bluuebunny/crossref_metadata_2025_split huggingface dataset:
P53 protein over-expression but not p53 gene mutation is a poor prognostic marker and a predictive marker for survival benefit from adjuvant chemotherapy in non-small cell lung cancer (NSCLC) in the JBR.10 Trial
Authors: Tsao M. S. , Aviel-Ronen S. , Ding K. , Lau D. , Liu N. , Whitehead M. , Seymour L. , Winton T. , Shepherd F. A. 
Published: March 2020

7577 Background: JBR.10, a phase III inter-group trial randomized 482 patients with resected stage IB & II NSCLC to receive 4 cycles of adjuvant cisplatin + vinorelbine or observation alone. Chemotherapy patients had an overall survival (OS) benefit (Hazard Ratio [HR] 0.69, p=0.04). P53 has important regulatory roles in cell cycle progression, apoptosis, gene transcription and DNA repair. We evaluated the prognostic and predictive value of p53 in JBR.10. Methods: P53 protein expression was evaluated by immunohistochemistry (IHC) on tissue micro-arrays (282 available blocks). We used the DO7 antibody, and defined ≥15% nuclear staining as the cutoff for over- expression. Mutations in exons 5–9 were determined by denaturing high performance liquid chromatography (446 available samples), followed by sequencing of aberrant PCR products. Results: Successful assays: p53 mutation, 403/446 patients; p53 IHC, 254/282 patients. P53 gene mutations were found in 126/403 (31%) patients. In the observation arm, mutations were not prognostic of poorer survival (HR = 1.18, 95% CI 0.77–1.81; p= 0.45). Adjuvant chemotherapy effect was not significantly different in p53 mutated and wild type patients (interaction p = 0.66), the estimated HR was 0.68 (95% CI 0.46–1, p=0.047) for patients with wild type p53, and 0.79 (95% CI 0.47–1.33, p=0.37) for mutated patients. P53 protein over-expression was found in 133/254 (52%) patients. Patients with over-expression in the observation arm had a higher risk of death than patients with low expression (HR 1.89, 95% CI 1.07–3.34, p=0.03). However, the adjuvant chemotherapy effect was significantly better in p53 over-expressing patients (interaction p= 0.018), with an estimated HR of 0.53 (95% C.I. 0.31–0.90, p=0.03) for p53 over-expressing patients, and 1.40 (95% C.I. 0.78–2.52, p=0.26) for low expressing patients. Conclusions: P53 protein overexpression but not p53 gene mutation is both a significant prognostic marker of poorer survival in the JBR 10 population and a significant predictive marker for the benefit of adjuvant chemotherapy. [Table: see text]
Creation of an epidemic: The tobacco industry (TI) and smoking-related adenocarcinoma (AD) of the lung
Authors: Strauss G. M. , Jemal A. , McKenna M. B. , Strauss J. A. , Cummings K. M. 
Published: March 2020

7583 Background: When epidemiologic research first demonstrated an association between cigarette smoking (CS) and lung cancer (LC) in the 1950s, AD comprised about 5% of LCs and was only weakly related to CS. In the 1960s and 1970s, AD increased sharply, and became strongly related to CS. Methods: We conducted an epidemiological and ecological analysis correlating time trends in LC histology with changes in cigarette design and TI actions over the past 30 yrs. We utilized SEER data on 307,797 LCs diagnosed from 1975 to 2003 to analyze time trends of age-standardized incidence rates of each LC subtype: AD, squamous (SQ), small cell, and large cell. Comparisons were drawn based on sex, race, and age. Because SEER contains no data on CS, other sources were utilized to correlate changing histology to time trends in smoking prevalence, the changing cigarette, and TI actions. Results: Among all pts, AD surpassed SQ by 1980–84 to become the most common histology. AD increased 62% from 1975–79 to 1995–99, but fell 8% in 2000–03. SQ peaked in 1980–84 and dropped 35% by 2000–03. AD surpassed SQ in 1985–89 in men, while AD was already most common in women by 1975–79. AD rose 38% in men from 1975–79 to 1995–99, while it doubled in women during this interval. Among whites, AD surpassed SQ by 1980–84, although this did not occur among blacks for another decade. Nonetheless, AD incidence has consistently been higher in black men than in other subgroups. AD was already most common in pts <50 yrs by 1975–79, while AD rapidly increased and surpassed SQ in all other age groups by 1990–94. By 2000–03, AD comprised 47% of all LCs (42% in men; 52% in women; 59% in pts <50 yrs). Currently, AD is the most common histology in both sexes, races, and in all age groups. Trends in AD correlate with the wide-scale adoption by smokers of filtered and low tar cigarettes, and with increasing nitrosamine levels in cigarettes. Conclusions: The rise of AD, particularly in women and younger persons, is consistent with the hypothesis that changes in cigarette design and composition was responsible for this rise. These changes were introduced by the TI in response to mounting evidence that CS caused other forms of LC. While low tar cigarettes do not reduce LC risk, their adoption appears to be responsible for creating an epidemic of smoking-related lung AD. No significant financial relationships to disclose.
Mutational analysis of EGFR signaling pathway genes in lung adenocarcinomas
Authors: Marks J. L. , McLellan M. D. , Kasai Y. , Fulton L. A. , Mardis E. R. , Wilson R. K. , Zakowski M. F. , Rusch V. W. , Varmus H. E. , Pao W. 
Published: March 2020

7584 Background: About fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode signaling proteins in the EGFR signaling pathway, i.e. EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other somatic mutations that could contribute to lung tumorigenesis. Methods: We analyzed genomic DNA from 261 resected, clinically well-annotated non-small cell lung cancer (NSCLC) specimens. 90% of tumors were adenocarcinomas, and 10% were squamous cell carcinomas. The coding sequences of 39 genes, encoding proteins mostly in the EGFR signaling cascade and FGFR1–4, were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Results: First-pass analysis of 9 MB of tumor sequence identified 199 distinct types of genetic variants that differed from published reference sequences. At least one variant was found in each gene analyzed. In addition to 6 variants found in RAS genes, we further examined the 94 variants localized to exons encoding the kinase domain of respective proteins. We have thus far identified known somatic mutations in EGFR, KRAS, BRAF, and PIK3CA, in addition to a number of previously unreported single nucleotide polymorphisms (SNPs). Conclusions: Mutational profiling of genes that encode for components of the EGFR signaling pathway has revealed multiple putative genetic variants in lung adenocarcinomas. Further analysis of potential somatic mutations is in progress. No significant financial relationships to disclose.
The significant influence of smoking status and gender on the clinical outcome in the patients with non-small cell lung cancer: The large cohort based study
Authors: Kawaguchi T. , Tamura T. , Takada M. , Kusunoki Y. , Matsumura A. , Iuchi K. , Fukai S. , Komatsu H. , Tamura A. , Kawahara M. 
Published: March 2020

7587 Background: To determine retrospectively whether smoking status and gender affect the treatment outcome and survival for the Japanese patients with non-small cell lung cancer. Methods: Using the database from the lung cancer registry of the National Hospital Study Group for Lung Cancer between 1987 and 2002, detailed demographic and survival information were obtained. A total of 18,346 (70%) documented smokers including the former and the current and 7,755 (30%) documented never smokers with non-small cell lung cancer were studied. A minimal follow-up period was two years. Among them, the 2,546 patients with stage IV lung adenocarcinoma were studied to examine the relationship between the smoking status or the gender and the chemotherapy effect. Multivariate analysis was performed using the Cox regression method. Results: There was an increased percentage of female subjects (72%) in the never smokers, and an increased percentage of male subjects (90%) in the smokers. The never smokers had lower performance status (PS) and lower clinical stage than the smokers (p<0.001). There was an increased percentage of adenocarcinoma (83%) in the never smokers. Multivariate analysis for all the patients demonstrated that the lower clinical stage, the lower PS, younger age, female and never smoking was an independent good prognostic factor The hazard ratio (HR) and its 95% CI was 3.73 (3.58–3.88), 2.69 (2.59–2.79), 1.21 (1.17–1.25), 1.15 (1.09–1.20), and 1.08 (1.04–1.14), respectively. Multivariate analysis for the stage IV adenocarcinoma also showed that the lower PS, female and never smoking was an independent good prognostic factor. The HR and its 95% CI was 2.37 (2.15–2.61), 1.35 (1.19–1.52) and 1.17 (1.04–1.32) respectively. In the treatment of chemotherapy for the stage IV adenocarcinoma patients, the never smokers had higher disease control rates (CR+PR+SD) than the smokers (p=0.08) and the females had higher response rates (CR+PR) than the males (p=0.02). Conclusions: The never smokers and females with non-small cell lung cancer were found to have a distinct and improved clinical outcome. No significant financial relationships to disclose.
A randomized phase II study of 500 mg/m2 and 1,000 mg/m2 of pemetrexed in patients (pts) with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had prior chemotherapy
Authors: Ichinose Y. , Nakagawa K. , Tamura T. , Kubota K. , Yamamoto N. , Adachi S. , Nambu Y. , Nishiwaki Y. , Saijo N. , Fukuoka M. 
Published: March 2020

7590 Background: Pemetrexed (Pem) 500 mg/m2 (Pem 500) is currently the standard treatment for pts with locally advanced or metastatic NSCLC who had prior chemotherapy. In a recent Japanese phase I study with full vitamin supplementation, 1,000 mg/m2 was determined as the recommended dose. This study was to determine if Pem 1,000 mg/m2 (Pem 1,000) could lead to a better treatment outcome with an acceptable toxicity profile compared with Pem 500 in pts with NSCLC in a 2nd or 3rd line setting. Methods: Pts with PS 0–2, measurable, Stage III/IV NSCLC, who had previously received 1 or 2 chemotherapy regimens, were randomized to receive either Pem 500 or Pem 1,000 on day 1 of a 21-day cycle. The primary endpoint was overall response rate (ORR) based on the RECIST. Secondary endpoints included progression-free survival (PFS), duration of response (DR) and toxicity profile. The planned total sample size for the study was 214 pts. Results: From October 2004 to March 2006, 244 pts were enrolled at 28 centers, 226 pts were randomized and treated, and 216 pts were evaluable for efficacy. Baseline patient characteristics (Pem 500/Pem 1,000: 108/108) were: Males 63%/64%; median age 62/62 years (total range: 26–74); PS 0–1 94%/94%; Stage IV 81%/80%. The median number of treatment cycles completed on both arms was 3 (range 1–20+ for Pem 500 and 1–15+ for Pem 1,000). 11% of the Pem 500 pts and 6% of the Pem 1,000 pts completed at least 10 cycles. ORRs were 18.5% (90% CI: 12.6%-25.8%) for Pem 500 and 14.8% (90% CI: 9.5%- 21.6%) for Pem 1,000, and the respective disease control (PR+SD) rates were 55.6% and 46.3%. Median PFS with Pem 500 and Pem 1,000 was 3.0 and 2.4 months and median DR was 4.7 and 3.8 months, respectively. Grade 4 toxicities observed in more than 1% of pts were neutropenia (3.5% with Pem 500, 3.6% with Pem 1,000) and decreased lymphocyte count (2.6%, 1.8%). One drug related death for interstitial lung disease was reported with Pem 500. Conclusions: Pem 1,000 as well as Pem 500 showed remarkable efficacy outcomes with tolerable toxicity. Since Pem 1,000 showed treatment outcomes similar to Pem 500, this study supports the use of Pem 500 for Japanese pts with NSCLC in a 2nd or 3rd line setting. [Table: see text]
14–3-3 σ and checkpoint with forkhead and ring finger (CHFR) methylation in serum in erlotinib-treated non-small-cell lung cancer (NSCLC) patients (p) with EGFR mutations
Authors: Reguart N. , Porta R. , Provencio M. , Cardenal F. , Cuello M. , Ramirez J. L. , Mayo C. , Lianes P. , Taron M. , Rosell R. 
Published: March 2020

7600 Background: 14–3-3 proteins have 130 potential binding partners, including Cbl. 14–3-3 expression can prevent mutant EGFR binding to Cbl, impairing ubiquitination and endocytosis. 14–3-3s is frequently methylated in NSCLC; we hypothesized that in the presence of EGFR mutations, methylated 14–3-3s could permit the formation of the EGFR-Cbl complex. CHFR is a checkpoint that delays entry into metaphase in response to mitotic stress. Methods: 73 stage IV NSCLC p with EGFR exon 19 deletion or exon 21 L858R mutation received first- or second-line erlotinib single therapy. 14–3-3s and CHFR methylation was examined in the baseline serum of these p. Results: Median age, 63 (range, 26–83); females, 48 p (65.8%); Caucasian, 72 p, Asian, 1 p; never-smokers, 45 p, ex-smokers, 21 p, smokers, 7 p; adenocarcinoma, 64 p, large cell carcinoma, 9. PS: 0, 19 p, 1, 42 p, 2–3, 12 p. 14–3-3s was methylated in 39.7% and CHFR in 42.5% of p. No differences in p characteristics were observed according to methylation status. Complete response was observed in 11.1% of p, and partial response in 75.4%. Overall response was 86.5%. There was a trend toward a higher response rate in p with unmethylated CHFR (94.4% vs 76.6%; P=ns). Overall median time to progression (TTP) and survival (MS) have not been reached either in first- or second-line. However, when split according to methylation status, there was a trend toward better TTP and MS in both first- and second-line in p with methylated 14–3-3s. TTP in second-line in p with methylated 14–3-3s has not been reached, while it was 10.8 months (m) for p with unmethylated 14–3-3s (P=ns). TTP in second-line in p with methylated CHFR was 5.2 m but was not reached for p with unmethylated CHFR (P=0.05). Conclusions: Methylated 14–3-3s can permit Cbl binding to mutant EGFR and predict longer-lasting response to erlotinib in p with EGFR mutations. The precise role of CHFR warrants further research. Complete data will be presented. No significant financial relationships to disclose.
A phase II study of erlotinib treatment in advanced non-small cell lung cancer after failure of gefitinib: Is a clinical benefit still achievable?
Authors: Cho B. , Im C. , Choi H. , Shin S. , Sohn J. , Kim J. , Kim S. , Moon J. , Kim Y. 
Published: March 2020

7609 Background: To evaluate the efficacy and toxicity of erlotinib in patients (pts) with advanced NSCLC who had progression after treatment with gefitinib. Methods: The study included stage IIIB/IV recurrent or metastatic NSCLC pts who have received 2 or 3 prior chemotherapy regimens and showed documented disease progression during or within 4 months after treatment with gefitinib. Pts received erlotinib 150 mg daily until disease progression or unacceptable toxicity. We analyzed EGFR mutations and other genetic abnormality from available tumor samples. Results: Pts and disease characteristics (n = 21) included median age 56 years; number of prior chemotherapy regimens (two, n=10; three, n=11); male (n=10); adenocarcinoma (n=15); and smoking status (never, n=11; former, n=3; current, n=7). Among the 17 pts with tumor samples available, EGFR mutation were detected in 5 (29.4 %). The DCR and RR for all pts were 28.6% (95% CI, 16.7 to 59.6%) and 9.5% (95% CI, 5.6 to 19.8%). All responders were EGFR nonmutants, with long duration of disease control on prior gefitinib therapy (>180 days). The median duration of disease control was 125 days (95% CI, 73–261 days). The median progression-free survival and overall survival were 60 days (95% CI, 43–77 days) and 158 days (95% CI, 141–175 days), respectively. Pts who had SD on gefitinib showed significantly higher DCR (75% vs. 17.6% in non-SD pts, P= 0.050) and RR (50.0% vs. 0% in non-SD pts, P= 0.029). These pts also showed longer median PFS (140 vs. 37 days in non-SD pts, P= 0.005) and OS (not reached vs. 120 days in non-SD pts, P= 0.043). Among 17 pts with biomarker results available, EGFR nonmutants who had SD on gefitinib showed significantly higher DCR (100% vs. 21.4% in non-SD and/or EGFR mutants, P= 0.029) and RR (RR, 66.7 % vs. 0 % in non-SD and/or EGFR mutants, P= 0.022). Conclusions: Erlotinib seems to be a potential therapeutic option for the treatment of selected pts with gefitinib-nonresponsive, EGFR nonmutant, advanced NSCLC. No significant financial relationships to disclose. [Table: see text]
A phase II study of erlotinib (E) and bevacizumab (B) in patients (pts) with previously untreated stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: Groen H. J. , Smit E. F. , Dingemans A. 
Published: March 2020

7625 Background: In advanced NSCLC, E and B either as a single agent (E) or in combination with chemotherapy (B) show improved survival. Combinations of targeted agents may prove to be effective and better tolerated than chemotherapy. Methods: This is a multi-center 2-stage phase II study (Simon's optimal design; p0=40%, p1=60%, a=0.05, β=0.20). Primary endpoint is non-progression (NPR) at 6 weeks defined by CT and FDG-PET. If 7 or less of the first 16 pts had NPR, the study would close. If 24/46 pts had NPR at 6 wks treatment would be declared to have sufficient activity for further testing. Pts (PS 0–2) with advanced non- squamous NSCLC who had received no prior chemotherapy were treated with E (150 mg/day) plus B (15 mg/kg every 21 days) until PD or unacceptable toxicity. Results: Between 30/01/06 and 08/12/06, 38 pts were included; 33 pts are evaluable for safety, 32 for efficacy. M/F 17/16; median age 59 (range 34–80); stage IIIB/IV 8/25; PS 0/1/2: 16/13/4; smoking status: current/former/never 12/17/4. Treatment-related adverse events (all grades) were: rash (32%); diarrhea (18%); hemorrhage (2.6%); hypertension (2.7%); and thrombosis (2.7%). Grade 3/4 events were rash (9.9%); thrombosis (1.8%); diarrhea (0.9%); and hypertension (0.9%). Six pts withdrew early from the study: 2 due to toxicity (trombosis and mucositis); 2 due to death (1 death for unknown reason, 1 due to pneumonia); 2 for treatment unrelated reasons. Six pts had E dose reductions due to toxicity. Five pts had delays of less than 2 wks before receiving B. Percentage of NPR at 6 weeks is 75% (24/32). The median follow-up: 6.3 months (95% CI 3.5–9.2). Median TTP: 5.5 months (95% CI 1.9 - 9.2), At time of analysis 22/33 patients are alive, 17 patients are without PD. Conclusions: E + B regimen is well tolerated, with a low rate of grade 3/4 adverse events and no unexpected toxicities. The primary endpoint has already been met. Updated results including correlative imaging studies will be presented. No significant financial relationships to disclose.
Observing patients with advanced non-small cell lung cancer (NSCLC): An overview of real world treatments and outcomes in Europe
Authors: Bischoff H. G. , Anderson H. , van den Borne B. , Langer F. , Leschinger M. I. , Moneley C. , Pimentel F. , Riska H. , Thatcher N. , Thomas M. 
Published: March 2020

7626 Background: ACTION (Assessment of Costs and ouTcomes of chemotherapy In an Observational setting in patients with advanced NSCLC) is a prospective, pan-European observational study. The objective of ACTION is to describe advanced NSCLC treatment in routine clinical practice. Methods: Chemonaive patients (pts) aged = 18 yrs with stage IIIb/IV NSCLC were observed for 18 months from presentation for initiation of chemotherapy (CT). All pt care, including CT given, was at the discretion of the pt/physician. Pts were excluded if participating in a clinical trial. Results: 975 pts [Germany (571), UK (193), Finland (99), Netherlands (76), Portugal (36)] were enrolled from April 2003 to September 2004 and observations completed June 2006. Median age was 65 yrs (32–90) with 28.3% of pts aged =70 yrs; 71.3% were male; 65.2% had stage IV disease. WHO performance status (PS) was 0/1 (86.2%), 2 (10.0%), 3/4 (3.8%). Of 487 pts who experienced weight loss, 172 (33.4%) lost >10% body weight in 4 weeks prior to start of CT. First-line CT given: gemcitabine (gem) 10.3%, vinorelbine (vin) 4.3%, gem+platinum 45.0%, vin+platinum 14.6%, taxane+platinum 11.7%, other 14.2%. Complete response (CR) to first-line CT was observed in 1.8% of pts, partial response (PR) 37.9%, stable disease (SD) 28.5%, progressive disease (PD) 17.8%, unknown 13.8%. Second-line CT was planned for 29.2% (285) pts. Median time from initiation of 1st-line to initiation of 2nd-line CT was 5.8 months. Median age was 62 yrs (32–84); 69.8% were male; WHO PS at initiation of 2nd line CT: 0/1 (79%), 2 (17%), 3/4 (4%). Best response to 2nd-line CT: CR 0.4%, PR 9.1%, SD 19.3%, PD 48.8%, unknown 14.3%. Unadjusted median survival time for all pts: 9.3 months (95% CI 8.6–10.3). Overall estimated 1-yr survival was 39.5%. Conclusions: ACTION was the first large-scale observational study in pts with advanced NSCLC in Europe. Overall response rates and survival were consistent with clinical trial results, even though approximately one- third of pts enrolled may have been excluded from clinical trials on the basis of their baseline demographics. No significant financial relationships to disclose.
Impact of second hand smoke (SHS) exposure on the likelihood of mutations in epidermal growth factor receptor (EGFR) gene in patients with non-small cell lung cancer (NSCLC) who had never smoked
Authors: Lee Y. , Cho B. , Choi H. , Sohn J. , Kang S. , Kim S. , Bae S. , Ryoo H. , Kim J. 
Published: March 2020

7633 Background: The presence of EGFR mutations in NSCLC has strongly associated with never-smoking history. SHS exposure is associated with higher risk of lung cancer. We have conducted this study to evaluate the association between SHS exposure and likelihood of mutations in EGFR gene in NSCLC patients who had never smoked. Methods: SHS exposure information from a total of 93 never smokers (<100 lifetime cigarettes) with newly diagnosed primary NSCLC was obtained using a standardized questionnaire. Patients were asked whether they were regularly exposed to SHS at home or work places, respectively. Nucleotide sequencing of the kinase domain of EGFR (exons 18 to 21) was performed using nested PCR amplification of individual exons. Results: Patient characteristics (n=93) included median age 57 years; female (n= 81); adenocarcinoma ± bronchoalveolar carcinoma (n= 82); EGFR mutation (1 mutation in exon 18 G719, 31 in-frame deletions in exon 19, 10 mutations in codon 858 in exon 21). Fifty-two (55.9%) of the patients reported having been exposed to SHS, including 46 (49.5%) exposed at home and 13 (14.0%) exposed at work. The incidence of EGFR mutations was not associated with female gender and adenocarcinoma histology. Patients with SHS exposure showed a trend towards lower incidence of EGFR mutations (36.5% vs. 56.1%, P= 0.060) and a significantly lower incidence of deletion mutations in exon 19 (57.9% vs. 87.0%, P= 0.033). When the incidence of EGFR mutations was compared, no difference between SHS exposure at home and work places was found. No significant differences were found for other clinicopathological factors according to SHS exposure. Conclusions: Our results indicate weak evidence of relationship between likelihood of mutation in EGFR gene and SHS exposure. The deletion mutations in exon 19 were significantly less common in patients with SHS exposure. No significant financial relationships to disclose.