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George R. Simon
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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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MA 18 - Global Tobacco Control and Epidemiology II (ID 676)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Epidemiology/Primary Prevention/Tobacco Control and Cessation
- Presentations: 1
- Moderators:H. Kawai, Christian Klaus Manegold
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 511 + 512
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MA 18.08 - Assessment of Baseline Symptom Burden in Treatment-Naïve Patients with Lung Cancer (ID 10246)
16:30 - 16:35 | Presenting Author(s): George R. Simon
- Abstract
- Presentation
Background:
While most cancer therapies are associated with toxicities, a major component of cancer treatment is to reduce cancer-related symptoms and impairment of function. Assessing how well this goal is achieved is dependent on accurate assessments of baseline symptoms prior to initiation of therapy. The objectives of this study were to describe the symptom burden of treatment-naïve lung cancer patients and to examine demographic and disease factors that correlate with symptom severity.
Method:
Symptom data from 460 treatment-naïve patients with lung cancer were obtained using the validated MD Anderson Symptom Inventory via a 0-10 numeric rating scale. Descriptive statistics were used to summarize patient demographic and clinical characteristics. Differences in symptom severity, symptom interference and quality of life by disease stage and histology were examined using either t-test or ANOVA. Multiple linear regression analysis was performed using age, gender, tumor stage and histology to determine significant predictors of pain and shortness of breath.
Result:
The most severe symptoms were fatigue, disturbed sleep, distress, pain, shortness of breath, sadness and drowsiness. About 62% of patients had at least one moderate to severe (rated 5 or greater) symptom, while 48% had at least one severe (rated 7 or greater) symptom. Disturbed sleep, distress, shortness of breath, sadness, and drowsiness were reported to be severe by at least 16% of the patients. As expected, patients with advanced stage had significantly more severe symptoms. Patients with small-cell carcinoma reported the most severe pain and shortness of breath. Multiple linear regression analysis showed that stage was a significant predictor of pain severity while controlling for histology, age and gender. Patients with advanced stage had a pain level that was 1.2 higher than patients with early stage disease (95% CI= 0.5 – 1.8, p<0.001. For shortness of breath, both histology and stage were significant predictors of severe levels while controlling for age and gender. Patients with advanced stage had a shortness of breath level that was 0.9 higher than patients with early stage disease (95% CI= 0.4 – 1.6, p<0.001). Patients with small cell carcinoma had a shortness of breath level that was 1.5 higher than those with adenocarcinoma (95% CI= 0.35 – 2.6, p<0.01).
Conclusion:
In conclusion, as much as 62% of treatment-naïve patients with lung cancer reported at least one moderate-to-severe symptoms prior to initiation of cancer therapy. This high burden suggests that symptoms should be assessed routinely and tracked in parallel with cancer treatment.
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OA 01 - The New Aspect of Radiation Therapy (ID 652)
- Event: WCLC 2017
- Type: Oral
- Track: Radiotherapy
- Presentations: 1
- Moderators:M. Hiraoka, S.H. Kim
- Coordinates: 10/16/2017, 11:00 - 12:30, F201 + F202 (Annex Hall)
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OA 01.07 - Tracking Major Symptom Burden from Chemotherapy Concurrent with 3D vs. IMRT vs. Proton Beam Radiotherapy for NSCLC (ID 9443)
12:05 - 12:15 | Author(s): George R. Simon
- Abstract
- Presentation
Background:
During standard concurrent chemoradiotherapy (CRT), patients with NSCLC often report severe symptoms that should be routinely assessed and managed. According to the United States FDA specified standards, patient-reported outcome (PRO) instruments used in clinical trials should have good measurement properties of reliability, validity, and the ability to detect change. This quantitative study used a validated PRO symptom-assessment tool, the MD Anderson Symptom Inventory-Lung Cancer (MDASI-LC), to compare a cluster of CRT-related symptoms in NSCLC patients receiving CRT, and to investigate the sensitivity of a composite score of these symptoms.
Method:
We enrolled patients with locally advanced NSCLC (n=118) who underwent intensity-modulated radiation therapy (IMRT, n=33), 3-dimensional conformal radiation therapy (3DCRT, n=22), or proton-beam therapy (PBT, n=63). Patients completed the MDASI-LC weekly for up to 12 weeks. Two criteria used for item selection to form a subscale for CRT-related symptoms: MDASI-LC items rated 4-10 in >25% of observations, and that increased significantly during therapy (by mixed-effect models). A CRT-symptom score (MDASI-LC-CRT) was generated by averaging scores from those symptoms. The MDASI-LC-CRT’s responsiveness to treatment was examined by within-person change over time and effect size (ES) statistics.
Result:
Six symptoms—pain, fatigue, drowsiness, lack of appetite, sore throat, coughing—were identified as the most-severe CRT-related symptoms during and after therapy. Before CRT, MDASI-LC-CRT scores did not differ by treatment (3DCRT 2.2±1.8, IMRT 1.6±1.5, PBT 1.8±1.7, p=0.329). At the end of CRT, MDASI-LC-CRT was highest for 3DCRT (4.85±2.40), followed by IMRT (3.18±1.85) and PBT (2.29±1.65). A large ES (1.24) was found for 3DCRT vs. PBT; medium ES were found for 3DCRT vs. IMRT (0.78) and IMRT vs. PBT (0.51). The ES for pre-CRT vs. post-CRT difference (1.8±1.7 vs. 3.0±2.1) was medium (0.63) for all patients, large for 3DCRT (1.25) and IMRT (0.93), and small for PBT (0.28). The MDASI-LC-CRT score increased significantly over treatment (estimated weekly increase=0.21, p<0.0001), peaking at week 7 (95%CL=6.2-7.8, p<.0001) and then decreasing to week 12 (est=0.18, p=0.001). Significantly larger weekly increase was reported by 3DCRT and IMRT patients, compared with PBT patients (all p<0.0001).
Conclusion:
The MDASI-LC-CRT is a sensitive indicator of dynamic change in major symptom burden during CRT. This subscale could be routinely used for symptom monitoring while patients are going through CRT and appropriate supportive measures could be instituted early. PBT was the best tolerated of the radiation modalities when given concurrently with chemotherapy with the least worsening of symptoms over the CRT period.
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OA 14 - New Paradigms in Clinical Trials (ID 681)
- Event: WCLC 2017
- Type: Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Alex Adjei, Eun Kyung Cho
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 311 + 312
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OA 14.04 - Discussant - OA 14.01, OA 14.02, OA 14.03 (ID 10777)
11:30 - 11:45 | Presenting Author(s): George R. Simon
- Abstract
- Presentation
Abstract not provided
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P1.10 - Nursing/Palliative Care/Ethics (ID 696)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Nursing/Palliative Care/Ethics
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.10-005 - Generation of Symptom Burden Patient-Reported Outcomes for Patients with Lung Cancer (ID 8675)
09:30 - 09:30 | Presenting Author(s): George R. Simon
- Abstract
Background:
Systematic collection of patient experience of disease and treatment through validated patient-reported outcome measures (PROs) is recommended for research and practice. Symptom burden, the combined impact of disease- and therapy-related symptoms on daily functioning, is important to patients and appropriate for PRO measurement. PRO development should include literature reviews, patient input, and expert opinion for content domain specification and item generation. Our purpose is to describe initial development of symptom burden PROs for malignant pleural mesothelioma (MPM) and small-cell lung cancer (SCLC).
Method:
The MD Anderson Symptom Inventory (MDASI) Core is a 13-symptom-item (pain, fatigue, nausea, sleep disturbance, distress, shortness of breath, trouble remembering, appetite loss, drowsiness, dry mouth, sadness, vomiting, and numbness or tingling) and 6-functional-item (general activity, mood, work, relations with others, walking, enjoyment of life) PRO measuring cancer symptom burden. Additional symptoms for specific diseases and treatments can be added. We performed systematic literature reviews for symptoms of MPM and SCLC. We conducted open-ended interviews with 20 patients with MPM and 25 patients with SCLC about their disease and treatment experiences. Descriptive exploratory analysis identified symptoms. Expert panels of physicians, other healthcare providers, patients, and family caregivers rated the relevance of symptoms from patient interviews. Symptoms consistently found in literature, mentioned in ≥ 20% of interviews, or with mean relevance ratings of “relevant/very relevant” were added to the MDASI Core to form the MDASI-MPM and MDASI-SCLC.
Result:
For MPM: Literature review found 5 major symptoms, patient interviews identified 24 symptoms, and experts rated 13 symptoms “relevant/very relevant.” Five symptoms were added to the MDASI Core to make the MDASI-MPM. For SCLC: Literature review found 8 major symptoms, patient interviews identified 37 symptoms, and experts rated 20 symptoms “relevant” or “very relevant.” Nine symptoms were added to the MDASI Core to make the MDASI-SCLC. Lung cancer-specific symptoms common to the two groups are: coughing, muscle weakness, malaise, and trouble with balance or falling. The additional MPM symptom was chest tightness. Additional SCLC symptoms were dizziness, constipation, difficulty concentrating, headache, and foot swelling.
Conclusion:
Patient report of the experience of MPM or SCLC frequently includes symptoms and how those symptoms interfere with daily activities. The MDASI-MPM and MDASI-SCLC are undergoing psychometric testing and may be modified based on the results. They will be the only validated measures of the symptom burden of MPM and SCLC.
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P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
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P2.01-036 - Symptom Trajectories During Chemotherapy Predict Overall Survival in Patients with Advanced Non-Small Cell Lung Cancer (ID 9393)
09:00 - 09:00 | Author(s): George R. Simon
- Abstract
Background:
Patient–reported symptoms have shown prognostic value for patients with advanced non-small-cell lung cancer (NSCLC). The value of persistently high levels of critical symptoms during chemotherapy for predicting survival is seldom addressed. We examined symptom trajectories during first 15 weeks of chemotherapy and their relations to 3-year overall survival (OS) in patients with advanced NSCLC.
Method:
Stage IIIB-IV NSCLC patients scheduled to receive either intravenous chemotherapy or the oral tyrosine kinase inhibitor erlotinib were enrolled in a multicenter longitudinal study. Patients rated 15 symptoms on the MD Anderson Symptom Inventory-Lung (MDASI-LC) before chemotherapy and weekly thereafter for 15 weeks, on 0-10 severity scales. Group-based trajectory analysis was used to categorize patients into groups according to the level and trajectory of symptom severity (either high or low) that patients experienced over time. The 3-year OS was compared between high/low groups via Kaplan-Meier analysis. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) were estimated by Cox regression modeling, with adjustment for demographic and clinical factors.
Result:
We analyzed data from 140 patients (90 died by end of study). High-severity trajectories of three symptoms (fatigue, shortness of breath (SOB), lack of appetite (LOA)) significantly predicted 3-year OS. Patients in the high-fatigue group (n=60) began with moderate fatigue (4.1±3.4) that increased significantly during weeks 1-4 of therapy (5.7±4.5 at week 4; estimated weekly change=0.33, p=0.0004) and remained at this level to week 15. Compared with patients in the low-fatigue group (mean=2.0±1.8, no significant change over time), high-fatigue patients had shorter OS (median=290 vs. 623 days, HR=2.3, 95%CI=1.4-3.8, p=0.001). The high-SOB group (n=62) maintained a moderate level of SOB (4.6±3.5) over 15 weeks and had lower 3-year OS rate than did patients in the low-SOB group (median=256 vs. 566 days; HR=2.7, 95%CI=1.6-4.4, p<0.0001). Compared with patients in the low-LOA group (n=66, mean=0.8±1.8, no change over time), high-LOA patients (n=74, mean=3.2±3.1, no change over time) had shorter OS (median=261 vs. 566 days, p=0.019). The prognostic value of LOA was insignificant after adjusting for other factors.
Conclusion:
Our results suggest that, through longitudinal patient-reported symptom profiling during chemotherapy, persistently high symptom burden can independently predict overall survival in patients with advanced NSCLC. Patients with persistently high symptoms should be targeted for alerts to providers about the need for symptom control during chemotherapy in routine care for advanced NSCLC. Such information could also be used as reference parameters for clinical trial/research design.
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P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.04-014 - Computing the Impact of Immunotherapy on NSCLC Landscape: The Advanced Non-Small Cell Lung Cancer Holistic Registry (ANCHoR) (ID 9505)
09:30 - 09:30 | Presenting Author(s): George R. Simon
- Abstract
Background:
Anti-PD-1 and anti-PD-L1 antibodies including pembrolizumab, nivolumab and atezolizumab have entered clinical practice in the management of metastatic NSCLC as monotherapy and immunotherapy-based combinations. We have established a real-world Advanced Non-Small Cell Lung Cancer Holistic Registry (ANCHoR) to understand how the emergence of immunotherapy impacts choice of treatment, clinical outcomes, and patient reported outcomes (PROs) in the different histo-molecular subtypes of metastatic NSCLC. The objectives of ANCHoR are to determine the treatment choice and treatment sequence by PD-L1 status in the various histo-molecular categories of NSCLC and to understand the impact of such treatment choice on response rates, progression-free survival (PFS), and overall survival (OS). Additionally we will measure the impact the treatment choices have on the PROs by utilizing the validated instruments, EuroQol-5D version 5L (EQ-5D-5L) and MD Anderson Symptom Inventory module specific to lung cancer (MDASI-LC).
Method:
The study will enroll patients with metastatic NSCLC diagnoses who are treated at MD Anderson Cancer Center (MDA) between January 1, 2017 and December 31, 2020. The study period will end on June 30, 2021 to allow a minimum of six months of follow-up. Trained abstractors will collect demographic, diagnostic, clinical, molecular (biomarker and PD-L1), treatment (regimens utilized in sequence and reason for discontinuation), response and survival (including PFS and OS), health care resource utilization and PRO (EQ-5D-5L and MDASI-LC) information that will be integrated in a comprehensive database. Information from the MDA electronic medical record will be extracted and populated in the GEnomic Marker-guided therapy INItiative (GEMINI) database and the PRO database which are linked. EQ-5D-5L followed by MDASI-LC will be completed directly by the patients and these will be automatically populated in the web-based PRO database at treatment initiation, at the time of response assessments and when switching lines of therapy.
Result:
Interim analysis will be conducted every six months to measure the impact of immunotherapy over time. Study results will be presented using descriptive statistics for continuous variables (mean, standard deviation, median, and interquartile range), categorical variables (frequency and proportions), and time-to-event variables (Kaplan-Meier). Regression models will be used for estimating the relationship between dependent variable and one or more predictors. Cox proportional hazards model will be used to estimate hazard ratios for time-to-event outcomes.
Conclusion:
The ANCHoR study is the first comprehensive registry of its kind that will enable the quantification of the changing impact of immunotherapy on the real-world NSCLC treatment landscape.
