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D. Harpole
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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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OA19.01 - A Standardized and Validation of Prognostic Gene Expression Signatures for Squamous Cell Lung Carcinoma by the SPECS Lung Consortium (ID 4329)
11:00 - 11:10 | Author(s): D. Harpole
- Abstract
- Presentation
Background:
High-throughput gene expression profiling led to proposal of multiple expression-based prognostic signatures for squamous cell lung carcinoma (SCC), but none has been validated. A multi-institutional squamous lung cancer consortium of investigators is developing prognostic signatures through the US NCI Lung SPECS (Strategic Partnership for Evaluation of Cancer Signatures) program. Six institutions contributed tumor specimens and published/unpublished expression-based prognostic signatures for validation using standardized sample cohorts (a primary validation cohort comprising institutional cases, and additional validation cohorts from two prospective cooperative group studies) and quality controlled assessment in independent laboratory and statistical cores. Here, we report the results of the primary validation.
Methods:
Cases of primary SCC (by central pathology review) meeting clinical (Stage I-II; surgical treatment only; 3-year followup) and specimen quality criteria (Tumor cellularity >= 50%; necrosis <= 20%) were submitted. Clinical, pathological and outcome data were uploaded to a central database. Frozen tumor samples underwent centralized mRNA extraction (Qiagen Symphony), quality control (RIN >= 6.0) and microarray profiling (Affymetrix U133) in core labs. An independent statistical core assessed validation of 7 pre-existing mRNA signatures and generated new models using MCP clustering.
Results:
Among 250 cases meeting entry criteria, median age was 70 (43-92), 161 (65%) were male, and most were former (70%) or current (28%) smokers. Surgery was pneumonectomy: 5%; bilobectomy: 2%; lobectomy: 74%; sublobar: 18%. Pathologic staging was T1: 49%; T2: 50%; T3: 1%; N0: 88%; N1: 12%, and grade was G1: 4%; G2: 50%; G3: 44%. At followup, 148 (59%) were deceased. Three mRNA signatures demonstrated significant univariable association with OS and added independent prognostic value (see Figure) to a multivariable model accounting for age, sex and stage (c-index = 0.641).
Conclusion:
The validated signatures, along with two novel signatures generated from the current dataset, are currently undergoing further validation studies using two prospective co-operative group cohorts. Figure 1
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P1.05 - Poster Session with Presenters Present (ID 457)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Early Stage NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.05-001 - Creation and Early Validation of Prognostic miRNA Signatures for Squamous Cell Lung Carcinoma by the SPECS Lung Consortium (ID 6088)
14:30 - 14:30 | Author(s): D. Harpole
- Abstract
Background:
Despite overall favorable prognosis for operable early stage non-small cell lung cancer, predicting outcome for individual patients has remained challenging. Small retrospective studies have reported potential non-coding micro(mi)RNAs that might have prognostic significance; however, these studies lacked statistical power and validation. To refine these initial findings to clinical application, the investigators have undertaken a collaborative, structured evaluation of multiple signatures putatively prognostic for lung squamous cell carcinoma (SCC) under a NCI/SPECS (Strategic Partnerships fo Evaluating Cancer Signatures) award. The study design specifies a primary validation cohort comprising institutional cases, and additional validation cohorts of Cooperative Group cases, all profiled via a common pipeline.
Methods:
Completely resected SCC (confirmed by central pathology review) meeting clinical (Stage I-II; complete 3-year follow-up) and specimen quality criteria (Tumor cellularity ≥ 50%;necrosis ≤ 20%) were submitted by 6 institutions. Clinical, pathological and outcome data were uploaded to a central database. Lysates from 5 um sections of FFPE SSC tumor samples were run on the HTG EdgeSeq Processor (HTG Molecular Diagnostics, Tucson, AZ) using the miRNA whole transcriptome assay in which an excess of nuclease protection probes (NPPs) complimentary to each miRNA hybridize to their target. S1 nuclease then removes un-hybridized probes and RNA leaving behind only NPPs hybridized to their targets in a 1-to-1 ratio. Samples were individually barcoded (using a 16-cycle PCR reaction to add adapters and molecular barcodes), individually purified using AMPure XP beads (Beckman Coulter, Brea, CA) and quantitated using a KAPA Library Quantification kit (KAPA Biosystems, Wilmington, MA). Libraries were sequenced on the Illumina HiSeq platform (Illumina, San Diego, CA) for quantification. Standardization and normalization was provided to the project statistical core for validation of two pre-existing signatures and generation of new models (MCP clustering).
Results:
Among 224 cases with miRNA data, median age was 70 (43-92), 143 (64%) male, with 67% former (67%) and current (26%) smokers. All patients were completely resected stage I or II. . At follow-up, 59 (26%) had documented recurrence and 129 (58%) were deceased. To date, we have been unable to validate the previous models, but have created a novel signature of three miRNAs (see Figure) that is being validated in the second phase of the project using an independent, blinded multi-institutional cohort.
Conclusion:
The Squamous Lung Cancer SPECS Consortium has established well-annotated and quality-controlled resources for validation of prognostic miRNA signatures. A new candidate 3-miRNA signature has been identified for further development as a clinically useful biomarker.
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P1.05-027 - Novel Prognostic Gene Expression Signatures for Squamous Cell Lung Carcinoma: A Study by the SPECS Lung Consortium (ID 4490)
14:30 - 14:30 | Author(s): D. Harpole
- Abstract
Background:
A multi-institutional squamous lung cancer consortium of investigators is developing prognostic signatures through the US NCI Lung SPECS (Strategic Partnership for Evaluation of Cancer Signatures) program. Six institutions contributed tumor specimens and published/unpublished expression-based prognostic signatures for validation using standardized sample cohorts (a primary validation cohort comprising institutional cases, and additional validation cohorts from two prospective cooperative group studies) and quality controlled assessment in independent laboratory and statistical cores. Here, we report on de novo prognostic signatures derived using the pooled institutional dataset.
Methods:
Highly quality-controlled cases of primary SCC from the pooled cohort (N=249) were analyzed to generate de novo prognostic signatures from among the 147 genes comprising pre-existing signatures, and from among all profiled genes. Minimax Concave Penalty (MCP) selection and Ward’s minimum variance clustering yielded survival analyses with 2 clusters that were evaluated using Cox regression and bootstrap cross validation (bCV; 500 iterations).
Results:
Two significantly prognostic models were generated (see Figure): Pooled Model A (PMA) was the optimal 2-cluster model using probesets representing 6 genes selected from components of pre-existing signatures: CASP8, MDM2, SEL1L3, RILPL1, LRR1, COPZ2. Pooled Model B (PMB) was the optimal 2-cluster model using probesets representing 6 genes selected from among all those profiled: SSX1, DIAPH3, LOC619427, CASP8, EIF2S1, HSPA13. PMA and PMB each remained independently prognostic in multivariable analyses incorporating an a priori baseline model (age, sex, stage; c-index = 0.641).
Conclusion:
Two de novo prognostic signatures were derived using a pooled multi-institutional cohort of SCC assembled for validation of pre-existing signatures. PMA and PMB were each found to be independently prognostic, accounting for established clinical predictors. Both now move forward, along with validated pre-existing signatures, to additional assessment of discrimination, calibration and clinical usefulness using additional independent prospective US co-operative group cohorts of cases. Figure 1
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P2.03a - Poster Session with Presenters Present (ID 464)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03a-050 - Elevated Expression of CCP Genes is Associated with Absolute Chemotherapy Benefit in Early Stage Lung Adenocarcinoma Patients (ID 4204)
14:30 - 14:30 | Author(s): D. Harpole
- Abstract
Background:
A validated RNA molecular expression signature based on cell cycle progression (CCP) genes [CCP score] and a molecular Prognostic Score [(mPS) combination of CCP score and pathological stage] are significant prognostic markers of cancer-specific mortality in patients with early stage lung adenocarcinoma. Additionally, preliminary data suggest a significant association between CCP score and absolute benefit with platinum-based adjuvant chemotherapy in early stage lung adenocarcinoma patients. The aim of this study is to further demonstrate the effectiveness of CCP score and mPS in predicting platinum-based chemotherapy benefit in a large, multi-institutional cohort of stage IB and IIA lung adenocarcinoma patients who underwent definitive surgical resection with and without adjuvant chemotherapy.
Methods:
Formalin-fixed paraffin-embedded surgical tumor samples from approximately 1000 patients diagnosed with stage IB and II adenocarcinoma who underwent definitive surgical treatment with adjuvant platinum-based chemotherapy (n = 400) and without (n = 600) will be analyzed for 31 proliferation genes by quantitative RT-PCR. The associations of CCP score and mPS with absolute benefit from platinum-based chemotherapy will be separately examined using Cox proportional hazards regression with an outcome of 5-year lung cancer survival.
Results:
To date, lung tumor samples have been accrued from 388 patients treated with a platinum-based chemotherapy and 590 untreated patients. We hypothesized that the absolute treatment benefit will increase as CCP score or mPS increases. Results will be shown for continuous CCP score and mPS as well as pre-defined binary CCP score and binary mPS.
Conclusion:
This study will determine the abilities of CCP score and mPS as predictive tools for absolute chemotherapy benefit and 5-year lung cancer survival in patients with early stage lung adenocarcinoma thereby furthering the clinical utility for these signatures to identify patients with high risk disease who should receive adjuvant chemotherapy.
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P3.04 - Poster Session with Presenters Present (ID 474)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.04-013 - The Role of Extent of Surgical Resection and Lymph Node Assessment for Clinical Stage I Pulmonary Lepidic Adenocarcinoma (ID 6050)
14:30 - 14:30 | Author(s): D. Harpole
- Abstract
Background:
This study examined the association of extent of lung resection, pathologic nodal evaluation, and survival for patients with clinical stage I (cT1-2N0M0) adenocarcinoma with lepidic histology in the National Cancer Database (NCDB).
Methods:
The association between extent of surgical resection and long-term survival for patients in the NCDB between the years of 2003-2006 with clinical stage I lepidic adenocarcinoma who underwent lobectomy or sublobar resection was evaluated using Kaplan-Meier and Cox proportional hazards regression analyses.
Results:
Of the 1,991 patients with cT1-2N0M0 lepidic adenocarcinoma who met study criteria, 1,544 patients underwent lobectomy and 447 underwent sublobar resections. Patients treated with sublobar resection were older, more likely to be female, had higher Charlson/Deyo comorbidity scores, but had smaller tumors and lower T-status. Of patients treated with lobectomy, 6% (n=92) were upstaged due to positive nodal disease, with a median of 6 lymph nodes sampled (IQR: 3,10). In an analysis of the entire cohort, lobectomy was associated with a significant survival advantage over sublobar resection in univariate analysis (median survival 9.2 vs. 7.5 years, p=0.022; 5-year survival 70.5% vs. 67.8%) and following multivariable adjustment (hazard ratio [HR]: 0.81 [95% [CI]: 0.68-0.95], p=0.011), (Figure 1). However, lobectomy was no longer independently associated with improved survival when compared to sublobar resection (HR: 0.99 [95% CI: 0.77-1.27], p= 0.905) in a multivariable analysis of a subset of patients that compared only those patients who underwent sublobar resection that included lymph node sampling to patients treated with lobectomy. Figure 1
Conclusion:
Surgeons treating patients with stage I lung adenocarcinoma with lepidic features should cautiously utilize sublobar resection rather than lobectomy and must always perform adequate pathologic lymph node evaluation.
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P3.07 - Poster Session with Presenters Present (ID 493)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Regional Aspects/Health Policy/Public Health
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.07-012 - Disparities in Guideline-Concordant Treatment for Node-positive Non-Small Cell Lung Cancer Following Surgery (ID 4382)
14:30 - 14:30 | Author(s): D. Harpole
- Abstract
Background:
To examine guideline concordance across a national sample and to determine the relationship between socioeconomic factors, use of recommended post-operative therapy, and outcomes for patients with pN1 or pN2 non-small cell lung cancer (NSCLC).
Methods:
All margin-negative pT1-3 N1-2 M0 NSCLC treated with lobectomy or pneumonectomy without induction therapy in the National Cancer Data Base (NCDB) between 2006-2011 were included for analysis. Use of guideline-concordant adjuvant therapy, defined as chemotherapy for pN1 disease and chemoradiation therapy for pN2 disease, were examined regarding pathologic, demographic, and socioeconomic factors. Multivariable regression models were developed to estimate predictors of guideline adherence and outcomes. Survival was estimated using the Kaplan-Meier method.
Results:
A total of 9,300 patients were identified. Of these, 7,137 had pN1 disease and 2,163 had pN2 disease. Guideline-concordant adjuvant therapy was utilized in 4,477 (62.7%) pN1 patients and 646 (29.9%) pN2 patients. After multivariable adjustment, patient age (OR 0.59 per decade, 95% confidence interval [CI]: 0.56-0.63), uninsured status (OR 0.52, 95%CI:0.39-0.71), N2 disease (OR 0.21, 95%CI:0.18-0.23), pneumonectomy (OR 0.75, 95%CI:0.65-0.86), longer postoperative length of stay (OR 0.96/day, 95%CI:0.95-0.97) and unplanned readmission (OR 0.76, 95%CI:0.61-0.95) were associated with significantly worse guideline concordance, while higher education levels (OR 1.07 per quartile, 95%CI:1.01-1.14) and increasing T-stage (OR 1.08, 95%CI:1.01-1.16) were associated with significantly higher concordance. Overall, patients treated with guideline-concordant therapy had superior survival (5-year survival: 50.4 vs. 35.3%, p<0.001; Figure).Figure 1
Conclusion:
Socioeconomic factors, including lack of insurance, are associated with disparities in use of adjuvant therapy as recommended by National Comprehensive Cancer Network guidelines. These disparities have significant impact on patient outcomes. Future work should focus on improving access to appropriate adjuvant therapies among the uninsured and socioeconomically disadvantaged.
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SC08 - IASLC- ESTS Joint Symposium: The Borderline Patient (ID 332)
- Event: WCLC 2016
- Type: Science Session
- Track: Pulmonology
- Presentations: 1
- Moderators:J. Kuzdzal, H. Hoffmann
- Coordinates: 12/05/2016, 16:00 - 17:30, Hall C7
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SC08.03 - Surgical Issues in the Borderline Patient: Sublobar versus Standard Resection (ID 6630)
16:40 - 17:00 | Author(s): D. Harpole
- Abstract
- Presentation
Abstract not provided
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