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: X 2 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% (n¼101) and they were independently associated with never-smokers and Asian ancestry. KRAS mutations were found in 20.4% (n¼91) of cases and were independently associated with smoking. The frequency BRAF mutations was of 1% (n¼4), being all of them non-V600 BRAF. The frequency of ALK rearrangements was 2.25% (n¼10) 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 (n¼1/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.
Background:The microbiota community is considered as an organ of the human body. Recent studies have found that gut microbiota may impact on the interaction between immune regulation and tumor treatment. The aim of this study is to characterize the gut microbiota in advanced NSCLC patients, and its relationship with response to immune checkpoint blockade (ICB).Methods: Stool samples from 84 advanced NSCLC patients were collected prior ICB as first or second line treatment. 16S rRNA gene sequencing and SILVA_release_132 database were used for taxonomic profiling. Diversity indices, including Chao1, Shannon and Inverse Simpson index (IDI), abundance of certain taxa, clinicopathological characteristics, dietary habits and antibiotic usage were evaluated for association with clinical benefit (CB) [complete or partial response, stable disease vs. progressive disease (PD), according to RECIST1.1]. Continuous variables were stratified into high or low using median as cut-off. For survival analysis, Cox Regression and Kaplan Meier curves with log-rank test were performed.Results: From 84 NSCLC patients, 60 presented PD-L1 positive tumors and 39 were treated with ICB as first line. A total of 8872307 sequencing reads were obtained and clustered in 357 genera, being the most frequent Bacteroides (27.9%) and Alistipes (7.1%). Patients with CB exhibited higher IDI compared with those with PD (p¼0.004). Moreover, higher IDI was associated with prolonged progression-free survival (PFS) (p¼0.014). High abundance of Butyricimonas in the samples was correlated with increased RR (p¼0.01) and longer PFS (p¼0.011) compared to low abundance. On the other hand, high frequency of Dialister was associated with reduced RR (p¼0.002) and shorter PFS (p¼0.003). Finally, the expression of PD-L1 was associated with increased response rate (RR) (p¼0.020). Conclusions:This study shows that diversity of gut microbiota is related to the ICB treatment response. In addition, high abundance of Butyricimonas and low abundance of Dialister could be considered as potential predictors of clinical benefit and PFS. Further analyses are being undertaken to find a compositional signature with predictive value. Funded by CB16/12/00350 from CIBEROnc, Arnal Planelles Foundation, AMACMA, GIDO group and PI18/00226 from ISCIII.
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