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BACKGROUND: Lung cancer is associated with the greatest cancer mortality as it typically presents with incurable distributed disease. Biomarkers relevant to risk assessment for the detection of lung cancer continue to be a challenge because they are often not detectable during the asymptomatic curable stage of the disease. A solution to population-scale testing for lung cancer will require a combination of performance, scalability, cost-effectiveness, and simplicity. METHODS: One solution is to measure the activity of serum available enzymes that contribute to the transformation process rather than counting biomarkers. Protease enzymes modify the environment during tumor growth and present an attractive target for detection. An activity based sensor platform sensitive to active protease enzymes is presented. A panel of 18 sensors was used to measure 750 sera samples from participants at increased risk for lung cancer with or without the disease. RESULTS: A machine learning approach is applied to generate algorithms that detect 90% of cancer patients overall with a specificity of 82% including 90% sensitivity in Stage I when disease intervention is most effective and detection more challenging. CONCLUSION: This approach is promising as a scalable, clinically useful platform to help detect patients who have lung cancer using a simple blood sample. The performance and cost profile is being pursued in studies as a platform for population wide screening.
Lung cancer is responsible for more deaths worldwide than all other cancers. It is often detected with the appearance of symptoms when treatment is limited and outcomes for the patient are much worse. While imaging chest scans can detect disease, they are poorly used even in the United States where it is an approved screening method. When cancer is present, protease enzymes are responsible for making space and modifying the lung tissue for the growing tumor. This report describes a panel of 18 sensors that release a fluorescent signal when these enzymes are present in a blood sample. The signal acts like a fingerprint of activity that can be used to identify people with lung cancer. This sensor platform can detect patients with curable lung cancer and could provide a platform for screening very large populations of at-risk individuals.
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OBJECTIVES: Early detection of lung cancer is pivotal for an optimal prognosis. CT screening is currently implemented in USA. To decrease the amount of CT scans, the application of a blood-based biomarker as part of screening criteria is desirable. MATERIALS AND METHODS: The EarlyCDT® Lung test was performed in a high-risk cohort composed 246 patients referred from their GP on suspicion of lung cancer. Blood samples were taken at first visit and patients underwent diagnostic workup on suspicion of lung cancer resulting in either a malignant diagnosis or ruled out cancer. Sensitivity and specificity of the EarlyCDT® Lung were calculated in the cohort and subgroups based on age, smoking history, sex and lung cancer stage. RESULTS: Overall sensitivity in the cohort was 33 % for lung cancer and 31 % for primary lung cancer and lung metastases combined. Sensitivity in age groups was 11 % (60 years or below), 31 % (61-75 years) and 55 % (>75 years). In patients with at least 10 tobacco pack years, sensitivity was 33 % while the sensitivity in patients with at least 50 tobacco pack years was 44 %. The assay sensitivity in stage I-II lung cancer patients was 21 %, while this was 40 % in stage III-IV lung cancer patients. In a subgroup of patients that met current CT screening criteria (age 55-80 years and minimum 30 tobacco pack years) the sensitivity was 37 %. CONCLUSION: The rationale of screening for lung cancer is to find patients in an early and resectable stage. However, the EarlyCDT® Lung test performed best in elderly, late stage lung cancer patients with a heavy smoking history. Based on these results, the current study finds insufficient sensitivity of the EarlyCDT® Lung test to be used as part of inclusion criteria in a low-dose CT program for detection of lung cancer.
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Neoplasias Pulmonares , Anciano , Anciano de 80 o más Años , Detección Precoz del Cáncer , Humanos , Pulmón , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiología , Tamizaje Masivo , Persona de Mediana Edad , Estadificación de Neoplasias , Tomografía Computarizada por Rayos XRESUMEN
Diagnosing lung cancer requires invasive procedures with high risk of complications. Methylated tumor DNA in bronchial lavage has previously shown potential as a diagnostic biomarker. We aimed to develop and validate methylated HOXA9 in bronchial lavage as a diagnostic biomarker of lung cancer. Participants were referred on suspicion of lung cancer. Ten mL lavage fluid was collected at bronchoscopy for analysis of methylated HOXA9 based on droplet digital PCR according to our previously published method. HOXA9 status was compared with the final diagnosis. The Discovery and Validation cohorts consisted of 101 and 95 consecutively enrolled participants, respectively. In the discovery cohort, the sensitivity and specificity were 73.1% (95% CI 60.9-83.2%) and 85.3% (95% CI 68.9-95.0%), respectively. In the validation cohort, the values were 80.0% (95% CI 66.3-90.0%) and 75.6% (95% CI 60.5-87.1%), respectively. A multiple logistic regression model including age, smoking status, and methylated HOXA9 status resulted in an AUC of 84.9% (95% CI 77.3-92.4%) and 85.9% (95% CI 78.4-93.4%) for the Discovery and Validation cohorts, respectively. Methylated HOXA9 in bronchial lavage holds potential as a supplementary tool in the diagnosis of lung cancer with a clinically relevant sensitivity and specificity. It remained significant when adjusting for age and smoking status.
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AIM: The aim of the study was to compare ctDNA response rate and objective response rate as surrogate markers for overall survival (OS) in patients with metastatic cancer treated with chemotherapy. METHODS: The study included 420 patients distributed in five cohorts with colorectal, ovarian, and non-small cell lung cancer. It represents a retrospective analysis of patients enrolled in prospective biomarker studies and clinical trials. All patients had ctDNA measured before start of treatment and at the first evaluation of objective response. ctDNA response rate was defined as the fraction of patients converting from a measurable level at baseline to an unmeasurable level at the first evaluation of objective response. Aberrant, tumour specific, methylated DNA was measured in plasma. The method involves DNA isolation, bisulphite conversion and droplet digital PCR. The primary outcome measure was the correlation between ctDNA response rate, overall response rate (ORR) and median survival. RESULTS: There was moderate correlation between ctDNA response rate and objective response at first evaluation (R2 = 0.68). The same applied to ctDNA response rate and ORR (R2 = 0.57). ctDNA held prognostic information in all the investigated tumour types (p < 0.05). There was a high correlation between ctDNA response and median survival across the included tumour types and treatments (R2 = 0.99) clearly outperforming both response at first evaluation and ORR (R2 = 0.70 and 0.57, respectively). CONCLUSION: The results suggest that ctDNA response might serve as a surrogate marker for OS. If validated, it may have great implications on the approval of new drugs.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Determinación de Punto Final , Neoplasias/tratamiento farmacológico , Proyectos de Investigación , Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/sangre , Ensayos Clínicos como Asunto , Femenino , Humanos , Masculino , Neoplasias/sangre , Neoplasias/genética , Neoplasias/mortalidad , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Circulating tumor DNA (ctDNA) has been suggested as a biomarker in non-small cell lung cancer. The optimal target for measuring ctDNA has not yet been established. This study aimed to investigate methylated Homeobox A9 (meth-HOXA9) as an approach to detect ctDNA in advanced lung adenocarcinoma and compare it with mutated Kirsten rat sarcoma viral oncogene homolog (mut-KRAS) in order to determine the mutual agreement. DNA was purified from formalin-fixed, paraffin-embedded non-malignant lung tissue and lung adenocarcinoma tissue, and plasma from healthy donors and lung adenocarcinoma patients, respectively. KRAS mutations in tumor tissue were identified by next-generation sequencing and quantified in tumor and plasma by droplet digital polymerase chain reaction (ddPCR). The meth-HOXA9 analysis was based on bisulfite-converted DNA from tumor and plasma and quantified by ddPCR. Samples consisted of 20 archival non-malignant lung tissues, 48 advanced lung adenocarcinomas with matched plasma samples, and 100 plasma samples from healthy donors. A KRAS mutation was found in the tumor in 34/48 (70.8%) adenocarcinoma patients. All tumors were positive for meth-HOXA9, while none of the non-malignant lung tissues were. Meth-HOXA9 was detected in 36/48 (75%) of plasma samples, and the median level was 0.7% (range of 0-46.6%, n = 48). Mut-KRAS was detected in 29/34 (85.3%) of the plasma samples, and the median level was 1.2% (range of 0-46.1%, n = 34). There was a good correlation between meth-HOXA9 and mut-KRAS in plasma (Spearman's rho 0.83, p < 0.001). Meth-HOXA9 is present in tissue from incurable lung adenocarcinoma but not in non-malignant lung tissue. It may be used as an approach for detecting ctDNA. The results demonstrated a high agreement between meth-HOXA9 and mut-KRAS in patients with advanced lung adenocarcinoma.