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Y. Yatabe
Moderator of
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OA06 - Prognostic & Predictive Biomarkers (ID 452)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 8
- Moderators:F. Shepherd, Y. Yatabe
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 1
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OA06.01 - Clinical Utility of Circulating Tumor DNA (ctDNA) Analysis by Digital next Generation Sequencing of over 5,000 Advanced NSCLC Patients (ID 6096)
14:20 - 14:30 | Author(s): P. Mack, K.C. Banks, J.W. Riess, O.A. Zill, S.A. Mortimer, D.I. Chudova, J. Odegaard, C.E. Lee, R.J. Nagy, H. Eltoukhy, A. Talasaz, R.B. Lanman, D.R. Gandara
- Abstract
- Presentation
Background:
Detection of actionable genomic alterations is now required for NCCN guideline-compliant work-up of NSCLC adenocarcinoma. Next-generation sequencing (NGS) of ctDNA, if sufficiently sensitive and specific, could provide a non-invasive, comprehensive genotyping platform relevant to clinical decision-making when tissue is insufficient or at time of progression on targeted therapies.
Methods:
A highly accurate, deep-coverage (15,000x) ctDNA plasma NGS test targeting 54-70 genes (Guardant360) was used to genotype 5,206 advanced-stage NSCLC patients accrued between 6/2014 – 4/2016. The frequency and distribution of somatic alterations in key genes were compared to those described in TCGA (Pearson and Spearman correlations). The clinical impact of ctDNA testing was evaluated by identification of resistance mechanisms emergent at progression on targeted therapies, and through analysis of additional driver mutations detected by ctDNA at baseline in 362 consecutive NSCLC patients with tissue mutation data available. The positive predictive value (PPV) of ctDNA sequencing was assessed in 229 patients with known tumor driver alterations.
Results:
ctDNA alterations were detected in 86% of cases; EGFR mutations in 25%, KRAS mutations in 17%, MET amplification in 4%, BRAF mutations in 3% and other rare but potentially actionable alterations in 9%. Mutation patterns among driver oncogenes were highly consistent with those from TCGA (Pearson r=0.92, 0.99, 0.99 for EGFR, KRAS, and fusion breakpoint location). PPV of ctDNA-detected variants was 100% for EGFR[L858R], 98% for EGFR[E19del], 96% for ALK, RET, or ROS1 fusions, and 100% for KRAS[G12/G13/Q61] mutations. In 362 cases with tissue information available, 63% (229/362) were tissue quantity-insufficient or undergenotyped (QNS/UG). ctDNA analysis identified driver mutations in 51 of the 229 QNS/UG cases, a 38% increase in detection rate over tissue alone. Among 1,111 EGFR-mutant cases, resistance mutations were identified at progression at frequencies consistent with published literature: EGFR[T790M] 47%, MET amp 5%, ERBB2 amp 5%, FGFR3 fusions 0.4%, ALK/other fusions 1%, BRAF mutations 1.8%, PTEN inactivation 2.5%, NF1 inactivation 3%, RB1 inactivation 3%, KRAS mutations 1.9%. In 143 consecutive NSCLC patients with detailed follow-up and serial analysis seen at the UC Davis Cancer Center, informative driver mutations were observed in 48 (34%).
Conclusion:
This series represents the largest NSCLC ctDNA study to date. Genotypic patterns of truncal mutations were highly consistent with TCGA in terms of frequency and distribution. At baseline, ctDNA augmented tissue analysis by identifying additional, actionable mutations when tissue was QNS/UG. ctDNA NGS conducted at progression identified emergent resistance mutations that could inform subsequent courses of therapy.
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OA06.02 - Mutational Load Predicts Survival in LDCT Screening-Detected Lung Cancers (ID 5577)
14:30 - 14:40 | Author(s): G. Sozzi, C. Verri, C. Borzi, T. Holscher, M. Dugo, A. Devecchi, K. Drake, S. Sestini, P. Suatoni, E. Romeo, M. Boeri, U. Pastorino
- Abstract
- Presentation
Background:
The issue of overdiagnosis in low-dose computed tomography (LDCT) screening trials for lung cancer has to be addressed by the development of complementary biomarkers able to improve detection of aggressive disease. We previously identified a 24 plasma miRNA signature endowed with good performance in terms of sensitivity and specificity in subjects enrolled in independent LDCT screening trials. However, the relationship between circulating miRNAs in plasma and the molecular heterogeneity of the patients’ tumors needs to be considered. Linking tumor genomics to circulating miRNA profiles represent an attractive approach. In fact a plasma miRNA assay able to classify molecular subclasses of tumors could constitute a sort of “liquid biopsy” endowed with not only diagnostic but also prognostic and, potentially, therapeutic value.
Methods:
We evaluated the mutation profile by targeted Next-Generation Sequencing (NGS) analysis (Cancer Hotspot Panel v.2) in 94 Low Dose Computed Tomography (LDCT) screening-detected lung tumors resected from subjects participating in 3 screening trials for lung cancer. Mutation profile was associated with clinicopathologic, survival features and with a plasma MSC risk level of patients. The mutational profile obtained was compared with the mutations of a selected dataset of clinically detected lung tumors through The Cancer Genome Atlas (TCGA).
Results:
We showed alterations in the main genetic drivers in 79% of screening lung tumors whereas 21% of tumor samples had no alteration within these amplicons. Significant associations between TP53, squamous histology and smoking intensity as well as KRAS mutations with worse OS were detected. EGFR alterations were present in 4 tumors from heavy smokers. The 5-year overall survival (OS) of screening patients with and without mutations in the tumors was 64% and 100%, respectively (p=0.019). By combining the mutational status with the MSC risk profile, patients were stratified into 3 groups with 5-year OS ranging from 41% to 96% (p<0.0001) and the prognostic value was significant even when controlling for stage (p=0.017). A similar mutational profile and mutation frequency was observed in screening- and in clinical (TCGA) tumors, whereas difference in 5-year OS between subjects with and without mutations was exclusively detected in screening patients.
Conclusion:
The mutation profile of screening-detected tumors, while similar to that of clinically-detected tumors, was a strong predictor of OS. The combination of tumor mutational status with a circulating miRNA-based risk classifier predicts tumor aggressiveness and clinical outcome and may find rapid application in LDCT screening programs by reducing the number of unnecessary interventions and helping plan targeted treatment
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OA06.03 - Transcriptome Analysis of ATM-Deficient NSCLC (ID 6196)
14:40 - 14:50 | Author(s): L.F. Petersen, E. Enwere, M. Konno, O. Kovalchuk, D..G. Bebb
- Abstract
- Presentation
Background:
Current targeted therapy options in lung cancer, such as EGFR and ALK inhibitors, are effective, though limited in use by the low percentage of patients that carry targetable mutations for these biomarkers. Targeting a broader biological process like DNA damage response (DDR), as with recent synthetic lethality exploits in BRCA-deficient tumours, may offer a form of precision therapy for a larger number of patients. We have shown that NSCLC cells deficient in the DDR protein ATM, exhibit similar synthetic lethality when treated with a PARP1 inhibitor, and that NSCLC patients lacking detectable ATM have poorer overall survival. In vitro, ATM deficient, or “ATMic” cells show increased sensitivity to chemotherapeutics at much lower levels when given in combination with PARP inhibitor. This data suggests that ATM status may be an important determinant for treatment modalities including low dose radiation or platin therapy, or novel synthetic lethality therapies. Here, we seek to determine the cause of ATM loss in NSCLC patients through targeted sequencing, and thorough transcriptomic and epigenetic analysis.
Methods:
We perform whole-transcriptome analysis on NSCLC patient samples previously characterized as normal or ATMic, to detect differences in intracellular pathway activation in these tumours. Additional analysis using OncoFinder software identifies possible effective therapies based on which signalling pathways are most active in the normal or ATMic patients. We also perform targeted NGS on these samples. To our knowledge, no sequencing of ATM has been performed on samples that have also been characterized through other methods (i.e. quantitative IHC) to be ATM deficient.
Results:
We have generated a substantial body of evidence showing that ATM loss has significant impact on the cell sensitivity to several therapeutic modalites. As such ATMic tumours may be treated more effectively using specific treatment strategies than their ATM competent counterparts. Initial analysis of NSCLC cell lines using the outlined methodologies distinguishes ATM status and identifies different therapeutic agents based on inherent molecular differences. A complete analysis of the transcriptome profiles of ATMic NSCLC patients will be presented and discussed.
Conclusion:
This research helps complete the overall picture of what the therapeutic implications of ATM loss in NSCLC actually are and how ATMic tumours can best be identified in the clinic. Together, these analyses will give us a stronger understanding of the mechanism for ATM loss in NSCLC, as well as allow us to develop an ATMic “signature” for reliably determining ATM status in patients for directing their treatment options.
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OA06.04 - Discussant for OA06.01, OA06.02, OA06.03 (ID 6962)
14:50 - 15:05 | Author(s): R. Soo
- Abstract
- Presentation
Abstract not provided
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OA06.05 - Proteomic Analysis of ERCC1 Predicts Benefit of Platinum Therapy in NSCLC: A Reevaluation of Samples from the TASTE Trial (ID 5361)
15:05 - 15:15 | Author(s): J. Soria, K. Olaussen, F. Cecchi, E. An, C. Yau, M. Wislez, G. Zalcman, D. Moro-Sibilot, D. Perol, B. Besse, F. Morin, T. Hembrough
- Abstract
- Presentation
Background:
It is hypothesized that low or absent expression of the excision repair cross-complementation group 1 (ERCC1) protein predicts improved survival in NSCLC patients treated with platinum-based therapy. However, the International Adjuvant Lung Cancer Trial Collaborative Group concluded that current ERCC1 assessment methods are inadequate for clinical decision-making. Due to the unreliability of ERCC1 immunohistochemistry (IHC), the IFCT-0801 TASTE (Tailored Postsurgical Therapy in Early-Stage NSCLC) trial of adjuvant therapy for NSCLC was discontinued. We reevaluated a subset of samples from the TASTE trial using mass spectrometry-based proteomics to quantitate ERCC1 protein. We correlated ERCC1 proteomic status with survival after chemotherapy with cisplatin/pemetrexed and compared it to ERCC1 IHC ranking.
Methods:
Formalin-fixed, paraffin-embedded NSCLC tumor tissues were laser microdissected, solubilized, digested, and proteomically analyzed. A multiplexed, selected reaction monitoring mass spectrometric assay was used to quantitate levels of multiple proteins including ERCC1. The Kaplan-Meier method and univariate Cox analysis assessed overall survival (OS) and relapse-free survival (RFS). A chi-squared test compared binary proteomic levels of ERCC1 (detectable vs. undetectable) with the IHC status assessed using an anti-ERCC1 antibody (8F1) during the TASTE trial.
Results:
Of 146 evaluable patients, 33 (22.6%) had undetectable ERCC1 by quantitative proteomics. Proteomics found no detectable ERCC1 protein in 8/36 (22.2%) IHC-positive patients nor in 8/22 (19.3%) IHC-indeterminate patients. ERCC1 was detected in 71/88 (80.7%) IHC-negative patients (range: 36-137 amol/µg total tumor protein). Undetectable ERCC1 by proteomics was prognostic of OS (hazard ratio [HR]: 5.45; p=0.031). In survival analyses of cisplatin-treated patients (n=122), only one of the 15 deaths occurred among the patients with undetectable ERCC1 protein. These patients had better OS than cisplatin-treated patients with detectable ERCC1, although the difference statistically nonsignificant (HR: 3.98; p=0.102). RFS was similar between patients with and without detectable ERCC1. GARFT protein (predictive of response to pemetrexed) was quantified in 100% of patients (range: 492-4006 amol/µg). The 10 cisplatin/pemetrexed-treated patients with GARFT levels >900 amol/µg had nonsignificantly worse OS than their counterparts with lower GARFT levels (p=0.08).
Conclusion:
Although underpowered to detect statistically significant survival differences, this study clearly demonstrates that quantitative proteomics can increase accuracy in identifying NSCLC patients who will respond to platinum-based therapy because they do not express ERCC1. Approximately 28% of such patients were misclassified by ERCC1 IHC in the TASTE trial. Clinicians should be aware that multiplexed quantitative proteomics can quantitate ERCC1 simultaneously with multiple clinically relevant proteins in lung tumors and small biopsies.
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OA06.06 - Druggable Alterations Involving Crucial Carcinogenesis Pathways Drive the Prognosis of Squamous Cell Lung Carcinoma (SqCLC) (ID 5342)
15:15 - 15:25 | Author(s): S. Pilotto, M. Simbolo, I. Sperduti, S. Novello, C. Vicentini, U. Peretti, S. Pedron, R. Ferrara, M. Caccese, M. Milella, A. Mafficini, P. Visca, M. Volante, F. Facciolo, A. Santo, L. Carbognin, M. Brunelli, M. Chilosi, A. Scarpa, G. Tortora, E. Bria
- Abstract
- Presentation
Background:
We previously built and validated a risk classification model for resected SqCLC by combining clinicopathological predictors to discriminate patients’ (pts) prognosis (Pilotto JTO 2015). Here we (AIRCMFAG project no. 14282) investigate the molecular portrait of prognostic outliers to identify differentially expressed, potentially druggable alterations.
Methods:
Based on the published 3-class model, 176 and 46 pts with good and bad prognosis, respectively, were identified. Somatic Mutations (SM) and Copy Number Alterations (CNA) were evaluated with Next Generation Sequencing (NGS) for 59 genes (Ion Proton system, Ion Ampliseq custom panel). Moreover, RNA expression assays, immunohistochemistry (IHC) and immunofluorescence (FISH) were performed. Descriptive statistic was adopted and continuous variables were dichotomized according to AUC or medians.
Results:
Herein, the analysis of 60 pts (good/poor 27/33) is reported. In the overall population, the median rate of SM (3.3%) is lower compared to the median rate of CNA (28.3%), without significant differences between the two prognostic groups. The most frequent SM resulted to be missense (66.7%) and nonsense (20.3%) mutations, whereas the copy number gain is the most common CNA (76.7%), The distribution of relevant alterations in the main carcinogenesis pathways in term of SM, CNA and expression (by RNA, IHC and FISH), according to the prognostic subgroups, are reported in the table.Pathway Gene [method] Good [%] Poor [%] p-value Squamous differentiation SOX [CNA] 74.1 51.5 0.11 TP63 [CNA] 37.0 21.2 0.25 Epithelial to mesenchymal transition SNAI1 [RNA] 59.2 90.9 0.006 Vimentin [RNA] 44.4 69.7 0.07 mTOR PI3KCA [SM] 0 9.0 0.24 RICTOR [CNA] 3.7 27.3 0.017 p-mTOR [IHC] 11.1 18.1 0.5 Tyrosine kinase receptors DDR2 [SM] 11.1 0 0.085 FSR2 [CNA] 3.7 18.1 0.12 MET [FISH] 11.1 24.2 0.32 FGFR3 [FISH] 25.9 42.4 0.28 Cell cycle regulators CDKN2A [CNA] 22.2 3.0 0.38 SMAD4 [CNA] 33.3 57.6 0.074 Immune checkpoints PD-L1 [IHC] 18.5 6.1 0.23 PD-1 [RNA] 51.8 93.9 <0.0001
Conclusion:
Although performed on a limited number of pts, such comprehensive analysis of DNA, RNA and proteins, using different methodologies, is feasible and allow identifying potentially druggable prognostic modulators, such as RICTOR/PI3K/mTOR signaling pathway. The possibility to inhibit this pathway with selective agents is currently under investigation in in vitro preclinical models.
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- Abstract
- Presentation
Background:
Veliparib is a potent poly(ADP-ribose) polymerase (PARP)-1 and PARP-2 inhibitor that has synthetic lethality interaction with cancers harboring homologous recombination deficiency. In preclinical models, it has also been shown to delay the repair of DNA damage induced by chemotherapeutics (platinum, alkylators, topoisomerase inhibitors). Clinically meaningful improvements in progression-free survival and overall survival were observed in a phase 2 trial of veliparib with carboplatin/paclitaxel in previously untreated metastatic or advanced NSCLC (M10-898 study). Intriguingly, smoking history had a major impact on veliparib effect—smokers benefited most from veliparib addition. The underlying mechanism for this observation remains unclear. The efficacy benefit of veliparib in smokers is not dependent on tobacco exposure during study treatment, but correlates with the duration of smoking history, suggesting a genetic basis.
Methods:
Genomic signatures in NSCLC associated with smoking status have been identified by The Cancer Genome Atlas (TCGA) Lung Cancer Project. Relevant observations were leveraged in the reported analysis. To comprehensively identify genes or genomic features that are associated with smoking status and veliparib response, patient tumor samples from the M10-898 trial were subjected to whole-exome (N = 38) and RNA sequencing (N = 75) analysis. Alexandrov somatic mutational signature was calculated from exome sequencing data.
Results:
Data from TCGA show that cancer genomes in smokers harbor significantly more genetic alterations than those in non-smokers. These alterations include high mutational burden, high C>A transversion, high mutation frequency of key cancer genes (particularly TP53), and high homologous recombination defect signature. Similar observations were confirmed in the M10-898 study. Of the 38 patients with exome data, 26 were determined to be positive for a smoking-related signature—signature 4. Elevated mutational burden was observed among current and former smokers, with a mean of 199 somatic mutations in current or former smokers vs 60 in never-smokers (p = 0.004). The small sample size of our genomic cohort nevertheless precludes conclusive association of genomic signatures and veliparib benefits.
Conclusion:
Cancer genomes in smokers are enriched with genetic alterations associated with poor outcome using standard chemotherapy, as well as with vulnerability factors that can prime tumors to respond to veliparib. For further validation, a targeted sequencing assay to detect key DNA damage and repair genes as well as key genomic signatures has been established and will be used in all phase 3 veliparib trials.
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OA06.08 - Discussant for OA06.05, OA06.06, OA06.07 (ID 7006)
15:35 - 15:50 | Author(s): M. Gottfried
- Abstract
- Presentation
Abstract not provided
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WS08 - Special Session: CAP/IASLC/AMP Guidelines for Molecular Testing in Lung Cancer (ID 481)
- Event: WCLC 2016
- Type: Workshop
- Track:
- Presentations: 1
- Moderators:M.S. Tsao, E. Bernicker, Y. Yatabe
- Coordinates: 12/05/2016, 07:30 - 08:30, Strauss 1
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Special Session: CAP/IASLC/AMP Guidelines for Molecular Testing in Lung Cancer (ID 7220)
07:30 - 08:30 | Author(s): Y. Yatabe
- Abstract
- Presentation
Abstract not provided
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Author of
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P1.03 - Poster Session with Presenters Present (ID 455)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.03-044 - EUS-Guided Sampling of Mediastinal Lymph Nodes and Abdominal Lesions in Lung Cancer (ID 5147)
14:30 - 14:30 | Author(s): Y. Yatabe
- Abstract
Background:
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS–TBNA) was introduced to provide access to mediastinal and hilar lymph nodes. However, it is difficult to use EBUS to approach the aortopulmonary window and paraesophagaeal stations. Transesophageal endoscopic ultrasound (EUS) was introduced to provide access to this area. In addition, transgastroduodenal endoscopic ultrasound can evaluate abdominal lesions.
Methods:
Endoscopic ultrasound fine needle aspiration (EUS-FNA) was performed under conscious sedation with the administration of intravenous midazolam and pethidine hydrochloride. It was performed with a convex array echoendoscope connected to an ultrasound scanning system. Lymph nodes of paraesophageal, subcarinal, lower paratracheal, subaortic, and upper paratracheal regions were evaluated from esophagus. Left adrenal gland and right adrenal gland were evaluated from stomach and duodenum, respectively. Abdominal lesions were also evaluated from stomach and duodenum. After obtaining tissue via EUS-FNA, the tissue was reviewed immediately (rapid on-site cytopathological evaluation: ROSE) by a cytopathologist. Subsequent punctures in the same patient were not performed before confirming the results of ROSE so as to minimize the complications.
Results:
As to the lymph node level, the lower mediastinum and the aortopulmonary window are particularly important for detection by transesophageal EUS, whereas pretracheal and hilar lymph nodes are out of reach because of the interposition of air from the trachea and bronchi. EUS was chosen to assess the posterior mediastinum nodes (#5, 7, 8, or 9) but not the anterior ones. A final diagnosis was obtained by EUS-FNA in 76 patients. The lesions sampled were mediastinal lymph nodes (n=64; #5, 7, 8, or 9), abdominal lymph nodes (n=8), and adrenal gland (n=4).
Conclusion:
Repeat tumor biopsies from patients with acquired resistance were initially obtained through research efforts to ascertain mechanisms of resistance, but are now recommended to help select second-line therapies. However, such biopsies are associated with both risk and discomfort and may not always supply enough tumor tissue for genetic analyses. Although EUS–FNA does not provide access to pretracheal and hilar lymph nodes, EUS-FNA is an accurate, safe, and minimally invasive modality for evaluating mediastinal lymphadenopathy and abdominal lesions in patients suspected of having lung metastases.
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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: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-007 - Clinical Outcomes of Patients with LS-SCLC Treated with Chemoradiotherapy. Can We Find Candidates for Salvage Surgery? (ID 5288)
14:30 - 14:30 | Author(s): Y. Yatabe
- Abstract
Background:
Although small cell lung cancer (SCLC) is generally considered a systemic disease even in patients with limited stage (LS). Selected recurrent LS-SCLC patients after chemoradiation treatment have been reported long survival with receiving salvage surgery. Purpose of this study was to find candidates for salvage surgery.
Methods:
We retrospectively reviewed the charts of 43 consecutive patients who were treated with chemoradiotherapy for LS-SCLC at our hospital from January 2011 to December 2015 to search for the patients with locoregional progression without mediastinal lymph node involvement.
Results:
Of the 43 patients, the median age was 69 (38-83), 91% were male and all of them had ECOG PS 0 or 1. Clinical stage: IIA (12%), IIIA (53%), IIIB (35%). 35 (81%) received hyperfractionated RT (45Gy/30fr/3w). Objective response rate was 95%. One patient died of pneumonia. The median survival time was 1584 days and the median progression free survival was 280 days. 33 (77%) demonstrated disease progression. The first progression site was distant (include pulmonary metastasis and malignant pleural effusion) in 17, locoregional in 11, lymph node metastasis out of the radiation field in 2 and both distant and locoregional in 3. In the locoregional progression patients, 6 developed mediastinal lymph node progression in their clinical courses. Finally, 5 in 33 progressive patients had locoregional progression without mediastinal lymph node progression, and were thought possible candidates for salvage surgery.
Conclusion:
Most of the patients experienced distant metastasis and/or mediastinal lymph node progression. About 15% of patients who presented with apparently localized disease at the primary pulmonary site after chemoradiation might become possible candidates for salvage surgery.
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P1.08 - Poster Session with Presenters Present (ID 460)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.08-032 - Impact of the Oncogenic Status on the Mode of Recurrence in Resected Non-Small Cell Lung Cancer (ID 5392)
14:30 - 14:30 | Author(s): Y. Yatabe
- Abstract
Background:
Surgical resection is employed in patients with resectable non-small cell lung cancer (NSCLC). Despite complete resection, recurrence is sometimes observed. Oncogenic mutations promote initiation and progression of lung cancer, and mutation status predicts treatment outcome of advanced NSCLC; however, their impact on the recurrence patterns remain poorly understood.
Methods:
We retrospectively studied 401 patients showing recurrence after complete resection of NSCLC. Clinicopathological factors were reviewed for time to recurrence (TTR), and recurrence patterns were compared according to oncogenic status and examined according to EGFR mutational subtype.
Results:
Among 401 patients, 185 with EGFR mutation, 46 with KRAS mutation, 15 with ALK rearrangement, and 155 with triple negative mutation (TN) were identified. Multivariate analysis following univariate analyses showed that younger age, well–moderately differentiated histology, earlier pathologic stage, and presence of EGFR or ALK mutation were favorable prognostic factors for TTR. Locoregional recurrence was observed in 53.3% of ALK-positive patients, being significantly common in these patients than in EGFR- and KRAS-positive patients. EGFR-positive patients mostly experienced pleural recurrence, the incidence of which was significantly higher in TN patients. Adrenal recurrence was observed in 7.2% of TN patients, but it was rarely identified in EGFR-positive patients. (Figure) Among EGFR-positive patients, the incidence of brain metastases was significantly higher in L858R cohort than in Del Ex19 cohort. Figure 1
Conclusion:
In resected NSCLC, younger age, well–moderately differentiated histology, earlier pathologic stage, and presence of EGFR or ALK mutation were favorable factors for TTR, and distinct recurrence patterns were revealed according to oncogenic mutation status and mutational EGFR subtype. Our results may provide suggestions for developing a strategy for follow-up and adjuvant therapies after resection.
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-021 - Reproducibility of Comprehensive Histologic Assessment and Refining Histologic Criteria in P Staging of Multiple Tumour Nodules (ID 5365)
14:30 - 14:30 | Author(s): Y. Yatabe
- Abstract
Background:
Multiple tumor nodules (MTNs) are being encountered, with increasing frequency with the 8[th] TNM staging system recommending classification as separate primary lung cancers (SPLC) or intrapulmonary metastases (IM). Pathological staging requires assessment of morphological features, with criteria of Martini and Melamed supplanted by comprehensive histologic assessment of tumour type, predominant pattern, other histologic patterns and cytologic features. With publication of the 2015 WHO classification of lung tumours, we assessed the reproducibility of comprehensive histologic assessment and also sought to identify the most useful histological features.
Methods:
We conducted an online survey in which pathologists reviewed a sequential cohort of resected multifocal tumours to determine whether they were SPLC, IM, or a combination. Specific histological features for each nodule were entered into the database by the observing pathologist (tumour type, predominant adenocarcinoma pattern, and histological features including presence of lepidic growth, intra-alveolar cell clusters, cell size, mitotic rate, nuclear pleomorphism, nucleolar size and pleomorphism, nuclear inclusions, necrosis pattern, vascular invasion, mucin content, keratinization, clear cell change, cytoplasmic granules¸ lymphocytosis, macrophage response, acute inflammation and emperipolesis). Results were statistically analyzed for concordance with submitting diagnosis (gold standard) and among pathologists. Consistency of each feature was correlated with final determination of SPLC vs. IM status (p staging) by chi square analysis and Fisher exact test.
Results:
Seventeen pathologists evaluated 126 tumors from 48 patients. Kappa score on overall assessment of primary v. metastatic status was 0.60. There was good agreement as measured by Cohen’s Kappa (0.64, p<0.0001) between WHO histological patterns in individual cases with SPLC or IM status but proportions for histology and SPT or IM status were not identical (McNemar's test, p<0.0001) and additional histological features were assessed. There was marked variation in p values among the specific histological features. The strongest correlations (<0.05) between p staging status and histological features were with nuclear pleomorphism, cell size, acinus formation, nucleolar size, mitotic rate, nuclear inclusions, intra-alveolar clusters and necrosis pattern. Correlation between lymphocytosis, mucin content, lepidic growth, vascular invasion, macrophage response, clear cell change, acute inflammation keratinization and emperipolesis did not reach a p value of 0.05.
Conclusion:
Comprehensive histologic assessment shows good reproducibility between practicing lung pathologists. In addition to main tumour type and predominant patterns, nuclear pleomorphism, cell size, acinus formation, nucleolar size, and mitotic rate appear to be useful in distinguishing between SPLC and IM.
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P3.01-023 - Quality Assessment of Resampling Specimens in Primary Lung Cancers with Acquired Resistance to the Initial Therapy (ID 5543)
14:30 - 14:30 | Author(s): Y. Yatabe
- Abstract
Background:
Most patients treated against molecular targets eventually develop resistance even after an initial dramatic response. Although rebiopsy of tumors at progression provide information for next-line therapy, it is expected that the tumor tissues would be modified by the therapy.
Methods:
We retrospectively examined histologic features in the resampled specimens in lung cancer patients with resistance to the initial therapy. Furthermore, we also analyzed the differences of tumor cell contents and molecular testing performance according to each biopsy site.
Results:
A total of 315 resampled specimens were submitted to pathology department from 260 patients. Of 315 samples, 116 (37%) were obtained from the lung and 96 (30%) from pleural effusion, 42 (13%) from lymph node, 16 (5%) from liver, 12 (4%) from cerebrospinal fluid (CSF), 10 (3%) from pleura and pericardial effusion, 7 (2%) from bone and 6 (2%) from other biopsy sites. When we compared 48 paired lung tissues between initial and rebiopsies, rebiopsy specimens had significantly less extents of tumor cells and more fibrosis than those in initial biopsy, and these differences were statistically significant with digital quantitation. Resampled sites affect the tumor cell extents and those were high in the order of liver, subcutaneous tissue, lymph node and lung biopsy, whereas pleura and bone samples had a tendency to contain a less number of tumor cells. Molecular testing was performed in 272 samples (from 222 patients). Of 272 samples, 223 (82%) were successfully analyzed, whereas 49 samples were unsuitable for the testing due to low tumor-cell content or complete absence of tumor cells. Higher success rates for molecular testing were seen in the liver and lymph nodes and the value of bone was lowest. Resistant T790M mutations were also differently detected and the higher detection rates were seen in liver, pleura and pericardial effusions.
Conclusion:
Resampled specimens had different property in terms of tumor extents, which differed among the biopsy sites. For molecular testing using resampled specimens, the difference should be taken into account.
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SC21 - Predictive Biomarkers for Outcome of Systemic Therapy in NSCLC (ID 345)
- Event: WCLC 2016
- Type: Science Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:K. Kerr, T. Mitsudomi
- Coordinates: 12/06/2016, 16:00 - 17:30, Hall C7
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SC21.01 - Predictive Biomarkers in NSCLC: The Impact of Tumor Heterogeneity (ID 6685)
16:00 - 16:20 | Author(s): Y. Yatabe
- Abstract
- Presentation
Abstract not provided
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WS08 - Special Session: CAP/IASLC/AMP Guidelines for Molecular Testing in Lung Cancer (ID 481)
- Event: WCLC 2016
- Type: Workshop
- Track:
- Presentations: 1
- Moderators:M.S. Tsao, E. Bernicker, Y. Yatabe
- Coordinates: 12/05/2016, 07:30 - 08:30, Strauss 1
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Special Session: CAP/IASLC/AMP Guidelines for Molecular Testing in Lung Cancer (ID 7220)
07:30 - 08:30 | Author(s): Y. Yatabe
- Abstract
- Presentation
Abstract not provided
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