scholarly journals Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer

2021 ◽  
Vol 9 (8) ◽  
pp. e002891
Author(s):  
Marcelo V Negrao ◽  
Ferdinandos Skoulidis ◽  
Meagan Montesion ◽  
Katja Schulze ◽  
Ilze Bara ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Outcome ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Clinical Benefit ◽  
Multivariable Analysis ◽  
Immune Checkpoint Blockade ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

BackgroundNon-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome.MethodsThree cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy [MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients)] were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression.ResultsHigh PD-L1 expression (PD-L1 ≥50%) rate was 19%–20% in classic EGFR, EGFR exon 20 and HER2-mutant tumors, and 34%–55% in tumors with ALK, BRAF V600E, ROS1, RET, or MET alterations. Compared with KRAS-mutant tumors, BRAF non-V600E group had higher TMB (9.6 vs KRAS 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (p<0.001). In the two clinical cohorts treated with ICB, molecular groups with EGFR, HER2, ALK, ROS1, RET, or MET alterations had short progression-free survival (PFS; 1.8–3.7 months), while BRAF V600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vs KRAS 3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vs KRAS 24%; PFS 7.4 vs KRAS 2.8 months, HR 0.36, p=0.026). KRAS G12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis, BRAF V600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, p<0.001) were associated with longer PFS.ConclusionsHigh TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring BRAF mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile EGFR and HER2 mutations and ALK, ROS1, RET, and MET fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations.

scholarly journals Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non–small cell lung cancer

2019 ◽  
Vol 216 (4) ◽  
pp. 982-1000 ◽  
Author(s):  
Bo Gong ◽  
Kazuma Kiyotani ◽  
Seiji Sakata ◽  
Seiji Nagano ◽  
Shun Kumehara ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Transmembrane Domain ◽  
Xenograft Model ◽  
Immune Checkpoint Blockade ◽  
Small Cell ◽  
Small Cell Lung ◽  
Antibody Treatment ◽  
Nsclc Patients

Immune checkpoint blockade against programmed cell death 1 (PD-1) and its ligand PD-L1 often induces durable tumor responses in various cancers, including non–small cell lung cancer (NSCLC). However, therapeutic resistance is increasingly observed, and the mechanisms underlying anti–PD-L1 (aPD-L1) antibody treatment have not been clarified yet. Here, we identified two unique secreted PD-L1 splicing variants, which lacked the transmembrane domain, from aPD-L1–resistant NSCLC patients. These secreted PD-L1 variants worked as “decoys” of aPD-L1 antibody in the HLA-matched coculture system of iPSC-derived CD8 T cells and cancer cells. Importantly, mixing only 1% MC38 cells with secreted PD-L1 variants and 99% of cells that expressed wild-type PD-L1 induced resistance to PD-L1 blockade in the MC38 syngeneic xenograft model. Moreover, anti–PD-1 (aPD-1) antibody treatment overcame the resistance mediated by the secreted PD-L1 variants. Collectively, our results elucidated a novel resistant mechanism of PD-L1 blockade antibody mediated by secreted PD-L1 variants.

Effect of BIM and mTOR expression on clinical outcome to erlotinib in EGFR-mutant non-small cell lung cancer (NSCLC) patients (p).

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 8072-8072
Author(s):  
Niki Karachaliou ◽  
Ana Drozdowskyj ◽  
Ana Gimenez Capitan ◽  
Andres Felipe Cardona Zorrilla ◽  
Radj Gervais ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Outcome ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Mutant ◽  
Nsclc Patients

scholarly journals Reasons for lack of referral to medical oncology for systemic therapy in stage IV non-small-cell lung cancer: comparison of 2003–2006 with 2010–2011

2017 ◽  
Vol 24 (6) ◽  
pp. 486 ◽  
Author(s):  
J.J. Ko ◽  
R. Tudor ◽  
H. Li ◽  
M. Liu ◽  
K. Skolnik ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Systemic Therapy ◽  
Medical Oncology ◽  
Multivariable Analysis ◽  
Stage Iv ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

IntroductionOnly approximately 25% of stage iv non-small-cell lung cancer (nsclc) patients receive systemic therapy. For such patients, we examined factors affecting referral to a cancer centre (cc) and to medical oncology (mo), and use of systemic therapy.Methods Using the Glans–Look Lung Cancer database, we completed a chart review of stage iv nsclc patients diagnosed in Southern Alberta during 2003–2006 and 2010–2011, comparing median overall survival (mos), referral, and treatment in the two cohorts.Results Of the 922 patients diagnosed in 2003–2006 and the 560 diagnosed in 2010–2011, 94% and 82% respectively were referred to a cc, with 22% and 23% receiving traditional chemotherapy (tctx). Referral to a cc or mo and use of tctx correlated with survival (p < 0.0001): The mos duration was 11.2 months in those receiving tctx and 1.0 months in those not referred to a cc. The overall mos duration was similar in the two cohorts (4.1 months vs. 3.9 months, p = 0.47). Major reasons for lack of referral to mo included poor functional status, rapid decline, and patient wish, which were similar to the reasons for forgoing tctx. In the two cohorts, 87 (9.4%) and 42 (7.5%) patients received epidermal growth factor inhibitors, with a mos duration of 16.2 months. Multivariable analysis showed that male sex [hazard ratio (hr): 1.16; p = 0.008] and pulmonary embolus (hr: 1.2; p = 0.002) correlated with worse survival. In contrast, receipt of chemotherapy (hr: 0.5; p < 0.001) and enrolment in a clinical trial (hr: 0.76; p = 0.049) correlated with better survival.Conclusions Our experience confirms that, over time, uptake of systemic therapy, including tctx and targeted therapy, changed little despite their established efficacy. Most of the factors limiting systemic therapy uptake appear to be non-modifiable at the time of referral. Rapid diagnosis and the availability of well-tolerated drugs for all nsclc patients will likely be the most important factors in increasing systemic therapy uptake in this population.

scholarly journals Small Extracellular Vesicles in Pre-Therapy Plasma Predict Clinical Outcome in Non-Small-Cell Lung Cancer Patients

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2041
Author(s):  
Eleni-Kyriaki Vetsika ◽  
Priyanka Sharma ◽  
Ioannis Samaras ◽  
Alexandra Markou ◽  
Vassilis Georgoulias ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Outcome ◽  
Small Cell Lung Cancer ◽  
Extracellular Vesicles ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Response To Therapy ◽  
Small Cell Lung ◽  
Western Blots ◽  
Nsclc Patients

The potential use of plasma-derived small extracellular vesicles (sEV) as predictors of response to therapy and clinical outcome in chemotherapy-naïve patients with non-small-cell lung cancer (NSCLC) was explored. sEV were isolated by size-exclusion chromatography from the plasma of 79 chemotherapy-naïve NSCLC patients and 12 healthy donors (HD). sEV were characterized with regard to protein content, particle size, counts by qNano, morphology by transmission electron microscopy, and molecular profiles by Western blots. PD-1 and PD-L1 expression on circulating immune cells was analysed by flow cytometry. Pre-treatment levels of total sEV protein (TEP) were correlated with overall (OS) and progression-free survival (PFS). The sEV numbers and protein levels were significantly elevated in the plasma of NSCLC patients compared to HD (p = 0.009 and 0.0001, respectively). Baseline TEP levels were higher in patients who developed progressive disease compared to patients with stable disease (p = 0.007 and 0.001, stage III and IV, respectively). Patient-derived sEV were enriched in immunosuppressive proteins as compared to proteins carried by sEV from HD. TEP levels were positively correlated with CD8+PD-1+ and CD8+PD-L1+ circulating T cell percentages and were independently associated with poorer PFS (p < 0.00001) and OS (p < 0.00001). Pre-therapy sEV could be useful as non-invasive biomarkers of response to therapy and clinical outcome in NSCLC.

Sarcopenia as a negative predictive marker for treatment with pembrolizumab as a second line in patients with metastatic non-small cell lung cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21541-e21541
Author(s):  
Milla Petrova ◽  
Gerogi Valchev ◽  
Nikolay Vladimirov Conev ◽  
Eleonora Dimitrova ◽  
Bozhil Robev ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Clinical Benefit ◽  
Multivariable Analysis ◽  
Small Cell ◽  
Line Treatment ◽  
Second Line ◽  
Small Cell Lung ◽  
Change Rate

e21541 Background: In this multicentric retrospective study we evaluated the incidence of clinical benefit rate (CBR) and its relation to Neutrophil-Lymphocyte Ratio (NLR) and psoas major muscle area (PMMA), as well as their dynamics in patients with Non-small Cell Lung Cancer (NSCLC) treated with pembrolizumab (P) as a second line. Methods: Patients with metastatic NSCLC (n = 84) whose tumors expressed PD-L1≥1% were retrospectively analyzed between Apr 2017 and Dec 2019. All patients received platinum-containing chemotherapy (CT) as a first line treatment. Absolute neutrophil, and absolute lymphocyte count enabled calculation of NLR; NLR1 - before CT, NLR2 – before P infusion. ΔNLR was calculated. Area of PMMA was calculated at L3 position on computed tomography. CBR was defined as the proportion of patients with a partial response or stable disease for at least six months since no patients with complete response were recorded. PMMA was calculated before CT and before the P infusion; (% change rate of PMMA = ([1-PMMA before P / PMMA before CT]*100). Patients with the change rate of PMMA≥10% were considered with sarcopenia - 30 (35.7%). Results: CBR was 72.6%. There were not significant correlations between NLR, PMMA and their dynamics. Patients without clinical benefit (CB) had significantly higher values of ΔNLR (1.38±2.2) and ΔPMMA (11.2±10.7) than patients with CB - ΔNLR (0.12±1.88; p = 0.023) and ΔPPMA (8.9±13.5; p = 0.001). ROC analysis revealed that at the optimal cutoff values of all markers, ΔPMMA achieved the greatest AUC = 0.738 (95% CI, 0.77-0.93) and could distinguish between patients with or without CB with sensitivity of 77.3% and specificity of 83.6%. Sarcopenic patients had significantly shorter mean progression-free survival (PFS) – 6.5 months (95%, CI 5.1-8.1) than the rest – 20.8 months (95%, CI 16.7-24.1). Moreover in the multivariable analysis, ΔNLR (HR 1.19, 95% CI 1.05-1.38, p = 0.01) and ΔPPMA ≥10 % (HR 5.4, 95% CI 2.82-10.19, p < 0.001) were found to be independent predictive factors for shorter PFS. Conclusions: Our data suggests that ΔPMMA and ΔNLR are potential predictive markers, which may identify patients appropriate for immunotherapy as a second line treatment.

scholarly journals PD-L1 Polymorphism Can Predict Clinical Outcome of Brazilian Non-Small Cell Lung Cancer Patients After Postoperative Adjuvant Treatment

2020 ◽  
Author(s):  
Juliana Machado-Rugolo ◽  
Tabatha Gutierrez Prieto ◽  
Alexandre Todorovic Fabro ◽  
Edwin Roger Parras Cuentas ◽  
Vanessa Karen Sá ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Outcome ◽  
Small Cell Lung Cancer ◽  
Cell Carcinoma ◽  
Cell Lung Cancer ◽  
Adjuvant Treatment ◽  
Small Cell ◽  
Small Cell Lung ◽  
Programmed Death ◽  
Nsclc Patients

Abstract BackgroundAlthough the incidence and mortality of non-small cell lung cancer (NSCLC) remains high with poor prognosis, programmed death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) pathway are promising prognostic and predictive biomarker of NSCLC. The polymorphisms on PD‐L1 gene may be associated with their protein expressions and affect the adjuvant treatment and outcome of NSCLC patients. The goal of this study was to evaluate the clinicopathologic values of PD-L1 expression and single-nucleotide polymorphisms (SNPs) in the PD-L1 gene in lung adenocarcinoma (ADC), squamous cell carcinoma (SqCC), and large cell carcinoma (LCC). MethodsThe 70 NSCLC samples consisted of 33 samples of ADC, 24 of SqCC and 13 of LCC. All tissue microarray paraffin blocks were used for PD-L1 multiplex immunofluorescence assays with Cell Signaling E1L3N clone. Fifteen polymorphisms in the PD-L1 gene were investigated by deep targeted sequencing.ResultsThe PD-L1 expression was higher in ADC than in SqCC and LCC. Three polymorphisms rs4742098, rs4143815, and rs7041009 were significantly associated with tumor recurrence (P=0.01; P=0.05; P=0.02, respectively). According to the recurrence of the disease, carriers of the G allele were less likely to relapse (P=0.01) compared to the homozygous AA genotype for rs4742098. As in rs4143815, individuals with the C allele were also less likely to relapse (P=0.05). As for rs7041009, individuals with AG or GG genotypes were more likely to relapse. The G allele of rs7041009 also showed a significant correlation with age, younger patients, 16 (41.0%) and status, among 11 (39.3%) compared to carriers of the A allele (P=0.02 and P<0.01, respectively). The rs7041009 AG genotype was inversely associated with E1L3N clone PD-L1 labeling in NSCLCs but did not reach statistical significance. Kaplan-Meier survival curves showed that the prognosis of patients with NSCLC was strongly dependent on the alternative allele G (genotype AG or GG) of rs4742098, alternative allele C (genotype CG or CC) of rs4143815 and individuals with GG genotype of rs7041009 (P=0.02; P=0.05 and P<0.01, respectively). Multivariate analysis by the Cox Regression model showed genotype GG of rs7041009 independently associated with cancer recurrence and patients without adjuvant radiotherapy (hazard ratio [HR] = 7.59, 95% confidence interval [CI] = 1.06-54.03, and HR = 9.24, CI = 1.13-75.16).ConclusionsPD-L1 rs7041009 GG polymorphisms may be useful for the prediction of clinical outcome of radiotherapy in NSCLC. Further studies are needed to confirm our findings and to understand the role of PD-L1 in the radiotherapy outcome of NSCLC patients.

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