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1.  Nomogram to Predict the Benefit of Radiation for Older Patients With Breast Cancer Treated With Conservative Surgery 
Journal of Clinical Oncology  2012;30(23):2837-2843.
Purpose
The role of radiation therapy (RT) after conservative surgery (CS) remains controversial for older patients with breast cancer. Guidelines based on recent clinical trials have suggested that RT may be omitted in selected patients with favorable disease. However, it is not known whether this recommendation should extend to other older women. Accordingly, we developed a nomogram to predict the likelihood of long-term breast preservation with and without RT.
Methods
We used Surveillance, Epidemiology, and End Results–Medicare data to identify 16,092 women age 66 to 79 years treated with CS between 1992 and 2002, using claims to identify receipt of RT and subsequent mastectomy. Time to mastectomy was estimated using the Kaplan-Meier method. Cox proportional hazards models determined the effect of covariates on mastectomy-free survival (MFS). A nomogram was developed to predict 5- and 10-year MFS, given associated risk factors, and bootstrap validation was performed.
Results
With a median follow-up of 7.2 years, the overall 5- and 10-year MFS rates were 98.1% (95% CI, 97.8% to 98.3%) and 95.4% (95% CI, 94.9% to 95.8%), respectively. In multivariate analysis, age, race, tumor size, estrogen receptor status, and receipt of RT were predictive of time to mastectomy and were incorporated into the nomogram. Nodal status was also included given a significant interaction with RT. The resulting nomogram demonstrated good accuracy in predicting MFS, with a bootstrap-corrected concordance index of 0.66.
Conclusion
This clinically useful tool predicts 5- and 10-year MFS among older women with early breast cancer using readily available clinicopathologic factors and can aid individualized clinical decision making by estimating predicted benefit from RT.
doi:10.1200/JCO.2011.41.0076
PMCID: PMC3410401  PMID: 22734034
2.  G-Protein Coupled Receptor Family C, Group 5, Member A (GPRC5A) Expression Is Decreased in the Adjacent Field and Normal Bronchial Epithelia of Patients with Chronic Obstructive Pulmonary Disease and Non–Small-Cell Lung Cancer 
Introduction
Understanding oncogenes and tumor suppressor genes expression patterns is essential for characterizing lung cancer pathogenesis. We have previously demonstrated that mGprc5a/hGPRC5A is a lung-specific tumor suppressor evidenced by inflammation-mediated tumorigenesis in Gprc5a-knockout mice. The implication of GPRC5A in human lung cancer pathogenesis, including that associated with inflammatory chronic obstructive pulmonary disease (COPD), a risk factor for the malignancy, remains elusive.
Methods
We sought to examine GPRC5A immunohistochemical expression in histologically normal bronchial epithelia (NBE) from lung disease-free never- and ever-smokers (n = 13 and n = 18, respectively), from COPD patients with (n = 26) and without cancer (n = 24) and in non-small cell lung cancers (NSCLCs) (n = 474). Quantitative assessment of GPRC5A transcript expression in airways (n = 6), adjacent NBEs (n = 29) and corresponding tumors (n = 6) from 6 NSCLC patients was also performed.
Results
GPRC5A immunohistochemical expression was significantly lower in tumors compared to uninvolved NBE (p < 0.0001) and was positively associated with adenocarcinoma histology (p < 0.001). GPRC5A airway expression was highest in lung disease-free NBE, decreased and intermediate in NBE of cancer-free COPD patients (p = 0.004) and further attenuated and lowest in epithelia of COPD patients with adenocarcinoma and SCC (p < 0.0001). Furthermore, GPRC5A mRNA was significantly decreased in NSCLCs and corresponding NBE compared to uninvolved normal lung (p = 0.03).
Conclusions
Our findings highlight decreased GPRC5A expression in the field cancerization of NSCLC, including that associated with lung inflammation. Assessment of the use of GPRC5A expression as a risk factor for NSCLC development in COPD patients is warranted.
doi:10.1097/JTO.0b013e31826bb1ff
PMCID: PMC3622592  PMID: 23154545
Field cancerization; Chronic obstructive pulmonary disease; Non–small-cell lung cancer; g-protein coupled receptor family C; group 5; member A; gene expression
3.  Young Onset HER2 Positive Breast Cancer is Associated with Germline TP53 Mutations 
Cancer  2011;118(4):908-913.
Background
Germline TP53 mutations predispose to early onset breast cancer (BC) in women and are associated with the Li Fraumeni syndrome. Published data on the pathological characteristics of breast cancer among women with TP53 mutations is limited.
Methods
We retrospectively reviewed clinical records of women who had genetic testing for suspected germline TP53 mutations and who were diagnosed with BC between 2000 to 2011. The pathological characteristics of the breast tumors from women testing positive (cases) for a mutation were compared to those testing negative (controls).
Results
Patients who tested positive for germline TP53 mutations (N=30) were compared to (N=79) controls. Human epidermal growth factor receptor 2 (HER2) amplification and/or overexpression was found in 67% of the tumors from the cases, compared to 25% for the controls (p=0.0001). Among patients with a mutation, 70% had estrogen receptor and/or progesterone receptor positive tumors, compared to 68% in the control group (p= 0.87). After adjusting for age at BC diagnosis, having a HER2 positive tumor increased the odds of testing positive for a germline TP53 mutation (OR, 6.9, 95% CI, 2.6 to 18.2). For each yearly increments in age at BC diagnosis, there was decreased likelihood of having a TP53 mutation by 5% (OR=0.95, CI 0.91 to 0.99).
Conclusion
This study suggests an association between germline TP53 mutations and early onset HER2 positive breast cancer. If confirmed in a larger cohort, these results could guide genetic testing strategies, lead to chemoprevention trials incorporating HER2 targeted therapies, and elucidate some of the molecular pathways involved in breast cancer.
doi:10.1002/cncr.26377
PMCID: PMC3527897  PMID: 21761402
4.  Proliferative Changes in the Bronchial Epithelium of Former Smokers Treated With Retinoids 
Background
Retinoids have shown antiproliferative and chemopreventive activity. We analyzed data from a randomized, placebo-controlled chemoprevention trial to determine whether a 3-month treatment with either 9-cis-retinoic acid (RA) or 13-cis-RA and α-tocopherol reduced Ki-67, a proliferation biomarker, in the bronchial epithelium.
Methods
Former smokers (n = 225) were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg), 13-cis-RA (1 mg/kg) and α-tocopherol (1200 IU), or placebo. Bronchoscopic biopsy specimens obtained before and after treatment were immunohistochemically assessed for changes in the Ki-67 proliferative index (i.e., percentage of cells with Ki-67–positive nuclear staining) in the basal and parabasal layers of the bronchial epithelium. Per-subject and per–biopsy site analyses were conducted. Multicovariable analyses, including a mixed-effects model and a generalized estimating equations model, were used to investigate the treatment effect (Ki-67 labeling index and percentage of bronchial epithelial biopsy sites with a Ki-67 index ≥ 5%) with adjustment for multiple covariates, such as smoking history and metaplasia. Coefficient estimates and 95% confidence intervals (CIs) were obtained from the models. All statistical tests were two-sided.
Results
In per-subject analyses, Ki-67 labeling in the basal layer was not changed by any treatment; the percentage of subjects with a high Ki-67 labeling in the parabasal layer dropped statistically significantly after treatment with 13-cis-RA and α-tocopherol treatment (P = .04) compared with placebo, but the drop was not statistically significant after 9-cis-RA treatment (P = .17). A similar effect was observed in the parabasal layer in a per-site analysis; the percentage of sites with high Ki-67 labeling dropped statistically significantly after 9-cis-RA treatment (coefficient estimate = −0.72, 95% CI = −1.24 to −0.20; P = .007) compared with placebo, and after 13-cis-RA and α-tocopherol treatment (coefficient estimate = −0.66, 95% CI = −1.15 to −0.17; P = .008).
Conclusions
In per-subject analyses, treatment with 13-cis-RA and α-tocopherol, compared with placebo, was statistically significantly associated with reduced bronchial epithelial cell proliferation; treatment with 9-cis-RA was not. In per-site analyses, statistically significant associations were obtained with both treatments.
doi:10.1093/jnci/djm205
PMCID: PMC3441140  PMID: 17971525
5.  Defining and Ranking Effects of Individual Agents Based On Survival Times of Cancer Patients Treated with Combination Chemotherapies 
Statistics in medicine  2011;30(15):1777-1794.
Summary
An important problem in oncology is comparing chemotherapy (chemo) agents in terms of their effects on survival or progression free survival time. When the goal is to evaluate individual agents, a difficulty commonly encountered with observational data is that many patients receive a chemo combination including two or more agents. Because agents given in combination may interact, quantifying the contribution of each individual agent to the combination’s overall effect is problematic. Still, if on average combinations including a particular agent confer longer survival, then that agent may be considered superior to agents whose combinations confer shorter survival. Motivated by this idea, we propose a definition of individual agent effects based on observational survival data from patients treated with many different chemo combinations. We define an individual agent effect as the average of the effects of the chemo combinations that include the agent. Similarly, we define the effect of each pair of agents as the average of the effects of the combinations including the pair. Under a Bayesian regression model for survival time in which the chemo combination effects follow a hierarchical structure, these definitions are used as a basis for estimating the posterior effects and ranks of the individual agents, and of all pairs of agents. The methods are illustrated by a data set arising from 224 pediatric brain tumor patients treated with over 27 different chemo combinations involving seven chemo agents.
doi:10.1002/sim.4249
PMCID: PMC3115413  PMID: 21590700
Bayesian analysis; Brain tumors; Hierarchical model; Ranking; Survival analysis
6.  Abnormalities of the TITF-1 lineage-specific oncogene in NSCLC: Implications in lung cancer pathogenesis and prognosis 
PURPOSE
Emerging evidence suggests that aberrant expression of oncogenes contributes to development of lung malignancy. The thyroid transcription factor 1 (TITF-1) gene functions as a lineage survival gene abnormally expressed in a significant fraction of NSCLCs, in particular lung adenocarcinomas.
EXPERIMENTAL DESIGN
To better characterize TITF-1 abnormality: patterns in NSCLC, we studied TITF-1’s gene copy number using fluorescent in situ hybridization (FISH) and quantitative PCR, as well as its protein expression by immunohistochemistry analysis in a tissue microarray comprised of surgically resected NSCLC (N=321) including 204 adenocarcinomas and 117 squamous cell carcinomas (SCCs). TITF-1 copy number and protein expression were correlated with patients’ clinicopathologic characteristics, and in a subset of adenocarcinomas with EGFR and KRAS mutation status.
RESULTS
We found that increased TITF-1 protein expression was prevalent in lung adenocarcinomas only and was significantly associated with female gender (p<0.001), never smokers (p=0.004), presence of EGFR mutations (p=0.05) and better overall survival (all stages, p=0.0478. stages I and II, p=0.002). TITF-1 copy number gain (CBG) was detected by FISH analysis in both adenocarcinomas (18.9%; high CNG, 8.3%) and SCCs (20.1%; high CNG, 3.0%), and correlated significantly with the protein product (p=0.004) and presence of KRAS mutations (p=0.008) in lung adenocarcinomas. Moreover, multivariate analysis revealed that TITF-1 copy number gain was an independent predictor of poor survival of NSCLC (p=0.039).
CONCLUSIONS
Our integrative study demonstrates that the protein versus genomic expression patterns of TITF-1 have opposing roles in lung cancer prognosis and may occur preferentially in different subsets of NSCLC patients with distinct oncogene mutations.
doi:10.1158/1078-0432.CCR-10-1412
PMCID: PMC3078948  PMID: 21257719
NSCLC; TITF-1; gene copy gain; lineage-specific oncogenes
7.  miR-200 Inhibits Lung Adenocarcinoma Cell Invasion and Metastasis by Targeting Flt1/VEGFR1 
The microRNA-200 (miR-200) family is part of a gene expression signature that predicts poor prognosis in lung cancer patients. In a mouse model of K-ras/p53-mutant lung adenocarcinoma, miR-200 levels are suppressed in metastasis-prone tumor cells, and forced miR-200 expression inhibits tumor growth and metastasis, but the miR-200 target genes that drive lung tumorigenesis have not been fully elucidated. Here, we scanned the genome for putative miR-200 binding sites and found them in the 3′-untranslated region (3′-UTR) of 35 genes that are amplified in human cancer. Mining of a database of resected human lung adenocarcinomas revealed that the levels of one of these genes, Flt1/VEGFR1, correlate inversely with duration of survival. Forced miR-200 expression suppressed Flt1 levels in metastasis-prone lung adenocarcinoma cells derived from K-ras/p53-mutant mice, and negatively regulated the Flt1 3′-UTR in reporter assays. Cancer-associated fibroblasts (CAFs) isolated from murine lung adenocarcinomas secreted abundant VEGF and enhanced tumor cell invasion in coculture studies. CAF-induced tumor cell invasion was abrogated by VEGF neutralization or Flt1 knockdown in tumor cells. Flt1 knockdown decreased the growth and metastasis of tumor cells in syngeneic mice. We conclude that miR-200 suppresses lung tumorigenesis by targeting Flt1.
doi:10.1158/1541-7786.MCR-10-0497
PMCID: PMC3232024  PMID: 21115742
9.  CREB Overexpression: A Feature Associated with Negative Prognosis in Never-Smokers with NSCLC 
Cancer research  2008;68(15):6065-6073.
Lung cancer is the leading cause of cancer deaths worldwide. Recent advances in targeted therapies hold promise for the development of new treatments for certain subsets of cancer patients by targeting specific signaling molecule. Based on the identification of the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB) as an important regulator of growth of several types of cancers and our recent findings of its importance in normal differentiation of bronchial epithelial cells, we hypothesized that CREB plays an important pathobiologic role in lung carcinogenesis. We conducted this initial study to determine whether the expression and activation status of CREB are altered in non-small cell lung cancer (NSCLC) and of any prognostic importance in NSCLC patients. We found that the expression levels of mRNA and protein of CREB and phosphorylated CREB (p-CREB) were significantly higher in most of the NSCLC cell lines and tumor specimens than in the normal human tracheobronchial epithelial (NHTBE) cells and adjacent normal lung tissue, respectively. Analysis of CREB mRNA expression and the CREB gene copy number showed that CREB overexpression occurred mainly at the transcriptional level. Immunohistochemical analysis of tissue microarray (TMA) slides containing sections of NSCLC specimens obtained from 310 patients showed that a decreased survival duration was significantly associated with overexpression of CREB or p-CREB in never-smokers but not in current or former smokers with NSCLC. These are the first reported results illustrating the potential of CREB as a molecular target for the prevention and treatment of NSCLC, especially in never-smokers.
doi:10.1158/0008-5472.CAN-07-5376
PMCID: PMC3058903  PMID: 18676828
CREB overexpression; prognosis; NSCLC; adenocarcinoma; squamous cell carcinoma
10.  Frequent expression of MAGE1 tumor antigens in bronchial epithelium of smokers without lung cancer 
Melanoma antigens (MAGE) are frequently expressed in lung cancer and are promising targets of anticancer immunotherapy. Our preliminary data suggested that MAGE may be expressed during early lung carcinogenesis, raising the possibility of targeting MAGE as a lung cancer prevention strategy. The purpose of this study was to investigate MAGE activation patterns in the airways of chronic smokers without lung cancer. MAGE-A1, -A3 and -B2 gene expression was determined in bronchial brush cells from chronic former smokers without lung cancer by reverse transcription-PCR (RT-PCR). The results were correlated with clinical parameters. The 123 subjects had a median age of 57 years, a median of 40 pack-years smoking history, and had quit smoking for at least one year prior to enrollment. Among the subjects, 31 (25%), 38 (31%), and 46 (37%) had detectable MAGE-A1, -A3 and -B2 expression, respectively, in their bronchial brush samples. Expression of MAGE-A1 and -B2 positively correlated with pack-years smoking history (P=0.03 and 0.03, respectively). The frequency of expression did not decrease despite a prolonged smoking cessation period. In conclusion, MAGE-A1, -A3 and -B2 genes are frequently expressed in the bronchial epithelial cells of chronic smokers without lung cancer, suggesting that chronic exposure to cigarette smoke activates these genes even before the malignant transformation of bronchial cells in susceptible individuals. Once activated, the expression persists despite long-term smoking cessation. These data support the targeting of MAGE as a novel lung cancer prevention strategy.
doi:10.3892/etm.2010.176
PMCID: PMC3440643  PMID: 22977481
melanoma antigens; airway; smokers; lung cancer; prevention
11.  Emax model and interaction index for assessing drug interaction in combination studies 
1. ABSTRACT
Applying the Emax model in a Lowe additivity model context, we analyze data from a combination study of trimetrexate (TMQ) and AG2034 (AG) in media of low and high concentrations of folic acid (FA). The Emax model provides a sufficient fit to the data. TMQ is more potent than AG in both low and high FA media. At low TMQ:AG ratios, when a smaller amount of the more potent drug (TMQ) is added to a larger amount of the less potent drug (AG), synergy results. When the TMQ:AG ratio reaches 0.4 or larger in low FA medium, or when the TMQ:AG ratio reaches 1 or larger in high FA medium, synergy is weakened and drug interaction becomes additive. In general, synergistic effect in a dilution series is stronger at higher doses that produce stronger effects (closer to 1−Emax) than at lower dose levels that produce weaker effects (closer to 1). The two drugs are more potent in the low compared to the high FA medium. Drug synergy, however, is stronger in the high FA medium.
PMCID: PMC2974574  PMID: 20036904
additivity; antagonism; confidence interval estimation; Emax model; Loewe additivity model; nonlinear regression; synergy; trellis plot
12.  Bayesian Clinical Trials at the University of Texas M. D. Anderson Cancer Center 
Background
The Bayesian approach is being used increasingly in medical research. In particular, it has become a standard in designing clinical trials at the University of Texas M. D. Anderson Cancer Center.
Purpose/Methods
To address the extent and nature of Bayesian trials conducted at M. D. Anderson, we reviewed the protocols registered in the Protocol Document Online System between 2000 and early 2005. We summarize our findings and give details for three innovative trials that typify those in which a Bayesian approach has played a major role at the center.
Results
Of 964 protocols reviewed, 59% were conducted solely at M. D. Anderson and the rest were multicenter trials. Bayesian designs and analyses were used in about 20% (195/964) of the protocols that we reviewed. Of the 520 protocols identified as phase I or II drug trials, about 34% were Bayesian. Most of the 195 Bayesian trials were designed by M. D. Anderson statisticians. The Bayesian design features most commonly used were the continuous reassessment method in phase I (toxicity) trials, adaptive randomization in phase II trials, and designs to monitor efficacy and toxicity simultaneously. We also provide an insider's view regarding some practical considerations that have made the design and implementation of so many Bayesian trials possible.
Limitations
We reviewed only a subset of all M. D. Anderson protocols, but did not exclude any available in electronic form.
Conclusions
The large number of Bayesian trials conducted at M. D. Anderson testifies to the receptivity to the Bayesian approach within the center, including principal investigators, regulatory review committees, and patients. Statisticians who take a Bayesian perspective can successfully work to establish a culture of innovation in clinical trial design.
doi:10.1177/1740774509104992
PMCID: PMC2913209  PMID: 19528130
Adaptive randomization; continuous reassessment method; dose finding; hierarchical modeling; predictive probability; toxicity and efficacy monitoring
13.  Loss and Reduction of Fus1 Protein Expression is a Frequent Phenomenon in the Pathogenesis of Lung Cancer 
Purpose
FUS1, a novel tumor-suppressor gene located in the chromosome 3p21.3 region, may play an important role in lung cancer development. Currently, FUS1-expressing nanoparticles have been developed for treating patients with lung cancer. However, the expression of Fus1 protein has not been examined in a large series of lung cancers and their sequential preneoplastic lesions.
Experimental Design
Using tissue microarrays, we examined Fus1 immunohistochemical expression in 281 non – small cell lung carcinoma (NSCLC) and 22 small cell lung carcinoma tissue specimens and correlated the findings with patients’ clinicopathologic features. To investigate the expression of Fus1 in the early sequential pathogenesis of NSCLC, we studied Fus1 expression in 211 histologically normal and mildly abnormal bronchial epithelia, and 118 bronchial and alveolar preneoplastic lesions obtained from patients with lung cancer.
Results
Loss and reduction of expression was detected in 82% of NSCLCs and 100% of small cell lung carcinomas. In NSCLCs, loss of Fus1 immunohistochemical expression was associated with significantly worse overall survival. Bronchial squamous metaplastic and dysplastic lesions expressed significantly lower levels of Fus1 compared with normal (P = 0.014 and 0.047, respectively) and hyperplastic (P = 0.013 and 0.028, respectively) epithelia.
Conclusions
Our findings show a high frequency of Fus1 protein loss and reduction of expression in lung cancer, and suggests that this reduction may play an important role in the early pathogenesis of lung squamous cell carcinoma. These findings support the concept that FUS1 gene and Fus1 protein abnormalities could be used to develop new strategies for molecular cancer therapy for a significant subset of lung tumors.
doi:10.1158/1078-0432.CCR-07-1252
PMCID: PMC2833352  PMID: 18172250
14.  Expression Signatures of Metastatic Capacity in a Genetic Mouse Model of Lung Adenocarcinoma 
PLoS ONE  2009;4(4):e5401.
Background
Non-small cell lung cancer (NSCLC) is the foremost cause of cancer-related death in Western countries, which is due partly to the propensity of NSCLC cells to metastasize. The biologic basis for NSCLC metastasis is not well understood.
Methodology/Principal Findings
Here we addressed this deficiency by transcriptionally profiling tumors from a genetic mouse model of human lung adenocarcinoma that develops metastatic disease owing to the expression of K-rasG12D and p53R172H. We identified 2,209 genes that were differentially expressed in distant metastases relative to matched lung tumors. Mining of publicly available data bases revealed this expression signature in a subset of NSCLC patients who had a poorer prognosis than those without the signature.
Conclusions/Significance
These findings provide evidence that K-rasG12D; p53R172H mice recapitulate features of human NSCLC metastasis and will provide a useful platform on which to study the biologic basis for lung adenocarcinoma metastasis and its prevention by novel agents.
doi:10.1371/journal.pone.0005401
PMCID: PMC2671160  PMID: 19404390
15.  Fibulin-2 Is a Driver of Malignant Progression in Lung Adenocarcinoma 
PLoS ONE  2013;8(6):e67054.
The extracellular matrix of epithelial tumors undergoes structural remodeling during periods of uncontrolled growth, creating regional heterogeneity and torsional stress. How matrix integrity is maintained in the face of dynamic biophysical forces is largely undefined. Here we investigated the role of fibulin-2, a matrix glycoprotein that functions biomechanically as an inter-molecular clasp and thereby facilitates supra-molecular assembly. Fibulin-2 was abundant in the extracellular matrix of human lung adenocarcinomas and was highly expressed in tumor cell lines derived from mice that develop metastatic lung adenocarcinoma from co-expression of mutant K-ras and p53. Loss-of-function experiments in tumor cells revealed that fibulin-2 was required for tumor cells to grow and metastasize in syngeneic mice, a surprising finding given that other intra-tumoral cell types are known to secrete fibulin-2. However, tumor cells grew and metastasized equally well in Fbln2-null and -wild-type littermates, implying that malignant progression was dependent specifically upon tumor cell-derived fibulin-2, which could not be offset by other cellular sources of fibulin-2. Fibulin-2 deficiency impaired the ability of tumor cells to migrate and invade in Boyden chambers, to create a stiff extracellular matrix in mice, to cross-link secreted collagen, and to adhere to collagen. We conclude that fibulin-2 is a driver of malignant progression in lung adenocarcinoma and plays an unexpected role in collagen cross-linking and tumor cell adherence to collagen.
doi:10.1371/journal.pone.0067054
PMCID: PMC3677922  PMID: 23785517

Results 1-15 (15)