• What is EGFR?
  • EGFR in Lung Cancer
  • EGFR No Mutation Detected
  • Clinical Trials

EGFR

Epidermal growth factor receptor (EGFR) belongs to a family of receptor tyrosine kinases (RTKs) that include EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB4. The binding of ligands, such as epidermal growth factor (EGF), induces a conformational change that facilitates receptor homo- or heterodimer formation, thereby resulting in activation of EGFR tyrosine kinase activity. Activated EGFR then phosphorylates its substrates, resulting in activation of multiple downstream pathways within the cell, including the PI3K-AKT-mTOR pathway, which is involved in cell survival, and the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation (Figure 1).

mapk-pk13.png

Figure 1.
Schematic of EGFR signaling pathway. Growth factor binding to EGFR results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. EGFR. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/egfr/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

EGFR in Non-Small Cell Lung Cancer (NSCLC)

Approximately 10% of patients with NSCLC in the US and 35% in East Asia have tumor associated EGFR mutations (Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004). These mutations occur within EGFR exons 18–21, which encodes a portion of the EGFR kinase domain (Figure 1). EGFR mutations are usually heterozygous, with the mutant allele also showing gene amplification (Soh et al. 2009). Approximately 90% of these mutations are exon 19 deletions or exon 21 L858R point mutations (Ladanyi and Pao 2008​). These mutations increase the kinase activity of EGFR, leading to hyperactivation of downstream pro-survival signaling pathways (Sordella et al. 2004).

Regardless of ethnicity, EGFR mutations are more often found in tumors from female never smokers (defined as less than 100 cigarettes in a patient's lifetime) with adenocarcinoma histology (Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004). However, EGFR mutations can also be found in other subsets of NSCLC, including in former and current smokers as well as in other histologies.

In the vast majority of cases, EGFR mutations are non-overlapping with other oncogenic mutations found in NSCLC (e.g., KRAS mutations, ALK rearrangements, etc.).

egfr-nsclc.png

Figure 1.
Schematic of EGFR mutations. Exons 18–21 of the EGFR kinase domain are depicted. Mutations above the schematic are associated with sensitivity to EGFR TKIs. Mutations listed below the schematic are associated with EGFR TKI resistance. 
NOTE: a While most exon 20 insertions are associated with decreased EGFR TKI sensitivity, the EGFR A763_Y764insFQEA mutation is an exception and has been associated in retrospective studies with increased EGFR TKI sensitivity (Yasuda et al. 2013).

 

​​​​

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. EGFR in Non-Small Cell Lung Cancer (NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/egfr/ (Updated June 18).

Last Updated: June 18, 2015

No EGFR Mutation Detected in Non-Small Cell Lung Cancer

Properties
Location of mutation N/A
Frequency of no EGFR mutation detected in NSCLC 72–90% (COSMIC; Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004)
Implications for Targeted Therapeutics
Response to EGFR TKIs Confers decreased sensitivity
Response to anti-EGFR antibodies Currently no role for EGFR mutation in predicting response in NSCLC

Approximately 72–90% of NSCLCs tested have no EGFR mutation detected (COSMIC; Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004). Importantly, however, the likelihood of finding a mutation in EGFR depends on the specific testing method used on the tumor sample. For example, a test for a single mutation (e.g., L858R) will miss all variants except one; alternately, whole genome sequencing will capture most variants present. See Types of Molecular Tumor Testing for more information.

Of note, EGFR “no mutation detected” means that tumors were tested for one or more EGFR mutations and none were detected. EGFR with no mutation detected is sometimes referred to as EGFR “wild type.” However, these two nomenclatures do not necessarily refer to the same thing. Strictly speaking, the EGFR mutation status should be qualified based on the testing method used. For example, if the testing only included sequencing of EGFR exons 19 and 21 (the location of the two most common EGFR mutations) and no mutation is detected, then the EGFR mutation status for that tumor is “wild type at exons 19 and 21.”

Compared to lung cancers with EGFR activating mutations, tumors with no mutation detected in EGFR are less sensitive to the EGFR TKIs, erlotinib (Tarceva) and gefitinib (Iressa; Mok et al. 2009). In a phase III study comparing the EGFR TKI erlotinib to docetaxel in NSCLC patients with no mutations detected in EGFR, patients treated with docetaxel experienced higher response rates and longer overall survival (Garassino et al. 2013). However, erlotinib was approved for use in the second/third-line setting for unselected NSCLC (in other words, NSCLC where EGFR status is unknown), based upon a 2-month survival benefit vs. placebo (Shepherd et al. 2005).

Table 1. Clinical Trial Summary.​​​​​

Reference Study Type / Phase Line of Treatment Treatment Agent Mutation Status # Pts in Study Response Rate PFS (Months) OS (Months)
Janne et al. 2012 Phase II 1st erlotinib (Tarceva) No EGFR mutation detected 48 8% 2.8 15.4
carboplatin / paclitaxel with erlotinib No EGFR mutation detected 57 31% 4.8 13.7
Mok et al. 2009 Phase III 1st gefitinib (Iressa) No EGFR mutation detected 91 1% 1.5  
carboplatin / paclitaxel No EGFR mutation detected 85 24% 5.5  
Garassino et al. 2013 Phase III (TAILOR) 2nd erlotinib (Tarceva) No EGFR mutation detected 112 3% 2.4 5.4
docetaxel No EGFR mutation detected 110 15.5% 2.9 8.2

NOTES: PFS = progression-free survival; Pts = patients; OS = overall survival; “No EGFR mutation detected” means that tumors were tested for one or more EGFR mutations.

​​​​​​​

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. No EGFR Mutation Detected in Non-Small Cell Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/egfr/79/ (Updated October 15).

Last Updated: October 15, 2015

My Cancer Genome has released its new and improved cancer clinical trials search tool on our beta website. Please visit beta.padiracinnovation.org to check it out!

Disclaimer: The information presented at padiracinnovation.org is compiled from sources believed to be reliable. Extensive efforts have been made to make this information as accurate and as up-to-date as possible. However, the accuracy and completeness of this information cannot be guaranteed. Despite our best efforts, this information may contain typographical errors and omissions. The contents are to be used only as a guide, and health care providers should employ sound clinical judgment in interpreting this information for individual patient care.