bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical antitumor activity of oral silibinin-meglumine in combination with erlotinib or gefitinib in the treatment of erlotinib- and gefitinib-resistant EGFR-mutant NSCLC mouse xenografts.
Authors: Bosch-Barrera Joaquim , Cufi Silvia , Vazquez-Martin Alejandro , Oliveras-Ferraros Cristina , Corominas-Faja Bruna , Bonavia Rosa , Visa Joana , Martin-Castillo Begoña , Barrajon-Catalan Enrique , Carcereny Enric , Micol Vicente , Menendez Javier A. 
Published: March 2020

e19003 Background: Silibinin (SLB), a bioactive flavonolignan isolated from the dried fruits of milk thistle (Silybum marianum), suppresses the resistance to erlotinib (ERL) caused by the EGFR T790M mutation in NSCLC xenograft models. Poor water solubility and low bioavailability might severely limit the efficacy of SLB. The ability of SLB to overcome ERL resistance attributed to mechanisms other than the second-site EGFR mutations remains completely unexplored. Methods: Using PC-9 cells harboring the ERL-sensitizing EGFR exon 19-mutation ΔE746-A750, we developed ERL-refractory derivatives (PC-9 ERL-R) that lacked EGFR T790M mutation. An oral formulation of milk thistle extract enriched (30%) with a water-soluble form of SLB complexed with the excipient amino-sugar meglumine (SLB-m) was explored for its ability to inhibit the growth of PC-9 ERL-R xenografts. Results: In the absence of second-site EGFR mutations or the alternative activation of MET or AXL, acquired cross-resistance to ERL and GEF correlated with enhanced epithelial-to-mesenchymal transition (EMT) features. Single-agent SLB-m significantly decreased the overall tumor volumes of PC-9 ERL-R xenografts, which exhibited enhanced engraftment and faster growth compared with the ERL-/GEF-sensitive PC-9 parental xenografts. Combination treatment with ERL + SLB-m or GEF + SLB-m significantly suppressed tumor growth (> 90%) compared with single-agent treatment. The SLB-m treatment fully inhibited the development of an EMT phenotype in the ERL-/GEF-refractory cells in vitro. Systemic SLB-m treatment significantly affected the expression of EMT-related transcription factors in the ERL-/GEF-refractory xenografts. Conclusions: The oral administration of SLB-m delays tumor progression in ERL-/GEF-refractory EGFR-mutant NSCLC mouse xenografts. Given that the EMT phenomenon is required by a multiplicity of mechanisms of acquired resistance mechanisms to ERL, our data might facilitate the design of clinical trials to test the administration of SLB-m in combination with ERL or GEF in patients with EGFR-mutated tumors that progress to these drugs.
Dynamic treatment regimen analysis to determine which treatment sequence can prolong survival of NSCLC patients.
Authors: Koba Taro , Imamura Fumio , Morita Satoshi , Mori Masahide , Komuta Kiyoshi , Kijima Takashi , Namba Yoshinobu , Nishino Kazumi , Yamamoto Suguru , Takahashi Ryo , Nakazawa Yukie , Minami Seigo , Ogata Yoshitaka , Kumanogoh Atsushi 
Published: March 2020

e19010^ Background: We often experience the re-challenge of EGFR-TKI on practice. However, it has not been reported which treatment sequence for EGFR-TKI re-challenge will contributes to long-term survival of NSCLC patients. Methods: We extracted information from retrospective cohort of advanced NSCLC patients with the following inclusion criteria: 1) Japanese patients who were diagnosed by October 2010 and treated with gefitinib after July 2002. 2) Performance status (PS) 0-2. 3) PR, CR, or long SD (6 months or more) by gefitinib. 4) Patients who had not received curative surgical operation or radiation therapy. The primary objective was to evaluate the effects of treatment histories on Overall Survival (OS). We also conducted a “Dynamic Treatment Regimen Analysis (DTRA)”. DTRA can be used to compare multiple treatment strategies/sequences in terms of time-to-event data like overall survival time. Results: A total of 335 NSCLC patient details were extracted. Sixty five patients experienced gefitinib re-challenge. There was a statistical difference in OS between gefitinib re-challenge group and non re-challenge group (median OS was 1272 days vs 774 days; p<0.001). We confirmed this result using DTRA, “Gefitnib-Singlet chemo-Gefitinib” treatment sequence extended survival most out of all treatment sequence. Conclusions: This study suggests that gefitinib re-challenge may have significant affects on OS in long survivors after responding gefitinib treatment. Clinical trial information: UMIN000006913. [Table: see text]
Which do patients prefer as a first-line therapy, EGFR-TKI or chemotherapy, if they have NSCLC harboring EGFR mutation? A Vignettes study (LOGIK0903).
Authors: Sasaki Jiichiro , Tokunaga Shoji , Suetsugu Takayuki , Ebi Noriyuki , Fukuda Minoru , Nagata Nobuhiko , Takayama Koichi , Tsuruta Nobuko , Ishida Masayuki , Nishida Chinatsu , Kashiwabara Kosuke , Akamine Shinji , Komiya Kazutoshi , Nakagaki Noriaki , Kishi Hiroto , Seto Takashi , Saeki Sho , Uchitomi Yosuke , Ichinose Yukito ,   Lung Oncology Group in Kyushu, Japan
Published: March 2020

e19016 Background: Treatment decision-making is associated with potential decisional conflict of patients. Aim of this study was to determine the preferences of advanced NSCLC patients for EGFR-TKI or chemotherapy as first-line therapy if they were in the situation of having a lung cancer harboring EGFR mutation, and to investigate the variables considered important to that preference. Methods: Three vignettes were designed to assess the patients’, the physicians’ or medical staff members’ preferences for treatment decision-making and the reasons classified into five category such as “evidence level”, “type of drug administration”, “therapeutic efficacy”, “adverse events”, and “influence to ordinary life” behind the decision. HADS, FACT-L and characteristics of participants including gender, age, and performance status (PS) are also investigated in this analysis. Results: Total 377 individuals containing 100 patients, 100 physicians, and 177 medical staff members were analyzed in this study, and 322 participants (85.4%) preferred to EGFR-TKI than chemotherapy as a first-line therapy. Preference rate of EGFR-TKI in patients was statistically significantly lower than those in physicians and medical staffs, 73%, 88% and 91%, respectively. Among the reasons we investigated, “therapeutic efficacy” was the only marginal significant reason for preference in patients (odds ratio: 3.88, p=0.06). In addition to “therapeutic efficacy”, “type of drug administration” and “influence to ordinary life” was the significant reasons for their preference in physicians (odds ratio: 11.57, 22.57 and 20.5, respectively). In pre-planned analysis, we found the difference of value between the patients and the physicians in “influence to ordinary life”. Conclusions: If the patients have an advanced lung cancer with EGFR mutation, they may prefer EGFR-TKI as a first-line therapy to chemotherapy as well as physicians and medical staff members. However the reasons of those preferences among them may be different. We should consider continuation of patients’ ordinary life when we discuss about treatment decision-making with patients. Clinical trial information: UMIN000003532.
Phase II, open-label study of erlotinib (ERL) in patients with NSCLC with activating mutations of the EGFR identified on tissue samples, plasma DNA, and CTC-trigger.
Authors: Crino Lucio , Santoro Armando , Chella Antonio , Barbieri Fausto , Venturino Paola , Marchetti Antonio , Milella Michele , Brandes Ariela , De Pas Tommaso 
Published: March 2020

e19020 Background: Patients (pts) with advanced NSCLC and activating mutations of EGFR represent a biologically distinct disease that shows exquisite sensitivity to the reversible EGFR-TK inhibitors (TKIs) as ERL, demonstrated in phase III randomized studies. Unfortunately, tumor tissue needed for mutation analysis is in some cases insufficient for an accurate molecular characterization of the tumor before treatment and re-biopsies after treatment are challenging. Therefore it is crucial to develop new diagnostics techniques. Methods: Pts with histologically or cytologically confirmed stage IIIB/IV NSCLC, previously untreated with chemotherapy who present activating mutations of EGFR received ERL 150 mg/d until PD. The primary endpoint was 12-month PFS. Secondary endpoints included: ORR; OS; correlation between EGFR testing results obtained from basal tumor biopsies, from circulating tumor cells (CTC), from plasma DNA and by immunoistochemical detection; primary and secondary resistances and correlation to response and safety and tolerability. Results: Between 03-2011 and 11-2012, a total of 50 pts were enrolled from 7 centers. Median age was 63 years; 98% had adenocarcinoma, 54% had never smoked and 68% were female. Exon 19 deletions were more common (70%) than exon 21 (30%). EGFR screening methods applied at a site level were different: pyrosequencing (41%), Sanger (29%), SSCP (8%), Pyrosequencing and DNA melting (4%) and others (18%). Central evaluation confirmed the presence of an EGFR mutation in all cases. EGFR testing from CTC and from plasma DNA resulted feasible. EGFR mutations were identified by next generation sequencing in CTC preparations from 31 (84%) of 37 pts so far examined, corresponding to those present in matching tumor tissue. Treatment discontinuation was observed in 25 pts, mainly due to PD (30%) and death (10%). Results of plasma DNA and of immunoistochemical detection at baseline are ongoing as well as analysis on CTC and plasma DNA at progression. Conclusions: This trial confirms the feasibility of new diagnostics techniques and will help in improving understanding in the resistance mechanisms to EGFR TKIs. Clinical trial information: EudraCT Number: 2010-023892-24.
Phase II study of bevacizumab (Bv) in combination with paclitaxel-carboplatin (PC) as first-line chemotherapy for nonsquamous (SQ) non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE).
Authors: Tamiya Motohiro , Hirashima Tomonori , Tamiya Akihiro , Okamoto Norio , Suzuki Hidekazu , Yamadori Tadahiro , Morishita Naoko , Shiroyama Takayuki , Otsuka Tomoyuki , Kitai Kanako , Yasue Tomomi , Asami Kazuhiro , Minomo Shojiro , Sonobe Syoko , Nakao Keiko , Kawaguchi Tomoya , Atagi Shinji , Kawase Ichiro 
Published: March 2020

e19021 Background: Vascular endothelial growth factor (VEGF) plays an important role in NSCLC with MPE, but the evidence regarding the efficacy of Bv with PC for treatment of NSCLC with MPE is lacking. Therefore, we prospectively evaluated the efficacy and safety of Bv and PC in non-SQ NSCLC pts. Methods: Chemotherapy-naive non-SQ NSCLC pts with MPE were eligible to participate. Pleurodesis before chemotherapy was not allowed. The treated pts received PC without Bv in the first cycle to prevent Bv-induced delayed wound healing after chest drainage. Subsequently, they received 2–6 cycles of PC with Bv. Patients who completed more than 3 cycles of PC and Bv without disease progression or severe toxicities continued to receive Bv alone as a maintenance therapy. The primary endpoint was overall response, although an increase in MPE was allowed in the first cycle. The plasma and MPE VEGF levels were measured at baseline and the plasma VEGF levels after 3 cycles of chemotherapy. Results: Between September 1, 2010 and June 30, 2012, 23 pts were enrolled. The overall response rate was 60.8%, and the disease control rate was 87.0%. No pts showed complete response, 14 showed partial responses, 6 showed stable disease, 2 showed disease progression, and 1 died in the first cycle. Sixteen pts received maintenance therapy, following a median of 3 cycles. The median progression-free survival period for all pts was 200 days (95% CI, 156–263 days), whereas the median overall survival was 328 days (95% CI, 206–415 days). All pts experienced high levels of hematological toxicities, with most pts experiencing neutropathic toxicities above grade 3. However, none of the pts experienced severe bleeding events. The median baseline MPE VEGF level was 1798.6 (range, 223.4–35,633.4) pg/mL. The plasma VEGF levels showed a significant decrease after 3 chemotherapy cycles (baseline, 513.6 ± 326.4 pg/mL; post-chemotherapy: 25.1 ± 14.1 pg/mL; p < 0.01), regardless of the degree of efficacy. Conclusions: The combination of PC with Bv was confirmed to be effective and reasonably well-tolerated in chemotherapy-naïve non-SQ NSCLC pts with MPE. Clinical trial information: UMIN000005284.
Pharmacogenetic study of Japanese patients with advanced nonsquamous non-small cell lung cancer treated with pemetrexed plus cisplatin.
Authors: Imai Hisao , Serizawa Masakuni , Takahashi Toshiaki , Mori Keita , Ono Akira , Akamatsu Hiroaki , Taira Tetsuhiko , Nakamura Yukiko , Kenmotsu Hirotsugu , Naito Tateaki , Murakami Haruyasu , Koh Yasuhiro , Endo Masahiro , Nakajima Takashi , Yamamoto Nobuyuki 
Published: March 2020

e19050 Background: Pemetrexed (PEM) inhibits multiple enzymes in the folate (F) pathway. Several studies show that genetic polymorphisms in these enzymes influence the efficacy and toxicity of PEM. We aimed to investigate the relationship between genetic polymorphisms associated with the F pathway and clinical outcomes of Japanese patients with advanced non-squamous non-small cell lung cancer (NSQ-NSCLC) treated with PEM plus cisplatin (CIS). Methods: We analyzed 38 polymorphisms in 15 genes associated with the F pathway in NSQ-NSCLC patients treated with PEM plus CIS: ABCC11, ADA, ATIC, CBS, DHFR, ERCC1, FPGS, GGH, MTHFD1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, and TYMS. These polymorphisms were compared with clinical outcomes such as response, toxicity, and progression-free survival (PFS) using Pearson’s χ2 test and the log-rank test. Results: All 56 patients were Japanese, with a median age of 62 years; 57.1% were male, 96.4% had an Eastern Cooperative Oncology Group Performance Status of 0–1, 96.4% had stage IV disease, and 94.6% had adenocarcinoma. The response rate, disease control rate, and median PFS were 32.2%, 78.6%, and 4.7 months, respectively. Of the 38 polymorphisms tested, none were associated with response or toxicity, but 2 single nucleotide polymorphisms (SNPs) (in the gamma-glutamyl hydrolase [GGH 452C>T] and methionine synthase [MTR 2756A>G] genes) were significantly associated with PFS. Patients harboring the GGH-C452C variant had significantly longer PFS (5.6 vs 2.8 months; p < 0.0001) than those with the C452T or T452T variants. Further, patients harboring the MTR-A2756A variant had significantly longer PFS (5.3 vs 3.7 months; p = 0.036) than those with the A2756G variant. In addition, among patients with the GGH-C452C variant, those harboring the MTR-A2756A variant had significantly longer PFS (5.9 vs 4.3 months; p = 0.044) than those with the A2756G variant. Conclusions: SNPs in GGH and MTR seem to predict differences in PFS in NSQ-NSCLC patients treated with PEM plus CIS, and a combination of these 2 SNPs may predict differences in PFS more accurately. These results should be validated in larger, adequately designed prospective studies.
Comparison of clinical outcome between gefitinib and erlotinib treatment in patients with non-small cell lung cancer harboring an epidermal growth factor receptor exon 19 or exon 21 mutations.
Authors: Lim Sung Hee , Lee Ji Yoon , Sun Jong-Mu , Ahn Jin Seok , Park Keunchil , Ahn Myung-Ju 
Published: March 2020

e19051 Background: Gefitinib and erlotinib are small-molecule kinase inhibitors that inhibit signaling via EGFR and both agents showed dramatic response rate and prolonged PFS in patients harboring activating EGFR mutation. We investigated the clinical outcomes between gefitinib- and erlotinib-treated patients with recurrent or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations. Methods: A total 375 patients with recurrent or metastatic NSCLC who had either an exon 19 deletion or L858R mutation on exon 21 and received gefitinib (n=228) or erlotinib (n=147) therapy between August 2007 and December 2011 were retrospectively reviewed. By using a matched-pair case-control study design, 121 pairs of gefitinib-treated and erlotinib-treated patients were matched according to sex, smoking history, ECOG performance status, and types of EGFR mutation. Results: The median age of all patients was 58 years (range, 30-84) and more than half of patients were never smokers (63.6%). Most patients had adenocarcinoma (98.3%) and good ECOG performance status (0, 1) (90.9%). Of 242 patients, 64 (26.4%) received an EGFR TKI as first line therapy. The overall response rates and disease control rates in the gefitinib-treated and erlotinib-treated groups were 85.5% versus 79.8 % (p=.375) and 94.0% versus 89.1%, respectively (p=.242). There was no statistically significant difference noted with regard to OS (median, 38.9 vs 37.5; p=.642) and PFS (median, 12.9 vs 10.1; p=.135) between the gefitinib-treated and erlotinib-treated groups. For a subgroup which patients were treated with TKI as first line therapy, the overall response rates were higher than those of patients who had progressed on prior chemotherapy (90.3% vs 79.9%; p=.063). However, there was no significant difference in PFS (median, 13.3 vs 10.3; p=.134) between subjects with first line TKI therapy and more than second line treatment. Conclusions: Both gefitinib and erlotinib showed similar effective activity in selected population of NSCLC that harbored an EGFR mutation and further studies are needed to evaluate the efficacy of EGFR TKI as first line treatment.
Survival versus intrinsic and acquired resistance in advanced non-small cell lung cancer.
Authors: Stewart David J. , Saintigny Pierre , Goss Glenwood D. , Lu Charles 
Published: March 2020

e19066 Background: While advanced NSCLC responds to platinum-based therapy (PBT), intrinsic and acquired resistance limits efficacy. We assessed impact of resistance patterns on overall survival (OS). Methods: Using serial measurements of tumor diameters from 130 NSCLC patients on PBT, we calculated % incremental change in tumor size compared to the most recent prior scan and % overall change from pre PBT. Results: 98/130 (75%) had measurable tumor shrinkage (TS) at 1st repeat scan (RS) post 2 cycles, of whom 81 had a 2nd RS post 4 cycles. Of these, 20 (25%) had tumor growth (TG) at the 2nd RS. Only 1 had initial TG then followed by TS. Of 41 with a 3rd RS <4 weeks post cycle 6, 13/41 (32%) had TG. The greatest % incremental TS (compared to most recent prior scan) was seen early (at 1st RS) for 76% of patients. Rate of TS decreased with later cycles in these patients. 11 patients had rapid TS on 1st RS, then gradual further shrinkage over >3 subsequent scans, while 15 had progressive gradual TS over >4 scans without initial rapid TS. By Spearman coefficients, maximum % TS from pre PBT over all scans correlated with OS (r=0.46, p<0.0001), time to progression (TTP) (r=0.69, p<0.0001) and post-progression survival (PPS) (r=0.30, p=0.001). TTP also correlated with OS (r=0.63, p<0.0001), TTP correlated with PPS (r=0.44, p<0.0001), and OS correlated with PPS (r=0.95, p<0.0001). Median OS (11.0 months for all patients) varied with TS pattern (p<0.0001): OS for patients with first TG at 1st, 2nd, 3rd and 4th RS was 5.9, 10.8, 10.5 and 15.1 months. OS was 18.2 months in patients with most TS at 1st RS followed by gradual further TS over later scans, and was 30.5 months with progressive gradual TS without rapid TS at 1st RS. OS with RECIST partial response (23% of patients), minor TS (52%), minor TG (13%) and RECIST progressive disease (13%) was 16.9, 12.4, 9.8 and 4.0 months (p<0.0001). Conclusions: OS, TTP and PPS correlate strongly with response (degree of TS/TG) and with resistance pattern. OS is longest with progressive further TS over multiple scans. Within this group, partial acquired resistance (decreased TS rate after initial rapid TS) has shorter OS than with sustained incremental TS. The underlying biological factors driving clinical resistance remain undefined.
SUV max of the most intense lesion on fdgpet/CT scan at baseline as a potential prognostic factor in stage IV (NSCLC): A retrospective review.
Authors: Kodali Manga Devi , Takalkar Amol , Shi Runhua , Peddi Prakash , Mills Glenn Morris , Jafri Syed Hasan Raza 
Published: March 2020

e19070 Background: Lung cancer is the leading cause of mortality in United States and worldwide. Stage IV lung cancer has poor prognosis with 5-year survival of 2%. Limited numbers of factors are known to predict survival in stage IV NSCLC (Non Small Cell Lung Cancer) including stage at diagnosis, Performance Status (PS), genomic expression profile. Earlier studies have found SUV max (Maximum Standardized Uptake Value) of primary lung tumor on FDGPET/CT (Fluoro Deoxy Glucose –Positron Emission Tomography/Computed Tomography) correlates with tumor doubling time and survival. However prior studies included stage I-IV NSCLC patients and SUVmax of primary lung tumor. Hence we performed this study with only clinical stage IVNSCLC who underwent FDGPET/CT scan at baseline to determine whether SUVmax value of most intense lesion has any prognostic significance. Methods: Retrospective review identified 46 patients (September 2004- September 2011) that were diagnosed with stage IV NSCLC at our institution. SUVmax of most intense lesion on FDG PET/CT scan was determined utilizing an automated program on a dedicated PET/CT workstation by a single nuclear medicine specialist. Cox regression analysis and Log-rank test were used to analyze data. Results: Descriptive statistics: Median age 61.6 (43.8-77.8), Females 17 (36%), African Americans 26 (56%), Performance status 0-1=36 (80%), number of metastatic sites 1-2=30 (65%), Adenocarcinoma 32 (70%), Chemotherapy 31 (61%), SUV max- primary (65%), other sites (35%). The patient population was subdivided into two groups using the median SUVmax of 17.8. The median survival of patients having SUV max ≤17.8 and SUVmax > 17.8 was 13.4 months and 4.5 months respectively (P =0.0269). Multivariate analysis indicated PS (HR=2.8), any chemotherapy (HR=2.56) and SUV max ≤ 17.8 (HR=1.98, P=0.04) predicted survival. Conclusions: SUV max of the most intense lesion at the time of presentation predicts worse outcome in stage IVNSCLC and needs to be validated in a prospective study. PETCT may be able to predict the areas that harbor resistant clones of cells, described in previous studies as tumor heterogeneity, which may confer prognostic significance.