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Eduardo Caetano Albino Da Silva
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EP1.04 - Immuno-oncology (ID 194)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.04-11 - Frequency of Microsatellite Instability (MSI) in Brazilian TKI Non-Treatable Non-Small Cell Lung Cancer (NSCLC) Patients (Now Available) (ID 2304)
08:00 - 18:00 | Author(s): Eduardo Caetano Albino Da Silva
- Abstract
Background
Lung cancer is the most common cause of cancer deaths worldwide. Personalized medicine based on driver mutations has improved tailored treatment for patients with non-small cell lung cancer (NSCLC). However, only a subset of patients is benefited with tyrosine kinase inhibitors. Non-treatable advanced NSCLC patients may be eligible for treatment with immunotherapies. Recently, microsatellite instability (MSI) phenotype was reported as a predictive biomarker of response to immunotherapy, making it a crucial biomarker for clinical management for NSCLC patients. This study aimed to determine MSI frequencies in Brazilian NSCLC patients who are not eligible for TKi therapy.
Method
522 patients diagnosed with NSCLC patients at Barretos Cancer Hospital (Brazil) were evaluated. All samples were molecularly analyzed for EGFR (exons 18, 19, 20 and 21), KRAS (codons 12/13) and BRAF (exon 11 and 15) mutations by PCR followed by Sanger direct sequencing. The molecular MSI evaluation was performed using a hexa-plex marker panel by PCR followed by fragment analysis.
Result
The mean age of the patients was 61y (22-87) and 54% were male. EGFR, KRAS, and BRAF wild-type status were identified in 62.6% (327/522) of cases. In 297 EGFR/KRAS/BRAF wild-type cases, MSI analysis was performed and we observed the presence of MSI-H in only three (1%) cases. Overall, two out of these three patients were female and one was male, the age at the diagnosis ranged from 55 to 76 years old, they were current or former smokers and all three cases were diagnosed at stage IV. Of note, one of the patients with MSI-high status received treatment with immune checkpoint inhibitor, and he is the only one out of the three patients that remains alive with 51-months survival.
Conclusion
The frequency of MSI-high status is low in Brazilian NSCLC patients, in accordance with other population literature. Nevertheless, these MSI-positive patients are eligible for immunotherapy approaches.
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-13 - Genomic Landscape of Brazilian Non-Small Cell Lung Cancer (ID 1296)
09:45 - 18:00 | Author(s): Eduardo Caetano Albino Da Silva
- Abstract
Background
Non-Small Cell Lung Cancer (NSCLC) is the most common type of lung cancer with low survival rates. Therefore, NSCLC patients may be benefited by tailored treatment based on genomic profiling. However, the genomic landscape of Brazilian NSCLC remains unknown. Thus, our aim was to evaluate the genomic profiling of NSCLC of a Brazilian series.
Method
We analyzed 96 NSCLC patients from Barretos Cancer Hospital, Brazil. Exome sequencing of paired tumor/blood DNA was performed by Illumina HiSeq2500™ and VarScan was applied for germline alterations exclusion, variant calling, and annotation. Cancer Genome Interpreter was employed for identification of driver genes. Mutational Signatures were performed using Somatic Signature. Copy Number Variations (CNV) were determined using Circular Binary Segmentation. Gene expression analysis was assessed by NanoString and pathway enrichment was performed using KEGG.
Result
Overall, 61 cases were adenocarcinomas, 34 squamous cell carcinomas and 1 was adenosquamous (I, n=19; II, n=14; III, n=23; IV, n=40). Regarding smoking, 82 patients were current/former smokers and 12 patients were never smokers and most of the cases presented the mutational signature 4. More than 30,000 mutations were identified and 733 were classified as drivers (known: 90; predicted: 643). TP53 gene was the most recurrently mutated gene (56% of the cases). Besides of TP53 gene, recurrent mutations were found in KRAS (23%), EGFR (12.5%), NFE2L2 (9%), HERC2 (9%), STK11, ROS1, PIK3CA and CDKN2A (8%). KRAS, EGFR, STK11 and ROS1 mutations were mutually exclusive. CNV gain was observed in 1q21.3, 1q22, 3q26, 31q29, 7q11.21, 7p11.1-q11.1, 8p11.1-q11.1, 19q13. Downregulation of DKK1, IBSP, LAMC2, NGFR and LAMB3 and upregulation of LAMC3, MAPK8IP1, IL5RA, NR4A1, AXIN2, PLA2G4E, COL6A6, CACNA2D2, LRP2, NR4A3, FOS, BMP5, and FGFR2 were observed in disease stages I/II indicating enrichment of PI3K-Akt, MAPK, Ras, Rap1 and Wnt signaling pathways. Downregulation of MCM2, VEGFA, E2F1, HMGA1, CCNE1, CHEK1, RAD51, FOSL1, CCNB1, GNG4, IL11 and IL8 and upregulation of WNT10B, MAPK10, GNG7, WNT4, IL7R, PIK3CG, and FGFR2 were observed in never smokers indicating enrichment of Cell cycle, Pathways in cancer and PI3K-Akt signaling. Differential expression of KRAS-mutated tumors indicated enrichment of ECM-receptor interaction, Focal adhesion, and PI3K-Akt pathway and TP53-mutated tumors indicated enrichment of Cell Cycle.
Conclusion
The genomic profiling of Brazilian NSCLC indicated remarkable driver mutations and genomic amplifications. Gene expression profiling indicates the enrichment of key pathways enrolled in TP53- and KRAS-driven tumors. Our results may contribute for improving the knowledge about the molecular pathogenesis of Brazilian NSCLC.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-07 - Frequency of Driver Genes (EGFR, KRAS, BRAF, ALK, RET and ROS1) Alterations in Brazilian Patients with Lung Adenocarcinoma (ID 1841)
10:15 - 18:15 | Author(s): Eduardo Caetano Albino Da Silva
- Abstract
Background
Lung cancer is the deadliest cancer in the world. Several oncogenic drivers are observed in non-small cell lung cancer (NSCLC) and they have been used as therapeutic targets. The frequency of the major driver genes in lung adenocarcinoma varies based on ethnicity and the impact in the Brazilian admixture population has not been explored. Thus, we aimed to investigate the presence gene mutations of EGFR, KRAS, and BRAF, and ALK, RET and ROS1 rearrangements in Brazilian lung adenocarcinoma and to associate the presence of these alterations with clinicopathological characteristics and genetic ancestry.
Method
We evaluated 444 patients diagnosed with lung adenocarcinoma at Barretos Cancer Hospital. The presence of EGFR, KRAS and BRAF mutations in hotspot regions were evaluated by direct sequencing. For EGFR/KRAS/BRAF wild-type samples, we investigated the presence of ALK, RET and ROS1 rearrangements by the NanoString platform. Genetic ancestry was assessed by a multiplexed 46-ancestry informative markers panel. Stats: X2 test and Cox regression model.
Result
Overall, 232 were male (52%) and 212 female (48%) and the average mean at diagnosis was 61 years. The majority of the patients were self-reported as white (77%), smokers (68%) and most patients were diagnosed at stage IV (74%). The median overall survival in patients at stage IV was 8.8 months. The frequency of EGFR mutations was 22.7% (n=101) and they were independently associated with never-smokers and Asian ancestry. KRAS mutations were found in 20.4% (n=91) of cases and were independently associated with smoking. The frequency BRAF mutations was of 1% (n=4), being all of them non-V600 BRAF. The frequency of ALK rearrangements was 2.25% (n=10) and was associated with younger age, the presence of metastases and advanced disease stage at diagnosis. RET and ROS1 rearrangements were only observed in 0.2% each (n=1/each) of cases. All the alterations identified in the oncogenic drivers were mutually exclusive.
Conclusion
The evaluation of the major driver genes for NSCLC, EGFR, KRAS, BRAF, ALK, RET and ROS1 can guide better clinical strategies for Brazilian lung adenocarcinoma, and the frequencies observed of these genes are in line with reported in other populations.
