bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proposed staging system modifications for advanced bronchioloalveolar carcinoma supported with a population-based validation study
Authors: Zell J. A. , Ou S. , Ziogas A. , Anton-Culver H. 
Published: March 2020

7559 Background: Concordant with surgical series, our prior analysis of US SEER data demonstrates improved survival for BAC patients with stage IIIB disease due to multiple lesions in the same lobe compared to other stage IIIB patients, and also for patients with ipsilateral multicentric BAC compared to those with distant metastasis. In order for the BAC staging system to accurately reflect survival for these distinct patient subsets, we propose a revised staging system for advanced BAC and validate this system using California Cancer Registry (CCR) data. Methods: A case-only analysis of incident BAC cases in CCR during 1999–2003 was conducted. Based on modeling from our prior SEER analysis, the T4 descriptor for multiple tumors in the same lobe was downstaged to T3, and the M1 descriptor for ipsilateral multicentric BAC was downstaged to T4. The primary outcome measured was overall survival (OS). OS univariate analyses were conducted using the Kaplan-Meier method; multivariate survival analyses were performed using Cox proportional hazards ratios. Results: 1909 incident cases of histologically-confirmed BAC were analyzed. Using the proposed criteria, 162 (25%) of the 654 advanced BAC cases were reclassified: 73 cases with multiple lesions in the same lobe as T3 (stage II T3N0M0 [n=53] or T3NXM0 [n=1], stage IIIA T3N1–2M0 [n=18], stage IIIB T3N3M0 [n=1]); 89 cases with ipsilateral intrapulmonary metastasis were reclassified as T4 (stage IIIB, T4N1- 3M0). Univariate OS analysis of this validation set reveals an improved fit for the proposed staging system compared to the existing staging system ( Table 1 ). Analysis by stage reveals improvement in this proposed prognostic model over the existing staging system on multivariate survival analysis after adjustment for relevant clinicopathologic variables ( Table ). Conclusions: Our proposed BAC staging system modifications more accurately reflect survival characteristics for this unique type of non-small-cell lung cancer. [Table: see text]
Updated molecular analyses of exons 19 and 21 of the epidermal growth factor receptor (EGFR) gene and codons 12 and 13 of the KRAS gene in non-small cell lung cancer (NSCLC) patients treated with erlotinib in National Cancer Institute of Cancer
Authors: Shepherd F. A. , Ding K. , Sakurada A. , Da Cunha Santos G. , Zhu C. , Seymour L. , Whitehead M. , Kamel-Reid S. , Squire J. , Tsao M. S. 
Published: March 2020

7571 Background: BR.21 demonstrated significant survival benefit from erlotinib for NSCLC patients (Shepherd, NEJM 2005). EGFR gene point mutations in exon 21 and deletions in exon 19 predict response to EGFR TKIs, but the predictive value of EGFR mutations (Mut) or high copy number (Amp) on survival remains unclear. Methods: The sensitivity of PCR-sequencing to detect EGFR mutations may be suboptimal. Thus, we re-analyzed all BR.21 samples with available material using a fluourescent-based PCR technique (Pan, JMD 2005;7:396) and ScorpionIM kits (DxS, Manchester, UK) as they may detect mutations in samples with only 5–10% tumor DNA. 204 samples were analyzed successfully for EGFR Mut, 206 for KRAS Mut and 159 by FISH for EGFR Amp. Results: Exon 19 deletion and/or exon 21 L858R Mut were identified in 34 patients (overall Mut rate 17%). EGFR high polysomy or true amplification was present in 61 patients (38%), and 30 patients (15%) had KRAS Mut. Overall response rates were EGFR wildtype (WT)/Mut: 7%/27%, p=0.03; KRAS WT/Mut: 10%/5%, p=0.69; No Amp/Amp: 5%/21%, p=0.02. Hazard ratios for survival benefit were EGFR WT: 0.74 (0.52–1.05, p=0.09), Mut: 0.55 (0.25–1.19, p=0.12); KRAS WT: 0.69 (0.9–0.97, p=0.03), Mut: 1.67 (0.62–4.50, p=0.31); no Amp: 0.80 (0.49–1.29, p=0.35), Amp: 0.43 0.23–0.78, p=0.004). The test for interaction was borderline for KRAS Mut (0.09) but was not significant for EGFR Mut (p=0.47) or EGFR Amp (0.12). It was significant only for non-smokers with EGFR Amp (p=0.04). In the multiple Cox regression model, including all markers, EGFR Amp was both prognostic for poorer survival (p=0.005) and predictive of a differential survival benefit from erlotinib (p=0.009). EGFR and KRAS Mut were not significant prognostic or predictive markers. Conclusion: EGFR genotype and copy number are predictive of objective response to erlotinib. In BR.21, EGFR gene copy number is the strongest molecular prognostic marker and the only significant molecular predictor of a differential survival benefit from treatment. [Table: see text]
Combined inhibition of mTOR and EGFR with everolimus (RAD001) and gefitinib in patients with non-small cell lung cancer who have smoked cigarettes: A phase II trial
Authors: Kris M. G. , Riely G. J. , Azzoli C. G. , Heelan R. T. , Krug L. M. , Pao W. , Milton D. T. , Moore E. , Rizvi N. A. , Miller V. A. 
Published: March 2020

7575 Background: Most non-small cell lung cancers (NSCLC) are primarily resistant to the EGFR tyrosine kinase inhibitor gefitinib. One strategy to overcome resistance is to block parallel or downstream effectors that maintain tumor growth and proliferation. Preclinical data supports this hypothesis as inhibition of the PIK3CA/Akt/mTOR pathway restores gefitinib sensitivity in resistant cells. In a phase I study, gefitinib (250 mg) and the mTOR inhibitor everolimus (5 mg) were safely administered orally once-a-day (Milton Proc ASCO 2005). This combination induced regressions in patients with NSCLC. To assess the efficacy of this regimen, we designed this phase II trial. Methods: Two cohorts of patients with measurable stage IIIB/IV NSCLC were entered: (1) untreated with chemotherapy and (2) previously treated with cisplatin or carboplatin and docetaxel. A Simon two-stage design proposed to enroll up to 31 patients in each cohort. Response was assessed after 1 month then every 2 months. Pretreatment tumor specimens were collected on all patients. Results: To date, 25 patients have entered, 11 untreated and 14 previously treated. The median age was 66 years and KPS 80%. 52% were women, 68% had adenocarcinoma, and all were current (n=1) or former smokers. Partial responses (RECIST) have been observed in 4 of 23 evaluable patients (17%, 95% CI 5 to 39%) One of these 4 tumors harbored a KRAS mutation and one an EGFR exon 19 deletion. Responses lasted 3, 4, 9+, and 16+ months. Responses were observed in 2 of 13 untreated and 2 of 10 previously treated individuals. Toxicities: Grade 2/3 diarrhea in 13%, Grade 2 pustular rash in 25%, and Grade 2 mucosal ulcerations in 38%. 8% had dose reductions. There were no Grade 4 toxicities or treatment-related deaths. Conclusions: The combination of everolimus and gefitinib produced a 17% partial response rate in smokers with NSCLC, a group less likely to benefit from gefitinib. Enough responses have been seen in both untreated and previously treated cohorts to complete enrollment according to the two stage design of this trial. We plan to correlate outcomes with the molecular profile of tumors. Supported by Novartis, USA No significant financial relationships to disclose.
Increased incidence of brain metastases in ERCC1-negative NSCLC patients treated with adjuvant cisplatin-based chemotherapy
Authors: Besse B. , Massard C. , Haddad V. , André F. , Dunant A. , Pirker R. , Olaussen K. A. , Brambilla E. , Fouret P. , Soria J. 
Published: March 2020

7581 Background: We have recently demonstrated that ERCC1 is a predictor of the benefit of cisplatin-based adjuvant chemotherapy in resected non-small cell lung cancer (NSCLC). Non-squamous carcinomas have an increased risk of brain metastases (BM). Since brain is considered as a sanctuary site for chemotherapy, we hypothesised that there was an increased incidence of BM in ERCC1- negative non-squamous NSCLC patients treated with adjuvant cisplatin-based chemotherapy. Methods: Incidence of BM and histo- clinical parameters were analyzed in a population of 783 patients enrolled in the IALT trial. A subgroup analysis was performed in ERCC1 negative non-squamous NSCLC patients. Results: One hundred and one patients out of 783 (13%) developed BM alone or in association with other metastatic sites. In multivariate analysis, the clinical parameters associated with the occurrence of BM were nodal status (p=0.02), histological type (p=0.001) and pleural invasion (p=0.02). There is no effect of chemotherapy on BM (HR 1.38 [0.91–2.07], p=0.13). In patients with non-squamous histology (n=335) adjuvant chemotherapy was associated with an increased risk of BM (HR=2.10, [1.01–4.32], p=0.04) for ERCC1-negative tumours whereas there was no evidence of an effect on brain metastasis for ERCC1-positive tumours (HR=1.07 [0.38–2.99] p=0.90). These 2 effects are nevertheless not different (p for interaction=0.30) possibly by lack of power in this subsample. Conclusions: This study would suggest that cisplatin-based adjuvant chemotherapy is associated with an increased risk of BM in resected NSCLC patients with chemosensitive tumors. This data, if confirmed, could provide a rationale to evaluate prophylactic strategies in this subset of patients. No significant financial relationships to disclose.
Clinical and molecular characteristics of advanced non-small cell lung cancer (NSCLC) patients (pts) with rapid progressive disease (RPD) on gefitinib therapy (G)
Authors: Fidler M. J. , Buckingham L. , Gale M. , Coon J. , Mauer A. , Villaflor V. , Kaiser K. A. , McCormack S. , Morrison L. , Bonomi P. 
Published: March 2020

7592 Background: Prognostic factors associated with better outcomes (EGFR mutations (mut), high EGFR gene copy number, never smoking) can be used to select pts for EGFR tyrosine kinase inhibitor (TKI) combination trials, but would exclude the majority of NSCLC pts. Excluding pts with the worst likely outcomes is another strategy that may result in more pts who could benefit from the combination of a TKI with other agents. Our objective was to identify clinical and molecular characteristics associated with RPD (=70 days) and shorter progression-free survival (PFS) in previously treated NSCLC pts receiving G. Methods: Consecutive Expanded Access Trial pts with >1 week G were included for analysis. Tissue from 87 pts was evaluated for EGFR, pAKT and PTEN protein expression by immunohistochemistry; 58 tumors were analyzed for mut and sum of CA dinucliotide repeats (ΣCA rpts) by SSCP, PCR and sequencing. Results: There were 150 pts; 77 female, median (md) age 67. Md follow-up was 5.8 months (mo). Objective response was 8% (2CR, 10PR, 56 SD, 82 RPD). Md Kaplan-Meier PFS and survival were 2.0 and 5.8 mo, respectively. See table for univariate results. Smoking, Mut-PTEN-, EGFR-PTEN- and EGFR-pAKT- tumors were associated with shorter PFS. Separate clinical and molecular multivariate models were developed. In logistic regressions, non-adenocarcinoma histology (N- A), p=0.004, =12 mo from diagnosis to G (dx-G =12 mo), p=0.0009, lack of mut (p=0.0298) and ΣCA rpts <34 (p=0.0622) were associated with RPD. In Cox regressions, N-A (p=0.0256), dx-G =12 mo (p=0.0166) and lack of mut (p=0.0298) were associated with shorter PFS. Conclusions: N-A, dx-G =12 mo and lack of mut were associated with RPD and shorter PFS in univariate and multivariate analyses. ΣCA rpts <34 and double-negative molecular combinations were also related to worse outcome. These clinical and molecular characteristics may warrant further study as exclusion criteria for TKI combination clinical trials. [Table: see text] [Table: see text]
The quantification of epidermal growth factor receptor (EGFR) in plasma is a prognostic factor in advanced non-small cell lung cancer (NSCLC) patients
Authors: Camps C. , Sirera R. , Muñoz-Navarro M. , Lopez-Vivanco G. , Alonso G. , Provencio M. , Gonzalez-Larriba J. , de las Peñas R. , Taron M. , Rosell R. 
Published: March 2020

7597 Background: EGFR has an extracellular ligand-binding domain that can be proteolitically cleaved from the cell surface and can be accurately quantified in blood by ELISA. We have investigated the usefulness of plasma EGFR measurements as prognostic marker in advanced NSCLC. Methods: The cohort consisted in 329 patients (p) with advanced NSCLC that received first-line therapy with cisplatin and docetaxel. The concentration levels of the EGFR extracellular binding domain were determined by a sandwich quantitative ELISA in the baseline, before therapy. Results: Median age was 61, range [39–80], 84% males, 100% caucasian, 68% stage IIIB and 32% IV and 99% PS 0–1. The histological subtypes were: 31% squamous cell carcinoma, 49% adenocarcinoma, 15% large cell, and 5% undifferentiated. 181 p achieved complete response (CR), partial response (PR) or stable disease (SD) and 109 p progressive disease (PD). Median patient's plasma levels of EGFR were 32.4 ng/ml. There were not differences in p according to histology, site of metastasis and ECOG. There were differences in response to therapy; CR+PR+SD p presented median EGFR of 31.97 ng/ml [13.2–48.6] vs 30 ng/ml [16.9–46.8] in the PD group (p=0.024). Dividing the cohort in two sets according to EGFR median we found two significantly different groups in terms of Overall Survival (OS) and Time To Progression (TTP). Patients with EGFR<32.4 ng/ml had a median TTP of 3.9 months (m) [3.3–4.6] while for EGFR>32.4 ng/ml was 4.7 m [4.0–5.4], (p=0.024). OS when EGFR<32.4 ng/ml was 6.9 m [5.9–7.8] and for EGFR>32.4 ng/ml was 9.1 m [8.2–10.1], (p=0.038). Conclusions: Patients with PD presented significantly lower levels of serum EGFR than those patients with CR+PR+SD. There is a relationship among lower EGFR concentration in serum with a worst prognosis in advanced NSCLC p in terms of TTP and OS. No significant financial relationships to disclose.
Excision repair cross complementing 6 (ERCC6) single nucleotide polymorphism (SNP) and outcome to gemcitabine (gem)/cisplatin (cis) or docetaxel (doc)/cis in stage IV non-small cell lung cancer (NSCLC) patients (pts)
Authors: Etxaniz O. , Provencio M. , Terrasa J. , Carrato A. , Lianes P. , Bover I. , Perez-Cano M. , Sanchez J. , Taron M. , Rosell R. 
Published: March 2020

7605 Background: ERCC6 (alternate name CSB) is involved in both transcription coupled and base excision DNA repair, and the ERCC6 C-6530>G SNP is involved in gene regulation. Different levels of ERCC6 mRNA expression have been observed in cells according to ERCC6–6530 genotype. Methods: We investigated the ERCC6 C-6530>G SNP in 309 stage IV NSCLC pts treated with doc/cis (196 pts) and gem/cis (113 pts). DNA was extracted from peripheral lymphocytes and Taqman assay was used for SNP typing. Results: Distribution of ERCC6 genotypes was: CC 113 pts (36.6%); CG 157 pts (50.8%); GG 39 pts (12.6%). No differences in genotype were observed according to age, gender, performance status (PS), histology, chemotherapy regimen or second-line treatment. Overall time to progression (TTP) was 5.4 months (m) and median survival (MS) 9.9 m. No differences in TTP or MS were observed according to ERCC6 SNP types. However, when pts were broken down by chemotherapy regimen, TTP was 7 m for 31 CC pts treated with gem/cis and 5.4 m for 71 CC pts treated with doc/cis (P=0.04) ( Table ). MS was longer for CC pts treated with gem/cis (11 m) than for CC pts treated with doc/cis (8.9 m) (P=0.46). Differences were also observed in pts with PS 0 and in younger pts. Conclusions: ERCC6 C-6530>G SNP may confer differential sensitivity to gem or doc in combination with cis. We hypothesize that ERCC6 6350 CC is a surrogate of ERCC6 transcript, where lower ERCC6 expression levels may increase the activity of gem/cis in comparison to doc/cis. No significant financial relationships to disclose. [Table: see text]
A phase II multicenter trial comparing two schedules of lapatinib (LAP) as first or second line monotherapy in subjects with advanced or metastatic non-small cell lung cancer (NSCLC) with either bronchioloalveolar carcinoma (BAC) or no smoking history
Authors: Smylie M. , Blumenschein G. R. , Dowlati A. , Garst J. , Shepherd F. A. , Rigas J. R. , Hassani H. , Berger M. S. , Zaks T. , Ross H. J. 
Published: March 2020

7611 Background: LAP (GW572016) is an oral reversible, dual tyrosine kinase inhibitor of EGFR (ERBB1) and HER2/neu (ERBB2). This study was designed to test the activity of 2 dose schedules of LAP in chemotherapy naïve pts with NSCLC; it was amended to target patients with either BAC or no smoking history in the first or second line and to evaluate the relationship of mutations in target genes to responses. Methods: LAP was given orally 1,500 mg once (QD) or 500 mg twice daily (BID) until progression or intolerance. Safety and efficacy (RECIST) were assessed every 4 & 8 weeks. The primary endpoint was response. The target (BAC/no smoking) and non- target populations were assessed for efficacy, and tumor tissue was analyzed for ERBB1 and ERBB2 mutations and/or amplifications. Results: The study was stopped for futility after 131 pts were randomized (65 QD, 66 BID). Median age 66 (range 32–86); female 56%; BAC 20%, No BAC 71%; previously untreated 98.5%; current/former smokers 70%, never smoker 30%. There were no complete responses. Of 56 pts in the target population, 1 (2%) achieved partial response (PR), 11 (20%) had stable disease (SD) of ≥24 wks; in the non-target population, 1 pt had a PR (1.3%) and 12 (16%) had SD of ≥24 wks. 3 pts had ERBB1 mutations (G719S, S768I, KRAS G12S; L858R and T790M; L858R) but none of them responded. There were no ERBB2 mutations. Three of 77 pts evaluated had ERBB1 gene copy increase (none of whom responded) and 2 had ERBB2 gene copy increase (one had a 51% decrease in tumor size). The most common adverse events were grade 1/2 diarrhea, nausea, rash, vomiting and fatigue, and were similar in both groups. Conclusions: LAP was well-tolerated, with no notable difference in toxicity between the QD and BID groups. Very few responses were seen, stable disease was sometimes prolonged. The prevalence of mutations was low even in the target population. Given the preclinical synergy between LAP and other agents, further studies will be necessary to determine whether LAP is active in combination with other agents for the treatment of NSCLC. [Table: see text]
Expression profile of 29 genes by real-time quantitative PCR (RT-QPCR) in early-stage (I-IIIA) squamous cell carcinoma of the lung (SCCL)
Authors: Skrzypski M. , Jassem E. , Mendez P. , Chaib I. , Szymanowska A. , Rzyman W. , Gulida G. , Jassem J. , Taron M. , Rosell R. 
Published: March 2020

7612 Background: 5-year survival for surgically resected SCCL patients (p) is still limited. cDNA microarray studies have identified gene expression patterns that correlate with survival. We have examined the expression pattern of 29 genes selected by these studies to test their clinical prognostic value in early-stage SCCL. Methods: From 2000 to 2004, freshly frozen primary tumor specimens were obtained at the time of surgery from 66 Polish SCCL p. Sections were taken from blocks of tumor tissue for RNA extraction, and gene expression of the 29 genes was assessed by RT-QPCR (AB7900HT) using low density arrays (LDAs, Applied Biosystems). Expression values were dichotomized using the median value as the cut-off. Results: The univariate analysis showed 10 genes with prognostic value: PH4 (P=0.01); macrophage- colony stimulating factor (CSF1) (P=0.002); EGFR (P=0.05); KIAA0974 (P=0.02); ANLN (P=0.02); carbonic anhydrase IX (CA IX) (P=0.007); VEGFC (P=0.03); neurotrophic tyrosine receptor kinase 1 (P=0.04); fibronectin (P=0.002); insulin receptor (P=0.03). In the multivariate analysis of survival, CSF1, EGFR, CA IX and tumor size emerged as significant variables ( Table ). Conclusions: Tumor cells secrete CSF1, which attracts macrophages and induce them to express EGF, which in turn binds to EGFR in tumor cells. CA IX is regulated by hypoxia and plays a role in chemoresistance. Our findings highlight the relevance of tumor size and these markers in selecting p to receive adjuvant chemo- and targeted therapy. No significant financial relationships to disclose. [Table: see text]
Extent of nodal dissection and patient age impact recurrence-free survival (RFS) after surgery for non-small cell lung cancer (NSCLC)
Authors: Dy G. K. , Dy P. K. , Chua P. C. , Nelson G. D. , Foster N. R. , Mandrekar S. , Jett J. R. , Yang P. , Deschamps C. 
Published: March 2020

7613 Background: Factors influencing the pattern of disease relapse after curative surgical resection in early stage NSCLC is unknown. We sought to evaluate the effect of tumor- and patient-related characteristics on the pattern of disease recurrence (local relapse and/or metastatic disease) and survival in relation to surgical resection for NSCLC. Methods: A consecutive retrospective series of 488 patients seen at Mayo Clinic Rochester who had complete resection of NSCLC between 1997 and 1998 was utilized. Cox proportional hazards model was used to evaluate the effect of age, gender, smoking status, TNM stage, number of lymph node (LN) involved, number of LN resected, and histopathologic diagnosis on RFS. Logistic regression was used to evaluate the effect on recurrence or death within the first 2 years after surgical resection. Results: Data on 342 patients with a median follow-up of 85 months (range: 0.1 to 162) are reported. 60% were male, and 81% had N0 stage at diagnosis. There were 26 (7.6%) never smokers. Median number of LN resected was 20 (interquartile range [IQR]: 14–29). Median age at surgery was 71 years (IQR: 64 to 76). A bi-modal pattern of local recurrence (N=62) after surgery for early stage NSCLC was observed, with 57% of patients having a local recurrence within 2 years and 21% of patients having a local recurrence from 5–7 years post-surgery. The median duration from surgery to first documented recurrence was 16 months (IQR: 8 to 39). While age, N stage, number of LN involved, and T stage were significant predictors of RFS univariately, only lesser LN resected (p=0.008), older age (p<0.0001) and higher T-stage (p=0.003) were significant adverse predictors of RFS in the multivariate analysis when adjusted for all factors. Higher T-Stage was associated with a significantly increased risk of recurrence or death within the first 2 years after surgical resection (p =0.004). Updated results using data from all 488 patients will be presented in the meeting. Conclusions: A trend towards a bimodal distribution of local recurrences after surgical resection of early stage NSCLC was observed. Increased number of LN resected, younger age and lower T stage were associated with better RFS. No significant financial relationships to disclose.