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Yoon-La Choi
Moderator of
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OA 18 - Lung Cancer Pathology and Genetics (ID 687)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 9
- Moderators:George R. Simon, Yoon-La Choi
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 316
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OA 18.01 - Paired Tumor-Normal Next-Generation Sequencing (NGS) to Identify Pathogenic / Likely Pathogenic Germline Mutations in Lung Cancer Patients (ID 10326)
14:30 - 14:40 | Presenting Author(s): Rongrong Chen | Author(s): Y. Yi, P. Dai, C. Zhu, J. Huan, T. Liu, M. Zhao, Y. Guan, L. Yang, X. Xia, X. Yi
- Abstract
- Presentation
Background:
Comprehensive NGS panel based genetic testing is becoming more common to help clinicians select appropriate therapies. It has been recommended that matched tumor-normal sequencing analyses are essential for precise identification and interpretation of genetic somatic mutations. Though it has been reported germline EGFR T790M mutations result in a unique hereditary lung cancer syndrome, little is known about germline mutation of other common hereditary cancer syndrome genes in lung cancer patients.
Method:
We reviewed the germline variants of 1000 consecutive lung cancer patients who had paired tumor-normal NGS panel sequencing in our institute between 2016 and 2017. Hybridization capture-based NGS panel sequencing enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations at least 59 genes (range 59 – 1021 genes). Germline variants were interpreted following ACMG guidelines, and the variants were classified into pathogenic, likely pathogenic, variant of unknown significance, likely benign, and benign 5 classes.
Result:
Twenty-seven cases were identified to carry germline pathogenic or likely pathogenic mutations in 12 gene (2.7%): 5 with ATM ; 4 with BRCA1, BRCA2 or MSH2 respectively; 2 with CHEK2 or PMS2 respectively; 1 in ATR, CDKN2A, FANCC, MSH3, PTCH2 or RET respectively (details in table). Mean age at diagnosis was 58 (30 – 84 years) for the patients with germline mutations and 61 (29-93 years) for those without. Interestingly, none of the patients had been diagnosed with other tumors. The incidence of actionable somatic mutations of the 27 patients was similar to others: 10 patients with EGFR mutation, 3 patients with KRAS mutation, 1 patient with KIF5B-RET fusion, MET copy number gain or BRCA1 mutation respectively.No. Gene cHGVS pHGVS Mutation type 1 ATM c.1402_1403delAA p.K468Efs*18 frameshift 2 ATM c.1898+1G>C . splice 3 ATM c.2143_2144delCT p.L715Cfs*22 frameshift 4 ATM c.6019dupG p.E2007Gfs*11 frameshift 5 ATM c.903dupT p.A302Cfs*3 frameshift 6 ATR c.80_81insA p.N27Kfs*16 frameshift 7 BRCA1 c.4185+1G>A . splice 8 BRCA1 c.962G>A p.W321* nonsense 9 BRCA1 c.3340delG p.E1114Kfs*3 frameshift 10 BRCA1 c.81-2A>G . splice 11 BRCA2 c.3968_3971delAATA p.K1323Ifs*11 frameshift 12 BRCA2 c.5054C>G p.S1685* nonsense 13 BRCA2 c.6132_6135delCTTT p.F2045Hfs*5 frameshift 14 BRCA2 c.6485_6486delAA p.K2162Tfs*13 frameshift 15 CDKN2A c.73delG p.V25* frameshift 16 CHEK2 c.1010delC p.A337Efs*10 frameshift 17 CHEK2 c.1684C>T p.R562* nonsense 18 FANCC c.1257_1258insC p.T420Hfs*15 frameshift 19 MSH2 c.1165C>T p.R389* nonsense 20 MSH2 c.1A>T p.0? init-loss 21 MSH2 c.2785C>T p.R929* nonsense 22 MSH2 c.340delG p.E114Rfs*60 frameshift 23 MSH3 c.802C>T p.R268* nonsense 24 PMS2 c.1053delG p.L351Ffs*5 frameshift 25 PMS2 c.943C>T p.R315* nonsense 26 PTCH2 c.2441_2442delCT p.S814* frameshift 27 RET c.2410G>A p.V804M missense
Conclusion:
Germline mutations in common hereditary cancer syndrome genes is not rare in lung cancer patients, and it can be identified on routine matched tumor-normal NGS sequencing. Retrospective family history analysis and genetic counseling for those patients are underway.
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OA 18.02 - The Landscape of Alteration of DNA Integrity-Related Genes and Their Association with Tumor Mutation Burden in Non-Small Cell Lung Cancer (ID 10440)
14:40 - 14:50 | Presenting Author(s): Michael F Sharpnack | Author(s): J.H. Cho, F. Oezkan, M. Koenig, I. Kim, G. Otterson, K. Huang, David P Carbone, K. He
- Abstract
- Presentation
Background:
A key hallmark of cancer cells is the ability to proliferate despite remarkable levels of DNA damage. Non-small cell lung cancers (NSCLC) tend to have high mutation rates, frequently related to smoking. While many genes have been functionally implicated in maintaining the integrity of the genome, for the majority of these genes there remains a lack of evidence of a direct relationship between loss-of-function and increased tumor mutation burden (TMB). Recent studies suggested an association between high TMB and cancer response to immunotherapies. The aim of this study was to comprehensively analyze the relationship between DNA integrity-related genes and TMB in NSCLC.
Method:
Whole exome DNA sequencing and copy number array data were downloaded from TCGA lung adenocarcinoma (LAC) and squamous cell carcinoma (LSCC) datasets, and mutation burdens were calculated for each of 974 tumors. We identified 150 genes across 7 pathways and 9 groups known to be involved in repairing or compensating for DNA damage. To test each gene, tumors were placed into one of three groups according to the gene’s mutation status; wild-type, homozygous deleted or mutated with loss-of-function, and non-synonymous missense mutated. We then compared the average mutation burden in each of these groups. This workflow was then repeated with pathways instead of genes.
Result:
Our comprehensive analysis demonstrates a landscape of significant alterations to genes and pathways responsible for maintaining DNA integrity in NSCLC. A loss of function mutation or homozygous deletion in at least one signature gene occurred in 49% of LAC and 59% of LSCC. We searched for genes in this signature associated with significantly higher tumor mutation burdens (one sided t-test, p < 0.05) and found 4 in LAC (RRM1 1%, TP53 17%, FANCE 1%, and MLH1 2%) and 8 in LSCC (NEIL1 0.5%, POLE 4%, POLG 0.5%, FANCE 3%, GEN1 1%, MLH1 4%, MSH6 1%, and RPA1 2%) datasets. Of note, tumors with nonsense mutations, indels, or homozygous deletions in the FANCE or MLH1 genes have significantly higher TMB in both LAC and LSCC. We repeat this process to find pathways significantly associated with increased TMB.
Conclusion:
We present a comprehensive study of the association between genes responsible for maintaining DNA integrity and TMB in NSCLC. These findings are important to the search for potential predictive biomarkers for immunotherapy.
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OA 18.03 - Genomic Profiling Reveals Hedgehog Pathway Alterations in Vismodegib Sensitive Lung Squamous Cell Carcinoma (ID 10599)
14:50 - 15:00 | Presenting Author(s): Sai-Hong Ignatius Ou | Author(s): Siraj M Ali, K. Fedorchak, P.J. Stephens, Jeffrey S. Ross, V.A. Miller, A.B. Schrock, A. Dowlati, S. Ignatius Ou
- Abstract
- Presentation
Background:
The objective response rate of squamous cell carcinoma of the lung (SCCL) to checkpoint inhibitors, as well as the frequency of known NSCLC oncogenic drivers, is low. We performed comprehensive genomic profiling (CGP) on a large set of SCCL cases to identify new opportunities for potential benefit from targeted or immunotherapies.
Method:
Hybrid-capture based CGP of up to 315 genes was performed prospectively on DNA isolated from tissue-based FFPE samples of SCCL, and tumor mutational burden (TMB) was assessed as described previously (PMID: 28420421).
Result:
From a dataset of 958 unique SCCL cases, we identify 2.6% of cases harboring alterations in PTCH1, 0.3% in SMO1, and 01.2% in SUFU, which were primarily mutually exclusive Genes known to be oncogenic drivers in NSCLC were altered at the following frequencies in SCCL 8.0% KRAS, 6.8% EGFR, 3.4% MET, 1.9% BRAF, and less than 1% each for ALK, ROS, and RET. In PTCH1-mutated cases 96% did not harbor alterations in these driver genes (1/23 positive for co-occurrence).. The overall SCCL population has a median TMB of 9.0, with 11.3%) cases higher than 20 mutations/Mb (m/Mb). Two index cases with PTCH1 mutations and no alterations in established NSCLC driver genes were identified. A year 77-year-old male with a 40 pack-year smoking history was diagnosed with metastatic SCCL, basaloid variant, harboring PTCH1 s799fs*29 with TMB of 3.7 m/Mb, and he had a year-long complete response to vismodegib. A 69-year-old male with poorly differentiated SCCL harboring PTCH1 W197* and W460* had a 7 month response to vismodegib. On progression, biopsy of recurrent disease after vismodegib failure demonstrated the same PTCH1 alterations as well as acquisition of the 11q13 (CCND1/FGF3/FGF4/FGF19) amplicon. Both biopsies had TMB > 45 m/mb. Nine additional cases not in this series identified as the basaloid variant of SCCL by expert thoracic pathology review were assayed by CGP and 11% (1/9) harbored PTCH1 mutation, but no other alterations of the hedgehog pathway were identified.
Conclusion:
The index cases presented here suggest a subset of PTCH1-mutated SCCL may see clinical benefit from hedgehog inhibitors, regardless of TMB. In a small series of expert diagnosed basaloid histology in SCCL cases, this histology may enrich for hedgehog pathway alterations. Further investigation of underlying PTCH1 LOH and TMB will be undertaken to assess which SCCL cases can respond to respond to hedgehog pathway inhibitors.
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OA 18.04 - Whole Genome Tumor-Normal Sequencing Reveals Potential False Positives Versus Standard CGP Sequencing in Patients with NSCLC (ID 10453)
15:00 - 15:10 | Presenting Author(s): C.P. Garner | Author(s): J..Z. Sanborn, S. Benz, P. Soon-Shiong, S. Rabizadeh, Sandeep Bobby Reddy
- Abstract
- Presentation
Background:
Matched tumor-normal sequencing analyses are essential for precise identification and interpretation of somatic and germline alterations. A 2015 study of 815 paired tumor and normal genomes showed that both genomes are required for precise identification and interpretation of both somatic and germline variation. In this study, we further demonstrate the critical importance of both tumor and germline sequencing using a selected panel of genes that are relevant to cancer prognosis and treatment.
Method:
Tumor and normal (germline) genomes were sequenced using the Illumina HiSeqX platform. Data was aligned to GRCh37 using methods described previously. Tumor versus matched-normal variant analysis was performed using the NantOmics Contraster analysis pipeline to determine somatic and germline genomic variants. RNA-Seq libraries were prepared from tumor samples using KAPA stranded RNA-Seq with RiboErase kit and sequencing on the Illumina platform. RNA sequencing reads were aligned and variants were identified using methods that have been previously described.
Result:
44 patients with NSCLC with tumor-normal sequencing were analyzed. 29 patients also had RNA-Seq whole transcriptome data available for analysis. Focusing on somatic SNVs in ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, KMT2A (MLL), NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET; 427 germline plus somatic variants were detected in these 25 genes in 44 patients; 386 out of 427 (90%) variants detected in somatic tissue were also present in germline (true positive germline variant, false positive somatic variant). 5 out of 29 patients (17%) did not have detectable expression in at least one somatic variant. Focusing on germline SNVs in APC, MYH, MLH1, MSH2, MSH6, PMS2, EPCAM, POLE, POLD1, BMPR1A, PTEN, STK11; 350 germline plus somatic variants were detected in these 12 genes in 44 patients, 10 out of 44 patients (23%) had at least one variant detected in their tumor DNA in these 12 genes that was not detected in the patient’s germline DNA (false positive germline variant, true positive somatic variant).
Conclusion:
Somatic-only sequencing may lead to false positive variant calls which has important clinical implications for highly actionable targets and for the veracity of mutational load algorithms. Calling germline variants from somatic DNA has a false positive risk---called variants may truly be somatic mutations. This is further complicated by the presence of circulating tumor DNA which may also lead to a false positive “germline” result in the absence of a true normal comparator.
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OA 18.05 - Discussant - OA 18.01, OA 18.02, OA 18.03, OA 18.04 (ID 10768)
15:10 - 15:25 | Presenting Author(s): Maria E Arcila
- Abstract
- Presentation
Abstract not provided
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OA 18.06 - Three-Dimensional Assessment of Spread Through Air Spaces in Lung Adenocarcinoma: Insights and Implications (ID 8826)
15:25 - 15:35 | Presenting Author(s): Yukako Yagi | Author(s): K. Tabata, Natasha Rekhtman, Takashi Eguchi, X. Fu, J. Montecalvo, Prasad S. Adusumilli, M. Hameed, William D Travis
- Abstract
- Presentation
Background:
Tumor spread through air space (STAS) is a newly recognized form of invasion in lung adenocarcinoma and squamous cell carcinoma and growing evidence shows it is associated with recurrence and survival. The observation that tumor STAS clusters/nests or single cells within air spaces on two-dimensional H&E slides raised the question of how these cells could survive within air spaces without a vascular supply and this has led some to speculate STAS is an artifact. Herein, we perform the high resolution-high quality 3D reconstruction and visualization of normal lung and tumor in a lung adenocarcinoma to investigate the invasive pattern of STAS.
Method:
A formalin-fixed paraffin embedded block of invasive adenocarcinoma with micropapillary pattern and extensive STAS was studied. Following our histology 3D reconstruction standard procedure, 3D reconstruction was performed for analysis from 200 serial sections of H&E stained 20x (0.5um/pixel resolution) whole slide images. The relationship to alveolar walls between micropapillary structures within the tumor and STAS clusters in lung parenchyma distant from the tumor was evaluated.
Result:
3D reconstruction and analysis demonstrated the following novel features – a) in the main tumor area, micropapillary structures within airspaces were connected to alveolar walls, b) unlike in 2D evaluation where STAS appeared as ‘free-floating’ micropapillary clusters, in 3D evaluation many STAS clusters within air spaces are attached to alveolar walls, and c) STAS clusters that appear ring-like in 2D by 3D evaluation they are actually balls of tumor cells surrounding a central space.
Conclusion:
Our 3D reconstructed image analysis for the first-time demonstrates that most STAS cells are not ‘free-floating’, rather attached to the alveolar walls. In addition within the main tumor micropapillary clusters are attached to alveolar walls. These findings raise an intriguing hypothesis that STAS cells are clusters of tumor cells spread within alveolar spaces in a non-contiguous fashion to reattach to the alveolar walls at a distance possibly by co-option of alveolar wall capillaries to support their growth. This form of spread is analogous to the phenomenon of vascular spread where tumor cells spread freely within blood vessels to distant sites where they attach to endothelium and extravasate through the vessel walls to form metastases. It is possible the ball-like configuration of STAS clusters may facilitate movement through alveolar spaces distant from the main tumor. The frequent alveolar wall attachment of STAS observed on serial 3D imaging disputes the concept this is an artifact.
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OA 18.07 - 3D Low-Attachment Culture: A Putative Model for STAS And "Floating" Cancer Cells (ID 8320)
15:35 - 15:45 | Presenting Author(s): Toshiro Niki | Author(s): Tomoyuki Nakano, Taichiro Yoshimoto, Y. Kanai, T. Shibano, Daisuke Matsubara, S. Endo
- Abstract
- Presentation
Background:
Cancer cells “floating” in stroma, air space, or lymphovascular channels are often found in aggressive lung adenocarcinomas. Recently, the concept of STAS (spread through alveolar space) has been proposed, and studies have shown that STAS predicts early recurrence and poor patient prognosis. However, the biologic basis for the aggressive phenotype of the tumor with these histologic features remains elusive. In this study, we tested whether 3D (three-dimensional) low-attachment culture could be an in vitro model for STAS and “floating” cancer cells.
Method:
Lung adenocarcinoma cell lines harboring diverse driver mutations (EGFR, KRAS, BRAF, HER2, RET) were used. Cells were subjected to detached condition by using low-attachment culture dishes to generate “floating” cancer cells in vitro. Cell growth assay, immunohistochemistry and Western blotting were used to characterize the biologic properties of “floating” cancer cells. Cancer cells were inoculated in pleural cavity or left ventricle of the heart of NOD/SCID mice to test their metastatic potential in vivo.
Result:
Upon detachment, cancer cells formed solid, micropapillary, or hollow ring-like structures, admixed with single cells, recapitulating a histologic spectrum of STAS in primary tumors. Outlining with MUC1, a feature of micropapillary lung adenocarcinoma, was also demonstrated in the in-vitro-generated micropapillary clusters as well. Detached cells initially showed retarded cell growth, but some cell lines regained growth potential with time in culture. Expression analysis of various biomarkers revealed that detached cells showed features of cell stress and altered metabolism, as indicated by increased expression of phospho-p38 (a stress-activated MAP kinase) and GLUT-1 (glucose transporter-1), respectively, and these findings were confirmed by analysis of primary tumors. Finally, cancer cells that adapted to detached conditions exhibited increased metastasis in vivo. Figure 1
Conclusion:
3D low-attachment culture may be a convenient model to study the biology of aggressive lung cancer with STAS and “floating” cancer cells.
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OA 18.08 - FLI1 Circular RNAs Promote Metastasis of Small Cell Lung Cancer Cells by Direct Binding to miR-584-3p (ID 8894)
15:45 - 15:55 | Presenting Author(s): Jiuwei Cui | Author(s): L. Li, W. Li, J. Hu, W. Song
- Abstract
- Presentation
Background:
Small cell lung cancer (SCLC) is regarded as the most devastative type of human lung malignancies, with their rapid growth and we have discovered that there are FLI1 circular RNAs (circFLI1s) aberrantly expressed in SCLC tissues, such as circFLI1E2-4 and circFLI1E2-5 which are derived from exon 2-exon 4 and exon 2-exon 5 of FLI1, respectively. This study investigated the role of circFLI1s in the biological processes of SCLC.
Method:
The expression level of circFLI1s was evaluated by fluorescence in situ hybridization(FISH) in 54 primary SCLC and 50 non-small cell lung cancer (NSCLC) patients with known follow-up data. Correlation between circFLI1s expression and clinical characteristics was assessed with logistic regression. Cellular proliferation, apoptosis, cell cycle, migration and ability of colony formation were used to investigate the function of circFLI1s in SCLC. Ulteriorly, we explored the possible mechanism of circFLI1s via luciferase reporter assay, RT-PCR and FISH.
Result:
The expression of circFLI1E2-4 and circFLI1E2-5 were up-regulated in SCLC tissues compared with NSCLC tissues . The high expression of these circFLI1s was significantly associated with positive lymph nodal involvement (p < 0.05). The silencing of circFLI1E2-4 and circFLI1E2-5 but not FLI1 mRNA significantly inhibited migration of highly aggressive SCLC cell lines in vitro and vivo, while did not affect their proliferation, cell cycle, apoptosis and colony formation. Via bioinformatic analysis and luciferase screening assay, circFLI1s were observed to sponge to 2 miRNAs with 6 potential binding sites. Specifically, we showed that these circFLI1s directly binded to miR-584-3p and inhibited miR-584-3p activity, further to regulate the transcriptional activity of its target gene ROCK1 and the RhoA/ROCK1 signal pathway.
Conclusion:
This study uncovers that circFLI1s is an important driving factor that promotes tumor metastasis in SCLC through , and may serve as an attractive target for therapeutic intervention of SCLC.
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OA 18.09 - Discussant - OA 18.06, OA 18.07, OA 18.08 (ID 10769)
15:55 - 16:10 | Presenting Author(s): Alain Borczuk
- Abstract
- Presentation
Abstract not provided
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Author of
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-001 - Detection of Gene Fusions in NSCLC Using NGS Fusion Assay (ID 10033)
09:30 - 09:30 | Presenting Author(s): Yoon-La Choi
- Abstract
Background:
ALK/RET/ROS and MET exon 14 skipping detection are important to guide of treatment in non-small cell lung cancer (NSCLC) patients. Next generation sequencing (NGS) platform has been implemented in the daily practice for the diagnosis. However, the validation of the NGS-based panel is still complicated and difficult.
Method:
We developed NGS-based fusion assay panel to detect 183 total fusion variants including ALK/RET/ROS as well as MET exon 14 skipping. The fusion call agreement between OCP-50 NGS assay and Nanostring was performed. The result was compared with the FISH and IHC results. This study describes the validation of the assay to define assay parameters, performance characteristics and reproducibility across laboratories.
Result:
For the 55 samples analyzed, the results are as follows;ALK Fusion ROS1 Fusion RET Fusion METD14 NGS(+) NGS(-) Total NGS(+) NGS(-) Total NGS(+) NGS(-) Total NGS(+) NGS(-) Total NS (+) 20 0 20 6 0 6 5 0 5 0 0 0 NS (-) 1 33 34 1 47 48 0 49 49 2 52 54 Total 21 33 54 7 47 54 5 49 54 2 52 54
Conclusion:
The results of our study will be of help in learning the process of establishing, validating and applying the fusion gene detection method in NSCLCs. Furthermore, NGS based OCP-50 assay for fusion detection is more accurate and reliable method for the diagnosis.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-088f - Droplet Digital PCR-Based EGFR Mutation Detection with an Internal Quality Control Index to Determine the Quality of DNA (ID 9895)
09:30 - 09:30 | Author(s): Yoon-La Choi
- Abstract
Background:
Formalin-fixed paraffin-embedded tissue (FFPET) samples are invaluable sources for both clinical research and in vitro diagnostics. However, accurate detection of genetic mutations in FFPET is a major challenge due to artifactual results, due to sample age and quality.
Method:
In a pre-clinical study, we used 315 non-small cell lung cancer (NSCLC) FFPET-derived DNA (FFPET-DNA) samples to establish sample criteria reflecting the minimum DNA quality suitable for PCR by comparing the results of droplet digital PCR-based mutation test (ddEGFR test) and qPCR-based EGFR mutation test (cobas[®] EGFR test). Using this criteria, we conducted a retrospective comparative clinical study of the ddEGFR and cobas EGFR tests of 171 NSCLC FFPET-DNA samples.
Result:
Based on the pre-clinical study, the FFPET-DNA sample criterion was established as internal quality control (iQC) index ≥ 0.5 (iQC copies ≥ 500, using 3.3 ng [1000 genome equivalents] of FFPET-DNA), indicating that more than half of the input DNA was amplifiable. Based on this iQC index, an independent clinical study revealed that both tests were significantly concordant (overall percent agreement (OPA) = 92.98%). Discordants not detected by the cobas EGFR test were detected using the ddEGFR test, indicating that the higher sensitivity of the ddEGFR test is due to its lower limit of detection.
Conclusion:
iQC index is a reliable indicator of the quality of FFPET-DNA and could be used to prevent incorrect diagnoses arising from low-quality samples. Compared with the cobas EGFR test, the ddEGFR test exhibited superior analytical performance and at least equivalent clinical performance.
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P3.04 - Clinical Design, Statistics and Clinical Trials (ID 720)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.04-011 - A Prospective Study to Optimize the Extent of Pulmonary Resection According to Decision-Making Algorithm in cStage IA NSCLC (ID 10047)
09:30 - 09:30 | Author(s): Yoon-La Choi
- Abstract
Background:
Recent advances in imaging technology and the widespread use of low-dose computed tomography screening have greatly increased the chance of detecting small-sized non-small cell lung cancer (NSCLC) with indolent features (radiologically ground-glass opacity and histopathologically lepidic pattern adenocarcinoma). This change in the disease pattern of NSCLC has led to a resurgence of interest in sublobar resection. The purpose of this study is to determine the outcome of patients with clinical stage IA NSCLC treated by 3 types of surgical resection (wide wedge resection, segmentectomy, or lobectomy) according to the institutional decision-making algorithm.
Method:
In this study, we are planning to prospectively enroll 1,000 patients with clinical stage IA NSCLC undergoing curative-intent surgical resection. Our decision-making algorithm regarding the optimal extent of pulmonary resection has been developed based on our institutional consensus building meetings. We are planning to prospectively measure radiologic features such as tumor diameter and consolidation/tumor (CT) ratio. For ≤ 2cm tumors with CT ratio of ≤ 0.25, wide wedge resection needs to be performed. For ≤ 2cm tumors with CT ratio of 0.25 to 0.5 or 2-3cm tumors with CT ratio of ≤ 0.5, segmentectomy should be chosen. When CT ratio is larger than 0.5, lobectomy is required regardless of tumor size. When either parenchymal or bronchial resection margin is found to be insufficient during surgery, segmentectomy or lobectomy should be done even when a lesser resection was planned. Resection margins greater than the maximal tumor diameter (lesions less than 2cm) or at least 2cm gross margins (lesions larger than 2cm) should be achieved. Hilar and mediastinal lymph node dissection or at least systematic lymph node sampling is strongly recommended for any kind of pulmonary resection.
Result:
The primary objective is to determine disease-free survival following sublobar resection and lobectomy. The secondary objectives are (1) to determine overall survival following surgery, (2) to determine rates of loco-regional and systemic recurrence following surgery, (3) to compare postoperative pulmonary function between 3 different resection types, (4) to explore the relationship between radiologic parameters and pathologic subtypes, and (5) to determine the predictors of unexpected nodal involvement.
Conclusion:
This study is registered with ClinicalTrials.gov, number NCT03066297 (“OREX-IA” study) and we started recruiting patients in February, 2017 and will also be planning to follow up patients for at least 5 years to analyze their survival and recurrences.
