EGFR (epidermal growth factor receptor) is a protein found on the surface of cells that acts as a switch, turning on signals that tell the cell to grow and divide. In normal tissue, EGFR switches on and off in a controlled way. In some lung cancers, a mutation in the EGFR gene permanently locks the switch in the “on” position, driving uncontrolled growth of cancer cells. These EGFR mutations are found in approximately 10–15% of lung cancers in North American and European patients, and in up to 40–50% of lung cancers in East Asian patients. The importance of identifying an EGFR mutation cannot be overstated: it predicts a dramatic response to a class of targeted oral medications called EGFR tyrosine kinase inhibitors (TKIs), which are far more effective — and generally better tolerated — than chemotherapy alone in EGFR-mutated lung cancer. Testing for EGFR mutations is now a mandatory part of the initial workup for all patients with advanced non-small cell lung cancer.
What the test looks for
The EGFR gene encodes the EGFR protein, which sits on the surface of cells and receives growth signals from the surrounding environment. When growth signals arrive, EGFR activates an internal signalling cascade that tells the cell to divide. In normal cells, this process is tightly regulated. In EGFR-mutated lung cancers, genetic changes keep the EGFR protein continuously active — even in the absence of growth signals — driving relentless tumour growth.
Several different types of EGFR mutations have been identified in lung cancer. They are not all equivalent: some predict an excellent response to EGFR-targeted drugs, some predict resistance, and some fall into intermediate or uncertain categories. The most important mutations to understand are:
- Exon 19 deletions. The most common sensitising EGFR mutation accounts for approximately 45% of all EGFR mutations in lung cancer. A small segment of DNA is deleted from exon 19 of the gene, altering the protein’s shape and making it both hyperactive and exquisitely sensitive to EGFR TKI drugs. Patients with exon 19 deletions typically respond very well to EGFR-targeted therapy.
- Exon 21 L858R substitution. The second most common sensitising mutation accounts for approximately 40% of EGFR mutations. A single DNA letter change at position 858 in exon 21 causes a leucine amino acid to be replaced by an arginine, again locking the protein in its active state. Like exon 19 deletions, L858R mutations predict strong responses to EGFR TKIs, though there is some evidence that exon 19 deletions respond slightly better to certain drugs.
- Exon 20 T790M substitution. This mutation at position 790 in exon 20 is the most common mechanism by which EGFR-mutated lung cancers develop resistance to first- and second-generation EGFR TKIs. It is rarely present at diagnosis but emerges in approximately 50–60% of patients whose cancers progress after treatment with an earlier-generation TKI. Third-generation TKIs — particularly osimertinib (Tagrisso) — are specifically designed to overcome T790M resistance and are effective against it.
- Exon 20 insertions. A distinct group of mutations in which extra DNA is inserted into exon 20 of the gene. Unlike exon 19 deletions and L858R, exon 20 insertions are generally resistant to first-, second-, and third-generation EGFR TKIs at standard doses. They are an important exception because patients with these mutations require different treatment approaches. Newer drugs specifically targeting exon 20 insertions — including amivantamab (Rybrevant) and mobocertinib — are approved for this subset.
- Other uncommon mutations (exons 18, 20, and 21). A variety of less common mutations exist in other exons, including G719X (exon 18), S768I (exon 20), and L861Q (exon 21). These “atypical” EGFR mutations are less well characterised. Some respond to second-generation EGFR TKIs such as afatinib (Gilotrif), while others do not. Patients with uncommon EGFR mutations should discuss their specific mutation with their oncologist, as the evidence base for each variant differs.
Why is the test done
- To determine eligibility for EGFR-targeted therapy. EGFR tyrosine kinase inhibitors are highly effective in EGFR-mutated lung cancers but have essentially no activity in EGFR wild-type (unmutated) tumours. Testing identifies which patients will benefit from these drugs.
- To select the most appropriate EGFR TKI. Multiple generations of EGFR TKIs are available — osimertinib (Tagrisso) is currently the preferred first-line agent for exon 19 deletions and L858R, while different drugs are needed for exon 20 insertions and T790M-mediated resistance. Knowing the specific mutation guides the choice of drug.
- To avoid unnecessary chemotherapy. In patients with sensitising EGFR mutations, EGFR TKI therapy is significantly more effective than platinum-based chemotherapy as initial treatment, with a higher response rate, longer time to progression, and a more favourable side-effect profile. Testing ensures these patients receive the most appropriate treatment from the outset.
- To monitor for acquired resistance. When an EGFR-mutated lung cancer progresses after TKI therapy, repeat testing — often using a liquid biopsy — can identify the mechanism of resistance and guide the next line of treatment.
- To provide prognostic information. In general, EGFR-mutated lung cancers have a somewhat more favourable course than EGFR wild-type lung cancers, particularly when appropriately treated with targeted therapy.
Who should be tested
Current guidelines recommend EGFR mutation testing for:
- All patients with advanced or metastatic non-small cell lung cancer (NSCLC) — regardless of histological subtype, though EGFR mutations are most common in adenocarcinoma.
- Patients with resected early-stage lung adenocarcinoma, because osimertinib is approved as adjuvant therapy (treatment after surgery to reduce the risk of recurrence) for patients with stage IB–IIIA EGFR-mutated NSCLC.
- Never-smokers or light smokers with NSCLC, in whom EGFR mutation rates are substantially higher than in heavy smokers.
- Patients being considered for second-line treatment after progression on first- or second-generation EGFR TKI therapy, to test for T790M or other resistance mechanisms.
In practice, most major cancer centres now test all NSCLC patients for EGFR mutations as part of a comprehensive molecular panel at the time of diagnosis, regardless of clinical features.
How the test is performed
EGFR mutation testing can be performed on tumour tissue or on blood (liquid biopsy), and often both are used in complementary ways.
Tissue-based testing
The standard approach uses tumour tissue obtained from a biopsy or surgical specimen. DNA is extracted from the tumour cells and analysed using molecular testing methods — most commonly next-generation sequencing (NGS), which simultaneously assesses EGFR along with dozens or hundreds of other cancer-related genes in a single test. NGS is the preferred approach because it provides comprehensive information on all potentially targetable mutations in a single run, avoiding the need for multiple sequential single-gene tests.
Older methods, such as polymerase chain reaction (PCR)-based assays, are also used and can detect common mutations with high sensitivity, though they assess fewer mutations simultaneously than NGS.
Liquid biopsy
A liquid biopsy tests circulating tumour DNA (ctDNA) shed by cancer cells into the bloodstream. A blood sample is drawn, and the cell-free DNA in the plasma is analysed for EGFR mutations. Liquid biopsy has several advantages: it is non-invasive, can be repeated easily over time to monitor for resistance mutations, and can capture tumour heterogeneity across multiple sites better than a single tissue biopsy. Its main limitation is sensitivity — it may miss mutations present at low levels in the tumour, particularly in early-stage disease or when ctDNA shedding is low. For this reason, a negative liquid biopsy result does not rule out an EGFR mutation; tissue testing should follow if the liquid biopsy is negative and an EGFR mutation is clinically suspected.
Testing at resistance
When a lung cancer that was initially EGFR-mutated progresses after TKI therapy, repeat molecular testing is recommended to identify the resistance mechanism. This is often done with a liquid biopsy as a first step because it is non-invasive and can be performed quickly. If the liquid biopsy is uninformative, a repeat tissue biopsy from a progressing site may be performed.
How results are reported
EGFR mutation results are reported by specifying the mutation type, its location in the gene (exon number), and whether it is a sensitising mutation, a resistance mutation, or a mutation of uncertain significance. A typical report might read:
- “EGFR exon 19 deletion detected” — a sensitising mutation, predicting likely response to EGFR TKI therapy.
- “EGFR p.L858R (exon 21) detected” — a sensitising mutation.
- “EGFR p.T790M (exon 20) detected” — a resistance mutation, most commonly identified at disease progression after first- or second-generation TKI therapy.
- “EGFR exon 20 insertion detected” — a distinct mutation class requiring different treatment.
- “No EGFR mutation detected” / “EGFR wild-type” — no mutation found in the regions tested.
Reports may also note the variant allele frequency (VAF) — the proportion of DNA copies in the sample that carry the mutation. A low VAF on liquid biopsy may indicate a small tumour burden or low ctDNA shedding and should be interpreted in the clinical context.
What each result means
- Exon 19 deletion detected. A sensitising EGFR mutation is present. The cancer is expected to respond well to an EGFR TKI. Osimertinib (Tagrisso) is the current standard first-line treatment for advanced disease, based on the FLAURA trial, which demonstrated superior outcomes compared to earlier-generation TKIs. For early-stage resected disease, adjuvant osimertinib for three years reduces the risk of recurrence.
- L858R (exon 21) detected. A sensitising EGFR mutation is present. Treatment approach is the same as for exon 19 deletions — osimertinib is the preferred first-line agent for advanced disease. Some data suggest that exon 19 deletions may respond slightly better to osimertinib than L858R mutations, but both are strong predictors of benefit from EGFR TKI therapy.
- T790M (exon 20) detected. In the context of prior EGFR TKI therapy and disease progression, this result identifies the most common resistance mechanism to first- and second-generation TKIs. Osimertinib (Tagrisso) was specifically designed to overcome T790M resistance and is the standard treatment at progression in this setting. If osimertinib was already used as first-line therapy and T790M is detected at progression, it indicates ongoing EGFR-driven disease and may prompt consideration of osimertinib continuation combined with other agents — your oncologist will discuss the options.
- Exon 20 insertion detected. This mutation class is generally resistant to standard EGFR TKIs. It requires a different treatment strategy. Amivantamab (Rybrevant) — a bispecific antibody targeting both EGFR and MET — and mobocertinib are approved specifically for exon 20 insertion-positive NSCLC. Clinical trials are ongoing for additional agents. Patients with this result must be managed at a centre with expertise in this specific mutation.
- Uncommon EGFR mutation detected (e.g., G719X, S768I, L861Q). The significance of these atypical mutations is less well established than for the common sensitising mutations. Some — particularly G719X, S768I, and L861Q — have shown responsiveness to second-generation EGFR TKIs such as afatinib. Others may have variable or uncertain sensitivity. Discussion with an oncologist with expertise in thoracic oncology, or access to a molecular tumour board, is recommended.
- No EGFR mutation detected (wild-type). No targetable EGFR mutation was found in the regions tested. EGFR-targeted therapy is not expected to be effective for this cancer. Testing for other actionable mutations — including ALK, ROS1, KRAS, MET, RET, BRAF, NTRK, and others — should be completed (and is typically performed simultaneously as part of a comprehensive NGS panel). The full molecular profile, tumour stage, and PD-L1 expression will guide treatment.
EGFR mutations and other lung cancer biomarkers
EGFR mutations rarely occur together with other major driver mutations such as ALK rearrangements, ROS1 fusions, or KRAS mutations. Each of these mutations typically drives the cancer independently. For this reason, when an EGFR mutation is found, it is generally the primary actionable finding — though comprehensive NGS panels will still report on other genes simultaneously. The exception is co-mutations in tumour suppressor genes (such as TP53) and copy number changes, which can occur alongside EGFR mutations and may influence prognosis or resistance patterns.
PD-L1 expression — a marker used to predict response to immunotherapy drugs called checkpoint inhibitors — is also routinely tested in all NSCLC patients. Immunotherapy alone is generally not the preferred first-line treatment for EGFR-mutated lung cancers, as clinical trials have shown limited benefit from checkpoint inhibitors in this setting and potential for significant toxicity when combined with EGFR TKIs. In EGFR-mutated disease, EGFR-targeted therapy takes priority.
EGFR mutations: germline vs. somatic
Unlike BRCA1 and BRCA2 mutations, EGFR mutations found in lung cancer are almost always somatic — meaning they arose in the lung cancer cells during a person’s lifetime and were not inherited. Germline EGFR mutations are extremely rare and are associated with a hereditary lung cancer predisposition syndrome, but this is not a concern for the vast majority of patients. Patients do not need to worry that their EGFR mutation can be passed to their children, and family members do not require EGFR screening on this basis.
What happens next
- If a sensitising EGFR mutation is found (exon 19 deletion or L858R), your oncologist may recommend EGFR TKI therapy. For advanced disease, osimertinib is currently the standard first-line option. For early-stage resected disease, adjuvant osimertinib will be discussed. Treatment typically begins within a few weeks of diagnosis.
- If an exon 20 insertion is found, your oncologist may discuss options specific to this mutation class that differ from standard EGFR TKI therapy. Referral to a specialist in thoracic oncology or a cancer centre with a molecular tumour board is advisable.
- If T790M is found at progression, Osimertinib (if not already used) is the standard next step. If osimertinib was already the first-line agent, your oncologist will discuss clinical trial options and other strategies.
- If no EGFR mutation is found, the comprehensive molecular panel results will be reviewed in full. Other targetable mutations may be present. If no targetable mutation is identified, treatment will be guided by PD-L1 expression and may include immunotherapy, chemotherapy, or a combination of both.
- During treatment, liquid biopsy testing may be repeated at intervals to monitor for emerging resistance mutations and to guide treatment decisions at progression.
Questions to ask your doctor
- Has my tumour been tested for EGFR mutations? If so, what was the result?
- Which specific EGFR mutation was found — an exon 19 deletion, L858R, exon 20 insertion, or something else?
- Which EGFR-targeted drug is recommended for my specific mutation, and why?
- How is osimertinib taken, and what side effects should I expect?
- If my EGFR test was performed via liquid biopsy and was negative, should tissue testing also be performed?
- What other biomarkers are being tested alongside EGFR?
- If my cancer progresses on EGFR-targeted therapy, what are the next steps, and will retesting be done?
- Is immunotherapy a treatment option for me, given that I have an EGFR mutation?
- Are there clinical trials I should know about based on my EGFR mutation?
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