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G.J. Weiss
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MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:P. Lara, A. Mohn-Staudner
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 3
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MA11.10 - Prospective Study of Genome-Wide Strexome and Transcriptome Profiling in Patients with Small Cell Lung Cancer Progressing after 1st Line Therapy (ID 4197)
15:26 - 15:32 | Author(s): G.J. Weiss
- Abstract
- Presentation
Background:
Small cell lung cancer (SCLC) that has progressed after 1[st] line therapy has few effective treatments and no new class of approved therapies in over 20 years. Paired tumor-normal exome and transcriptome sequencing efficiency, coverage, cost, and analytics has improved over the last decade and has begun to be applied in the clinic. In this prospective study, we used genome-wide strexome (exome+structural variation) plus whole transcriptome sequencing (NGS) to identify genomic events and associated expression changes in advanced SCLC and attempt to prescribe systemic therapy based on the results (NCT02297087, study was funded by SU2C).
Methods:
After informed consent a prospective fresh frozen tumor biopsy was obtained. Germline DNA was extracted from PBMC and reference normal tissue RNA was obtained commercially. Strexome and RNA-seq libraries were prepped and NGS, data analysis, and reporting were performed in a CLIA-certified CAP accredited environment.
Results:
The study completed its accrual goal of 12 evaluable patients. There was one screen failure due to anticipated inadequate sample yield because of tumor location. The cohort included 10 women, median age was 56.5 years and had 3 never smokers. All patients received prior platinum-based chemotherapy and were receiving >1[st] line systemic treatment while awaiting NGS results. The minimum tumor content for successful NGS was 20%. The median turnaround time from sample collection to report was 27 days (range 21-38). Average strexome coverage was 420X (tumor), 200X (germline), with an average of 277 million RNA reads generated for tumors. All patients had ³2 clinically actionable targets identified (associated with a commercially available, FDA-approved drug by predefined rules), median 4 targets (range 2-8). Three patients received treatment identified by NGS. One has continuing partial response by RECIST 1.1 >8 months on a clinical trial involving PD-1 inhibitor+irinotecan (MLH1 mutation); treatment linked to NGS was already initiated prior to the report becoming available. One is too early to evaluate on olaparib (PARP1 mutation), and one had disease progression on dasatinib (KIT overexpression) as best overall response. One patient has not yet received NGS recommended therapy, and the remaining 8 evaluable patients had clinical deterioration or died before NGS recommended therapy was initiated.
Conclusion:
SCLC after 1[st] line therapy tends to have more rapid progression and deterioration making NGS application for systemic therapy challenging. Either applying NGS earlier in the earlier stages of disease course or further improvements in turnaround time may better address these challenges.
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OA19 - Translational Research in Early Stage NSCLC (ID 402)
- Event: WCLC 2016
- Type: Oral Session
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:G. Heller, G. Goss
- Coordinates: 12/07/2016, 11:00 - 12:30, Schubert 3
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OA19.05 - High Oncofetal Chondroitin Sulfate Expression is an Independent Prognostic Factor of Poor Survival in Early-Stage NSCLC (ID 5601)
11:45 - 11:55 | Author(s): G.J. Weiss
- Abstract
- Presentation
Background:
Most human cancers express proteoglycans modified with distinct oncofetal chondroitin sulfate (CS) chains that are normally restricted to placental tissue. Oncofetal CS chains can be conveniently detected and targeted by recombinant VAR2CSA (rVAR2) proteins derived from the malaria parasite Plasmodium falciparum. In the present study, we have analyzed the expression landscape of oncofetal CS modifications in early-stage non-small cell lung cancer (NSCLC).
Methods:
Tissue microarrays from four separate patient cohorts representing a total of 493 clinically annotated stage I-II NSCLC cases were stained for oncofetal CS using rVAR2. Data were analyzed for correlation between low and high oncofetal CS presentation by immunohistochemical (IHC) staining of tumor and stroma compartments in respect to EGFR and KRAS mutations, as well as to clinical characteristics including relapse-free survival (RFS) and overall survival (OS).
Results:
There were 351 patients with low (IHC score 0-1) and 142 with high (IHC score 2-3) expressing tumors. We identified 331 adenocarcinomas, 145 squamous cell carcinomas, and 12 cases with other NSCLC subtypes. There were 314 stage I and 179 stage II cases by AJCC 7[th] edition. High oncofetal CS expression was significantly associated with shorter RFS (vs. high expressiors; 58 vs. 39 months, respectively, p=0.034) and OS (vs. high expressors; 69 vs. 51 months, respectively, p=0.044). High oncofetal CS expression was significantly associated with shorter RFS vs. low expression in men (p=0.024), smokers (p=0.011), and in patients with squamous cell tumors (p=0.012). High oncofetal CS was also significantly associated with shorter OS in men (p=0.005) and smokers (p=0.028). There were no significant RFS or OS differences in oncofetal CS expressions when stratifying the patients according to their EGFR or KRAS statuses. In multivariate survival analyses, histology, stage, and high oncofetal CS expression was significantly associated with shorter RFS vs. high expression (HR, 1.8; 95% CI, 1.32–2.48; p < 0.001).
Conclusion:
This is the first study showing that high oncofetal CS expression is an independent prognostic factor of poor RFS in NSCLC and validates high oncofetal CS expression as a prognostic factor of poor OS. In contrast to non-smoker females, oncofetal CS appears to be a prognostic for OS in males and smokers. Our work promotes oncofetal CS as a candidate target for rVAR2-based therapeutic intervention in NSCLC patients with poor RFS/OS.
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P1.04 - Poster Session with Presenters Present (ID 456)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Pulmonology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.04-019 - Final Analysis of Lung Microbiome from Patients Undergoing Bronchoscopy (ID 4201)
14:30 - 14:30 | Author(s): G.J. Weiss
- Abstract
Background:
Recent studies have demonstrated diversity in the lung microbiomes of chronic obstructive pulmonary disease and healthy individuals. Lung microbial communities may not just serve as a predictor of cancer development, but also as a target of pharmacological cancer prevention strategies. We sought to characterize the lung microbiome diversity within patients with lung cancer for comparison to those with other cancers and those without cancer.
Methods:
Signed informed consent was obtained from patients ages ≥18 years undergoing a clinically indicated bronchoscopy. A bronchial lavage (BAL) was collected for research purposes after completing routine bronchoscopic procedures. Samples were prepped and DNA was extracted and 515F/806R 16S rRNA primers used to amplify Variable Region 4. Amplicons were sequenced and grouped into 100% operational taxonomic units (OTUs) using vsearch. Taxonomy was assigned, a phylogenetic tree was constructed, and sequences aligned for phylogenetic diversity calculations, including Faith's Phylogenetic Diversity and weighted and unweighted UniFrac. OTUs that were significantly different across sample categories were identified using DESeq2.
Results:
There were 137 unique BAL samples collected. One patient had an adverse research procedure event that resolved after temporary supplemental oxygen and overnight observation. BALs were from 68 non-small cell lung cancer (NSCLC), 12 small cell lung cancer (SCLC), 52 other cancers, and 5 non-cancer patients. 58 NSCLC were current/former smokers (average 43 pack-years), while all the SCLC were current/former smokers (average 56 pack-years). 22 other cancers were current/former smokers (average of 27 pack-years). Overall, 51 samples (37.2%) had sufficient sequencing reads (>20,000) for subsequent analyses. There were multiple bacterial taxonomic groups in each sample, however, phylogenetic diversity was low compared to other body sites. There were no statistical differences in alpha/beta diversity between ever-smokers and never-smokers, NSCLC vs SCLC, lung cancer vs non-cancer, and location of BAL collection (upper vs lower airways and right vs left lung). There were a number of statistically significant differences by taxonomy (False Discovery Rate adjusted p<0.01 and listing genus only). Adenocarcinoma vs non-adenocarcinoma had more Streptococcus and Veillonella; less Haemophilus. For NSCLC vs SCLC, Rothia was more prevalent in SCLC. BALs from the upper airways had more prevalent Streptococcus. BALs from the right lung had more prevalent Capnocytophaga and Parvimonas; less Moraxella and Selenomonas.
Conclusion:
We report significant taxonomic differences by tumor type and location of BAL sampling and overall low phylogenetic diversity. Future validation of this work can be used to modify bacterial colonization in a lung cancer prevention strategy or for early diagnostics/therapeutics.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 2
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-023 - NGS May Discriminate Extreme Long-Term versus Short-Term Survival in Patients with Stage IV Small-Cell Lung Cancer (SCLC) (ID 5660)
14:30 - 14:30 | Author(s): G.J. Weiss
- Abstract
Background:
Molecular underpinnings that may prognosticate survival and could increase our understanding of tumor progression are far less understood processes in highly aggressive malignancies such as SCLC. We aimed to describe the clinocopathological characteristics and biomarker profiling of short versus long-term SCLC survivors using the latest, most clinically actionable genomic and immunohistochemical (IHC) alterations.
Methods:
Consecutive 876 metastatic SCLC patients receiving standard of care therapy were evaluated between 2000 and 2013 at the National Koranyi Institute of Pulmonology. Long-term (LT) (overall survival (OS) > 24 months) and short-term (ST) survivors (OS range 2-9 weeks) with histologically confirmed stage IV SCLC were included in this retrospective analysis. DNA and RNA were isolated from FFPE tissues. A comprehensive next-generation sequencing test (NGS) was performed to analyze gene mutations, copy number variations (CNV), mRNA expression, and protein expression by IHC (PCDx, Paradigm). Multiplex sequencing analysis had coverage >5,000x. We then evaluated the associations amongst these various biomarkers and clinicopathological characteristics.
Results:
Four LT and 11 ST were identified for NGS. There were five mutually exclusive gene mutations, previously not described in SCLC (EP300: c.650A>G p.N217S; c.4561G>A p.E152K; ERBB4: c.949G>A p.E317K; BRCA1: c.4981G>A p.E1661N; and EGFR (ERBB1): c.2225T>C p.V742A). Mismatch repair (MMR) deficiency, CNV and PD-L1 in tumor-infiltrating lymphocytes (TIL)/tumor cells were not found in any of the samples. TOP1 was highly elevated in both groups, supporting campothecins as effective drugs in SCLC. Certain mRNA genes appeared to be linked in a similar or overlapping pathway. HENT1 (SLC29A1) with 50-79% protein concordance and survivin (BIRC5) mRNAs were high in most of the ST vs. LT. All LT survivors, but none of the ST survivors, received consolidation thoracic radiation therapy (RT) along with standard of care chemotherapy. SSTR2 mRNA expressions were higher in LT survivors (vs. ST survivors) treated with first-line platinum-etoposide. Molecular testing revealed that ST survivors treated with cyclophosphamide, epirubicin, and vincristine were not predicted to be sensitive to doxorubicin or epirubicin. LT survivors proved to be sensitive to irinotecan/topotecan and lanreotide/octreotide but not to platinum (BRCA1 and/or survivin mRNA was not present).
Conclusion:
Consolidation RT and certain linked pathways may discriminate between LT and ST survivors in SCLC. NGS profiling of extreme survivors may improve classification of SCLC and possibly identify clinically-relevant new targets.
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P1.07-042 - Neutrophil-Lymphocyte and Platelet-Lymphocyte Ratios Predict Prognosis in Early-Stage Resected Small-Cell Lung Cancer Patients (ID 5657)
14:30 - 14:30 | Author(s): G.J. Weiss
- Abstract
Background:
Surgical resection is rarely possible in small-cell lung cancer (SCLC), a highly aggressive malignancy with limited treatment options. However, although in the past decades, for selected early-stage cases, a curative intent surgery is often performed, there is no biomarker to help the selection of patients eligible for surgery. Because previous studies - predominantly from East Asia - showed that high neutrophil to lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) correlate with poor prognosis in several types of tumors including SCLC, the aim of our study was to investigate the prognostic value of NLR and PLR in Caucasian patients with resected SCLC.
Methods:
Consecutive patients with histologically confirmed and surgically resected SCLC evaluated between 2000 and 2013 at the National Koranyi Institute of Pulmonology were analyzed in this retrospective analysis. Patients were divided into "high" and "low" groups according to their NLR and PLR at diagnosis. The cut-off NLR and PLR values were 3 and 110, respectively. Next, we evaluated the associations of preoperative NLR or PLR with vascular involvement, tumor necrosis, peritumoral inflammation, tumor grade, clinicopathological characteristics (including age, gender, stage) and overall survival (OS) in univariate and multivariate analyses.
Results:
There were a total of 65 patients (39 men and 26 women) with a median age of 57.7 years (range, 40-79). The pathological stages were 1, 2 and 3A in 23, 23 and 14 cases by AJCC 7[th] edition (in five patients no pTNM was available). PLR was high (HPLR) in 41 (63%) and low (LPNR) in 24 (37%) patients. NLR was high (HNLR) in 35 (66%) and low (LLNR) in 17 (33%) patients. PLR significantly correlated with pathologic lymph node status (p<0.001) and NLR (p=0.007). HPLR was associated with shorter OS (vs. LPLR, HR, 2.2; 95% CI, 1.13–4.29; p=0.02). There was a non-significant trend towards longer OS in patients with LNLR (vs. HNLR, p=0.078). There were no significant associations between NLR or PLR and age, gender, stage, vascular involvement, tumor necrosis, peritumoral inflammation and tumor grade.
Conclusion:
This is the first study in Caucasian patients with resected SCLC which shows that LPLR (<110) before surgical resection may be a favorable prognostic factor for longer OS. We also conclude that preoperative HPLR may predict lymph node involvement. PLR but not NLR may help in selecting patients for surgery in the future. Further prospective studies are needed to confirm these observations.
