of nAChR/VDCC-mediated Ca2+ influx significantly suppresses NNK-induced IGF2 exocytosis, transformation and tumorigenesis of lung epithelial cells. Publicly available database reveals inverse correlation between use of calcium channel blockers and lung cancer diagnosis. Our data indicate that NNK disrupts the regulated pathway of IGF2 exocytosis and promotes lung tumorigenesis.
The binding of tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to nicotinic acetylcholine receptors (nAChRs) induces calcium signalling. Here the authors show that NKK-induced calcium influx in airway epithelial cells triggers IGF2 secretion and tumourigenesis.
doi:10.1038/ncomms12961
PMCID: PMC5052689  PMID: 27666821
11.  Rational Clinical Experiment: Assessing Prior Probability and Its Impact on the Success of Phase II Clinical Trials 
Journal of Clinical Oncology  2015;33(26):2914-2919.
Purpose
Despite a robust clinical trial enterprise and encouraging phase II results, the vast minority of oncologic drugs in development receive regulatory approval. In addition, clinicians occasionally make therapeutic decisions based on phase II data. Therefore, clinicians, investigators, and regulatory agencies require improved understanding of the implications of positive phase II studies. We hypothesized that prior probability of eventual drug approval was significantly different across GI cancers, with substantial ramifications for the predictive value of phase II studies.
Methods
We conducted a systematic search of phase II studies conducted between 1999 and 2004 and compared studies against US Food and Drug Administration and National Cancer Institute databases of approved indications for drugs tested in those studies.
Results
In all, 317 phase II trials were identified and followed for a median of 12.5 years. Following completion of phase III studies, eventual new drug application approval rates varied from 0% (zero of 45) in pancreatic adenocarcinoma to 34.8% (24 of 69) for colon adenocarcinoma. The proportion of drugs eventually approved was correlated with the disease under study (P < .001). The median type I error for all published trials was 0.05, and the median type II error was 0.1, with minimal variation. By using the observed median type I error for each disease, phase II studies have positive predictive values ranging from less than 1% to 90%, depending on primary site of the cancer.
Conclusion
Phase II trials in different GI malignancies have distinct prior probabilities of drug approval, yielding quantitatively and qualitatively different predictive values with similar statistical designs. Incorporation of prior probability into trial design may allow for more effective design and interpretation of phase II studies.
doi:10.1200/JCO.2015.61.4362
PMCID: PMC4554752  PMID: 26261263
12.  Adaptive Designs for Identifying Optimal Biological Dose for Molecularly Targeted Agents 
Clinical trials (London, England)  2014;11(3):319-327.
Background
Traditionally, the purpose of a dose-finding design in cancer is to find the maximum tolerated dose based solely on toxicity. However, for molecularly targeted agents, little toxicity may arise within the therapeutic dose range and the dose-response curves may not be monotonic. This challenges the principle that more is better, which is widely accepted for conventional chemotherapy.
Methods
We propose three adaptive dose-finding designs for trials evaluating molecularly targeted agents, for which the dose-response curves are unimodal or plateaued. The goal of these designs is to find the optimal biological dose, which is defined as the lowest dose with the highest rate of efficacy while safe. The first proposed design is parametric and assumes a logistic dose-efficacy curve for dose finding; the second design is nonparametric and uses the isotonic regression to identify the optimal biological dose; and the third design has the spirit of a “semiparametric” approach by assuming a logistic model only locally around the current dose.
Results
We conducted extensive simulation studies to investigate the operating characteristics of the proposed designs. Simulation studies show that the nonparametric and semiparametirc designs have good operating characteristics for finding the optimal biological dose.
Limitations
The proposed designs assume a binary endpoint. Extension of the proposed designs to ordinal and time-to-event endpoints worth further investigation.
Conclusion
Among the three proposed designs, the nonparametric and semiparametirc designs yield consistently good operating characteristics and thus are recommended for practical use. The software to implement these two designs is available for free download at http://odin.mdacc.tmc.edu/~yyuan/.
doi:10.1177/1740774514529848
PMCID: PMC4239216  PMID: 24844841
dose-finding; optimal biological dose; Bayesian adaptive design; isotonic regression; molecularly targeted agent
13.  Prognostic Implications of Tumoral Expression of Insulin-like Growth Factor (IGF)-1 and -2 in Patients with Non-small Cell Lung Cancer 
Clinical lung cancer  2014;15(3):213-221.
Introduction/Background
The currently available systemic therapies for non-small cell lung cancer (NSCLC) have limited efficacy. Our previous report indicate the association of elevated insulin-like growth factor (IGF)-1 receptor (IGF-1R) and insulin receptor (IR) expression levels with poor survival in NSCLC patients. To better understand the molecular biomarkers involved in the IGF signaling pathway in NSCLC, we characterize the expression levels of IGF-1 and IGF-2 and to evaluate their association with IGF-1R and phosphorylated IGF-1R (pIGF-1R) expression in NSCLC.
Methods
A total of 352 patients who underwent NSCLC resection with curative intent were studied. The expression patterns of the IGF-1, IGF-2, IGF-1R and pIGF-1R proteins were assessed immunohistochemically using tissue microarrays.
Results
The IGF-1 expression was higher in patients with adenocarcinoma (ADC) than in those with squamous cell carcinoma (SCC), whereas the IGF-2 score was higher in patients with SCC than those with ADC. Likewise, the IGF-1 score was higher in patients with mutated EGFR (mtEGFR) than in those with wild type EGFR (wtEGFR), while the IGF-2 score was higher in patients with wtEGFR than in those with mtEGFR. Patients with low levels of IGF-1 expression had longer overall survival (OS) than those with high IGF-1 expression, and subgroup analyses revealed a significant difference in OS in ADC patients only.
Conclusions
The overexpression of IGF-1 predicts poor survival among patients with NSCLC, especially those with ADC. These results might serve as a future guide for clinical trials involving IGR-1R-targeting agents.
doi:10.1016/j.cllc.2013.12.006
PMCID: PMC4572464  PMID: 24485233
Carcinoma; Non-Small-Cell Lung; IGF Type 1; Prognosis; and Survival
14.  Adding Erlotinib to Chemoradiation Improves Overall Survival but not Progression-Free Survival in Stage III Non-Small-Cell Lung Cancer 
Background
Concurrent chemoradiotherapy is the standard of care for inoperable stage III non-small cell lung cancer (NSCLC) for patients who can tolerate it. We explored if adding erlotinib would increase the effectiveness of chemoradiotherapy without increasing toxicity in a single-arm prospective phase II trial.
Methods
Forty-eight patients with previously untreated NSCLC received intensity-modulated radiation therapy (63 Gy/35 fractions) on Monday–Friday, with chemotherapy (paclitaxel 45 mg/m2, carboplatin AUC=2) on Mondays, for 7 weeks. All patients also received the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib (150 mg orally 1/day) on Tuesday–Sunday for 7 weeks followed by consolidation paclitaxel–carboplatin. The primary endpoint was time to progression; secondary endpoints were overall survival (OS), toxicity, response, and disease control and whether any endpoint differed by EGFR mutation status.
Results
Of 46 patients evaluable for response, 40 were former or never-smokers and 41 were evaluable for EGFR mutations (37 wild-type [wt] and 4 [mutated; all adenocarcinoma]). Median time to progression was 14.0 months and did not differ by EGFR status. Toxicity was acceptable (no grade 5, one grade 4, eleven grade 3). Twelve patients (26%) had complete responses (10 wt, 2 mutated), 27 (59%) partial (21 wt, 2 mutated, 4 unknown), and 7 (15%) none (6 wt, 2 mutated, 1 unknown) (P=0.610). At 37.0 months’ follow-up (range 3.6–76.5 months) for all patients, median OS time was 36.5 months and 1-, 2-, and 5-year OS rates were 82.6%, 67.4%, and 35.9%; none differed by mutation status. Twelve patients had no progression and 34 had local and/or distant failure. Eleven of 27 distant failures were in the brain (7 wt, 3 mutated, 1 unknown).
Conclusions
Toxicity and OS were promising, but time to progression did not meet expectations. The prevalence of distant failures underscores the need for effective systemic therapy.
doi:10.1016/j.ijrobp.2015.02.005
PMCID: PMC4432249  PMID: 25968826
epidermal growth factor receptor; tyrosine kinase inhibitor; Tarceva; prospective phase II trial; locally advanced non-small cell lung cancer; NCT00563784
15.  drexplorer: A tool to explore dose–response relationships and drug–drug interactions 
Bioinformatics  2015;31(10):1692-1694.
Motivation: Nonlinear dose–response models are primary tools for estimating the potency [e.g. half-maximum inhibitory concentration (IC) known as IC50] of anti-cancer drugs. We present drexplorer software, which enables biologists to evaluate replicate reproducibility, detect outlier data points, fit different models, select the best model, estimate IC values at different percentiles and assess drug–drug interactions. drexplorer serves as a computation engine within the R environment and a graphical interface for users who do not have programming backgrounds.
Availability and implementation: The drexplorer R package is freely available from GitHub at https://github.com/nickytong/drexplorer. A graphical user interface is shipped with the package.
Contact: jingwang@mdanderson.org
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btv028
PMCID: PMC4426846  PMID: 25600946
16.  CD147 and Ki-67 overexpression confers poor prognosis in squamous cell carcinoma of oral tongue: A tissue microarray study 
Squamous cell carcinoma of the oral tongue (SCCOT) exhibits high risk for recurrence and regional metastasis even after surgical resection. We assessed the clinicopathologic and prognostic significance of a group of functionally related biomarkers. We used a tissue microarray consisting SCCOT from 32 patients for this study. These patients were treated at the UT- M.D. Anderson Cancer Center from 1995 to 2008. Biomarker expression levels were examined by immunohistochemistry and graded semiquantitatively to determine their prognostic significance. CD147 and Tp63 expressions were significantly associated with a higher T-stage and Ki-67 labelling index as well as shorter overall survival (OS). Expression of Tp63 associated positively with poorly-differentiated histology. There was significant association of Tp63 with the expression levels of CD147 and Glut-1. Glut-1 overexpression was marginally associated with a higher T-stage. There was no prognostic significance of CD44v6 expression in SCCOT. SCCOT with CD147 overexpression in combination with high Ki-67 labelling index had poor OS. CD147 and Ki-67 overexpression is associated with aggressive disease with poor prognosis in SCCOT.
doi:10.1016/j.oooo.2014.12.022
PMCID: PMC4397137  PMID: 25747176
Oral cancer; Squamous cell carcinoma of oral tongue; Biomarkers; CD147; Tp63; CD44v6; Glut-1; Ki-67; Overall and recurrence free survival
17.  Concordance of oral HPV prevalence between patients with oropharyngeal cancer and their partners 
Background
Human papilloma virus (HPV) is a known causative factor in oropharyngeal squamous cell cancer (OPC). In this prospective study, we sought to define the risk of HPV transmission between OPC patients and their sexual partners by performing HPV genotyping on oral cytology brushings.
Methods
Newly diagnosed OPC patients and their sexual partners underwent oral mouth swabs and answered a risk factor questionnaire. Patient tumor samples and oral swabs from both the patient and partner were assessed for HPV status and genotyped using Easy-Chip HPV Blot PCR.
Results
We enrolled 227 patient-partner pairs and obtained sufficient analyzable DNA from both members in 198 pairs. Of 144 patients with available OPC tumor tissue, 128 (89 %) had HPV-positive tumors by either in situ hybridization or p16 immunohistochemical analysis (104 or 121, respectively). In total, there were 28 patients and 30 partners who were HPV positive by oral swab. The prevalence rate of oral HPV in partners was 15 %. There were 39 patient-partner pairs who had one or both members returning positive for HPV in the oral swab, and 49 % of these pairs were concordant for their HPV-genotype. Female partners had a higher oral HPV prevalence (16 %) than did male partners (11 %). Patients who were non-white were also found to have a higher oral prevalence of HPV (p = 0.032) by mouth swab.
Conclusions
Partners of OPC patients may have a higher prevalence of oral HPV and should be studied prospectively to understand their OPC risk. Additional future research is needed to identify oral HPV persistence in partners to OPC patients and to determine the optimal sampling methods and technologies to screen patients at high risk for HPV-related disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s13027-016-0066-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13027-016-0066-9
PMCID: PMC4847345  PMID: 27123042
HPV; Partner transmission; Oropharyngeal cancer
18.  Tissue Effects in a Randomized Controlled Trial of Short-term Finasteride in Early Prostate Cancer☆ 
EBioMedicine  2016;7:85-93.
Background
In the Prostate Cancer Prevention Trial, finasteride selectively suppressed low-grade prostate cancer and significantly reduced the incidence of prostate cancer in men treated with finasteride compared with placebo. However, an apparent increase in high-grade disease was also observed among men randomized to finasteride. We aimed to determine why and hypothesized that there is a grade-dependent response to finasteride.
Methods
From 2007 to 2012, we randomized dynamically by intranet-accessible software 183 men with localized prostate cancer to receive 5 mg finasteride or placebo daily in a double-blind study during the 4–6 weeks preceding prostatectomy. As the primary end point, the expression of a predefined molecular signature (ERβ, UBE2C, SRD5A2, and VEGF) differentiating high- and low-grade tumors in Gleason grade (GG) 3 areas of finasteride-exposed tumors from those in GG3 areas of placebo-exposed tumors, adjusted for Gleason score (GS) at prostatectomy, was compared. We also determined androgen receptor (AR) levels, Ki-67, and cleaved caspase 3 to evaluate the effects of finasteride on the expression of its downstream target, cell proliferation, and apoptosis, respectively. The expression of these markers was also compared across grades between and within treatment groups. Logistic regression was used to assess the expression of markers.
Findings
We found that the predetermined molecular signature did not distinguish GG3 from GG4 areas in the placebo group. However, AR expression was significantly lower in the GG4 areas of the finasteride group than in those of the placebo group. Within the finasteride group, AR expression was also lower in GG4 than in GG3 areas, but not significantly. Expression of cleaved caspase 3 was significantly increased in both GG3 and GG4 areas in the finasteride group compared to the placebo group, although it was lower in GG4 than in GG3 areas in both groups.
Interpretation
We showed that finasteride's effect on apoptosis and AR expression is tumor grade dependent after short-term intervention. This may explain finasteride's selective suppression of low-grade tumors observed in the PCPT.
Highlights
•We studied 183 men with early prostate cancer receiving 5 mg finasteride or placebo daily for 4–6 weeks preprostatectomy.•Expression of androgen receptor and cleaved caspase 3 was dependent on tumor grade.•Finasteride's demonstrated effects in tissue may explain earlier seminal findings in the Prostate Cancer Prevention Trial.
This study advances the fields of prostate cancer biology and prostate cancer treatment because it demonstrates effects of finasteride in prostatectomy tissues that offer an explanation for the mixed results of the 18,882-subject randomized and controlled Prostate Cancer Prevention Trial (PCPT). Initial results showing a 25% reduction in prevalence in prostate cancer in men in the finasteride group while revealing an apparent increase in high-grade disease among those in the same group suggested a grade-associated response to finasteride. The results of this present study indicate finasteride's effects are grade dependent, which may explain the split findings of the PCPT.
doi:10.1016/j.ebiom.2016.03.047
PMCID: PMC4909608  PMID: 27322462
GG, Gleason grade; AR, androgen receptor; PCPT, Prostate Cancer Prevention Trial; REDUCE, Reduction by Dutasteride of Prostate Cancer Events; REDEEM, Reduction by Dutasteride of Clinical Progression Events in Expectant Management; DHT, dihydrotestosterone; CRFs, case report forms; DCP, Division of Cancer Prevention; HE, hematoxylin and eosin; ERβ, estrogen receptor β; UBE2C, ubiquitin-conjugating enzyme E2C; SRD5A2, 3-oxo-5α-steroid 4-dehydrogenase 2; VEGF, vascular epithelial growth factor; GS, Gleason score; PZ, peripheral zone; TZ, transition zone; CZ, central zone; Prostate cancer; 5α-reductase inhibitors; Finasteride; Cancer prevention; Biomarkers
19.  Relationship between tumor size and survival in non-small cell lung cancer (NSCLC): an analysis of the Surveillance, Epidemiology, and End Results (SEER) registry 
INTRODUCTION
Tumor size is a known prognostic factor for early stage non-small cell lung cancer (NSCLC), but its significance in node-positive and locally invasive NSCLC has not been extensively characterized. We queried the Surveillance, Epidemiology and End Results (SEER) database to evaluate the prognostic value of tumor size for early stage as well as node-positive and locally invasive NSCLC.
METHODS
Patients in SEER registry with NSCLC diagnosed between 1998 and 2003 were analyzed. Tumor size was analyzed as a continuous variable. Other demographic variables included age, gender, race, histology, primary tumor extension, node status and primary treatment modality (surgery vs radiation). The Kaplan-Meier method was used to estimate overall survival (OS). Cox proportional hazard model was used to evaluate whether tumor size was an independent prognostic factor.
RESULTS
52,287 eligible patients were subgrouped based on tumor extension and node status. Tumor size had a significant effect on OS in all subgroups defined by tumor extension or node status. In addition, tumor size also had statistically significant effect on OS in 15 of 16 subgroups defined by tumor extension and nodal status after adjustment for other clinical variables. Our model incorporating tumor size had significantly better predictive accuracy than our alternative model without tumor size.
CONCLUSIONS
Tumor size is an independent prognostic factor, for early stage as well as node positive and locally invasive disease. Prediction tools, such as nomograms, incorporating more detailed information not captured in detail by the routine TNM classification, may improve prediction accuracy of OS in NSCLC.
doi:10.1097/JTO.0000000000000456
PMCID: PMC4368494  PMID: 25590605
Non-small cell lung cancer; Tumor Size; Survival; SEER
20.  Commentary on Hey and Kimmelman 
Clinical trials (London, England)  2015;12(2):110-112.
doi:10.1177/1740774514568875
PMCID: PMC4492278  PMID: 25649110
21.  Prediction of survival in resected non-small cell lung cancer using a protein-expression based risk model: Implications for personalized chemoprevention and therapy 
Purpose
Patients with resected non-small cell lung cancer (NSCLC) are at risk for recurrence of disease but we do not have tools to predict which patients are at highest risk. We set out to create a risk model incorporating both clinical data and biomarkers.
Methods
We assembled a comprehensive database with archival tissues and clinical follow-up from patients with NSCLC resected between 2002-2005. Twenty-one proteins identified from our preclinical studies as related to lung carcinogenesis were investigated, including pathways related to metabolism, DNA repair, inflammation and growth factors. Expression of proteins was quantified using immunohistochemistry. Immunohistochemistry was chosen because it is widely available and can be performed on formalin-fixed paraffin-embedded specimens. Cox models were fitted to estimate effects of clinical factors and biomarkers on recurrence free survival (RFS) and overall survival (OS).
Results
370 patients are included in our analysis. With median follow-up of 5.3 years, median overall survival is 6.4 years. 209 cases with recurrence or death were observed. Multicovariate risk models for RFS and OS were developed including relevant biomarkers, age and stage. Increased expression of pAMPK, pmTOR, EpCAM, and CASK were significant (p<0.05) predictors for favorable RFS; insulin receptor, CXCR2, and IGF1R predicted for unfavorable RFS. Significant (p<0.05) predictors for favorable OS include pAMPK, pmTOR, and EpCAM; CXCR2 and FEN1 predicted unfavorable OS.
Conclusions
We have developed a comprehensive risk model predictive for recurrence in our large retrospective database, which is one of the largest reported series of resected NSCLC.
doi:10.1158/1078-0432.CCR-13-1959
PMCID: PMC4018222  PMID: 24366692
Lung cancer; biomarkers; risk modeling
22.  Adaptive clinical trial designs in oncology 
Adaptive designs have become popular in clinical trial and drug development. Unlike traditional trial designs, adaptive designs use accumulating data to modify the ongoing trial without undermining the integrity and validity of the trial. As a result, adaptive designs provide a flexible and effective way to conduct clinical trials. The designs have potential advantages of improving the study power, reducing sample size and total cost, treating more patients with more effective treatments, identifying efficacious drugs for specific subgroups of patients based on their biomarker profiles, and shortening the time for drug development. In this article, we review adaptive designs commonly used in clinical trials and investigate several aspects of the designs, including the dose-finding scheme, interim analysis, adaptive randomization, biomarker-guided randomization, and seamless designs. For illustration, we provide examples of real trials conducted with adaptive designs. We also discuss practical issues from the perspective of using adaptive designs in oncology trials.
doi:10.3978/j.issn.2304-3865.2014.06.04
PMCID: PMC4369921  PMID: 25811018
Adaptive design; adaptive randomization; interim analysis; seamless design; biomarker-guided design
23.  Simulation Study for Evaluating the Performance of Response-Adaptive Randomization 
A response-adaptive randomization (RAR) design refers to the method in which the probability of treatment assignment changes according to how well the treatments are performing in the trial. Holding the promise of treating more patients with the better treatments, RARs have been successfully implemented in clinical trials. We compared equal randomization (ER) with three RARs: Bayesian adaptive randomization, sequential maximum likelihood, and sequential posterior mean. We fixed the total number of patients, considering as patient horizon, but varied the number of patients in the trial. Among the designs, we compared the proportion of patients assigned to the superior arm, overall response rate, statistical power, and total patients enrolled in the trial if adding an efficacy early stopping rule. Without early stopping, ER is preferred when the number of patients beyond the trial is much larger than the number of patients in the trial. RAR is favored for large treatment difference or when the number of patients beyond the trial is small. With early stopping, the difference between these two types of designs was reduced. By carefully choosing the design parameters, both RAR and ER methods can achieve the desirable statistical properties. Within three RAR methods, we recommend SPM considering the larger proportion in the better arm and higher overall response rate than BAR and similar power and trial size with ER. The ultimate choice of RAR or ER methods depends on the investigator’s preference, the trade-off between group ethics and individual ethics, and logistic considerations in the trial conduct, etc.
doi:10.1016/j.cct.2014.11.006
PMCID: PMC4314433  PMID: 25460340
allocation probability; Bayesian adaptive design; efficacy early stopping; operating characteristics; patient horizon
24.  Unique Molecular Landscapes in Cancer: Implications for Individualized, Curated Drug Combinations 
Cancer research  2014;74(24):7181-7184.
With increasing lysophisticated technologies in molecular biology and ‘omic’ platforms to analyze patients’ tumors, more molecular diversity and complexity in cancer are being observed. Recently, we noted unique genomic profiles in a group of patients with metastatic breast cancer based on an analysis with next generation sequencing (NGS); amongst 57 consecutive patients, no two had the same molecular portfolio (1). Applied genomics therefore appears to represent a disruptive innovation in that it unveils a heterogeneity to metastatic cancer that may be ill suited to canonical clinical trials and practice paradigms. Upon recognizing that patients have unique tumor landscapes, it is possible that there may be a ‘mismatch’ between our traditional clinical trials system that selects patients based on common characteristics in order to evaluate a drug (drug-centric approach), and optimal treatment based on curated, individualized drug combinations for each patient (patient-centric approach).
doi:10.1158/0008-5472.CAN-14-2329
PMCID: PMC4292868  PMID: 25326492
Clinical trials; Genomics; Personalized medicine
25.  Mutational landscape of aggressive cutaneous squamous cell carcinoma 
Purpose
Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC.
Experimental Design
Whole exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias.
Results
Despite the very high mutational background caused by UV exposure, 23 candidate drivers were identified including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3 and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion.
Conclusions
The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC.
doi:10.1158/1078-0432.CCR-14-1768
PMCID: PMC4367811  PMID: 25303977
Head and neck/oral cancers; Melanoma/skin cancers; Mutagenesis; Oncogenes; Suppressor genes; Somatic alterations and genetic and environmental risk factors; cutaneous squamous cell carcinoma; cSCC; genomics

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