Rising importance of BRAF in NSCLC

BRAF mutation in NSCLC

1) BRAF mutation in NSCLC

Well-mutation in NSCLC is EGFR(For more information about EGFR in NSCLC visit here). On the other hand, BRAF mutations are detected in approximately 2% to 4% of lung cancer, hence occurring at a lower frequency than EGFR mutations (10–15%) and probably in a slightly smaller subpopulation than ALK rearrangements (3–5%). These mutations have been predominantly diagnosed in the adenocarcinoma histological subtype, without obvious ethnicity or gender predominance. Additionally, BRAF V600E mutations are mostly mutually exclusive with most druggable abnormalities present in this tumor. BRAF V600E mutations account for 50% of these cases, and the remaining BRAF mutations are non-V600E. [1, 2, 3]

2) Why is BRAF mutation important for NSCLC?

When we look through the statistical data of NSCLC patients, we can find out that the proportion of BRAF mutation as a driver mutation is not that high. In the below graph, BRAF takes only 7.2%(early stage) and 5.5%(metastatic stage).(figure2) As opposed to BRAF, KRAS takes 29.1%(early stage) and 29.9%(metastatic stage), and EGFR takes 14.2%(early stage) and 30.3%(metastatic stage). [5]

Nevertheless, BRAF is one of the most important mutation genes in NSCLC. We can guess the reason through the NCCN guide. According to the NCCN guide, broader molecular profiling is recommended with the goal of identifying mutations that have effective drugs that may already be available. [6] For BRAF, several drugs were already developed to cure melanoma, and there were several clinical trials to confirm the effectiveness of these drugs on NSCLC. 

For example, Vemurafenib was developed to cure melanoma. With low toxicity and rapid response, it rapidly entered the clinical trials stage and received FDA approval in 2011. [7] After its approval, several studies proceeded to confirm the efficacy of vemurafenib on other cancers like colorectal cancer, NSCLC, and thyroid cancer. One of these studies found that vemurafenib monotherapy is effective for the treatment of NSCLC patients with BRAF V600 mutations and claimed that a routine biomarker screening for NSCLC patients should include the BRAF V600 mutations. [8]

In this research, 118 NSCLC patients (101 patients with BRAF V600 mutations and 17 with BRAF non-V600 mutations) with BRAF mutations were proposed vemurafenib 960 mg twice daily. This study was conducted between October 2014 and July 2018, and the result was impressive. In the BRAF non-V600 cohort, no objective response was observed. However, in the BRAF V600 cohort, more than half of the patients showed an objective response. The success rate was 44.9% (95% confidence interval 35.2%~54.8%), and the median duration was 6.4 months. Moreover, the median PFS(Progression Free Survival) was 5.2% months (95% CI 3.8~6.8), and OS was ten months. The injection of Vemurafenib improved most of the evaluation indexes. [8]

Owe to these amazing results, NCCN specified that the molecular testing of BRAF should be carried out for NSCLC patients. Through this point, we can guess that the proportion of mutation genes is not a big deal. Whether it can be treated by a specific mutation gene inhibitor is a real matter to doctors. As long as BRAF inhibitors are effective for NSCLC patients, they will be treated as an important mutation gene.

3) Important mutation of BRAF

The most important mutations of BRAF are BRAF V600 mutations. According to the two key studies, BRAF mutation can be categorized into three classes. Classification standard is based on important biochemical and signaling aspects. 1) Kinase activity, 2) Ras-dependency, and 3) Dimerization status. The below table is the classification of prevalent BRAF mutants. [9]

Among them, Class 1 BRAF mutations consist of BRAF V600 mutations and carry a high percentage of total BRAF mutations (44.9%). Generally, mutation takes a high rate as long as it places on the core domain of the gene. Each domain usually takes an important role in the gene function.

Typically, BRAF V600E mutation is found on the activation segment that has kinase activity. Due to this mutation occurring in the main domain, BRAF V600 mutations are the most commonly found in human tumors. Not only that, but it also occupies a high rate of melanoma thyroid, histiocytosis, colorectal cancer, and other cancers. [9] This is the main reason that BRAF V600 mutations are treated importantly.

REFERENCE

[1] BRAF-Mutated Non-Small Cell Lung Cancer : Current Treatment Status and Future Perspective. Front. Oncol., 2022, 12: 863043

[2] Clinical development of BRAF plus MEK inhibitor combinations. CellPress Rev. Trends in Cancer, 2020, 6(9): 797-810

[3] BRAF Alterations as Therapeutic Targets in Non–Small-Cell Lung Cancer, Jour. of Thoracic Oncol. 2015. 10(10): 1396-1403

[4] Precision Cancer Medicines & Immunotherapy for Lung Cancer, CancerConnect News, 2021

[5] Skoulidis, F., & Heymach, J. V. (2019). Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nature reviews. Cancer, 19(9), 495–509.

https://doi.org/10.1038/s41568-019-0179-8

[6] NCCN Guidelines Version3.2022 Non-Small Cell Lung Cancer

[7] Kim, A., & Cohen, M. S. (2016). The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma. Expert opinion on drug discovery, 11(9), 907–916. https://doi.org/10.1080/17460441.2016.1201057

[8] Mazieres, J., Cropet, C., Montané, L., Barlesi, F., Souquet, P. J., Quantin, X., Dubos-Arvis, C., Otto, J., Favier, L., Avrillon, V., Cadranel, J., Moro-Sibilot, D., Monnet, I., Westeel, V., Le Treut, J., Brain, E., Trédaniel, J., Jaffro, M., Collot, S., Ferretti, G. R., … Blay, J. Y. (2020). Vemurafenib in non-small-cell lung cancer patients with BRAFV600 and BRAFnonV600 mutations. Annals of oncology : official journal of the European Society for Medical Oncology, 31(2), 289–294. https://doi.org/10.1016/j.annonc.2019.10.022

[9] Dankner, M., Rose, A., Rajkumar, S., Siegel, P. M., & Watson, I. R. (2018). Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations. Oncogene, 37(24), 3183–3199. https://doi.org/10.1038/s41388-018-0171-x