Squamous Cell Lung Cancer Patients Research Articles

Research status on targeted therapy for squamous cell lung cancer

随着肺癌驱动基因研究的逐步深入，肺癌靶向治疗已取得较大进展。与肺腺癌相比，肺鳞癌的靶向治疗进展明显滞后。对肺腺癌临床疗效确切的靶向药物，如：表皮生长因子受体-酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitor, EGFR-TKI）、棘皮类微管相关样蛋白-4（echinodern microtubule-associated-protein-like 4, EML4）-间变型淋巴瘤激酶（anaplastic lymphoma kinase, ALK）融合基因抑制剂等，均对肺鳞癌疗效欠佳，目前肺鳞癌缺少有效的靶向治疗药物。因此，迫切需要对肺鳞癌的驱动基因和靶向治疗进行更深入的研究。本文将对肺鳞癌靶向治疗的研究现状作一综述。

Abstract 1194: Multiplexed molecular profiling of Japanese squamous cell lung cancers.

Abstract Background: Little advancement has been achieved in the development of efficacious molecular targeted therapies for squamous cell lung cancer, though great progress has been made in the treatment of lung adenocarcinoma in the past decade. However, results of comprehensive genome-wide characterization of squamous cell lung cancer have recently been reported and candidates for druggable targets were revealed. Thus it is becoming increasingly important to genotype squamous cell lung cancer as in the case of lung adenocarcinoma in which molecular profiles are incorporated into the lung cancer clinic. We conducted the Shizuoka lung cancer mutation study to analyze driver mutations in patients with thoracic malignancies and here we report the results of squamous cell lung cancer. Methods: Based on the biobanking system in conjunction with the clinic including the pathology lab, we have developed a multiplexed mutational panel designed to assess 23 mutations in 9 genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN and HER2), EGFR, MET, PIK3CA, FGFR1 and FGFR2 amplifications, and EML4-ALK translocations using pyrosequensing plus capillary electrophoresis, qRT-PCR, and RT-PCR, respectively. These results are communicated to clinicians for assigning patients to appropriate therapy and/or clinical trials. A written informed consent was obtained upfront from all patients enrolled into this study. Results: Between July 2011 and July 2012, sixty-eight squamous cell lung cancer patients were included in this study. Patients’ characteristics were as follows: median age (range) 72 (38-92) years; male 85%; smoker 97%; stage I/II/III/IV 18/35/26/21 %; well/moderate/poor/undetermined differentiated 6/34/40/20 %; surgically resected snap-frozen samples 46% and formalin-fixed paraffin-embedded (FFPE) samples 54%. We detected driver mutations in 47% of all cases. Mutations found: EGFR 2 (3%), KRAS 3 (4%), PIK3CA 9 (13%), NRAS 1 (1%), EGFR amplification 2 (3%), PIK3CA amplification 5 (7%), FGFR1 amplification 3 (4%). The frequency of FGFR1 amplification was much lower in our study than that in previous reports in Caucasian population. Seven patients harbored simultaneous driver mutations (EGFR + other 5 (7%), PIK3CA amplification + other 2 (3%)). Driver mutations were more frequently detected in surgically resected snap-frozen samples than in FFPE samples (65% v.s. 32%). Tumor differentiation was not significantly correlated with the presence or absence of driver mutations. Conclusions: Driver mutations were detected in 47% of squamous cell lung cancer patients in this study. PIK3CA mutation seemed to be relatively frequent in squamous cell lung cancer as reported in other studies, while FGFR1 amplification seemed less frequent. This multiplexed mutational profiling should be incorporated into lung cancer clinic to facilitate personalized cancer medicine in patients with squamous cell lung cancer. Citation Format: Hirotsugu Kenmotsu, Masakuni Serizawa, Yasuhiro Koh, Mitsuhiro Isaka, Toshiaki Takahashi, Haruyasu Murakami, Takehito Shukuya, Hiroaki Akamatsu, Kazushige Wakuda, Tomohiro Maniwa, Isamu Hayashi, Masahiro Endo, Takashi Nakajima, Yasuhisa Ohde, Nobuyuki Yamamoto. Multiplexed molecular profiling of Japanese squamous cell lung cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1194. doi:10.1158/1538-7445.AM2013-1194

Update on HER1–3 in Advanced Non–Small-Cell Lung Cancer

Update on HER1–3 in Advanced Non–Small-Cell Lung Cancer

FGFR1 Amplification in Squamous Cell Carcinoma of The Lung

Amplification of fibroblast growth factor receptor 1 (FGFR1) has been reported in squamous cell lung carcinoma and may be a molecular target for therapy. Little is known, however, about the clinical and demographic correlates of FGFR1 amplification. The study is an Institutional Review Board approved retrospective analysis of 226 patients with squamous cell lung cancer seen at the Massachusetts General Hospital from 2005 to 2011. Clinical and demographic characteristics of all patients were obtained, as well as treatment details including surgery, radiation, and chemotherapy, and overall survival. fluorescence in situ hybridization was performed for FGFR1 on formalin-fixed paraffin-embedded tumor tissue. Clinical genotyping results were also reviewed where available. Thirty-seven of 226 patients (16%) with squamous cell lung cancer were found positive for amplification using a definition of amplification of a gene to copy number control ratio of 2.2 or higher. FGFR1 amplification status was not associated with age, sex, stage, histologic subtype within squamous cell, smoking history, or pack-years of smoking. We found no significant difference in overall survival by FGFR1 amplification status as a whole; in the advanced stage subset, our findings are inconclusive because of the small sample size. FGFR1 amplification was found in 16% of a clinical cohort of squamous cell lung cancer patients. The lack of any specific clinicodemographic features that correlates with FGFR1 amplification suggests that all squamous cell patients should be tested for this genomic change.

1247P - Randomised Phase II Trial of Oral Vinorelbine (N) and Cisplatin (P) or Pemetrexed and C (PC) in First Line Advanced Non Squamous (NSCC) Non Small Cell Lung Cancer (NSCLC) Patients (PTS). Navotrial01: Final Results

ABSTRACT Background Individualized treatments in NSCLC are now based on molecular and/or histological data. This randomized trial (2/1) was set up to assess the efficacy of NC compared to PC for pts with nSCC. The primary end-point was disease control rate (DCR) including overall response rate (ORR) and stable disease (SD). Methods Pts received N60-80 mg/m2 D1, D8 + C80 mg/m2 D1 or P500 mg/m2 + C75 mg/m2 D1 for 4 cycles q3w; pts with DCR received single agent continuation maintenance (CM) until progression or toxicity. Results From 10/09 to 02/11, 151 pts were treated with NC or PC. ITT = 151 NC n = 100 PC n = 51 Male/Stage IV (%) 62.0/87.0 64.7/88.2 Median age (y, range) 61.0 (38.4-75.1) 63.8 (40.3-75.5) Combination: (%) ITT(95% CI) DCR 75.0 (65.3-83.1) 74.5 (60.4-85.7) ORR 21.0 (13.5-30.3) 23.5 (12.8-37.5) Combination + CM:(%) ITT (95% CI) n= 53 n = 33 DCR 75 (65.3-83.1) 76.5 (62.5-87.2) ORR 24 (16.0-33.6) 31.4 (19.1-45.9) Median PFS ITT (m,range) 4.2 (3.6-4.7) 4.2 (3.2-5.6) PFS ITT at 6/12/18m (%) 33.0/10.3/5.5 27.5/7.4/2.5 Median OS ITT (m,range) 10.6 (7.8-12.1) 10.8 (7.0-14.5) Related toxicities G3/4 (%pts) NC/PC during Combination: anemia 9.0(G3)/8.2, leucopenia 26.0/10.2, neutropenia 44.0/18.3, febrile neutro 2.0/2.0, thrombocytopenia 0/6.1, fatigue(G3) 7.0/3.9, hyperglycemia 4.0/7.8, nausea(G3) 5.0/0, vomiting(G3) 7.0/2.0, stomatitis(G3) 0/2.0, pneumonia(G3) 0/2.0, deep vein thrombosis(G3) 0/2.0, pulmonary embolism(G4) 0/2.0. During Maintenance: anemia 5.0/4.1, leucopenia 2.0/10.2, neutropenia 11.0/20.4, febrile neutro 3.8/0, fatigue (G3) 3.8/0, stomatitis(G3) 1.9/ 3.0, pain 3.8/6.0, Respiratory disorders 0/4.0, deep vein thrombosis (G3)0/2.0. Deaths potentially related to CT 2/1. Conclusions NC and PC had similar efficacy. In the present economic context, the acquisition cost of the two platinum based doublets should be considered in the treatment decision making of pts with advanced nSCC NSCLC. Disclosure S. Malasse: Statistician of the study Employment for the sponsor. F. Biville-Hedouin: Medical Project Manager of the study Employment for the sponsor. All other authors have declared no conflicts of interest.

The Impact of Timeliness of Care on Survival in Non-small Cell Lung Cancer Patients

It is uncertain whether timeliness improves clinical outcomes in lung cancer patients. The goal of the study was to analyse the influence of patient's and doctor's delays on survival of unselected population of NSCLC patients. From 1995 to 1998, 8705 squamous cell lung cancer patient's and 1881 adenocarcinoma patient's were registered in Pulmonary Outpatients Clinics in all parts of Poland and subsequently in National Tuberculosis and Lung Diseases Research Institute Register (NTLDRIR). The median time from first symptom(s) to the beginning of a treatment was 92 days (mean -138.5 days).The median waiting time between first symptom(s) and first visit to a doctor's was 30 days (mean 57 days) and from first visit to a doctor's to referral to a chest physician - was 17 days (mean 41days). Diagnosis of the NSCLC was established in a mean time of 71 days (median 40 days), but chest physician diagnosed patients in a mean time of 51days (median 28 days). The multivariate analysis revealed that ECOG performance status (PS) 2 (HR = 1.4) and 3+4 (HR = 2.23), clinical stage of the disease II (HR = 1.32), III (HR = 1.41), and IV (HR = 1.82) were independent negative predictors of survival. Non-surgically treated patients had worse prognosis than patients treated surgically (HR = 3.03). Lack of patient's delay had a significant positive impact on survival (HR = 0.88), particularly for patients in PS 0+1 (HR = 0.9) and 3+4 (HR = 0.9). Lack of doctor's delay was a negative predictive factor of survival (HR = 1.14). It was observed particularly in patients in performance status 2 (HR = 1.28). The patient's delay and lack of doctor's delay had a negative impact on survival of NSCLC patients.

Definition of a fluorescence in situ hybridization score identifies high- and low-level FGFR1 amplification types in squamous cell lung cancer

Lung cancer is one of the major cancer-related causes of death in developed countries. Especially squamous cell lung cancer (SCC) patients have scarce therapeutic options. We recently reported fibroblast growth factor receptor-type 1 (FGFR1) amplification to be associated with therapeutically tractable FGFR1 dependency in SCC. This makes FGFR1 a novel target for directed therapy in SCC.

Clinical characteristics and natural history of patients with squamous cell lung carcinoma with FGFR1 amplification.

1533 Background: FGFR1 amplifications have been described as a promising oncogenic target in squamous cell lung cancer. Here we aimed at describing the clinical characteristics and natural history of FGFR1amplified squamous cell lung cancer patients. Methods: From 01/2011 to 01/2012 we screened 553 squamous cell lung cancer patients in our Network for Molecular Screening of Lung Cancer for the presence of FGFR1 amplifications by FISH analysis in accordance with the local ethics committee. FGFR1 was defined as amplified if the ratio of FGFR1 copies to centromeric copies was above 2 or if more than 50% of tumor cells showed 5 copies or if more than 15% of tumor cells demonstrated clusters of FGFR1. Clinical data were collected by extracting information from medical records, the local cancer registry and by questioning treating physicians and patients. Results: FGFR1FISH analysis could be performed in 95% of the cases and was amplified in 16%. Of the amplified cases 75 % were male and 25% female without significant enrichment for male or female. The median age of the patients at diagnosis was 67 yrs (range 46 - 82). Stage at presentation was: 16% I; 17.3% II; 26.7% IIIa, 40% IIIb/IV. 97,3% of the patients were former or active smokers with a median of 40 pack years. The median progression free survival of patients with stage IIIb/IV disease was 11 months (95% CI 8-14; n=14). The median overall survival was not yet reached after a median follow-up time of 14 months (95% CI 11 - 17; n=24). We further screened for co-existing genetic lesions such as mutations in EGFR, BRAF, KRAS, PIK3CA as well as translocations of ALK and amplifications of ERBB2. Two patients demonstrated co-occurring PIK3CA mutations and one a BRAFmutation. Conclusions: Screening for FGFR1 is feasible under routine clinical conditions. By implementation of a regional molecular screening network the ability to screen for FGFR1 amplification was successfully expanded to non-academic centers and private practices. FGFR1 amplifications in squamous cell cancer of the lung are frequent (16%) and associated with smoking history. Screening for FGFR1 might pave the way for the application of new FGFR1 directed targeted drugs in squamous cell lung cancer.

FGFR1 amplification and EGFR mutation in Chinese squamous cell lung cancer.

7545 Background: Squamous cell lung cancer (SCC) lacks for effective targeted therapies. FGFR1 amplification has emerged as a potential biomarker. This study aimed to explore clinicopathologic characteristics of FGFR1 amplification in Chinese SCC patients and further explore the correlation between FGFR1 amplification and EGFR mutations. Methods: One hundred seventy-seven SCC patients were included in this retrospective study. Gene copy number of FGFR1 and EGFR mutations were detected by fluorescence in situ hybridization (FISH) and denaturing high-performance liquid chromatography (DHPLC), respectively. Results: FGFR1 amplifications were detected in 24.9% (44/177) Chinese SCC patients. FGFR1 amplification in SCC was more common in male (28.0%, 40/143) and smokers (28.7%, 39/136) than female (11.8%, 4/34, p=0.049) and nonsmokers (12.2%, 5/41, p=0.032). FGFR1 amplification and EGFR mutations were mutually exclusive (p=0.006), fourty-one of 139(29.4%) patients with wild-type EGFR had FGFR1 amplification, while 3 of 38 (7.9%) patients with EGFR mutation had FGFR1 amplification. Conclusions: FGFR1 amplification was common in Chinese squamous cell lung cancer, and mutually exclusive with EGFR mutations.

Abstract 2004: Ribonucleotide reductase subunit M2 regulates Bcl-2 in human cancer: A potential target for cancer therapy

Abstract Ribonucleotide reductase subunit M2 (RRM2) is an essential regulator of DNA synthesis and replication that plays an active role in tumor progression. B-cell lymphoma-2 (Bcl-2) is an anti-apoptotic protein known to promote cell survival. Elevated levels of Bcl-2 have been observed in many cancer types that predict clinical drug resistance. Both RRM2 and Bcl-2 were identified as prognostic factors and indicators of poor patient outcome in several cancers. Therefore, we hypothesized that RRM2 and Bcl-2 proteins might have cooperative functions in cancer progression. We examined correlations of RRM2 and Bcl-2 protein in tissue samples of head and neck squamous cell carcinoma (HNSCC) and non small cell lung cancer (NSCLC) patients by using quantum dots (QDs)-immunofluorescence (IHF) which allows quantification of biomarkers simultaneously in the same tissue slide. A total of 19 cases in each of HNSCC and NSCLC were analyzed. Spearman's correlation coefficient was estimated to measure the relationship between these two proteins. Our data demonstrate highly significant positive correlation between RRM2 and Bcl-2 in both types of cancer (HNSCC: R=0.98, p-value <0.0001; NSCLC: R=0.85, p-value <0.0001). We further investigated the action mechanism of RRM2 and Bcl-2 in cancer progression and explored the role of RRM2 by utilizing siRNA-mediated gene silencing. siRNA knockdown of RRM2 strongly inhibited cell growth and led to apoptosis. Our results demonstrated that overexpression of Bcl-2 protected cells from apoptosis triggered by RRM2 knockdown, indicating that Bcl-2 is a key determinant in controlling intrinsic apoptosis. We further analyzed whether Bcl-2 was regulated by RRM2 at the transcriptional level or at the protein level by post-translational modification. RRM2 most likely regulates Bcl-2 not only at a transcriptional level but also at the post-translational level. We found that RRM2 and Bcl-2 proteins were co-localized and directly interacted. RRM2 depletion significantly increased the rate of Bcl-2 protein degradation, reducing its half-life from ∼9 hours to ∼2 hours. Our study offers a promising approach to Bcl-2 inhibition through targeting RRM2 with siRNA in HNSCC and NSCLC. A protein network-based functional mechanism is defined by which RRM2 regulates Bcl-2-mediated apoptosis. Our novel findings add to the emerging regulatory effects of RRM2 on tumor growth by modulation of Bcl-2. (This work is supported by grants from NIH U01CA151802, P50CA128613 and DOD W81XWH-07-1-0306). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2004. doi:1538-7445.AM2012-2004

Genetic insight and therapeutic targets in squamous-cell lung cancer

Squamous-cell lung cancer is one of the most prevalent subtypes of lung cancer worldwide and its pathogenesis is closely linked with tobacco exposure. Unfortunately, squamous-cell lung cancer patients do not benefit from major advances in the development of targeted therapeutics such as epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors that show exquisite activity in lung adenocarcinomas with EGFR mutations or echinoderm microtubule associated protein like-4 (EML4)-ALK fusions, respectively. Major efforts have been launched to characterize the genomes of squamous-cell lung cancers. Among the new results emanating from these efforts are amplifications of the fibroblast growth factor receptor 1 gene and mutations of the discoidin domain receptor 2 gene as potential novel targets for the treatment of squamous-cell lung cancer patients. Here, we provide a review on these discoveries and their implications for clinical trials in squamous-cell lung cancer assessing the value of novel therapeutics addressing these targets.

Fucosylated glycoproteomic approach to identify a complement component 9 associated with squamous cell lung cancer (SQLC)

Human lung cancer is a major cause of cancer mortality worldwide. Understanding the pathophysiological features and the development of novel biomarkers for diagnosis as well as treatment are major tasks. In the present study, sera from ten SQLC patients and healthy control (HEC) were collected and pooled, respectively. The pooled sera were depleted via an immunoaffinity method and further subjected to fucosylation enrichment. Enriched fucosylated glycoproteins were resolved by SDS-PAGE and subsequently analyzed by LC-ESI-MS/MS. From comparative proteomic analysis, we selected the C9 protein. C9 protein levels were validated by Western blot, protein arrays and the fucosylation levels of C9 by hybrid lectin ELISA (HLE) in the sera of 120 HEC and 118 SQLC patients. The C9 protein level was 6.4-fold higher in SQLC patients compared to HEC, as determined by Western blot analysis. The results were concurrently confirmed by a protein array that showed a C9 level significantly higher in SQLC patients, as compared to HEC, with a sensitivity of 53% and a specificity of 89%. C9 fucosylation levels were significantly higher in SQLC patients compared to HEC (p<0.05) when tested by HLE. These findings suggest that C9 and fucosylated form could serve as a useful marker for SQLC.

Comparative outcomes of squamous and non-squamous non-small cell lung cancer (NSCLC) patients in phase II studies of ASA404 (DMXAA) - retrospective analysis of pooled data.

ASA404 (5,6-dimethylxanthenone-4-acetic acid) is a small-molecule, flavonoid tumor-vascular disrupting agent. Pooled data from phase II studies were analyzed retrospectively to compare safety and efficacy between squamous and non-squamous non-small cell lung cancer (NSCLC) patients. Data from previously untreated patients with stage IIIb/IV NSCLC who were randomized to receive up to six cycles of carboplatin (C; AUC 6 mg/ml•min) and paclitaxel (P; 175 mg/m(2)) alone or with ASA404 (1200 mg/m(2)), or enrolled in an extension study to receive CP and ASA404 (1800 mg/m(2)), were analyzed. Differences between subgroups were calculated using Fisher's exact test. Of the 108 enrolled patients, safety data from the 104 patients included in the safety population were pooled to compare results between histological subgroups (squamous vs non-squamous) and treatment (CP alone vs CP + ASA404). Addition of ASA404 to the standard chemotherapy regimen did not appear to substantially increase toxicity, and there were no serious adverse events associated with bleeding, pulmonary hemorrhage, or hemoptysis. Activity with CP + ASA404 appeared improved over CP alone, with median survival 10.2 vs 5.5 months in squamous, and 14.9 vs 11.0 months in non-squamous populations, respectively. This analysis is limited by its retrospective nature, and by the small size of the overall group, treatment and disease subgroups. However, as ASA404 appears to have a similar safety and activity profile in patients with squamous and non-squamous NSCLC, the findings support inclusion of both groups of patients in ongoing definitive phase III trials of ASA404 (NCT00832494).

A chronic obstructive pulmonary disease related signature in squamous cell lung cancer

The epidemiological relationship between squamous cell lung cancer (SCC) and chronic obstructive pulmonary disease (COPD), both smoking-related diseases, suggests that they have also a genetic basis. We compared 35 SCC patients with and without COPD with whole-genome gene expression profiles of laser microdissected tissue. Validation of differential expression was performed for 25 genes using quantitative (q)RT-PCR. Subsequently, we performed array-based CGH on the same tumor samples. We found that 374 probes were differentially expressed in SCC from patients with and without COPD. Forty-four probes were derived from genes with mitochondrial functions and 34 probes were located on 5q. All these probes showed a lower expression level in SCC from non-COPD patients. For a random selection of 25 mitochondrial and 5q genes, we confirmed the differential expression by qRT-PCR. Loss of 3p, 5q and 9p was observed, via array-CGH, to be more frequent in SCC from non-COPD patients as compared to SCC from COPD patients. Combination of chromosomal aberrations and the location of the differentially expressed genes showed significant association for loss of the 5q31.2–31.3 region and reduced expression of the 5q genes. In conclusion, a more frequent loss of 5q and a low expression of genes located on 5q in SCC tumors of non-COPD patients compared to tumors from COPD patients was identified suggesting that different oncogenetic pathways are operational in patients with and without COPD.

Impact and interactions between smoking and traditional prognostic factors in lung cancer progression

Background Cigarette smoking is a well-known risk factor of lung carcinogenesis. The clinical impact of smoking on lung cancer metastases and survival remains unclear. We sought to investigate the effect of smoking intensity on lung cancer treatment failure (represented by overall survival), and the interactions between smoking and clinicopathological factors in lung cancer progression. Methods Clinical information was obtained from four non-small cell lung cancer patient cohorts ( n = 347). Twenty patients were excluded from the analysis because their smoking history was not available. The distribution of smoking intensity on patient age (≥60 years or <60 years), gender, tumor differentiation (poor, moderate and well differentiated), and clinical stage (1, 2, or 3) was assessed with Kruskal–Wallis rank sum tests. The effect of smoking on cause-specific lung cancer mortality was estimated by using Cox proportional hazard models and Kaplan–Meier analysis. The interactions between clinicopathological factors and smoking intensity with regard to lung cancer overall survival were evaluated with analysis of variance (ANOVA) for Cox modeling. Results Greater smoking intensity at diagnosis was found in older patients (≥60 years; p = 0.022), male ( p = 1.35e−7), poorly differentiated tumors ( p = 8.51e−5), patients with tumor stage 2 ( p = 0.031), and squamous cell lung cancer patients ( p = 2.2e−16). Patients who smoked more than 61 packs/year had an increased risk for lung cancer recurrence (hazard ratio = 1.41, 95% CI: [1.03, 1.94], log-rank p = 0.032) and shorter overall survival period (log-rank p = 0.033, Kaplan–Meier analysis) than those who smoked less than 61 packs/year. ANOVA analysis showed that smoking intensity ( p = 0.03) and tumor stage ( p = 1.2e−6) are the only significant prognostic factors of lung cancer, whereas patient age, gender, and tumor differentiation were not significant in lung cancer prognostication. There were significant interactions between smoking and clinical stage ( p = 0.02) as well as patient age and tumor differentiation ( p = 0.03) in lung cancer progression. Conclusion Smoking intensity at diagnosis is an independent, significant prognostic factor of non-small cell lung cancer. This factor could be used in patient selection for chemoprevention of tumor metastases and relapse. Additionally, the information may be used for clinically relevant tobacco prevention and intervention messages.

Squamous Cell Carcinoma Antigen in Lung Cancer and Nonmalignant Respiratory Diseases

Squamous cell carcinoma antigen (SCC) has been found in elevated amounts in patients with squamous cell lung cancer (SQLC). Elevated levels have also been found among patients with nonsquamous cell lung cancer (NSQLC) and in subjects with nonmalignant pulmonary disease (NMPD). The purpose of the current study was to evaluate SCC levels among a large number of patients with SQLC, NSQLC, and NMPD. Six hundred thirty-nine lung cancer patients, including 201 SQLC patients and 299 patients with NMPD, who were diagnosed at our hospital up to 2006 were entered. Serum SCC levels were measured with a commercially available kit. Elevated levels (>1.5 ng/ml) of SCC were observed in 52.7% of SQLC patients, but in only 14.2% of NSQLC patients. There was a statistically significant difference in positive rate between SQLC and NSQLC patients. None of the NSQLC patients had serum SCC levels greater than 40.0 ng/ml. Among subjects with NMPD, 28.4% had elevated levels of SCC. However, none of the NMPD patients had serum SCC levels greater than 20.0 ng/ml. Serum levels of SCC can be elevated (<20.0 ng/ml) in some NMPD patients without coexisting SQLC. Patients with NSQLC and NMPD with elevated SCC levels greater than 40 ng/ml may have coexisting SQLC or squamous cell carcinoma in an extrapulmonary site.

Toward an early diagnosis of lung cancer: An autoantibody signature for squamous cell lung carcinoma

Serum-based diagnosis offers the prospect of early lung carcinoma detection and of differentiation between benign and malignant nodules identified by CT. One major challenge toward a future blood-based diagnostic consists in showing that seroreactivity patterns allow for discriminating lung cancer patients not only from normal controls but also from patients with non-tumor lung pathologies. We addressed this question for squamous cell lung cancer, one of the most common lung tumor types. Using a panel of 82 phage-peptide clones, which express potential autoantigens, we performed serological spot assay. We screened 108 sera, including 39 sera from squamous cell lung cancer patients, 29 sera from patients with other non-tumor lung pathologies, and 40 sera from volunteers without known disease. To classify the serum groups, we employed the standard Naïve Bayesian method combined with a subset selection approach. We were able to separate squamous cell lung carcinoma and normal sera with an accuracy of 93%. Low-grade squamous cell lung carcinoma were separated from normal sera with an accuracy of 92.9%. We were able to distinguish squamous cell lung carcinoma from non-tumor lung pathologies with an accuracy of 83%. Three phage-peptide clones with sequence homology to ROCK1, PRKCB1 and KIAA0376 reacted with more than 15% of the cancer sera, but neither with normal nor with non-tumor lung pathology sera. Our study demonstrates that seroreactivity profiles combined with statistical classification methods have great potential for discriminating patients with squamous cell lung carcinoma not only from normal controls but also from patients with non-tumor lung pathologies.

Comparison of safety and efficacy between squamous and non-squamous non-small cell lung cancer (NSCLC) patients in phase II studies of DMXAA (ASA404)

8072 Background: DMXAA (ASA404) is a tumor vascular disrupting agent recently evaluated in phase II trials in NSCLC. A randomized trial compared DMXAA 1,200 mg/m2 plus carboplatin and paclitaxel (CP) with CP alone (median survival 14.0 vs 8.8 months). A single-arm study evaluated DMXAA 1,800 mg/m2 plus CP (median survival 14.9 months). Both trials included squamous and non-squamous patients. We examined whether the safety or efficacy of DMXAA varied with histology. Methods: Patients had chemotherapy-naïve stage IIIb/IV NSCLC. Phase II data were pooled by histology and treatment, with aggregation of the two DMXAA doses. We compared efficacy and safety between squamous and non-squamous patients receiving the same treatment. Then for each histology we compared patients receiving and not receiving DMXAA. Results: Numbers of patients evaluable for safety (efficacy) were: in the CP arm of the randomized study, 11 (11) squamous and 25 (25) non-squamous; in the CP + DMXAA 1,200 mg/m2 arm of the randomized study, 11 (11) squamous and 26 (23) non-squamous; and in the CP + DMXAA 1,800mg/m2 single arm study, 11 (10) squamous and 20 (20) non-squamous. Pooling data from the two DMXAA dose groups should not introduce bias because they contain similar proportions of squamous patients. Conclusions: Addition of DMXAA to CP was generally well tolerated in both squamous and non- squamous patients. There was no evidence that DMXAA induced hemoptysis in either group. In both squamous and non-squamous patients, efficacy findings including survival were consistently better with DMXAA plus CP than with CP alone. The forthcoming phase III trial will therefore include both squamous and non-squamous patients. Safety and Efficacy Squamous Non-squamous All histologies CP CP + DMXAA CP CP + DMXAA CP CP + DMXAA % patients with ≥1 adverse event NCI-CTC grade ≥3/severe 72.7% (n=11) 68.2% (n=22) 64.0% (n=25) 60.9% (n=46) 66.7% (n=36) 63.2% (n=68) Response rate* 14.3% (n=7) 40.0% (n=20) 25.0% (n=20) 31.7% (n=41) 22.2% (n=27) 34.4% (n=61) Median time to tumor progression (months) 1.6 (n=11) 5.6 (n=21) 4.8 (n=25) 5.5 (n=43) 4.4 (n=36) 5.5 (n=64) Median survival (months) 5.5 (n=11) 10.2 (n=21) 11.0 (n=25) 14.9 (n=43) 8.8 (n=36) 14.5 (n=64) * 12 patients evaluable for other efficacy parameters were not evaluable for response. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Antisoma

Thymidine phosphorylase levels and dihydropyrimidine dehydrogenase levels in non-small cell lung cancer tissues

Thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) are the major catabolic enzymes of 5-FU. In this study, we analyzed the concentration of TP and DPD in non-small cell lung cancer tissue by enzyme-linked immunosorbent assay. We measured the TP and DPD levels in 25 adenocarcinoma tissues and 25 squamous cell carcinoma tissues. The mean TP concentration in non-small cell lung cancer tissue was statistically higher than that of normal lung tissue as was the mean DPD concentration. The ratio of the TP level to DPD level in tumor tissue was higher in squamous cell carcinoma than in adenocarcinoma. No significant difference could be detected between the TP level, DPD level, or TP/DPD level and the tumor size or lymph node metastasis. In conclusion, chemotherapy with 5-FU may be more effective in squamous cell lung cancer patients than lung adenocarcinoma patients from the result of the ratio of TP to DPD.

Elderly patients with squamous lung carcinoma: faring better or worse?

Nonsmall cell lung cancer is increasingly diagnosed at an advanced age and squamous cell carcinoma is the commonest histological type encountered in older patients. The clinical course, management, and outcome of squamous lung cancer in the elderly have not been thoroughly studied to date. We retrospectively analyzed 236 squamous cell lung cancer patients diagnosed in two reference hospitals and compared key epidemiological, clinical, and management features between elderly (>70 years) and younger patients. Sixty-four were aged more than 70 years at diagnosis while 172 were up to 70 years of age. There were no differences between the two groups in gender or stage distribution. No differences were observed in the nature or duration of presenting symptoms, the appearance of pleurisy, atelectasis or vascular invasion, the incidence of distant metastatic spread, or the response to combination chemotherapy. Elderly patients were less fit (performance status 2/3 30 vs 20%, p=0.03), developed hemoptysis more often (56 vs 42%, p=0.04), and presented with smaller tumor primaries (median 4 vs 8 cm, p=0.004). When metastases were present, older patients exhibited a tropism for bony (64 vs 29%, p=0.03) and rarity of brain (5 vs 14%, p=0.03) deposits. Though elderly subjects received chemotherapy (63 vs 82%, p=0.003) or radiotherapy (29 vs 48%, p=0.009) less often than their younger counterparts, they tolerated it well and achieved comparable median time to treatment failure and overall survival (median 17 vs 18 months, log-rank p=0.22). Platinum-based chemotherapy and potentially curative management were applied less often in older patients. Older patients are less fit, develop bony but not brain metastases, receive antineoplastic treatment less often, and survive as long as younger patients. Squamous lung carcinoma may follow a more indolent clinical course in the elderly, a hypothesis worth validating by case-cohort studies and molecular profiling, with the hope to rationally individualize patient treatment.