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I.I. Wistuba
Moderator of
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O04 - Molecular Pathology I (ID 126)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Pathology
- Presentations: 8
- Moderators:I.I. Wistuba, W.A. Cooper
- Coordinates: 10/28/2013, 10:30 - 12:00, Parkside Ballroom A, Level 1
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O04.01 - Identification of CD74-NRG1, a new recurrent fusion gene in invasive mucinous lung adenocarcinomas of never smokers (ID 4022)
10:30 - 10:40 | Author(s): L. Fernandez-Cuesta, D. Plenker, H. Osada, R. Sun, R. Menon, F. Leenders, M. Peifer, W. Vogel, I. Dahmen, G. Wright, P. Russell, Z. Wainer, B. Solomon, E. Brambilla, H.N. Mignotte, D. Moro-Sibilot, C.G. Brambilla, S. Lantuejoul, J. Altmüller, C. Becker, P. Nürnberg, J.M. Heuckmann, E. Stoelben, J.H. Clement, J. Sänger, M. Vingron, T. Zander, J. Wolf, S. Perner, S. Ansen, S.A. Haas, Y. Yatabe, R. Thomas
- Abstract
- Presentation
Background
Lung adenocarcinoma (AD) of patients who have never smoked frequently bear targetable genome kinase alterations, such as EGFR mutations and translocations affecting ALK, ROS1, and RET genes. These mutations correlate with kinase inhibitor sensitivity in mouse models or in patients. Unfortunately, therapeutically relevant kinase alterations are not present in all lung cancer specimens. Thus, additional genome alterations need to be discovered in order to provide a therapeutic opportunity for the remaining patients.Methods
We collected a cohort of 25 AD specimens of never smokers lacking mutations in KRAS or EGFR, in which we performed transcriptome sequencing with the aim of identifying new oncogenic driver genes.Results
We were able to identify known kinase fusions affecting ALK, ROS1 and RET genes in 3 cases each. Moreover, we detected one sample carrying a novel chimeric transcript fusing the first six exons of CD74 to the EGF-like domain of the NRG1 III-β3 isoform, leading to the expression of its EGF-like domain in an otherwise NRG1-negative tumor tissue. The fusion gene was further detected in four additional cases out of 94 pan-negative* ADs of never smokers. In total, all 5 cases were identified in stage I invasive mucinous lung adenocarcinomas (IMA) of never smoker females. This tumor type frequently presents with multifocal unresectable disease, for which no effective treatment has been yet established. IMA is highly associated with KRAS mutations; indeed, out of 15 IMA analysed, 6 carried a KRAS mutation (40%), and 4 the CD74-NRG1 fusion (27%). Given the fact that NRG1 signals through ERBB3 and ERBB4 receptors, we aimed to determine which receptor CD74-NRG1 provides the ligand for. We observed that ERBB4 was not expressed in the index case, while ERBB3 was relatively highly expressed and this expression also correlated with a positive phospho-ERBB3 (p-ERBB3) signal in the tumoral tissue of all 5 CD74-NRG1 positive cases. In order to test if this phosphorylation of ERBB3 was statistically significant, we stained a cohort of 241 ADs and found that p-ERBB3 was only positive in 6 of them (p-value<0.0001). Additionally, although both EGFR and ERBB2 were expressed in the index case, only ERBB2 expression correlated with a p-ERBB2 positive signal. These data suggest that CD74-NRG1 might provide the ligand for ERBB3, which may form heterodimers with ERBB2, since ERBB3 is devoid of intrinsic kinase activity and cannot support linear signaling in isolation. This is in line with previous studies showing that NRG1 induces an oncogenic signal through ERBB2-ERBB3 heterodimers engaging the PI3K-AKT pathway. This was further supported by the activation of the PI3K-AKT, but not the MAPK pathway, in CD74-NRG1 transduced H2052 lung cells, after 24h starvation. *pan-negative: EGFR, KRAS, ALK, HER2, BRAF, ROS1 and RET wild-typeConclusion
Altogether, these data shows that CD74-NRG1 is a new recurrent oncogenic fusion gene, highly associated with IMA of never smokers. It also suggests that CD74-NRG1 fusion protein signals through the ERBB2-ERBB3 receptors complex leading to the activation of the PI3K-AKT pathway, providing a therapeutic opportunity for a tumor type with, so far, no effective treatment.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O04.02 - Using NGS for Mutational Profiling of NSCLC in the Clinical Setting (ID 2571)
10:40 - 10:50 | Author(s): S. Roy Chowdhuri, M. Routbort, K. Patel, R. Singh, R. Broaddus, A. Lazar, K. Aldape, R. Luthra, I.I. Wistuba, G.R. Simon
- Abstract
- Presentation
Background
Recent advances in molecular characterization of lung cancer have led to the identification of potential therapeutic targets that play key roles in regulating cell growth and proliferation. With the introduction of new targeted therapies, it becomes increasingly important to accurately characterize mutation status in lung cancer patients to provide personalized care that define prognosis and predict response to therapy. The advent of next generation sequencing (NGS) platforms in the realm of clinical molecular diagnostics has made multi-gene mutational profiling an affordable and highly successful methodology for massively parallel sequencing using small quantities of DNA.Methods
Tumor specimens from 262 distinct samples of primary lung carcinoma including adenocarcinoma (n=228), squamous cell carcinoma (n=15), non small cell cancer not otherwise specified (NSC-NOS) (n=8), poorly differentiated carcinoma (n=4), neuroendocrine carcinoma (n=2), small cell carcinoma (n=1) and pleomorphic carcinoma (n=4) were tested by NGS. Tumor samples included formalin-fixed paraffin-embedded surgical core needle biopsies, resection specimens, cytopathology cell blocks, as well as cytopathology direct smears. Ten ng of DNA from each sample was tested for mutations in hotspot regions of 46 cancer related genes (Ion AmpliSeq Cancer Panel) using either a 316 chip or a 318 chip on an Ion Torrent Personal Genome Machine (PGM) Sequencer (Life Technologies, CA).Results
Mutations were detected in 222/240 (93%) patients with a histologic diagnosis of adenocarcinoma, NSC-NOS or PDC. EGFR mutations were detected in 47 (20%) of these patients and double EGFR mutations identified in 13 cases, including acquired resistance mutations T790M (n=6) and S768I (n=3). KRAS mutations were detected in 61 (25%) cases, most commonly involving codons 12 and 13 (n= 58) and less frequently involving codons 61 and 146 (n= 3). TP53 was most frequently mutated (n=65; 27%) and was often seen in conjunction with EGFR mutations (n=14; 5%) and KRAS mutations (n=15; 6%). Mutations were detected in 10/15 (67%) squamous cell carcinomas with mutations in TP53 (n=5), CDKN2A (n=3) and PIK3CA (n=2) most frequently seen. Additional mutations detected at a lower frequency from the entire dataset were STK11, ATM, BRAF, PIK3CA, CTNNB1, IDH1, NRAS, CDKN2A, KDR, RET, MET, FBXW7, APC, RB1, FLT3, GNAS, ABL1, HRAS, PTPN11, JAK3, NOTCH1, SMAD4, SMARCB1, SMO, MLH1, AKT1, and ERBB4.Conclusion
In summary, our results show that NGS-based mutational profiling using small amounts of DNA derived from FFPE as well as cytology smears can provide important information regarding mutation status of genes that play key roles in growth and progression of tumor in lung cancer patients and can provide insight into directing personalized cancer therapy.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O04.03 - Oncogene Mutations and Novel Transcript Fusions in Lung Adenocarcinoma from Never Smokers (ID 2939)
10:50 - 11:00 | Author(s): J. Jen, J.S. Jang, A. Lee, J. Li, Y. Asmann, M. Erickson-Johnson, A.O. Bungum, V. Simon, E.S. Edell, K.J. Kopp, B. Eckloff, A. Oliveira, E. Wieben, M.C. Aubry, E. Yi, D.A. Wigle, P. Yang, R.B. Diasio
- Abstract
- Presentation
Background
Lung adenocarcinoma from never smoker represents a unique disease entity in that they often involve females of younger age and have a distinct mutation spectrum compared to those of smoker population. Mutations from the tumors of these patients often involve oncogenes that can be targeted for therapy by small molecule kinase inhibitors. We surveyed for tumor specific genetic changes in lung adenocarcinomas from never smokers for common oncogene mutations and transcript fusions.Methods
We first developed a multiplex assay detecting187 mutations in 10 actionable oncogenes frequently affected in lung cancer. We used this assay to examine 89 lung adenocarcinomas from never smokers identified through the Mayo Clinic Epidemiology and Genetics of Lung Cancer Program. NextGen sequencing (RNASeq) was used to identify transcript fusions affecting either a known kinase or an oncogene in 20 of 89 tumors. RT-PCR, FISH and IHC were used to verify the novel fusion identified in this study.Results
Sixty-four tumors had mutation in at least one of the tested oncogenes involving EGFR (49 cases, 55%), k-RAS (5 cases, 6%), MET (9 cases, 10%), BRAF (4 cases, 5%), PIK3CA (2 cases, 2%), and ERBB2 (4 cases, 5%). RNAseq identified five transcript fusions among the 20 tested tumors, involving known fusions of EZR- ROS1 or KIF5B-RET and three novel fusions involving SND1-BRAF, EML4-BIRC6, and GMEB2-TERT genes. We used RT-PCR to confirm the presence of the SND1-BRAF fusion transcript that involved exons 1-9 of SND1 with exon 2 to 3’ end of the BRAF on chromosome 7. Screening all 89 tumors by RT-PCR identified a total of three tumors with the identical fusion. Interestingly, two of these three tumors with a BRAF fusion also had a concurrent mutation in EGFR gene (S768I) and a third tumor had an additional mutation in the ERBB2 gene (M774_A775ins). Four additional samples were positive for EML4-ALK fusion by IHC and FISH.Conclusion
In our study of a primarily Caucasian population, a majority of lung adenocarcinomas from never smokers (70/89, or 78.6%) carry at least one genetic mutation in a targetable gene. For the first time, we report the presence of a transcript fusion involving SND1-BRAF in lung adenocarcinoma and that these fusions are present in tumors also having EGFR or ERBB2 mutations. Combined together, activation of BRAF by either point mutation or transcript fusion is one of the most frequent events in our study accounting for 7/89 (8%) cases. These findings support a rapid and targeted gene mutation testing strategy for lung adenocarcinoma from never smokers, as the knowledge of these mutations can be readily used to augment therapeutic management.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O04.04 - DISCUSSANT (ID 3982)
11:00 - 11:15 | Author(s): I.I. Wistuba
- Abstract
- Presentation
Abstract not provided
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O04.05 - Epidemiology of PI3K pathway alterations in patients with metastatic non-small cell lung cancer (NSCLC): findings from the international BASALT-1 study (ID 1810)
11:15 - 11:25 | Author(s): G.K. Dy, J. Vansteenkiste, M. Thomas, T. De Pas, F. Grossi, J. De Grève, E. Felip, J. Canon, J. Gray, F. De Braud, M. Reck, S. Thongprasert, D. Planchard, C. Gridelli, P. Roussou, M. Gurnani, G. Atalla, D.W. Sternberg, J.A. Engelman
- Abstract
- Presentation
Background
Buparlisib (BKM120) is an oral PI3K inhibitor that inhibits all four isoforms of class I PI3K (α, β, γ, δ) and has demonstrated antiproliferative, proapoptotic, and antiangiogenic activity in multiple preclinical cancer models. NSCLC cell lines with PIK3CA mutations (muts) have demonstrated increased sensitivity to buparlisib in vitro. BASALT-1 – an ongoing, multicenter, open-label, two-stage Phase ll study (NCT01297491) – evaluates the safety and efficacy of single-agent buparlisib in patients (pts) with NSCLC and an activated PI3K pathway. Here we report data on the prevalence of PI3K pathway alterations in pts with squamous (sq) or non-squamous (non-sq) NSCLC prescreened for entry into BASALT-1.Methods
Pts prescreened for BASALT-1 were ≥18 years of age with previously treated metastatic NSCLC of sq or non-sq histology. PI3K pathway activation (defined as PIK3CA mut and/or PTEN mut and/or PTEN negative [neg; <10% protein expression at 1+ by immunohistochemistry]) was measured in archival or newly acquired tumor tissue collected at prescreening. PIK3CA (exons 1, 5, 7, 9, and 20) and PTEN (exons 1–9) muts were detected primarily using Sanger sequencing in a centralized fashion. Local analysis was permitted at selected sites where a SnapShot approach was most commonly used.Results
As of April 10, 2013, 1183 pts had submitted tumor samples to be assayed (1179 tumors had known histology). PI3K pathway activation was detected in 16.0% of sq and 11.3% of non-sq tumors. In sq tumors (N=612), loss of PTEN protein expression (8.2%) was the most common single alteration observed, followed by PIK3CA mut only (3.1%) and PTEN mut only (2.9%). In non-sq tumors (N=567), PTEN mut only was the most common alteration (4.9%), followed by PIK3CA mut only (2.6%) and PTEN neg only (2.1%). Frequencies of co-existing genetic alterations were: PTEN mut + PTEN neg only (1.0% sq vs 0.4% non-sq), PIK3CA mut + PTEN neg only (0.7% sq vs 0.4% non-sq), PIK3CA mut + PTEN mut only (0% sq vs 0.9% non-sq), and PIK3CA mut + PTEN mut + PTEN neg (0.2% sq vs 0% non-sq). No clear gender, age or ethnicity effects were observed (Table). Figure 1Conclusion
The findings from our large dataset indicate that genetic alterations in the PI3K pathway occur in a clinically significant proportion of pts with sq and non-sq relapsed NSCLC. An accurate characterization of PI3K pathway alteration frequencies in NSCLC will help guide the design of future clinical trials of PI3K inhibitors.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O04.06 - An international standardization study using the ALK IHC antibody D5F3 and a sensitive detection kit demonstrates high concordance between ALK IHC and ALK FISH and between evaluators (ID 2875)
11:25 - 11:35 | Author(s): M.W. Wynes, M. Dietel, E. Schuuring, L.M. Sholl, M. Tsao, Y. Yatabe, R.R. Tubbs, F. Hirsch
- Abstract
- Presentation
Background
The goal of personalized medicine is treating patients with a therapy predicted to be efficacious based on the molecular characteristics of the tumor, thereby sparing the patient futile or detrimental therapy. Anaplastic lymphoma kinase (ALK) inhibitors are effective against ALK positive non-small cell lung cancer (NSCLC) tumors, but to date the only US Food and Drug Administration approved companion diagnostic is a break-apart fluorescence in situ hybridization (FISH) assay. Immunohistochemistry (IHC) is a clinically applicable cost-effective test that is sensitive and specific for ALK protein expression. The purpose of this study was to assemble an international team of expert pathologists to evaluate and standardize the interpretation of a new automated standardized ALK IHC assay.Methods
Archival NSCLC tumor specimens (n=103) previously tested for ALK rearrangement by FISH were provided by the international collaborators. These specimens were stained by IHC with the anti-ALK (D5F3) primary antibody (Ventana Medical Systems, Inc) combined with OptiView DAB IHC detection and OptiView amplification (Ventana Medical Systems, Inc). The evaluators went through an interpretation training session and scored the specimens as positive, if strong granular cytoplasmic brown staining was present in tumor cells, or negative. IHC results were compared to the FISH results and inter-evaluator agreement comparisons made.Results
Overall for the 100 evaluable cases the ALK IHC assay was highly sensitive (90%), specific (95%) and accurate (93%) relative to the ALK FISH results. Similar results were observed using a majority score. For the discrepant cases IHC negativity was scored by 7/7 on 3 FISH positive cases and 6/7 evaluators on 2 additional FISH positive cases. IHC positivity was scored on 2 FISH negative cases by 7/7 readers. There was agreement among 7/7 and 6/7 readers on 88% and 96%% of the cases before a consensus review, respectively, and following a review there was agreement among 7/7 and 6/7 on 95% and 97% of the cases, respectively.Conclusion
Based on expert evaluation the ALK IHC assay using the D5F3 antibody combined with Optiview Detction and Optiview amplification is sensitive, specific and accurate, relative to FISH, and a majority score of multiple readers does not improve these results over an individual reader’s score. Excellent inter-reader agreement was observed for the IHC assay. These data support the algorithmic use of ALK IHC as a screening procedure for ALK protein expression in NSCLC.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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- Abstract
- Presentation
Background
Owing to use of high-resolution computed tomography (CT) scan for lung cancers, small nodules could be detected, so that more patients are identified carrying more than one lesion in lung synchronously at the time of diagnosis. Under this circumstance, precisely distinguish multiple primary lung cancers from intrapulmonary metastasis has important significance on clinical staging and appropriate therapy design.Methods
We comprehensively compared genomic aberration profiles of each tumor in the patients with multifocal pulmonary lesions, assuming that metastasis shared a certain portion of genetic aberrations with the lesion it was originated. Therefore, whole-genome/exome sequencing were applied on 15 intrapulmonary tumors that had highly similar histological diagnosis, and 1 lymph node metastasis derived from six patients with synchronous multifocal lung cancers. The somatic nucleotide variations (SNVs) detected by whole-genome/exome sequencing were validated by either mass spectrometry or the Sanger sequencing.Results
A total of 344 non-synonymous somatic point mutations were detected in whole genome sequencing analysis (3 lesions and 1 lymph node metastasis in 1 patient), corresponding to 306 unique mutation sites. Among the 70 mutations detected in the lymph node metastasis, 36 (51.4%) were also found in lesion 1 of the 3 intrapulmonary lesions, whereas no shared mutation were detected between the metastasis and either of the other two lesions. Meanwhile, there was only 1 common mutation between lesion 2 and 3, while no shared mutations were observed between lesion 1 and 2 or lesion 1 and 3. These results suggested that the metastasis was originated from lesion 1 and the 3 lesions were independent primary tumors. In whole exome sequencing analysis (12 lesions from 5 patient), among the 389 somatic non-synonymous mutations detected, we observed a similarity between each pair of tumors within one patient ranged from 0% to 5.3%, suggesting that all the lesions were independent primary tumors rather than intrapulmonary metastasis. We also reached a same conclusion when we included all somatic mutations found across the genome/exome in the analysis. These genomic abnormality profile-based diagnosis were consistent with the diagnosis based on histological examination except one lesion in patient 5, which had been considered as an intrapulmonary metastasis by histological judgment. At the same time, EGFR or KRAS mutations, which are therapy targets for adenocarcinoma in lung were detected in 7 or 3 out of the 15 tumors in 3 or 2 patients, respectively. Heterogeneity was also observed in mutation status of these two genes among different lesions in a single patient.Conclusion
Comprehensive genomic aberration profiling is powerful for identification of multiple primary lung cancers. The lymph node metastasis in the study stands as a positive control, compared with which we could tell that lesions from multifocal primary lung cancers shared too few somatic mutations to be intrapulmonary metastasis. Considering the heterogeneous mutation status of EGFR or KRAS among different tumors derived from a single patient with multifocal primary lung cancer, molecular diagnosis should be taken for each accessible lesion when targeted adjuvant therapy is under consideration.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O04.08 - DISCUSSANT (ID 3983)
11:45 - 12:00 | Author(s): S. Dacic
- Abstract
- Presentation
Abstract not provided
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Author of
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MS11 - Next Generation Technology for Detection and Treatment of Lung Cancer (ID 28)
- Event: WCLC 2013
- Type: Mini Symposia
- Track: Biology
- Presentations: 1
- Moderators:S. Toyooka, V.N. Tran
- Coordinates: 10/29/2013, 14:00 - 15:30, Bayside Auditorium B, Level 1
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MS11.3 - The Role of Current Pathologic Techniques in the Next Gen World (ID 508)
14:45 - 15:05 | Author(s): I.I. Wistuba
- Abstract
- Presentation
Abstract
Over the past decade, significant progress has been made in the characterization of molecular and genetic abnormalities tumors from patients with non-small cell carcinoma (NSCLC) that are being used as molecular targets and predictive biomarkers to select patients for targeted therapy. Recent advances in expanding the available NSCLC targeted therapies require the analysis of a broad panel of molecular abnormalities in tumor specimens, including gene mutations, gene amplifications, gene fusions and protein expression by applying different methodologies to tumor tissue (biopsy) and cell (cytology) samples. The rapid development of technologies for large-scale sequencing (next-generation sequencing, NGS) has facilitated high-throughput molecular analysis holding various advantages over traditionally sequencing including the ability to fully sequence large numbers of genes in a single test and simultaneously detect deletions, insertions, copy number alterations, translocations, and exome-wide base substitutions (including known hot-spot mutations) in all known cancer-related genes [1,2]. Currently, NGS platforms, including whole genome, whole exome and targeted gene sequencing, represent emerging diagnostic methodologies for the detection of oncogenes fusions and mutations in tumor tissue specimens, including formalin-fixed and paraffin-embedded (FFPE) samples [3]. Technical challenges include sequencing samples of low quality and/or quality, reliable identification of structural and copy number variation, and assessment of intratumoral heterogeneity. In addition, the clinical use of the NGS sequencing data is not straightforward and there are several challenges related to data analysis, data storage and report generation [4]. There is growing consensus that tumor tissue specimens must represent the setting of the disease to be treated, and increasingly, more tissue samples are being obtained for molecular testing of advanced, metastatic and chemo-refractory NSCLC tumors (e.g., MD Anderson BATTLE Lung Cancer Program) [5]. However, the biopsy and cytology samples available for molecular testing in those metastatic refractory NSCLC tumors are likely to be more challenging samples for molecular testing, including NGS platforms. The role of the pathologist is becoming increasingly important to adequately integrate routine histopathology assessments and molecular testing, including NGS, with clinical pathology for the most accurate tumor diagnosis and subsequent selection of the most appropriate therapy. References: 1. Meyerson M, Gabriel S, Getz G: Advances in understanding cancer genomes through second-generation sequencing. Nat Rev Genet 11:685-96, 2010 2. Mwenifumbo JC, Marra MA: Cancer genome-sequencing study design. Nat Rev Genet 14:321-32, 2013 3. Ross JS, Cronin M: Whole cancer genome sequencing by next-generation methods. Am J Clin Pathol 136:527-39, 2011 4. Ulahannan D, Kovac MB, Mulholland PJ, et al: Technical and implementation issues in using next-generation sequencing of cancers in clinical practice. Br J Cancer 109:827-35, 2013 5. Kim ES, Herbst RS, Wistuba, II, et al: The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov 1:44-53, 2011Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O04 - Molecular Pathology I (ID 126)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Pathology
- Presentations: 1
- Moderators:I.I. Wistuba, W.A. Cooper
- Coordinates: 10/28/2013, 10:30 - 12:00, Parkside Ballroom A, Level 1
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O04.04 - DISCUSSANT (ID 3982)
11:00 - 11:15 | Author(s): I.I. Wistuba
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
