Validation of Molecular Diagnostic Thecnologies for Lung Cancer Patients.

Study Overview
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Brief Summary
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This is a non-interventional multi-center with investigational sites in Chile and Brasil diagnostic study to validate novel diagnostic technologies, such as Next Generation Sequencing (NGS) from both tissue and blood compared to the current gold standard. As a non-interventional study, patients will receive the treatment indicated by their doctor independently of their participation on this study. Many cancer cells look the same under the microscope. But as these cells are studied at the molecular level, some genetic alterations or defects that are more common to certain types of cancer are identified. In some cases, these defects are what make the cells grow and multiply abnormally. Biomarkers are the molecular fingerprints of these genetic defects. By testing a sample of your tumor for biomarkers, doctors can learn if your cancer has one of these defects, and that may point to a specific treatment choice. One of the genetic biomarkers that are believed to cause some cancers to grow is the ALK fusion gene. About 3% to 5% of people with NSCLC may test positive for ALK. ROS1 is a receptor found in 1 to 2% of people with this type of cancer. The present study is designed to advance the molecular testing methodologies to identify ALK+ and ROS1+ NSCLC patients. A positive correlation with these new technologies will mean an efficient, more accurate diagnostic test, which could impact a greater number of cancer patients around world.

Detailed Description
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B. Lung Cancer Non-small cell lung cancer (NSCLC) is a common cause of cancer mortality throughout the world. In 2007, there were 1.5 million new lung cancer cases diagnosed worldwide, including around 733,100 cases in the South American Region.6 Approximately 85% of lung cancer is histologically defined as non small cell and the remaining 14% as small cell. The majority of patients with NSCLC present with inoperable locally advanced (Stage IIIB) or metastatic (Stage IV) disease for which no curative treatment is yet available. In newly diagnosed patients with good performance status, platinum based doublet-combination chemotherapies are associated with a median overall survival (OS) of 7.4 to 9.9 months. 7, 8, 9, 10, 11, 12 Therefore, newer agents with novel mechanisms of action are still desperately needed for this serious life-threatening disease. 15,16 The rapid and efficient identification of key driver genes in non-small-cell lung cancer (NSCLC) is becoming increasingly important.17 Clinical screening efforts have revealed that the most common mutations in lung cancer specimens involve EGFR and KRAS, along with 10 other genes that show a prevalence of mutation in 5% or less of tumors. The ALK gene is rearranged in around 3%-5% of patients with NSCLC and has been the focus of intense basic and clinical research, suggesting that the frequency of the gene rearrangement is similar in Asian and Western patients. ROS1 is a receptor tyrosine kinase of the insulin receptor family. Chromosomal rearrangements involving the ROS1 gene were originally described in glioblastomas, where ROS1 (chromosome 6q22) is fused to the FIG gene (chromosome 6q22 immediately adjacent to ROS1), 16 and have been shown to be transforming in transgenic mice.17 More recently, ROS1 fusions were identified as potential driver mutations in an NSCLC cell line (HCC78; SLC34A2-ROS1) and an NSCLC patient sample (CD74-ROS1). 18 These fusions led to constitutive kinase activity and were associated with sensitivity in vitro and in vivo to crizotinib. As of December 2013, 16 different variants have been found.16, 17, 18 The present study is designed to advance the molecular testing methodologies to identify ALK+ and ROS1+ NSCLC patients. Advanced next generation sequencing screening methodologies will be used to identify NSCLC patients whose tumors contain a ROS1 gene inversion or translocation or an ALK translocation. A parallel test for ALK+ by either the Abbott ALK FISH test or the Ventana ALK IHC test is necessary to validate the NGS test in all samples. A parallel test for ROS1+ by either the Kreatech FISH test or the D4D6 ROS1 IHC test may be necessary to validate the NGS test in all samples.

Official Title
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NON INTERVENTIONAL MULTICENTER STUDY, FOR THE VALIDATION OF MOLECULAR DIAGNOSTIC TECHNOLOGIES IN SUBJECTS WITH NON SMALL CELL LUNG CANCER (NSCLC) PROTOCOL N° X9001083

Conditions
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Lung Neoplasms

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male, 18 years of age or older. Patients with histologically or cytological proven diagnosis of NSCLC, pathologically identified as adenocarcinoma. Patient naïve in lung cancer treatment Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all the pertinent aspects of the study prior to enrollment. Patients must give consent to the research use of their archived or tumor FFPE tissue, and if available, 2 blood tubes. Exclusion Criteria: Prior chemotherapy treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Prevalence of Anaplastic Lymphoma Kinase (ALK) Biomarker | ALK status was measured by NGS- Oncomine focus assay (OFA) and Immuno histo chemistry (IHC) Ventana. Ventana -ALK and NGS-OFA were the assay procedures performed for ALK. The corresponding analysis of a specimen had 2 possible test results including ALK positive and ALK negative. True positives (tp) were defined as NGS-OFA and Ventana positive results, whereas false negatives (fn) were defined as NGS-OFA negative results and IHC-Ventana positive results. False positives (fp) were defined as NGS-OFA positive results and IHC-Ventana negative results. True negatives (tn) were defined as NGS-OFA and IHC Ventana negative results. | 40 months | 
| Percentage of Concordance (Agreement) Between Ventana and NGS ALK Result | In this outcome measure, index of concordance with accuracy, sensitivity, specificity, positive predictive value and negative predictive value were measured. Accuracy (Acc): [tp+tn]/[tp+fp+fn+tn] *100; Sensitivity (Ss): tp/[tp+fn] *100; Specificity (Sp): tn/[fp+tn] *100; Positive Predictive Value (PPV): tp/[tp+fp] *100; Negative Predictive Value (NPV): tn/[fn+tn] *100. | 40 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Prevalence of Anaplastic Lymphoma Kinase (ALK) Biomarker by Type of Participants | Participants were categorized on the basis of prospective and retrospective. Prospective participants were those participants whose samples were taken after the informed consent. Retrospective participants were those participants whose samples were taken before the date of signature of the informed consent. | 40 months | 
| Number of Participants With Association of Anaplastic Lymphoma Kinase (ALK) Rearrangement by Smoking (Tobacco Use) History | The categories of smoker (tobacco use) were as follows: Never Smoker: No smoking exposure, Current Smoker: Currently uses tobacco in either cigarette, cigar or similar method (tobacco chewers excluded), Former Smoker: Participant at one time smoked but then later quit. Smoking status unknown: Participant whose smoking status is unknown. | 40 months | 
| Number of Participants With Association of Anaplastic Lymphoma Kinase (ALK) Rearrangement by Stage and Classification of Biopsy | Stage was defined at time of initial diagnosis of NSCLC and participants were staged according to the guidelines set by the NCCN version 7.2015. Participant's stage was categorized as: stage 0, stage IA, stage IB, stage IIA, stage IIB, stage IIIA, stage IIIB, and stage IV. Biopsy NSCLC class was categorized as adenocarcinoma, neuroendocrine tumors, other known type of NSCLC and squamous cell carcinoma. | 40 months | 
| Number of Participants With Association of Anaplastic Lymphoma Kinase (ALK) Rearrangement by Location | Locations were categorized as lungs, pleura, node mediastinal and others. | 40 months | 
| Number of Participants With Association of Anaplastic Lymphoma Kinase (ALK) Rearrangement by Gender and Age | In this outcome measure, participants were categorized according to their gender (female/male) and different age ranges (18-30 / 31-40 / 41-60 / 60 and above). | 40 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Next generation sequencing, Lung cancer, target therapies