bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical impact of EGFR mutation fraction and tumor cellularity in EGFR mutation positive NSCLC.
Authors: Martin Petra , Shiau Carolyn Jane , Pasic Maria D , Tsao Ming Sound , Kamel-Reid Suzanne , Le Lisa , Higgins Brian Patrick , Cheng Susanna Y. , Burkes Ronald L. , Ng Matilda , Arif Saroosh , Roxana Tudor , Lin Stephanie Chen Xing , Ellis Peter Michael , Hubay Stacey , Kuruvilla Sara , Laurie Scott Andrew , Li Jing , Shepherd Frances A. , Leighl Natasha B. 
Published: March 2020

e19077 Background: We investigated the impact of mutation fraction, tumour sample cellularity, and diagnostic specimen type on EGFR TKI response, time to treatment failure (TTF) and overall survival in advanced EGFR mutation positive NSCLC patients. Methods: From March 2010 to May 2012, EGFR testing in the province of Ontario (Canada) was conducted at a single centre, using fragment analysis for exon 19 deletion and Sau961 restriction enzyme digest for exon 21 mutation. Patients with EGFR mutation positive samples were identified, tumour cellularity, mutation fraction (percent tumour cells mutated) and clinical outcome data collected. Regression analysis was undertaken to assess the association between demographic variables, mutation fraction, tumour cellularity and sample type on clinical outcomes. Results: Of 173 patients identified to date, 153 received EGFR TKI and are included in this analysis, with median follow up of 10.6 months (range 0-44). Most are female (73%), never smokers (65%), have exon 19 deletions (55%; 45% exon21 L858R), and median age 64 years (range 34 to 95). Tumour specimens tested include resection (36%), cytology (32%), and core biopsy samples (32%). Median EGFR mutation fraction is 30% (range 1% to 96%); 18% had a low (<10%) mutation fraction. Responses (any reduction) were seen in 66%, mixed response or stable disease in 28%, and progression in 7%. Median TTF of EGFR TKI therapy is 13.8 months. Median OS from TKI start is 24.1 months, with 1-, 2- and 3-year rates of 75%, 51% and 42%. In multivariable analysis, increasing mutation fraction was associated with EGFR TKI response (OR 2.5, p<0.01), but not TTF or OS. Female sex was associated with TTF (HR 0.49, p=0.007), and testing of larger samples (lobectomy, wedge, excision) was associated with TTF and OS (HR 0.45, p=0.007; HR 0.26, p=0.0002). Exon 19 deletions are associated with a higher risk of death (HR 2.41, p=0.02) and a lower probability of response than L858R (OR 0.31, p=0.004). Conclusions: Pathologic features may be relevant to clinical outcomes in EGFR mutation positive NSCLC, including mutation fraction, sample cellularity, specimen tested and mutation type. Validation of the use of EGFR mutation fraction in clinical decision-making is ongoing.
Extensive surgical resection in stage IV non-small cell lung cancer patients after tailored chemotherapy.
Authors: Guo Huiqin , Zhao Yu , Lu Jiangyang , Christiani David C. , Lin Xihong , Wang Zhaoxi 
Published: March 2020

e19080 Background: The treatment of stage IV non-small cell lung cancer patients is a problem for thoracic surgeons and the optimal treatment is discussed controversially. ERCC1, class III β-tubulin, p53, and RRM1 are predictive molecular biomarkers reported for neoadjuvant chemotherapy. Here we report a prospectively enrolled case series that patients were treated with extensive surgical resection after personalized chemotherapy tailored by these 4 markers. Methods: Patients with previously untreated stage IV NSCLC, ECOG PS of 0-2 were enrolled. The expression of ERCC1, class III β-tubulin, p53, and RRM1 was tested with IHC staining method for the tumor samples by bronchoscopy biopsy or percutaneous lung biopsy. Patients were treated with 2 of four drugs including cisplatin, taxol, gemcitabine and vinorelbine, selected by the expression of ERCC1, class III β-tubulin, RRM1 and p53, respectively. Then patients received surgical resection after evaluation with continuing adjuvant chemotherapy. A follow-up CT was performed after every 2 cycles chemotherapy and every 3 months post chemotherapy. PFS and OS were estimated by the Kaplan-Meier method. Results: 26 patients were included from May 2008 to Dec 2011 with a follow-up period 12–58 months till Nov 2011. 8 (30.8%) patients died within Follow-up period. The overall response (CR+PR) rate of tailored neoadjuvant chemotherapy was 88.5% with 23 PR. A complete resection (R0) was achieved in 24 (92.3%) patients and R1 in 2 (7.7%) patients. Median PFS was 27.0 months (95% CI: 21.0–32.9 months) and median OS was 41.6 months (95% CI: 23.1–60.0 months). Conclusions: Our study suggest extensive surgical resection in stage IV non-small cell lung cancer patients after tailored chemotherapy should be performed because it may improve survival dramatically over conservative chemotherapy. Surgery within multimodality approach will be a promise treatment option in the future.
Bevacizumab (Bv) in non small cell lung cancer (NSCLC) patients ≥75 years old with pre-existing cardiovascular disease (CVD): Experience at a tertiary referral center.
Authors: Strimpakos Alexios S , Vassos Demetrios , Panagiotarakou Meropi , Syrigos Konstantinos N. 
Published: March 2020

e19087 Background: Bv is a novel anti-angiogenic agent used in many advanced solid tumours, including non-squamous NSCLC. In contrast to clinical studies where enrolled pts are fit, many elderly NSCLC pts suffer from co-morbidities and often have history of a CVD. Methods: Medical records of 2,672 pts diagnosed with NSCLC between 2001-2012 were screened. We identified and examined pts ≥75 yrs old treated with Bv, for their demographics, clinical data and treatment (Tx) details. We focused on those elderly pts with stable pre-existing cardiovascular disease. Results: 356/2672 NSCLC pts received Bv at any Tx line. 33/356 (9.2%) were ≥75 yrs old. Of those, 29 had various co-morbidities including 19 pts with stable CVD on medical Tx. In the 19 pts with CVD the male:female ratio was 17:2 and median age 76 yrs (range 75-86). 8/19 pts had impaired renal function. All pts were of Performance Status ECOG 0/1. Median number of Bv cycles was 5 (range 2-11). 17/19 pts experienced ≥1 side effects (11 epistaxis and haemoptysis, 5 proteinuria, 4 hypertension) which led to treatment discontinuation in 5 pts. No major/fatal adverse events were noted. 8/19 pts (42%) showed radiological partial response and 5 (19%) stable disease (total disease control rate 61%). Median survival from initiation of Bv till death/last follow up was 7 months (range 2-28, 95% CI 5.14-12.55). Conclusions: Treatment with Bevacizumab seems to be safe and effective in elderly NSCLC patients with controlled pre-existing cardiovascular disease and good PS. These patients might benefit from participation in clinical trials similarly to younger NSCLC patients.
Effectiveness of erlotinib in lung adenocarcinomas with classic and alternative EGFR mutations detected by Roche 454 GS-FLX next-generation sequencing (NGS).
Authors: Ostoros Gyula , Sarosi Veronika , Mandoky Laszlo , Pinter Ferenc , Schwab Richard , Petak Istvan , Urban Laszlo 
Published: March 2020

e19090^ Background: Next generation sequencing (NGS) detects all possible mutations with a higher sensitivity than Sanger sequencing. EGFR mutations are important predictors of sensitivity and resistance to EGFR tyrosine kinase inhibitors including erlotinib. The clinical significance of alternative (“rare”) EGFR mutation types, and mutation present in a small fraction of tumor cells detected by NGS is less known. Methods: For the present retrospective analysis, 100 lung adenocarcinoma tumor samples were collected from patients who participated in a previous observational cohort study of erlotinib (MOTIVATE). In this study only patients with advanced (IIIb/IV) K-RAS wild type tumors refractory to one or two previous chemotherapy were enrolled. Four exons (18, 19, 20, 21) of EGFR gene were PCR amplified and sequenced by Roche 454 GS FLX sequencer. Differences in overall survival (OS), and progression free survival (PFS) were statistically analyzed (Log Rank). Results: 47 mutations of the EGFR tyrosine kinase domain were detected in the 35 out of 100 tumors. 14 mutations were present in less than 10% of alleles. 16 tumors contained known („classic”) sensitizing mutations: nine deletions in exon 19, five L858R, one L861Q mutation in exon 21, one G719A mutation in exon 18 and one known resistance mutation D770_N771insY in exon 20. 18 tumors contained only alternative mutations with unknown functional relevance. The median PFS of patients with tumors harbouring EGFR wild type gene, classic EGFR mutations and alternative mutations were 2.9 months, 13.2 months (p<0.001) and 3.0 months (P=0.43) respectively. The median OS of patients with tumors containing wild type EGFR tumors, and alternative mutations was 7.2 and 5.5 months respectively (P=0.68). The median OS of patients harbouring classic EGFR mutations was not reached. The mean OS of these patients was 29.0 months. Conclusions: NGS is a sensitive and reliable diagnostic method to detect EGFR mutations with known functional significance. Alternative mutations need further one by one functional interpretation and analytical validation before being used as positive predictors in clinical decisions.
Gefitinib combined biologic therapy for advanced lung adenocarcinoma.
Authors: Li Baoping , Zhang Lei 
Published: March 2020

e19098 Background: Gefitinib is an effective treatment for non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations. However, due to the limited genetic testing methods and other constraints, a large proportion of patients did not benefit from it. In order to overcome the limitation of genetic testing and other constraints, we use gefitinib with the immune-biotherapy to treatment advanced lung adenocarcinoma. Methods: From February 2011 to December 2012, we use gefitinib combined with immune-therapy to treat 59 cases with advanced lung adenocarcinoma. These patients completes at least one cycle of therapy. The efficacy and quality of life were investigated. The prognostic factors were analyzed using Cox regression model. Results: CRF0, PR:46, SD:13, the PD:0. The overall response rate = 77.97%. FACT-L: 100%. The response rate and scores of quality of life are higher than the reported data. COX regression analysis showed that the complete remission after the treatment is significant factor(P <0.01), but the factors such as the disease control status, gender, tumor stage, smoking history were not significant. Conclusions: Gefitinib and biological therapy combined, can significantly improve short-term effect of advanced lung adenocarcinoma. Its possible mechanism of gefitinib to reduce interstitial fluid pressure may increase immunocompetent cells into the tumor tissues, thereby enhancing efficacy.
Erlotinib as a salvage treatment for patients with advanced non-small cell lung cancer after failure of gefitinib treatment: Is there a rationale for a clinical trial?
Authors: Salesi Nello , Di Cocco Barbara , Calabretta Francesca , Ciorra Alida Armida , Cirino Crescenzo , Cauchi Carolina , Pistillucci Giorgio , Sciacca Venerina , Rossi Rosalinda , Veltri Enzo 
Published: March 2020

e19099 Background: Patients (pts) with advanced NSCLC and sensitizing EGFR mutations who initially respond to gefitinib or erlotinib eventually develop acquired resistance to the TKIs. Our goal was to determine the effects of erlotinib 150 mg/d in EGFR mutated pts resistant to gefitinib 250 mg/d, because the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib. Methods: Retrospective review of 5 EGFR mutated (exon 19 deletions) patients that were given gefitinib and subsequently erlotinib. Results: All pts responded to gefitinib with median progression-free survival of 13 months (95% confidence interval, 4-16). After gefitinib resistance, 60% (3 of 5) of these pts displayed progressive disease while on erlotinib with progression-free survival of 2 months (95% confidence interval, 2-3). These pts acquired the T790M mutation. 2 gefitinib-resistant pts with the acquired L858R-L747S EGFR, which in vitro is sensitive to achievable serum concentrations of erlotinib 150 mg/d, achieved a partial response to erlotinib. In literature doesn’t exist a prospective study about the stratification of pts ordered by PS, age, gender, smoker/non-smoker, which could test the efficiency of the erlotinib after gefitinib in pts with different EGFR mutations. We only have at our disposal few studies control-case in non-selected pts which show a potential efficiency of erlotinib after the failure of the gefitinib, nevertheless, without an evident increase of the overall survival. Conclusions: In EGFR mutated tumors resistant to gefitinib 250 mg/d, a switch to erlotinib 150 mg/d does not lead to responses in most pts. These findings are consistent with preclinical models, because the common mechanisms of TKI resistance (T790M and MET amplification) in vitro are not inhibited by clinically achievable doses of gefitinib or erlotinib. Alternative strategies to overcome TKI resistance must be evaluated.
EGFR-activating mutations and treatment with tyrosine-kinase inhibitors (TKI) to revert poor-prognosis (PP) associated with liver metastases (LM) in stage IV non-small cell lung cancer (NSCLC) patients (pts).
Authors: Castanon Eduardo , Lozano Maria D. , Fusco Juan Pablo , Arevalo Estefania , Carranza Omar Esteban , López-Picazo José María , Perez-Gracia Jose Luis , Gurpide Alfonso , Gil-Bazo Ignacio 
Published: March 2020

e19106 Background: LM appear in 20-30% of pts diagnosed with NSCLC and they confer PP. However, whether the clinical outcome of NSCLC pts with LM harboring molecular alterations in EGFR, KRAS and EML4-ALK genes is substantially different depending on their distinct status is still unknown. Methods: A total of 268 consecutive stage IV NSCLC pts were included. The tumor molecular analysis for EGFR, KRAS and EML4-ALK was available in 205 pts (76.5%), 136 pts (50.7%) and 31 pts (11.6%), respectively. An EGFR mutation was observed in 32 pts (15.6%), KRAS was mutated in 28 pts (20.6%) and EML4-ALK gene rearrangement was observed in 3 pts (9.6%). We aimed to determine whether the molecular status of EGFR, KRAS and EML4-ALK has an impact on the clinical outcome of stage IV NSCLC pts. Results: Most of the pts were men (71.3%). The most common histology was adenocarcinoma (59.3%). Overall, 34% of the pts showed LM at any time of the disease course. Among the whole cohort, median OS for LM pts was 16 months vs 42 months for pts with metastases other than LM (p<0.001). Among pts with LM and EGFR mutations, the one-year survival rate was 85.7% vs 54.3% for pts with LM and EGFR wild-type (p=0.03). We analyzed whether pts received EGFR TKI or standard chemotherapy (SC). For the subgroup of pts carrying EGFR mutations and receiving TKI, the 18-month survival rate was 75% for those showing LM vs 80% (p=0.44) for those without LM. In contrast, for the subgroup of EGFR wild-type pts receiving SC, the 18-month survival rate was 32.4% for those showing LM vs 74.9% for those without LM (p<0.001). No impact of KRAS or EML4-ALK molecular alterations on OS of pts with LM was observed. Conclusions: The presence of LM at any time of the disease curse negatively impacts on the clinical outcome of NSCLC pts. However, the presence of EGFR activating mutations significantly improves the OS of those with liver spread, reaching a similar OS to subjects with no LM. Pts with EGFR mutations and LM may revert the PP associated to LM when an EGFR TKI is prescribed.
VEGF-A 165 family of isoforms as predictive biomarkers in patients with nonsquamous non-small cell lung cancer (NSCLC) treated with bevacizumab.
Authors: Garcia-Foncillas Jesus , Domine Manuel , Rojo Federico , Hernandez Tatiana , Zazo Sandra , Serrano Gloria , Chamizo Cristina , Carames Cristina , Carvajal Nerea , Moreno Irene , Perez-Gonzalez Nuria , Leon Ana , Auz Carmen Laura , Martin-Valades Jose Ignacio , Madoz Juan , Lobo Francisco 
Published: March 2020

e19109 Background: Bevacizumab is a recombinant monoclonal humanized antibody to vascular endothelial growth factor (VEGF) that improves Time to Progression (TTP) in patients with advanced non-squamous NSCLC in combination with a doublet of platins, but currently no proven predictive markers exist. The VEGF-A 165 splice variant has been described as the most abundant and active isoform in cancer. Exon 8 splice modifications of VEGF 165 generates the VEGF-A 165a family of isoforms, which has a pro-angiogenic effect, and VEGF-A 165b family, with an anti-angiogenic activity. This study is aimed to explore the role of VEGF165a and VEGF165b expression in tumors as predictive biomarkers of efficacy in patients with NSCLC treated with platins plus bevacizumab. Methods: 22 patients were included (20 adenocarcinomas and 2 large cell carcinomas): 5 received carboplatin-taxol-bevacizumab, 14 carboplatin-taxotere-bevacizumab and 3 cisplatin-gemcitabine-bevacizumab. Total RNA was isolated by RNeasy FFPE procedure. VEGF165a and VEGF165b expression was analyzed by RT-qPCR using appropriate specific primers and probes. Individual VEGF165a and VEGF165b family of isoforms expression was calibrated to normal tissue and the ratio between both isoforms was calculated. Results: VEGF165a overexpression was detected in 14 (63.6%) cases and VEGF165b overexpression in 15 (68.2%). Individual overexpression for each family of isoforms was not predictive of benefit to bevacizumab therapy (p=0.933 and 0.166). However, the ratio between VEGF165a and VEGF165b was associated with TTP, correlating a predominant expression of pro-angiogenic VEGF165a with a significant benefit compared with cases with predominant VEGF165b expression (median TTP, 15 vs. 8 months respectively, p=0.005). The expression of both isoforms did not impact on OS (p=0.477). Conclusions: The overexpression of VEGF165a and low expression of VEGF165b family of isoforms correlated with benefit to anti-angiogenic therapy in NSCLC patients, supporting a potential use as predictive biomarkers for bevacizumab treatment in stage IV non-squamous NSCLC.
Thymidylate synthase (TS) polymorphisms (Pol) in buffy coat-derived genomic DNA as a clinical outcome predictor in non-Asian stage III/IV non-small cell lung cancer (NSCLC) patients (pts) receiving pemetrexed (Pem).
Authors: Arevalo Estefania , Lopez Ines , Fotuño Maria Antonia , Castanon Eduardo , Collado Victor , Rodriguez Maria , Olarte Alicia , Andueza Maria Pilar , Perez Gracia Jose Luis , Patiño-García Ana , Gil-Bazo Ignacio 
Published: March 2020

e19112 Background: TS is the main biological target of the antifolate Pem. Some TS Pol may confer a short survival and a poor response to antifolate-treated colo-rectal cancer pts. Whether TS genotype has an independent prognostic/predictive impact on non-Asian advanced NSCLC pts treated with Pem is unknown. Methods: Twenty-five non-Asian advanced NSCLC pts treated with Pem-based regimens (1st, 2nd or 3rd line) were included. Genomic DNA was isolated from periferal blood prior to treatment. The variable number of tandem repeat (VNTR) Pol, the G>C single nucleotide Pol (SNP) and the TS 6-bp insertion/deletion (6/6) in the 3' untranslated region (UTR) Pol were analyzed and correlated with response rate (RR), progression-free survival (PFS), overall-survival (OS) and toxicity (Tx). Results: Regarding the VNTR Pol, most of the pts showed 2R/2R or 3R/2R Pol (17 pts; 68%), and 8 pts (32%) showed 3R/3R or 3R/4R Pol. A SNP (G>C) in VNTR was observed in 18 pts (72%). The Pol found in the 3´UTR region were +6/+6 in 12 pts (48%), +6/-6 in 11 pts (44%) and -6/-6 in 2 pts (8%). In the subgroup of T3-T4 pts, there was a higher RR among those showing 3R/3R Pol than those with 2R/2R Pol (100% vs 83.8%; p=0.029). The genotype +6/+6 predicted a higher RR among active/former smokers (A/FS) compared to +6/-6 (100% vs 37.5%; p=0.026). A 3R/3R Pol followed by 2R/2R and 2R/3R Pol predicted a superior RR in pts with EGFR mutations (p=0.018). Overall, a trend towards a better PFS in pts showing 2R/2R Pol was found (p=0.076). The cohort’s median overall survival (OS) was not reached during follow-up. The most frequent Tx was grade (G)1 anemia (28%) and nausea (20%) and G2 leucopenia (40%). G3-4 anemia (4%), leucopenia (16%), neutropenia (4%), astenia (8%) and dyspnea (4%) were uncommon but more frequent in pts with 2R/2R Pol (p=0.545). Conclusions: In this cohort of NSCLC pts 3R/3R Pol among T3-T4 pts and EGFR mutant pts and +6/-6 bp among A/FS significantly predicted a higher RR to Pem and may aid in treatment selection. Tx was not significantly correlated with a specific TS genotype. These interesting preliminary data warrant further validation in larger series.
Thyroid transcription factor 1 (TTF-1) and overall survival in wild type EGFR patients treated with erlotinib.
Authors: Fidler Mary J. , Basu Sanjib , Hensing Thomas A. , Buckingham Lela , Pool Mark , Mahon Brett , Batus Marta , Walters Kelly Kaiser , Bonomi Philip D. 
Published: March 2020

e19113 Background: TTF-1 is a transcription factor involved in regulating epithelial to mesenchymal transition. TTF-1 has a favorable prognosis in early stage lung adenocarcinoma, although it’s prognostic value in erlotinib treated patients remains unknown (Somaiah ASCO 2011). The goal of this study was to validate the relationship between TTF-1 expression and clinical outcomes in wild-type (WT) stage IV non-small cell lung cancer (NSCLC) patients (pts) treated with erlotinib. Methods: Pts that received erlotinib were retrospectively analyzed by IHC for TTF-1 expression (positive = greater than 5% of tumor cells with moderate (2+) or strong (3+) nuclear staining). Pts’ tumors were considered WT if no mutations were detected in Exon 19 or L858R (Exon 21) using single-strand conformation polymorphism and sequence-specific polymerase chain reaction (PCR). Log Rank was used to correlate TTF-1 positivity with outcomes. Results: 216 pts were analyzed. EGFR activating gene mutations were found in 11.6% of cases. TTF-1 positivity was strongly correlated with the presence of an activating EGFR mutation (p=.0006, negative predictive value=97.7%). Of WT pts: median age was 65, 61% female, 15% never smokers. TTF-1 was positive in 8% of squamous cell and 71% of adenocarcinoma pts. In EGFR WT pts, the median progression free survival (PFS) in TTF-1 positive and negative pts was 2.1 vs. 1.6 months respectively, p=.255. TTF-1 strongly correlated with prolonged overall survival (OS) on erlotinib therapy in WT pts (6.2 vs. 3.2 months, log rank p=.004). After excluding for squamous cell histology, in TTF-1 positive EGFR WT pts there was still a highly significant correlation with prolonged OS on erlotinib (6.2 vs. 2.8 months, p=.001) and a trend toward prolonged PFS (2.2 vs. 1.4 months, p=.05). Conclusions: TTF-1 is related to the presence of exon 19 and 21 EGFR mutations in this group of NSCLC pts, and, similar to early stage lung cancer, TTF-1 appears to be at least a prognostic indicator for OS in stage IV WT EGFR NSCLC pts treated with erlotinib. Exploration of the potential predictive value of this readily available marker should be considered in pts with EGFR WT tumors treated with erlotinib.