Non-Coding RNAs as Prognostic Biomarkers: A miRNA Signature Specific for Aggressive Early-Stage Lung Adenocarcinomas

Lung cancer burden can be reduced by adopting primary and secondary prevention strategies such as anti-smoking campaigns and low-dose CT screening for high risk subjects (aged >50 and smokers >30 packs/year). Recent CT screening trials demonstrated a stage-shift towards earlier stage lung cancer and reduction of mortality (~20%). However, a sizable fraction of patients (30–50%) with early stage disease still experience relapse and an adverse prognosis. Thus, the identification of effective prognostic biomarkers in stage I lung cancer is nowadays paramount. Here, we applied a multi-tiered approach relying on coupled RNA-seq and miRNA-seq data analysis of a large cohort of lung cancer patients (TCGA-LUAD, n = 510), which enabled us to identify prognostic miRNA signatures in stage I lung adenocarcinoma. Such signatures showed high accuracy (AUC ranging between 0.79 and 0.85) in scoring aggressive disease. Importantly, using a network-based approach we rewired miRNA-mRNA regulatory networks, identifying a minimal signature of 7 miRNAs, which was validated in a cohort of FFPE lung adenocarcinoma samples (CSS, n = 44) and controls a variety of genes overlapping with cancer relevant pathways. Our results further demonstrate the reliability of miRNA-based biomarkers for lung cancer prognostication and make a step forward to the application of miRNA biomarkers in the clinical routine.

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Baseline Plasma EGFR Circulating Tumour DNA Levels in a Pilot Cohort of EGFR-Mutant Limited-Stage Lung Adenocarcinoma Patients Undergoing Radical Lung Radiotherapy

Case Reports in Oncology ◽

10.1159/000508932 ◽

2020 ◽

Vol 13 (2) ◽

pp. 896-903

Author(s):

Brendan Seng Hup Chia ◽

Wen Long Nei ◽

Sabanayagam Charumathi ◽

Kam Weng Fong ◽

Min-Han Tan

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Cancer Patients ◽

Early Stage ◽

Early Stage Disease ◽

Lung Cancer Patients ◽

Limited Stage ◽

Potential Biomarker ◽

Egfr Mutant

The use of circulating cell-free tumour DNA (ctDNA) is established in metastatic lung adenocarcinoma to detect and monitor sensitising EGFR mutations. In early-stage disease, there is very little data supporting its role as a potential biomarker. We report on a prospective cohort of 9 limited-stage EGFR mutant lung cancer patients who were treated with radical radiotherapy. We looked at baseline plasma EGFR ctDNA and noted the detection rates to be higher in locally advanced disease. At a median follow-up of 13.5 months, an association between a detectable pre-radiotherapy plasma EGFR ctDNA and early tumour relapse (155 days vs. NR, p = 0.004) was noted. One patient with persistent plasma EGFR ctDNA predated radiological progression. The role of ctDNA in early-stage lung cancer is developing. Plasma EGFR ctDNA could be a useful biomarker in lung cancer patients undergoing radical treatments for staging, prognostication, and follow-up. These preliminary findings should be explored in larger studies.

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Surgery in Small-Cell Lung Cancer

Cancers ◽

10.3390/cancers13030390 ◽

2021 ◽

Vol 13 (3) ◽

pp. 390

Author(s):

Nicola Martucci ◽

Alessandro Morabito ◽

Antonello La Rocca ◽

Giuseppe De Luca ◽

Rossella De Cecio ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Early Stage ◽

Small Cell ◽

Stage I ◽

Phase Iii ◽

Small Cell Lung ◽

Early Stage Disease ◽

Stage Disease

Small-cell lung cancer (SCLC) is one of the most aggressive tumors, with a rapid growth and early metastases. Approximately 5% of SCLC patients present with early-stage disease (T1,2 N0M0): these patients have a better prognosis, with a 5-year survival up to 50%. Two randomized phase III studies conducted in the 1960s and the 1980s reported negative results with surgery in SCLC patients with early-stage disease and, thereafter, surgery has been largely discouraged. Instead, several subsequent prospective studies have demonstrated the feasibility of a multimodality approach including surgery before or after chemotherapy and followed in most studies by thoracic radiotherapy, with a 5-year survival probability of 36–63% for patients with completely resected stage I SCLC. These results were substantially confirmed by retrospective studies and by large, population-based studies, conducted in the last 40 years, showing the benefit of surgery, particularly lobectomy, in selected patients with early-stage SCLC. On these bases, the International Guidelines recommend a surgical approach in selected stage I SCLC patients, after adequate staging: in these cases, lobectomy with mediastinal lymphadenectomy is considered the standard approach. In all cases, surgery can be offered only as part of a multimodal treatment, which includes chemotherapy with or without radiotherapy and after a proper multidisciplinary evaluation.

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The pathway to diagnosis and treatment for surgically managed lung cancer patients

Family Practice ◽

10.1093/fampra/cmz064 ◽

2019 ◽

Author(s):

Victoria White ◽

Rebecca J Bergin ◽

Robert J Thomas ◽

Kathryn Whitfield ◽

David Weller

Keyword(s):

Lung Cancer ◽

Primary Care ◽

Cancer Patients ◽

Secondary Care ◽

Primary Care Physicians ◽

Treatment Time ◽

Early Stage ◽

Diagnosis And Treatment ◽

Early Stage Disease ◽

Lung Cancer Patients

Abstract Background Most lung cancer is diagnosed at an advanced stage, resulting in poor survival. This study examined diagnostic pathways for patients with operable lung cancer to identify factors contributing to early diagnosis. Methods Surgically treated lung cancer patients (aged ≥40, within 6 months of diagnosis), approached via the population-based Cancer Registry, with their primary care physicians (PCPs) and specialists completed cross-sectional surveys assessing symptoms, diagnostic route (symptomatic or ‘investigation’ of other problem), tests, key event dates and treatment. Time intervals to diagnosis and treatment were determined, and quantile regression examined differences between the two diagnostic routes. Cox proportional hazard regression analyses examined associations between survival and diagnostic route adjusting for stage, sex and age. Results One hundred and ninety-two patients (36% response rate), 107 PCPs and 55 specialists participated. Fifty-eight per cent of patients had a symptomatic diagnostic route reporting an average of 1.6 symptoms, most commonly cough, fatigue or haemoptysis. Symptomatic patients had longer median primary care interval than ‘investigation’ patients (12 versus 9 days, P < 0.05) and were more likely to report their PCP first-ordered imaging tests. Secondary care interval was shorter for symptomatic (median = 43 days) than investigation (median = 62 days, P < 0.05) patients. However, 56% of all patients waited longer than national recommendations (6 weeks). While survival estimates were better for investigation than symptomatic patients, these differences were not significant. Conclusion Many operable lung cancer patients are diagnosed incidentally, highlighting the difficulty of symptom-based approaches to diagnosing early stage disease. Longer than recommended secondary care interval suggests the need for improvements in care pathways.

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Genomic profiling of early-stage lung cancer for patterns of recurrence.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e23126 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e23126-e23126

Author(s):

Costanzo A DiPerna ◽

Leah Fine

Keyword(s):

Lung Cancer ◽

Cancer Patients ◽

Early Stage ◽

Molecular Profiling ◽

Stage I ◽

Genomic Profiling ◽

Early Stage Lung Cancer ◽

Lung Cancer Patients ◽

Adjuvant Therapies ◽

Stage Lung Cancer

e23126 Background: Currently there is no evidence to support molecular profiling for early stage resected lung cancer patients. However, up to 50% of patients experience recurrence following resection. This is a first-of-a-kind study utilizing comprehensive genomic profiling technology to characterize genomic patterns for risk of recurrence in early stage lung cancer patients within the community hospital setting who have undergone lung surgery. Methods: A total of 60 Stage I-II lung cancer patients, all having undergone pulmonary resection, were evaluated with molecular profiling of their primary lung cancer tissue using Foundation Medicine’s FoundationOneÒ test. Patient age in years ranged from 39-86, and all patients were confirmed Stage I or II based on final pathologic analysis. Samples were taken from three community hospitals that are part of the Addario Lung Cancer Foundation Centers of Excellence program. Patients whose tumors were resected between the years of 2009-2017 were included in this combined retrospective and prospective study. Results: More than 300 genes were evaluated using FoundationOneÒ and patients were segmented to establish similarities and differences. Analysis of segments include gender, recurrence, smoking status among others. Gene patterns across segments are beginning to reveal possible predictive profiles. Final analysis will be completed shortly. Conclusions: Genomic profiling could help predict lung cancer recurrence for early stage lung cancer patients. Similarities amongst patients with recurrences imply that early genomic profiling of lung cancer patients could help predict those patients who would benefit from adjuvant therapies including conventional chemotherapy. Genomic profiling for early stage lung cancer should be studied further and in greater detail to help predict those patients who would benefit from potentially early adjuvant therapies.

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Circulating tumor DNA (ctDNA) mutation and epigenomic patterns in early-stage lung cancer patients and its utility in identifying patients at high risk for early recurrence.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14557 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14557-e14557

Author(s):

Jong Ho Cho ◽

Il-Jin Kim ◽

Junghee Lee ◽

Hong Kwan Kim ◽

Jinseon Lee ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Patients ◽

Somatic Mutations ◽

Early Stage ◽

Circulating Tumor Dna ◽

Stage I ◽

Early Stage Lung Cancer ◽

Lung Cancer Patients ◽

Tumor Dna ◽

Stage Lung Cancer

e14557 Background: Circulating tumor DNA (ctDNA) analysis has been successfully applied to therapy selection and treatment monitoring in advanced cancer patients. However, it is not yet established whether ctDNA can be used clinically for early cancer detection or predicting tumor recurrence in early stage lung cancer patients. Methods: We analyzed pre-operative plasma samples from 55 early stage NSCLC patients (stages I-IIIA) using next-generation sequencing to detect somatic mutations and differential epigenomics patterns, including methylation signatures. Results: Using somatic mutation analysis alone, ctDNA was detected in 42% (23/55) of patients, whereas combined mutational and epigenomic analysis detected ctDNA in 71%. ctDNA detection rate also varied markedly between lung squamous cell carcinoma (SCC) and adenocarcinoma (ADC);using combined analysis of somatic mutations and epigenomic patterns, ctDNA was detected in all SCC patients, while only 55% of ADC (12/22) were ctDNA-positive (p= 0.006). Within the ADC subgroup, ctDNA detection rates using the combined approach were dependent on disease stage: 47% (8/17) in stage I, 100% (2/2) in stage II, and 100% (2/2) in stage IIIA. Importantly, pre-operative ctDNA status was correlated with tumor recurrence post-resection; three of eight (38%) ctDNA-positive stage I ADC patients recurred within 2 years of resection, while only one of nine (11%) ctDNA-negative stage I ADC patients recurred (p= 0.29). Conclusions: Taken together, we show that the combination of somatic mutation detection and epigenomic analysis outperforms each individual biomarker in the detection of ctDNA in early stage lung cancer. Importantly, we also demonstrate that pre-operative ctDNA detection may identify a high-risk population of early stage lung cancer patients that may benefit from (neo)adjuvant therapy.

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Multiomic Characterization of Stage I Lung Adenocarcinoma Reveals Distinct Genetic and Immunologic Features of Recurrent Disease

10.1101/2021.05.20.444915 ◽

2021 ◽

Author(s):

Johannes R Kratz ◽

Jack Z Li ◽

Jessica Tsui ◽

Jen C Lee ◽

Vivianne W Ding ◽

...

Keyword(s):

Lung Cancer ◽

High Risk ◽

Lung Adenocarcinoma ◽

Early Stage ◽

Stage I ◽

Early Stage Lung Cancer ◽

Risk Of Recurrence ◽

Adaptive Immune ◽

Mutation Burden ◽

Lung Adenocarcinomas

Background: Recurrence after surgery for early-stage lung cancer is common, occurring between 30-50% of the time. Despite the popularization of prognostic gene signatures in early-stage lung cancer that allow us to better predict which patients may recur, why patients recur after surgery remains unclear. Methods: Using a large cohort of lung adenocarcinoma patients with complete genetic, genomic, epigenetic and clinical profiling, a recurrence classifier was developed which identifies patients at highest risk of recurrence. The genetic, genomic, and epigenetic profiles of stage I patients with low- vs. high-risk of recurrence were compared. To characterize the tumor immune microenvironment of recurrent stage I tumors, single cell RNA-seq was performed on fresh tissue samples undergoing lung adenocarcinoma resection at UCSF to identify unique immune population markers and applied to the large stage I lung adenocarcinoma cohort using digital cytometry. Results: Recurrence high-risk stage I lung adenocarcinomas demonstrated a higher mutation burden than low-risk tumors, however, none of the known canonical lung cancer driver mutations were more prevalent in high-risk tumors. Transcriptomic analysis revealed widespread activation of known cancer and cell cycle pathways with simultaneous downregulation of immune response pathways including antigen presentation and Th1/Th2 activation. Tumors at high-risk of recurrence displayed depleted adaptive immune populations, and depletion of adaptive immune populations was independently prognostic of recurrence in stage I lung adenocarcinomas. Conclusion: Recurrent stage I lung adenocarcinomas display distinct features of genomic and genetic instability including increased tumor mutation burden, neoantigen load, activation of numerous mitotic and cell cycle genes, and decreased genome-wide methylation burden. Relative depletion of infiltrating adaptive immune populations may allow these tumors to escape immunosurveillance and recur after surgery.

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Automated imaging-based stratification of early-stage lung cancer patients prior to receiving surgical resection using deep learning applied to CTs.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.1552 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 1552-1552

Author(s):

Felipe Soares Torres ◽

Shazia Akbar ◽

Srinivas Raman ◽

Kazuhiro Yasufuku ◽

Felix Baldauf-Lenschen ◽

...

Keyword(s):

Lung Cancer ◽

Deep Learning ◽

Cancer Patients ◽

Surgical Resection ◽

Mortality Risk ◽

Early Stage ◽

Stage I ◽

Early Stage Lung Cancer ◽

Lung Cancer Patients ◽

Stage Lung Cancer

1552 Background: Computed tomography (CT) imaging is an important tool to guide further investigation and treatment in patients with lung cancer. For patients with early stage lung cancer, surgery remains an optimal treatment option. Artificial intelligence applied to pretreatment CTs may have the ability to quantify mortality risk and stratify patients for more individualized diagnostic, treatment and monitoring decisions. Methods: A fully automated, end-to-end model was designed to localize the 36cm x 36cm x 36cm space centered on the lungs and learn deep prognostic features using a 3-dimensional convolutional neural network (3DCNN) to predict 5-year mortality risk. The 3DCNN was trained and validated in a 5-fold cross-validation using 2,924 CTs of 1,689 lung cancer patients from 6 public datasets made available in The Cancer Imaging Archive. We evaluated 3DCNN’s ability to stratify stage I & II patients who received surgery into mortality risk quintiles using the Cox proportional hazards model. Results: 260 of the 1,689 lung cancer patients in the withheld validation dataset were diagnosed as stage I or II, received a surgical resection within 6 months of their pretreatment CT and had known 5-year disease and survival outcomes. Based on the 3DCNN’s predicted mortality risk, patients in the highest risk quintile had a 14.2-fold (95% CI 4.3-46.8, p < 0.001) increase in 5-year mortality hazard compared to patients in the lowest risk quintile. Conclusions: Deep learning applied to pretreatment CTs provides personalised prognostic insights for early stage lung cancer patients who received surgery and has the potential to inform treatment and monitoring decisions.[Table: see text]

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Management and outcomes of patients with chronic obstructive lung disease and lung cancer in a public healthcare system

PLoS ONE ◽

10.1371/journal.pone.0251886 ◽

2021 ◽

Vol 16 (5) ◽

pp. e0251886

Author(s):

John R. Goffin ◽

Sophie Corriveau ◽

Grace H. Tang ◽

Gregory R. Pond

Keyword(s):

Lung Cancer ◽

Respiratory Infections ◽

Early Stage ◽

Multivariable Analysis ◽

Chronic Obstructive Lung Disease ◽

Stage I ◽

Public Healthcare ◽

Chronic Obstructive ◽

Early Stage Disease ◽

Stage Disease

Hypothesis There is limited data on the care and outcomes of individuals with both chronic obstructive pulmonary disease (COPD) and lung cancer, particularly in advanced disease. We hypothesized such patients would receive less cancer treatment and have worse outcomes. Methods We analyzed administrative data from the province of Ontario including demographics, hospitalization records, physician billings, cancer diagnosis, and treatments. COPD was defined using the ICES-derived COPD cohort (1996–2014) with data from 2002 to 2014. Descriptive statistics and multivariable analyses were undertaken. Results Of 105 304 individuals with lung cancer, 43 375 (41%) had stage data and 36 738 (34.9%) had COPD. Those with COPD were likely to be younger, have a Charlson score ≤ 1, have lower income, to live rurally, and to have stage I/II lung cancer (29.8 vs 26.5%; all p<0.001). For the COPD population with stage I/II cancer, surgery and adjuvant chemotherapy were less likely (56.8 vs. 65.9% and 15.4 vs. 17.1%, respectively), while radiation was more likely (26.0 vs. 21.8%) (p all < 0.001). In the stage III/IV population, individuals with COPD received less chemotherapy (55.9 vs 64.4%) or radiation (42.5 vs 47.5%; all p<0.001). Inhaler and oxygen use was higher those with COPD, as were hospitalizations for respiratory infections and COPD exacerbations. On multivariable analysis, overall survival was worse among those with COPD (HR 1.20, 95% CI 1.19–1.22). Conclusions A co-diagnosis of COPD and lung cancer is associated with less curative treatment in early stage disease, less palliative treatment in late stage disease, and poorer outcomes.

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EU Policy on Lung Cancer CT Screening 2017

Biomedicine Hub ◽

10.1159/000479810 ◽

2017 ◽

Vol 2 (Suppl. 1) ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

John K. Field ◽

Javier Zulueta ◽

Giulia Veronesi ◽

Matthijs Oudkerk ◽

David R. Baldwin ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Screening ◽

Early Stage ◽

Lung Cancer Screening ◽

Expert Group ◽

Early Stage Disease ◽

Ct Screening ◽

Stage Disease ◽

Eu Commission ◽

The Eu

Background: Lung cancer kills more Europeans than any other cancer. In 2013, 269,000 citizens of the EU-28 died from this disease. Lung cancer CT screening has the potential to detect lung cancer at an early stage and improve mortality. All of the randomised controlled trials and cohort low-dose CT (LDCT) screening trials across the world have identified very early stage disease (∼70%); the majority of these LDCT trial patients were suitable for surgical interventions and had a good clinical outcome. The 10-year survival in CT screen-detected cancer was shown to be even higher than the 5-year survival for early stage disease in clinical practice at 88%. Methods: Setting up of an EU Commission expert group can be done under Article 168(2) of the Treaty on the Functioning of the European Union, to develop policy and recommendation for Lung cancer CT screening. The Expert Group would undertake: (a) assist the Commission in the drawing up policy documents, including guidelines and recommendations; (b) advise the Commission in the implementation of Union actions on screening and suggest improvements to the measures taken; (c) advise the Commission in the monitoring, evaluation and dissemination of the results of measures taken at Union and national level. Results: This EU Expert Group on lung cancer screening should be set up by the EU Commission to support the implementation and suggest recommendations for the lung cancer screening policy by 2019/2020. Conclusion: Reduce lung cancer in Europe by undertaking a well-organised lung cancer CT screening programme.

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Symptoms and Reason for a Medical Visit in Lung Cancer Patients

Acta Médica Portuguesa ◽

10.20344/amp.4229 ◽

2014 ◽

Vol 27 (3) ◽

pp. 318 ◽

Cited By ~ 3

Author(s):

Francisco-Javier Gonzalez-Barcala ◽

José-Antonio Falagan ◽

Jose-Maria Garcia-Prim ◽

Luis Valdes ◽

Jose-Martin Carreira ◽

...

Keyword(s):

Lung Cancer ◽

Early Stage ◽

Incidental Finding ◽

Malignant Tumour ◽

Medical Visit ◽

Early Stage Disease ◽

Lung Cancer Patients ◽

Stage Disease ◽

Initial Symptoms ◽

The Relationship

Background: Patients with lung cancer usually present with symptoms at the time of diagnosis, but it is common that neither the doctor nor the patient initially associate them with the possibility of a malignant tumour. Objectives: The aim of our study is to analyse the symptoms of patients with lung cancer and the relationship with the personal characteristics or the oncological disease. Material and Methods: A retrospective study was conducted on all patients diagnosed with lung cancer in the Pontevedra Health Area over a period of three years. The symptoms presented by the patient, the reason for the consultation and the agreement between both or any factors associated with either of the two are analysed. Results: A total of 358 patients, with a mean age of 68.7 years, and of whom 87% males, were included in the study. The most common initial symptoms were, constitutional in 30.4% of the cases, cough in 20.9% of cases, and in third place was chest pain, which was referred to by 12% of the patients. The most frequent reason for the consultation was dyspnea in 22.1% of patients, an incidental finding in 15.4%, and haemoptysis in 12.8%. There was a moderate association (correlation coefficient = 0.495) between the initial symptoms and the consulting symptom. Conclusions: A high percentage of patients with lung cancer had symptoms associated with the tumour at the time of diagnosis, even in early stage disease. Keywords: Lung Neoplasms/diagnosis; Spain.

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