Results: Patient with lung cancer (non-small cell) – somatic (tumour) BRAF variant identified

A 68-year-old female smoker is diagnosed with metastatic lung cancer (non-small cell). Somatic testing via a multi-target next-generation sequencing panel reveals a BRAF V600E variant.

The BRAF gene

• Activating mutations of the BRAF tyrosine kinase gene occur in around 1%–3% of lung cancer (non-small cell) cases, with a preponderance for adenocarcinoma.
• Mutations are grouped into three classes, contingent upon their effect on kinase activity:
  • class 1 mutations result in autonomous kinase activity;
  • class 2 are kinase-activating dimers; and
  • class 3 are kinase-inactivating heterodimers.
• The majority (50%–60%) of mutations occur at the V600 position, the vast majority of which are V600E (a class 1 mutation).
• Non-V600 mutations are functionally heterogenous. Examples of recurrent BRAF variants in lung cancer (non-small cell) include G469A (increased kinase activity) and D594G (impaired kinase activity) variants.

Clinical characteristics

• There is an increased frequency of BRAF mutations in tumours of affected women.
• Most patients with non-V600 mutations are smokers. The percentage of smokers is less in the V600E cohort.
• A number of studies have reported a lack of chemo-sensitivity and worse prognosis in patients with a BRAF V6000E mutation treated with platinum chemotherapy.

BRAF V600E mutations

• BRAF V600E mutations render tumours sensitive to inhibition of BRAF +- MEK.
• In England, the combination of dabrafenib and trametinib is currently available via the Cancer Drugs Fund as a treatment option for BRAF-positive metastatic lung cancer (non-small cell) instead of chemotherapy to reduce risk of immunosuppression as an interim measure during the Covid-19 pandemic, although this treatment regimen has not been formally approved by NICE.

Non-V600 mutations

• These are a heterogenous group.
• Differing effects on the kinase activity of BRAF means that these patients may not benefit from BRAF +- MEK inhibition. They were not included in many trials investigating BRAF +- MEK inhibitors.
• These patients may be eligible for clinical trials.

For clinicians

• ESMO: Consensus guidelines for treatment of advanced lung cancer (2020) – includes recommendations for molecular testing and treatment (PDF, 71 pages)
• NHS England: National Genomic Test Directory and eligibility criteria
• NICE: Guidance relevant to lung cancer – many guidelines related to treatments following somatic (tumour) molecular testing
• NICE: NHS England interim treatment options during the COVID-19 pandemic
• NICE: Pathways for lung cancer – see advanced non-squamous (stages IIIB and IV) non-small-cell lung cancer: ALK-positive

References:

• Noeparast A, Teugels E, Giron P and others. ‘Non-V600 BRAF mutations recurrently found in lung cancer predict sensitivity to the combination of Trametinib and Dabrafenib‘. Oncotarget 2016: volume 8, issue 36, pages 60,094–60,108. DOI: 10.18632/oncotarget.11635
• Planchard D, Smit EF, Groen HJM and others. ‘Dabrafenib plus trametinib in patients with previously untreated BRAF V600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial‘. The Lancet Oncology 2017: volume 18, pages 1,307–1,316. DOI: 10.1016/S1470-2045(17)30679-4

For patients

• American Lung Association: BRAF and lung cancer