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Manuel Fernández-Bruno
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-31 - BRAF Mutations: Classes I, II and III in NSCLC Patients Included in the SLLIP Trial, Targeted Treatment According to Class (Now Available) (ID 897)
09:45 - 18:00 | Author(s): Manuel Fernández-Bruno
- Abstract
Background
BRAF V600 mutations have been found in 2% of non-small cell lung cancer (NSCLC) patients, with FDA approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50-80% of BRAF mutations in lung cancer are non-V600, and can be class 2, with intermediate to high kinase activity and RAS independence, or class 3, with impaired kinase activity, upstream signaling dependence and consequently sensitivity to receptor tyrosine kinase (RTK) inhibitors. Non-V600 tumors require combinatory therapy with RAF/MEK inhibitors and blockers of RTK signaling, like SHP2 (PTPN11) inhibitors.
Method
Plasma DNA of 185 newly diagnosed advanced lung adenocarcinoma patients was examined for BRAF and other mutations with a clinically validated cell-free DNA (cfDNA) assay (Guardant360, Guardant Health Inc. CA, U.S), and results were correlated with patient outcome. In addition, two NSCLC cell lines and one Triple Negative Breast Cancer (TNBC), H1395 (class 2 BRAF mutation), H1666 (class 3 BRAF mutation) and MDA-MB-231 (class 2 BRAF mutation) were treated with single or combined BRAF, MEK and SHP2 inhibitors and cell viability was assessed.
Result
BRAF mutations were found in 17/185 (9%) and BRAF amplification in five patients (3%). Three patients had BRAF V600E mutations (2%) and 14 patients non-V600 BRAF mutations (8%), including four class 2 and four class 3 mutations. Patients were treated with chemotherapy and/or immunotherapy, or targeted therapy for other co-alterations. PFS was 1.8, 6.1, 5.0, 5.3 and 5.3 months for Class 1, 2, 3, other BRAF, and BRAF amplification, respectively. These low survival rates indicate that new treatment options are urgently needed. In vitro results confirm sensitivity of class 3, and resistance of class 2 BRAF mutations to single SHP2 inhibition with RMC-4550 and SHP099, with similar results in TNBC and lung cancer cells. Combined dabrafenib and trametinib treatment indicated antagonistic effects, especially in the class 3 BRAF mutant cell line. Concomitant MEK and SHP2 inhibition was synergistic in both class 2 and 3 BRAF mutations.
Conclusion
It is evident that different classes of BRAF mutations require distinct treatments, which could even outweigh tumor type. Therefore, we should examine BRAF class in daily clinical practice. Upfront targeting of the MAPK signaling pathway combined with SHP2 inhibitors reveals synergistic interactions, and additional inquisition may pave the way for new treatment options in the most frequently found mutations in BRAF patients.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-56 - Copy Number Gains (CNGs) of Clinically Relevant Genes in Advanced NSCLC Patients (ID 2519)
10:15 - 18:15 | Author(s): Manuel Fernández-Bruno
- Abstract
Background
Somatic copy number variations (CNV; i.e. amplifications and deletions) have been implicated in the origin and development of multiple cancers and some of these aberrations are designated targets for therapies, such as amplified ERBB2 in breast cancer. In the case of NSCLC patients, MET alterations are receiving increasing attention as targets in precision medicine, and several clinical trials of anti-MET agents are ongoing. Routine testing for these potential targets on formalin-fixed paraffin embedded (FFPE) samples is mainly carried out by in-situ hybridization (FISH) approaches covering only a single gene of interest. Although this methodology is still the gold standard of CNV detection, it presents several drawbacks. Here we aimed to determine the potential of next generation sequencing (NGS) to simultaneously determine CNGs across many in FFPE samples
Method
FFPE biopsies from 140 stage IIIb-IV NSCLC patients (p) of our institution were prospective tested. Of them, 110 corresponded to samples at diagnostic and 30 after progression to targeted therapies. DNA was purified submitted to NGS using the 16-gene QIAact Lung Panel (Genereader®, Qiagen). Coverages for the genes analyzed were normalized using the total coverage of the panel. Cut-off values for CNVs were established as the average normalized coverage for each gene plus two times the standard deviation. Representative samples were analyzed by FISH
Result
Validation analyses in 8 cell lines showed 100% concordance between FISH and NGS for detection of EGFR, MET and ERBB2 amplifications. Among the 140 NSCLC p, MET was the gene showing a higher frequency of CNGs, followed by PIK3CA, NRAS, EGFR and KRAS (Table 1). In contrast, only one p was found to harbor a ROS1 CNG. Among the 17 samples with MET CNG (12%), 6 corresponded to p progressing to targeted therapies. In addition, 8 of the 17 samples with MET CNGs were submitted to FISH, 6 of them were positive and the remaining 2 samples had copy numbers higher than 3.5 by this technique. In the case of EGFR, CNGs were associated with sensitizing mutations, with 5 samples showing both alterations concomitantly. In contrast, PIK3CA, NRAS, ALK, BRAF, HER2, PDGFRA, KIT and MET CNGs were not associated with mutations (Table 1).
n CNG
%
n MUTANT
MET
17
12.1
0
PIK3CA
12
8.6
0
NRAS
10
7.1
0
EGFR
10
7.1
5
KRAS
10
7.1
2
ALK
8
5.7
0
BRAF
8
5.7
0
ERBB2
8
5.7
0
PDGFRA
6
4.3
0
KIT
6
4.3
0
ROS1
1
0.7
0
Conclusion
CNGs in clinically relevant genes are present in a significant percentage of advanced NSCLC patients and, except in the case of EGFR, are not associated with driver mutations. Further research is warranted to determine the clinical implications of this finding.
