• What is ERBB2?
  • ERBB2 in Lung Cancer
  • HER2 Exon 20 Insertion
  • Clinical Trials

HER2 (ERBB2)

HER2 belongs to a family of receptor tyrosine kinases (RTKs) that includes EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB4. The gene for HER2 is located on chromosome 17 and has been found to be amplified with an increased copy number in several cancers (Jorgensen 2010). Amplification of HER2 has been found to promote tumorigenesis and to be involved in the pathogenesis of several human cancers (Moasser 2007).

To date, no ligand has been identified for HER2. However, HER2 appears to be the preferential dimerization partner for all members of the ERBB family (Graus-Porta et al. 1997). The binding of ligand followed by HER2 hetero-dimerization results in activation of HER2 tyrosine kinase activity. Activated HER2 then phosphorylates its substrates, leading to 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).

her2.png

Figure 1.
Schematic of HER2 signaling pathway. Growth factor binding results HER2 heterodimerization and 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., Chanjuan Shi, M.D., Ph.D., Graham T. Watson, M.D., Leora Horn, M.D., M.Sc., Paula Pohlmann, M.D., Ph.D., Laura W. Goff, M.D.

Suggested Citation: Lovly, C., C. Shi, G. Watson, L. Horn, P. Pohlmann, L. Goff. 2015. HER2 (ERBB2). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/erbb2/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

HER2 (ERBB2) in Non-Small Cell Lung Cancer (NSCLC)

HER2 mutations are detected in approximately 2–4% of NSCLC (Buttitta et al. 2006; Shigematsu et al. 2005; Stephens et al. 2004). The most common mutation is an in-frame insertion within exon 20. HER2 mutations appear to be found more commonly in never smokers (defined as less than 100 cigarettes in a patient's lifetime) with adenocarcinoma histology (Buttitta et al. 2006; Shigematsu et al. 2005; Stephens et al. 2004). However, HER2 mutations can also be found in other subsets of NSCLC, including in former and current smokers as well as in other histologies (Buttitta et al. 2006; Shigematsu et al. 2005; Stephens et al. 2004). The exon 20 insertion results in increased HER2 kinase activity and enhanced signaling through downstream pathways, resulting in increased survival, invasiveness, and tumorigenicity (Wang et al. 2006).

HER2 amplification does not appear to coincide with HER2 mutation (Buttitta et al. 2006; Stephens et al. 2004). Unlike in breast cancer, there is currently no role for HER2 amplification as a prognostic or predictive marker in NSCLC.

In the vast majority of cases, HER2 mutations are non-overlapping with other oncogenic mutations found in NSCLC (e.g., EGFR mutations, ALK rearrangements, etc.).

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. HER2 (ERBB2) in Non-Small Cell Lung Cancer (NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/erbb2/ (Updated June 18).

Last Updated: June 18, 2015

HER2 (ERBB2) Exon 20 Insertion in Non-Small Cell Lung Cancer

Properties
Location of mutation Kinase domain (exon 20)
Frequency of HER2 mutations in NSCLC 2–4% (Arcila et al. 2012; Buttitta et al. 2006; Shigematsu et al. 2005; Stephens et al. 2004)
Frequency of HER2 exon 20 insertion mutations in HER2-mutated NSCLC 83–100% (Arcila et al. 2012; Buttitta et al. 2006; Shigematsu et al. 2005; Stephens et al. 2004)
Implications for Targeted Therapeutics
Response to HER2 TKIs Unknown at this timea
Response to anti-HER2 antibodies Unknown at this timeb
Response to EGFR TKIs Unknown at this timec
Response to anti-EGFR antibodies Unknown​ at this time​

HER2 exon 20 insertions occur within exon 20, which encodes part of the kinase domain. This mutation occurs with a frequency of approximately 2–4% of all NSCLC (Arcila et al. 2012; Buttitta et al. 2006; Shigematsu et al. 2005; Stephens et al. 2004). In cohorts of EGFR/KRAS/ALK-negative NSCLC specimens, the frequency of HER2 mutations is 6% (Arcila et al. 2012).

a In a phase I study, 2 out of 6 evaluable patients with NSCLC harboring HER2 Exon 20 insertion mutations demonstrated a partial response when treated with the HER2 inhibitor neratinib in combination with the mTOR inhibitor temsirolimus (Gandhi et al. 2014). In a small phase II trial, 3 of 3 patients with heavily pretreated advanced NSCLC all with documented HER2 exon 20 mutations each had a partial response to afatinib treatment (De Greve et al. 2012​). In a retrospective analysis of patients with NSCLC harboring HER2 exon 20 mutations, 4 patients treated with afatinib monotherapy experienced a 100% disease control rate. The two patient cohorts in these two studies of afatinib did not overlap. ​In contrast, 2 patients treated with lapatinib monotherapy did not demonstrate a response (Mazières et al. 2013).

b Several studies have failed to show any significant benefit to adding trastuzumab to traditional cytotoxic chemotherapy in unselected patient populations (Gatzemeier et al. 2004; Langer et al. 2004). By contrast, trastuzumab, a humanized monoclonal antibody against HER2, may be effective against HER2-mutated lung cancers. For example, cell lines containing a HER2 exon 20 insertion are sensitive to trastuzumab (Wang et al. 2006). There is a case report of a patient whose lung adenocarcinoma harbored a HER2 exon 20 mutation (G776L) that responded to trastuzumab given with weekly paclitaxel (Cappuzzo, Bemis, and Varella-Garcia 2006). Furthermore, in a retrospective analysis, 15 NSCLC patients with HER2 exon 20 mutations treated with trastuzumab in combination with chemotherapy demonstrated a 96% disease control rate (Mazières et al. 2013).

c Preclinical data suggests that the presence of this mutation is associated with primary resistance to the first generation EGFR TKIs, erlotinib and gefitinib (Wang et al. 2006). However, cells expressing the HER2 exon 20 mutation are sensitive to the irreversible dual EGFR and HER2 TKIs neratinib and afatinib (Li et al. 2008; Shimamura et al. 2006).

It should also be noted that HER2 mutations are usually found in tumors wild type for EGFR, ALK, and other driver mutations.

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

Suggested Citation: Lovly, C., L. Horn, O. Gautschi, W. Pao. 2015. HER2 (ERBB2) Exon 20 Insertion in Non-Small Cell Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/erbb2/65/ (Updated June 18).

Last Updated: June 18, 2015

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