bluuebunny/crossref_metadata_2025_split huggingface dataset:
FISHing for lung cancer: Promising findings using multi-targeted interphase fluorescence in situ hybridization (FISH) for lung cancer detection in sputum
Authors: Franklin W. A. , Byers T. , Wolf H. J. , Braudich S. , Hirsch F. R. , Miller Y. E. , Keith R. L. , Kennedy T. C. , Belinsky S. , Varella-Garcia M. 
Published: March 2020

7567 Background: Lung CT imaging shows promise for early lung cancer detection, but may be insensitive for central lesions and will create a need for complementary biomarkers to guide clinical decisions. Methods: We have been conducting a prospective study to assess the performance of various biomarkers in sputum to detect lung cancer. Within a cohort of 3,269 people at high risk for lung cancer (over 30 pack-years of cigarette use and chronic obstructive lung disease) we have conducted a nested case-control study to assay stored samples from 85 incident lung cancer cases and 73 controls for cytologic morphology, DNA methylation, and multi-targeted FISH assays (LAVysion, Vysis/Abbott Molecular). The FISH assay targeted DNA sequences from centromere 6, 5p15.2, 7p12 (EGFR), and 8q24 (cMYC). Cytology was classified as abnormal if moderate or greater atypia was observed, methylation was abnormal if three or more of 8 selected genes were methylated, and FISH was abnormal if two or more scored cells were observed to contain chromosomal aneuploidy indicated by signal gain for at least two targets or signal gain for one and signal loss for two or more targets. Results: Among all subjects, regardless of the time between sputum collection and diagnosis, FISH was abnormal in 49/87 cases (56%) and 5/73 controls (7%) (odds ratio (OR) = 17.5, 95% CI = 6.4 to 47.8). Considering only the cases for which sputum had been collected within 18 months before the lung cancer diagnosis, FISH was abnormal in 37/49 cases (75%) and in 3/38 controls (8%) (OR = 36.0, 95% CI = 9.4 to 138). For this same time period, cytological atypia was abnormal in 37% of cases and 22% of controls (OR = 2.1, 95% CI = 0.8 to 5.3) and methylation was abnormal in 64% of cases and 36% of controls (OR = 4.5, 95% CI = 1.0 to 19.8). Conclusions: The LAVysion FISH assay is more sensitive than other currently available sputum tests for the prediction of invasive carcinoma in subjects and is highly specific with a low frequency of false positive and false negative results. The results suggest that chromosomal aneuploidy and by extrapolation, missegregation, are features of advanced premalignancy and should identify patients who are proximate to clinically overt lung cancer. [Table: see text]
What we could know from the semiannually repeated screening with low-dose helical CT in a high-risk cohort over 10 years: Update of Anti-Lung Cancer Association project
Authors: Seki N. , Eguchi K. , Kaneko M. , Ohmatsu H. , Kakinuma R. , Matsui E. , Kusumoto M. , Tsuchida T. , Nishiyama H. , Moriyama N. 
Published: March 2020

7568 Background: There have been several randomized trials of low-dose helical CT (LDCT) screening for lung cancer. However, all trials are in progress. Therefore, before they are completed, we summarized what we could know from an update of Anti-Lung Cancer Association project, which was regarded as a longer-term study with LDCT performed at shorter intervals and with a larger number of detected cancers than any other single-armed studies. Methods: Among 2,120 participants, 1,877 (mean age 64 years, 88% male, and 84% smoker) underwent semiannually repeated screening from 1993 to 2004 (median, 3.5 years). We investigated (1) survival of patients with screening detected lung cancers, (2) presence of a stage shift (indicator of a mortality benefit), (3) appropriate duration of repeated screening, (4) identification of high-risk group by age, sex, and smoking, and (5) appropriate screening intervals by high-risk group (6 months or 1 year). Results: (1) The 5- and 10-year survival rates were 84.5% and 84.5%, respectively, in repeated screening group (n = 57) and were 68.7% and 38.1%, respectively, in initial screening group (n = 19) (P = 0.208). (2) Only in invasive adenocarcinoma, both proportion of stage II to IV and tumor size were negatively correlated with duration of repeated screening (r = −0.77, P = 0.007 and r = − 0.60, P = 0.029, respectively). (3) Detection rate of all incidence cancers were positively correlated with duration of repeated screening (r = 0.50, P = 0.020). However, detection rate remained unchanged until 5 years of repeated screening. Moreover, stage shift did not occur until 5 years of repeated screening. (4) Female sex (HR 2.9, P = 0.015) and smoking (HR 2.7, P = 0.046) were demographic risk factors for lung cancer detection at repeated screening. The accumulated 10-year detection rates for female smokers (n = 91), male smokers (n = 1,557), and non-smokers (n = 229) were 15.1%, 6.2%, and 4.3%, respectively (P = 0.002). (5) The estimated relative cancer detection powers of annual screening to semiannual screening were 50% and 57% for female and male smokers with lung cancer, respectively. Conclusions: Semiannually repeated LDCT screening over 5 years might be beneficial to smokers, especially female smokers. No significant financial relationships to disclose.
Smoking history and frequency of somatic KRAS mutations in adenocarcinoma of the lung
Authors: Miller V. A. , Riely G. J. , Kris M. G. , Rosenbaum D. , Marks J. , Li A. , Chitale D. , Nafa K. , Pao W. , Ladanyi M. 
Published: March 2020

7573 Background: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are more common in patients with adenocarcinoma, especially those who smoked < 15 pack years (py). KRAS mutations are found in ∼25% of lung adenocarcinomas, most commonly in codons 12 and 13 of exon 2 (∼85%) and have been associated with poor prognosis in resected disease [Winton NEJM 2005] and resistance to EGFR tyrosine kinase inhibitors [Pao PLoS Med 2005]. KRAS mutations are uncommon in non-small cell lung cancer histologies other than adenocarcinoma. We sought to determine the association between quantitative measures of cigarette smoking and presence of KRAS mutations in lung adenocarcinomas. Methods: Standard direct sequencing techniques were used to identify KRAS codon 12 and 13 mutations in lung adenocarcinoma specimens from surgical resections between 2001 and 2006 and tumor specimens sent for KRAS molecular analysis in 2006. Surgical specimens were obtained from an institutional tumor bank. Detailed smoking history (age at first cigarette, packs per day, years smoked, years since quitting smoking) was obtained from the medical record and a patient-completed smoking questionnaire. Results: KRAS mutational analysis was performed on 408 lung adenocarcinomas from 242 women and 166 men. Median age was 68 (range 33–89). KRAS mutations were present in 19% (78/408, 95% CI 15 to 23%). The frequency of KRAS mutation was not associated with age or gender. The presence of KRAS mutations was not related to smoking history with 15% (9/61) of never smokers having KRAS mutations compared with 19% (51/275) of former smokers. When compared with never smokers, there was no significant difference in frequency of KRAS mutations for tumors from patients with 1–5 py (5%, p=0.44), 6- 10 py (12%, p=0.99), 11–15 py (25%, p=0.45), 16–25 py (16%, p=0.99), 26–50 py (25%, p=0.129), 51–75 py (20%, p=0.48), >75 py (20%, p=0.47) history of cigarette smoking. Conclusions: While the incidence of EGFR mutations has a strong inverse relationship with the amount of cigarettes smoked, allowing the selective molecular testing for EGFR mutations, the frequency of KRAS mutations cannot be predicted by age, gender, or smoking history. KRAS mutational analysis of all adenocarcinomas is required to reliably identify patients with KRAS mutations. No significant financial relationships to disclose.
Paraffin-based molecular diagnosis of lung cancer reproduces morphologic and molecular subtypes of lung cancer
Authors: Hayes D. N. , Schallheim J. , Roberts P. , Lee C. , Thorne L. , Perou C. , Parsons A. , Socinski M. A. , Funkhouser W. , Bernard P. 
Published: March 2020

7579 Background: Molecular profiling of lung cancer by gene expression analyses has documented potential to guide therapy. However, quality ‘fresh’ tissue for RNA analyses is generally unavailable in clinical practice. We introduce a (q)RT-PCR assay and analytic method for profiling lung cancers from clinically obtained formalin-fixed paraffin-embedded tissues. Methods: Approximately 1,000 DNA microarrays were analyzed to select genes distinguishing the major histological variants (adenocarcinoma, small cell carcinoma, etc) and previously described molecular subtypes of lung cancer. Based on gene expression, a classifier of 62 genes was constructed to assign each sample to its morphologic tumor type, as well as to risk stratify by molecular subtypes. A real-time qRT-PCR assay was developed to evaluate the expression of the 62 genes from paraffin-embedded samples. This assay was used to profile RNA extracted from a cohort of surgically treated lung cancer patients. Samples were procured as fresh frozen and formalin-fixed, paraffin-embedded and were archived between 1–15 years. Results: Fifty-eight of 62 genes passed performance criteria and were used for analyses. Normalized gene expression was used for sample classification. The cohort contained a broad spectrum of tumors in proportions consistent with clinical practice. Gene amplification was successful in 139 of 142 (98%) lung cancer samples. Matched frozen-paraffin and replicate paraffin samples had mean correlations of approximately 80%. Linear discriminant analysis of gene expression data agreed with morphologic classification by light microscopy in >99% of cases. More importantly, the method successfully re-identified molecular subtypes of lung cancer for the first time through the use of a paraffin-based assay. Clinical outcomes previously associated with molecular tumor subtypes, including differential survival and metastatic patterns, were again seen in our cohort. Conclusions: We describe for the first time a clinically meaningful and robust molecular diagnosis of a clinical cohort of lung cancer patients which is complementary to morphologic cancer diagnosis. This assay is easily implemented using specimens routinely collected in current patient care. No significant financial relationships to disclose.
Quality of life (QOL) impact of adjuvant chemotherapy for early stage non-small cell lung cancer (NSCLC): Final analysis of JBR.10 randomized trial
Authors: Bezjak A. , Lee C. W. , Ding K. , Winton T. , Brundage M. , Graham B. , Whitehead M. , Seymour L. , Shepherd F. A. 
Published: March 2020

7585 Background: Adjuvant chemotherapy for early stage NSCLC is now standard of care, but its impact on QOL is not known. We report the final QOL analysis of JBR.10, a North American intergroup randomized trial of adjuvant cisplatin/vinorelbine compared to observation in patients (pts) with completely resected stage IB/II NSCLC (n=482). Methods: QOL, a secondary endpoint of JBR.10, was assessed using the EORTC QLQ-C30 and a trial-specific checklist at baseline, weeks 5 and 9 for those on chemotherapy, and at 3, 6, 9, 12, 18, 24, 30 and 36 months of follow up. A 10-point change in QOL scores from baseline was considered clinically significant. Results: QOL assessment was not mandatory for all pts; 186/242 (76.9%) pts randomized to chemotherapy completed the baseline QOL assessment, compared to 173/240 (72.1%) pts on the observation arm. The overall survival of pts contributing QOL data, and the effect of adjuvant chemotherapy, was not different from the entire study population. Baseline QOL in the two study arms was comparable, with low global QOL scores and a significant symptom burden, especially pain and fatigue, following thoracotomy. A significantly greater proportion of chemotherapy pts experienced worsening symptoms including fatigue (p=0.02), appetite, hair loss, nausea and vomiting. At 6 months, a higher proportion of pts on the observation arm reported improved QOL in the global (p = 0.002), physical (p=0.02) and functional domains, compared to pts on the chemotherapy arm. However, by the 9 month time-point, global QOL of patients on chemotherapy was comparable to QOL of patients on observation, as were the five functional domains. Numbness (change scores: 22 vs 6, p<0.01) and pins & needles in fingers/toes (change scores: 21 vs 5, p<0.01) were the only symptoms that persisted, up to 24 months. Conclusion: Patients on adjuvant chemotherapy experience an initial slower recovery of QOL after thoracotomy, but following completion of treatment reach levels comparable to patients treated with surgery alone, in most aspects of QOL. [Table: see text]
Final results of ECOG 3503: A pilot study to determine if downstream markers of EGFR linked signaling pathways predict response to erlotinib (OSI-774) in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC)
Authors: Kolesar J. , Brahmer J. , Lee J. , Guaglianone P. , Patel J. , Keppen M. , Hidalgo M. , Carbone D. , Schiller J. 
Published: March 2020

7588 Background: Predictors of response and survival in patients (pts) who benefit from Erlotinib (Elb) remain controversial. The primary objective is to prospectively identify downstream markers of EGFR linked signaling pathways that are predictive of response. The secondary objectives are to estimate response rate (RR), disease control rate (dcr), time to progression (ttp), survival, and if a grade (gr) 2 rash is predictive of survival. Methods: Pts with advanced NSCLC (Stage IIIB with pleural effusion and IV, no prior systemic treatment, performance status 0–2, no symptomatic CNS metastasis, and adequate renal, hepatic and hematologic function) were accrued to this single arm study. Elb was taken orally once a day until disease progression or unacceptable toxicity. Starting at 150 mg per day, the dose was escalated by 25 mg once every 2 weeks until a gr 2 rash developed, other toxicities precluded escalation, or 250 mg dose reached. Paraffin- fixed tumor tissue was collected on pts for correlative studies including quantitative immunohistochemistry (IHC) for pMAPK. Results: Of 137 pts recruited, 118 were eligible and 57 pts had adequate tissue to do IHC. Dose escalation occurred in 60/118 pts, with 15 getting up to 250 mg. The RR, by RECIST criteria, was 7% (8/112, 1 CR) with dcr of 46% (51/112). Most pts went off trial because of progression of disease (69%). Median survival was 7.9 months (mo), and median ttp was 3.5 mo. Of the 134 pts evaluated for toxicity, 43 (32%), 66 (49%), and 13 (10%) had a gr 1, 2 and 3 rash respectively. pMAPK was not a predictor for response. Using a median score of 20 as the cutoff for pMAPK as positive or negative, negative pMAPK tended to have a longer survival (7.6 mo vs. 5.3 mo, p=0.051). A gr ≥ 2 rash trended towards an association with prolonged survival (12.6 mo vs. 6.4 mo, p=0.099). Conclusions: Elb used as first-line treatment in an unselected population has a response rate and survival similar to first-line chemotherapy. Negative pMAPK may predict for prolonged survival but does not predict response. EGFR mutation and FISH analysis will be available at the meeting. No significant financial relationships to disclose.
Correlative analyses of plasma cytokine/angiogenic factor (C/AF) profile, gender and outcome in a randomized, three-arm, phase II trial of first-line vandetanib (VAN) and/or carboplatin plus paclitaxel (CP) for advanced non-small cell lung cancer (NSCLC)
Authors: Hanrahan E. O. , Lin H. Y. , Du D. Z. , Yan S. , Kim E. S. , Lee J. J. , Ryan A. J. , Tran H. T. , Johnson B. E. , Heymach J. V. 
Published: March 2020

7593 Background: VAN (ZD6474) is an oral inhibitor of VEGFR, EGFR and RET. In a phase II trial, 181 patients with advanced NSCLC were randomized to 1st-line treatment with VAN, CP or VAN + CP. Progression free survival (PFS) was prolonged for VAN + CP vs CP (Heymach et al, submitted for ASCO 2007). Exploratory subgroup analyses suggest gender differences in PFS benefit for VAN + CP vs CP (HR 0.47 in females vs 1.05 in males). We performed exploratory analyses of plasma levels of 35 C/AFs to investigate gender differences and potential prognostic or predictive markers. Methods: Plasma was collected at baseline (n = 123; VAN 55, CP 32, VAN + CP 36), day (D) 8 (n = 104), D22 (n = 95), and D43 (n = 83). We used multiplex bead assays to measure 33 plasma C/AFs, including VEGF, basic FGF, EGF, HGF, E-selectin, ICAM-1, MMP-9, multiple chemokines and interleukins (IL). Osteopontin and sVEGFR-2 were measured by ELISA. Cox models were applied on PFS to identify prognostic/predictive markers after rank transformation and adjusted for covariates. Results: Significant gender differences in baseline C/AF levels were seen for IL-15, IL-1RA, IL-2R, MIG, and MIP-1A (all higher in females, all p = 0.022). Controlling for gender and treatment, high baseline E-selectin (p = .01), IL-6 (p = 0.018), and IL-2R (p = 0.008) were adverse prognostic indicators for PFS. Controlling for gender, the tests for treatment by factor interactions (to assess whether treatment effect was different in patients with low and high C/AF levels) were significant for baseline HGF (p = 0.04) and IL-2R (p = 0.008). For both HGF and IL- 2R, low levels were associated with prolonged PFS in the VAN arm, but were not associated with differences in the CP or VAN + CP arms. Significant changes in VEGF (rise) and sVEGFR-2 (decrease) occurred with treatment in the VAN arm; IL12, IL-1RA, MMP-9 and MCP-1 changed in the CP and VAN + CP arms. Conclusions: There are gender differences in PFS benefit from VAN and in plasma C/AF profile. Several C/AFs were of prognostic value, whereas low HGF and IL-2R were predictive of benefit in the VAN but not CP and VAN + CP arms. These gender differences and markers warrant further investigation. [Table: see text]
Clinicopathologic features and prognostic implications of epidermal growth factor receptor (EGFR) gene mutations detected by denaturing high-performance liquid chromatography (dHPLC) in non-small cell lung cancer (NSCLC)
Authors: Cohen V. , Agulnik J. S. , Ang C. , Kasymjanova G. , Chong G. , Tejada N. A. , Pepe C. , Batist G. , Small D. , Miller W. H. 
Published: March 2020

7594 Background: Somatic mutations of the EGFR gene predict sensitivity to erlotinib and gefitinib and confer a favorable prognosis in patients (pts) with NSCLC. We have recently shown that dHPLC is an efficient and more sensitive method for mutation screening compared with DNA sequencing. The goal of this study was to describe the relationship between EGFR status (mutation status and type) and clinicopathologic factors. Methods: Tumor samples were analysed for EGFR exon 19 deletions and exon 21 L858R point mutations. DNA was extracted from paraffin-embedded tumor specimens and genotyped using dHPLC. The results were correlated with gender, smoking status, pathologic subtype, disease stage, and overall survival. Results: 215 NSCLC pts were genotyped. Mutations were present in 25% of cases (54 of 215). Among pts with mutations, 70% (38 of 54) had an exon 19 mutation whereas 30% had EGFR L858R. EGFR mutations were more common in women (31% vs 14%; p=0.008), in nonsmokers than ever-smokers (54% vs 17%; p<0.001), in adenocarcinomas/BAC than with other NSCLC histologies (31% vs 11%; p=0.004) and more frequently detected in advanced-stage than in early-stage disease (36% vs 15%; p=0.001). Median survival times of pts with stage IIIB-IV disease with and without EGFR mutations were 20 and 14 months, respectively. Those with exon 19 deletion mutations had a longer median survival than pts with L858R point mutations. Data describing the impact of tyrosine kinase inhibitor therapy on survival outcomes are pending and will be presented. Conclusion: dHPLC is a reliable tool for EGFR mutation detection. Mutations were preferentially observed in women, nonsmokers, adenocarcinomas/BAC and in patients with advanced disease. Pts with mutations experienced improved survival and those harboring deletions fared better than those with point mutations. These observations warrant confirmation in large prospective trials and exploration of the biological mechanisms of the differences between mutation types. No significant financial relationships to disclose.
Phase II randomized trial of docetaxel plus cetuximab or bortezomib in patients with advanced NSCLC and performance status (PS) 2—CALGB 30402
Authors: Lilenbaum R. , Wang X. , Gu L. , Kirshner J. , Vokes E. 
Published: March 2020

7595 Background: There is no standard treatment for patients (pts) with advanced NSCLC and PS 2. Docetaxel (D) is active and well tolerated on a weekly schedule. Cetuximab (C) and Bortezomib (B) are new agents with activity in NSCLC. We explored these two new combinations in PS 2 pts. Methods: In a multi-center randomized phase II trial, untreated pts with advanced NSCLC and PS 2 were randomized to D 30 mg/m2 d1,8,15 q. 28 days in combination with either C 400 mg/m2 week 1 then 250 mg/m2 weekly, or B 1.6 mg/m2 d1,8,15 q. 28 days for 4 cycles. Pts with CR/PR/SD were allowed to continue C or B until PD. The study was non-comparative and the primary endpoint was progression-free survival (PFS) rate at 6 months. The trial had a type I error of 0.0746 and power of 0.9 to differentiate a 6-mo PFS of <20% vs. >42%. Results: 64 pts were enrolled between 7/05 and 9/06. 5 were ineligible and 3 never received protocol treatment. Results are reported for 55 pts (27 D+C; 28 D+B). Most pts had stage IV adenoCa and 13% had brain metastases. Median age was 70 (range, 35–88) and 65% were male. Response: 10.5% for D+C and 13.6% for D+B. Median PFS was 3.1 mo for D+C and 1.8 mo for D+B. PFS rates at 4 mo (data not yet mature for 6-mo): 33% and 28%, respectively. Median survival: 3.8 mo for D+C and 3.3 mo for D+B. Gr 3/4 hematologic toxicity was 17% in both arms. Gr 3/4 non-heme toxicities were 44% in D+C and 36% in D+B arm. 5 pts died of treatment-related toxicities (3 D+C; 2 D+B). Conclusions: These results confirm the poor prognosis associated with a PS of 2. Based on our preliminary analysis, neither combination produced results that justify further research in this subset of patients. The treatment of PS 2 patients with advanced NSCLC remains a vexing problem and new approaches are urgently needed. No significant financial relationships to disclose.