bluuebunny/crossref_metadata_2025_split huggingface dataset:
A prospective phase II trial of erlotinib in advanced non-small cell lung cancer (NSCLC) patients (p) with mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR)
Authors: Paz-Ares L. , Sanchez J. M. , García-Velasco A. , Massuti B. , López-Vivanco G. , Provencio M. , Montes A. , Isla D. , Amador M. L. , Rosell R. 
Published: March 2020

7020 Background: The EGFR TK inhibitor erlotinib is a standard treatment in previously treated NSCLC p. Recently, EGFR gene mutations have been reported to be a predictor of efficacy of this and related compounds. This phase II trial evaluated the efficacy and safety of erlotinib in untreated p with advanced NSCLC and mutated EGFR. Methods: Eligibility criteria included stage IIIB-IV chemotherapy-naive p with confirmed NSCLC and mutated EGFR, PS 0–2, age ≥ 18 years, adequate organ functions, measurable disease and written informed consent. DNA was extracted by laser capture microdissection. Exon 19 deletions were examined by Genscan and the L858R and T790M mutations with a TaqMan assay. Mutations were confirmed by sequencing. Erlotinib was given orally at 150 mg per day. Results: From March to December 2005, 37 (12.5%) of 297 tumors screened were found to have mutations in the TK domain of the EGFR gene (25 deletions; 11 L858R; no T790M). Median age: 68 years; 12 males, 25 females; histology: 28 adenocarcinoma, 4 BAC, 4 large cell carcinoma; 9 smokers. Response has been evaluated in 21 p so far: complete response, 6 p; partial response, 13 p; progressive disease, 2 p; overall response rate, 90% (95% CI:70%-90%). Responses occurred in 100% of tumors with exon 19 deletions and in 75% of those with L858R. All responses are ongoing (up to ≥8 months) and all but one p are still alive. Toxicity profile was predictable (mild to moderate rash, diarrhea, asthenia and emesis). No drug related severe adverse events occurred. Conclusions: Single-agent erlotinib produces a high response rate in previously untreated p with advanced NSCLC and mutated EGFR. In-frame deletions in exon 19 seem particularly predictive for response in this setting. [Table: see text]
A genomic strategy to refine prognosis in early stage non-small cell lung carcinoma (NSCLC)
Authors: Harpole D. H. , Petersen R. , Mukherjee S. , Bild A. , Dressman H. , Kratzke R. , Kelley M. J. , Garst J. , Crawford J. , Nevins J. R. , Potti A. 
Published: March 2020

7026 Background. Although stage-specific classification identifies appropriate populations for adjuvant chemotherapy, this is likely an imprecise predictor for the individual patient with early stage NSCLC. Methods. Using previously-described methodologies that employ DNA microarray data, multiple gene expression profiles (‘metagenes’) that predict risk of recurrence in patients with stage I disease were identified. This analysis used an initial ‘test’ cohort of patients with NSCLC (n = 89) that represented an equal mix of squamous cell and adenocarcinoma. Also, each histologic subset had equal number of patients who survived more than 5 years and those who died within 2.5 years of initial diagnosis. The performance of the metagene-based model generated on the training cohort was then evaluated in independent ‘validation’ sets, including two multi-center cooperative group studies (ACOSOG Z0030 and CALGB 9761). Importantly, the CALGB validation was performed in a blinded fashion. Results. Classification tree analyses that sample multiple gene expression profiles were used to develop a model of recurrence, termed the Lung Metagene Model, that accurately assesses prognosis (risk of recurrence and survival), performing significantly (p<0.001, odds ratio: 16.1, multivariate analysis) better than pathologic stage, T-size, nodal status, age, gender, histologic subtype and smoking history. The accuracy of prognosis using the Lung Metagene Model exceeded 90% (leave-one-out cross validation) in the initial training set (n = 89), 72% in the ACOSOG (n = 25), and 81% in the CALGB (n = 84) datasets. The prognostic accuracy was consistent across histologic subtypes and stages of NSCLC. Importantly, this provides an opportunity to re-classify stage IA patients to identify a subset of ‘high risk’ patients that may benefit from adjuvant chemotherapy. Further, stage IB and II patients identified as ‘low risk’ for recurrence, and who present co-morbidities, could potentially be candidates for observation, and those patients predicted to be at ‘high risk’ may benefit from novel therapeutic trials. Conclusions. The Lung Metagene Model provides a mechanism to refine the estimation of an individual patient’s risk for disease recurrence and thus guide the use of adjuvant chemotherapy in NSCLC. No significant financial relationships to disclose.
Proteomic analysis of lung cancer tumors
Authors: Kikuchi T. , Massion P. P. , Shyr Y. , Altorki N. K. , Dannenberg A. J. , Li M. , Gonzalez A. , Chaurand P. , Caprioli R. , Carbone D. P. 
Published: March 2020

7028 Background: In this study we assess the utility of direct tumor tissue MALDI-MS in a large prospective collection of surgically resected lung cancers to distinguish cancer from non-cancer, histology, occult lymph node involvement, and survival. Methods: 175 non-small cell lung cancer specimens and 62 histologically normal lung tissues obtained at the time of surgery were used in this analysis. Twelve micron thick frozen sections were placed on conductive glass slides. Sections were stained with Cresyl Violet and matrix applied to areas identified by a pathologist under microscopic guidance as containing greater than 80% tumor before three separate areas involved with tumor was analyzed by MALDI MS. Relative intensities of selected peaks were used for class comparison. A class prediction model was built based on the weighted flexible compound covariate method of analysis (WFCCM). Results: We created a prediction model from a training cohort consisting 81 tumors and 19 histologically normal tissue samples. A total of 221 peaks were used for statistical analysis. In tumor/normal discrimination, 46 peaks were used for the prediction model (p<0.0001), while, 22 were used (p<0.005) to predict histology, 11 (p<0.05) to predict nodal involvement, and 14 (p<0.005) in survival prediction. Using these prediction models, classification accuracy was 90% in normal/tumor discrimination, 81.8% in histology and 61.7% in nodal involvement prediction. In the survival prediction model, patients with longer than median survival could be distinguished from those with shorter than median survival (p<0.0001, Log-rank test). We then validated the same features in a blind test set from the remaining 93 tumors and 43 normals. For tumor/normal discrimination, prediction accuracy in test cohort was 94.3%. Histology prediction accuracy was 93.9% in predicting squamous cell carcinoma. Nodal involvement prediction accuracy was 49.3%. Longer or shorter median survival was also predicted in this set with statistical significance p<0.08. (Log rank test). Conclusion: We report the analysis of a large set of tumor and normal samples by MALDI MS and confirm similar accuracy in tumor/normal, histology and survival discrimination to previous our report. This project was supported by the Lung SPORE P50 CA90949 (DPC) and NCI 5R33CA86243 (RMC). No significant financial relationships to disclose.
CALGB 9761: A prospective analysis of IHC and PCR based detection of occult metastatic disease in stage I NSCLC
Authors: Maddaus M. A. , Wang X. , Vollmer R. T. , Abraham N. Z. , D’Cunha J. , Herzan D. L. , Patterson A. , Kohman L. J. , Green M. R. , Kratzke R. A. 
Published: March 2020

7030 Background: CALGB 9761 was a prospective trial of tumor and lymph node collection during planned surgical resection in patients with clinical stage I NSCLC. The primary objective was to determine if occult micrometastases (OM) detected by immunohistochemistry (IHC) or real time PCR of CEA in histologically negative lymph nodes is associated with poorer survival. Methods: 502 patients with clinical stage I NSCLC were accrued. 302 (60%) were eligible for analysis. 200 were ineligible due to postoperative stage change or change in diagnosis. At surgical resection samples of primary tumor and N2 and N1 lymph nodes were harvested. Lymph nodes were split in half, one half was sent for standard surgical pathologic analysis and the other half snap frozen and sent for IHC analysis using a polyclonal anticytokeratin antibody cocktail. Results: Of 302 eligible patients, 173 were T1N0 and 129 T2N0 by routine postoperative pathology. The median follow-up time for eligible patients is 5.25 years. Overall survival at 5 years is 63.22%. Median survival is not yet estimable. 14% of patients had IHC positive tissue in lymph nodes, a rate lower than expected compared to published single institution studies. Overall survival for this group at 5 years is 55.96% compared to 65.65% for the IHC negative group (p=0.38). The failure free survival at 5 years is 41.74% for the IHC positive group and 60.25% for the IHC negative group (p=0.16). RT-PCR data is currently being analyzed. Data on the first 50 patients analyzed demonstrated presence of CEA in nodal tissues and potential upstaging in approximately 50% of the patients. Conclusions: In a multi-institutional setting, IHC detection of OM by use of a polyclonal cytokeratin cocktail in stage I NSCLC has limited capacity to detect OM and poorly predicts recurrence and survival. No significant financial relationships to disclose.
Effect of gender on outcome in two randomized phase III trials of paclitaxel poliglumex (PPX) in chemonaïve pts with advanced NSCLC and poor performance status (PS2)
Authors: Ross H. , Bonomi P. , Langer C. , O’Brien M. , O’Byrne K. , Paz-Ares L. , Sandler A. , Socinski M. , Oldham F. , Singer J. 
Published: March 2020

7039 Background: Women with NSCLC are younger and are more likely to be non-smokers than the overall NSCLC population. Estrogen seems to contribute to these differences in lung cancer biology, but its effect on treatment efficacy has not been well described. Methods: Two phase III trials in chemo-naïve PS2 patients with advanced NSCLC compared PPX to either gemcitabine or vinorelbine (STELLAR 4), or PPX/carboplatin to paclitaxel/carboplatin (STELLAR 3). Eligibility criteria were identical and pts were stratified for gender and age. Analysis of overall survival (OS), the primary study endpoint, showed similar survival between treatment arms. A trend to improvement with PPX for females but not males in both studies prompted an exploratory combined analysis of the 198 women in STELLAR 3 (93/400 pts) and STELLAR 4 (105/381 pts) using univariate and multivariate Cox regression analysis of OS. Results: Combined log-rank analysis of STELLAR 3 and 4 shows improved OS for females receiving PPX vs control (9.5 mo vs 7.8 mo; HR=0.70; p=0.03) and no difference in males (7.3 mo vs 6.9 mo; HR=1.06; p=0.53). Cox multivariate analysis identified treatment with PPX (HR=0.64; p=0.019), smoking (HR=1.50; p=0.037), and presence of extra-thoracic metastases (HR=1.76; p=0.003) as independent prognostic factors in these women. In the combined analysis, median survival advantage for PPX-treated pts was greater in women <55 years old (10.0 vs 5.2 mo, p=0.038) compared to women 55 or older (8.9 vs 8.6 mo, p=0.134). Pretreatment estrogen levels were available for 86 pts in STELLAR 3; pts with estrogen >30 pg/dl had a significant survival benefit when receiving PPX compared to paclitaxel (10.2 vs 5.5 mo; p=0.039). Conclusions: While the efficacy of PPX is comparable to other treatment options in NSCLC, PPX may be more effective female pts, particularly premenopausal women, compared to females in the control arms. Preclinical data suggest that estrogen enhances PPX distribution to lung tissue and upregulates the rate-limiting metabolic enzyme cathepsin B in NSCLC. To prospectively test the effect of estrogen on OS, a phase III trial (PIONEER) has been initiated to compare PPX to paclitaxel in chemo-naïve PS2 females with NSCLC. [Table: see text]
Bone sialoprotein is predictive of bone metastases in resectable non-small cell lung cancer: A case-control study and prevalence data
Authors: Scagliotti G. , Kalebic T. , Volante M. , Cappia S. , Novello S. , Bacillo E. , Borasio P. , Chiusa L. , Papotti M. 
Published: March 2020

7049 Background: Bone metastases (BM) in non small cell lung cancer (NSCLC) may be present at diagnosis or develop in the follow up, are associated with a worse prognosis, and currently there are no chemical or biological markers predicting their clinical onset. Methods: Thirty cases of resected NSCLC which subsequently develop BM (group A - mean follow up time 27.2 months) were matched for several clinico-pathological parameters (including age, sex, stage of the disease, histology, differentiation grade, adjuvant therapy) to 30 cases of resected NSCLC without any metastases (group B - mean follow up time 75.1 months) and 26 resected NSCLC with non-bone metastatic (group C - mean follow up 21.1 months). Primary tumor samples were investigated by immunohistochemistry for 10 markers previously recognized to be involved in bone resorption or metastatization process (cathepsin K, bone sialoprotein [BSP], VEGF, MMP-2, p53, RECK, TIMP-1, CD-117, Ki-67 and TRAcP). For statistical analysis the intensity of the staining was assessed by a semi-quantitative score (0, <10%, 10–50%, >50% +ve tumor cells). Differences among groups were estimated by X-square test, whereas the prognostic impact of clinico-pathological parameters and markers expression was evaluated by univariate and multivariate analyses. Results: Among the different markers investigated, BSP was strongly associated to bone dissemination (p < 0.001) and, independently, to poor outcome (p = 0.02 by Mantel-Cox test). None of the other markers was differentially expressed within the groups or demonstrated a prognostic impact, both in terms of overall survival and of time interval to metastases. Based on these findings, the prevalence of BSP in NSCLC was further estimated in a large series of 120 resected lung carcinomas (M:F ratio 3:1; mean age 67 years; adenocarcinomas 55%, squamous cell carcinoma 39%, others 6%; stages: I 54%, II 17%, III 29%). BSP prevalence reached 40%, without any statistically significant difference according to histotype or other clinico-pathological parameters. Conclusions: BSP protein expression in resected NSCLC strongly predicts bone dissemination, and may therefore be useful in selecting patients for treatments targeted to inhibit bone metastatic spread. [Table: see text]
Mitotic checkpoint gene CHFR methylation in pretreatment serum DNA of docetaxel (doc)/cisplatin (cis)-treated stage IV non-small cell lung cancer (NSCLC) patients (p)
Authors: Isla D. , Salazar F. , Ramirez J. , Sanchez Ronco M. , Cobo M. , Montes A. , Sanchez J. , Catot S. , Taron M. , Rosell R. 
Published: March 2020

7056 Background: CHFR (checkpoint with forkhead-associated and ring finger) regulates a prophase delay in cells exposed to agents that disrupt microtubules. Epigenetic inactivation of CHFR is a frequent event in human tumors, leading to impaired checkpoint function and enhanced sensitivity to docetaxel. We hypothesized that serum DNA methylation of CHFR could be a predictor of longer survival in p treated with doc/cis. Methods: Sodium bisulfite modified serum DNAwas used as the template for methylation-specific PCR assay. DNA was obtained from 600 doc/cis-treated stage IV NSCLC p. Results: Preliminary data on 301 p is available. The frequency of CHFR hypermethylation was 32.6%. There was no association between methylation and performance status (PS), age, gender, histology, response, 14–3-3σ serum DNA methylation, polymorphisms in lymphocyte DNA (ERCC1 118 C/T, ERCC1 C8092A, XRCC3 241 ThrMet), or tumor ERCC1 mRNA levels. Overall, there was a tendency to better median survival (MS) for p with methylated CHFR. In p with PS 0, MS was 33 months (m) for 41 p with methylated CHFR and 12 m for 64 p with unmethylated CHFR (P = 0.23). In p >66 years (y), MS was not reached for 31 p with methylated CHFR and 9.6 m for 80 p with unmethylated CHFR (P = 0.01), while in p <66 y, MS was 9.4 m for 67 p with methylated CHFR and 10 m for 123 p with unmethylated CHFR (P = 0.62). p with both 14–3-3σ and CHFR methylation showed a tendency to longer survival. Final data on 600 p will be presented. Conclusions: Early findings indicate that CHFR methylation in elderly p predicts a significant survival benefit in doc/cis-treated NSCLC. No significant financial relationships to disclose.
EGFR mutation-based phase II multicenter trial of gefitinib in advanced non-small cell lung cancer (NSCLC) patients (pts): Results of West Japan Thoracic Oncology Group trial (WJTOG0403)
Authors: Okamoto I. , Kashii T. , Urata Y. , Hirashima T. , Kudoh S. , Ichinose Y. , Ebi N. , Satoh T. , Tamura K. , Fukuoka M. 
Published: March 2020

7073 Background: Recently several retrospective analyses have reported that somatic activating mutations in the EGFR tyrosine kinase domain underlie responsiveness to gefitinib. In the present study, we have prospectively assessed whether these specific mutations in EGFR gene affect the clinical outcomes of NSCLC pts treated with gefitinib. Method: Pts with a histologically confirmed, recurrent or metastatic NSCLC that harbored EGFR mutations were eligible for the study. Direct sequencing using DNA extracted from paraffin-embedded tumor specimens to detect mutations in EGFR (exons 18, 19 and 21) was performed in a central laboratory. Eligible pts with measurable lesions, ECOG PS of 0–2, adequate organ functions and less than 2 prior chemotherapy regimens were treated with gefitinib 250 mg orally once daily. The primary objective of this study was to determine the objective response rate of single-agent gefitinib in NSCLC pts with EGFR mutations. With the target activity level of 50% and the lowest response rate of interest set at 25%, 23 eligible patients were required with an 80% power to accept the hypothesis and a 5% significance level to reject the hypothesis. Allowing for a 10% loss to follow-up rate, a total of 25 patients with EGFR mutations were planned to enroll. Results: Between March 2005 and December 2005, 104 patients were recruited from fifteen study centers in Japan and screened for the presence of EGFR mutations. EGFR mutations were detected in 28 pts (27%). Twenty-five of the 28 pts have been enrolled onto this study; 12 pts had deletional mutations in exon 19 and 13 pts had missense mutations (L858R) in exon 21. Of the 25 pts with EGFR mutations: adenocarcinoma (24), female (17), never smoker (18), and PS 0–1 (22). Median age was 69 years (range, 54 to 89 years). Previous therapy included surgery in 9 pts (36%), chemotherapy in 7 pts (28%), and radiotherapy in 1 pts (4%). Conclusions: Efficacy and safety data will be mature in March 2006 and will be presented at the ASCO meeting. These are the first prospective studies targeted at NSCLC pts harboring EGFR mutations. No significant financial relationships to disclose.
Phase II study of gefitinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) gene mutations detected by PNA-LNA PCR clamp
Authors: Sutani A. , Nagai Y. , Udagawa K. , Uchida Y. , Murayama Y. , Tanaka T. , Miyazawa H. , Kanazawa M. , Hagiwara K. , Kobayashi K. 
Published: March 2020

7076 Background: The responsiveness to gefitinib has been reported to closely link to the presence of EGFR gene mutations. We developed a method, PNA-LNA PCR clamp, capable of detecting EGFR mutations in the presence of 100-fold background of wild type EGFR from normal cells (Can Res. 2005;65:7276). This study was prospectively designed to evaluate 1) the sensitivity and the specificity of the PNA-LNA PCR clamp (sample size > 100 pts) and 2) a phase II study of gefitinib for NSCLC patients (pts) with EGFR gene mutations (sample size > 25 pts to show the lower limit of 95% CI > 50%). Methods: Clinical samples (sputum, pleural effusion, bronchial fluid and paraffin tissue) were obtained from consecutive NSCLC pts with informed consent in our institution, and were tested by the PNA-LNA PCR clamp. After the second informed consent, for PS 0–2, inoperable stage III and IV pts with EGFR mutations, gefitinib (250mg P.O. daily) was given as the second treatment after docetaxel containing chemotherapy. In case of poor PS pts, the first line chemotherapy was omitted. Results: From Sept. ’04 to Oct. ’05, samples from 100 of a total of 107 pts were informative of EGFR mutation status. PNA-LNA PCR clamp detected EGFR mutations in 38 pts (38%) (15 males/23 females; median age:62; adenoca.:33 pts). Exon 19 deletions, L858R and L861Q were found in 25 (66%), 12 (32%) and 1 (2%) patients, respectively. But 62 pts (51 males/11 females; median age:66; Ad:43 pts) were judged to have wild type EGFR. Between positive and negative pts in EGFR mutation, there was significant difference in the distinction of sex (p = 0.00001). Gefitinib was given to 26 pts with EGFR mutations as the first line (4 pts) or the second line treatment (22 pts). One patient and 20 patients showed CR and PRs, respectively, and the response rate was 81% (95% CI: 61–94%). For patients with wild EGFR genes, gefitinib was given to 5 patients and one patient (20%) showed PR. The response rate was significantly different between wild and mutant EGFR genes detected by the PNA-LNA PCR clamp (p = 0.017). Conclusions: PNA-LNA PCR clamp could reliably detect EGFR mutations, indicating the method is useful to detect EGFR mutations in clinical specimens. Updated data will be presented at the meeting. No significant financial relationships to disclose.