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Table of Contents
REVIEW ARTICLE - BIOMARKER SERIES
Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 97-104

A narrative review of ERBB2 in non-small cell lung carcinoma


1 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Center, New Delhi, India
2 Department of Pathology (Molecular Diagnostics), Rajiv Gandhi Cancer Institute and Research Center, New Delhi, India

Date of Submission31-Dec-2021
Date of Decision01-Mar-2022
Date of Acceptance02-Mar-2022
Date of Web Publication31-Mar-2022

Correspondence Address:
Ullas Batra
Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Center, Sector 5, Rohini, Sir Chhotu Ram Marg, New Delhi - 110 085
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_323_21

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  Abstract 


The plethora of biomarkers and the availability of targeted treatment have revolutionized the therapeutic profile of non-small cell lung cancer (NSCLC). Erythroblastic oncogene B (ERBB2) has been reported in 1%–4% cases of lung adenocarcinoma and recognized as a prognostic marker in a myriad of cancers like pancreatic, gastric, and breast carcinomas. It is more commonly recognized as human epidermal growth factor receptor 2 (HER2). Molecular characterization of NSCLC based on the mechanism of HER2 activation, including mutation, amplification, and overexpression, has recently been widely adopted owing to the differences in prognosis and predictive outcomes. This narrative review of ERBB2 is intended to describe the molecular biology, historical perspective, clinical profile, and therapeutic options for HER2-activated NSCLC. For the purpose of this review, we performed a comprehensive and detailed search in PubMed, Scopus, and My Cancer Genome databases using the keywords “HER2/neu,” “HER2,” “NSCLC,” “pertuzumab,” “trastuzumab,” and “T-DM1.” A total of 59 articles were included in the review.

Keywords: HER2, HER2/neu, NSCLC, pertuzumab, T-DM1, trastuzumab


How to cite this article:
Sharma M, Dewan A, Diwan H, Nathany S, Batra U. A narrative review of ERBB2 in non-small cell lung carcinoma. Cancer Res Stat Treat 2022;5:97-104

How to cite this URL:
Sharma M, Dewan A, Diwan H, Nathany S, Batra U. A narrative review of ERBB2 in non-small cell lung carcinoma. Cancer Res Stat Treat [serial online] 2022 [cited 2022 May 21];5:97-104. Available from: https://www.crstonline.com/text.asp?2022/5/1/97/341255




  Introduction Top


Identification of driver oncogenic alterations in genes like epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS1, which are amenable to targeted therapies, has led to improved prognosis and better survival of patients with non-small cell lung carcinoma (NSCLC). With the advent of next-generation sequencing (NGS) and recognition of many driver and targetable mutations in genes like erythroblastic oncogene B (ERBB2), rearranged during transfection (RET), MET, BRAF, and NTRK, the therapeutic landscape of NSCLC has changed drastically. Although alterations in these genes are observed in a small fraction of NSCLC cases, the availability of targeted therapy for these alterations renders testing for them essential.

Alterations in human epidermal growth factor receptor 2 (HER2) have been documented in 4% cases of lung adenocarcinoma by The Cancer Genome Atlas (TCGA)[1] and in 3% cases by the Lung Cancer Mutation Consortium (LCMC) project.[2] HER2 is located on the long arm of chromosome 17 and encodes the HER2 protein, which is activated by heterodimerization with other members of the EGFR tyrosine kinase family, leading to intracellular phosphorylation of the tyrosine residue. HER2 alterations lead to constitutive activation of the downstream signaling cascade. HER2 has long been identified as a predictive biomarker with successful targeted therapy in breast, gallbladder, stomach, and pancreatic carcinomas. HER2-mutant NSCLCs have a poor prognosis and respond poorly to chemoradiation. Moreover, HER2 mutations have emerged as a resistance mechanism to tyrosine kinase inhibitors in EGFR-mutant NSCLC.

This review is focused on the molecular biology, oncogenesis, epidemiology, detection methods, and treatment options for HER2-mutant NSCLC.


  Methods Top


This is a narrative review, and therefore, systematic analysis or meta-analysis was not performed. We did not devise any specific inclusion/exclusion criteria for the selection of articles. A Preferred Reporting Items for Systemic Reviews and Meta-analysis (PRISMA) diagram was, therefore, not prepared. The PubMed, EMBASE, Scopus, and My Cancer Genome databases were searched using the keywords “HER2/neu,” “HER2,” “NSCLC,” “pertuzumab,” “trastuzumab,” and “T-DM1.” A total of 59 articles were included in the review.


  Historical Perspective Top


The HER2 saga began in 1982–1984 in the laboratory of Robert Weinberg with the recognition of the neu clone, like EGFR, when DNA from tumors induced by carcinogens was transfected into normal fibroblasts.[3] The collaborative efforts of the Massachusetts Institute of Technology, Rockefeller University, and Harvard University resulted in the identification of the human ortholog of neu called HER2. The putative oncogenic role of neu was first demonstrated in carcinogen-induced neuroblastoma.[4] HER2 amplification was henceforth observed in 20%–25% of invasive breast carcinomas.[5]


  Molecular Biology Top


HER2, also known as ERBB2, belongs to the EGFR tyrosine kinase family, which comprises four proteins: EGFR (ERBB1, HER1), ERBB2 (HER2, neu in rodents), ERBB3 (HER3), and ERBB4 (HER4).[6],[7],[8],[9] All of them are transmembrane proteins with similar structures and consist of extracellular, transmembrane, and intracellular domains,[10] as depicted in [Figure 1]. ERBB2 is peculiar in being ligandless, but heterodimerizes with other member proteins.[9],[10],[11] The extracellular domain of ERBB2 is made of leucine-rich repeats 1 (L1), leucine-rich repeats 2 (L2), cysteine-rich 1 (CR1), and cysteine-rich 2 (CR2) domains. As ERBB2 does not undergo ligand binding, the extracellular domain is secured in an extended conformation to assure interaction with other members of the EGFR tyrosine kinase family, as reported by various crystallographic studies.[9],[10],[11],[12],[13]
Figure 1: Structure of ERBB2 (HER2). HER2 is a transmembrane protein comprising the following: 1. Extracellular domain consisting of two leucine-rich domains (L1 and L2) and two cysteine-rich domains (CR1 and CR2). 2. Transmembrane domain, and 3. Intracellular domain comprising the tyrosine kinase domain and the C-terminal region (NH-amino, CH-carboxy)

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In the inactive state, ERBB2 is in close association with a chaperone heat shock protein 90 (HSP90) and a co-chaperone CDC37.[14] On ligand binding to other receptors, ERBB2 gets activated by heterodimerization and dissociation from chaperone proteins. Further signaling of ERBB2 depends on the type of heterodimer formed [Figure 2].
Figure 2: Downstream signaling pathways for HER2 receptor activation (HER = human epidermal growth factor receptor, PI3K = phosphatidylinositol 3-kinase, PKC = protein kinase C, PLC = phospholipase C, MAPK = mitogen-activated protein kinase)

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  Spectrum of HER2 Alterations in Cancer Top


HER2-mutant NSCLCs can be subcategorized as HER2-mutant NSCLCs, HER2-amplified NSCLCs, and HER2 protein overexpressing NSCLCs.[15] HER2 positivity in NSCLC can be detected by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and NGS.[16]

HER2 Mutation

HER2 is a protooncogene located on chromosome 17 (17q21).[17] HER2 mutations are reported in 1%–4% cases of NSCLC and are seen predominantly in non-smokers.[2] HER2 mutation as a primary oncogenic driver is reported to be mutually exclusive of other oncogenic drivers like EGFR, ALK, ROS1, and KRAS alterations.[2] The most commonly encountered HER2 mutations are ascribed to the kinase domain and more commonly occur in exons 18–21.[18]

The exon 20 non-frameshifting insertions constitute 83% of all HER2-mutant cases,[19] with the YVMA insertion at codon 75 being the most common variant.[16] Less-frequent mutations affecting the tyrosine kinase domain may also occur. These genetic alterations in the adenosine triphosphate (ATP)-binding pocket result in the constitutive activation of the kinase domain and promote increased downstream signaling, thereby prompting enhanced proliferation and decreased apoptosis of tumor cells.[19] Additionally, mutations affecting the extracellular ligand-binding domain are also known, which cause continuous heterodimerization and receptor activation. HER2 mutations may not be accompanied by HER2 amplification or overexpression, implying that the three molecular subtypes have distinct mechanisms, and hence, varied and heterogenous clinical courses and prognoses.

HER2 Amplification

HER2 amplification is seen in 10% and 3% patients with and without prior treatment with EGFR tyrosine kinase inhibitors, respectively.[15],[20],[21] HER2 amplification is observed in NSCLCs, but not as frequently as in breast carcinomas. This subcategory is associated with never-smoker female patients with tumors of adenocarcinoma histology. These patients are often noted to have malignant pleural effusion. FISH is the method of choice to detect HER2 amplification. In case of tissue unavailability, NGS on liquid biopsy can be performed.[15],[20],[21]

HER2 Overexpression

This molecular subtype comprises 2%–20% of all HER2-altered cases of lung cancer and is associated with poor prognosis.[15],[20],[21] Tumors with HER2 overexpression often show adenocarcinoma histology with a papillary pattern. A consensus on the scoring method for HER2 protein overexpression has not yet been arrived at.

HER2 Fusion

HER2 fusion with ZNF207, MDK, or NOS2 causes continuous activation of HER2 in gastric cancers.[22] However, HER2 fusions have not been reported in lung carcinoma till date.


  Detection Methods Top


Detection of HER2 overexpression and amplification has been traditionally carried out using IHC and FISH. Detection of mutations and fusions from the tumor tissue or liquid biopsies requires the use of more sophisticated molecular techniques such as polymerase chain reaction (PCR)-based methods and NGS using both DNA and RNA. A detailed description of these methods is provided in [Table 1]. Other methods of detection include the NanoString technology, which is approved in malignancies of the breast. However, a detailed discussion of these methods is beyond the scope of this review.
Table 1: Detailed summary of clinical trials with anti-HER2/neu agents in non-small cell lung cancer

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  Clinical Aspects of HER2/neu Alterations in NSCLC Top


HER2/neu mutations in NSCLC have a female preponderance and are observed commonly among non-smokers with tumors of adenocarcinoma histology.[29],[30] Though uncommon, HER2 mutations have been documented in heavy smokers, males, as well as in cases of squamous cell carcinoma.[31] These findings suggest that HER2 alterations are not restricted to a particular clinicodemographic subgroup, and that clinical characteristics alone cannot predict the molecular characteristics of the tumor.[32]

Regardless of the systemic treatment used, the median overall survival (OS) for patients with HER2/neu alterations remains approximately 2 years. This may be attributed to patient selection, including non-smokers, those with good performance status, and women; good referral systems; and the potential prognostic value of HER2 mutations.[32] Kuyama et al.[33] showed a remarkable association between the presence of HER2/neu amplification and survival in patients with locally advanced NSCLC treated with concurrent chemoradiation. HER2/neu-positive patients with advanced NSCLC have worse outcomes and are relatively insensitive to concurrent chemoradiation.[34]

HER2-mutant NSCLC portends worse outcomes in comparison to other oncogenic driver mutations. Therefore, development of drugs targeting these mutations might improve the prognosis for this subgroup of patients.[2]

HER2 mutations have emerged as a resistance mechanism to tyrosine kinase inhibitors in EGFR-mutant NSCLCs. In addition, they may also cause resistance to platinum-based chemotherapy regimens.[35],[36]

Goss et al.[37] performed a secondary ad hoc analysis of the LUX-Lung 8 trial in patients with advanced squamous cell carcinoma of the lung with ERBB mutation treated with afatinib. Over one-fifth (53/245) of the patient population had at least one ERBB mutation.[32]

There is considerable agreement between serum and tissue HER2 levels in patients with stages III and IV breast cancer, and serum HER2 levels are significantly associated with imaging findings.[38] Similarly, serum HER2 level in patients with metastatic lung cancer can be studied as an emerging biomarker.


  Indian Data Top


Mehta et al.[39] analyzed the data of 145 patients with metastatic NSCLC who underwent NGS between 2015 and 2019. HER2/neu mutations were detected in 4.8% cases, which is in agreement with data reported by TCGA (4%) and LCMC (3%).[39] The most common HER2/neu alteration reported by Mehta et al.[39] was p.E770_A771insAYVM as a result of a non-frameshifting insertion of 12bp, in contrast to the most commonly reported insertion of YVMA at codon 75 (p.A771_ Y772insYVMA).


  HER2 Concomitance with Other Biomarkers Top


Mazieres et al.[25] retrospectively analyzed the data of patients with advanced NSCLC harboring mutations in exon 20 of the HER2 gene. Although HER2 mutations do not usually coexist with other driver alterations, concomitant EGFR mutations (5%), ALK translocations (1%), and ROS1 translocations (1%) have been observed occasionally.[25]


  HER2-Targeted Therapy Top


Contrary to EGFR- and ALK-directed therapies, HER2/neu-targeted therapy is not yet a standard of care in the upfront management of NSCLC.[40] Over the past two decades, several studies have been conducted to evaluate the potential clinical implications of sensitivity to anti-HER2/neu agents; however, they have shown conflicting results [Table 1].[41]

Trastuzumab

Following the excellent results obtained with trastuzumab in HER2-overexpressing (IHC score 3+) and/or -amplified breast cancers, the utilization of HER2-targeted agents in NSCLC was initially decided on the basis of protein overexpression on IHC (patients with low-to-intermediate IHC expression were also included) or HER2 amplification by FISH; the results were, however, modest. The use of a single agent, trastuzumab, in a Phase II trial of patients with clinically advanced NSCLC with HER2 overexpression on IHC (score ≥2/3) did not demonstrate a clinical benefit.[42] Similar results were seen in combination trials of trastuzumab and chemotherapy in patients with tumors showing HER2 overexpression, both in randomized and non-randomized settings.[24],[32] In one trial, a response rate of 83% was demonstrated in 6 patients with either HER2 expression on IHC (score of 3+) or amplification on FISH.[24] Cappuzzo et al.[43] first demonstrated sustained activity of trastuzumab-based chemotherapy in a heavily pretreated group of patients with HER2-mutant NSCLCs and hypothesized that HER2 mutation, rather than amplification, is an oncogenic driver in NSCLC. Mazieres et al.[32] retrospectively demonstrated that the use of HER2-directed therapy as a single agent or its addition to standard chemotherapy in pretreated patients with HER2-mutant NSCLC showed a higher response rate (50%). They noted a 93% disease control rate (DCR) for trastuzumab-based therapies.[32] The EUHER2 cohort showed similar outcomes with an objective response rate (ORR) of 50%, DCR of 75%, and progression-free survival (PFS) of 5.1 months with trastuzumab-based chemotherapy.[25]

Pertuzumab

Few studies have been conducted to assess the clinical efficacy of pertuzumab in HER2-mutant NSCLC. The initial studies were conducted in an unselected cohort and did not reveal any significant activity of pertuzumab.[44],[45] The IFCT-1703 R2D2 non-randomized Phase II trial[23] studied the effect of the combination of pertuzumab, trastuzumab, and docetaxel in patients with advanced, platinum-pretreated HER2-mutant NSCLC and reported an ORR of 29% and median PFS of 6.8 months, with stable disease observed in 56% of patients. The authors concluded that the combination was suitable for advanced, pretreated HER2-mutant NSCLC.[23] However, more studies are required to define the role of pertuzumab in this setting.

Trastuzumab Emtansine (T-DM1)

T-DM1 is an antibody–drug conjugate in which trastuzumab is attached through a secure linker to a microtubule-inhibiting cytotoxic drug (DM1). It has been studied in a Phase II basket trial conducted in patients with pretreated NSCLC harboring HER2 mutations. An ORR of 44% was observed in this trial. More recently, T-DM1 demonstrated an ORR of 20% in HER2-overexpressing NSCLCs with an IHC score of 3+ and 0% in NSCLCs with an IHC score of 2+.[46] A review of seven studies on T-DM1 use in HER2-aberrant NSCLCs revealed an ORR of 19.35%. Subgroup analyses showed that T-DM1 led to an ORR of 35% in patients with HER2 mutation, 42.8% in those with HER2 amplification, 2.78% in those with HER2 protein overexpression, and 80% in those with amplification, overexpression, as well as mutation. These observations highlight the efficacy of T-DM1 in patients with HER2-mutant and -amplified NSCLCs, especially in cases where mutations coexist with amplifications.[47] However, more data are required to further clarify the role of T-DM1 in HER2-aberrant NSCLC.

Small Molecule Inhibitors

Data regarding small molecule HER2 inhibitors are presently conflicting, with variable activity noted in HER2-mutant NSCLC. The EUHER2 study[25] assessed various treatment modalities in 101 pretreated patients with advanced NSCLC harboring HER2 mutation, and noted an ORR of only 7.4% with neratinib, lapatinib, and afatinib. Afatinib, however, has shown modest clinical activity in other studies, with durable responses in NSCLCs with certain types of mutations.[31] A multicenter retrospective review of data from 28 patients with advanced, pretreated HER2-mutant NSCLC treated with afatinib revealed an ORR of 19% and a DCR of 69%. In a subgroup of 10 patients who had a p.A775_G776insYVMA insertion, 40% received afatinib for more than a year.[48] In another study in a similar population, afatinib demonstrated partial responses in 13% and stable disease in 57%. All partial responses were noted in patients harboring exon 20 insertions in HER2, including one patient with VAG and two with YVMA insertions. Most patients who received afatinib for over 6 months had a YVMA insertion.[27] Mazieres et al.[32] noted a DCR of 100% in 3 patients. A single-arm, Phase II trial was conducted in which afatinib was administered to pretreated patients with advanced NSCLC harboring a HER2 mutation; however, patient accrual was stopped early as the trial failed to demonstrate a prespecified DCR of 75%.[49] Another study showed a response in two out of six patients with an oral irreversible pan-HER inhibitor, poziotinib.[31] A Phase II study documented durable partial responses with dacomitinib, an irreversible inhibitor of HER2, EGFR, and HER4 tyrosine kinases, in 12% of patients with advanced HER2-mutant NSCLC.[50] However, unlike afatinib, no response was seen in patients harboring the A775_G776insYVMA mutation. Neratinib as a single agent did not show any response, but demonstrated an ORR of 21% in combination with temsirolimus in another randomized Phase II trial of 27 patients.[26] Zhou et al.[51] evaluated the role of pyrotinib (an irreversible, pan-HER inhibitor) in a single-arm, Phase II study in patients with advanced, pretreated HER2-mutant NSCLC and reported an ORR of 30% and median PFS of 6.9 months.

There is still an unmet need to identify patients who will respond to these small molecule inhibitors of HER2, given the wide spectrum of HER2 alterations in lung cancer and the differential responses seen with individual drugs to specific aberrations.

Trastuzumab Deruxtecan (T-DXd)

T-DXd comprises an anti-HER2 antibody attached to a topoisomerase I inhibitor via a cleavable tetrapeptide-based linker. In an initial Phase I trial on pretreated patients with NSCLC harboring HER2 mutation, T-DXd demonstrated an ORR of 73% and median PFS of 11.3 months.[52] The ongoing DESTINY-Lung01 trial[53] evaluated T-DXd in 42 patients with HER2-mutant NSCLC of non-squamous histology, with nearly 45% patients showing metastasis to the brain. An interim analysis revealed a DCR of 90.5%, ORR of 61.9%, and median PFS of 14 months. However, 64.3% of patients exhibited grade 3 adverse events and 11.9% developed interstitial lung disease.

Immunotherapy in HER2-mutant NSCLC

Lai et al.[54] reported an ORR of 12% and a median PFS of 1.9 months in 26 patients with HER2-mutant NSCLC who received immunotherapy in the second or later lines. They also noted that patients with HER2 mutation had lower programmed death-ligand 1 (PD-L1) expression and similar tumor mutational burden compared to an unselected cohort of 122 patients with lung cancer. Similarly, the IMMUNOTARGET registry[55] showed that 29 patients with HER2 alterations demonstrated an ORR of 7% and a median PFS of 2.5 months, and this was higher than that observed in smokers. However, another study in 23 patients with HER2 mutations demonstrated an ORR of 27% and a median PFS of 2.2 months with immunotherapy in the second and later lines, which is comparable to the ORR and PFS for unselected patient cohorts. These findings may be attributed to a higher number of PD-L1–expressing tumors, as well as a greater number of patients who received immunotherapy in earlier lines of treatment. Data regarding the role of single-agent immunotherapy and chemo-immunotherapy in the first-line setting are scarce. A case series of five patients with advanced disease (including one patient with squamous cell carcinoma) and HER2 alterations who received chemo-immunotherapy in the first line demonstrated a median PFS of 8 months. All patients had PD-L1–negative tumors.[56] At present, the role of immunotherapy in this subset of patients is uncertain, with the consensus being that immunotherapy is not as efficacious in this subset of patients as it is in the non-biomarker–driven population. Further larger population-based studies can help confirm these findings.


  Current Guideline Recommendations Top


The National Comprehensive Cancer Network (NCCN)[57] and European Society for Medical Oncology (ESMO) guidelines[58] recommend testing of patients with metastatic lung adenocarcinoma for HER2 alterations and potential treatment with T-DM1 and T-DXd (Category 2A recommendation). As per the NCCN guidelines, single-agent trastuzumab and afatinib are not currently recommended because of lower response rates with these drugs. The ESMO guidelines recommend testing for HER2 alterations to select candidates who could benefit from specific inhibitors and enrolling them in clinical trials. The patients should be counseled and thoroughly explained about the potential risks and limited evidence available to support the benefits. Similarly, the American Society of Clinical Oncology (ASCO)[59] has not formulated any guidelines for or against the use of T-DM1 or pyrotinib at present. Guidelines also recommend retesting the tumor tissue to identify various complex and heterogeneous resistance mechanisms (including T790M, MET amplification, ERBB2 alterations, etc.) for patients who progress on targeted therapies.


  Conclusion Top


HER2-mutant NSCLC, although rare, is an entity where targeted therapies have been successfully incorporated in the management of advanced disease. Currently, the NCCN and ESMO recommend the use of T-DM1 and T-DXd in HER2-mutant lung carcinoma. HER2/neu-directed therapies are not yet considered the standard of care in the upfront management of NSCLC, and clinical trials targeting HER2 alterations in NSCLC have shown conflicting results. This could be attributed to the different mechanisms of the three different molecular subtypes of HER2-aberrant NSCLCs, inviting more research and trials with different strategies. With increased utilization of NGS, the ability to detect HER2 mutations is likely to increase, especially in tumors where complete genotyping is necessary for optimal treatment decision-making.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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