-
Barrera Collins posted an update 6 months, 3 weeks ago
018), such as MET or ERBB2 amplification, and small cell lung cancer transformation. In the validation cohort, we found that patients with low T790M RAF (<20%) had significantly lower objective response rates (ORRs) (0
68.8%, P=0.03) and disease control rates (DCRs) (60%
100%, P=0.048) in response to osimertinib compared to patients with high T790M RAF.
In patients with progressive NSCLC post 1
generation EGFR-TKI treatment, plasma T790M RAFs of less than 20% can be used to identify patients who carry concurrent resistance mechanisms, and can predict a poorer response to osimertinib.
This study was registered on http//www.chictr.org.cn (registration number ChiCTR-DDD-16007900).
This study was registered on http//www.chictr.org.cn (registration number ChiCTR-DDD-16007900).
Malignant pleural mesothelioma (MPM) is an aggressive tumor but approximately 12% of patients survive more than 3 years. The biological differences underlying better outcomes are not known. Several targeted agents and immunotherapy have been ineffective. Hedgehog (Hh) is one emerging pathway. We compared the biological profiles of patients with different survival, investigating the most frequently altered genes, including the Hh pathway.
We analyzed 56 MPM. A 36-month overall survival (OS) cut-off divided patients into 32 normo (NS) and 24 long (LS) survivors. We used next generation sequencing to test 21 genes, immunohistochemistry to evaluate SMO expression. Mutation differences between NS and LS and their associations with clinical features were analysed by Fisher’s test, OS with the Kaplan-Meier method and its association with mutations by univariate and multivariate Cox proportional hazard models.
Clinical features were similar in both groups. Eighteen out of 56 patients (32%) were wild-type for the genes analysed. At least five had mutations in
,
,
,
and
with no significant differences between the groups except for
.
, a member of the Hh pathway, was mutated only in NS (15.6%) and only
mutations were significantly associated with poor prognosis at univariate (HR =4.36, 95% CI 2.32-8.18, P<0.0001) and multivariate (HR =9.2, 95% CI 3.0-28.4, P=0.0001) analysis. All
mutated patients expressed high protein levels.
mutations were clearly associated with worse prognosis. SMO may be a therapeutic target but this needs to be confirmed in a prospective trial.
SMO mutations were clearly associated with worse prognosis. SMO may be a therapeutic target but this needs to be confirmed in a prospective trial.
Smoking can cause non-small cell lung cancer (NSCLC). However, the effects of preoperative smoking on tumor progression are not well-known. In addition, the duration of smoking cessation that can provide NSCLC patients with smoking history similar postoperative prognosis as that of nonsmokers remains unknown. This study aimed to investigate the period of smoking cessation that may “compensate” for past smoking history regarding postoperative survival in cases of resected pathological stage I NSCLC by examining the relationship between clinicopathological factors and preoperative smoking.
We retrospectively examined clinicopathological factors including preoperative smoking status and postoperative survival in 453 patients with pathologically proven stage I NSCLC at our Institute. Smoking status was evaluated using the following four parameters cigarettes per day, number of years of smoking, pack-years, and number of years since smoking cessation.
Pathological factors that reflect tumor invasiveness inclinomas in the future.
Accumulative smoking habit correlated with VI and PL, particularly in 2-3 cm adenocarcinoma, whereas larger adenocarcinomas and non-adenocarcinomas of any size appear to grow and become invasive independent of preoperative smoking status. Longer smoking cessation ≥10 years can result in postoperative survival similar to that of non-smokers with adenocarcinomas ≤3 cm. Current smokers should quit smoking immediately to ensure longer survival even though they suffer from small-sized lung adenocarcinomas in the future.
Recent studies of advanced lung cancer patients have shown that circulating tumor DNA (ctDNA) analysis is useful for molecular profiling, monitoring tumor burden, and predicting therapeutic efficacies and disease progression. However, the usefulness of ctDNA analysis in surgically resected lung cancers is unclear.
This study included 20 lung cancer patients with clinical stage IIA-IIIA disease. Preoperative and postoperative (3-12 days) plasma samples were collected for ctDNA analysis. Cancer personalized profiling by deep sequencing, which can detect mutations in 197 cancer-related genes, was used for ctDNA detection. The cohort consisted of 18 men and 2 women with a median age of 69 (range, 37-88) years. Sixteen patients (80%) had a history of smoking. Histologically, there were four squamous cell carcinomas, 13 adenocarcinomas, two adenosquamous cell carcinomas, and one small cell carcinoma.
At the time of data analysis, the 20 patients had been monitored for a median follow-up of 12 months. Eight patients (40%) were positive for preoperative ctDNA, and this was significantly correlated with tumor size (≥5
. <5 cm, P=0.018). Selleckchem Fructose Four patients (20%) were positive for postoperative ctDNA, and this was significantly correlated with histological grade (3
. 1 or 2, P=0.032). Postoperative positivity for ctDNA also predicted shorter recurrence-free survival (RFS) (P=0.015), while pre- and post-operative carcinoembryonic antigen levels (P=0.150 and P=0.533, respectively) and preoperative positivity for ctDNA (P=0.132) were not correlated with RFS.
Detecting ctDNA postoperatively was a poor prognostic factor in surgically resected lung cancer patients that may suggest there is minimal residual disease (MRD).
Detecting ctDNA postoperatively was a poor prognostic factor in surgically resected lung cancer patients that may suggest there is minimal residual disease (MRD).
Tyrosine kinase inhibitor (TKI) resistance is a major obstacle in treatment of non-small cell lung cancer (NSCLC).
amplification drives resistance to EGFR-TKIs in 5-20% of initially sensitive.
mutated NSCLC patients, and combined treatment with EGFR-TKIs and MET-TKIs can overcome this resistance. Yet, inevitably MET-TKI resistance will also occur. Hence, knowledge on development of this sequential resistance is important for identifying the proper next step in treatment.
To investigate sequential resistance to MET-TKI treatment, we established a two-step TKI resistance model in
-mutated HCC827 cells with
amplification-mediated erlotinib resistance. These cells were subsequently treated with increasing doses of the MET-TKIs capmatinib or crizotinib in combination with erlotinib to establish resistance.
In all the MET-TKI resistant cell lines, we systematically observed epithelial-to-mesenchymal transition (EMT) evident by decreased expression of E-cadherin and increased expression of vimentin and ZEB1.