The PI3K (phosphatidylinositol 3-kinase)-AKT pathway is one of the most important signaling networks in cancer. There is growing evidence that activation of this pathway plays a significant role in ...melanoma, frequently in the setting of concurrent activation of RAS-RAF-MEK-ERK signaling. This evidence includes the identification of genetic and epigenetic events that activate this pathway in melanoma cell lines and clinical specimens. In addition, functional experiments have demonstrated important roles for the PI3K-AKT pathway in both melanoma initiation and therapeutic resistance. The availability of many inhibitors against the PI3K-AKT pathway is rapidly leading to the development of trials that will ultimately determine its clinical significance in this disease. The rational development of such therapies will be facilitated by strategies that utilize the growing understanding of the complexity of the regulation and roles of this pathway.
Two of the biggest challenges in medicine today are the need to detect diseases in a noninvasive manner and to differentiate between patients using a single diagnostic tool. The current study targets ...these two challenges by developing a molecularly modified silicon nanowire field effect transistor (SiNW FET) and showing its use in the detection and classification of many disease breathprints (lung cancer, gastric cancer, asthma, and chronic obstructive pulmonary disease). The fabricated SiNW FETs are characterized and optimized based on a training set that correlate their sensitivity and selectivity toward volatile organic compounds (VOCs) linked with the various disease breathprints. The best sensors obtained in the training set are then examined under real-world clinical conditions, using breath samples from 374 subjects. Analysis of the clinical samples show that the optimized SiNW FETs can detect and discriminate between almost all binary comparisons of the diseases under examination with >80% accuracy. Overall, this approach has the potential to support detection of many diseases in a direct harmless way, which can reassure patients and prevent numerous unpleasant investigations.
Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma
. We investigated this regimen in ...patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate
. The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3-4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response (P = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial
, provide further confirmation of the efficacy and safety of this new immunotherapy regimen.
Long non-coding RNAs compose an important level of epigenetic regulation in normal physiology and disease. Despite the plethora of publications of lncRNAs in human cancer, the landscape is still ...unclear.
Microarray analysis in 44 NSCLC paired specimens was followed by qPCR-based validation in 29 (technical) and 38 (independent) tissue pairs. Cross-validation of the selected targets was achieved in 850 NSCLC tumours from TCGA datasets.
Twelve targets were successfully validated by qPCR (upregulated: FEZF1-AS1, LINC01214, LINC00673, PCAT6, NUTM2A-AS1, LINC01929; downregulated: PCAT19, FENDRR, SVIL-AS1, LANCL1-AS1, ADAMTS9-AS2 and LINC00968). All of them were successfully cross validated in the TCGA datasets. Abnormal DNA methylation was observed in the promoters of FENDRR, FEZF1-AS1 and SVIL-AS1. FEZF1-AS1 and LINC01929 were associated with survival in the TCGA set.
Our study provides through multiple levels of internal and external validation, a comprehensive list of dysregulated lncRNAs in NSCLC. We therefore envisage this dataset to serve as an important source for the lung cancer research community assisting future investigations on the involvement of lncRNAs in the pathogenesis of the disease and providing novel biomarkers for diagnosis, prognosis and therapeutic stratification.
Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms of resistance remain incompletely understood. To address ...this, we recently studied a cohort of melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) and identified immune markers of response and resistance. Building on these studies, we performed deep molecular profiling including T cell receptor sequencing and whole-exome sequencing within the same cohort and demonstrated that a more clonal T cell repertoire was predictive of response to PD-1 but not CTLA-4 blockade. Analysis of CNAs identified a higher burden of copy number loss in nonresponders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was nonredundant, suggesting the potential utility of a combinatorial biomarker to optimize patient care with checkpoint blockade therapy.
Epigenetic biomarkers in lung cancer Liloglou, Triantafillos; Bediaga, Naiara G; Brown, Benjamin R.B ...
Cancer letters,
01/2014, Volume:
342, Issue:
2
Journal Article
Peer reviewed
Abstract Lung cancer mortality is strongly associated with the predominant diagnosis of late stage lesions that hampers effective therapy. Molecular biomarkers for early lung cancer detection is an ...unmet public health need and the lung cancer research community worldwide is putting a lot of effort to utilise major lung cancer population programmes in order to develop such molecular tools. The study of cancer epigenetics in the last decade has radically altered our views in cancer pathogenesis, providing new insights in biomarker development for risk assessment, early detection and therapeutic stratification. DNA methylation and miRNAs have rapidly emerged as potential biomarkers in body fluids showing promise to assist the clinical management of lung cancer. These new developments are exemplified in this review, demonstrating the huge potential of clinical cancer epigenetics, but also critically discussing the necessary validation steps to bring epigenetic biomarkers towards clinical implementation and the weaknesses of current biomarker studies.
Here we present an optimized workflow for global proteome and phosphoproteome analysis of tissues or cell lines that uses isobaric tags (TMT (tandem mass tags)-10) for multiplexed analysis and ...relative quantification, and provides 3× higher throughput than iTRAQ (isobaric tags for absolute and relative quantification)-4-based methods with high intra- and inter-laboratory reproducibility. The workflow was systematically characterized and benchmarked across three independent laboratories using two distinct breast cancer subtypes from patient-derived xenograft models to enable assessment of proteome and phosphoproteome depth and quantitative reproducibility. Each plex consisted of ten samples, each being 300 μg of peptide derived from <50 mg of wet-weight tissue. Of the 10,000 proteins quantified per sample, we could distinguish 7,700 human proteins derived from tumor cells and 3100 mouse proteins derived from the surrounding stroma and blood. The maximum deviation across replicates and laboratories was <7%, and the inter-laboratory correlation for TMT ratio-based comparison of the two breast cancer subtypes was r > 0.88. The maximum deviation for the phosphoproteome coverage was <24% across laboratories, with an average of >37,000 quantified phosphosites per sample and differential quantification correlations of r > 0.72. The full procedure, including sample processing and data generation, can be completed within 10 d for ten tissue samples, and 100 samples can be analyzed in ~4 months using a single LC-MS/MS instrument. The high quality, depth, and reproducibility of the data obtained both within and across laboratories should enable new biological insights to be obtained from mass spectrometry-based proteomics analyses of cells and tissues together with proteogenomic data integration.
Summary Background Dabrafenib plus trametinib treatment provides significant benefits over BRAF-inhibitor monotherapy in patients with BRAFV600E -mutant or BRAFV600K -mutant advanced melanoma; ...however, in many patients the disease progresses, leading to death. With many treatment options available, understanding clinical factors that predict long-term response and survival for treatments is important for optimisation of patient management. We aimed to identify clinical factors associated with long-term response and survival using pooled data from randomised trials of dabrafenib plus trametinib in patients with metastatic BRAF -mutant melanoma. Methods We did a retrospective individual data analysis based on all published randomised trials that included treatment-naive patients with BRAFV600E -mutant or BRAFV600K -mutant metastatic melanoma who received the approved dose of dabrafenib 150 mg twice daily plus trametinib 2 mg once daily. Data were pooled from patients in the BRF113220 (part C; March 26, 2010, to Jan 15, 2015), COMBI-d (May 4, 2012, to Jan 12, 2015), and COMBI-v (June 4, 2012, to March 13, 2015) randomised trials. Patients with untreated brain metastases were not permitted to enrol in these trials. Baseline factors, identified a priori based on known melanoma clinical or prognostic characteristics, were analysed for association with progression-free survival and overall survival using univariate and multivariate analyses and assessed for hierarchical effect on outcomes using regression tree analyses. We also analysed factors identified after baseline, on treatment, and at progression, for associations with survival after progression. The trials included in this analysis are registered with ClinicalTrials.gov : BRF113220, number NCT01072175 ; COMBI-d, number NCT01584648 ; COMBI-v, number NCT01597908. Findings 617 patients were included in this analysis with a median follow-up of 20·0 months (range 0−48·0, IQR 10·1−24·8); 396 patients had progression events (ie, disease progression or death) and 290 patients had died. Median progression-free survival (11·1 months 95% CI 9·7−12·9), median overall survival (25·6 months 23·1−34·3), 1-year progression-free survival (48% 44–52) and overall survival (74% 71–78), and 2-year progression-free survival (30% 26–34) and overall survival (53% 49–57) were consistent with those in the individual trials. Patients with normal lactate dehydrogenase (LDH) concentration and fewer than three organ sites containing metastases (n=237) had the longest 1-year progression-free survival (68% 95% CI 62–74) and overall survival (90% 87–94) and 2-year progression-free survival (46% 40–54) and overall survival (75% 70–81), whereas patients with LDH concentration at least two times the upper limit of normal (n=70) had the shortest 1-year progression-free survival (8% 3–19) and overall survival (40% 29–55) and 2-year progression-free survival (2% 0–13) and overall survival (7% 3–19). Of patients with disease progression (n=379), survival after progression was longest in those with progression in baseline or new non-CNS lesions (n=205; median 10·0 months 95% CI 7·9−12·0) and shortest in those with new CNS lesions or concurrent progression in baseline and new lesions (n=171; median 4·0 months 3·5−4·9). Interpretation Several patient and clinical characteristics at and after baseline are associated with outcomes with dabrafenib plus trametinib, and durable benefit is possible with targeted treatment in defined patient subsets. Funding Novartis.
We report the experience with 2,000 consecutive patients with advanced cancer who underwent testing on a genomic testing protocol, including the frequency of actionable alterations across tumor ...types, subsequent enrollment onto clinical trials, and the challenges for trial enrollment.
Standardized hotspot mutation analysis was performed in 2,000 patients, using either an 11-gene (251 patients) or a 46- or 50-gene (1,749 patients) multiplex platform. Thirty-five genes were considered potentially actionable based on their potential to be targeted with approved or investigational therapies.
Seven hundred eighty-nine patients (39%) had at least one mutation in potentially actionable genes. Eighty-three patients (11%) with potentially actionable mutations went on genotype-matched trials targeting these alterations. Of 230 patients with PIK3CA/AKT1/PTEN/BRAF mutations that returned for therapy, 116 (50%) received a genotype-matched drug. Forty patients (17%) were treated on a genotype-selected trial requiring a mutation for eligibility, 16 (7%) were treated on a genotype-relevant trial targeting a genomic alteration without biomarker selection, and 40 (17%) received a genotype-relevant drug off trial. Challenges to trial accrual included patient preference of noninvestigational treatment or local treatment, poor performance status or other reasons for trial ineligibility, lack of trials/slots, and insurance denial.
Broad implementation of multiplex hotspot testing is feasible; however, only a small portion of patients with actionable alterations were actually enrolled onto genotype-matched trials. Increased awareness of therapeutic implications and access to novel therapeutics are needed to optimally leverage results from broad-based genomic testing.
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