|Year : 2021 | Volume
| Issue : 2 | Page : 110-111
BRAF Mutations and Resistance of Non-Small Cell Lung Cancer to BRAF-Targeted Therapies Using Liquid Biopsy
Ming Li1, Xiaoying Zhang2
1 Department of Nursing, Zhangqiu People's Hospital of Jinan City, Jinan, China
2 Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, China
|Date of Submission||06-Oct-2020|
|Date of Acceptance||18-Nov-2020|
|Date of Web Publication||29-Jan-2021|
MD Xiaoying Zhang
Department of Geriatrics, Qilu Hospital of Shandong University, Jinan
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Li M, Zhang X. BRAF Mutations and Resistance of Non-Small Cell Lung Cancer to BRAF-Targeted Therapies Using Liquid Biopsy. Asia Pac J Oncol Nurs 2021;8:110-1
|How to cite this URL:|
Li M, Zhang X. BRAF Mutations and Resistance of Non-Small Cell Lung Cancer to BRAF-Targeted Therapies Using Liquid Biopsy. Asia Pac J Oncol Nurs [serial online] 2021 [cited 2021 Oct 19];8:110-1. Available from: https://www.apjon.org/text.asp?2021/8/2/110/308303
Lung cancer is the most frequently diagnosed and fatal cancer worldwide. The 5-year overall survival rate of patients with any type of lung cancer in developing countries, including the Chinese mainland, is markedly lower than that of patients with other leading cancers. Non-small cell lung cancer (NSCLC) is the main subtype of lung cancer and accounts for approximately 80%–85% of all lung cancers. BRAF is one of the most important genes implicated in NSCLC. The mutations that activate BRAF can activate constitutive kinases and thereby trigger downstream signaling pathways related to cancer cell proliferation. Approximately 2%–3% of patients with NSCLC develop BRAF-activating mutations. In these patients, the response rates (RRs) to BRAF inhibitor monotherapy were 33%–42%., The co-administration of BRAF inhibitor and trametinib increases the RR to 64%. Therefore, both the U.S. Food and Drug Administration and European Medicines Agency have approved the combination therapy of BRAF inhibitor and trametinib for the treatment of BRAF-mutant metastatic NSCLC. Although BRAF inhibitors have achieved encouraging therapeutic effects, they are effective only temporarily as almost all patients develop resistance to the treatment within a few months., Many molecular mechanisms of drug resistance in cancer cells have been discovered, including changes in drug transporter expression, influences of tumor microenvironment, and pathological transition., Moreover, the resistance mechanisms of BRAF-targeted therapy in patients with NSCLC are poorly understood; this restricts the development and application of related targeted therapeutic strategies.
Currently, liquid biopsy has been extensively used in cancers to detect cancer mutations, monitor therapeutic responses, detect cancer recurrences, predict patient outcomes, and identify drug resistance mechanisms., Indeed, cancer mutations detected in the plasma have been used to determine the potential molecular mechanisms of drug resistance of metastatic NSCLC., In a recent prospective study, Ortiz-Cuaran et al. assessed the clinical utility of circulating tumor DNA-targeted sequencing in identifying BRAF mutations and BRAF-targeted therapy resistance-associated genomic alterations in patients with advanced BRAF-mutant NSCLC.
In this study, we enrolled 78 patients with BRAF-mutant metastatic NSCLC from 27 centers in France. A total of 208 blood samples were collected from the participants, including 47 (22.6%) from patients who had never undergone BRAF-targeted therapy, 115 (55.3%) from those under treatment and without disease progression, and 46 (22.1%) from those with disease progression while receiving BRAF-targeted therapy. The circulating tumor DNA isolated from the blood samples was examined by InVisionFirst®-Lung assay. The potential effects of the circulating tumor DNA alterations were predicted by in silico structural modeling. Moreover, BRAF V600E mutation was found in the circulating tumor DNAs from 35 (74.5%) patients with NSCLC who also had never undergone BRAF-targeted therapy. The BRAF mutation was determined to be associated with the signal transducers and protein kinases of MAPK and/or PI3K signaling pathways in 10 (29%) samples. In addition, BRAF mutations in the circulating tumor DNA detected during disease progression and at the first radiographic evaluation under treatment were associated with poor overall survival. Furthermore, we identified resistance-associated driver genomic alterations to either BRAF-targeted monotherapy or BRAF/MEK combination targeted therapy in 46% of patients. These resistance-associated genomic alterations included mutations that activate MAPK and PI3K signaling pathway effectors and alterations in genes such as IDH1, U2AF1, and CTNNB1.
The present study findings revealed that circulating tumor DNA-targeted sequencing is an accurate and efficient method in identifying BRAF-activating mutations upon diagnosis, monitoring patient response upon receipt of BRAF-targeted therapy, and identifying the molecular mechanisms of BRAF-targeted therapy resistance in patients with BRAF-mutant NSCLC. Moreover, consistent with previous findings, the resistance mechanism critical in BRAF-targeted monotherapy or BRAF/MEK combination targeted therapy implicates MAPK signaling pathway reactivation. This study has several limitations. First, the heterogeneity of blood sample collection and treatment regimens might have influenced the data interpretation of survival analyses. Second, the patient cohort with resistance to BRAF-targeted therapy was relatively small. Therefore, a larger prospective patient cohort is necessary to validate the observations of this study. Third, the DNA samples from the white blood cells of the enrolled patients were not sequenced; thus, potential false-positive mutations caused by clonal hematopoiesis cannot be ruled out. Fourth, we did not characterize in vitro and in vivo the potential resistance effectors found in patients with NSCLC who also received BRAF-targeted therapy and did not provide suggestions or methods in overcoming challenges in therapy resistance. Despite these limitations, this study provides useful information that would help oncologists understand the pathophysiology of BRAF-mutant NSCLC and promote the development of successful BRAF-targeted therapeutic strategies for patients with BRAF-mutant NSCLC.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Miller KD, Fidler-Benaoudia M, Keegan TH, Hipp HS, Jemal A, Siegel RL, et al.
Cancer statistics for adolescents and young adults, 2020. CA Cancer J Clin 2020;70:443-59.
Feng RM, Zong YN, Cao SM, Xu RH. Current cancer situation in china: Good or bad news from the 2018 global cancer statistics? Cancer Commun (Lond) 2019;39:22.
Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83:584-94.
Paik PK, Arcila ME, Fara M, Sima CS, Miller VA, Kris MG, et al.
Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol 2011;29:2046-51.
Barlesi F, Mazieres J, Merlio JP, Debieuvre D, Mosser J, Lena H, et al.
Routine molecular profiling of patients with advanced non-small-cell lung cancer: Results of a 1-year nationwide programme of the french cooperative thoracic intergroup (IFCT). Lancet 2016;387:1415-26.
Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, et al.
Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 2015;373:726-36.
Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, et al.
Dabrafenib in patients with BRAF (V600E)-positive advanced non-small-cell lung cancer: A single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol 2016;17:642-50.
Planchard D, Smit EF, Groen HJ, Mazieres J, Besse B, Helland A, et al
. Dabrafenib plus trametinib in patients with previously untreated BRAF (V600E)-mutant metastatic non-small-cell lung cancer: An open-label, phase 2 trial. Lancet Oncol 2017;18:1307-16.
Chen Y, Tang WY, Tong X, Ji H. Pathological transition as the arising mechanism for drug resistance in lung cancer. Cancer Commun (Lond) 2019;39:53.
Kartal-Yandim M, Adan-Gokbulut A, Baran Y. Molecular mechanisms of drug resistance and its reversal in cancer. Crit Rev Biotechnol 2016;36:716-26.
Zhang J, Tian C, Lv F, Wang J, Han W, Nie J, et al.
Molecular analysis of cell-free DNA identifies distinct molecular features in patients with chemosensitive and chemorefractory small cell lung cancer. Cancer Commun (Lond) 2019;39:20.
Shen L. Liquid biopsy: A powerful tool to monitor trastuzumab resistance in HER2-positive metastatic gastric cancer. Cancer Commun (Lond) 2018;38:72.
Guibert N, Hu Y, Feeney N, Kuang Y, Plagnol V, Jones G, et al.
Amplicon-based next-generation sequencing of plasma cell-free DNA for detection of driver and resistance mutations in advanced non-small cell lung cancer. Ann Oncol 2018;29:1049-55.
Remon J, Caramella C, Jovelet C, Lacroix L, Lawson A, Smalley S, et al.
Osimertinib benefit in EGFR-mutant NSCLC patients with T790M-mutation detected by circulating tumour DNA. Ann Oncol 2017;28:784-90.
Ortiz-Cuaran S, Mezquita L, Swalduz A, Aldea M, Mazieres J, Leonce C, et al
. Circulating tumor DNA genomics reveals potential mechanisms of resistance to BRAF-targeted therapies in BRAF-mutant metastatic non-small cell lung cancer patients. Clin Cancer Res 2020;26:6242-53.