BRAF mutation-positive lung cancer

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OVERVIEW

肺癌患者的鼠类肉瘤病毒癌基因同源物B1（BRAF）基因突变阳性
各种因素引起的BRAF基因突变
除可针对性应用BRAF抑制剂治疗外，总体上与其他类型肺癌大致相同
BRAF突变阳性肺癌恶性程度高，易发生转移，且治疗手段有限，预后较差

Definition

  • BRAF mutation-positive lung cancer is a molecular typing of lung cancer, and the significance of the typing is to guide clinical diagnostic and therapeutic decisions.
  • BRAF is an abbreviation for a gene located on chromosome 7q34, known in Chinese as V-RAF mouse sarcoma virus oncogene homolog B1.
  • BRAF is a member of the RAF kinase family and plays a key role in cell growth, proliferation and differentiation through the mitogen-activated protein kinase (MAPK) pathway.
  • In addition to mutations in the BRAF gene, missense mutations, deletions, and a number of BRAF fusions known as “unknown function mutations” have been identified.
  • Although the proportion of BRAF mutations in non-small cell lung cancer (NSCLC) is relatively low, patients with mutations are prone to metastasis, have a poor prognosis, and have limited therapeutic options. With the continuous development of targeted therapy, the prognosis of advanced patients can be improved, but the side effects are obvious and drug resistance is inevitable.

    • Classification

    BRAF mutations are classified into the following three categories based on signaling mechanism and kinase activity:

    Kinase-activated monomers with V600E mutations (Class I)

  • Includes BRAF V600 D/E/K/R/M mutations, of which BRAF V600E mutations are the most predominant, accounting for approximately 50% of all BRAF mutation cases.
  • Most common in solid tumors, these mutations result in strong activation of BRAF kinase activity and constitutive activation of the MAPK pathway, independent of the RAS, which is inhibited through a negative feedback loop triggered by ERK activation.

    • Kinase-activated dimers (class II)

  • Includes L597Q/R, G464V/A, G469A/V/R/S, K601E/N/T, E451Q, A712T, and fusion.
  • Classified as high or medium kinase activity based on MAPK pathway activation, these mutants signal as constitutively active dimers. RAS-independent and resistant to RAF inhibitors.

    • Kinase-inactivating heterodimers (class III)

    Including G469E, G466V/E/A, N581S/I, D594G/N, and G596R, etc., with low or absent kinase activity. These mutants are RAS-dependent and sensitive to ERK-feedback-dependent RAS, and activate ERK by enhancing its binding to RAS, and require molecular coexistence to activate RAS in tumors to be effective.

    Because V600E mutations account for about 50% of BRAF mutations, the other types are collectively referred to as non-V600E mutations, and this article focuses on BRAF V600E mutations.

    Incidence

  • BRAF mutation is a rare mutation in lung cancer, which mainly occurs in patients with the histologic type of adenocarcinoma, and the prevalence in non-small cell lung cancer (NSCLC) ranges from 1.5% to 3.5% [3].
  • The most common mutation in BRAF is a valine-to-glutamate amino acid substitution (V600E) at codon 600, and V600E mutations account for approximately 50% of all BRAF mutation cases [2].
  • BRAF V600E mutations have been reported to be more common in female patients and are not associated with a history of smoking, whereas non-V600E mutations are more likely to be found in men with a history of smoking [5].
  • Globally, BRAF mutations are predominant in men (61%) and smokers (81%), with variable differences between mutation categories [6].

    • Diagnosis

    BRAF mutation-positive lung cancers are all tested for BRAF mutations based on the diagnosis of lung cancer, and the results of genetic testing do not affect clinical staging.

    Diagnostic basis

    The diagnosis of BRAF mutation-positive lung cancer is a further diagnosis based on the diagnosis of lung cancer.

    For more information about the diagnosis of lung cancer, please refer to the Lung Cancer article, which only introduces the diagnostic basis of “BRAF mutation-positive”.

    Recommendations for testing

    Patients with advanced NSCLC should be evaluated for the presence or absence of driver mutations in their tumors, which can be determined by technical methods to guide treatment. It is recommended that all patients with advanced NSCLC, particularly those with invasive adenocarcinoma of the lung (or NSCLC with an adenocarcinoma component) who are to receive targeted therapy, should routinely undergo genetic testing at the time of diagnosis.

    Detection Methods

    There are several methods for detecting BRAF gene mutations in NSCLC, but no gold standard has been established.

    Existing diagnostic-related technologies include Sanger sequencing, fluorescence in situ hybridization (FISH), immunohistochemistry, next-generation sequencing (NGS), and reverse transcription-PCR (RT-PCR).

    Sanger测序
  • Advantage: Can directly read a given DNA sequence and identify new mutation sites.
  • Disadvantage: Higher requirements on the content and proportion of tumor cells in the sample, not suitable for small biopsies or cytology specimens.
    • FISH
  • Advantage: A variety of samples can be used, such as tissue samples, cytology samples, etc., and the sample size requirement is low, so it is the “gold standard” for genetic translocation detection. High throughput (number of genes and types of variants), high sensitivity and specificity, but related to the coverage of the product probe design and bioinformatic analysis capability.
  • Disadvantages: poor cost performance, false negatives for rare variant types. Longer testing period, usually 3 to 5 working days.
    • 免疫组化
  • Advantage: Short testing cycle, lower cost.
  • Disadvantages: only single test, low sensitivity and specificity.
    • NGS

    Next-generation sequencing (NGS) is more relevant to optimizing treatment by revealing the mutational profile of each NSCLC.

  • Advantage: Multiple samples are available, such as tissue, cytology, and body fluids. High-throughput detection (number of genes and types of variants), high sensitivity and specificity, but related to product probe design coverage and bioinformatic analysis capability.
  • Disadvantages: High sample quality requirement, long testing cycle, usually more than 7 working days.
    • RT－PCR
  • Advantage: simple operation, high sensitivity.
  • Disadvantages: Higher cost, unable to detect unknown fusion type, high requirement for RNA quality.

    • Differential diagnosis

    BRAF mutation-positive lung cancer is the final diagnosis and does not need to be differentiated from other diseases.

    Treatment

  • Aim of treatment: to maximize the control of tumor progression, prolong the survival time of patients, and improve the quality of life of patients.
  • Treatment principle: The treatment of BRAF mutation-positive lung cancer should adopt the principle of combining multidisciplinary comprehensive treatment (MDT) and individualized treatment. That is to say, according to the patient’s physical condition, the pathological and histological type and molecular typing of the tumor, the extent of invasion and development tendency, the MDT mode should be adopted, and surgery, radiotherapy, chemotherapy, molecular targeting therapy and immunotherapy should be applied in a planned and reasonable way.

    • Special Reminder

  • The treatment of BRAF mutation-positive lung cancer is generally the same as that of other types of lung cancer, but the difference is the treatment of BRAF target, i.e., the application of BRAF inhibitors. The following content is only for general reference, please consult with professional oncologists for the specific treatment plan, and follow the doctor’s instruction strictly, and don’t purchase and use drugs on your own.
  • The diversity and functional heterogeneity of BRAF mutations have hindered the development of therapeutic strategies for BRAF non-V600E mutant lung cancer, and there is still a lack of effective targeted therapeutic options. Several studies have shown that ICI therapy may be a superior option to targeted therapy.

    • 【Tips】For more information about the overall treatment of lung cancer, please refer to read Lung Cancer

    Related drugs

    Vemurafenib (Vemurafenib)

    Vemurafenib is a potent inhibitor of the BRAF mutation family [5].

    适用情形

    It is used in patients with NSCLC in the presence of BRAF-positive mutations.

    不良反应

    The most common side effects are arthralgia, rash, nausea, photosensitivity, fatigue, pruritus, dulled palmoplantar sensation and squamous cell carcinoma of the skin.

    治疗效果

    In a study of vimofenib for BRAF V600E-positive NSCLC, the objective remission rate (ORR) in 19 patients was 42%, progression-free survival (PFS) was 7.3 months, and median overall survival (OS) has not yet been reached, but the preliminary annual overall survival rate was 66% [1].

    Darafenib (Dabrafenib).

    适用情形

    is used in patients with NSCLC in the presence of BRAF-positive mutations.

    不良反应

    The most common treatment-related adverse events include skin toxicity such as rash and keratosis pilaris, gastrointestinal reactions such as nausea, vomiting, and diarrhea, as well as fever, fatigue, and alopecia, which are generally tolerated by patients.

    治疗效果

    It has been shown that dabrafenib in treated NSCLC patients with the BRAF V600E mutation achieved an ORR of 32% and a disease control rate (DCR) of 56% [1].

    Clinical trials

    In addition to dabrafenib and vemofenib, which are more studied, other BRAF-selective inhibitors are still in clinical trials.

    Darafenib in combination with trametinib

    The results of a study [10] showed that dabrafenib plus trametinib had better antitumor activity and a manageable safety profile in previously untreated patients with BRAF V600E-mutated NSCLC.

    Encorafenib

    A phase I dose-escalation trial of Encorafenib (LGX818) and MEK162 in combination for the treatment of solid tumors with BRAF V600E mutations showed a favorable safety profile.

    Treatment Options

    An appropriate treatment regimen needs to be selected based on the patient’s clinical stage.

    In general, patients with stage I to III, even if they are positive for BRAF mutation, are not recommended to be treated immediately with relevant targeted agents, please refer to read the treatment section of stage I lung cancer, stage II lung cancer and stage III lung cancer for specific treatment.

    The treatment regimen for stage IV patients is as follows, please strictly follow the doctor’s instructions [11].

    First-line treatment of stage IV NSCLC with BRAF V600E mutation

  • In the guidelines, the general recommendations refer to the first-line treatment of stage IV driver gene-negative NSCLC.
  • The secondary recommendation is only to use dabrafenib in combination with trametinib.

    • Backline treatment of NSCLC with stage IV BRAF V600E mutation

    Targeted therapy or a backline treatment strategy with reference to stage IV driver-negative NSCLC is available.

    Prognosis

    The overall prognosis of BRAF mutation-positive lung cancer is roughly the same as that of other types of lung cancer, and is related to a variety of factors, including tumor stage, staging, biochemical indexes, and the patient’s physical health.

    Cure

    BRAF mutation-positive lung cancer is currently incurable, and statistics such as the 5-year survival rate can generally be used to assess a patient’s survival.

    Survival of BRAF mutation-positive lung cancer

    Overall, treated BRAF mutation-positive lung cancer patients show significant improvement in overall survival, and with the availability of related drugs, patients may be able to achieve even longer survival.

    One study showed that in patients with BRAF V600E mutation-positive NSCLC, the overall remission rate (ORR) after treatment with dabrafenib in combination with trametinib was above 60%, and the progression-free survival (PFS) was more than 10 months in all of them [4].

    Overall survival in lung cancer

    Survival of lung cancer patients can generally be evaluated in terms of 5-year survival rate and depends largely on the clinical stage and pathological type of the tumor at the time of disease detection.

    The study comprehensively analyzed the results of several larger-scale statistics from 2000 to 2012, which showed that the 5-year survival rates of non-small cell lung cancer and small cell lung cancer at various stages in China were as follows.

    非小细胞肺癌
    Stage 5-year survival rateStage I 75%Stage I75%Stage II 55%
    小细胞肺癌
    Stage II55%Stage III 20Stage III20%

    Stage IV 5%

  • Stage IV
  • 5%

    • Staged 5-year survival rate

    Stage I 45%

    Stage I

    45%

  • Stage II 25%
  • Stage II
  • 25%
  • Stage III 8%
  • Stage III

    • 8%

    Stage IV 3

    Stage IV

    3%

    Special Reminder

  • The overall survival time of lung cancer patients can be roughly predicted by the 5-year survival rate (the proportion of patients whose tumors survive for more than 5 years after various comprehensive treatments), and the probability of recurrence after 5 years is very low.
  • Statistics such as 5-year survival rate and median survival period are only used for clinical research and do not represent the specific survival period of an individual. The individual survival period of a lung cancer patient needs to be determined by combining various factors, and it is recommended to consult the physician consulted.
  • Prognostic factors
  • Prognostic factors are factors that have an impact on the overall survival and quality of life of patients.
  • There are no independent prognostic factors for BRAF mutation-positive lung cancer, but prognostic factors common to malignant tumors also influence the prognosis of patients with this disease.

    • These factors mainly include the degree of malignancy of the tumor, the stage of the tumor, lymph node metastasis, treatment, and personal constitution.

    Patients with low tumor malignancy have a better prognosis than those with high tumor malignancy.

  • In tumor staging, patients belonging to the early clinical stage have a better prognosis than those in the middle or late clinical stage.
  • Patients with no lymph node metastasis have a better prognosis than those with lymph node metastasis.
  • Patients with early regular treatment have better prognosis than those with late treatment; patients with good treatment effect have better prognosis than those with poor treatment effect.
  • Patients with good personal health have a better prognosis than those with poor health.
  • Daily
  • Daily considerations for BRAF mutation-positive lung cancer are no different from those for other types of lung cancer.

    • Just because lung cancer has been treated with surgery, radiotherapy or chemotherapy does not mean that one can let down one’s guard. Active and strict daily management can help the patient to better beat the cancer.

    Daily Management

  • Mindset and Emotions
  • Good emotions and mindset cannot be replaced by drugs.
  • After diagnosis, patients may develop a sense of fear. They may be afraid of pain, abandonment and death. With the encouragement and help from doctors, family and friends, patients need to get rid of the fear as soon as possible, face up to the disease, actively follow the doctor’s instructions, and have an optimistic attitude towards the prognosis.

    • Family members should pay attention to listening to the patient’s heart, improve the patient’s psychological tolerance and relieve anxiety symptoms.

    It is recommended that the patient’s family give support so that the patient can face the surgery and other treatments positively with a good mindset.

    During and after treatment, family members are advised to encourage the patient to do work and household chores that are within his/her ability to reintegrate into his/her social role.

    Healthy lifestyle

    For lung cancer patients, a healthy lifestyle can reduce recurrence and lower the risk of death.

    Ensure sleep: Patients should rest more and ensure enough sleep.

  • Maintain a healthy diet: Eat a diet rich in vegetables, fruits and whole grains, reduce the intake of excessive sugar, fatty foods, and red and processed meats, and minimize alcohol intake.
  • Maintain a healthy weight: Be appropriately active, such as slow walking, tai chi, qigong and breathing exercises, and avoid crowded places.

    • Take sun protection measures: Consider using physical barriers against the sun whenever possible, such as wearing hats, shirts with sleeves, and avoiding direct sunlight during midday.

    Use supplements with caution: Get your nutrition from food sources and do not rely on supplements. Routine intake of nutraceuticals is not recommended for cancer control.

    Prevent infection: Maintain good oral hygiene and treat any oral diseases promptly. Pay attention to fresh air in the environment and avoid going to public places or being close to people with upper respiratory tract infections.

    Avoid risk factors

    Lung cancer patients should avoid exposure to risk factors related to the development of lung cancer.

    Strictly quit smoking and stay away from second-hand smoke.

    Avoid living or working in an environment full of dust, smoke and chemical irritants.

    Avoid or reduce going out in smoggy weather. If you need to go out, you should wear an anti-haze mask.

    Disease monitoring

    Patients and family members should pay close attention to the symptoms caused by ALK inhibitor-related toxicity, and seek medical treatment promptly if there is any discomfort.

    Follow-up examination

    Regular review is required after lung cancer treatment. The purpose of review is to monitor the efficacy of treatment and to detect tumor recurrence and metastasis at an early stage. The examination is mainly based on imaging tests, such as chest CT, abdominal CT or ultrasound.

    Content of review

  • Since most of the BRAF mutation-positive lung cancer patients belong to the middle and late stages, the specific review plan and items need to strictly follow the doctor’s instructions.
  • In general, it is recommended to review once every 3 to 6 months, or as prescribed by the doctor.
  • Review programs may include chest and abdominal CT, bone scan and PET-CT.
  • Special Reminders
  • If symptoms such as severe cough, chest pain, hemoptysis, or other discomforts such as progressive fatigue occur during the follow-up period, you should return to the hospital for follow-up.
  • Prevention
  • BRAF mutation-positive lung cancer is only one molecular subtype of lung cancer, and lung cancer is the most common lung malignancy, so accurately speaking, the prevention of lung cancer in the general population should be the prevention of all lung malignancies.
  • Cancer prevention is mainly about reducing the risk of developing cancer. It can be broadly divided into daily prevention and regular screening.
  • Daily prevention means reducing or avoiding the risk factors of lung cancer and increasing the protective factors of lung cancer.

    • Regular screening means that the general population should do regular medical checkups, and high-risk groups are recommended to consult a specialized doctor and follow the doctor’s instructions for lung cancer screening.

    Causes

    The cause of lung cancer is still not completely clear, and may be related to genetic abnormalities and a combination of internal and external environmental cancer-causing factors.

  • The exact cause of why BRAF mutations occur in lung cancer is even less clear. Possible related factors found so far include age, smoking history, histologic factors, and so on.
  • Causative factors

    • It is currently believed that the development of lung cancer is related to smoking and passive smoking, occupational exposure, air pollution, radiological factors, genetic factors, and other factors (e.g., tuberculosis, chronic obstructive pulmonary disease, tuberculosis, idiopathic pulmonary fibrosis, scleroderma, etc.).

    Related Pathogenesis

    The BRAF gene is a member of the serine/threonine protein kinase (RAF) family and an important effector molecule of the mitogen-activated protein kinase (MAPK) signaling pathway.

    Activation of rat sarcoma (RAS) protein by the MAPK signaling pathway interacts with the accelerated fibrosarcoma (RAF) protein family (ARAF, BRAF, and CRAF), which in turn activates MAPK/ERK kinases.

    Activated ERK affects the regulation of cell growth, differentiation and proliferation by phosphorylating numerous important substrates that regulate the cell cycle, creating a cascading waterfall effect.

    Mutations in the BRAF gene are the most common mutations in the MAPK signaling pathway downstream of RAS.

    About 90% of BRAF gene mutations occur in exon 15 at the 1799th nucleotide site, where thymine is mutated to adenine in the 600th codon, replacing the originally encoded valine with glutamate, i.e., the BRAFV600E mutation.

    The occurrence of this mutation leads to RAS-independent activation of BRAF, which stimulates sustained activation of the MAPK signaling pathway, ultimately leading to tumorigenesis.

    The BRAF gene is an important effector molecule of the mitogen-activated protein kinase (MAPK) signaling pathway that produces BRAF protein. Normally, the BRAF protein is activated by another protein (RAS protein) before it can function and affect the regulation of cell growth, differentiation and proliferation.

    Mutations in the BRAF gene are the most common mutations in the MAPK signaling pathway. Mutations in the gene result in the production of proteins with different compositions, and some of these mutations affect the function of the proteins, causing uncontrolled cell proliferation and ultimately leading to the development of tumors.

    For example, the common BRAFV600E mutation is due to the mutation of thymine to adenine within the 600th codon, which replaces the originally encoded valine with glutamate, resulting in a sustained cell growth-promoting effect of BRAF that is not dependent on RAS activation.

    Symptoms

    症状清单

    Symptoms of BRAF mutation-positive lung cancer are not significantly different from those of other types of lung cancer, and it is not possible to determine whether or not it is a BRAF mutation-positive lung cancer by its symptoms.

  • Main symptoms
  • Generally, BRAF mutation-positive lung cancer is found in the middle or late stage, so the symptoms mainly show the symptoms of tumor invasion or metastasis, such as pleural effusion, hoarseness, phrenic nerve paralysis, dysphagia, etc. In addition, there are also symptoms caused by the primary tumor.
  • There may also be symptoms caused by the primary tumor, such as cough, hemoptysis, dyspnea and so on.
  • Seek medical attention
    • 病史清单
  • There is no significant difference between the medical consultation for BRAF mutation-positive lung cancer and other types of lung cancer.
  • Department of Medicine
  • Medical Oncology
  • When a diagnosis of BRAF mutation-positive lung cancer is confirmed, it is recommended to seek further professional advice from the Department of Medical Oncology.
    • 检查清单

    Thoracic Surgery

  • Patients who are suitable for surgery may visit the Department of Thoracic Surgery.
  • Preparation for medical treatment
  • Preparation for consultation: registration, preparation of documents, frequently asked questions
    • 用药清单

    Tips for your visit

    Patients may need to undergo a chest X-ray or CT examination, so please avoid wearing clothing with metal zippers or buttons, sequins, etc.

    参考文献
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    Roviello G, D’Angelo A, Sirico M,et al. Advances in anti-BRAF therapies for lung cancer. Invest New Drugs. 2021 Jun;39(3):879-890.
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    郏博, 吕超, 常建华, 等. 非小细胞肺癌非常见突变靶向治疗研究进展 [J] . 中华医学杂志, 2022, 102(13) : 969-976.
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    Mazieres J, Cropet C, et al. Vemurafenib in non-small-cell lung cancer patients with BRAFV600 and BRAFnonV600 mutations. Ann Oncol. 2020 Feb;31(2):289-294.
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    Roviello G, D’Angelo A, Sirico M, et al. Advances in anti-BRAF therapies for lung cancer. Invest New Drugs. 2021 Jun;39(3):879-890.
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    [9]
    Planchard D, Besse B, Groen HJM,et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016 Jul;17(7):984-993.
    [10]
    Planchard D, Smit EF, Groen HJM,et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017 Oct;18(10):1307-1316.
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    中国临床肿瘤学会指南工作委员会.中国临床肿瘤学会（CSCO）非小细胞肺癌诊疗指南2022[M]. 北京：人民卫生出版社，2022.