scholarly journals Anticipating EGFR Targeting in Early Stages of Lung Cancer: Leave No Stone Unturned

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2685
Author(s):  
Lorenzo Belluomini ◽  
Silvia Teresa Riva ◽  
Michele Simbolo ◽  
Riccardo Nocini ◽  
Ilaria Trestini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Early Stage ◽  
Target Therapy ◽  
Complete Response ◽  
Early Stage Lung Cancer ◽  
Early Stages ◽  
Resected Nsclc ◽  
Egfr Mutant ◽  
The Impact

 Background: The current treatment landscape of early stage lung cancer is rapidly evolving, particularly in EGFR mutant non-small cell lung cancer (NSCLC), where target therapy is moving to early stages. In the current review, we collected the available data exploring the impact of EGFR targeting in both neoadjuvant and adjuvant settings, underlying lights and shadows and discussing the existing open issues. Methods: We performed a comprehensive search using PubMed and the proceedings of major international meetings to identify neoadjuvant/adjuvant trials with EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. Results: Limited data are available so far about the activity/efficacy of neoadjuvant TKIs in EGFR mutant NSCLC, with only modest downstaging and pathological complete response rates reported. Differently, the ADAURA trial already proposed osimertinib as a potential new standard of care in resected NSCLC harboring an activating EGFR mutation. Conclusion: Anticipating targeted therapy to early stage EGFR mutant NSCLC presents great opportunities but also meaningful challenges in the current therapeutic/diagnostic pathway of lung cancer care. Appropriate endpoint(s) selection for clinical trials, disease progression management, patients’ and treatment selection, as well as need to address the feasibility of molecular profiling anticipation, represent crucial issues to face before innovation can move to early stages. 

scholarly journals The impact of emphysema on surgical outcomes of early-stage lung cancer: a retrospective study

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Seijiro Sato ◽  
Masaya Nakamura ◽  
Yuki Shimizu ◽  
Tatsuya Goto ◽  
Terumoto Koike ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Retrospective Study ◽  
Surgical Outcomes ◽  
Early Stage ◽  
Early Stage Lung Cancer ◽  
The Impact ◽  
Stage Lung Cancer

Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas

2017 ◽  
Vol 35 (26) ◽  
pp. 3065-3074 ◽  
Author(s):  
June-Koo Lee ◽  
Junehawk Lee ◽  
Sehui Kim ◽  
Soyeon Kim ◽  
Jeonghwan Youk ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Cell Transformation ◽  
Early Stage ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Complete Inactivation ◽  
Genetic Predictors ◽  
Egfr Mutant ◽  
Egfr Tki

Purpose Histologic transformation of EGFR mutant lung adenocarcinoma (LADC) into small-cell lung cancer (SCLC) has been described as one of the major resistant mechanisms for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the molecular pathogenesis is still unclear. Methods We investigated 21 patients with advanced EGFR-mutant LADCs that were transformed into EGFR TKI–resistant SCLCs. Among them, whole genome sequencing was applied for nine tumors acquired at various time points from four patients to reconstruct their clonal evolutionary history and to detect genetic predictors for small-cell transformation. The findings were validated by immunohistochemistry in 210 lung cancer tissues. Results We identified that EGFR TKI–resistant LADCs and SCLCs share a common clonal origin and undergo branched evolutionary trajectories. The clonal divergence of SCLC ancestors from the LADC cells occurred before the first EGFR TKI treatments, and the complete inactivation of both RB1 and TP53 were observed from the early LADC stages in sequenced tumors. We extended the findings by immunohistochemistry in the early-stage LADC tissues of 75 patients treated with EGFR TKIs; inactivation of both Rb and p53 was strikingly more frequent in the small-cell–transformed group than in the nontransformed group (82% v 3%; odds ratio, 131; 95% CI, 19.9 to 859). Among patients registered in a predefined cohort (n = 65), an EGFR mutant LADC that harbored completely inactivated Rb and p53 had a 43× greater risk of small-cell transformation (relative risk, 42.8; 95% CI, 5.88 to 311). Branch-specific mutational signature analysis revealed that apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)–induced hypermutation was frequent in the branches toward small-cell transformation. Conclusion EGFR TKI–resistant SCLCs are branched out early from the LADC clones that harbor completely inactivated RB1 and TP53. The evaluation of RB1 and TP53 status in EGFR TKI–treated LADCs is informative in predicting small-cell transformation.

Role of the total mutation burden (TMB) and tumor-infiltrating lymphocytes (TILs) on the development of second primary cancer after complete resection of non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21092-e21092
Author(s):  
Marie-Pier Gauthier ◽  
Maryam Karimi ◽  
Stefan Michiels ◽  
Lesley Seymour ◽  
Elisabeth Brambilla ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Genomic Instability ◽  
Early Stage ◽  
Performance Status ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Stage ◽  
Second Primary ◽  
Early Stage Lung Cancer ◽  
Risk Of Death ◽  
Resected Nsclc

e21092 Background: Risk of developing SPC after complete surgical resection of NSCLC has been reported to be 3-6% per person-year. We hypothesized that genomic instability, as assessed by high TMB, and the absence of TILs in the primary tumor might be associated with SPC. Methods: The LACE [Lung Adjuvant Cisplatin Evaluation])-BIO database was used, which includes 3 randomized trials. TMB and TILs were analyzed on FFPE specimens. TMB was categorized into tertiles (high > 7.8 mutations/MB, moderate i.e. > 4 and < = 7.8, low < 4) and TILs as marked vs. other. Associations on competing time-to-event endpoints (SPC, and death without developing SPC) were evaluated using the Fine and Gray model stratified by trail and adjusted on treatment, age, gender, tumor stage, nodal stage, histology, performance status and surgery type. Results: TMB and TILs assessments were available for 879 patients without missing clinical covariates; 85 patients had marked TILs. During follow-up, 47 SPCs had been observed and 392 deaths without developing SPC. Regarding TMB, a significant association was found between low TMB and death without SPC (sub-distribution hazard ratio SHR = 1.36(1.06-1.74), see Table), suggesting a higher risk of death without SPC among patient with low TMB compared to those with moderate TMB; no strong effect was observed for SPC. Regarding TILs, a trend was observed between marked TILS and a lower risk of death (SHR = 0.70 [0.47-1.04]) but to a lesser extent for SPC (SHR = 0.80 [0.28-2.28]). Conclusions: This is the first study of the effect of genomic instability (measured by TMB) and host immune response (measured by TILs) in completely resected NSCLC on competing events of SPC and death, suggesting associations between TMB, TILs and death-without-SPC . There was no statistically significant association with SPC. However, the number of SPCs was small; these findings requires validation in other early stage lung cancer cohorts. [Table: see text]

Polymorphisms in the CASPASE Genes and Survival in Patients With Early-Stage Non–Small-Cell Lung Cancer

2009 ◽  
Vol 27 (34) ◽  
pp. 5823-5829 ◽  
Author(s):  
Seung Soo Yoo ◽  
Jin Eun Choi ◽  
Won-Kee Lee ◽  
Yi-Young Choi ◽  
Sin Kam ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Early Stage ◽  
Disease Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Functional Polymorphisms ◽  
Resected Nsclc ◽  
The Impact

Purpose This study was conducted to determine the impact of potentially functional polymorphisms in the CASPASE (CASP) genes on the survival of early-stage non–small-cell lung cancer (NSCLC) patients. Patients and Methods Four hundred eleven consecutive patients with surgically resected NSCLC were enrolled. Nine potentially functional polymorphisms in the CASP3, CASP7, CASP8, CASP9, and CASP10 genes were investigated. The genotype and haplotype associations with overall survival (OS) and disease-free survival (DFS) were analyzed. Results Patients with the rs2227310 GG genotype had a significantly decreased OS and DFS compared with patients with the CC + CG genotype (adjusted hazard ratio [aHR] for OS, 1.67; 95% CI, 1.19 to 2.35; P = .003; aHR for DFS, 1.62; 95% CI, 1.19 to 2.22; P = .002). The rs4645981C>T genotype also had a significant effect on OS and DFS (under a recessive model; aHR for OS, 2.00; 95% CI, 1.04 to 3.85; P = .04; aHR for DFS, 2.76; 95% CI, 1.58 to 4.80; P = .0003). When the rs2227310 and rs4645981 genotypes were combined, patients with one or two bad genotypes had worse OS and DFS compared with those who had zero bad genotypes (aHR for OS, 1.75; 95% CI, 1.25 to 2.45; P = .001; aHR for DFS, 1.66; 95% CI, 1.23 to 2.26; P = .001). Conclusion The CASP7 rs2227310 and CASP9 rs4645981 polymorphisms may affect survival in early-stage NSCLC. The analysis of these polymorphisms can help identify patients at high risk for a poor disease outcome.

scholarly journals Forecasting the impact of stereotactic ablative radiotherapy for early-stage lung cancer on the thoracic surgery workforce

2016 ◽  
Vol 49 (6) ◽  
pp. 1599-1606 ◽  
Author(s):  
Janet P. Edwards ◽  
Indraneel Datta ◽  
John Douglas Hunt ◽  
Kevin Stefan ◽  
Chad G. Ball ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Thoracic Surgery ◽  
Early Stage ◽  
Stereotactic Ablative Radiotherapy ◽  
Early Stage Lung Cancer ◽  
The Impact ◽  
Stage Lung Cancer
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