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Junya Fujimoto,
Humam Kadara,
Melinda M Garcia,
Mohamed Kabbout,
Carmen Behrens, Diane D Liu,
J Jack Lee,
Luisa M Solis,
Edward S Kim,
Neda Kalhor,
Cesar Moran,
Amir Sharafkhaneh,
Reuben Lotan,
Ignacio I Wistuba
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ABSTRACT: : 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.
: 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.
: 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 corre sponding NBE compared to uninvolved normal lung (p = 0.03).
: 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.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 12/2012; 7(12):1747-54. · 4.55 Impact Factor
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Banu Arun,
Soley Bayraktar, Diane D Liu,
Angelica M Gutierrez Barrera,
Deann Atchley,
Lajos Pusztai,
Jennifer Keating Litton,
Vicente Valero,
Funda Meric-Bernstam,
Gabriel N Hortobagyi,
Constance Albarracin
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ABSTRACT: To compare the pathologic complete response (pCR) rate and relapse-free survival (RFS) and overall survival (OS) after neoadjuvant systemic chemotherapy (NST) in patients with breast cancer with and without deleterious BRCA1 and BRCA2 mutations.
A total of 317 women who underwent BRCA genetic testing and were treated with NST for breast cancer between 1997 and 2009 were included in the study. The Kaplan-Meier product-limit method was used to estimate RFS and OS rates. Logistic regression models were fit to determine the associations between BRCA status, pCR, and survival.
Fifty-seven (18%) and 23 (7%) patients had BRCA1 and BRCA2 mutations, respectively. Twenty-six (46%) of 57 BRCA1 carriers achieved a pCR, compared with three (13%) of 23 BRCA2 carriers and 53 (22%) of 237 BRCA noncarriers (P < .001). In the multivariate logistic model, BRCA1 status (odds ratio [OR] = 3.16; 95% CI, 1.55 to 6.42; P = .002), estrogen receptor (ER) negativity (OR = 1.96; 95% CI:1.05 to 3.65; P = .03) and concurrent trastuzumab use (OR = 4.18; 95% CI, 2.04 to 8.57; P < .001) remained as independent significant predictors for a pCR. At a median follow-up of 3.2 years, 69 patients (22%) experienced a disease recurrence or death. No significant differences were noted in survival outcomes with respect to BRCA status and type of NST received. However, among BRCA1 carriers, patients who achieved a pCR had better 5-year RFS (P = .001) and OS (P = .01) rates than patients who did not.
BRCA1 status and ER negativity are independently associated with higher pCR rates in patients with breast cancer. Overall prognosis of breast cancer in BRCA carriers is similar to sporadic breast cancers.
Journal of Clinical Oncology 09/2011; 29(28):3739-46. · 18.37 Impact Factor
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Amal Melhem-Bertrandt,
Jasmina Bojadzieva,
Kaylene J Ready,
Elias Obeid, Diane D Liu,
Angelica M Gutierrez-Barrera,
Jennifer K Litton,
Olufunmilayo I Olopade,
Gabriel N Hortobagyi,
Louise C Strong,
Banu K Arun
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ABSTRACT: Germline TP53 mutations predispose to early onset breast cancer in women and are associated with Li-Fraumeni syndrome. Published data on the pathological characteristics of breast cancer among women with TP53 mutations is limited.
We retrospectively reviewed the clinical records of women who underwent genetic testing for suspected germline TP53 mutations and who were diagnosed with breast cancer between 2000 and 2011. The pathological characteristics of the breast tumors from patients testing positive for a mutation (cases) were compared with those testing negative (controls).
Patients who tested positive for germlineTP53 mutations (n = 30) were compared with controls (n = 79). Human epidermal growth factor receptor 2 (HER2) amplification and/or overexpression was found in 67% of the tumors from the cases, compared with 25% for the controls (P = .0001). Among patients with a mutation, 70% had estrogen receptor- and/or progesterone receptor-positive tumors, compared with 68% in the control group (P = .87). After adjusting for age at breast cancer diagnosis, having a HER2-positive tumor increased the odds of testing positive for a germline TP53 mutation (odds ratio, 6.9; 95% confidence interval, 2.6-18.2). For each yearly increment in age at breast cancer diagnosis, there was decreased likelihood of having a TP53 mutation of 5% (odds ratio, 0.95; 95% confidence interval0.91-0.99).
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.
Cancer 07/2011; 118(4):908-13. · 4.77 Impact Factor
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ABSTRACT: 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.
Statistics in Medicine 07/2011; 30(15):1777-94. · 1.88 Impact Factor
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ABSTRACT: 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.
Experimental and therapeutic medicine 01/2011; 2(1):137-142.
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Jonathon D Roybal,
Yi Zang,
Young-Ho Ahn,
Yanan Yang,
Don L Gibbons,
Brandi N Baird,
Cristina Alvarez,
Nishan Thilaganathan, Diane D Liu,
Pierre Saintigny,
John V Heymach,
Chad J Creighton,
Jonathan M Kurie
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ABSTRACT: 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.
Molecular Cancer Research 01/2011; 9(1):25-35. · 4.29 Impact Factor
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ABSTRACT: Choroid plexus carcinomas (CPCs) are rare tumors with dismal outcome. While it has been established that surgery, radiotherapy, and chemotherapy improve survival, the best chemotherapy drugs for treating this disease still need to be identified. Since CPC is too rare to permit a prospective clinical trial, we performed a meta-analysis to evaluate the effects of individual drugs in patients with CPCs. We expanded a pre-existing database and included all cases of choroid plexus tumors, identified in PubMed through the end of 2007, for a total of 906 patients. At first, we restricted the analysis to patients with histologically confirmed CPC (n = 361) and with residual tumor after surgery (n = 130/361 patients), and we compared response and survival between patients who received a particular drug and those who did not. Response to chemotherapy was documented in 43 patients. Of the drugs used in these patients, etoposide was associated with the highest response rate (17/36). Next survival was compared among all CPC. Kaplan-Meier curves and log-rank tests suggested a statistically significant treatment benefit for cyclophosphamide, etoposide, and carboplatin, while the effect of vincristine was found to be marginally significant (P = 0.07, log rank). Of these, only etoposide's effect could be confirmed in a limited Cox multiple regression analysis. In conclusion, etoposide should be included in future standard treatment protocols. However the survival rates are still unsatisfactory, and additional novel drugs should be studied in prospective multicenter studies.
Journal of Neuro-Oncology 10/2010; 103(1):155-62. · 3.21 Impact Factor
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ABSTRACT: Determining the differential diagnosis between typical (TCs) and atypical carcinoid tumors (ACs) is imperative, as the distinction between TCs and ACs is currently based on histologic criteria that are not always correlated with the unfavorable clinical outcomes.
We conducted a retrospective study of patients who were diagnosed with carcinoid tumors between 1990 and 2005 at M. D. Anderson Cancer Center. We reviewed the slides for the following pathologic features: infiltrative growth; pleural, blood, or lymphatic vessel invasion; tumor stroma; presence of active fibroblastic proliferation; chromatin pattern; presence of nucleolus; and nuclear pleomorphism. We also evaluated the necrotic patterns. Finally, we evaluated three methods for calculating the number of mitoses: randomly selected, the most mitotically active in 10 high-power fields (HPFs), or overall mean mitotic count.
Our cohort consisted of 80 patients (68 with TCs and 12 with ACs). Older age (P=0.002), pathologic stage III or IV disease (P=0.04), active fibroblastic proliferation (P=0.041), and comedo-like necrosis (P=0.001) were significantly associated with tumor recurrence or patient's death. Among the three mitotic counting methods, the overall mean number of mitoses was significantly correlated with recurrence-free survival (P<0.0001). Our criteria for distinguishing AC from TC included the presence of comedo-like necrosis and/or an overall mean number of mitoses ≥0.2/HPF.
Using an overall mean number in counting mitoses and detecting comedo-like necrosis is important for classifying lung carcinoid tumors.
Lung cancer (Amsterdam, Netherlands) 05/2010; 71(1):34-41. · 3.14 Impact Factor
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ABSTRACT: Bevacizumab has recently been demonstrated to prolong overall survival when added to carboplatin and paclitaxel for chemotherapy-naïve patients with nonsquamous nonsmall-cell lung cancer (NSCLC). However, the effects of combining bevacizumab with other standard, front-line, platinum-based doublets have not been extensively explored. We designed this single treatment arm, phase 2 trial to determine whether the combination of carboplatin, docetaxel, and bevacizumab is tolerable and prolongs progression-free survival of chemotherapy-naïve patients with advanced, nonsquamous NSCLC.
Forty patients were treated with up to 6 cycles of carboplatin (AUC 6), docetaxel (75 mg/m(2)), and bevacizumab (15 mg/kg) on Day 1 every 21 days. Patients with an objective response or stable disease received maintenance bevacizumab (15 mg/kg) every 21 days until disease progression. The primary endpoint was median progression-free survival. Secondary endpoints included safety, response rates, and overall survival.
The median number of chemotherapy and maintenance bevacizumab cycles/patient was 6 and 2, respectively. Grades 3-5 adverse events included febrile granulocytopenia (10%), infections (13%), bleeding (13%), thrombotic events (13%), hypertension (5%), bowel perforation (5%), and proteinuria (3%). Median progression-free survival was 7.9 months and median overall survival was 16.5 months. Partial responses were observed in 21 patients (53%), and stable disease >or=6 weeks occurred in another 17 patients (43%), for a disease control rate of 95%.
Carboplatin, docetaxel, and bevacizumab were feasible and effective for front-line treatment of advanced, nonsquamous NSCLC. These data provide further evidence that bevacizumab may be used in combination with multiple standard, platinum-based doublets in this setting.
Cancer 03/2010; 116(10):2401-8. · 4.77 Impact Factor
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Edward S Kim,
Waun K Hong,
J Jack Lee,
Li Mao,
Rodolfo C Morice, Diane D Liu,
Carlos A Jimenez,
Georgie A Eapen,
Reuben Lotan,
Ximing Tang,
Robert A Newman,
Ignacio I Wistuba,
Jonathan M Kurie
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ABSTRACT: Non-small cell lung cancer is the primary cause of cancer-related death in Western countries. One important approach taken to address this problem is the development of effective chemoprevention strategies. In this study, we examined whether the cyclooxygenase-2 inhibitor celecoxib, as evidenced by decreased cell proliferation, is biologically active in the bronchial epithelium of current and former smokers. Current or former smokers with at least a 20 pack-year (pack-year = number of packs of cigarettes per day times number of years smoked) smoking history were randomized into one of four treatment arms (3-month intervals of celecoxib then placebo, celecoxib then celecoxib, placebo then celecoxib, or placebo then placebo) and underwent bronchoscopies with biopsies at baseline, 3 months, and 6 months. The 204 patients were primarily (79.4%) current smokers: 81 received either low-dose celecoxib or placebo and 123 received either high-dose celecoxib or placebo. Celecoxib was originally administered orally at 200 mg twice daily and the protocol subsequently increased the dose to 400 mg twice daily. The primary end point was change in Ki-67 labeling (from baseline to 3 months) in bronchial epithelium. No cardiac toxicities were observed in the participants. Although the effect of low-dose treatment was not significant, high-dose celecoxib decreased Ki-67 labeling by 3.85% in former smokers and by 1.10% in current smokers-a significantly greater reduction (P = 0.02) than that seen with placebo after adjusting for metaplasia and smoking status. A 3- to 6-month celecoxib regimen proved safe to administer. Celecoxib (400 mg twice daily) was biologically active in the bronchial epithelium of current and former smokers; additional studies on the efficacy of celecoxib in non-small cell lung cancer chemoprevention may be warranted.
Cancer Prevention Research 02/2010; 3(2):148-59. · 4.91 Impact Factor
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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.
Frontiers in bioscience (Elite edition) 01/2010; 2:582-601.
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ABSTRACT: 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.
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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.
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.
We reviewed only a subset of all M. D. Anderson protocols, but did not exclude any available in electronic form.
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.
Clinical Trials 07/2009; 6(3):205-16. · 1.92 Impact Factor
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ABSTRACT: Epithelial-to-mesenchymal transition is a process in which cells undergo a developmental switch from an epithelial to a mesenchymal phenotype. We investigated the role of this phenomenon in the pathogenesis and progression of adenocarcinoma and squamous cell carcinoma of the lung. Archived tissue from primary tumors (n=325), brain metastases (n=48) and adjacent bronchial epithelial specimens (n=192) were analyzed for immunohistochemical expression by image analysis of E-cadherin, N-cadherin, integrin-alpha v beta 6, vimentin, and matrix metalloproteinase-9. The findings were compared with the patients' clinicopathologic features. High expression of the epithelial-to-mesenchymal transition phenotype (low E-cadherin and high N-cadherin, integrin-alpha v beta 6, vimentin, and matrix metalloproteinase-9) was found in most lung tumors examined, and the expression pattern varied according to the tumor histologic type. Low E-cadherin membrane and high N-cadherin cytoplasmic expression were significantly more common in squamous cell carcinoma than in adenocarcinoma (P=0.002 and 0.005, respectively). Dysplastic lesions had significantly lower expression of the epithelial-to-mesenchymal transition phenotype than the squamous cell carcinomas, and integrin-alpha v beta 6 membrane expression increased stepwise according to the histopathologic severity. Brain metastases had decreased epithelial-to-mesenchymal transition expression compared with primary tumors. Brain metastases had significantly lower integrin-alpha v beta 6 membrane (P=0.04), N-cadherin membrane, and cytoplasm (P<0.0002) expression than the primary tumors. The epithelial-to-mesenchymal transition phenotype is commonly expressed in primary squamous cell carcinoma and adenocarcinoma of the lung; this expression occurs early in the pathogenesis of squamous cell carcinoma. Brain metastases showed characteristics of reversed mesenchymal-to-epithelial transition. Our findings suggest that epithelial-to-mesenchymal transition is a potential target for lung cancer chemoprevention and therapy.
Modern Pathology 03/2009; 22(5):668-78. · 4.79 Impact Factor
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Don L Gibbons,
Wei Lin,
Chad J Creighton,
Shuling Zheng,
Dror Berel,
Yanan Yang,
Maria Gabriela Raso, Diane D Liu,
Ignacio I Wistuba,
Guillermina Lozano,
Jonathan M Kurie
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ABSTRACT: 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.
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-ras(G12D) and p53(R172H). 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.
These findings provide evidence that K-ras(G12D); p53(R172H) 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.
PLoS ONE 02/2009; 4(4):e5401. · 4.09 Impact Factor
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Vassiliki Papadimitrakopoulou,
Julie G Izzo, Diane D Liu,
Jeffrey Myers,
Tania L Ceron,
Jan Lewin,
William N William,
Anthea Atwell,
J Jack Lee,
Ann Gillenwater,
Adel El-Naggar,
Xifeng Wu,
Scott M Lippman,
Walter N Hittelman,
Waun Ki Hong
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ABSTRACT: In a previous trial, we found that combined 13-cis-retinoic acid, IFN-alpha, and alpha-tocopherol more effectively reversed advanced premalignant lesions of the larynx than of the oral cavity and that cyclin D1 (CD1) G/A870 single nucleotide polymorphism correlated with cancer risk. We conducted the present trial primarily to confirm the clinical activity of the combination in advanced laryngeal premalignancy and to confirm and extend our findings on CD1, both genotype and protein expression, in association with cancer risk in this setting. Twenty-seven moderate-to-severe laryngeal dysplasia patients underwent induction with combined 13-cis-retinoic acid daily, alpha-IFN twice weekly, and alpha-tocopherol daily for 1 year; 14 nonprogressing patients then were randomized to maintenance fenretinide or placebo for 2 years. During induction, two patients had pathologic complete responses, six had partial responses (30% overall response rate), and five developed laryngeal cancer. There were no significant differences between maintenance fenretinide and placebo in response or cancer rates. Ten patients developed cancer overall. Twenty-four patients were evaluated for the CD1 G/A870 genotype, and 23 for pretreatment and posttreatment CD1 protein expression. Consistent with our earlier report, shorter cancer-free survival was associated with the CD1 AA/AG genotype (P = 0.05). Extending our earlier work, high CD1 expression was associated with worse cancer-free survival overall (P = 0.04) and within each CD1 genotype group. These findings support CD1 genotype and protein expression as important risk markers for laryngeal cancer and suggest future trials targeting upstream regulators of CD1 transcription.
Cancer Prevention Research 02/2009; 2(1):14-21. · 4.91 Impact Factor
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ABSTRACT: 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 AMP 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 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 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.
Cancer Research 09/2008; 68(15):6065-73. · 7.86 Impact Factor
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Manisha Bhutani,
Ashutosh Kumar Pathak,
You-Hong Fan, Diane D Liu,
J Jack Lee,
Hongli Tang,
Jonathan M Kurie,
Rodolfo C Morice,
Edward S Kim,
Waun Ki Hong,
Li Mao
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ABSTRACT: The lungs and oral cavity of smokers are exposed to tobacco carcinogens. We hypothesized that tobacco-induced molecular alterations in the oral epithelium are similar to those in the lungs, and thus the oral epithelium may be used as a surrogate tissue for assessing alterations in the lungs. We used methylation-specific PCR to analyze promoter methylation of the p16 and FHIT genes at baseline and 3 months after intervention in 1,774 oral and bronchial brush specimens from 127 smokers enrolled in a randomized placebo-controlled chemoprevention trial. The association between methylation patterns in oral tissues and bronchial methylation indices (methylated sites / total sites per subject) was analyzed in a blinded fashion. At baseline, promoter methylation in bronchial tissue was present in 23% of samples for p16, 17% for FHIT, and 35% for p16 and FHIT; these percentages were comparable to methylation in oral tissue: 19% (p16), 15% (FHIT), and 31% (p16 and FHIT). Data from both oral and bronchial tissues were available for 125 individuals, in whom the two sites correlated strongly with respect to alterations (P < 0.0001 for both p16 and FHIT). At baseline, the mean bronchial methylation index was far higher in patients with oral tissue methylation (in either of the two genes; 39 patients) than in patients without oral tissue methylation (86 patients): 0.53 +/- 0.29 versus 0.27 + 0.26 methylation index (P < 0.0001). Similar correlations occurred at 3 months after intervention. Our results support the potential of oral epithelium as a surrogate tissue for assessing tobacco-induced molecular damage in the lungs and thus have important implications for designing future lung cancer prevention trials and for research into the risk and early detection of lung cancer.
Cancer Prevention Research 06/2008; 1(1):39-44. · 4.91 Impact Factor
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ABSTRACT: Two- or three-stage designs are commonly used in phase II cancer clinical trials. These designs possess good frequentist properties and allow early termination of the trial when the interim data indicate that the experimental regimen is inefficacious. The rigid study design, however, can be difficult to follow exactly because the response has to be evaluated at prespecified fixed number of patients.
Our goal is to develop an efficient and flexible design that possesses desirable statistical properties.
A flexible design based on Bayesian predictive probability and the minimax criterion is constructed. A three-dimensional search algorithm is implemented to determine the design parameters.
The new design controls type I and type II error rates, and allows continuous monitoring of the trial outcome. Consequently, under the null hypothesis when the experimental treatment is not efficacious, the design is more efficient in stopping the trial earlier, which results in a smaller expected sample size. Exact computation and simulation studies demonstrate that the predictive probability design possesses good operating characteristics.
The predictive probability design is more computationally intensive than two- or three-stage designs. Similar to all designs with early stopping due to futility, the resulting estimate of treatment efficacy may be biased.
The predictive probability design is efficient and remains robust in controlling type I and type II error rates when the trial conduct deviates from the original design. It is more adaptable than traditional multi-stage designs in evaluating the study outcome, hence, it is easier to implement. S-PLUS/R programs are provided to assist the study design.
Clinical Trials 02/2008; 5(2):93-106. · 1.92 Impact Factor
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Ludmila Prudkin,
Carmen Behrens, Diane D Liu,
Xian Zhou,
Natalie C Ozburn,
B Nebiyou Bekele,
John D Minna,
Cesar Moran,
Jack A Roth,
Lin Ji,
Ignacio I Wistuba
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ABSTRACT: 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.
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.
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.
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.
Clinical Cancer Research 02/2008; 14(1):41-7. · 7.74 Impact Factor
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Walter N Hittelman, Diane D Liu,
Jonathan M Kurie,
Reuben Lotan,
Jin Soo Lee,
Fadlo Khuri,
Heladio Ibarguen,
Rodolfo C Morice,
Garrett Walsh,
Jack A Roth,
John Minna,
Jae Y Ro,
Anita Broxson,
Waun Ki Hong,
J Jack Lee
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ABSTRACT: 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 alpha-tocopherol reduced Ki-67, a proliferation biomarker, in the bronchial epithelium.
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 alpha-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 > or = 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.
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 alpha-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 alpha-tocopherol treatment (coefficient estimate = -0.66, 95% CI = -1.15 to -0.17; P = .008).
In per-subject analyses, treatment with 13-cis-RA and alpha-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.
CancerSpectrum Knowledge Environment 11/2007; 99(21):1603-12. · 14.07 Impact Factor
