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TESTING FOR EGFR EXON 20 INSERTION MUTATIONS IN NSCLC

The clinical management of non-small cell lung cancer (NSCLC) is tailored based on pathologic findings, clinical staging, and molecular profiling[1]


The European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network’s (NCCN) clinical guidelines recommend the use of molecular testing both at the initial diagnosis of NSCLC and once patients progress or relapse on therapy, to detect the presence of molecular biomarkers.[2][3] This can be conducted on samples obtained by tissue biopsy or minimally invasive blood testing.[2][3]

Discover how different molecular biomarkers are used to guide treatment and fight NSCLC.

EGFR mutation status is tested for in most European countries to help guide treatment[2]

EGFR testing recommendations appear in the European and U.S. guidelines:[2][3]

According to the ESMO guidelines

"EGFR testing should ensure that all mutations of exons 18 to 21 are assessed, including at a minimum the most common activating mutations (exon 19 deletion and exon 21 L858R point mutation)."[2]

Guidelines recommend routine testing for EGFR exon 20 insertion mutations, to help guide treatment[2][3][4][5]

The ESMO, German Leitlinien Programm Onkologie, Italian Association of Medical Oncology (AIOM), and NCCN clinical guidelines recommend routine testing for EGFR exon 20 insertion mutations – detection of these mutations can help guide treatment[2][3][4][5]

EGFR exon 20 insertion (ex20ins) mutations are generally resistant to currently approved EGFR-TKIs – so if these mutations are detected, chemotherapies are often prescribed as a first-line therapy.[6][7][8]

Discover how EGFR mutation status can inform clinical decision-making and help to fight cancer.

There are two main ways to identify EGFR mutations[2][3]

  1. The polymerase chain reaction (PCR)
  2. Next-generation sequencing (NGS)

PCR-based diagnostics have a limited ability to diagnose EGFR exon 20 insertion mutations

PCR (single-gene testing) is typically performed sequentially in order to identify only the most common genetic alterations.[9]However, these assays are limited in their ability to detect molecularly heterogenous mutations, including EGFR ex20ins mutations.[10][11][12]

They can also be time-consuming and require a relatively large tissue sample, which isn’t always available.[9] If only one single-gene test is ordered on a biopsy sample, the average success rate of reporting mutational status is 88%.[13] However, this success rate drops significantly with subsequent tests due to tissue exhaustion.[13] By the fifth recommended test (the current ESMO guidelines recommend testing for alterations in EGFR, ALK, ROS1, and BRAF as a minimum), success rates drop to 67% – which could mean a greater number of re-biopsies, adding to patient discomfort.[9][13]

NGS is a valuable method to detect the presence of NSCLC biomarkers, including EGFR exon 20 insertion mutations[9][10]

According to the ESMO clinical guidelines:

“Multiplex, massively parallel so-called NGS of various sorts is rapidly being adopted as the standard approach to screening adenocarcinomas for oncogenic targets.”[2]

Additionally, NGS is reliable and capable of testing simultaneously for multiple alterations, using a single tissue sample.[9]

NGS is a sensitive diagnostic tool, able to simultaneously test thousands of genes without prior sequence knowledge, whilst using only a single tissue sample.[9][14][15][16] This makes NGS a valuable tool to identify molecularly heterogenous sequence alterations, including the vast array of EGFR ex20ins mutations found in NSCLC.[10]

Additionally, NGS approaches are associated with shorter time-to-test results than exclusionary/sequential testing with PCR – so can help to reduce wait times for you and your patients.[9]

So far, 102 unique EGFR ex20ins mutation variants have been identified using NGS – each of which varies in size and/or genomic positioning.[10][11][12] Unfortunately, a large proportion of known EGFR ex20ins mutations are not identifiable via PCR.[10][11][12]

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48,6

In fact, one study showed that 48.6% of EGFR ex20ins mutations identified via NGS are missed by PCR[10]

Out of the 17 most common EGFR ex20ins mutation variants, only 4 can be identified via PCR.[10]

For every two EGFR exon 20 insertion mutations detected by NGS, PCR misses one.[10]

NGS diagnostics make EGFR exon 20 insertion mutations easier to spot, by capturing the full breadth of currently identified variants[17]

NGS strategies are rapidly being adopted as the standard approach to screening for oncogenic targets.[2]In fact, an analysis of the EGFR sequencing technology used to identify EGFR ex20ins mutations between 2011 and 2019 in the US revealed that PCR testing rates decreased from 85.7% to 11.3%, and NGS testing rates increased from 0% to 62.3%.[17] This shift in testing technology is associated with increased detection rates of EGFR ex20ins mutations in NSCLC.[17]

EGFR exon 20 insertion mutation detection rates among EGFR mutated NSCLC[17]

graph

Adapted from Lin et al. 2021[17]

Get a comprehensive molecular profile of your patient’s tumour and identify all possible EGFR exon 20 insertion mutations using NGS.[10][12]

Discover more about EGFR exon 20 insertion mutations and NSCLC here:

How can molecular biomarkers help us fight NSCLC?
What impact do EGFR ex20ins mutations have on lives?
Who do EGFR ex20ins mutations strike?

ALK, anaplastic lymphoma kinase; BRAF, v-Raf murine sarcoma viral oncogene homologue B; EGFR, epidermal growth factor receptor; ESMO, European Society for Medical Oncology; NCCN, National Comprehensive Cancer Network; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; PCR, polymerase chain reaction; ROS1; ROS proto-oncogene 1, receptor tyrosine kinase; TKI, tyrosine kinase inhibitor.