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1.  Feasibility of Image-Guided Transthoracic Core Needle Biopsy in the BATTLE Lung Trial 
As therapy for non-small cell lung cancer (NSCLC) patients becomes more personalized, additional tissue in the form of core needle biopsies (CNBs) for biomarker analysis is increasingly required for determining appropriate treatment and for enrollment into clinical trials. We report our experience with small-caliber percutaneous transthoracic (PT) CNBs for the evaluation of multiple molecular biomarkers in BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination), a personalized, targeted therapy NSCLC clinical trial.
The medical records of patients who underwent PTCNB for consideration of enrollment in BATTLE, were reviewed for diagnostic yield of 11 predetermined molecular markers, and procedural complications. Univariate and multivariate analyses of factors related to patient and lesion characteristics were performed to determine possible influences on diagnostic yield.
One hundred and seventy PTCNBs were performed using 20-gauge biopsy needles in 151 NSCLC patients screened for the trial. 82.9% of the biopsy specimens were found to have adequate tumor tissue for analysis of the required biomarkers. On multivariate analysis, metastatic lesions were 5.4 times more likely to yield diagnostic tissue as compared to primary tumors (p = 0.0079). Pneumothorax and chest tube insertion rates were 15.3% and 9.4%, respectively.
Image-guided 20-gauge PTCNB is safe and provides adequate tissue for analysis of multiple biomarkers in the majority of patients being considered for enrollment into a personalized, targeted therapy NSCLC clinical trial. Metastatic lesions are more likely to yield diagnostic tissue as compared to primary tumors.
PMCID: PMC3879952  PMID: 23442309
research biopsy; biomarker analysis; percutaneous transthoracic biopsy
2.  Targeting the Hepatocyte Growth Factor–cMET Axis in Cancer Therapy 
Journal of Clinical Oncology  2012;30(26):3287-3296.
The hepatocyte growth factor (HGF) and its receptor, the transmembrane tyrosine kinase cMET, promote cell proliferation, survival, motility, and invasion as well as morphogenic changes that stimulate tissue repair and regeneration in normal cells but can be co-opted during tumor growth. MET overexpression, with or without gene amplification, has been reported in a variety of human cancers, including breast, lung, and GI malignancies. Furthermore, high levels of HGF and/or cMET correlate with poor prognosis in several tumor types, including breast, ovarian, cervical, gastric, head and neck, and non–small-cell lung cancers. Gene amplification and protein overexpression of cMET drive resistance to epidermal growth factor receptor family inhibitors, both in preclinical models and in patients. It is increasingly apparent that the HGF-cMET axis signaling network is complex, and rational combinatorial therapy is needed for optimal clinical efficacy. Better understanding of HGF-cMET axis signaling and the mechanism of action of HGF-cMET inhibitors, along with the identification of biomarkers of response and resistance, will lead to more effective targeting of this pathway for cancer therapy.
PMCID: PMC3434988  PMID: 22869872
3.  Frequency of MET and PIK3CA copy number elevation and correlation with outcome in early stage breast cancer 
Cancer  2012;119(1):7-15.
To determine the frequency and association with relapse-free survival (RFS) of MET and PIK3CA copy number elevations in early stage breast cancer.
Tumor DNA was extracted from 971 formalin-fixed paraffin-embedded early breast cancers for molecular inversion probes arrays. Data was segmented using the SNP-FASST2 segmentation algorithm. Copy number gains were called when copy number of each segment was greater than 2.3 or 1.7 respectively. RFS was estimated by Kaplan-Meier. Cox proportional hazards models were fit to determine independent associations of copy number with RFS.
82 (8.44%) and 134 (13.8%) of tumors had MET or PIK3CA copy number elevation respectively, and 25.6% with MET copy number elevation had PIK3CA copy number elevation. Patients with either MET or PI3KCA high copy number tended to have poorer prognostic features (larger tumor size, higher grade, and hormone receptor negativity), Both, MET and PIK3CA high copy number were more likely to occur in triple negative disease (P=0.019 and <0.001, respectively). At a median follow-up of 7.4 years, there were 252 recurrences. Five-year RFS were 63.5%, and 83.1% for MET high copy number and MET normal/low copy number respectively, (P=0.06); and 73.1%, and 82.3% for PIK3CA high copy number and PIK3CA normal/low copy number respectively, (P=0.15). High copy number for either gene was not an independent predictor of RFS.
High copy number of MET or PIK3CA was associated with poorer prognostic features and triple negative disease. Co-amplification was frequent. Patients with high MET copy number tumors tended to have a worst RFS.
PMCID: PMC3461089  PMID: 22736407
MET; PIK3CA; gene copy number; breast cancer; prognosis
4.  cMET and phospho-cMET protein levels in breast cancers and survival outcomes 
To evaluate cMET and phospho-cMET (p-cMET) levels in breast cancer subtypes and its impact on survival outcomes.
Experimental Design
We measured protein levels of cMET and p-cMET in 257 breast cancers using reverse phase protein array. Regression tree method and Martingale residual plots were applied to find best cutoff point for high and low levels. Kaplan-Meier survival curves were used to estimate relapse-free (RFS) and overall (OS) survival. Cox proportional hazards models were fit to determine associations of cMET/p-cMET with outcomes after adjustment for other characteristics.
Median age was 51years. There were 140 (54.5%) hormone receptor (HR)-positive, 53 (20.6%) HER2-positive and 64 (24.9%) triple-negative tumors. Using selected cutoffs, 181 (70.4%) and 123 (47.9%) cancers had high levels of cMET and p-cMET, respectively. There were no significant differences in mean expression of cMET (P<0.128) and p-cMET (P<0.088) by breast cancer subtype. Dichotomized cMET and p-cMET level was a significant prognostic factor for RFS (HR:2.44,95%CI:1.34-4.44,P=0.003 and HR:1.64,95%CI:1.04-2.60,P=0.033) and OS (HR:3.18,95%CI:1.43-7.11,P=0.003 and HR:1.92,95% CI:1.08-3.44,P=0.025). Within breast cancer subtypes, high cMET levels were associated with worse RFS (P=0.014) and OS (P=0.006) in HR-positive tumors, and high p-cMET levels were associated with worse RFS (P=0.019) and OS (P=0.014) in HER2-positive breast cancers. In multivariable analysis patients with high cMET had a significantly higher risk of recurrence (HR:2.06; 95%CI:1.08-3.94,P=0.028) and death (HR:2.81; 95%CI:1.19-6.64,P=0.019). High p-cMET level was associated with higher risk of recurrence (HR:1.79,95%CI 1.08-2.95.77,P=0.020).
High levels of cMET and p-cMET were seen in all breast cancer subtypes and correlated with poor prognosis.
PMCID: PMC3821167  PMID: 22374333
cMET; phospho-cMET; breast cancer prognosis; breast cancer subtype
5.  Phase II Study of Cetuximab in Combination With Chemoradiation in Patients With Stage IIIA/B Non–Small-Cell Lung Cancer: RTOG 0324 
Journal of Clinical Oncology  2011;29(17):2312-2318.
Non–small-cell lung cancer (NSCLC) commonly expresses the epidermal growth factor receptor (EGFR), which is associated with poor clinical outcome. Cetuximab is a chimerized monoclonal antibody that targets the EGFR and, in preclinical models, it demonstrates radiosensitization properties. We report a phase II trial testing the combination of cetuximab with chemoradiotherapy (CRT) in unresectable stage III NSCLC.
Patients and Methods
Eligibility criteria included unresectable stage III NSCLC, Zubrod performance status ≤ 1, weight loss ≤ 5%, forced expiratory volume in 1 second ≥ 1.2 L, and adequate organ function. Patients received an initial dose of cetuximab (400 mg/m2) on day 1 of week 1 and then weekly doses of cetuximab (250 mg/m2) until completion of therapy (weeks 2 through 17). During week 2, patients started CRT (63 Gy in 35 fractions) with weekly carboplatin at area under the [concentration-time] curve (AUC) 2 and six doses of paclitaxel at 45 mg/m2 followed by carboplatin (AUC 6) and two cycles of paclitaxel (200 mg/m2) during weeks 12 through 17. Primary end points included safety and compliance of concurrent cetuximab and CRT.
In all, 93 patients were enrolled and 87 were evaluable. Median follow-up was 21.6 months. Response rate was 62% (n = 54), median survival was 22.7 months, and 24-month overall survival was 49.3%. Adverse events related to treatment included 20% grade 4 hematologic toxicities, 8% grade 3 esophagitis, and 7% grade 3 to 4 pneumonitis. There were five grade 5 events.
The combination of cetuximab with CRT is feasible and shows promising activity. The median and overall survival achieved with this regimen were longer than any previously reported by the Radiation Therapy Oncology Group.
PMCID: PMC3107747  PMID: 21555682
6.  Effect of KRAS Oncogene Substitutions on Protein Behavior: Implications for Signaling and Clinical Outcome 
Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in cancer cell growth and resistance to therapy. Most mutations occur at codons 12 and 13. In colorectal cancer, the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy. However, in non–small cell lung cancer (NSCLC), the evidence that KRAS mutation is a predictive factor is conflicting.
We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and tumor gene expression. Transcriptome microarray studies of patient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation. Molecular modeling was used to study the conformations of wild-type and mutant KRas proteins. Kaplan–Meier curves and Cox regression were used to analyze survival data. All statistical tests were two-sided.
Patients whose tumors had either mutant KRas-Gly12Cys or mutant KRas-Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas (P = .046, median survival = 1.84 months) compared with all other mutant KRas (median survival = 3.35 months) or wild-type KRas (median survival = 1.95 months). NSCLC cell lines with mutant KRas-Gly12Asp had activated phosphatidylinositol 3-kinase (PI-3-K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling, whereas those with mutant KRas-Gly12Cys or mutant KRas-Gly12Val had activated Ral signaling and decreased growth factor–dependent Akt activation. Molecular modeling studies showed that different conformations imposed by mutant KRas may lead to altered association with downstream signaling transducers.
Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.
PMCID: PMC3274509  PMID: 22247021
7.  Sunitinib in combination with paclitaxel plus carboplatin in patients with advanced solid tumors: phase I study results 
To evaluate the maximum tolerated dose (MTD), safety, and antitumor activity of sunitinib combined with paclitaxel and carboplatin.
Successive cohorts of patients with advanced solid tumors received oral sunitinib (25, 37.5, or 50 mg) for 2 consecutive weeks of a 3-week cycle (Schedule 2/1) or as a continuous daily dose for 3-week cycles (CDD schedule) in combination with paclitaxel (175–200 mg/m2) plus carboplatin (AUC 6 mg•min/mL) on day 1 of each of 4 cycles. Dose-limiting toxicities (DLTs) and adverse events (AEs) were evaluated to determine the MTD. Efficacy parameters were analyzed in patients with measurable disease.
Forty-three patients were enrolled (n = 25 Schedule 2/1; n = 18 CDD schedule). Across all doses, 6 DLTs were observed (grade 4 papilledema, grade 5 GI hemorrhage, grade 3 neutropenic infection, grade 4 thrombocytopenia [n = 3]). The MTD for Schedule 2/1 was sunitinib 25 mg plus paclitaxel 175 mg/m2 and carboplatin AUC 6 mg•min/mL. The MTD was not determined for the CDD schedule. Treatment-related AEs included neutropenia (77%), thrombocytopenia (56%), and fatigue (47%). Of 38 evaluable patients, 4 (11%) had partial responses and 12 (32%) had stable disease. PK data indicated an increase in maximum and total plasma exposures to sunitinib and its active metabolite when given with paclitaxel and carboplatin compared with sunitinib monotherapy.
Myelosuppression resulting in prolonged dose delays and frequent interruptions was observed, suggesting that this treatment combination is not feasible in the general cancer population.
PMCID: PMC3400085  PMID: 21140147
Sunitinib; Phase I; Solid tumor; NSCLC; Antiangiogenesis; Chemotherapy
8.  Phase II Study of Dasatinib in Patients With Advanced Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2010;28(30):4609-4615.
Src family kinases (SFKs) promote cancer progression and are commonly expressed in non–small-cell lung cancer (NSCLC), but the clinical effects of SFK inhibition in NSCLC are unknown. We conducted a phase II trial of the SFK inhibitor dasatinib for advanced NSCLC. We tested the hypotheses that the activation of epidermal growth factor receptor (EGFR) or SFK or modulation of serum cytokines may predict a response to dasatinib.
Patients and Methods
Patients received dasatinib as first-line therapy. Response was measured by tumor size on computed tomography scans and by metabolic activity on positron emission tomography scans. Tissue samples taken before patients received dasatinib were tested for EGFR and Kras mutation and phosphorylated SFK expression.
Thirty-four patients were enrolled. The overall disease control rate (partial responses plus stable disease) for dasatinib was 43%. One patient had a partial response to therapy. Eleven patients (32%) had a metabolic response to dasatinib. SFK activation and EGFR and Kras mutations in tumor tissue did not predict response to dasatinib. Significant toxicities included fatigue and dyspnea. The presence of a pleural effusion before dasatanib therapy predicted the development of a clinically significant effusion during therapy.
Dasatinib as a single agent had modest clinical activity that was lower than that generally observed in patients with NSCLC who receive chemotherapy. Pleural effusion was an expected and problematic toxicity that was successfully treated with steroids, diuretics, and dose interruptions. Marked activity in one patient and prolonged stable disease in four others suggested a potential subpopulation of patients with dasatinib-sensitive NSCLC.
PMCID: PMC2974341  PMID: 20855820
9.  Phase I Study of Celecoxib with Concurrent Irinotecan, Cisplatin, and Radiation Therapy for Patients with Unresectable Locally Advanced Non-Small Cell Lung Cancer 
Purpose: Preclinical findings suggest that adding targeted therapies to combination radiation-chemotherapy can enhance treatment efficacy; however, this approach may enhance normal tissue toxicity. We investigated the maximum tolerated dose, dose-limiting toxicities, and response rate when the selective cyclooxygenase-2 inhibitor celecoxib is added to concurrent irinotecan, cisplatin, and radiation therapy for patients with inoperable stage II–III non-small cell lung cancer (NSCLC). Methods and Materials: Eighteen patients were analyzed in a phase I clinical dose-escalation trial. Celecoxib was given daily beginning 5 days before radiation followed by maintenance doses for 12 weeks. Toxicity was graded with the Common Terminology Criteria for Adverse Events V3.0 and response with the World Health Organization system. Primary endpoints were maximum tolerated dose of celecoxib and treatment toxicity; secondary endpoints were response and survival rates. Results: The maximum tolerated dose of celecoxib was not reached, in part owing to discontinuation of the drug supply. At doses of 200 or 400 mg/day, no patients experienced any dose-limiting toxicity (acute grade ≥4 esophagitis or pneumonitis, neutropenic fever or thrombocytopenia requiring transfusion, or acute grade ≥3 diarrhea). Grade 3 toxicities were leukopenia (five patients), fatigue (3), pneumonitis (2), dyspnea (1), pain (1), and esophageal stricture (1). Interestingly, pulmonary fibrosis (a late toxicity) was no more severe in the higher-dose (400-mg) group and may have been less common than in the lower-dose group. The clinical response rate was 100% (8 complete, 10 partial). Two-year rates were: overall survival 65%; local-regional control 69%; distant metastasis-free survival 71%; and disease-free survival 64%. Conclusion: Although preliminary, our results suggest that adding celecoxib to concurrent chemoradiation for inoperable NSCLC is safe and can improve outcome without increasing normal tissue toxicity.
PMCID: PMC3355954  PMID: 22649768
celebrex; CPT-11; cyclooxygenase-2 inhibitor; concurrent chemoradiotherapy; stage II or III non-small cell lung cancer
10.  An epithelial-mesenchymal transition (EMT) gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance 
EMT has been associated with metastatic spread and EGFR inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene expression profiles from four platforms using NSCLC cell lines and patients treated in the BATTLE study.
We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from NSCLC patients. A 76-gene EMT signature was developed and validated using gene expression profiles from four microarray platforms of NSCLC cell lines and patients treated in the BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) study, and potential therapeutic targets associated with EMT were identified.
Compared with epithelial cells, mesenchymal cells demonstrated significantly greater resistance to EGFR and PI3K/Akt pathway inhibitors, independent of EGFR mutation status, but more sensitivity to certain chemotherapies. Mesenchymal cells also expressed increased levels of the receptor tyrosine kinase Axl and showed a trend towards greater sensitivity to the Axl inhibitor SGI-7079, while the combination of SGI-7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In NSCLC patients, the EMT signature predicted 8-week disease control in patients receiving erlotinib, but not other therapies.
We have developed a robust EMT signature that predicts resistance to EGFR and PI3K/Akt inhibitors, highlights different patterns of drug responsiveness for epithelial and mesenchymal cells, and identifies Axl as a potential therapeutic target for overcoming EGFR inhibitor resistance associated with the mesenchymal phenotype
PMCID: PMC3567921  PMID: 23091115
lung cancer; EMT; EGFR inhibition; PI3K inhibition; Axl
11.  Endobronchial Metastases in Breast Carcinoma 
Western Journal of Medicine  1978;129(3):177-180.
In a consecutive series of 1,628 patients with breast carcinoma, six cases of endobronchial metastases were diagnosed for an incidence of 0.4 percent. The median latent interval from the diagnosis of the primary carcinoma until the time of diagnosis of endobronchial metastases was 21 months. Endobronchial metastases can be the initial manifestation of recurrent cancer and can present with no abnormalities shown on x-ray films of the chest. Because of similar symptomatology, the diagnosis of endobronchial metastases may be confused with a central bronchogenic carcinoma but the histological appearance could differentiate the two entities. Local treatment with radiation therapy is usually inadequate and patients should also be treated with some form of systemic treatment such as chemotherapy. The median survival after the diagnosis of endobronchial metastases was 13 months.
PMCID: PMC1238308  PMID: 706354
12.  Combined Effects of Phytohemagglutinin and Staphylococcal Enterotoxin B on Deoxyribonucleic Acid Synthesis During Blast Transformation in Human Lymphocytes 
Infection and Immunity  1974;9(2):384-390.
Three mitogenic agents, phytohemagglutinin (PHA), staphylococcal enterotoxin B (SEB), and concanavalin A (Con A) were tested for their effects on deoxyribonucleic acid (DNA) synthesis in the normal human lymphocyte. When optimal concentrations of PHA and SEB were combined, tritiated thymidine incorporation in lymphocytes derived from several donors was enhanced significantly. In the presence of graded concentrations of one of these mitogens added to fixed optimal concentrations of the other, this enhancement was shown to be additive. By contrast, when PHA or SEB were combined with Con A, the resulting thymidine incorporation was slightly lower than for either mitogen alone. An inhibition of further thymidine incorporation when puromycin was added to lymphocytes incubated with PHA and SEB suggested that the additive effect of these mitogens was due to increased enzyme synthesis. To define potential differences in mechanisms of action underlying the additive effect of SEB and PHA, the relative contribution of the de novo and salvage pathways for pyrimidine biosynthesis was tested with cytidine, a specific salvage pathway inhibitor. Cytidine (10−3 M) inhibited synthesis through the salvage pathway, but did not significantly alter induction of carbamyl phosphate synthetase II, the rate-limiting enzyme for the de novo pathway. An inhibition of DNA synthesis by millimolar cytidine concentrations in lymphocytes incubated with PHA or SEB, singly or in combination, suggested that pyrimidines for the observed enhancement of DNA synthesis were derived largely via the salvage pathway.
PMCID: PMC414813  PMID: 4361297

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