Molecular testing in lung cancer

See ((Targeted therapy for NSCLC))

It is important to test patients with newly diagnosed advanced NSCLC for potentially significant molecular abnormalities prior to the initiation of treatment.

Testing with next-generation sequencing.

Biomarkers are important in the management of NSCLC and should be tested in all patients with metastatic disease as standard of care.

The most frequently altered genes in NSCLC are EGFR,10 to 35%, KRAS 25 to 30%, FGR 20%, ALK 3 to 7%, Met 2 to 4%, BRAF 1 to  percent, ros1 1 to 3%, and RET 1 to 3%.

Guidelines recommend patients must be tested for oncogenic drivers-EGFR alterations, ALK rearrangements, ROS1 gene rearrangement, BRAF V600E point mutations and NCR gene fusions and PD-L1 tumor expression level.

RET, MET exon 14 skipping, KRAS G12C, Microsatellite instability alterations and tumor mutation burden are additional assessments.

Management of NSCLC is dependent on the specific histologic subtype.

For example, pemetrexed and bevacizumab are not indicated for patients with squamous cell carcinoma.

Immunotherapy is unlikely to be effective in patients with anaplastic lymphoma, kinase translocation, ROS1 fusion, or a MET mutation.

Patients  with high PD-L1 expression should receive immunotherapy.

Necitumumab appears to be useful in squamous cell lung cancer.

The most common abnormalities seen in lung adenocarcinoma are KRAS mutations.

Therapies that target EGFR, ALK, and ROS1 rearrangements have increased progression-free survival (PFS) in patients with these mutations, with much less toxicity, compared with cytotoxic chemotherapy.

EGFR- epidermal growth factor receptor.

ALK- Anaplastic lymphoma kinase

ROS1- Proto-oncogene receptor tyrosine kinase 1.

NTRK – neurotropic receptor tyrosine kinase gene fusion.

Of the targetable abnormalities, activating mutations in the EGFR gene are the most common, followed by ALK translocations.

EGFR mutations are found in approximately 20% of patients with advanced NSCLC.

EGFR mutations in NSCLC is located primarily in the tyrosine kinase domaine at exons 18 to 21, with exon 19 deletions and exon 21L848R mutations representing the majority of EGFR mutations.

Exon 19 deletions and L858R in EGFR are the most common variants with sensitivity to EGFR-TKIs.

Resistant mutations include T790M and Exon 20 insertions.

The two most common mutations are EGFR L858R and EGFR exon 19 deletion.

EGFR signaling pathways influence angiogenesis in the activation and regulation of cellular proliferation.

EGFR up regulation due to kinase activating mutations or increased EGFR expression results in powerful protooncogenic functions causing uncontrolled proliferation and expansion of mutated tumor cells.

Patients with EGFR mutations are treated with EGFR tyrosine kinase inhibitors including:gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib.

In stage IIa -III a NSCLC completely resected, epidermal growth factor receptor sensitizing mutations, had a disease free survival rate that was dramatically higher with the use of adjuvant osimertinib than the placebo group: osimertinib is approved for a adjuvant therapy and patients with EGFR exon 19 deletions or exon 21L858 R mutations.

All patients with lung adenocarcinoma and all never/light smokers, regardless of histology, should be tested for molecular abnormalities.

people who have never smoked how much more likely to have EGFR mutations and ALK translocations than those who did who do smoke.

All patients, especially those whose tumors do not harbor EGFR mutations or ALK translocations, should be tested for programmed death ligand 1 expression

Clinical trials comparing specific epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors vs chemotherapy in the first-line setting in patients whose tumors harbor the respective mutations: none of the studies have shown an overall survival benefit with targeted agents, but they all uniformly show an increase in response rates, as well as improved PFS, compared with cytotoxic chemotherapy.

Molecularly targeted agents are better tolerated.

In a phase I study of ROS1-rearranged NSCLC, treatment with crizotinib showed an objective response rate of 72% and produced a median PFS of 19.2 months.

Similarly, the BRF113928 study of patients with BRAF V600E mutation positive metastatic NSCLC using a combination of dabrafenib and trametinib and resulted in a greater than 60% response rate patients in patients with metastatic lung cancer whose tumors harbor these driver mutations.

Among patients with NSCLC, MET exon 14 skipping mutations occur in 3 to 4% of patients, and MET amplifications occur in 1-6%.

MET exon 14 skipping mutations typically occurs in the absence of other driver mutations and is associated with poor prognosis.

Capmatinib, a selective inhibitor of the MET receptor, and shows activity in the MET exon 14 skipping mutation advanced non-small cell lung cancer.

liquid bio or less sensitive than solid tumor, biopsies for molecular testing.

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