bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective analysis of the epidermal growth factor receptor gene mutations in non-small cell lung cancer in Japan
Authors: Morikawa N. , Inoue A. , Suzuki T. , Fukuhara T. , Suzuki S. , Kondo T. , Moriya T. , Saijo Y. , Nukiwa T. 
Published: March 2020

7077 Background: Previous clinical trials have revealed that gefitinib is more likely to be effective in non-small cell lung cancer (NSCLC) with activating somatic mutations of epidermal growth factor receptor (EGFR). Most of those reports evaluated NSCLC patients who had post-operative recurrence and then received gefitinib retrospectively using their surgical specimens. However, many NSCLC patients are inoperable at diagnosis. Thus we conducted this study to examine EGFR mutation status by diagnostic tumor samples before gefitinib treatment and investigate the correlation between EGFR mutation and the efficacy of gefitinib. Methods: We prospectively evaluated various tumor samples obtained from NSCLC patients who had never received gefitinib for EGFR mutations in exon 18–23. For patients treated with gefitinib after the examination of EGFR mutations, the response to gefitinib was also evaluated. Results: From June 2004 to November 2005, 91 patients with advanced or post-operative recurrent NSCLC enrolled onto this study and 104 tumor samples were obtained from transbronchial biopsies, effusions, as well as surgical specimens. Thirty-two mutations including deletions in exon 19 in 23 patients and L858R in 9 patients were detected among those 91 patients; 30 in 81 adenocaricinoma, 1 in 2 adenosquamous cell carcinoma, and 1 in 5 large cell carcinoma. The mutations were found more frequently in female (51.9%) than male (12.8%), in never smoker (52.0%) than smoker (14.6%). Response rate of gefitinib in patients with EGFR mutations was 65.0% (13 of 20) compared to 37.5% (3 of 8) in patients without mutations. Among 7 patients with EGFR mutations who were examined multiple tumor samples, 3 had the discrepancy of EGFR gene status between different samples obtained at different time points, suggesting genetic heterogeneity of their tumors. The EGFR status of the most recent samples is likely to be correlated to the response to gefitinib. Conclusions: The EGFR mutation analysis was possible not only from surgical specimens but also from daily available diagnostic samples. For patients with EGFR mutations, gefitinib could achieve a promising high response rate. We propose to examine the most recent tumor samples to predict the sensitivity to gefitinib reliably. No significant financial relationships to disclose.
Dose intensive chemotherapy (Cx) in advanced thymoma: Initial report of Japan Clinical Oncology Group trials (JCOG 9605 and 9606)
Authors: Kunitoh H. , Tamura T. , Fukuda H. , Nakagawa K. , Takeda K. , Nishiwaki Y. , Katagami N. , Yokoyama A. , Noda K. , Saijo N. 
Published: March 2020

7080 Background: Thymoma is considered to be sensitive to Cx. Dose intensive Cx might well be suitable for such tumors, especially in combination with local therapy. Objectives of the trials were to evaluate the safety and efficacy of the dose intensive CODE (cisplatin[C]- vincristine[O]- doxorubicin[D]- etoposide[E]) Cx in thymoma. The primary endpoint was progression-free survival time (PFS). Methods: Patients (pts) with 15–70 years of age with histologically documented Cx-naïve thymoma with stage IVa/IVb disease (JCOG 9605) or unresectable stage III disease (JCOG 9606) were eligible. Tumors of other histology, such as thymic carcinoma, carcinoid or lymphoma were excluded; pts were to have ample organ function and ECOG PS of 0–2. Myasthenia was allowed. Signed consent form was obtained. Pts received CODE Cx of 9 weeks (w): C 25 mg/m2 Cx day 1 on each w1–9; O 1mg/m2 d1 on w1,2,4,6,8; D 40 mg/m2 d1 and E 80 mg/m2 d1,2,3 on w 1,3,5,7,9. Cx courses were supported by GCSF. Steroids were used only for antiemesis. Those with stage III disease (JCOG 9606) went on to surgery, if judged to be resectable, and post-operative radiotherapy (RT) of 48Gy; those with unresectable disease received 60Gy RT. Results: From Jul./97 to Apr./05, 53 pts were entered to the studies. Five were found ineligible because of different histology. Pt characteristics and response to the Cx were summarized in the table . Toxicity of the Cx was mainly hematologic and generally well tolerated, with no toxic death; 70% of the pts completed planned 9 weeks. Thirteen pts in JCOG 9606 (stage III) received thoracotomy; tumor was resected in 11 pts, completely in 9 (39% of enrolled pts). Pathologic CR was observed in 3. The median PFS was 9.5m for stage IV and 4.5 y for stage III diseases. Overall survival at 2 & 5 yrs were 82% & 57% for stage IV and 96% & 77% for stage III pts. Conclusions: Short-course, dose intensive Cx was active against thymoma. Although it does not seem to bring long PFS in stage IV pts, it could improve resectability in limited disease. [Table: see text] No significant financial relationships to disclose.
Phase II study of weekly cisplatin, etoposide and irinotecan (PE/CPT) for refractory relapsed small cell lung cancer (SCLC)
Authors: Kim Y. , Goto K. , Nishiwaki Y. , Kubota K. , Omatsu H. , Tamura T. , Ohe Y. , Kunitoh H. , Sekine I. , Yamamoto N. , Saijo N. 
Published: March 2020

7088 Background: There is no standard treatment for relapsed SCLC. Irinotecan and etoposide has been studied in several phase II trials as active agents for relapsed SCLC. We reported the efficacy and tolerability of irinotecan combined with weekly cisplatin and etoposide (PE) in patients (pts) with sensitive relapsed SCLC (Goto, et al. Br J Cancer 2005). Methods: We conducted a phase II study to evaluate the efficacy and toxicity of PE/CPT regimen in pts with refractory relapsed SCLC, who had relapsed within 8 weeks after completion of first-line therapy. Pts must have measurable or assessable disease, age of 75 years or younger, performance status of 0 to 2 (ECOG), and adequate organ function. PE/CPT regimen consisted of cisplatin 25 mg/m2 on day 1 at one-week intervals for 9 weeks (at least 6 weeks), etoposide 60 mg/m2 on days 1–3 on week 1, 3, 5, 7, 9 (at least on week 1, 3, 5), and irinotecan 90 mg/m2 on day 1 on weeks 2, 4, 6, 8 (at least on week 2, 4, 6). After day 1 on week 2, G-CSF was administered on days when cytotoxic drugs were not given. Results: From May 2000 to January 2005, 30 pts were enrolled in this study. Pt characteristics were median age 64 years (range 44–75); 23 male and 7 female; 3 LD and 27 ED. Prior chemotherapy included PE in 13 pts, cisplatin and irinotecan in 7, carboplatin and etoposide in 5, and others in 5. 23 pts (77%) completed 6 or more weeks of chemotherapy. 2 CR and 19 PR were observed and the overall response rate was 70% (95% CI 50.6–85.3%). Grade 3/4 neutropenia, anemia and thrombocytopenia were observed in 60%, 73% and 47%, respectively. Grade 3/4 diarrhea was observed in only 7%. Coclusions: PE/CPT regimen was active and well tolerated for refractory relapsed SCLC. No significant financial relationships to disclose.
Gemcitabine (G) plus carboplatin (C) at AUC 5 demonstrates reduced grade 4 thrombocytopenia rate compared to AUC 5.5 in first line therapy of patients with advanced stage NSCLC
Authors: Treat J. , Belani C. P. , Schiller J. , Monberg M. J. , Cunneen J. , Chen R. , Ye Z. , Obasaju C. K. 
Published: March 2020

7130 Background: GC is a commonly used regimen in first-line therapy of advanced stage NSCLC. Various dosing of carboplatin in the GC regimen produces different toxicity profiles. This report summarizes three recent large clinical trials, including the Coalition Trial, using GC regimens that had comparable efficacy to other modern doublets. Methods: Three trials using GC as first-line treatment for advanced NSCLC with recent best response and toxicity data were selected. Pt populations were similarly defined, including measurable or evaluable Stage IIIB (with pleural effusion) or IV disease. All utilized similar 21-d regimens of G 1000 mg/m2 d 1,8 and C AUC 5.5 or 5.0 d1. Results: Despite a grade 4-thrombocytopenia rate of 12% in Trial 1 (Coalition) there was no difference in serious bleeding events compared to the other arms (paclitaxel/carboplatin and paclitaxel/gemcitabine). Discussion: In these three trials, 1126 pts with advanced NSCLC were treated with first-line GC. This database of 743 patients assessed for safety suggests that GC AUC 5 results in a 4.7% (95% CI: 3.3–6.5%) grade 4-thrombocytopenia rate with similar anti-tumor efficacy. The regimen of G 1000 mg/m2 on d1, 8 with C AUC 5 on d1 of a 21-d cycle may be optimal for treatment of advanced NSCLC. [Table: see text] [Table: see text]
Dual blockade of epidermal growth factor receptor (EGFR) and cyclooxygenase 2 (COX 2) may be dependent upon the EGFR mutational status in non-small cell lung cancer (NSCLC) cell lines
Authors: Gadgeel S. M. , Ali S. , Philip P. , Wozniak A. , Sarkar F. 
Published: March 2020

7170 Background: Recent data has shown that the benefit of EGFR TKIs (tyrosine kinase inhibitors) in NSCLC is in patients with tumors that have EGFR mutations and /or gene amplification. Even among these patients, the median survival with EGFR TKIs is only 22 months. Pre-clinical data has shown that dual blockade of EGFR and COX 2 pathways may be beneficial. A recent clinical trial conducted at our center suggested that this combination primarily impacted NSCLC tumors that have the EGFR biomarkers. We therefore hypothesized that the EGFR biomarker status determines the outcome of dual blockade of these pathways in NSCLC. Methods: Three different cell lines with varying biomarker status and sensitivities to EGFR TKIs were used- H3255 (L858R; gene amplified), H1650 (del E746-A750; gene amplified), H1781 (wild type). Cells were treated with erlotinib, EGFR TKI- 10nM-100nM or celecoxib, COX 2 inhibitor- 5 μM and with the combination of two drugs. Cell survival was determined by a standard MTT assay and apoptosis was measured by ELISA method. Western blot analysis was conducted to assess COX 2, EGFR and pAkt levels. Results: Celecoxib by itself had no effects on any of the cell lines. Erlotinib showed a concentration dependent growth inhibition of both H3255 (IC50–41.72nM; surviving fraction at 50nM was 52%) and H1650 (IC50 > 100nM; Surviving fraction at 50nM was 70%) but had no effect on H1781. Celecoxib added to erlotinib significantly enhanced the growth inhibition of H3255 (p = 0.001) and H1650 (p = 0.014) as well as apoptosis (H3255- p = 0.016; H1650- p = 0.011) at all concentrations of erlotinib but had no effect in H1781 cells. In western Blot analysis the combination significantly reduced levels of COX-2, EGFR and pAkt compared to baseline and either agent alone in H3255 cells. Conclusions: The addition of celecoxib to erlotinib has a differential effect in NSCLC cell lines based on their EGFR biomarker status. This beneficial effect of celecoxib addition may be through improved inhibition of each pathway. [Table: see text]
EGFR mutation and intron 1 CA repeat polymorphism as predictive markers of gefitinib responsiveness in non-small cell lung cancer (NSCLC)
Authors: Han S. W. , Kim T. Y. , Lee K. W. , Oh D. Y. , Lee S. H. , Kim D. W. , Chung D. H. , Im S. A. , Heo D. S. , Bang Y. J. 
Published: March 2020

7173 Background: EGFR mutation is significantly associated with objective response and prolonged survival in NSCLC patients treated with gefitinib. However, presence of mutant nonresponses and nonmutant responses mandates investigation of other molecular markers for more effective prediction of gefitinib sensitivity in NSCLC. It is unclear whether low CA repeat number in EGFR intron 1 has such a predictive role. Methods: Advanced NSCLC patients received gefitinib 250mg/day. EGFR mutation in exons 18 - 21 were identified by direct sequencing of PCR products of DNA extracted from archival paraffin embedded tissue. Number of CA repeat in intron 1 of EGFR was determined by GeneScan with tumoral DNA. Baseline characteristics, mutational status, CA repeat number and efficacy of gefitinib were analyzed in respect to each other. Results: To date, 73 patients were evaluable for EGFR mutation, CA repeat and gefitinib responsiveness. 14 patients (19.2%) harbored EGFR mutation (7 deletion in exon 19, 4 L858R, 1 L861Q, 1 G719A, and 1 insertion in exon 20). Most common CA repeat genotype was 20/20 repeat (31 patients) followed by 16/20 repeat (15 patients). Patients were classified as having either low CA repeat (sum of both allele ≤ 37 repeats) or high CA repeat (≥ 38 repeats). 34 patients (46.6%) had low repeat, whereas 39 patients (53.4%) had high repeat. Patients with EGFR mutation showed better objective response (response rate [RR] 57.1% vs. 10.2% in wild type [WT], p < 0.001), time-to-progression (TTP) (p = 0.031, median 5.1 vs. 1.9 months in WT), and overall survival (OS) (p = 0.051, median14.5 vs. 7.4 months in WT). In the whole study population, low CA repeat was not associated with RR (p = 0.38), TTP (p = 0.15), or OS (p = 0.51). However, in the 59 patients without an EGFR mutation, patients with low CA repeat tended to have better objective response (RR 17.2% [5/29] in low repeat vs. 3.3% [1/30] in high repeat, p = 0.10) and significantly better TTP (p = 0.019, median 2.2 months in low repeat vs. 1.2 months in high repeat). Conclusions: Our results suggest that low number of CA repeats in EGFR intron 1 may have possible role in prediction of gefitinib responsiveness when analyzed together with EGFR mutational status. [Table: see text]
Epidermal growth factor receptor (EGFR) mutation testing in non-small cell lung cancer (NSCLC) patients (pts)
Authors: Sequist L. V. , Joshi V. A. , Jänne P. A. , Fidias P. , Muzikansky A. , Meyerson M. , Haber D. A. , Kucherlapati R. , Johnson B. E. , Lynch T. J. 
Published: March 2020

7177 Background: Somatic mutations in EGFR are associated with response to therapy and prolonged overall survival (OS) of NSCLC pts treated with tyrosine kinase inhibitors (TKI). We began EGFR mutation screening in 2004 with a CLIA certified test. We determined the characteristics of pts tested, EGFR mutations identified, and analyzed response to therapy and OS. Methods: We performed a retrospective cohort study of all NSCLC pts referred for EGFR testing over 1 year. Samples underwent direct sequence analysis of EGFR exons 18–24. We used multivariable logistic regression models to examine associations between mutation and pt characteristics. We used chi-square tests to assess differences in response to therapy by EGFR status and analyzed OS with Cox proportional hazard models, adjusting for age, gender and stage. Results: We screened 269 NSCLC pts for EGFR mutations, including 188 (71%) with unresectable disease and 245 (91%) with adenocarcinoma. Mutations were identified in 62 (23%) pts. 15 samples (6%) yielded insufficient DNA for testing. Mutation was more likely in the 59 never-smokers compared to the 185 ever-smokers [odds ratio (OR) 4.8, 95% confidence interval (CI) 2.5–9.2]. Each added pack-year of smoking history lowered the odds of mutation by 5% (OR 0.95, 95% CI 0.94–0.97). Mutation was more likely in the 12 Asians than in the 212 of all other races (OR 3.7, 95% CI 1.1–12.0). In multivariable analyses, pack-years of smoking remained predictive of mutation (OR 0.96, 95% CI 0.94–0.99). Among 44 pts with unresectable disease undergoing subsequent TKI therapy, the 20 EGFR positive pts had an increased response rate (RR) compared to the 24 EGFR negative pts (60% v. 4%, p < 0.0001). In 27 pts given subsequent chemotherapy, RR was 33% and did not differ by EGFR status. Median follow-up was 9.8 months (mo) (range 0.2–135.8 mo). Among pts with unresectable disease, median OS is estimated to be 22.7 mo in EGFR negative pts and is not reached in EGFR positive pts (HR 0.22, 95% CI 0.80–0.63). Conclusions: Sequencing EGFR for somatic mutations is feasible in routine care of NSCLC pts. 23% of screened pts tested positive, and never smoking was the strongest predictor of mutation. Among patients with unresectable disease, EGFR mutation was associated with an increased RR to TKI therapy and OS. [Table: see text]
Prognostic significance of immunohistochemical markers in non-small cell lung cancer
Authors: Renouf D. , Wood-Baker R. , Ionescu D. , Leung S. , Massoudi H. , Gilks B. , Laskin J. 
Published: March 2020

7211 Background: The purpose of this study is to use a large patient population to identify immunohistochemical (IHC) biomarkers to enable improved prognostication in patients with non-small cell lung cancer (NSCLC). Methods: A tissue microarray was constructed using duplicate 0.6 mm cores of formalin-fixed paraffin embedded tissue blocks from 609 patients with NSCLC. IHC was used to detect 11 biomarkers including EGFR, HER2, HER3, p53, p63, Bcl-1, Bcl-2, TTF-1, CEA, Ch, and SNP. A clinical database was created prospectively at the time of tissue collection. Survival outcomes were obtained from a Provincial Cancer Registry database. Results: Male to female ratio was 400:209; median age 63yrs (range 35–82); median survival 3.5yrs (mean 5.7). All specimens were reviewed: 243 adenocarcinoma (ACA), 272 squamous cell carcinoma (SCC), 35 large cell carcinoma, 32 non-small cell carcinoma NOS, and 6 other (giant cell carcinoma). 21 patients with other histologies were excluded. Survival data for 535 cases was available. As of June 2005, 429 patients (80%) had died; of these 286 (54%) died of lung cancer, 117 (22%) died of other known causes, and for 26 (5%) the cause of death was not available. Bcl-2 (p = 0.007) was the only biomarker to predict better overall survival (OS). Bcl-2 (p = 0.021) and p63 (p = 0.025) were significant for disease specific survival (DSS) in all NSCLC. Analysis of the subgroups indicated that p63 was significant (p = 0.039) for DSS in squamous cell carcinoma (SCC) but not for adenocarcinoma (ACA) (p = 0.81). Bcl-2 was not significant for DSS in either subgroup (p = 0.28 for SCC, p = 0.112 for ACA). EGFR expression was associated with improved DSS in SCC (p = 0.012) but not for ACA. Co-expression of EGFR-HER3 was more likely in SCC then in ACA (p = 0.033). There was no correlation between outcome and any combination or clustering of biomarkers. Conclusions: The biomarkers p63 and Bcl-2 are predictive of DSS in NSCLC. EGFR expression is predictive of DSS in SCC. Sub-classification of NSCLC by histopathology is important as the relevance of some biomarkers (EGFR) would be lost if pooled. p63, Bcl-2, and EGFR may be used as prognostic markers in patients with NSCLC. Co-expression of EGFR-HER3 is more likely in SCC then in ACA. This may help explain the differential response to EGFR inhibitors in SCC versus ACA. No significant financial relationships to disclose.
The role of F-18 FDG PET within randomized multicenter phase III trials for multi-modality treatment of non-small cell lung cancer stage III
Authors: Schmuecking M. , Schneider C. P. , Scheithauer M. , Presselt N. , Leonhardi J. , Hoeffken K. , Baum R. P. , Wendt T. G. , Mueller K. M. , Bonnet R. 
Published: March 2020

7213 Background: To evaluate the role of F-18 FDG PET within clinical trials for staging, therapy management, molecular radiation treatment planning (MRTP), early therapy response and its effect on survival as compared to histopathologic tumor response, findings in 156 patients with NSCLC are analyzed prospectively in a randomized, open, multicenter phase III trial (LUCAS-MD). Methods: Inclusion criteria: histologically confirmed NSCLC stage IIIA/IIIB. ECOG PS 0–1, adequate hematologic, renal, hepatic function. Primary end points: OS, DFS. Secondary end points: TTP, QoL, RR. Neoadjuvant treatment: 2–3 cycles of chemotherapy with paclitaxel/carboplatin and a block of chemoradiation (45Gy, 1.5Gy b.i.d., concomitant paclitaxel/carboplatin) followed by surgery. Randomization: early vs. late chemoradiation. Staging: PET in addition to CT and/or MRI after randomization. Second PET after completion of neoadjuvant therapy. Assessment of standardized uptake values (SUV) in primary tumor (PT) and all metastatic lymph nodes (LN). Documentation of involved LN as detected by PET and LN sampling during surgery according to Naruke/ATS-LCSG classification. Image fusion of PET with CT data followed by molecular radiation treatment planning. Evaluation of histological regression grade (RG) and correlation with PET for PT and each LN. Statistical analyses: Wilcoxon-, chi-square-, Mantel-Haenszel-test, Kaplan-Meier-method, multivariate Cox-regression. Results: Upstaging in 11 pts. due to distant metastases. Downstaging in 5 pts. Complete vs. incomplete metabolic remission after 48 months: 60% vs. 34% (p = 0.0058). RG III/IIb (no/less than 10% of vital tumor cells) vs. RGIIa/I (more than 10% vital tumor cells) after 48 months: 59% vs. 27% (p = 0.0006). Multivariate Cox-regression for SUV: p > 0.05. Statistical power of the tests: 75% so far. Due to PET findings, the planning target volume for MRTP was reduced substantially in 23%, increased in 10%. Conclusions: Integration of PET in clinical trials enables a more accurate MRTP and therapy management (10% stage migration). Histological regression grade correlates well with metabolic remission as detected by PET. F-18 FDG PET may predict (long term) therapeutic outcome in stage III NSCLC. No significant financial relationships to disclose.
Low expression of bax predicts poor prognosis in resected non-small cell lung cancer patients with nonsquamous histology
Authors: Choi J. , Lim H. , Kang S. , Jung Y. , Kim H. , Oh Y. , Choi H. , Hwang S. , Park K. , Han J. 
Published: March 2020

7215 Background: Both p53 and bax proteins are known to promote apoptosis, and decreased expression of bax and mutation of p53 have been associated with poor progosis in several malignancies. Methods: We investigated the expression of these proteins and their association with clinicopatholgic characteristics including disease-free survival (DFS) and overall survival (OS) in 209 non-small cell lung cancer (NSCLC) patients (pts) who underwent surgical resection (stage I: 97, II: 46, IIIA: 45, IIIB: 17, IV: 4) using immunohistochemistry. Ninety-one pts (44%) received adjuvant treatment (chemotherapy: 9, radiotherapy: 24, both: 58). Results: While 82 pts (39%) had overexpression of p53 (>50% tumor cells positive), low expression of bax (no or weak staining in intensity) was observed in 159 pts (76%), which was significantly associated with male gender (p < 0.0001), squamous cell carcinoma (p < 0.0001), and overexpression of p53 (p = 0.028). With a median follow-up of 65 months (34–133 months) in survivors, 5-year DFS and OS of total pts were 38% and 46%, respectively, excluding 7 deaths from postoperative complications. Neither overexpression of p53 nor low expression of bax was associated with poor DFS (p = 0.728, p = 0.335) and OS (p = 0.927, p = 0.261). However, in pts with nonsquamous histology (111 pts), low expression of bax was significant independent predictor of poor DFS (p = 0.004) in addition to advanced stage (p < 0.0001) and large primary tumor size (>4 cm) (p = 0.005) in multivariate analysis. Furthermore, low expression of bax was associated with poor OS (p = 0.048) along with advanced stage (p = 0.01) and pneumonectomy (p = 0.003). Conclusions: Low expession of bax was significantly associated with poor prognosis in NSCLC pts with nonsquamous histology. No significant financial relationships to disclose.