Pathogenic Variants in Genes Associated With Lung Adenocarcinoma

Official title

Prevalence of Pathogenic or Likely Pathogenic Germline Variants in Cancer Predisposition Genes Among Patients With Lung Adenocarcinoma

Overview

The goal of this observational study is to describe the prevalence of germ line-pathogenic variants in Mexican patients with lung adenocarcinoma. The main questions it aims to answer are: 1. What is the prevalence of pathogenic variants in genes associated with lung adenocarcinoma in Mexican patients younger than fifty? 2. Which clinical-pathological characteristics are associated with germ-line pathogenic variants in patients with lung adenocarcinoma? 3. How actionable somatic mutations are associated with germ line-pathogenic variants of patients with lung adenocarcinoma? Participants will be asked to sign an informed consent; after that, they will be instructed to donate 10 ml of peripheral blood by venipuncture in the morning and before the patient has taken morning medication and the first meal, following a period of 8-12 hr fasting.

Detailed description

This is an observational, descriptive, and longitudinal study.

The sample size was calculated with a proportion difference formula for a known population, considering the Local Institutional Personalized Medicine Laboratory tests 100 blood samples per year from patients with non-small cell lung cancer (NSCLC). It was considered a 95% confidence level and an 80% power. In addition, a 10% loss in follow-up was estimated.

After reviewing the inclusion and exclusion criteria, signing the informed consent, and peripheral blood sampling. Total DNA (tDNA) will be extracted using the DNAeasy Blood \& Tissue (Qiagen) kit.

Likewise, for the determination of pathogenic variants, the Sophia HCS Community panels (Sophia genetics) will be used to carry out Next-generation (NGS) sequencing in a NextSeq 550 (Illumina) platform.

To determine the clinical significance of genomic variants, the data analysis will be performed on the SOPHiA Alamut™ Visual Plus which is a comprehensive, full genome browser for efficient and user-friendly variant interpretation.

Primary outcome measures

• PV in patients with lung carcinoma [Time frame: One peripherial blood sample (day 1) at baseline of study.]

Secondary outcome measures (2)

• OS [Time frame: From date of confirmed diagnosis until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months]
• PFS [Time frame: From date of first line of treatment initiation (guided therapy) until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months]

Eligibility criteria

Inclusion criteria

• Both sexes
• ≥ 16 years old, according the institutional protocols for new patients admittances.
• histologically confirmed lung adenocarcinoma (LUAD)
• Signed written informed consent form
• A life expectancy greater than 8 weeks.
• Histologically confirmed LUAD and one of the following conditions: i) LCFH, defined as having one first-degree relative (FDR) or two or more second-degree relatives with LC, irrespective of the age at diagnosis. ii) Age at diagnosis ≤50 years, or ≤60 with a pack-years index. iii) Presence of ≥1 AGAs (EGFR, ALK, ROS1, KRAS, BRAF, MET exon 14 skipping, or RET).

Exclusion criteria

• A sample of peripheral blood that is not accessible.
• Insufficient clinical pathological information in the electronic clinical record.

Elimination Criteria:

• Withdrawal
• Insufficient DNA quality and quantity for genomic sequencing analyses.
• Lost of follow up

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Case-only

Study locations

Mexico · 1 center

• Thoracic Oncology Unit and Personalized Medicine Laboratory, Instituto Nacional de Cancero — Mexico City

Publications

• Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022 Jan;72(1):7-33. doi: 10.3322/caac.21708. Epub 2022 Jan 12. PMID 35020204
• Kumar R, Castillero F, Bhandari S, Malapati S, Kloecker G. The Hispanic Paradox in Non-Small Cell Lung Cancer. Hematol Oncol Stem Cell Ther. 2022 Jun 1;15(2):21-29. doi: 10.1016/j.hemonc.2021.02.004. PMID 33775613
• Mukherjee S, Bandlamudi C, Hellmann MD, Kemel Y, Drill E, Rizvi H, Tkachuk K, Khurram A, Walsh MF, Zauderer MG, Mandelker D, Topka S, Zehir A, Srinivasan P, Esai Selvan M, Carlo MI, Cadoo KA, Latham A, Hamilton JG, Liu YL, Lipkin SM, Belhadj S, Bond GL, Gumus ZH, Klein RJ, Ladanyi M, Solit DB, Robson ME, Jones DR, Kris MG, Vijai J, Stadler ZK, Amos CI, Taylor BS, Berger MF, Rudin CM, Offit K. Germ PMID 35477182
• Sorscher S, LoPiccolo J, Heald B, Chen E, Bristow SL, Michalski ST, Nielsen SM, Lacoste A, Keyder E, Lee H, Nussbaum RL, Martins R, Esplin ED. Rate of Pathogenic Germline Variants in Patients With Lung Cancer. JCO Precis Oncol. 2023 Sep;7:e2300190. doi: 10.1200/PO.23.00190. PMID 37992258
• Peng W, Li B, Li J, Chang L, Bai J, Yi Y, Chen R, Zhang Y, Chen C, Pu X, Jiang M, Li J, Zhong R, Xu F, Chen B, Xu L, Wang N, Huan J, Dai P, Guan Y, Yang L, Xia X, Yi X, Wang J, Yu F, Wu L. Clinical and genomic features of Chinese lung cancer patients with germline mutations. Nat Commun. 2022 Mar 10;13(1):1268. doi: 10.1038/s41467-022-28840-5. PMID 35273153
• Carrot-Zhang J, Soca-Chafre G, Patterson N, Thorner AR, Nag A, Watson J, Genovese G, Rodriguez J, Gelbard MK, Corrales-Rodriguez L, Mitsuishi Y, Ha G, Campbell JD, Oxnard GR, Arrieta O, Cardona AF, Gusev A, Meyerson M. Genetic Ancestry Contributes to Somatic Mutations in Lung Cancers from Admixed Latin American Populations. Cancer Discov. 2021 Mar;11(3):591-598. doi: 10.1158/2159-8290.CD-20-1165. PMID 33268447
• Gerson R, Zatarain-Barron ZL, Blanco C, Arrieta O. Access to lung cancer therapy in the Mexican population: opportunities for reducing inequity within the health system. Salud Publica Mex. 2019 May-Jun;61(3):352-358. doi: 10.21149/10118. PMID 31276352
• Wang Y, McKay JD, Rafnar T, Wang Z, Timofeeva MN, Broderick P, Zong X, Laplana M, Wei Y, Han Y, Lloyd A, Delahaye-Sourdeix M, Chubb D, Gaborieau V, Wheeler W, Chatterjee N, Thorleifsson G, Sulem P, Liu G, Kaaks R, Henrion M, Kinnersley B, Vallee M, LeCalvez-Kelm F, Stevens VL, Gapstur SM, Chen WV, Zaridze D, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, PMID 24880342

Identifiers

NCT: NCT06181812 · (022/056/ICI)(CEI/057/22)

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗