Efectividad, eficiencia y seguridad de la biopsia líquida para el diagnóstico, adecuación del tratamiento, pronóstico y seguimiento del cáncer de pulmón.
Authors: Aguilera-Cobos Lorena , García-Sanz Patricia , Rosario-Lozano Maria Piedad , Blasco-Amaro Juan Antonio 
Published: October 2024

Introduction Cancer is one of the leading causes of morbidity and mortality worldwide, and its extent is reflected by the large number of new cases estimated in the coming decades, reaching 30.2 million patients each year by 2040. The most frequent cancers are breast and lung cancer. In Spain, cancer is also a significant cause of morbidity and mortality, as shown by the 276 239 cases diagnosed in 2021. Among these, the most common cancers are the colon, rectum, prostate, breast, lung, and urinary bladder. The diagnosis and treatment of lung cancer involve tumor characterization, which has traditionally been performed by tissue biopsy (BT) obtained through surgery, fine needele aspiration (FNAB), or core needle biopsy (CNB). However, getting a representative and good-quality sample through these techniques has certain drawbacks, and, in addition, the heterogeneity of the tumor itself can result in false negatives. As an alternative, liquid biopsy (LB) is a less invasive technique performed on blood or other body fluid samples to look for cancer cells or biomolecules released by them. BL has the advantage of improving early tumor detection and follow-up. This potential for improvement and the less invasive nature of the test justifies the need to evaluate LB for its use in the diagnosis, therapeutic appropriateness, prognosis, and follow-up of lung cancer. Objective The main objective of this report is to evaluate the effectiveness, safety, and efficiency of BL concerning the diagnosis, therapeutic appropriateness, prognosis, and follow-up of lung cancer. Methods The methodology of this report is based on a central systematic review (SR) limited to SRs, the results of which were supplemented for some biomarkers and appropriate care purposes with a SR of clinical trials, which allowed disagregated meta-analyses (MA) for these biomarkers. First, a literature search was conducted, including databases: Medline, Embase, Cochrane Library, INAHTA, WOS, CINAHL, and PubMed, as well as TripDataBase and websites of health technology assessment agencies. The search was limited to SR and MA. The filtering process was documented in a flowchart according to the PRISMA statement guidelines and peer-reviewed using the Covidence reference manager. After filtering, the quality of the included studies was assessed with the AMSTAR-II tool, and data were extracted for the summary of findings table that captured the main variables. Secondly, a new complementary literature search was performed for those biomarkers and care purposes where it was possible to compare studies to perform a MA. Specifically, two new searches were performed: one focused on KRAS, BRAF, and ALK limited by date to 2019 and another on EGFR limited by date to 2020. The quality of new clinical trials (CT) was assessed with QUADAS-II. Results In the first search, 63 SRs were included (out of a total of 1463 peer-reviewed studies) corresponding to three therapeutic purposes: 47 SRs for diagnosis, 13 SRs for prognosis, and 12 SRs for treatment appropriateness (some of the included SRs address more than one care purpose). The main omics alterations analysed in the SRs included were: alterations in methylation patterns, alterations in ctDNA expression, lncRNA, CTC detection, ctDNA quantification, NGS analysis of point mutations, alterations in miRNA expression, and analysis of exosome content. Enough evidence was only found to perform an MA (according to the pre-established criteria) on biomarkers that consisted of the detection of mutations in KRAS, BRAF, ALK, or EGFR in ctDNA or CTC DNA in BL, the purpose of which was/is the appropriateness of treatment for the NSCLC cancer type. A second complementary literature search of CE for these biomarkers was performed to expand the data extracted from these biomarkers and perform a higher-quality MA. The search for KRAS, ALK, and BRAF yielded 1329 CEs, and for EGFR yielded 1588 CEs, and after following the same pairwise filtering process as for SRs, 8 new CT for KRAS, ALK, and BRAF and 16 new CT for EGFR were included. Conclusions One of the main conclusions of the exhaustive study carried out in this report is that the analysis of lung cancer biomarkers in LB should be approached in a disaggregated manner, considering factors such as the biomolecule analysed, the type of biological sample and possible alterations in the analysis process or technique used. According to care purposes, the conclusions of this study indicate that, for lung cancer diagnosis, the biomarkers analysed in BL have a high specificity but a low sensitivity, with BT being the reference test. Regarding lung cancer prognosis, further studies are needed to establish the prognostic capacity of biomarkers in both BT and BL samples. On the other hand, mutations in EGFR, KRAS, BRAF, and ALK genes obtained in BL for the adequacy of lung cancer treatment show high concordance with those obtained in BT, with specificity being higher than sensitivity. Furthermore, it is noteworthy that patients who had not received chemotherapy or tyrosine kinase inhibitor (TKI) treatment had significantly higher concordance for EGFR mutations than those who had.