The impact of the molecular profile of the tumor microenvironment on the prognosis of NSCLC

Abstract Purpose The present study was performed to clarify the correlation between macrophages, tumor neo-vessels and programmed cell death-ligand 1 (PD-L1) in the tumor microenvironment (TME) and the clinicopathological features of non-small cell lung cancer (NSCLC) and to explore the prognostic factors of stromal features in NSCLC. Methods Tissue microarrays containing 92 NSCLC patients were studied with immunohistochemistry (IHC). The distribution and quantitative data of CD68- and CD206-positive tumor-associated macrophages (TAMs) in tumor islets and tumor stroma, and the expression of tumor neo‑vessels and PD-L1, were analyzed by inverted microscopy and Image-Pro Plus 6.0 software. Prognostic analyses with the clinicopathological characteristics and tumor microenvironment features were performed. Results The number of CD68-positive macrophages in each location of the tumor islets and tumor stroma was significantly higher than that of CD206-positive macrophages, and they were significantly correlated (P < 0.0001). Survival analysis revealed that CD68- and CD206-positive TAMs in the tumor stroma and tumor islets were significant prognostic factors (P < 0.05, respectively). Comprehensive analysis of CD206-positive stromal TAMs showed that CD105 and PD-L1 were significant prognostic factors (P=0.045). Moreover, CD68-positive TAMs in tumor islets and the expression of PD-L1 were independent predictors of poor prognosis for NSCLC. Conclusion Thus, the key elements in the tumor microenvironment, including tumor neo‑vessels, macrophages and PD-L1, were heterogenic in NSCLC tissues and had significant roles in cancer invasion and metastasis. The combined analysis of key components in the tumor microenvironment was an important prognostic factor.

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Feasibility and effectiveness of afatinib for poor performance status patients with EGFR-mutation-positive non-small-cell lung cancer: a retrospective cohort study

BMC Cancer ◽

10.1186/s12885-021-08587-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chiao-En Wu ◽

Ching-Fu Chang ◽

Chen-Yang Huang ◽

Cheng-Ta Yang ◽

Chih-Hsi Scott Kuo ◽

...

Keyword(s):

Lung Cancer ◽

Prognostic Factors ◽

Small Cell Lung Cancer ◽

Disease Control ◽

Performance Status ◽

Poor Performance ◽

Small Cell ◽

Poor Performance Status ◽

Small Cell Lung ◽

Nsclc Patients

Abstract Background Afatinib is one of the standard treatments for patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). However, data on the use of afatinib in patients with poor performance status (PS ≥ 2) are limited. This study aimed to retrospectively review the clinical outcomes and safety of afatinib treatment in EGFR-mutation-positive (EGFRm+) NSCLC patients with PS ≥ 2. Methods The data for 62 patients who were treated at Linkou Chang Gung Memorial Hospital from January 2010 to August 2019 were retrospectively reviewed. Patients’ clinicopathological features were obtained, and univariate and multivariate analyses were performed to identify possible prognostic factors. Data on adverse events were collected to evaluate general tolerance for afatinib therapy. Results Until February 2020, the objective response rate, disease control rate, median progression-free survival (PFS), and overall survival (OS) were 58.1% (36/62), 69.4% (43/62), 8.8 months, and 12.9 months, respectively. The absence of liver metastasis (PFS: p = 0.044; OS: p = 0.061) and good disease control (p < 0.001 for PFS and OS) were independent favorable prognostic factors for PFS and OS. Bone metastasis (p = 0.036) and dose modification (reduction/interruption, p = 0.021) were predictors of disease control. Conclusion Afatinib demonstrated acceptable efficacy and safety in the current cohort. This study provided evidence to support the use of afatinib as a first-line treatment in EGFRm+ NSCLC patients with poor PS.

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Clinical impact of subclonal EGFR T790M mutations in advanced-stage EGFR-mutant non-small-cell lung cancers

Nature Communications ◽

10.1038/s41467-021-22057-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Tereza Vaclova ◽

Ursula Grazini ◽

Lewis Ward ◽

Daniel O’Neill ◽

Aleksandra Markovets ◽

...

Keyword(s):

Kinase Inhibitor ◽

Progression Free Survival ◽

Small Cell ◽

Phase Iii ◽

Advanced Stage ◽

Small Cell Lung ◽

Nsclc Patients ◽

The Impact ◽

Egfr T790m

AbstractAdvanced non-small-cell lung cancer (NSCLC) patients with EGFR T790M-positive tumours benefit from osimertinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). Here we show that the size of the EGFR T790M-positive clone impacts response to osimertinib. T790M subclonality, as assessed by a retrospective NGS analysis of 289 baseline plasma ctDNA samples from T790M‐positive advanced NSCLC patients from the AURA3 phase III trial, is associated with shorter progression-free survival (PFS), both in the osimertinib and the chemotherapy-treated patients. Both baseline and longitudinal ctDNA profiling indicate that the T790M subclonal tumours are enriched for PIK3CA alterations, which we demonstrate to confer resistance to osimertinib in vitro that can be partially reversed by PI3K pathway inhibitors. Overall, our results elucidate the impact of tumour heterogeneity on response to osimertinib in advanced stage NSCLC patients and could help define appropriate combination therapies in these patients.

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Molecular profile of KRAS G12C-mutant colorectal and non-small-cell lung cancer

BMC Cancer ◽

10.1186/s12885-021-07884-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Luiz Henrique Araujo ◽

Bianca Mendes Souza ◽

Laura Rabelo Leite ◽

Sabrina A. F. Parma ◽

Natália P. Lopes ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Driver Mutations ◽

Molecular Profile ◽

Common Mutation ◽

Small Cell Lung ◽

The South ◽

Nsclc Patients

Abstract Background KRAS is the most frequently mutated oncogene in cancer, however efforts to develop targeted therapies have been largely unsuccessful. Recently, two small-molecule inhibitors, AMG 510 and MRTX849, have shown promising activity in KRAS G12C-mutant solid tumors. The current study aims to assess the molecular profile of KRAS G12C in colorectal (CRC) and non-small-cell lung cancer (NSCLC) tested in a clinical certified laboratory. Methods CRC and NSCLC samples submitted for KRAS testing between 2017 and 2019 were reviewed. CRC samples were tested for KRAS and NRAS by pyrosequencing, while NSCLC samples were submitted to next generation sequencing of KRAS, NRAS, EGFR, and BRAF. Results The dataset comprised 4897 CRC and 4686 NSCLC samples. Among CRC samples, KRAS was mutated in 2354 (48.1%). Most frequent codon 12 mutations were G12D in 731 samples (14.9%) and G12V in 522 (10.7%), followed by G12C in 167 (3.4%). KRAS mutations were more frequent in females than males (p = 0.003), however this difference was exclusive of non-G12C mutants (p < 0.001). KRAS mutation frequency was lower in the South and North regions (p = 0.003), but again KRAS G12C did not differ significantly (p = 0.80). In NSCLC, KRAS mutations were found in 1004 samples (21.4%). As opposed to CRC samples, G12C was the most common mutation in KRAS, in 346 cases (7.4%). The frequency of KRAS G12C was higher in the South and Southeast regions (p = 0.012), and lower in patients younger than 50 years (p < 0.001). KRAS G12C mutations were largely mutually exclusive with other driver mutations; only 11 NSCLC (3.2%) and 1 CRC (0.6%) cases had relevant co-mutations. Conclusions KRAS G12C presents in frequencies higher than several other driver mutations, and may represent a large volume of patients in absolute numbers. KRAS testing should be considered in all CRC and NSCLC patients, independently of clinical or demographic characteristics.

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Outcome of patients with small-cell lung cancer: effect of changes in staging procedures and imaging technology on prognostic factors over 14 years.

Journal of Clinical Oncology ◽

10.1200/jco.1990.8.6.1042 ◽

1990 ◽

Vol 8 (6) ◽

pp. 1042-1049 ◽

Cited By ~ 42

Author(s):

M P Dearing ◽

S M Steinberg ◽

R Phelps ◽

M J Anderson ◽

J L Mulshine ◽

...

Keyword(s):

Lung Cancer ◽

Prognostic Factors ◽

Brain Metastases ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Cox Proportional Hazards ◽

Small Cell ◽

Small Cell Lung ◽

Limited Stage ◽

The Impact

In a study of 411 patients with small-cell lung cancer (SCLC) entered on therapeutic clinical trials between 1973 and 1987, we analyzed whether changes in the prognostic importance of pretreatment factors had occurred during the 14-year time period. After adjusting for other prognostic factors, brain involvement was associated with shorter survival in patients treated before December 1979 (P = .024) but not in patients treated thereafter (P = .54). The patients diagnosed before 1979 had brain metastases documented by radionuclide scan while computed cranial tomography (CCT) was more commonly used after 1979. Patients who had brain metastases diagnosed by radionuclide scan lived a shorter period of time than patients who had the diagnosis made by the more sensitive CCT scan (P = .031). In contrast, Cox proportional hazards modeling showed that liver metastases in patients were associated with shorter survival in patients treated after 1979 (P = .0007) but not in patients treated before then (P = .30). A larger proportion of patients had a routine liver biopsy before 1979 than after 1979 when more patients had the liver staged with less sensitive imaging studies and biochemical parameters. Patients with SCLC whose cancer was confined to the thorax but had medical or anatomic contraindications to intensive chest radiotherapy had similar survival compared with patients with limited-stage SCLC who were treated with combination chemotherapy alone (P = .68). From these data we conclude: (1) the sensitivity of the staging procedures used can affect the impact on survival of cancer involvement of a given site; and (2) patients with cancer confined to their chest with medical or anatomic contraindications to chest radiotherapy do not have a shorter survival than patients with limited-stage disease treated with chemotherapy alone.

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Significance of accurate hilar and intrapulmonary lymph node examination and prognostication in stage IA–IIA non-small cell lung cancer, a retrospective cohort study

World Journal of Surgical Oncology ◽

10.1186/s12957-020-02027-y ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Wenyu Zhai ◽

Fangfang Duan ◽

Yuzhen Zheng ◽

Qihang Yan ◽

Shuqin Dai ◽

...

Keyword(s):

Lung Cancer ◽

Prognostic Factors ◽

Small Cell ◽

Small Cell Lung ◽

Term Survival ◽

Differentiation Degree ◽

Stage Ia ◽

Nsclc Patients

Abstract Background The examination of lymph nodes (LNs) plays an important role in the nodal staging of non-small cell lung cancer (NSCLC). For patients without LN metastasis, the main role of thorough LN examination is accurate staging, which weakens the effect of staging migration. To date, the role of hilar and intrapulmonary (N1) station LNs has not been fully appreciated. In this study, we aimed to confirm the significance of N1 LNs in long-term survival for stage IA–IIA NSCLC patients and to find the minimum number of LN to examine. Methods The data of patients who underwent radical lobectomy and were confirmed as having non-metastatic LNs from January 2008 to March 2018 were retrospectively screened. Pathology records were reviewed for the number of LNs examined. The Kaplan-Meier method and Cox regression model were used to identify survival and prognostic factors. Results The median number of resected N1 LNs was 8. The number of patients with 0–2 N1 LNs, 3–5 N1 LNs, 6–8 N1 LNs, 9–11 N1 LNs, and more than 11 N1 LNs examined was 181, 425, 477, 414, and 531, respectively. Sex (P = 0.004), age (P < 0.001), tumor size (P = 0.004), differentiation degree (P = 0.001), and number of N1 LNs examined (P = 0.008) were independent prognostic factors of overall survival. Gender (P = 0.006), age (P = 0.031), tumor size (P = 0.001), differentiation degree (P = 0.001), vascular invasion (P = 0.034), and number of N1 LNs examined (P = 0.007) were independent prognostic factors of disease-free survival. Compared with patients with 0–5 N1 LNs examined, patients with more than 5 N1 LNs examined had better OS (P = 0.015) and had better DFS (P = 0.015) if only a landmark 5-year follow-up was performed. Conclusion Increasing the number of N1 LN examination might improve the long-term survival of T1-2N0 NSCLC patients. These data indicate that at least 6 N1 nodes examined is an essential part in surgical and pathological management but cannot prove this. This finding should be confirmed in a large, prospective randomized clinical study.

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Clinical Model to Predict Survival in Chemonaive Patients With Advanced Non–Small-Cell Lung Cancer Treated With Third-Generation Chemotherapy Regimens Based on Eastern Cooperative Oncology Group Data

Journal of Clinical Oncology ◽

10.1200/jco.2005.04.177 ◽

2005 ◽

Vol 23 (1) ◽

pp. 175-183 ◽

Cited By ~ 167

Author(s):

Tien Hoang ◽

Ronghui Xu ◽

Joan H. Schiller ◽

Philip Bonomi ◽

David H. Johnson

Keyword(s):

Lung Cancer ◽

Prognostic Factors ◽

Small Cell Lung Cancer ◽

Eastern Cooperative Oncology Group ◽

Small Cell ◽

Third Generation ◽

Oncology Group ◽

Small Cell Lung ◽

Clinical Model ◽

Nsclc Patients

Purpose (1) Identify clinical factors that can be used to predict survival in chemotherapy-naive patients with advanced non–small-cell lung cancer (NSCLC) treated with third-generation chemotherapy regimens, and (2) build a clinical model to predict survival in this patient population. Patients and Methods Using data from two randomized, phase III Eastern Cooperative Oncology Group (ECOG) trials (E5592/E1594), we performed univariate and multivariate stepwise Cox regression analyses to identify survival prognostic factors. We used 75% of randomly sampled data to build a prediction model for survival, and the remaining 25% of data to validate the model. Results From 1993 to 1999, 1,436 patients with stage IV or IIIB NSCLC with effusion were treated with platinum-based doublets (involving either paclitaxel, docetaxel, or gemcitabine). The response rate and median survival time were 20% and 8.2 months, respectively. One- and 2-year survivals were 33% and 11%, respectively. In multivariate analysis, six independent poor prognostic factors were identified: skin metastasis (hazard ratio [HR], 1.88), lower performance status (ECOG 1 or 2; HR, 1.46), loss of appetite (HR, 1.62), liver metastasis (HR, 1.32), ≥ four metastatic sites (HR, 1.20), and no prior surgery (HR, 1.16). A nomogram using six pretreatment prognostic factors was built to predict 1- and 2-year survival. Conclusion Six pretreatment factors can be used to predict survival in chemotherapy-naive NSCLC patients treated with standard chemotherapy. Using our prognostic nomogram, 1- and 2-year survival probability of NSCLC patients can be estimated before treatment. This prognostic model may help clinicians and patients in clinical decision making, as well as investigators in research planning.

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