Recurrence In Early-Stage Lung Adenocarcinoma Research Articles

The Tumor Immune Microenvironment Is Associated With Recurrence in Early-Stage Lung Adenocarcinoma

IntroductionImmune checkpoint inhibitors have recently been approved for the treatment of early-stage NSCLC in the perioperative setting on the basis of phase 3 trials. However, the characteristics of such patients who are susceptible to recurrence after adjuvant chemotherapy or who are likely to benefit from postoperative immunotherapy have remained unclear. MethodsThis biomarker study (WJOG12219LTR) was designed to evaluate cancer stem cell markers (CD44 and CD133), programmed death-ligand 1 (PD-L1) expression on tumor cells, CD8 expression on tumor-infiltrating lymphocytes, and tumor mutation burden in completely resected stage II to IIIA NSCLC with the use of archived DNA and tissue samples from the prospective WJOG4107 trial. Tumors were classified as inflamed or noninflamed on the basis of the PD-L1 tumor proportion score and CD8+ tumor-infiltrating lymphocyte density. The association between each potential biomarker and relapse-free survival (RFS) during adjuvant chemotherapy was assessed by Kaplan-Meier analysis. ResultsA total of 117 patients were included in this study. The median RFS was not reached (95% confidence intervals [CI]: 22.4 mo–not reached; n = 39) and 23.7 months (95% CI: 14.5–43.6; n = 41) in patients with inflamed or noninflamed adenocarcinoma, respectively (log-rank p = 0.02, hazard ratio of 0.52 [95% CI: 0.29–0.93]). Analysis of the combination of tumor inflammation category and TP53 mutation status revealed that inflamed tumors without TP53 mutations were associated with the longest RFS. ConclusionsPD-L1 expression on tumor cells, CD8+ T cell infiltration, and TP53 mutation status may help identify patients with early-stage NSCLC susceptible to recurrence after adjuvant chemotherapy.

Circulating microRNA Panel for Prediction of Recurrence and Survival in Early-Stage Lung Adenocarcinoma.

Early-stage lung adenocarcinoma (LUAD) patients remain at substantial risk for recurrence and disease-related death, highlighting the unmet need of biomarkers for the assessment and identification of those in an early stage who would likely benefit from adjuvant chemotherapy. To identify circulating miRNAs useful for predicting recurrence in early-stage LUAD, we performed miRNA microarray analysis with pools of pretreatment plasma samples from patients with stage I LUAD who developed recurrence or remained recurrence-free during the follow-up period. Subsequent validation in 85 patients with stage I LUAD resulted in the development of a circulating miRNA panel comprising miR-23a-3p, miR-320c, and miR-125b-5p and yielding an area under the curve (AUC) of 0.776 in predicting recurrence. Furthermore, the three-miRNA panel yielded an AUC of 0.804, with a sensitivity of 45.8% at 95% specificity in the independent test set of 57 stage I and II LUAD patients. The miRNA panel score was a significant and independent factor for predicting disease-free survival (p < 0.001, hazard ratio [HR] = 1.64, 95% confidence interval [CI] = 1.51-4.22) and overall survival (p = 0.001, HR = 1.51, 95% CI = 1.17-1.94). This circulating miRNA panel is a useful noninvasive tool to stratify early-stage LUAD patients and determine an appropriate treatment plan with maximal efficacy.

Abstract 3744: A circulating microRNA panel predicts recurrence and survival in early-stage lung adenocarcinoma

Abstract Background: Early-stage lung adenocarcinoma (LUAD) patients have substantial risk for recurrence and disease-related death. Cisplatin-based adjuvant chemotherapy remains the standard for care of LUAD patients who have undergone surgical resection with a high risk of recurrence. However, adjuvant chemotherapy is associated with increased risk of toxicity including chemotherapy-related death, with only a modest survival benefit. Therefore, there is an unmet need of biomarkers for assessment and identification of those in an early stage who would likely benefit from adjuvant chemotherapy. Circulating miRNAs are stably present in blood and potentially reflect different expressions in cancerous and non-cancerous tissues, making them attractive biomarkers. The purpose of this study was to identify circulating miRNAs useful for predicting recurrence in early-stage LUAD. Materials and Methods: miRNA microarray analysis was performed with pooled pretreatment plasma samples from stage I LUAD patients who developed recurrence within two years after curative surgery or remained recurrence free over a six-year follow-up period, as well as from healthy controls. miRNA biomarker candidates were assayed in two independent plasma sample sets from 85 stage I LUAD (validation set) and from 57 stage I and II LUAD (test set) patients. Results: Based on miRNA microarray data and previous reports, predictive performance of miR-23a-3p, miR-23b-3p, miR-191-5p, miR-185-5p, miR-151a-3p, miR-320c, miR-21-5p, miR-125b-5p, miR-30d-5p, and miR-197-3p was evaluated in the validation set. Plasma levels of miR-23a-3p, miR-185-5p, miR-320c, miR-21-5p, miR-125b-5p, miR-30d-5p, and miR-197-3p were significantly higher in those with recurrence as compared to those without. A miRNA panel comprised of miR-23a-3p, miR-320c, and miR-125b-5p was developed based on a logistic regression, with yielding an AUC of 0.776 (95% confidence interval [CI] = 0.660 to 0.893). The three-miRNA panel with fixed coefficients yielded an AUC of 0.804 (95% CI = 0.688 to 0.920) with a sensitivity of 45.8% at 95% specificity in the test set. The miRNA panel score was a significant and independent factor for predicting disease-free survival (DFS; P &amp;lt; 0.001, HR = 1.64, 95% CI = 1.51-4.22) and overall survival (OS; P = 0.001, HR = 1.51, 95% CI = 1.17-1.94). Conclusion: This circulating miRNA panel may serve as a noninvasive blood test for predicting DFS and OS in early-stage LUAD patients. Our findings provide rationale for further investigation to stratify early-stage LUAD patients using blood-based biomarkers to increase the ability to provide more personalized care. Citation Format: Mei-Chee Tai, Leonidas E. Bantis, Gargy Parhy, Taketo Kato, Ichidai Tanaka, Chi-Wan Chow, Junya Fujimoto, Carmen Behrens, Tetsunari Hase, Koji Kawaguchi, Johannes F. Fahrmann, Edwin Ostrin, Kohei Yokoi, Toyofumi F. Chen-Yoshikawa, Yoshinori Hasegawa, Samir M. Hanash, Ignacio I. Wistuba, Ayumu Taguchi. A circulating microRNA panel predicts recurrence and survival in early-stage lung adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3744.

Tumoral Densities of T-Cells and Mast Cells Are Associated With Recurrence in Early-Stage Lung Adenocarcinoma

IntroductionLung cancer is the deadliest cancer in the United States and worldwide, and lung adenocarcinoma (LUAD) is the most prevalent histologic subtype in the United States. LUAD exhibits a wide range of aggressiveness and risk of recurrence, but the biological underpinnings of this behavior are poorly understood. Past studies have focused on the biological characteristics of the tumor itself, but the ability of the immune response to contain tumor growth represents an alternative or complementary hypothesis. Emerging technologies enable us to investigate the spatial distribution of specific cell types within the tumor nest and characterize this immune response. This study aimed to investigate the association between immune cell density within the primary tumor and recurrence-free survival (RFS) in stage I and II LUAD. MethodsThis study is a prospective collection with retrospective evaluation. A total of 100 patients with surgically resected LUAD and at least 5-year follow-ups, including 69 stage I and 31 stages II tumors, were enrolled. Multiplexed immunohistochemistry panels for immune markers were used for measurement. ResultsCox regression models adjusted for sex and EGFR mutation status revealed that the risk of recurrence was reduced by 50% for the unit of one interquartile range (IQR) change in the tumoral T-cell (adjusted hazard ratio per IQR increase = 0.50, 95% confidence interval: 0.27–0.93) and decreased by 64% in mast cell density (adjusted hazard ratio per IQR increase = 0.36, confidence interval: 0.15–0.84). The analyses were reported without the type I error correction for the multiple types of immune cell testing. ConclusionsAnalysis of the density of immune cells within the tumor and surrounding stroma reveals an association between the density of T-cells and RFS and between mast cells and RFS in early-stage LUAD. This preliminary result is a limited study with a small sample size and a lack of an independent validation set.

A Genomic-Pathologic Annotated Risk Model to Predict Recurrence in Early-Stage Lung Adenocarcinoma

Recommendations for adjuvant therapy after surgical resection of lung adenocarcinoma (LUAD) are based solely on TNM classification but are agnostic to genomic and high-risk clinicopathologic factors. Creation of a prediction model that integrates tumor genomic and clinicopathologic factors may better identify patients at risk for recurrence. To identify tumor genomic factors independently associated with recurrence, even in the presence of aggressive, high-risk clinicopathologic variables, in patients with completely resected stages I to III LUAD, and to develop a computational machine-learning prediction model (PRecur) to determine whether the integration of genomic and clinicopathologic features could better predict risk of recurrence, compared with the TNM system. This prospective cohort study included 426 patients treated from January 1, 2008, to December 31, 2017, at a single large cancer center and selected in consecutive samples. Eligibility criteria included complete surgical resection of stages I to III LUAD, broad-panel next-generation sequencing data with matched clinicopathologic data, and no neoadjuvant therapy. External validation of the PRecur prediction model was performed using The Cancer Genome Atlas (TCGA). Data were analyzed from 2014 to 2018. The study end point consisted of relapse-free survival (RFS), estimated using the Kaplan-Meier approach. Associations among clinicopathologic factors, genomic alterations, and RFS were established using Cox proportional hazards regression. The PRecur prediction model integrated genomic and clinicopathologic factors using gradient-boosting survival regression for risk group generation and prediction of RFS. A concordance probability estimate (CPE) was used to assess the predictive ability of the PRecur model. Of the 426 patients included in the analysis (286 women [67%]; median age at surgery, 69 [interquartile range, 62-75] years), 318 (75%) had stage I cancer. Association analysis showed that alterations in SMARCA4 (clinicopathologic-adjusted hazard ratio [HR], 2.44; 95% CI, 1.03-5.77; P = .042) and TP53 (clinicopathologic-adjusted HR, 1.73; 95% CI, 1.09-2.73; P = .02) and the fraction of genome altered (clinicopathologic-adjusted HR, 1.03; 95% CI, 1.10-1.04; P = .005) were independently associated with RFS. The PRecur prediction model outperformed the TNM-based model (CPE, 0.73 vs 0.61; difference, 0.12 [95% CI, 0.05-0.19]; P < .001) for prediction of RFS. To validate the prediction model, PRecur was applied to the TCGA LUAD data set (n = 360), and a clear separation of risk groups was noted (log-rank statistic, 7.5; P = .02), confirming external validation. The findings suggest that integration of tumor genomics and clinicopathologic features improves risk stratification and prediction of recurrence after surgical resection of early-stage LUAD. Improved identification of patients at risk for recurrence could enrich and enhance accrual to adjuvant therapy clinical trials.

Multi-kinase framework promotes proliferation and invasion of lung adenocarcinoma through activation of dynamin-related protein 1.

Recent studies revealed the role of dynamin-related protein 1 (DRP1), encoded by the DNM1L gene, in regulating the growth of cancer cells of various origins. However, the regulation, function, and clinical significance of DRP1 remain undetermined in lung adenocarcinoma. Our study shows that the expression and activation of DRP1 are significantly correlated with proliferation and disease extent, as well as an increased risk of postoperative recurrence in stage I to stage IIIA lung adenocarcinoma. Loss of DRP1 in lung adenocarcinoma cell lines leads to an altered mitochondrial morphology, fewer copies of mitochondrial DNA, decreased respiratory complexes, and impaired oxidative phosphorylation. Additionally, the proliferation and invasion are both suppressed in DRP1-depleted lung adenocarcinoma cell lines. Our data further revealed that DRP1 activation through serine 616 phosphorylation is regulated by ERK/AKT and CDK2 in lung adenocarcinoma cell lines. Collectively, we propose the multikinase framework in activating DRP1 in lung adenocarcinoma to promote the malignant properties. Biomarkers related to mitochondrial reprogramming, such as DRP1, can be used to evaluate the risk of postoperative recurrence in early-stage lung adenocarcinoma.

Targeted Next-Generation Sequencing Analysis for Recurrence in Early-Stage Lung Adenocarcinoma

BackgroundDespite surgical resection, early lung adenocarcinoma has a recurrence rate of 20–50%. No clear predictive markers for recurrence of early lung adenocarcinoma are available. Targeted next-generation sequencing (NGS) is rarely used to identify recurrence-related genes. We aimed to identify genetic alterations that can predict recurrence, by comparing the molecular profiles of patient groups with and without recurrence.MethodsTissues from 230 patients with resected stage I–II lung adenocarcinoma (median follow-up: 49 months) were analyzed via targeted NGS for 207 cancer-related genes. The recurrence-free survival according to the number and type of mutation was estimated using the Kaplan–Meier method. Independent predictive biomarkers related to recurrence were identified using the Cox proportional hazards model.ResultsRecurrence was observed in 64 patients (27.8%). In multivariate analysis adjusted for age, sex, smoking history, stage, surgical mode, and visceral pleural invasion, the CTNNB1 mutation and fusion genes (ALK, ROS1, RET) were negative prognostic factors for recurrence in early-stage lung adenocarcinoma (HR 4.47, p = 0.001; HR 2.73, p = 0.009). EGFR mutation was a favorable factor (HR 0.51, p = 0.016), but the CTNNB1/EGFR co-mutations were negative predictors (HR 19.2, p < 0.001). TP53 mutation was a negative predictor compared with EGFR mutation for recurrence (HR 5.24, p = 0.02). Conclusions: Targeted NGS can provide valuable information to predict recurrence and identify patients at high recurrence risk, facilitating selection of the treatment strategy among close monitoring and adjuvant-targeted therapy. Larger datasets are required to validate these findings.

Response to comment on ‘Clinical significance and inflammatory landscapes of a novel recurrence-associated immune signature in early-stage lung adenocarcinoma’

The prevalence of early-stage lung adenocarcinoma (LUAD) has increased alongside increased implementation of lung cancer screenings. Robust discrimination criteria are urgently needed to identify those patients who might benefit from additional systemic therapy. Here, to develop a reliable, individualized immune gene-set-based signature to predict recurrence in early-stage LUAD, a novel recurrence-associated immune signature was identified using a least absolute shrinkage and selection operator model, and a stepwise Cox proportional hazards regression model with a training set comprised of 338 early-stage LUAD samples form TCGA, which was subsequently validated in 226 cases from GSE31210 and an independent set of 68 frozen tumor samples with qRT-PCR data. This new classification system remained strongly predictive of prognoses across clinical subgroups and mutation status. Further analysis revealed that samples from high-risk cases were characterized by active interferon signal transduction, distinctive immune cell proportions and immune checkpoint profiles. Moreover, the signature was identified as an independent prognostic factor. In conclusion, the signature is highly predictive of recurrence in patients with early-stage LUAD, which may serve as a powerful prognostic tool to further optimize immunotherapies for cancer.

Clinical significance and inflammatory landscapes of a novel recurrence-associated immune signature in early-stage lung adenocarcinoma.

The prevalence of early-stage lung adenocarcinoma (LUAD) has increased alongside increased implementation of lung cancer screenings. Robust discrimination criteria are urgently needed to identify those patients who might benefit from additional systemic therapy. Here, to develop a reliable, individualized immune gene-set-based signature to predict recurrence in early-stage LUAD, a novel recurrence-associated immune signature was identified using a least absolute shrinkage and selection operator model, and a stepwise Cox proportional hazards regression model with a training set comprised of 338 early-stage LUAD samples form TCGA, which was subsequently validated in 226 cases from GSE31210 and an independent set of 68 frozen tumor samples with qRT-PCR data. This new classification system remained strongly predictive of prognoses across clinical subgroups and mutation status. Further analysis revealed that samples from high-risk cases were characterized by active interferon signal transduction, distinctive immune cell proportions and immune checkpoint profiles. Moreover, the signature was identified as an independent prognostic factor. In conclusion, the signature is highly predictive of recurrence in patients with early-stage LUAD, which may serve as a powerful prognostic tool to further optimize immunotherapies for cancer.

P3.02-090 Hypoxia-Induced Modifications of the Small Non-Coding RNA Transcriptome Delineates Risk of Recurrence in Early-Stage Lung Adenocarcinoma

P3.02-090 Hypoxia-Induced Modifications of the Small Non-Coding RNA Transcriptome Delineates Risk of Recurrence in Early-Stage Lung Adenocarcinoma

FDG-PET Maximum Standardized Uptake Value and Histological Subtype Predict High Risk for Recurrence in Early-Stage Lung Adenocarcinoma Treated with Stereotactic Body Radiation Therapy

FDG-PET Maximum Standardized Uptake Value and Histological Subtype Predict High Risk for Recurrence in Early-Stage Lung Adenocarcinoma Treated with Stereotactic Body Radiation Therapy

P1.05-056 Increased Risk of Postoperative Recurrence in EGFR-Positive Stage IA to IB Invasive Lung Adenocarcinoma

Somatic mutations of EGFR represent one of the most frequent genetic aberrations in lung adenocarcinoma and response to tyrosine kinase inhibitors (TKIs) has been favorable in EGFR-positive and advanced lung adenocarcinoma patients. The prognostic significance of EGFR mutations as oncogenic driver mutations in early-stage lung adenocarcinoma has yet to be determined. We aimed to evaluate the oncological significance of EGFR mutations in early-stage lung adenocarcinoma. Four hundred and seventy-three consecutive lung adenocarcinoma patients who underwent surgical resection for pathological N0M0 disease, between January 2007 and December 2013, were retrospectively reviewed. The prognostic significance of EGFR mutation status was evaluated in 407 cases from these patients. Overall survival (OS) and recurrence-free interval (RFI) curves were estimated using the Kaplan-Meier method and compared using a log-rank test. Univariate and multivariate analyses were performed using a Cox proportional hazards model. There was no statistical significance in the 5-year OS (89.3 vs. 95.3%, P = .20, HR = 1.605) or RFI (86.5 vs. 93.5%, P = .06, HR = 1.956) rates between the EGFR-positive (n=183) and EGFR-negative (n=224) groups. Considering the risk of recurrence and positive EGFR mutation status, OS and RFI rates were subsequently calculated among specific histological subtypes. After adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive mucinous adenocarcinoma (IMA) cases were excluded, all analyzed cases were ≤5.0 cm in tumor diameter and were classified as pathological Stage IA-IB. Among specific histological subtypes, the 5-year RFI (81.5 vs. 92.4%, P = .04, HR = 2.160) but not OS rate (86.8 vs. 94.3%, P = .31, HR = 1.499) was significantly poorer in EGFR-positive cases compared to EGFR-negative cases. Univariate analysis, excluding AIS, MIA, and IMA, identified a pathological tumor size of >3.0 cm, a highly malignant subtype (micropapillary or solid predominant adenocarcinoma), pleural/lymphatic/vascular invasion, and a positive EGFR mutation status as significant negative predictive factors for RFI. Multivariate analysis confirmed pleural invasion and a positive EGFR mutation status as independent negative predictive factors for RFI. EGFR mutation status is a predictive factor for postoperative recurrence in early-stage lung adenocarcinoma, with the exception of AIS, MIA, and IMA. The risk of recurrence should be considered with EGFR mutation status and predominant histological subtype in resected early-stage lung adenocarcinoma patients.