Therapy For Lung Cancer Patients Research Articles

338 BM-1252 (APG-1252): a potent dual specific Bcl-2/Bcl-xL inhibitor that achieves complete tumor regression with minimal platelet toxicity

we investigated the in vitro cytotoxicity of inhibitors against different components of the PI3K/AKT/mTOR pathways in RICTOR-amplified lung cancer cells. Results: The majority of cells possess normal copy numbers of RICTOR but 3 out of 27 non-small cell lung cancer (NSCLC) cell lines, including H23 (adenocarcinoma) and H1703 (squamous), were found to have ratio of RICTOR/control around 2, suggesting RICTOR amplification in those cell lines. Genetic knockdown of RICTOR by using either siRNA or inducible shRNA was associated with growth inhibition of RICTOR-amplified lung cancer cell lines. The growth of xenograft lung tumor was also inhibited by inducible RICTOR knockdown. Among 6 different kinase inhibitors against the PI3K/AKT/mTOR pathways, agents blocking both mTOR1 and mTOR2 were the most active in RICTOR-amplified lung cancer cells. Conclusions: Targeted genetic blockade of RICTOR led to growth inhibition of RICTOR-amplified lung cancer cells, indicating that selective targeting of RICTOR may represent a novel therapeutic strategy for the treatment of this subgroupof lung cancer patients. Our study also provides the rationale for utilizing dual mTOR1/2 inhibitors as a potential therapy for lung cancer patients harboring RICTOR amplification.

Incidence of Radiation Pneumonitis After Multiple Courses of Stereotactic Body Radiation Therapy for Lung Cancer Patients

Stereotactic body radiation therapy (SBRT) is a widely used therapy for primary and metastatic lung cancers. Radiation pneumonitis (RP) is one of the most important and potentially serious complications of SBRT, and recent studies have established the clinical and dosimetric risk factors for the development of RP in single course of SBRT. However, it is not well known how cumulative lung dose of multiple courses of SBRT impacts incidence of RP. The purpose of the present study is to evaluate incidence of RP after multiple courses of SBRT for lung cancers.

Dopamine D2 receptor agonists inhibit lung cancer progression by reducing angiogenesis and tumor infiltrating myeloid derived suppressor cells

We sought to determine whether Dopamine D2 Receptor (D2R) agonists inhibit lung tumor progression and identify subpopulations of lung cancer patients that benefit most from D2R agonist therapy. We demonstrate D2R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D2R expression and tumor stage. Lung cancer patients with a smoking history exhibited greater levels of D2R in lung endothelium. Our results suggest D2R agonists may represent a promising individualized therapy for lung cancer patients with high levels of endothelial D2R expression and a smoking history.

Individual profiling of circulating tumor cell composition in patients with non-small cell lung cancer receiving platinum based treatment.

Circulating tumor cells (CTC) could serve as a "liquid biopsy" for individualizing and monitoring treatment in patients with solid tumors as recently shown by our group. We assessed which non-hematopoietic cell types are identifiable in the peripheral blood of patients with non-small cell lung cancer (NSCLC) and correlated those to clinical characteristics. Blood from NSCLC patients (n=43) was processed as previously described. For subtype analyses CTC were negatively enriched by hematopoietic cell depletion. The remaining cell suspension included pre-enriched tumor cells and was spun onto glass slides and further characterized by multi-immunofluorescence staining against epithelial markers pan-cytokeratin (CK) and epithelial cell adhesion molecule (EpCAM), mesenchymal marker N-cadherin, stem cell marker CD133, hematopoietic marker CD45 and nuclear counterstain DAPI. Individual cell type profiles were analyzed and correlated to therapeutic outcome. Among other associations of CTC subtypes with clinical parameters Kaplan-Meier test revealed that an increased CD133-positive to pan-CK-positive cell type ratio (stem cell like to epithelial ratio) and the presence of mesenchymal N-cadherin+ cells, both were significantly associated to shortened PFS (2 vs. 8 months, P=0.003, HR =4.43; 5 vs. 8 months, P=0.03, HR =2.63). Our data suggest that different CTC populations are identifiable in peripheral blood and that these individual cell type profiles might be used to predict outcome to platinum based systemic therapies in lung cancer patients.

Effectiveness of Additional Acupuncture Therapy for Lung Cancer Patients - A single group before-and-after, preliminary study

This study is a single group before-and-after study aimed to evaluate the effectiveness of additional acupuncture therapy for lung cancer patients being treated with chemotherapy. Acupuncture therapy was conducted twice a day at least for a week. The effectiveness outcome measures were the Korean Functional Assessment of Cancer Therapy (FACT-L) and the Korean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at the baseline, discharge and four weeks after discharge, and visual analogue scale(VAS) checked daily from the baseline to discharge. Ten patients were enrolled, one patient had excluded due to acute exacerbation of lung cancer. The data of nine patients showed some improvement in all of FACT-L, FACIT-F and VAS, however, there were no statistical significance. Additional acupuncture therapy for lung cancer patients treated with chemotherapy might be beneficial to improve the quality of life(QoL) and to improve fatigue. Prospective trials with complex traditional Korean medicine interventions are needed to further investigation.

Abstract A13: Pharmacologic targeting of IL-6 suppresses tumor progression in a non-small cell lung cancer mouse model with K-ras mutation through re-educating the tumor microenvironment.

Abstract Activating mutations of K-ras are one of the most common molecular alterations associated with lung cancer development. Several attempts to develop therapies directly targeting K-ras have failed thus far, clearly state the need for new strategies to bring clinical benefits to patients displaying such molecular profile. Using a conditional K-ras mutated lung cancer mouse model (CC-LR) we previously showed that K-ras mutated lung tumors have intrinsic inflammatory characteristics and we also demonstrated that chronic obstructive pulmonary disease (COPD)-like airway inflammation, an independent risk factor for lung cancer, promotes lung tumor in this model. CC-LR mice shows high protein level of interleukin 6 (IL-6) and increased STAT3 (downstream signal to IL6) gene expression, and we have further shown that genetic ablation of IL-6 in CC-LR mice results in significant tumor reduction. High levels of IL-6 and up-regulation of STAT3 and its target genes have been observed in the lungs of smokers with COPD, and in 50% of human lung adenocarcinomas. These indicate an essential role for IL-6 in lung cancer promotion, and introduce IL-6 as a potential druggable target for lung cancer patients who harbor K-ras mutations. This prompted us to block IL-6 pathway using a monoclonal anti-IL-6 immunotherapy in our K-ras mutated lung cancer mouse model. Six week old CC-LR mice were injected intraperitoneally (I.P.) with 20 mg/kg dose of an anti-IL-6 monoclonal IgG1 antibody, twice a week, for a period of eight weeks. Flowcytometry analysis of total lung inflammatory cell population in non-treated CC-LR mice showed 2-fold increase in the population of tumor associated macrophage (TAM) (CD45+/CD11b+/GR1+/F4/80+/MCSFR+) during tumor progression from age 6 weeks to 14 weeks. qPCR analysis of total lung RNA from non-treated CC-LR mice showed that there is an increase in the level of Arginase-1 (3 fold) with no change in the level of inducible Nitric Oxide Synthetize (NOS2). This suggests that epithelial signal initiated by K-ras mutation may dictate the fate of lung microenvironment by creating an inflammatory pro-tumor type 2 response. Then we found that anti-IL-6 treatment suppresses tumor progression by ~78% (4.6-fold) in CC-LR mice which is associated with a significant reduction in the quantity of inflammatory cells in bronchoalveolar lavage fluid (BALF). It also decreased the expression of proliferation marker: Ki-67, and pro angiogenic factors: VEGF, MMP9 and CD31 and phospho-STAT3 in lung tissue. ELISA analysis of BALF from CC-LR mice also showed that anti-IL-6 treatment reduces TGFβ and KC protein levels with no change in level of IL-17. qPCR and flowcytometry analysis of total lung homogenate of CC-LR mice further showed that IL-6 blockade induces a significant decrease in Arginase1 expression (3-fold) and TAM population (5-fold). Taking together here we showed that K-ras mutated lung tumor drives an immunosuppressive pro-tumor microenvironment, with an M2 TAM polarization and blocking the suppressive actions of IL-6 shifts this to an anti-tumor lung microenvironment. Therefore we propose pharmacological targeting of IL-6 as a potential therapeutic strategy alone or in combination with conventional cytotoxic therapy for lung cancer patients with K-ras mutation. Funded by: American Cancer Society, RSG-11-115-01-CNE, and American Lung Association/LUNGevity Foundation, LCD-114696-N Citation Format: Mauricio S. Caetano, Amber M. Cumpian, Lei Gong, Cesar E. Ochoa, Seon H. Chang, Huiyuan Zhang, Stephanie Watowich, Cinthya Sternberg, Carlos G. Ferreira, Seyed J. Moghaddam. Pharmacologic targeting of IL-6 suppresses tumor progression in a non-small cell lung cancer mouse model with K-ras mutation through re-educating the tumor microenvironment. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A13.

Proton beam therapy for locally advanced lung cancer: A review.

Protons interact with human tissue differently than do photons and these differences can be exploited in an attempt to improve the care of lung cancer patients. This review examines proton beam therapy (PBT) as a component of a combined modality program for locally advanced lung cancers. It was specifically written for the non-radiation oncologist who desires greater understanding of this newer treatment modality. This review describes and compares photon (X-ray) radiotherapy (XRT) to PBT. The physical differences of these beams are described and the clinical literature is reviewed. Protons can be used to create treatment plans delivering significantly lower doses of radiation to the adjacent organs at risk (lungs, esophagus, and bone marrow) than photons. Clinically, PBT combined with chemotherapy has resulted in low rates of toxicity compared to XRT. Early results suggest a possible improvement in survival. The clinical results of proton therapy in lung cancer patients reveal relatively low rates of toxicity and possible survival benefits. One randomized study is being performed and another is planned to clarify the clinical differences in patient outcome for PBT compared to XRT. Along with the development of better systemic therapy, newer forms of radiotherapy such as PBT should positively impact the care of lung cancer patients. This review provides the reader with the current status of this new technology in treating locally advanced lung cancer.

Circulating tumor cells in lung cancer

Lung cancer is one of the most malignant tumors that damage human health and life.Metastasis and recurrence of lung cancer are the leading causes of death.Developing techniques that can detect lung cancer,particularly at an early stage,as well as predict recurrence and metastasis,is an important strategy to improve the outcome.Circulating tumor cell (CTC),regarded as liquid biopsy,open a new field for early diagnosis of lung cancer,as well as for prediction of metastasis,evaluation of prognosis and monitoring of recurrence.(Chin J Lab Med,2013,36:983-986) Key words: Circulating tumor cell; Lung cancer; Diagnosis; Metastasis; Prognosis

Cardiac comorbidity is an independent risk factor for radiation-induced lung toxicity in lung cancer patients

PurposeTo test the hypothesis that cardiac comorbidity before the start of radiotherapy (RT) is associated with an increased risk of radiation-induced lung toxicity (RILT) in lung cancer patients. Material and methodsA retrospective analysis was performed of a prospective cohort of 259 patients with locoregional lung cancer treated with definitive radio(chemo)therapy between 2007 and 2011 (ClinicalTrials.gov Identifiers: NCT00572325 and NCT00573040). We defined RILT as dyspnea CTCv.3.0 grade ⩾2 within 6months after RT, and cardiac comorbidity as a recorded treatment of a cardiac pathology at a cardiology department. Univariate and multivariate analyses, as well as external validation, were performed. The model-performance measure was the area under the receiver operating characteristic curve (AUC). ResultsPrior to RT, 75/259 (28.9%) patients had cardiac comorbidity, 44% of whom (33/75) developed RILT. The odds ratio of developing RILT for patients with cardiac comorbidity was 2.58 (p<0.01). The cross-validated AUC of a model with cardiac comorbidity, tumor location, forced expiratory volume in 1s, sequential chemotherapy and pretreatment dyspnea score was 0.72 (p<0.001) on the training set, and 0.67 (p<0.001) on the validation set. ConclusionCardiac comorbidity is an important risk factor for developing RILT after definite radio(chemo)therapy of lung cancer patients.

Stakeholder perceptions of thoracic rapid tissue donation: An exploratory study

Rapid autopsy or rapid tissue donation (RTD) is a novel method of tissue procurement in which ‘fresh’ tissue is collected within 2–6 h following the death of a patient. While the use of RTD offers many opportunities to develop new therapies for lung cancer patients, it raises ethical concerns. The purpose of this study was to examine knowledge, perceptions and ethical concerns about recruiting patients for an RTD program. To achieve research goals, we conducted six focus groups, each containing 5–10 participants (N = 38). Participants were cancer patients (n = 17) their caregivers (n = 6), physicians (n = 6) and clinic staff (n = 9) from the Thoracic Oncology Program at Moffitt Cancer Center, in Tampa, Florida, USA. All focus groups were audio-recorded and conducted using a semi-structured focus group guide. The transcripts were analyzed using hand-coding methods. Data were coded independently by at least two researchers, and an inter-rater reliability rate of ≥90% was achieved. Knowledge about RTD was low among all groups, with physicians having slightly higher knowledge; all groups agreed that RTD offered major benefits to cancer research; physicians and clinic staff were mainly concerned about making a patient feel uncomfortable and reducing hope, while, patients and family members were more concerned about logistics and how the family would be affected during tissue retrieval. All groups agreed the physician was the appropriate person to begin a discussion about RTD and that recruitment should be individualized. All groups reported that physician training is necessary, as well as an awareness campaign for patients and families to be more receptive about RTD. The results of this study suggested more education is needed for all stakeholders to learn about RTD prior to the initiation of a research program. Our approach of querying all stakeholders provides a firm foundation for future training modules regarding RTD programs in lung cancer.

The PARAMOUNT trial: Implications for Maintenance Therapy in Lung Cancer Patients

243 ISSN 1758-1966 10.2217/LMT.13.28 © 2013 Future Medicine Ltd Lung Cancer Manage. (2013) 2(4), 243–246 The maintenance strategic approach has been extensively investigated in hematologic malignancies and then in solid tumors. Among thoracic cancers, small-cell lung cancer has been the setting for several clinical trials of maintenance treatment. The most recent systematic review pooled the available trials evaluating maintenance therapy in small-cell lung cancer, producing a thorough picture of efficacy related to different pharmacological strategies. Despite an overall survival (OS) advantage reported for maintenance chemo therapy and interferon treatment, the results are not clinically relevant [1,2,101]. Maintenance therapy has only recently been accepted as a treatment strategy for advanced non-smallcell lung cancer (NSCLC) with the main goal of prolonging a favorable clinical state after induction first-line platinum-based combination chemo therapy in respect of an adequate tolerability and without impairing quality of life (QoL). This renewed interest has been raised with the availability of active and tolerable new drugs. Among these, pemetrexed, a new cytotoxic agent, is a potent inhibitor of thymidylate synthase and other folate-dependent enzymes. Based on its mechanism of action, pemetrexed was the first chemotherapeutic to be studied as a targeted agent. In fact, due to the evidence of the differential expression of thymidylate synthase between adenocarcinoma and squamous NSCLC, pemetrexed reported an increased efficacy in nonsquamous histology, and thus it is now registered only for the treatment of this histotype worldwide [3,4]. With adequate vitamin supplementation, pemetrexed was shown to be active and well tolerated, with grade ≥3 toxicities, when administered as a single agent, not exceeding 5–10% [5]. First, pemetrexed was tested as switch maintenance within the randomized Phase III trial JMEN. Advanced NSCLC patients of any histology not progressing after four cycles of platinum-based doublets, not including pemetrexed, were randomized to pemetrexed or placebo. Pemetrexed showed a statistically better progressionfree survival (PFS) and OS than placebo, which were more significant for nonsquamous histology [6]. These results led to the design of the PARAMOUNT study, a double-blind, multicenter, Phase III, randomized, placebocontrolled trial. The primary end point was PFS, chosen because this measure is not

MiR-133a suppresses cell proliferation, migration and invasion in human lung cancer by targeting MMP-14

Lung cancer is the leading cause of cancer‑related mortality worldwide. Over half of lung cancer cases are diagnosed after metastasis, for which the median survival time is approximately 8months. microRNAs (miRNAs), which are a class of single‑stranded endogenous non‑coding RNAs, are likely to be involved in most biological processes. miR‑133 plays roles in cardiac development and disease, and recent studies showed that miR‑133 is downregulated in various human malignancies, such as bladder and lung cancer. However, its detailed role in the processes of cancer remains to be determined. In the present study, we found that in the lung cancer cell lines A549 and NCI‑H1299 overexpression of miR‑133a suppressed cell proliferation, migration and invasion. The miR‑133a‑induced suppression of cell migration and invasion can be reversed by miR‑133a‑specific inhibitor. According to the mRNA sequence, matrix metalloproteinase (MMP)‑14, which is an important regulator of metastasis, is a predicted target of miR‑133a. This was confirmed by dual luciferase reporter assay. Moreover, miR‑133a overexpression decreases the mRNA and protein levels of MMP‑14. Collectively, these results suggest that miR‑133a may inhibit lung cancer metastasis by targeting MMP‑14 and may be used as an anti‑metastatic therapy in lung cancer patients.

TU‐G‐141‐06: Deformation Vector Fields (DVF)‐Driven Image Reconstruction for 4D‐CBCT

Purpose: High‐quality four dimensional cone‐beam CT (4D‐CBCT) can be obtained by deforming the planning CT in radiotherapy, where the deformation vector fields (DVF) is estimated by matching the forward projection of the deformed planning CT and measured 4D‐CBCT projections. Due to the presence of scatter signal in CBCT projection images, the accuracy of DVF estimation is degraded when the sum of squared intensity difference (SSID) is used as the matching criterion. The goal of this work is to improve the estimation accuracy of DVF by using normalized correlation coefficient (NCC) as the matching criterion to obtain high quality on‐treatment 4D‐CBCT of lung cancer patients in radiation therapy. Methods: The DVF used to deform the planning CT is estimated by maximizing the NCC between the projections of on‐treatment 4D‐CBCT and the forward projection of the deformed planning CT. A non‐linear conjugate gradient (NLCG) algorithm was used for the optimization. To obtain better initial DVF for NLCG optimization, demons registration was first performed between planning CT and 4D‐CBCT reconstructed by total variation (TV) minimization. A 4D NCAT phantom was used to quantitatively evaluate the performance of the algorithm, where the reconstruction error is calculated as the sum of squared difference between the reconstructed 4D‐CBCT and the phantom image. Results: NCC based DVF estimation improves the image reconstruction accuracy as compared to the results obtained using SSID criterion. The image reconstruction error of 4D‐CBCT obtained by NCC criterion is 61.5% smaller than that is obtained by SSID criterion. Conclusion: The accuracy DVF estimation and image reconstruction is substantially improved by using the NCC criterion, as compared to the results obtained by SSID criterion. High quality 4D‐CBCT can be a valuable tool in image‐guided radiation therapy for lung cancer patients. Cancer Prevention and Research Institute of Texas (RP110562)

TU‐A‐WAB‐05: Using 4DCT‐Ventilation Based Multi‐Modality Imaging to Assess Lung Function and Optimize Radiation Therapy for Lung Cancer Patients

Purpose: A new form of imaging has been developed to assess ventilation‐based lung function using 4DCT. Because 4DCTs are acquired as part of thoracic simulation, calculation of 4DCT‐ventilation maps enables exciting opportunities to assess pre‐treatment lung function and create functional avoidance radiotherapy plans. The purpose of our work was to use 4DCT‐ventilation to evaluate lung function differences between stage I and III lung cancer patients and investigate strategies to adapt plans to a patients ventilation profile. Methods: We retrospectively analyzed 40 stage I and 69 stage III lung cancer patients collected from 2 different institutions. Pre‐treatment ventilation maps were calculated using the simulation 4DCT, deformable image registration, and a density‐change based model. To assess ventilation homogeneity of stage I and III patients we studied visually observed ventilation defects, an ipsilateral/contralateral ventilation ratio, and the standard deviation (SD) of lung ventilation. Plans for both stage groups were created using ventilation‐based functional avoidance maps. The feasibility and quality of plans was assessed using dose‐volume and dose‐function metrics. Results: Fifteen percent of the stage I cohort and 33% of the stage III cohort had ventilation defects. The ipsilateral/contralateral ventilation ratio was significantly different (p=0.005) between stage I (ratio=1.06) and stage III (ratio=0.83) patients. Similarly, the SD of stage I and stage III patients was significantly different (p=0.023). Representative functional avoidance plans are presented for both stage I and III groups that improve dose sparing of functional lung. Conclusion: Patients at varying stages of lung disease have different functional profiles and require unique strategies to create functional avoidance plans. We present quantitative data to highlight the impaired lung function of advanced disease patients and explore the potential of using that functional information to adapt plans to a patients ventilation profile. Our study presents an important step of incorporating 4DCT‐based ventilation imaging into the clinic.

MO‐G‐137‐02: Experimental Validation of Clinical as Well as Monte Carlo Dose Calculation for Proton Therapy of Lung Cancer Patients

Purpose: Validate clinical pencil beam (PB) and Monte Carlo (MC) based dose calculations using a heterogeneous lung phantom and assess the clinical significance of these findings in lung patients. Methods: A modified IMRT lung phantom and a matrix‐array of ionization chambers was used to measure the distal fall‐off of the proton beam. The treatment was planned according to clinical protocols. We evaluated absolute and relative dose differences and the range where dose decreases to 50% of prescribed dose (range50). 10 patients treated with 32 beams were subsequently simulated using MC. Results: In the entrance region behind the ribs, the average deviation from the measured dose for MC and PB is 1.2% and 2.0%. Averaged over the 5 investigated depths in the distal falloff, the average error is 7.1% and 12.5% of prescribed dose for MC and PB respectively. Relative to the experimental point dose, the deviations in the distal falloff are 25.6%(MC) and 71.9%(PB). Discrepancies in relative dose in the distal falloff appear large due to the low absolute dose, sharp dose gradient and range differences. The average absolute error in range50 is 3.9mm(MC) and 7mm(PB) in lung tissue, which equals 1.3/2.3mm in water. Apart from differences in multiple Coulomb scattering caused by lateral inhomogeneities, MC generally predicts a larger low‐dose‐penumbra and lower target dose, confirmed by the measured dose profiles. These features also arise in the patients: mean dose and D95 in the clinical target volume are on average 1.8% and 2.3% lower for MC than PB, while normal lung V5 and mean lung dose increase by 5.1% and 2% respectively. Conclusion: For lung, MC increases dose calculation accuracy in the distal fall‐off significantly and reproduces measurements within experimental uncertainty. Differences in patient cases are small in the target, though at times significant in organs distal to the beam. This project was supported by the National Cancer Institute Grant No. R01 CA111590

Clinical next generation sequencing (NGS) to reveal high frequency of alterations to guide targeted therapy in lung cancer patients.

8020 Background: Cancer genomic profiling via NGS in a clinical setting can reveal additional actionable genomic alterations (GA) in patients with lung cancer (LC) previously tested only by hotspot analysis and leading to unanticipated avenues of targeted treatment. Methods: We performed an NGS-based diagnostic test (FoundationOne) to characterize all classes of GA across 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on 386 LC FFPE specimens in a CLIA-certified lab (Foundation Medicine). Specimens included fine needle aspirates, core needle biopsies, and malignant effusions. 95% of cases were NSCLC (367/386). Actionable GAs are defined as those linked to targeted anti-cancer therapies approved or being evaluated in clinical trials. NGS confirmed known hotspot results for EGFR, KRAS and EML4:ALK in 100% of cases. Results: Genomic profiles were generated from 364/386 (94%) of lung cancer cases, identifying 1205 GA, averaging 3.31 alterations per tumor (range 0 to 10). 85% of tumors (310) harbored at least one actionable GA, with a mean of 1.79 GA per tumor (range 0 to 6). In 68% of tumors (248), at least one GA was detected that would be missed by current ‘hotspot assays’. ERBB2 harbored base substitutions or indels in 1.3% of cases. BRAF and C-Kit were altered at frequencies of 2% and 1% respectively. The mTOR/PI3K pathway is likely to be activated via alterations in tumor suppressors STK11 (11%), NF1 (6%) and PTEN (4%), as well as by alterations of PIK3CA (10%) and in AKT1/2/3 (4%), suggesting possible benefit from mTOR/PI3K inhibitors. The Hedgehog pathway (PTCH1/SMO/SUFU) was altered in 2% of cases. ALK and RET were rearranged in 4% and 2% of cases, respectively, with several cases initially diagnosed negative by FISH testing. Conclusions: Profiling the tumor genomes of 364 LC patients led to the identification of a series of GA not detectable by hotspot testing that could significantly inform targeted treatment decisions. Moreover, actionable GA appeared in unexpected tumor type, i.e. an EGFR mutation in a SCLC, reinforcing the likely utility of clinical cancer genomic profiling for the personalized treatment of LC patients.

Clinical importance of circulating tumor cells in lung cancer patients.

e22109 Background: Assessment of the circulating tumor cells (CTCs) in lung cancer patients could prevent burdensome surgery in understaged cases. Therefore we have tested the hypothesis that the presence of CTCs is a negative prognostic factor in these patients and correlates with poor survival. Methods: This was a prospective study to test the presence of CTCs in peripheral blood, pulmonary blood and bone marrow in 108 lung cancer patients (75 males, 33 females; mean age 66.2 years, ranging from 29 to 82 years) at the time of surgery using real-time RT-PCR for carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), lung-specific X protein (LUNX) and hepatocyte growth factor receptor (c-met). Results: We found a statistically significant association between c-met expression level in the pulmonary blood and clinical stage (p&lt;0.044) and lymph node involvement (p&lt;0.0023). C-met marker also showed significantly higher positivity ratio in the peripheral (p&lt;0.034) and pulmonary (p&lt;0.04) blood in patients with histologically proven lymphatic metastases than in patients with negative lymph nodes. The positivity of CTCs in peripheral blood or bone marrow using c-met was independent of clinical stage, age, sex and grading using Cox regression analysis (p=0.006, resp. 0.001). 82 patients followed up for more than 1 year were involved into the overall survival (OS) analysis. 27 of them (32.9 %) died, the OS median was 19.8 months. The patients with the presence of CTCs in the peripheral blood or the bone marrow using c-met had significantly shorter OS and higher hazard ratio (p&lt;0.024; HR=4.39 [95% CI: 1.58-12.22], resp. p&lt;0.008; HR=5.08 [95% CI: 1.79-14.43]). In addition, patients with the presence of CTCs detected in bone marrow using CEA and/or c-met had significantly shorter OS (p&lt;0.025; HR=3.08 [95% CI: 1.26-7.5]). Conclusions: Our study demonstrates that the presence of CTCs is independent negative prognostic factor in lung cancer patients. The analysis of CTCs is clinically feasible, reproducible and further studies focused on early clinical stages should demonstrate its applicability in individualization of adjuvant therapy in lung cancer patients and identification of individuals who would not benefit from extensive lung surgery.

EGFR Tyrosine Kinase Inhibitors: Difference in Efficacy and Resistance

Lung cancer will be diagnosed in 230,000 patients in the U.S. in 2013. Adenocarcinoma will be the most common histology, and 10% of lung cancers will be diagnosed in never or former light smokers. These patients will be those most likely to harbor targetable mutations, in particular, mutations in epidermal growth factor (EGFR). Preclinical work beginning in the 1980s led to the development of EGFR-targeted therapy in lung cancer patients. Analysis of the responders to gefitinib and erlotinib led to the discovery of activating mutations underlying sensitivity to EGFR-directed treatment. Although EGFR-mutant patients have higher response rates, better quality of life, and longer progression free survival, all patients eventually develop resistance. Mutations in the tyrosine kinase domain that render tumors resistant to erlotinib and gefitinib are the most common mechanism of resistance. A second generation of EGFR inhibitors are now making their way to the clinic, with hopes of thwarting these resistance mechanisms or providing more durable responses via irreversible inhibition, as well as targeting of additional HER receptors. Here we review the evolution of EGFR as a target in lung cancer, and the second generation of EGFR inhibitors in development.

The CD36 dynamic change after radiation therapy in lung cancer patients and its correlation with symptomatic radiation pneumonitis

This study was carried out to investigate the relationship between serum CD36 levels and radiation pneumonitis in 30 patients irradiated for lung cancer. We found CD36 may become an important index for predicting the occurrence and development of radiation pneumonitis and evaluating the curative effect.

BRAF mutant non-small cell lung cancer and treatment with BRAF inhibitors.

Inhibitors targeting active protein kinases, such as EGFR or ALK, have demonstrated significant efficacy in the treatment of lung cancer. Activating mutations in the MAPK pathway, which includes the enzymes RAS, RAF, MEK, and ERK, result in constitutive signalling, leading to oncogenic cell proliferation and escape from apoptosis; therefore this pathway is a focus of crucial interest for the development of cancer drugs. In melanoma, the most commonly mutated gene is BRAF, with mutations usually occurring in about 50% of all tumours. The BRAF Val600Glu (V600E) mutation constitutes more than 90% of mutations in melanoma. V600E BRAF mutation shows a great dependency on MEK activity, and offers a rational therapeutic strategy for this genetically defined tumour subtype. The use of vemurafenib and dabrafenib, agents that block MAPK signaling in patients with melanoma and the BRAF V600E mutation, has been associated with prolonged survival and progression-free survival. The frequency of V600E BRAF mutation in lung adenocarcinoma is 1.5% to 2.8%. Treatment of V600E BRAF-mutant lung adenocarcinomas with dabrafenib is under evaluation in a phase 2 trial, and could represent another milestone in individualized therapy for lung cancer patients. The next step will be a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib.