A novel noninvasive biomarker based on peripheral PD-1posi CD8 T-cell receptor repertoire correlated with clinical outcomes to immunotherapy in non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14174-e14174
Author(s):  
Jie-Fei Han ◽  
Zhijie Wang ◽  
Hua Bai ◽  
Si Chen ◽  
Yuqi Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Cell Lung Cancer ◽  
Cell Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Non Invasive ◽  
Tcr Repertoire ◽  
Tcr Diversity

e14174 Background: Although advances on exploration of biomarkers personalized the immune checkpoint blockades (ICBs) delivery, non-invasive blood-based approach remainsan intriguing area for further investigation.This study investigated the feasibility of peripheral isolated PD-1posiCD8T cell receptor (TCR) repertoire profiling in predicting the clinical outcomes of ICBs treatment for non-small cell lung cancer (NSCLC) patients. Methods: The study comprised two independent cohorts (A and B), ultimately recruiting total 40 from 51 patients with stage IIIB-IV NSCLCs who received anti-PD-1/PD-L1 therapy between March 14, 2017 and May 2, 2018. Peripheral blood samples of pre- and post-ICBs (the timepoint of first imaging evaluation) were prospectively collected, and PD-1posiCD8 T cells were isolated by flow cytometry for TCR sequencing. The diversity and clonality of the TCR repertoire were calculated for biomarker profiling. Cohort A (n = 25) was used as a training set for discovery of TCR diversity in the prediction of response to ICBs, and cohort B (n = 15) as a validation set. Progression-free survival (PFS) and response to ICBs treatment were correlated with TCR diversity and clonality. Results: In cohort A, patients with high pre-ICBs PD-1posiCD8 TCR diversity had longer PFS than those with low diversity (6.5 vs. 2.6 months, p = .045), which were substantially validated in cohort B. By using the incorporated set, pre-ICBs PD-1posiCD8 TCR diversity exhibited an optimal Youden's index of 0.81 with a sensitivity of 0.87 and a specificity of 0.94 in clarifying clinical response of ICBs (PR+SD vs. PD). Patients with increased PD-1posiCD8 TCR clonality demonstrated significantly improved PFS (7.3 vs. 2.7 months, p = .005) compared to those with decreased TCR clonality. Interestingly, two patients with initial pseudo-PD exhibited similar change of TCR clonality and expansion of dominant TCR clones with those with PR, but not PD. Conclusions: Peripheral PD-1posiCD8 TCR repertoire sequencing might be a promising non-invasive approach for selecting patients who could benefit from ICBs treatment, which guaranteed the further investigation and validation by larger cohorts.

scholarly journals Genomic and TCR Repertoire Intratumor Heterogeneity of Small-cell Lung Cancer and its Impact on Survival

2020 ◽  
Author(s):  
Ming Chen ◽  
Runzhe Chen ◽  
Ying Jin ◽  
Jun Li ◽  
Jiexin Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cell Receptor ◽  
Small Cell ◽  
Intratumor Heterogeneity ◽  
High Recurrence Rate ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Tcr Repertoire

AbstractSmall-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, we revealed a rather homogeneous mutational landscape but extremely suppressed and heterogeneous T cell receptor (TCR) repertoire in SCLCs. Higher mutational burden, lower chromosomal copy number aberration (CNA) burden, less CNA ITH and less TCR ITH were associated with longer overall survival of SCLC patients. Compared to non-small cell lung cancers (NSCLCs), SCLCs had similar predicted neoantigen burden and mutational ITH, but significantly more suppressed and heterogeneous TCR repertoire that may be associated with higher CNA burden and CNA ITH in SCLC. Novel therapeutic strategies targeting CNA could potentially improve the tumor immune microenvironment and response to immunotherapy in SCLC.

scholarly journals Genomic and TCR Repertoire Intratumor Heterogeneity of Small-cell Lung Cancer and its Impact on Survival

2021 ◽  
Author(s):  
Ming Chen ◽  
Runzhe Chen ◽  
Ying Jin ◽  
Jun Li ◽  
Jiexin Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cell Receptor ◽  
Small Cell ◽  
Intratumor Heterogeneity ◽  
High Recurrence Rate ◽  
Small Cell Lung ◽  
Tcr Repertoire

Abstract Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry (IHC), we revealed a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC (LS-SCLC) tumors. Compared to localized non-small cell lung cancers (NSCLCs), LS-SCLCs had similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression were associated with longer overall survival (OS), while higher CNA burden were associated with shorter OS in patients with LS-SCLC.

scholarly journals Circulating serum exosomal miR-20b-5p and miR-3187-5p as efficient diagnostic biomarkers for early-stage non-small cell lung cancer

2020 ◽  
Vol 245 (16) ◽  
pp. 1428-1436
Author(s):  
Zhi-Jun Zhang ◽  
Xing-Guo Song ◽  
Li Xie ◽  
Kang-Yu Wang ◽  
You-Yong Tang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Early Stage ◽  
Small Cell ◽  
Small Cell Lung ◽  
Diagnostic Biomarkers ◽  
Non Invasive ◽  
Early Stage Nsclc ◽  
Nsclc Patients

Circulating exosomal microRNAs (ExmiRNAs) provide an ideal non-invasive method for cancer diagnosis. In this study, we evaluated two circulating ExmiRNAs in NSCLC patients as a diagnostic tool for early-stage non-small lung cancer (NSCLC). The exosomes were characterized by qNano, transmission electron microscopy, and Western blot, and the ExmiRNA expression was measured by microarrays. The differentially expressed miRNAs were verified by RT-qPCR using peripheral blood specimens from NSCLC patients ( n = 276, 0 and I stage: n = 104) and healthy donors ( n = 282). The diagnostic values were measured by receiver operating characteristic (ROC) analysis. The results show that the expression of both ExmiR-20b-5p and ExmiR-3187-5p was drastically reduced in NSCLC patients. The area under the ROC curve (AUC) was determined to be 0.818 and 0.690 for ExmiR-20b-5p and ExmiR-3187-5p, respectively. When these two ExmiRNAs were combined, the AUC increased to 0.848. When the ExmiRNAs were administered with either carcinoembryonic antigen (CEA) or cytokeratin-19-fragment (CYFRA21-1), the AUC was further improved to 0.905 and 0.894, respectively. Additionally, both ExmiR-20b-5p and ExmiR-3187-5p could be used to distinguish early stages NSCLC (0 and I stage) from the healthy controls. The ROC curves showed that the AUCs were 0.810 and 0.673, respectively. Combination of ExmiR-20b-5p and ExmiR-3187-5p enhanced the AUC to 0.838. When CEA and CYFRA21-1 were administered with the ExmiRNAs, the AUCs were improved to 0.930 and 0.928, respectively. In summary, circulating serum exosomal miR-20b-5p and miR-3187-5p could be used as effective, non-invasive biomarkers for the diagnosis of early-stage NSCLC, and the effects were further improved when the ExmiRNAs were combined. Impact statement The high mortality of non-small cell lung cancer (NSCLC) is mainly because the cancer has progressed to a more advanced stage before diagnosis. If NSCLC can be diagnosed at early stages, especially stage 0 or I, the overall survival rate will be largely improved by definitive treatment such as lobectomy. We herein validated two novel circulating serum ExmiRs as diagnostic biomarkers for early-stage NSCLC to fulfill the unmet medical need. Considering the number of specimens in this study, circulating serum exosomal miR-20b-5p and miR-3187-5p are putative NSCLC biomarkers, which need to be further investigated in a larger randomized controlled clinical trial.

P-946 Why do non smokers with non-small cell lung cancer (NSCLC) who receive erlotinib have better clinical outcomes than smokers?

Lung Cancer ◽  
2005 ◽  
Vol 49 ◽  
pp. S368 ◽  
Author(s):  
G. Clark ◽  
P. Cagnoni ◽  
M. Ptaszynski ◽  
M. Hamilton ◽  
P. Santabárbara ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung

Transient asymptomatic pulmonary opacities and interstitial lung disease in EGFR-mutated non-small cell lung cancer treated with osimertinib

2021 ◽  
pp. 030089162110478
Author(s):  
Gianluca Taronna ◽  
Alessandro Leonetti ◽  
Filippo Gustavo Dall’Olio ◽  
Alessandro Rizzo ◽  
Claudia Parisi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Clinical Variable ◽  
Small Cell Lung ◽  
Significant Difference ◽  
Egfr Mutated

Introduction: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved as first-line therapy for advanced EGFR-mutated non-small cell lung cancer (NSCLC). Some osimertinib-related interstitial lung diseases (ILDs) were shown to be transient, called transient asymptomatic pulmonary opacities (TAPO)—clinically benign pulmonary opacities that resolve despite continued osimertinib treatment—and are not associated with the clinical manifestations of typical TKI-associated ILDs. Methods: In this multicentric study, we retrospectively analyzed 92 patients with EGFR-mutated NSCLC treated with osimertinib. Computed tomography (CT) examinations were reviewed by two radiologists and TAPO were classified according to radiologic pattern. We also analyzed associations between TAPO and patients’ clinical variables and compared clinical outcomes (time to treatment failure and overall survival) for TAPO-positive and TAPO-negative groups. Results: TAPO were found in 18/92 patients (19.6%), with a median follow-up of 114 weeks. Median onset time was 16 weeks (range 6–80) and median duration time 14 weeks (range 8–37). The most common radiologic pattern was focal ground-glass opacity (54.5%). We did not find any individual clinical variable significantly associated with the onset of TAPO or significant difference in clinical outcomes between TAPO-positive and TAPO-negative groups. Conclusions: TAPO are benign pulmonary findings observed in patients treated with osimertinib. TAPO variability in terms of CT features can hinder the differential diagnosis with either osimertinib-related mild ILD or tumor progression. However, because TAPO are asymptomatic, it could be reasonable to continue therapy and verify the resolution of the CT findings at follow-up in selected cases.

The impact of high PD-L1 expression on the surrogate endpoints and clinical outcomes of anti-PD-1/PD-L1 antibodies in non-small cell lung cancer

Lung Cancer ◽  
2019 ◽  
Vol 128 ◽  
pp. 113-119 ◽  
Author(s):  
Kentaro Ito ◽  
Satoru Miura ◽  
Tadashi Sakaguchi ◽  
Kenta Murotani ◽  
Nobuyuki Horita ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Surrogate Endpoints ◽  
Small Cell Lung ◽  
The Impact

scholarly journals Clinical outcomes for EGFR-mutant adenocarcinomas (AC) that transform to small cell lung cancer (SCLC)

2017 ◽  
Vol 28 ◽  
pp. v540-v541 ◽  
Author(s):  
N. Marcoux ◽  
Z. Piotrowska ◽  
A.F. Farago ◽  
A.N. Hata ◽  
M.J. Mooradian ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Mutant
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