Expanded molecular routine testing for targetable mutations in non-small cell lung cancer to reveal frequent co-occuring mutations.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20596-e20596
Author(s):  
Anna Kostenko ◽  
Jana Fassunke ◽  
Susanne Steinhauser ◽  
Matthias Scheffler ◽  
Sabine Merkelbach-Bruse ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Molecular Diagnostics ◽  
Clinical Data ◽  
Single Gene ◽  
Genomic Medicine ◽  
Genetic Alterations ◽  
Clinical Diagnostics ◽  
Central Platform ◽  
The Impact

e20596 Background: Using next-gen sequencing of predefined gene panels in routine clinical diagnostics of lung cancer allows, in contrast to single-gene assays, assessment of co-occuring mutations, which might underly heterogeneity of response to targeted drugs and survival. The Network Genomic Medicine (NGM) performs high sensitive next generation sequencing (NGS) based routine molecular diagnostics on a central platform for about 5000 inoperable lung cancer patients (pts) annually in Germany. Methods: NGS panel used in NGM consists of 17 genes to cover potentially targetable aberrations. Mutation analyses were run on an Illumina (MySeq) platform, while FISH analyses were performed separately. In 2016, we have started the evaluation of all NGM pts with available clinical data who had received NGS-based molecular diagnostics. In particular, we have focused on non-squamous (non-sq) and squamous (sq) NSCLC pts with co-occurring mutations: their frequency, significance and impact on overall survival. Results: From 2014 molecular genotyping was performed for 7,893 NGM pts (n = 7,246 NSCLC (5,667 non-sq and 1,487 sq pts) and n = 489 SCLC) with eligible clinical data. Genetic alterations in transformation-associated pathways were found in 79 % of all NSCLC pts. Furthermore, co-occurring mutations were detected in 39 % of these pts: 40 % in non-sq and 37 % in sq NSCLC. 11 % of pts had more than 2 co-occurring mutations. 1 % of all pts had 5 co-occurring mutations. The most frequent paired mutations were KRAS, EGFR and MET each with TP53 in non-sq and FRGF1 and TP53 in sq NSCLC. The incidences and significance of 3, 4 and 5 co-mutations as well as the impact of these co-occurring mutations on overall survival will be presented. Conclusions: Frequent occurrence of co-occuring mutations in transformation – associated pathways underlines the genetic heterogeneity also of lung cancer with classical driver mutation and the impact of co-occurring mutations on survival. This work confirms the use of molecular multiplex testing in routine molecular diagnostics of NSCLC. Assessment of co-occuring mutations will help to further specify genetically defined subgroups of lung cancer with therapeutic relevance.

KEAP1 mutations in squamous cell lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21098-e21098
Author(s):  
Sophia Koleczko ◽  
Axel Hillmer ◽  
Abdel Hakim Bayarassou ◽  
Christian Grohé ◽  
Martin Buchenroth ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Squamous Cell ◽  
Cell Lung Cancer ◽  
Systemic Treatment ◽  
Genomic Medicine ◽  
Stage Iv ◽  
Squamous Cell Lung Cancer ◽  
Control Group ◽  
The Impact

e21098 Background: KEAP1 mutations have been shown to decrease the efficacy of both chemotherapy (CTX) and immune-checkpoint inhibition (ICI) in lung adenocarcinoma. However, few is known about their impact on systemic treatment of squamous cell lung cancer (SqCC). The aim of this study was to assess the impact of KEAP1 mutations on systemic treatment outcome in SqCC. Methods: Tumor biopsies of SqCC patients were analyzed within the German Network Genomic Medicine (NGM) using a next-generation DNA sequencing (NGS) panel comprising 17 genes. In subsets, PD-L1 expression was tested with immunohistochemistry (IHC). MET amplification and FGFR1 amplification was tested with fluorescence in situ hybridization (FISH). Overall survival was estimated using Kaplan Meier statistics. For comparisons, we used log rank. A cohort with KEAP1 wild-type patients from the same panel served as control group. Results: Out of 1399 SqCC patients analyzed, 151 had a KEAP1 mutation (11%). The most common co-occurring mutations besides TP53 were PTEN, KRAS and NFE2L2. The median overall survival (OS) of stage IV KEAP1 mutated patients (n = 82) compared to stage IV control group patients (n = 82) was 7.3 vs. 11.4 months (hazard ratio (HR) 0.87 [95% confidence interval (CI) 0.62-1.23], p = 0.43). The addition of a second treatment line with ICI led to marked OS improvements in both KEAP1 mutant patient group (18.7 vs. 6.6 months, HR 0.11, [95% CI 0.04-0.25], p < 0.0001) and control group (20.3 vs. 5.0 months, HR 0.12 [95% CI 0.06-0.24], p < 0.0001). PD-L1 expression did not differ significantly in both groups. Conclusions: KEAP1 mutations occur commonly in SqCC patients and do not impact the efficacy of ICI in terms of OS. To identify prognostic markers for response to ICI further research is needed.

scholarly journals Tumour islet Foxp3+ T-cell infiltration predicts poor outcome in nonsmall cell lung cancer

2015 ◽  
Vol 46 (6) ◽  
pp. 1762-1772 ◽  
Author(s):  
Dermot S. O'Callaghan ◽  
Elton Rexhepaj ◽  
Kathy Gately ◽  
Linda Coate ◽  
David Delaney ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
T Lymphocytes ◽  
Cell Lung Cancer ◽  
Positive Association ◽  
Nonsmall Cell Lung Cancer ◽  
T Cell Infiltration ◽  
Resected Nsclc ◽  
Lymphoid Infiltration ◽  
The Impact

The impact of host immunity on outcome in nonsmall cell lung cancer (NSCLC) is controversial. We examined the relationship between lymphoid infiltration patterns in NSCLC and prognosis.Tumour- and stroma-infiltrating CD3+, CD8+ and forkhead box P3 (Foxp3)+ T-lymphocytes were identified using immunohistochemistry and a novel image analysis algorithm to assess total, cytotoxic and regulatory T-lymphocyte counts, respectively, in 196 NSCLC cases. The median cell count was selected as a cut-point to define patient subgroups and the ratio of the corresponding tumour islet:stroma (TI/S) counts was determined.There was a positive association between overall survival and increased CD8+ TI/S ratio (hazard ratio (HR) for death 0.44, p<0.001) but an inverse relationship between Foxp3+ TI/S ratio and overall survival (HR 4.86, p<0.001). Patients with high CD8+ islet (HR 0.48, p<0.001) and Foxp3+ stromal (HR 0.23, p<0.001) counts had better survival, whereas high CD3+ and CD8+ stromal counts and high Foxp3+ islet infiltration conferred a worse survival (HR 1.55, 2.19 and 3.14, respectively). By multivariate analysis, a high CD8+ TI/S ratio conferred an improved survival (HR 0.48, p=0.002) but a high Foxp3+ TI/S ratio was associated with worse survival (HR 3.91, p<0.001).Microlocalisation of infiltrating T-lymphocytes is a powerful predictor of outcome in resected NSCLC.

Clinical relevance of clonal hematopoiesis in metastatic gastrointestinal malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16082-e16082
Author(s):  
Bill Diplas ◽  
Ryan Ptashkin ◽  
Andrea Cercek ◽  
Rona Yaeger ◽  
Kelly L Bolton ◽  
...  
Keyword(s):  
Overall Survival ◽  
Genetic Alterations ◽  
Smoking History ◽  
High Status ◽  
Tumor Type ◽  
Gastrointestinal Malignancies ◽  
Clonal Hematopoiesis ◽  
Multivariate Survival ◽  
Esophagogastric Cancer ◽  
The Impact

e16082 Background: Clonal hematopoiesis (CH) represents non-random clonal selection of bone marrow-derived cells marked by somatic mutations in certain genes. The presence of CH is associated with development of atherosclerosis and leukemia, and accelerated by toxic exposures (chemotherapy, radiation, smoking) and aging (Jaiswal et al. NEJM 2017; Abelson et al. Nature 2018). The impact of these genetic alterations on cellular function is unknown, especially in the broader context of immunity and in response to cancer therapy. To determine the contribution of CH to therapeutic response and hematologic toxicity in cancer patients, we examined the outcomes of patients treated with cytotoxic and immunotherapy in relationship to CH status. Methods: We evaluated patients with metastatic colorectal cancer (CRC) or esophagogastric cancer (EGC). DNA extracted from whole blood and tumor tissue were sequenced in tandem as part of the MSK-IMPACT hybridization capture-based sequencing assay. CH was defined as any mutation with a VAF of at least 2%, present in at least 10 reads, with at least 2:1 blood:tumor reads, or 1.5:1 blood:lymph node that was not found in gnomAD with a frequency > 0.005. Additional filtering and putative driver definitions (CH-PD) were described by Bolton et al. Nature Genetics 2020. Multivariate survival analyses were performed using a Cox Proportional Hazard model correcting for CH, CH-PD, prior smoking, prior chemotherapy, prior radiation, MSI status, and age at cancer diagnosis. Results: 654 patients with EGC (n = 348) and CRC (n = 306) who began treatment between 2006 and 2020 were included in the analysis. CH was present in 34.5% and 24.4% of each group, and 17.2% and 12.9% harbored CH-PD, respectively. CH and CH-PD were both associated with older age and smoking history, and CH was also associated with prior radiation and MSI-high status (p < 0.05). Patients with CH or CH-PD receiving first-line (1L) therapy for CRC or EGC demonstrated no difference in mPFS after multivariate analysis, though 1L EGC patients with CH-PD had inferior mOS (p = 9e-5). There was no difference in pre-1L WBC, ANC, or ALC, nor in G-CSF or PEG-G-CSF doses administered during 1L therapy between patients with CH or CH-PD versus those without. Similarly, presence of CH or CH-PD had no impact on mPFS or mOS in patients receiving immune checkpoint blockade (ICB) without concurrent chemotherapy after multivariate survival analysis. Conclusions: We confirmed that the mere presence of CH is not prognostic for overall survival, but that EGC patients with CH-PD mutations have inferior overall survival, which is consistent with previous findings. Presence of CH or CH-PD was not associated with differences in baseline leukocyte counts nor need for G-CSF support, nor did it impact PFS in either tumor type, suggesting limited utility of CH in solid tumor clinical decision-making.

Evaluating the Impact of Bevacizumab Maintenance Therapy on Overall Survival in Advanced Non–Small-Cell Lung Cancer

2013 ◽  
Vol 14 (2) ◽  
pp. 120-127 ◽  
Author(s):  
George Dranitsaris ◽  
Nancy Beegle ◽  
Arliene Ravelo ◽  
Traci Kalberer ◽  
Elaine Yu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Maintenance Therapy ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
The Impact

Identification and Characterization of Recurrent Venous Thrombosis In Cancer Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3328-3328
Author(s):  
Catherine Weber ◽  
Nelly G. Adel ◽  
Elyn Riedel ◽  
Gerald A. Soff
Keyword(s):  
Risk Factors ◽  
Lung Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Cancer Diagnosis ◽  
Hazard Ratio ◽  
Older Age ◽  
Recurrent Thrombosis ◽  
Recurrent Vte ◽  
The Impact

Abstract Abstract 3328 Background: Venous thromboembolism (VTE) is a common cause of morbidity and mortality in cancer patients. Standard of care for treatment is Low Molecular Weight Heparin, but recurrence of VTE remains a concern. We performed a retrospective analysis of our institutional experience, to characterize the patients who had a recurrence of VTE while on therapeutic doses of Dalteparin. Objectives: 1. To determine the VTE recurrence rate for cancer patients on therapeutic Dalteparin. 2. To elucidate potential risk factors for recurrence. 3. To determine the impact of recurrent VTE on overall survival. Methods: Patients beginning treatment for VTE with dalteparin between 1/1/2008 and 12/10/ 2009 were retrospectively identified through the hospital's electronic medical records system and cases of recurrent VTE were characterized. Overall survival was estimated using the Kaplan-Meier method and the influence of VTE recurrence on overall survival was analyzed as a time-dependent covariate using a Cox proportional hazards model. Results: 1,392 patients, treated for VTE with dalteparin were included in this study. 34 recurrent VTE episodes were identified. The overall incidence of recurrent thrombosis by six months was 2.3% (95% CI: 1.7%-3.3%). Older age was significantly associated with recurrence (p=0.04). Lung cancer patients had a significantly elevated risk of recurrence (5.6%, p=0.03). No other cancer types were associated with a significant trend to increased recurrent VTE rates. The incidence of recurrent VTE was higher among females compared to males (3.0% vs. 1.6%), although this trend was not statistically significant (P = 0.08). After adjusting for gender, sex and cancer diagnosis, developing a recurrent VTE was associated with a 3.0-fold hazard ratio of death (<0.0001). Conclusions: The rate of recurrent VTE in cancer patients at MSKCC is low in comparison with previously published reports. However, we identified both older age and lung cancer diagnosis as statistically significant risk factors for recurrent VTE. Females also experienced a higher rate of recurrent thrombosis when compared to males, although this result was not statistically significant. The hazard ratio for death was three times that for a patient with recurrent thrombosis when compared to one without subsequent VTE, suggesting recurrence of VTE remains an important influence on cancer-associated mortality. Disclosures: No relevant conflicts of interest to declare.

Conditional Expression of a Leukemogenic Fusion Oncogene in Murine Hematopoietic Stem Cells Results in Highly Invasive AML with Origin-Related Genetic Signatures of Prognostic Significance for the Human Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 779-779
Author(s):  
Vaia Stavropoulou ◽  
Susanne Kaspar ◽  
Laurent Brault ◽  
Sabine Juge ◽  
Alexander Tzankov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Overall Survival ◽  
Drug Resistance ◽  
Cell Migration ◽  
Hematopoietic Stem Cells ◽  
Genetic Alterations ◽  
Hematopoietic Stem ◽  
Genetic Signatures ◽  
The Impact

Abstract Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous disease. Chromosomal translocations causing fusions of the Mixed Lineage Leukemia (MLL) gene are associated with pediatric and adult de novo and therapy-related acute leukemia that are characterized by variable disease outcome. To date, only a limited number of genetic lesions have been implicated in AML disease variability. To address the impact of cellular origin on disease heterogeneity of AMLs, we studied AMLs originating from long-term hematopoietic stem cells (LT-HSCs) and more committed progenitors using a newly established inducible “iMLL-AF9” transgenic mouse model for the t(9:11)(p22;q23) translocation associated MLL-AF9 oncogene. Ex vivo immortalized cells displayed several origin-related growth and drug resistance characteristics and gene expression signatures. Only iMLL-AF9 expressing LT-HSCs formed novel, particularly dispersed colonies, expanded in lineage restrictive stem cell medium and were resistant to genotoxic stress. iMLL-AF9 induction in vivo resulted in fully reversible myelo-monoblastic AML in all animals. Intriguingly, induction of iMLL-AF9 in LT-HSCs caused a particularly aggressive AML phenotype in 15% of recipient mice while the remainder LT-HSCs, as well as short-term HSCs, common myeloid and granulocyte macrophage progenitors induced a more moderate AML. The aggressive LT-HSC-derived AMLs were all characterized by a drastically shorter latency (37 versus 72 days median latency), higher white blood counts, increased invasion capacity and chemo-resistance of leukemic blast, and were associated with expression of genes previously implicated in cell migration, invasion, inflammation and the epithelial-mesenchymal transition (EMT) of solid cancers. shRNA based knock-down experiments demonstrated functional importance of selected candidate genes in cell migration and invasion. Importantly, comparative gene expression analyses between mouse and human revealed that among the genes associated with aggressive AMLs in mice, elevated expression of 66, 11 and 40 human orthologous genes was significantly associated with poor overall survival of t(9;11) (n=21), 11q23-lesion positive, (n=54) and all AMLs (n=662) (p<0.05). Collectively, our data indicates that expression of MLL-AF9 in HSCs results in a particularly aggressive disease driven by expression of common MLL targets and origin-dependent targets previously associated with migration, invasion and EMT of aggressive solid cancers. Remarkably, origin-related genetic signatures associated with the aggressive murine disease revealed a large number of novel MLL-AF9 fusion targets and many highly significant genetic prognostic markers for the overall survival in human AML irrespective of the underlying genetic alterations. Our data experimentally support the previously disputed theory that human AML may also arise from stem and/or oligo-potent progenitors contributing thus to the great heterogeneity of AML including drug resistance and post therapy relapse. Validation of the novel identified target genes in a broader spectrum of human leukemia will facilitate the design of accurate personalized therapeutic interventions. Disclosures No relevant conflicts of interest to declare.

Impact of erlotinib activity on overall survival in non small cell lung cancer patients: Is the post progression survival a new paradigm?

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19086-e19086
Author(s):  
Tindara Franchina ◽  
Alessandro Russo ◽  
Claudia Proto ◽  
Giuseppe Chiofalo ◽  
Maria Picciotto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Statistical Tests ◽  
Small Cell ◽  
Cancer Evolution ◽  
Small Cell Lung ◽  
The Impact

e19086 Background: In the last few years, the treatment of non-small cell lung cancer (NSCLC) has been dramatically changed with the introduction of EGFR TK (Epidermal Growth Factor Tyrosine Kinase) inhibitors. Given its objectivity and the benefits derived by patients, overall survival (OS) has been historically considered the most important therapeutic objective in advanced NSCLC. However, little is known about postprogression survival (PPS) in NSCLC. This study evaluates the correlation between response to erlotinib and post progression survival (i.e. the time between disease progression and death) to estimate the impact of this drug on overall survival. Methods: We retrospectively analyzed 68 NSCLC unselected patients consecutively treated with second or third line erlotinib at our institution from 2007 to 2010, including in the responder group patients who progressed after stable disease on erlotinib for at least six months (n=20). The relationship between OS and PPS was evaluated by standard statistical tests. P-values <0.05 were considered statistically significant. Results: Survival was significantly prolonged in responders patients (18.6 vs 11.3) suggesting the important role of EGFR TK inhibitors in NSCLC management. In addition a significant increase of PPS was recorded in these patients (9.1 vs 4.6 p=0.02), allowing to perform further therapy lines to better control cancer evolution. Conclusions: These data underline the key role of EGFR in NSCLC growth and progression and the impact of erlotinib in cancer control evolution. Post progression therapy influence the effect on overall survival. This analysis suggests that a treatment strategy incorporating all active agents over the course of disease optimizes OS. Further investigations will be needed in selected patients harboring EGFR-activating mutations to better define the role of PPS as new indicator of erlotinib efficacy.

scholarly journals PTEN mutant NSCLC require ATM to suppress pro-apoptotic signalling and evade radiotherapy

2021 ◽  
Author(s):  
Thomas Fischer ◽  
Oliver Hartmann ◽  
Michaela Reissland ◽  
Cristian Prieto-Garcia ◽  
Kevin Klann ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Western Blot ◽  
Colony Formation ◽  
Ex Vivo ◽  
Radiation Sensitivity ◽  
Genetic Alterations ◽  
Altered Expression ◽  
The Impact

Background: Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy. Methods: Using CRISPR genome editing, we deleted PTEN in a human tracheal stem cell-like cell line as well generated primary murine NSCLC, proficient or deficient for Pten, in vivo. These models were used to verify the impact of PTEN loss in vitro and in vivo by immunohistochemical staining, western blot and RNA-Sequencing. Radiation sensitivity was assessed by colony formation and growth assays. To elucidate putative treatment options, identified via the molecular characterisation, PTEN pro- and deficient cells were treated with PI3K/mTOR/DNA-PK-inhibitor PI-103 or the ATM-inhibitors KU-60019 und AZD 1390. Changes in radiation sensitivity were assessed by colony-formation assay, FACS, western-blot, phospho-proteomic mass spectrometry and ex vivo lung slice cultures. Results: We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model. Conclusion: PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.

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