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Jean-Yves Blay
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MA12 - New Frontiers from Pathology to Genomics (ID 138)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Prasad S Adusumilli, Francisco Perez Ochoa
- Coordinates: 9/09/2019, 14:00 - 15:30, Melbourne (1991)
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MA12.01 - Redefining Malignant Pleural Mesothelioma Types as a Continuum Uncovers Immune-Vascular Interactions (Now Available) (ID 1773)
14:00 - 15:30 | Author(s): Jean-Yves Blay
- Abstract
- Presentation
Background
Malignant Pleural Mesothelioma (MPM) is a deadly disease. The current histopathologycal classification recognises three major types (epithelioid, biphasic, and sarcomatoid) with different prognosis, but showes high interobserver variability. This classification also has a role in the clinical decision-making although, ultimately, MPM becomes refractory to all conventional treatment modalities, and alternative therapeutic options have been evaluated with limited success.
Method
We have performed unsupervised analyses of publicly available RNA-seq data of 284 MPM tumours1,2 with no assumption of discreteness. We have performed an orthogonal validation in a subset of 187 samples, and we have replicated the findings in an independent series of 77 MPM from the French MESOBANK.
Result
A continuum of molecular profiles appeared to explain the prognosis of this disease better than discrete models based on the histopathological classification or on expression data. We identified the immune and vascular pathways as major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes across samples; the extrema of this continuum had very specific molecular profiles: a "hot" bad-prognosis profile (median survival of 7 months), with high lymphocyte infiltration, and high expression of immune checkpoints and pro-angiogenic genes; a "cold" bad-prognosis profile (median survival of 10 months), with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a better-prognosis profile (VEGFR2+/VISTA+, median survival of 36 months), with high expression of the immune checkpoint VISTA and the pro-angiogenic VEGFR2 gene. We selected five genes belonging to the immune and vascular pathways (CD8A, PDL1, VEGFR3, VEGFR2, and VISTA), which expression was enough to capture the three molecular profiles, to validate the expression of these genes at the protein level by immunohistochemistry on a subset of 187 samples from the discovery cohort, and to replicate the molecular profiles as well as their prognostic value in an independent series of 77 MPMs.
Conclusion
In this study we found that the prognosis of MPM is best explained by a continuous model, which extremes show characteristic molecular profiles with specific expression patterns of genes involved in the angiogenesis and immune response3. These data may inform future classifications of MPM and provides insights that may assist the clinical management of this disease.
1Bueno et al., Nat Genet 2016; 2Hmeljak et al., Cancer Discov 2018; 3Alcala et al., under review in Cancer Res; NA and LM equally contributed to this work; MF, FGS, and LFC jointly supervised this work
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MA21 - Non EGFR/MET Targeted Therapies (ID 153)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Benjamin Besse, Michael Thomas
- Coordinates: 9/10/2019, 14:30 - 16:00, Vienna (2016)
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MA21.07 - Circulating Tumor DNA Analysis Depicts Potential Mechanisms of Resistance to BRAF-Targeted Therapies in BRAF+ Non-Small Cell Lung Cancer (Now Available) (ID 1365)
14:30 - 16:00 | Author(s): Jean-Yves Blay
- Abstract
- Presentation
Background
Oncogenic BRAF-V600 mutations are observed in 1-2% of non-small cell lung cancer (NSCLC). Targeted therapies including vemurafenib (V), dabrafenib (D) or combination of dabrafenib plus trametinib (D+T) are associated with favorable outcomes in these patients (pts). The mechanisms of resistance to BRAF-targeted therapies (BRAF-TT) in NSCLC are largely unknown.
Method
We performed genomic profiling of serial circulating-tumor DNA (ctDNA) in a cohort of 79 metastatic BRAF-mutant NSCLC pts (96% V600E, 4% non-V600). BRAFmutational status was ascertained based on local testing. Plasma samples were collected, from 2014-2018 in 27 Hospitals, from pts treated with V (n=34), D (n=2) or D+T (n=23). We collected 41 plasma samples at baseline to BRAF-TT, 40 at progressive disease (PD) and ~200 samples during treatment follow-up, concomitant to routine radiological evaluation. Inivata InVisionSeq™ assay was used to detect the presence of SNVs, indels and CNAs in 36-cancer related genes.
Result
At baseline, 72,5% of BRAF mutations (V600E and non-V600E) were detected in plasma. BRAF-V600E detection in plasma was associated with the presence of liver metastasis, versus BRAF-V600E-negative cases (22% vs. 7%, respectively). Co-occurring molecular alterations at baseline, besides BRAF-V600E, were observed in 18/26 (70%) cases: FGFR2 (1pt), PIK3CA (2pts), ERBB2 (1pt), CTNNB1 (2pts) and IDH1 (2pts). FGFR2, PIK3CA or CTNNB1 alterations were associated with PD as the best response to the subsequent BRAF-TT. TP53 and STK11 mutations were observed in 54% (14/26) and 8% (2/26) of pts, respectively. Complete clearance of BRAF-V600E in plasma at baseline was observed at the first CT-scan evaluation in 42% (3/7) and 82% (9/11) pts treated with V or D+T, respectively. These pts were in complete or partial response, suggesting that monitoring BRAF-V600E levels in plasma on treatment may be a clinically useful marker of tumor response. At PD, a consistent rebound in BRAF-V600E plasma levels was observed in 60% (24/40) pts. Resistance to V was associated with alterations in the MAPK pathway: 1pt (KRAS), 1pt (GNA11), 1pt (NRAS and GNAS) and 1pt (MAP2K1 and NFE2L2). Activating PI3KCA mutations were observed in 4 pts who progressed in <6 months on V treatment. ctDNA analyses at PD under D+T revealed that, similar to what we observed in patients who progressed on V, alterations in KRAS, NRAS, PIK3CA and CTNNB1 are associated with D+T resistance. Prediction of the impact of these alterations, at the protein level, was assessed using in silico structure modeling and will be presented.
Conclusion
ctDNA monitoring might be an informative tool for assessing disease response and resistance in NSCLC pts treated with BRAF-TT. MAPK reactivation remains an important resistance mechanism to BRAFi-monotherapy or to BRAFi and MEKi combination therapy.
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OA08 - Advanced Models and "Omics" for Therapeutic Development (ID 133)
- Event: WCLC 2019
- Type: Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Luis M Montuenga, Julie George
- Coordinates: 9/09/2019, 11:00 - 12:30, Interlaken (1988)
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OA08.02 - A Multidisciplinary Multi-Omics Study of Spatial and Temporal Tumor Evolution in Thoracic Cancers with Clinical Implications (Now Available) (ID 2365)
11:00 - 12:30 | Author(s): Jean-Yves Blay
- Abstract
- Presentation
Background
In the context of the MESOMICS and lungNENomics projects1, we generated comprehensive molecular profiles of Malignant Pleural Mesothelioma (MPM)2 and pulmonary carcinoids (PCa)3. We showed that a continuous molecular model can better explain the prognosis of MPM than the three histologies, with strong differences in the expression of immune checkpoints and pro-angiogenic genes across samples. We also identified a new entity of PCa (supra-carcinoids) with carcinoid-like morphology yet the molecular and clinical features of LCNEC, which challenges the general believe that PCa have no relationship or genetic, epidemiologic, and clinical traits in common with LCNEC and SCLC. These two studies suggest an important role of heterogeneity in the biology of these tumors.
Method
Much progress has been made in revealing the evolutionary history of individual cancers, in particular using multi-region sequencing. However, most studies focused on a single ‘omic technique, and lacked temporal samples. Here we present the results of an innovative approach to study spatial and temporal tumor evolution based on (i) integration of whole-genome and transcriptome sequencing and EPIC 850K methylation arrays on multiple regions from 12 MPM, and (ii) a novel tumor-derived organoid-based strategy for studying the evolution of PCa.
Figure 1. Multi-omic multi-regional profiling of a MPM patient. A) Somatic Copy Number Variants (CNV), somatic Structural Variants (SV), kernel density plots of (top) somatic single nucleotide variants (SNVs) allelic fractions, (middle) expression normalized read counts, and (bottom) methylation array M-values. B) Projection of the transcriptomic profile of two tumoral regions into the Principal Component Analysis (PCA) space computed from 284 malignant pleural mesotheliomas2C) Expression (z-score of normalized read counts) for two clinically relevant genes with substantial inter-regional differences.
Biorepositories: French MESOBANK; LungNEN Network
Result
In the data analyses of the 12 MPM we detected significant intra-tumor heterogeneity (ITH) in the expression of immune checkpoints and pro-angiogenic genes (see example in Fig. 1). This might explain the modest and variable response to treatment in clinical trials assessing immunotherapies and antiangiogenic drugs. In the case of PCa, we are currently analysing the organoids genomic data and we will present the preliminary data for the temporal evolution of these diseases.
Conclusion
We found that our approach can detect clinically and biologically meaningful ITH. All the computational methods we developed for these evolutionary studies are available to the scientific community4.
1RareCancersGenomics.com
2Alcala et al., under review in Cancer Res
3Alcala et al., under review in Nat Commun
4https://github.com/IARCbioinfoLFC and MF co-supervised this work
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