• What is EGFR?
  • EGFR in Lung Cancer
  • EGFR Status Unknown
  • 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).

 

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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

EGFR Status Unknown in Non-Small Cell Lung cancer

Properties
Location of mutation N/A
Frequency of EGFR mutations in NSCLC ~10% in the USA
~35% in Asia
(Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004)
Implications for Targeted Therapeutics
Response to EGFR TKIs Uncertain
Response to anti-EGFR antibodies Currently no role for EGFR mutation in predicting response in NSCLC

Erlotinib was approved for use in the second/third-line setting for NSCLC with unknown EGFR status (also known as unselected NSCLC), based upon a 2-month survival benefit vs. placebo (Shepherd et al. 2005). 10-28% of NSCLCs tested have an EGFR mutation (COSMIC​; Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004). 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 patients with wild type EGFR NSCLC, patients treated with docetaxel experienced higher response rates and longer overall survival (Garassino et al. 2013).


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)
Sandler et al. 2006 Phase II/III 1st carboplatin / paclitaxel with bevacizumab EGFR status unknown 417 35% 6.2 12.3a
carboplatin / paclitaxel EGFR status unknown 433 15% 4.5 10.3a
Shepherd et al. 2005 Phase III 2nd / 3rd erlotinib (Tarceva) EGFR status unknown 488 8.9% 2.2 6.7
Thatcher et al. 2005 Phase III 2nd / 3rd gefitinib (Iressa) EGFR status unknown 1129 8.0% 3.0 5.6
Schiller et al. 2002 Phase III 1st 4 different regimens EGFR status unknown 1207 19% 3.7 8.0

NOTES: PFS = progression-free survival; Pts = patients; OS = overall survival; “EGFR status unknown” means that tumors were not tested for EGFR mutations. a Non-squamous NSCLC.

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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. 2014. EGFR Status Unknown in Non-Small Cell Lung cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/egfr/313/ (Updated June 19).

Last Updated: June 19, 2014

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