Progress in Treatment of Non-Small Cell Lung Cancer Harboring HER2 Aberrations
Received 31 March 2021
Accepted for publication 10 June 2021
Published 6 July 2021 Volume 2021:14 Pages 4087—4098
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Alberto Bongiovanni
Jun Ni, Li Zhang
Department of Pulmonary and Critical Care Medicine, Peking Union Medical Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People’s Republic of China
Correspondence: Li Zhang
Department of Pulmonary and Critical Care Medicine, Peking Union Medical Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, People’s Republic of China
Tel +86 13911339836
Email [email protected]
Abstract: Epidermal growth factor receptor 2 (HER2/ErbB2/neu), a member of ErbB receptor tyrosine kinase family, forms homo- or heterodimers with ErbB1 (HER1/EGFR), ErbB3 (HER3), or ErbB4 (HER4), to activate signal transduction pathways and promote proliferation, differentiation and tumorigenesis. Preliminary clinical trials of monoclonal antibodies, antibody conjugates and small-molecule tyrosine kinase inhibitors targeting HER2 have indicated that HER2 is a potential therapeutic target in non-small cell lung cancer (NSCLC). HER2 aberrations in NSCLC patients mainly include mutation, amplification, and overexpression. While there are significant differences in the outcome of NSCLC with these HER2 changes, no consensus has been reached for the incidence, detection method and targeted treatments for the three types of HER2 aberration. HER2 mutation is generally considered to have more clinical relevance and response to HER2-targeted therapies. In this review, we discuss HER2 alterations in NSCLC, including diagnostic challenges and treatment strategies particular to the HER2 mutation.
Keywords: HER2, non-small cell lung cancer, antibody conjugate, tyrosine kinase inhibitor
Lung cancer is currently the leading cause of cancer mortality worldwide for both men and women, and the rate continues to increase. In 2018, there were 2.10 million new lung cancer cases, accounting for 11.6% of all cancer cases, and 1.80 million deaths from lung cancer, accounting for 18.8% of all cancer-related deaths.1 In 2015, there were 733,000 new lung cancer cases and 610,000 lung cancer-related deaths in China.2 Non-small cell lung cancer accounts for 80–85% of all lung cancer cases.3 Despite the improvements in chemotherapy, the 5-year survival rate of patients with advanced NSCLC is less than 3%.3 With the continuous development of new targeted drugs, the objective response rate (ORR) has been improved and the overall survival (OS) has also been prolonged.4–8 In addition, advances in gene detection technologies have led to the identification of oncogenes in lung cancers, such as aberrations in the HER2 gene. Human epidermal growth factor receptor 2 (HER2/ERBB2) is a receptor tyrosine kinase of the epidermal growth factor receptor (ErbB) family, which includes EGFR (HER1/ERBB1), HER3 (ERBB3) and HER4 (ERBB4).9 The HER2 gene (also known as erbB2 or neu) is located on the long arm of chromosome 17 (17q21) and is a proto-oncogene. HER2 is a type I transmembrane growth factor receptor tyrosine kinase consisting of 1255 amino acids with a relative molecular weight of 185,000 Da. The HER2 protein is composed of three functional domains: an extracellular ligand-binding domain (ECD), an α-helical transmembrane domain (TMD) and an intracellular tyrosine kinase domain (TKD). Ligand binding promotes receptor dimerization and auto-phosphorylation of the intracellular TKD, which induces HER2 kinase activity, resulting in the initiation of a variety of signaling pathways related to cell proliferation, differentiation and migration, such as the RAS/MAPK and PI3K/Akt pathways. No endogenous ligand has been identified for HER2 thus far. Several studies have shown that HER2 overexpression and/or gene amplification drive the occurrence and development of various cancers,10 such as breast cancer, ovarian cancer and gastric cancer. In breast cancer, HER2-targeted therapies including trastuzumab and pertuzumab have achieved significant efficacy and huge survival benefits, and these treatments are now considered standard of care.11 However, HER2 alteration in NSCLC has different functional consequences compared with breast cancer12 and is associated with poor disease prognosis.13,14 Definition of HER2 alterations in NSCLC is still integrated and the question remains whether all these alterations are relevant oncogenic driving factors. Therefore, the detection methods for HER2 and treatment targets for NSCLC are still urgent clinical problems in treating NSCLC patients. Currently, the FDA recommends immunohistochemistry (IHC), in situ hybridization (ISH) and fluorescence in situ hybridization (FISH) for detection of HER2 protein or gene amplification (Supplementary Table 1).
In this review, we discuss HER2 aberrations in NSCLC, including the diagnostic challenges and treatment strategies. Better understanding of the mutation types and mechanisms of HER2 mutants in NSCLC will facilitate the individualized treatment of such patients in the future.
HER2 Mutation in NSCLC
In 2004, the Cancer Genome Project and Collaborative Group reported the presence of HER2 mutations in 4.2% of lung cancer patients, with a rate of approximately 9.8% in lung adenocarcinoma patients.9 A number of studies have since reported that the HER2 mutation rate in NSCLC patients is 2%–6%, with higher incidences in Asians, never smokers, women and lung adenocarcinoma patients9,15–19 (Supplementary Table 2). These trends are similar to those observed with patients with EGFR mutation. In addition, several retrospective studies have shown that the most common type of HER2 mutation was in-frame insertions in exon 20.15,16,18,20
Chen et al21 analyzed 54 tissue and blood samples of 48 patients with HER2 gene mutation or amplification and found that 36 samples harbored HER2 gene mutation and 23 samples showed HER2 gene amplification. Li et al22 identified four cases of HER2 gene mutation without gene amplification and overexpression by FISH and IHC, respectively. These findings indicate that HER2 gene mutation has no significant correlation with protein expression and gene amplification suggesting that HER2 gene and protein aberrations may have different therapeutic and prognostic values.
As the use of next-generation sequencing (NGS) is constantly expanding, the number of identified HER2 mutations will continue to grow, especially in NSCLC. The NCCN guideline for NSCLC (2021.V2) recommended NGS testing to identify rare oncogenic driver variants for which effective therapy may be available. The Memorial Sloan Kettering Cancer Center reported that 83% of HER2 gene mutations detected by NGS occur in exons 18–21, which encode the TKD, and the most common mutation is a duplicated insertion of 12 base pairs (encoding YVMA) at codon 775 of exon 20, which is known as the HER2YVMAsubtype, p.Y772_A775dupYVMA (c.2324_2325ins12).15,23 Mutation in the TKD leads to conformational changes that result in narrowing of the ATP binding pocket, increasing HER2 kinase activity, and enhancing downstream signal transduction pathways that mediate cell proliferation, expansion and invasion and tumor development.18,23,24 A total of 31 subtypes of HER2 mutation were found that the predominant subtype was HER2YMVA (42%), followed by G778_P780dup (9%), G776delinsVC (8%), S310F/Y (7%) and V776L (6%).25 In addition, Sai-Hong et al26,27 found germline mutations in the HER2 transmembrane domain (G660D, V659E). Both mutations lead to increased stability of the wild-type protein and activation of the AKT pathway, indicating that the TMD mutations are carcinogenic and can lead to hereditary and sporadic lung cancer. In 2020, Wei et al28 showed that non-TKD mutations accounted for 57.5% of HER2 mutant NSCLC cases. Among these mutations, a point mutation in exon 8 (S310F) was the most common, resulting in an altered kinase domain similar to that which was observed in the HER2YVMA subtype.29 The non-TKD mutations are considered potential targets for treatment. In our clinical practice, a middle-aged, never-smoking male patient with advanced lung adenocarcinoma had the HER2 S335C mutation. Partial response was achieved with a pan-HER inhibitor (pyrotinib), and the disease has been in remission for 10 months.30
NGS analysis of HER2 co-mutations showed that 51.6–66% patients had TP53 gene mutation (mostly in exons 5–8), followed by mutations in LRP1B (18.2%), EPHA5 (9.1%), MLL3 (9.1%) and RB1 genes (8.0%).31,32 HER2 gene mutation and TP53 gene mutation were found to be poor prognostic factors for NSCLC.19,32
Progress in HER2 Mutation–Targeted Therapy
Clinical trials have indicated the efficacy of small molecule tyrosine kinase inhibitors (TKIs) for HER2-mutated NSCLC; however, these studies are all Phase I–II trials using pan-HER TKIs with small sample sizes25,27,31,33–46 (Table 1). Compared with the efficacy of drugs direct to other NSCLC targets (EGFR, ALK, ROS-1), the ORR and progressive-free survival (PFS) of patients receiving HER2-targeted therapy are still insufficient.
Table 1 Results of Clinical Data Targeting HER2 Aberrations Among Lung Cancer Patients Reported in Various Trials
Afatinib is a powerful and irreversible double inhibitor of EGFR and HER2 tyrosine kinase.34 The ORR and disease control rate (DCR) in three independent cohorts were 13–19% and 70%, respectively.31,38,40 De Greve et al33,47 reported an ORR of afatinib in the treatment of HER2-mutated NSCLC of 3.8%–53.8%, and the PFS was 3.7–6.4 months. A retrospective analysis of 28 patients with HER2-mutated NSCLC treated with afatinib showed that the time of treatment failure was 2.9 months, and the duration of response (DoR) of the HER2YVMA subtype was 9.6 months.40 However, the response of patients with HER2 mutations to afatinib was different. Liu et al31 evaluated the clinical outcomes of 19 Chinese patients harboring ERBB2 20ins after afatinib treatment and found that patients with the G778_P780dup subtype achieved a longer median PFS (mPFS) and median OS (mOS) than patients with other 20ins (non-G778) subtypes (mPFS, 10 vs 3.3 months, P=0.32; mOS, 19.7 vs 7 months, P=0.16). Fang et al25 found that the ORR and PFS of afatinib for patients with G778_P780dup (c.2331_2339dup) and G776delinsVC (c.2326delinsTTGT) that were treated with afatinib was 40% (4/10) and 7.6 months (95% CI 4.9–10.4); the ORR and PFS for the HER2YVMA subtype was 0% (0/14) and 1.2 months (95% CI 0–2.4 months), and the ORR and PFS for HER2 missense mutation was 13% (1/8) and 3.6 months (95% CI 2.6–4.5). These results indicate that patients harboring G778_P780dup and G776delinsVC subtypes can achieve survival benefits from afatinib.
The above studies confirmed that patients with different subtypes of HER2 mutation have different sensitivities to afatinib, but the precise conclusions have been inconsistent. A prospective study with a large sample size is required to further clarify the therapeutic effect of afatinib on NSCLC harboring different HER2 mutant subtypes.
Neratinib is an irreversible TKI with an IC50 of 59 nM for HER2. Nagano et al23 reported that neratinib was more effective against the HER2YVMA subtype in NSCLC cell lines, while NSCLS cells with L775P and L775S showed resistance. Studies in patient-derived organoids showed that neratinib monotherapy highly induced tumor cell death. Compared with neratinib alone, the combination therapy of neratinib + trastuzumab or neratinib + sirolimus showed enhanced anti-cancer effects, with the combination of neratinib + sirolimus showing the best effect.48 The SUMMIT trial36 showed that the ORR of neratinib was only 3.8% (1/26) in HER2-mutant NSCLC patients, but the mPFS was 5.5 months because 6 patients had been treated with neratinib for more than 1 year.
Osimertinib was originally designed as a third-generation EGFR-TKI for NSCLC that acquired the TKI-resistant mutation T790M in EGFR. It was later found to have affinity for HER2 and it may be used as a monotherapy or combination therapy for HER2-mutated NSCLC. Early data suggested that although osimertinib was particularly effective against tumors with the EGFR T790M mutation, approximately 20% of EGFR T790M-negative patients also responded to osimertinib, suggesting that osimertinib may be effective for HER2-mutated NSCLC.49 Shortly afterwards, Nagano et al23 found that osimertinib demonstrated good efficacy against Ba/F3 cells expressing HER2 L755P and L755S mutations in vitro, which are the most common mutations in breast cancer, while it had a weak effect on cells harboring the HER2YVMA mutation compared with afatinib and neratinib. Liu et al50 reported the efficacy of osimertinib in the treatment of HER2-mutated NSCLC in vitro. An antitumor effect of osimertinib combined with the BET inhibitor JQ1 was observed, but there is no clinical trial data so far.50
Poziotinib is a newly developed TKI targeting HER2 with exon 20 mutation. It can overcome the conformational change of ATP-binding pocket caused by EGFR (HER1/ErbB1) and HER2 exon 20 mutation and has inhibitory effects on the EGFR/HER2/HER4 signaling pathway.42 Therefore, poziotinib is considered effective as an inhibitor of HER2 with the exon 20 mutation. In a preclinical trial of cell line– and patient-derived xenotransplantation models (PDXs), poziotinib inhibited EGFR, HER2 and HER4 more effectively than other pan-HER TKIs.42 In a Phase II clinical trial of poziotinib (16 mg daily) for NSCLC with HER2 exon 20 mutation (12 cases), the ORR reached 42% and the mPFS was 5.6 months.51 However, 60% of patients developed rash and diarrhea, and one case had drug-related pneumonia. In another study, mice harboring HER2YVMA were treated with poziotinib combined with trastuzumab emtansine (T-DM1), and the average tumor shrinkage rate was 47% compared with controls.42 Poziotinib is currently a potential drug to target the HER2 exon 20 mutation.
Dacomtinib is an irreversible pan-HER-TKI that targets EGFR, HER2 and HER4. A small sample phase II clinical study was designed to assess the efficacy and safety of dacomtinib therapy against HER2 aberrations in NSCLC.37 The trial included 30 patients (including 26 with HER2 mutations and 4 with HER2 gene amplification). The ORR of the overall patient group was only 10%, while the ORR of the patients with gene amplification was 0, and only three patients reached PR, including two cases HER2P780_P781insGSP and one case with HER2M774 delinsWLV, indicating that dacomtinib had poor effects on HER2 YVMA subtypes.
Pyrotinib is a class of irreversible pan-HER TKIs developed by China. In vitro and in vivo test results showed that the antitumor activity of pyrotinib was significantly better than that of afatinib and T-DM1 in organoids and PDXs harboring the HER2YVMA mutant subtype.45 The concentration of pyrotinib in animal blood was 10 times higher than afatinib, and the tumor shrinkage rate was 52.2%. In 2020, Zhou et al46 reported a single arm, open label, multi-center phase II clinical study of pyrotinib for the treatment of HER2-mutated NSCLC as second-line or above treatment, and the ORR was 31.7% (95% CI 18.8–43.2%) in 60 patients with stage IIIB and IV NSCLC with HER2 exon 20 mutation. The ORR was similar in different subtypes of NSCLC. The mDoR was 6.9 months (95% CI 4.9–11.1 months), the mPFS was 6.8 months (95% CI 5.5–8.3 months), and the mOS was 14.4 months (95% CI 12.3–21.3 months). Pyrotinib is expected to improve the outcome of NSCLC patients with HER2 exon 20 mutation.
Mobocertinib is a research-based oral EGFR/HER2 inhibitor for the treatment of NSCLC with EGFR/HER2 mutation, including the EGFR exon 20 insertion mutation (EGFR ex20ins). In the dose exploration study (NCT02716116), the ORR of the total population was 34.78% (EGFR ex20ins and HER2 ex20ins), and the standard dose was determined to be 160 mg daily. In the follow-up cohort expansion study (AACR 2020), an ORR of only 43% was published for EGFRex20ins NSCLC patients, and the mPFS was 7.3 months. Therefore, the efficacy of TAK-788 in refractory NSCLC patients with EGFR ex20ins seems to be better than other second-line treatment schemes in the real world. However, the efficacy of HER2ex20ins remains to be determined.
Tucatinib is a small oral TKI with high selectivity to the HER2 TKD. HER2 CLIMB research52 showed that in the comparison of the combination of tucatinib plus trastuzumab and capecitabine with placebo plus trastuzumab and capecitabine to treat HER2-positive breast cancer patients, the 1-year PFS rate was doubled (33.1% vs 12.3%, p < 0.001) and PFS (7.8 months vs 5.6 months, p < 0.001) and OS (21.9 months vs 17.4 months, p=0.005) were significantly longer in the combination treatment group. It is worth noting that tucatinib also has good brain entry activity. The triple-drug therapy reduces the risk of disease progression or death in patients with brain metastases by 52%, and thus has a significant effect on patients with brain metastases. In 2020, FDA approved this regimen for locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases who had previously received anti-HER2 regimens, individually or in combination. However, whether tucatinib is effective against HER2-mutated NSCLC has not been determined.
Monoclonal Antibodies and Antibody-Coupled Drugs
Trastuzumab is an IgG2 monoclonal antibody that targets the HER2 extracellular domain. Trastuzumab binds with HER2 extracellular domain region IV, blocks signal transduction, inhibits HER2 activity and promotes the immune system to recognize and kill tumor cells.53 A retrospective cohort study (EUHER2 study)54 showed that chemotherapy combined with trastuzumab was effective against HER2 mutant NSCLC, with a response rate as high as 50%. However, no study has compared trastuzumab with platinum containing dual drug chemotherapy.
Pertuzumab is another humanized monoclonal antibody against HER2 that binds to the extracellular domain II of HER2, inhibits the formation of heterodimer complexes between HER2 and other receptors, and inhibits the downstream signal transduction pathway. Hainsworth et al35 recruited 14 patients with NSCLC harboring HER2 mutation undergoing trastuzumab combined with pertuzumab (the MyPathway basket trial) and the ORR was 21% (3/14).
Trastuzumab Emtansine (T-DM1)
Trastuzumab emtansine is a type of antibody-drug conjugate (ADC) composed of the HER2 monoclonal antibody trastuzumab and emtansine (T-DM1), an inhibitor of microtubule aggregation. Degradation of the T-DM1 complex in lysosome results in the release of cytotoxic anti-tubule agents in HER2-positive tumor cells. In phase II clinical trials of T-DM1 treatment for second-line and above HER2-altered NSCLC55 (including mutations, gene amplification, and protein expression), the ORR reached 6.7%, and the ORR in the HER2 mutant NSCLC subgroup achieved 14.3%. In another phase II basket trial,39 T-DM1 monotherapy (3.6 mg/kg) was given to 18 patients with advanced HER2-mutant lung adenocarcinomas; the ORR was 44%, the mDoR reached 4 months (range 2–9 months), and the mPFS was 5 months (95% CI 3–9 months). The adverse reactions were mild, mainly including infusion reaction and myelosuppression. Based on the results of the T-DM1 trial, NCCN guidelines (2021.V2) recommend T-DM1 for the treatment of HER2-mutated NSCLC.56
Trastuzumab Deruxtecan (Enhertu, T-DXd, DS-8201)
Trastuzumab deruxtecan is a novel ADC that is composed of the humanized anti-HER2 antibody trastuzumab with the topoisomerase I inhibitor deruxtecan. The ratio of chemotherapy drug to antibody reaches approximately 7–8, which makes it effective in tumors with low HER2 expression.57 A Phase I clinical study (DS-8201-a-J101)44 showed that the ORR was 72.7% (8/11) and mPFS was 11.3 months (95% CI 8.1–14.3). In 2020, the American Society for Clinical Oncology (ASCO) released the interim analysis results of phase II clinical trials (Destiny-Lung-01)43 that showed that ORR was 61.9% and the mPFS was 14 months. DoR and OS data were not yet available. Stratification analysis based on HER2 mutation and protein expression (IHC 2 + or 3 +) showed no significant difference in efficacy among groups. The incidence of drug-related adverse reactions was 52.4% in patients with grade 3 tumors or above. Myelosuppression (neutropenia and anemia) was common. Approximately 11.9% of patients developed grade 2 drug-related interstitial pneumonia. DS-8201 showed a significant effect on HER2-altered advanced NSCLC and was recommended by NCCN guidelines (2021.V2).
Immune Checkpoint Inhibitors (ICIs)
ICIs, such as PD-1 inhibitors, PD-L1 inhibitors and CTLA-4 inhibitors, are drugs that unleash an immune system attack on cancer cells. Immunotherapy is currently approved by the FDA for treatment of lung cancer. A retrospective analysis was performed on the efficacy of immunotherapy in patients with driver gene-positive advanced NSCLC published by the European Association of Oncology (ESMO) in 2019.58 The results showed that the mPFS of HER2 mutation NSCLC was 2.5 months (95% CI 1.8–3.5 months); the 6-month and 12-month PFS rates were 22.7% and 13.6%, respectively; and the mOS was 20.3 months. Similar to NSCLC patients with EGFR mutation and ALK gene arrangement, HER2-mutated NSCLC patients do not benefit from immunotherapy. Lin et al59 suggested that the tumor microenvironment lacking CD8+ T cell infiltration may explain the poor efficacy of ICIs in the treatment of EGFR and HER2-driven NSCLC.
Secondary HER2 Mutation
HER2 mutation occurs in some EGFR-mutated NSCLC patients during EGFR-TKI treatment, and these mutations in HER2 are considered to be one of the acquired resistance mechanisms against EGFR-TKI drugs. In vitro experiments indicated that mutant HER2 forms heterodimers through HER2 and EGFR, resulting in phosphorylation of the intracellular tyrosine kinase and activation of downstream signal transduction pathways, leading to cell survival, invasion and tumorigenicity and eventual EGFR-TKI resistance.24 Hsu et al60 found that HER2 D16 is a new mechanism of osimertinib resistance independent of the SRC pathway. In the AURA study,61 one patient acquired HER2 mutation (HER2YVMA) during osimertinib treatment and was subsequently sensitive to T-DM1.
HER2 Gene Amplification
Compared with breast cancer, HER2 amplification is rare in NSCLC, with an incidence rate of approximately 2–4% in tumor samples.18,62 Fluorescence in situ hybridization (FISH) is the standard method for detection of HER2 gene amplification and shows high specificity, standardization and consistency in breast cancer.63,64 HER2 amplification is usually defined as HER2/CEP17 ≥ 2.0 (FISH testing by dual probe assay). If the number of chromosome 17 doubles in a single cell, the number of copies of HER-2/neu per cell is relatively increased (because of polyploidization of chromosome 17) or the activity of upstream promoter increased, which led to large expression of HER2 gene.14 The 2018 CAP/ASCO guideline recommendations for HER2 positivity criteria is an absolute HER2 gene copy number ≥6/cell or HER2/CEP17 was < 2. Whether high copy number of HER2 has a prognostic or predictive value is unclear.22,65 Future studies should distinguish between individuals with HER2 gene amplification and individuals with high HER2 copy number increase but without amplification. We are also exploring other methods to quantify HER2 gene amplification (mRNA level), such as quantitative polymerase chain reaction and real-time quantitative reverse transcriptase-polymerase chain reaction.66
HER2 Gene Amplification Therapy
Lapatinib is a dual TKI that blocks EGFR and HER2 tyrosine kinase activity by binding to the ATP-binding site of the receptor’s intracellular domain. In a randomized phase II study,67 lapatinib reduced the tumor size by 51% in two patients with HER2-amplified NSCLC. In 2005, Clamon and others proved that trastuzumab alone could not achieve clinical benefits in the treatment of NSCLC.63 Interestingly, in 2006, Cappuzzo first reported the case of a 60-year-old female nonsmoker with increased copy numbers of EGFR and HER2 genes by FISH who responded to trastuzumab.68 DNA sequencing later performed on the same tissue detected an EGFR exon 21 mutation (A859T) and a HER2 exon 20 mutation (G776L). MyPathway, an open-label, phase IIa multiple basket study,35 reported that in patients with HER-positive metastatic NSCLC (IHC3 + or HER2/CEP17 ≥2 or copy number ≥6), trastuzumab combined with pertuzumab had limited efficacy (ORR=13%). Li et al39 reported that the DCR of T-DM1 in 18 patients with HER2 mutation (NGS copy number increase or HER2/CEP17 > 2) was only 11% in a phase II study, and the mPFS was only 5 months.
Acquired HER2 Gene Amplification
In 2005, Cappuzzo et al68 reported that increased copy number of the HER2 gene in EGFR-positive NSCLC patients was associated with gefitinib sensitivity, supporting the use of HER2 FISH analysis for selection of patients for TKI therapy. HER2 amplification is one of the main mechanisms of EGFR-TKI acquired resistance in patients with EGFR+ NSCLC.69,70 In 2011, Yonesaka et al71 showed that activation of ERBB2 signaling in cell lines through ERBB2 amplification led to persistent extracellular signal-regulated kinase 1/2 signaling and consequently to cetuximab resistance, suggesting that ERBB2 inhibitors in combination with cetuximab may be a therapeutic strategy in patients with cetuximab-resistant cancers. In a preclinical study,69 the rate of HER2 amplification in EGFR-TKI-resistant NSCLC cells was found to be 12%. This mechanism of drug resistance has also been confirmed in clinical studies and later confirmed in re-biopsy of patients with NSCLC resistant to EGFR-TKIs, showing that HER2 gene amplification was about 13%.72 In addition, HER2 amplification was found in 1 of 9 EGFR T790M-NSCLC patients with primary resistance to osimertinib, suggesting that HER2 amplification and EGFR T790M mutation may be mutually exclusive.73,74 Although HER2 gene amplification may be a mechanism for EGFR-TKI resistance, it is necessary to distinguish between HER2 gene amplification, chromosome 17 numbers and co-mutations. Existing data has suggested that only high levels of HER2 amplification can drive tumor resistance, just as MET-dependent acquired gefitinib resistance occurs only in the presence of high levels of MET gene amplification (> 12 gene copies) and rarely occurs without pharmacological pressure.68
As outlined above, in the context of acquired drug resistance, clinical research should distinguish among the mechanisms leading to drug resistance, such as a high level of HER2 gene amplification driving tumor resistance, any level of HER2 amplification and the presence of EGFR mutation coexisting concomitant events. The high level of HER2 gene amplification is one of the reasons for the resistance of colorectal cancer to cetuximab, an EGFR monoclonal antibody.75
At present, there is no consensus on HER2 protein expression score and diagnostic criteria in NSCLC.76 There are currently two scoring systems for HER2 protein expression, the IHC scoring system and H-SCORE. The incidence of HER2 (IHC ≥ 2+) in NSCLC is approximately 24% and that of HER2 (IHC3+) is approximately 3–10%.77,78 H-SCORE, a semi-quantitative assessment performed by multiplying staining intensity with the percentage of positive tumor cells, ranges from 0 to 300 and the results are classified as high (≥200), intermediate (≥100–200) and negative (<100). The consistency among the different methods for HER2 expression assessment is poor, perhaps resulting in the heterogeneity in the positive rates of HER2 overexpression among different papers. The IHC scoring system for HER2 expression is currently he most common method of detection in pathological diagnosis in clinical practice.
Bunn et al79 found some correlation between the expression of HER2 protein on the cell surface evaluated by IHC and the increase of HER2 copy number evaluated by FISH in NSCLC cell lines.
HER2 Protein Overexpression Therapy
Although trastuzumab showed antitumor activity in NSCLC cell lines with HER2 overexpression in vitro, no clinical benefit was found in patients with IHC 2+ or 3+ NSCLC treated with trastuzumab alone.63 In addition to gemcitabine combined with cisplatin, trastuzumab was added to 103 patients with IHC 2+ or 3+ NSCLC; compared with chemotherapy alone, the mPFS of the patients treated with the combination therapy was 8.5 months.12 A phase II clinical study initiated by the Eastern Cancer Cooperation Group in 200480 to evaluate the efficacy of paclitaxel and carboplatin combined with trastuzumab in the treatment of NSCLC with HER2 overexpression (IHC 1+ to 3+), including IHC 1+ (38/139; 27%), IHC 2+ (31/139; 22%), and IHC 3+ (13/139; 9%), the survival rate of the combination group was similar to that of the chemotherapy group (mPFS, 3.3 months). Similarly, in 38 patients with NSCLC with HER2 overexpression, trastuzumab combined with pertuzumab had similar efficacy to chemotherapy, and there was no significant correlation between HER2 protein expression levels and PFS.81,82 Hotta et al55 found that among NSCLC patients with IHC 2+ or 3+ treated with T-DM1, the ORR was only 6.7% and the mPFS was 2.0 months. In further study on the effect of T-DM1 on patients with different HER2 protein expression levels,41 the ORR of the IHC 1+ cohort was 0% and that of the IHC 3+ cohort was 20%. The PFS and OS of the two groups were similar. Further analysis of co-mutations showed that 75% of patients in the IHC 3+ cohort harbored HER2 gene amplification. Therefore, HER2 protein level could not predict the effect of T-DM1. DS-8201 has strong antitumor activity in HER2-overexpressing NSCLC mice.57 Interim data analysis of the Destiny-Lung01 clinical study in 202043 indicated that the therapeutic effect was significant in HER2-overexpressing metastatic NSCLC with a confirmed ORR of 24.5%, and there was no apparent difference in ORR according to HER2 expression (IHC 3+ vs 2+).
Acquired HER2 Overexpression
HER2 protein overexpression is found in EGFR+ NSCLC patients, with an incidence of approximately 10%, and considered as a potential driving factor of EGFR-TKI resistance.69 De Langen et al83 found that HER2 protein expression level increased over time during EGFR-TKI treatment (median HER2 IHC 2+, H-score 100; median HER2 IHC 3+, H-score 240). These findings suggest that the selective pressure from long-term exposure to EGFR-TKIs may lead to the amplification of existing clones carrying specific gene changes; these clones may become dominant, leading to drug resistance to targeted drugs.83–85
An in vitro experiment84 suggested that T-DM1 may inhibit resistance in EGFR+ NSCLC by targeting the HER2 pathway. De Langen et al83 showed that in T-DM1-treated patients with acquired HER2 overexpression, the ORR was 46% (11/24) and the DoR was 5.6 months. Stratified analysis showed that the effective rate was significantly improved in patients with IHC 3+ (12 patients, ORR 67%) or HER2 copy number ≥ 10 (4 patients, ORR 100%); among cases with T-DM1 resistance, 66.7% (4/6) of patients showed negative HER2, indicating that T-DM1 targeted HER2 protein overexpression. Osimertinib combined with T-DM1 can improve the efficacy of osimertinib by delaying the drug resistance of EGFR+ NSCLC cell lines. The effect of HER2 protein expression was studied in PC9/HER2c1 xenotransplantation models, and the results showed that T-DM1 combined with osimertinib inhibited the growth of tumor cells and delayed drug resistance to osimertinib in some cell lines or tissues.77,78,86 These data suggested that EGFR-TKIs combined with ADC (T-DM1) may be an effective treatment strategy for EGFR+ NSCLC, with the main purpose of delaying the emergence of drug resistance. However, this idea is still in the preclinical research stage, and there are no in vivo data available.
The discovery of cancer-driving gene mutations in NSCLC, such as EGFR gene mutation, ALK gene rearrangement, ROS-1 gene rearrangement and others, has allowed for the development of molecular-targeted lung cancer therapies. NGS has become a standard diagnosis and treatment process for NSCLC patients and many potential targets have been found. HER2-positive NSCLC has gradually attracted clinical attention and is regarded as a unique molecular subtype of NSCLC. Whether co-mutation (for example, TP53 mutation) and background (primary and acquired drug resistance) and individualized treatment for patients may be the direction of future research.
Compared with the role of HER2 in other HER2-positive tumors (breast cancer and gastric cancer), HER2 mutation in NSCLC is considered to be more important than protein overexpression or gene amplification in the development and treatment of NSCLC. At present, many clinical studies are focused on treatments for HER2-positive NSCLC, including pan-HER TKIs, monoclonal antibodies, and ADCs, but they are limited to phase II clinical studies with small samples. So far, T-DM1 and DS-8201 have been recommended by NCCN guidelines.
Acquired HER2 mutation and HER2 gene amplification are considered to be the main mechanisms leading to EGFR-TKI resistance.24,49,62 HER2 overexpression is a potential factor contributing to EGFR-TKI resistance.55,77,87 There are acquired changes in HER2, and the efficacy of targeting HER2 drugs is still under further exploration.
Effective therapeutics and targets for NSCLC with HER2 aberration remain to be identified. Identification of the type of HER2 aberration in NSCLC (gene mutation, gene amplification, protein expression) and evaluation of the sensitivity of different drugs to HER2 aberrations and HER2 mutation subtypes (non-TKD region, HER2ex20ins, HER2YVMA) will be critical. Future treatment strategies for NSCLC should be developed according to the types of HER2 aberrations.
DCR, Disease control rate; DoR, Duration of response; EGFR, Epidermal growth factor receptor; ECD, Extracellular ligand-binding domain; ICI, Immune checkpoint inhibitor; IHC, Immunohistochemistry; NSCLC, Non-small cell lung cancer; NGS, Next generation sequencing; OS, Overall survival; PFS, Progression-free survival; PDX, Patient-derived xenotransplantation model; TKD, Tyrosine kinase domain.
The authors report no conflicts of interests in this work.
1. Clinton SK, Giovannucci EL, Hursting SD. The World Cancer Research Fund/American Institute for cancer research third expert report on diet, nutrition, physical activity, and cancer: impact and future directions. J Nutr. 2020;150(4):663–671. doi:10.1093/jn/nxz268
2. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–132. doi:10.3322/caac.21338
3. Peters S, Adjei AA, Gridelli C, et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(Suppl 7):vii56–vii64. doi:10.1093/annonc/mds226
4. Cetin K, Ettinger DS, Hei YJ, O’Malley CD. Survival by histologic subtype in stage IV nonsmall cell lung cancer based on data from the surveillance, epidemiology and end results program. Clin Epidemiol. 2011;3:139–148. doi:10.2147/CLEP.S17191
5. Mok T, Camidge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol. 2020;31(8):1056–1064. doi:10.1016/j.annonc.2020.04.478
6. Paik PK, Felip E, Veillon R, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 2020;383(10):931–943. doi:10.1056/NEJMoa2004407
7. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113–125. doi:10.1056/NEJMoa1713137
8. Wolf J, Seto T, Han JY, et al. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J Med. 2020;383(10):944–957. doi:10.1056/NEJMoa2002787
9. Stephens P, Hunter C, Bignell G, et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature. 2004;431(7008):525–526. doi:10.1038/431525b
10. Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009;9(7):463–475. doi:10.1038/nrc2656
11. Rimawi MF, Schiff R, Osborne CK. Targeting HER2 for the treatment of breast cancer. Annu Rev Med. 2015;66:111–128.
12. Gatzemeier U, Groth G, Butts C, et al. Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Ann Oncol. 2004;15(1):19–27. doi:10.1093/annonc/mdh031
13. Krug LM, Miller VA, Patel J, et al. Randomized phase II study of weekly docetaxel plus trastuzumab versus weekly paclitaxel plus trastuzumab in patients with previously untreated advanced nonsmall cell lung carcinoma. Cancer. 2005;104(10):2149–2155. doi:10.1002/cncr.21428
14. Liu L, Shao X, Gao W, et al. The role of human epidermal growth factor receptor 2 as a prognostic factor in lung cancer: a meta-analysis of published data. J Thorac Oncol. 2010;5(12):1922–1932. doi:10.1097/JTO.0b013e3181f26266
15. Arcila ME, Chaft JE, Nafa K, et al. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res. 2012;18(18):4910–4918. doi:10.1158/1078-0432.CCR-12-0912
16. Li C, Fang R, Sun Y, et al. Spectrum of oncogenic driver mutations in lung adenocarcinomas from East Asian never smokers. PLoS One. 2011;6(11):e28204. doi:10.1371/journal.pone.0028204
17. Li C, Sun Y, Fang R, et al. Lung adenocarcinomas with HER2-activating mutations are associated with distinct clinical features and HER2/EGFR copy number gains. J Thorac Oncol. 2012;7(1):85–89. doi:10.1097/JTO.0b013e318234f0a2
18. Mazieres J, Peters S, Lepage B, et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol. 2013;31(16):1997–2003. doi:10.1200/JCO.2012.45.6095
19. Tomizawa K, Suda K, Onozato R, et al. Prognostic and predictive implications of HER2/ERBB2/neu gene mutations in lung cancers. Lung Cancer. 2011;74(1):139–144. doi:10.1016/j.lungcan.2011.01.014
20. Yoshizawa A, Sumiyoshi S, Sonobe M, et al. HER2 status in lung adenocarcinoma: a comparison of immunohistochemistry, fluorescence in situ hybridization (FISH), dual-ISH, and gene mutations. Lung Cancer. 2014;85(3):373–378. doi:10.1016/j.lungcan.2014.06.007
21. Chen RZJ, Lin G, Liu L, Chen L, Hu X. NGS sequencing based liquid/tissue biopsy identiﬁed coexistence of HER2 ampliﬁcation and mutation in advanced NSCLC patients. J Thorac Oncol. 2017;12(11):S1830. doi:10.1016/j.jtho.2017.09.513
22. Li BT, Ross DS, Aisner DL, et al. HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers. J Thorac Oncol. 2016;11(3):414–419. doi:10.1016/j.jtho.2015.10.025
23. Nagano M, Kohsaka S, Ueno T, et al. High-throughput functional evaluation of variants of unknown significance in ERBB2. Clin Cancer Res. 2018;24(20):5112–5122. doi:10.1158/1078-0432.CCR-18-0991
24. Wang SE, Narasanna A, Perez-Torres M, et al. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell. 2006;10(1):25–38. doi:10.1016/j.ccr.2006.05.023
25. Fang W, Zhao S, Liang Y, et al. Mutation variants and co-mutations as genomic modifiers of response to afatinib in HER2-mutant lung adenocarcinoma. Oncologist. 2020;25(3):e545.
26. Notsuda H, Bradbury PA, Tsao MS. HER2 transmembrane domain mutations: rare new target for non-small cell lung cancer therapy. J Thorac Oncol. 2017;12(3):422–424. doi:10.1016/j.jtho.2017.01.007
27. Ou SI, Schrock AB, Bocharov EV, et al. HER2 Transmembrane Domain (TMD) mutations (V659/G660) that stabilize homo- and heterodimerization are rare oncogenic drivers in lung adenocarcinoma that respond to afatinib. J Thorac Oncol. 2017;12(3):446–457. doi:10.1016/j.jtho.2016.11.2224
28. Wei XW, Gao X, Zhang XC, et al. Mutational landscape and characteristics of ERBB2 in non-small cell lung cancer. Thorac Cancer. 2020;11(6):1512–1521. doi:10.1111/1759-7714.13419
29. Greulich H, Kaplan B, Mertins P, et al. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc Natl Acad Sci USA. 2012;109(36):14476–14481. doi:10.1073/pnas.1203201109
30. Ni J, Si XY, Zhang L. Non-small-cell lung cancer with ERBB2 mutation in non-tyrosine kinase domain benefits from pyrotinib: a case report. Thorac Cancer. 2021;12(8):1244–1247. doi:10.1111/1759-7714.13889
31. Liu Z, Wu L, Cao J, et al. Clinical characterization of ERBB2 exon 20 insertions and heterogeneity of outcomes responding to afatinib in Chinese lung cancer patients. Onco Targets Ther. 2018;11:7323–7331. doi:10.2147/OTT.S173391
32. Yuan B, Zhao J, Zhou C, et al. Co-occurring alterations of ERBB2 exon 20 insertion in Non-Small Cell Lung Cancer (NSCLC) and the potential indicator of response to afatinib. Front Oncol. 2020;10:729. doi:10.3389/fonc.2020.00729
33. De Greve J, Moran T, Graas M-P, et al. Phase II study of afatinib, an irreversible ErbB family blocker, in demographically and genotypically defined lung adenocarcinoma. Lung Cancer. 2015;88(1):63–69. doi:10.1016/j.lungcan.2015.01.013
34. Dziadziuszko R, Smit EF, Dafni U, et al. Afatinib in NSCLC with HER2 mutations: results of the prospective, open-label phase II NICHE trial of European Thoracic Oncology Platform (ETOP). J Thorac Oncol. 2019;14(6):1086–1094. doi:10.1016/j.jtho.2019.02.017
35. Hainsworth JD, Meric-Bernstam F, Swanton C, et al. Targeted therapy for advanced solid tumors on the basis of molecular profiles: results from MyPathway, an open-label, phase IIa Multiple Basket Study. J Clin Oncol. 2018;36(6):536–542. doi:10.1200/JCO.2017.75.3780
36. Hyman DM, Piha-Paul SA, Won H, et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2018;554(7691):189–194. doi:10.1038/nature25475
37. Kris MG, Camidge DR, Giaccone G, et al. Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors. Ann Oncol. 2015;26(7):1421–1427. doi:10.1093/annonc/mdv186
38. Lai WV, Lebas L, Barnes TA, et al. Afatinib in patients with metastatic or recurrent HER2-mutant lung cancers: a retrospective international multicentre study. Eur J Cancer. 2019;109:28–35. doi:10.1016/j.ejca.2018.11.030
39. Li BT, Shen R, Buonocore D, et al. Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. J Clin Oncol. 2018;36(24):2532–2537. doi:10.1200/JCO.2018.77.9777
40. Peters S, Curioni-Fontecedro A, Nechushtan H, et al. Activity of afatinib in heavily pretreated patients with ERBB2 mutation-positive advanced NSCLC: findings from a global named patient use program. J Thorac Oncol. 2018;13(12):1897–1905. doi:10.1016/j.jtho.2018.07.093
41. Peters S, Stahel R, Bubendorf L, et al. Trastuzumab Emtansine (T-DM1) in patients with previously treated HER2-overexpressing metastatic non-small cell lung cancer: efficacy, safety, and biomarkers. Clin Cancer Res. 2019;25(1):64–72. doi:10.1158/1078-0432.CCR-18-1590
42. Robichaux JP, Elamin YY, Tan Z, et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat Med. 2018;24(5):638–646. doi:10.1038/s41591-018-0007-9
43. Smit EFNK, Nagasaka M. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer: interim results of DESTINY-lung01[abstract]. J Clin Oncol. 2020;38(Abstract):9504. doi:10.1200/JCO.2020.38.15_suppl.9504
44. Tsurutani J, Iwata H, Krop I, et al. Targeting HER2 with trastuzumab deruxtecan: a dose-expansion, Phase I Study in multiple advanced solid tumors. Cancer Discov. 2020;10(5):688–701. doi:10.1158/2159-8290.CD-19-1014
45. Wang Y, Jiang T, Qin Z, et al. HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib. Ann Oncol. 2019;30(3):447–455. doi:10.1093/annonc/mdy542
46. Zhou C, Li X, Wang Q, et al. Pyrotinib in HER2-mutant advanced lung adenocarcinoma after platinum-based chemotherapy: a multicenter, open-label, single-arm, Phase II Study. J Clin Oncol. 2020;38(24):2753–2761. doi:10.1200/JCO.20.00297
47. De Greve J, Teugels E, Geers C, et al. Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer. 2012;76(1):123–127. doi:10.1016/j.lungcan.2012.01.008
48. Ivanova EBM, Aref A, Chen T, Taus L, Avogadri-Connors F. Short-term culture of patient derived tumor organoids identify neratinib/trastuzumab as an effective combination in HER2 mutant lung cancer. J Thorac Oncol. 2017;12(11):S1829–S1830. doi:10.1016/j.jtho.2017.09.512
49. Planchard D, Loriot Y, Andre F, et al. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015;26(10):2073–2078. doi:10.1093/annonc/mdv319
50. Liu S, Li S, Hai J, et al. Targeting HER2 aberrations in non-small cell lung cancer with osimertinib. Clin Cancer Res. 2018;24(11):2594–2604. doi:10.1158/1078-0432.CCR-17-1875
51. Park YH, Lee KH, Sohn JH, et al. A phase II trial of the pan-HER inhibitor poziotinib, in patients with HER2-positive metastatic breast cancer who had received at least two prior HER2-directed regimens: results of the NOV120101-203 trial. Int J Cancer. 2018;143(12):3240–3247. doi:10.1002/ijc.31651
52. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597–609. doi:10.1056/NEJMoa1914609
53. Cho HS, Mason K, Ramyar KX, et al. Structure of the extracellular region of HER2 alone and in complex with the herceptin fab. Nature. 2003;421(6924):756–760. doi:10.1038/nature01392
54. Mazieres J, Barlesi F, Filleron T, et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort. Ann Oncol. 2016;27(2):281–286. doi:10.1093/annonc/mdv573
55. Hotta K, Aoe K, Kozuki T, et al. A Phase II Study of trastuzumab emtansine in HER2-positive non-small cell lung cancer. J Thorac Oncol. 2018;13(2):273–279. doi:10.1016/j.jtho.2017.10.032
56. Ettinger DS, Wood DE, Aisner DL, et al. NCCN guidelines insights: non-small cell lung cancer, version 2.2021. J Natl Compr Canc Netw. 2021;19(3):254–266. doi:10.6004/jnccn.2021.0013
57. Doi T, Shitara K, Naito Y, et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a Phase 1 dose-escalation study. Lancet Oncol. 2017;18(11):1512–1522. doi:10.1016/S1470-2045(17)30604-6
58. Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321–1328. doi:10.1093/annonc/mdz167
59. Lin JJ, Gainor JF. Time to tackle the blood-brain barrier in HER2-mutant lung cancer. Cancer. 2019;125(24):4363–4366. doi:10.1002/cncr.32460
60. Hsu CC, Liao BC, Liao WY, et al. Exon 16-skipping HER2 as a novel mechanism of osimertinib resistance in EGFR L858R/T790M-positive non-small cell lung cancer. J Thorac Oncol. 2020;15(1):50–61. doi:10.1016/j.jtho.2019.09.006
61. Ramalingam SS, Yang JC, Lee CK, et al. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J Clin Oncol. 2018;36(9):841–849. doi:10.1200/JCO.2017.74.7576
62. Peters S, Zimmermann S. Targeted therapy in NSCLC driven by HER2 insertions. Transl Lung Cancer Res. 2014;3(2):84–88. doi:10.3978/j.issn.2218-6751.2014.02.06
63. Clamon G, Herndon J, Kern J, et al. Lack of trastuzumab activity in nonsmall cell lung carcinoma with overexpression of erb-B2: 39810: a phase II trial of cancer and leukemia group B. Cancer. 2005;103(8):1670–1675. doi:10.1002/cncr.20950
64. Press MF, Slamon DJ, Flom KJ, Park J, Zhou JY, Bernstein L. Evaluation of HER-2/neu gene amplification and overexpression: comparison of frequently used assay methods in a molecularly characterized cohort of breast cancer specimens. J Clin Oncol. 2002;20(14):3095–3105. doi:10.1200/JCO.2002.09.094
65. Al-Saad S, Al-Shibli K, Donnem T, Andersen S, Bremnes RM, Busund LT. Clinical significance of epidermal growth factor receptors in non-small cell lung cancer and a prognostic role for HER2 gene copy number in female patients. J Thorac Oncol. 2010;5(10):1536–1543. doi:10.1097/JTO.0b013e3181ea510a
66. Gazzaniga P, Gradilone A, Frati L, Agliano AM. Epidermal growth factor receptor mRNA expression in peripheral blood of bladder cancer patients: a potential marker to detect treatment failure. Clin Cancer Res. 2001;7(12):4288–4289.
67. Ross HJ, Blumenschein GR
68. Cappuzzo F, Janne PA, Skokan M, et al. MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients. Ann Oncol. 2009;20(2):298–304. doi:10.1093/annonc/mdn635
69. Takezawa K, Pirazzoli V, Arcila ME, et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov. 2012;2(10):922–933. doi:10.1158/2159-8290.CD-12-0108
70. Chong CR, Janne PA. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med. 2013;19(11):1389–1400. doi:10.1038/nm.3388
71. Yonesaka K, Zejnullahu K, Okamoto I, et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011;3(99):99ra86. doi:10.1126/scitranslmed.3002442
72. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19(8):2240–2247. doi:10.1158/1078-0432.CCR-12-2246
73. Ramalingam SSCY, Zhou C, Ohe Y, et al. Mechanisms of acquired resistance to ﬁrst-line osimertinib: preliminary data from the Phase III FLAURA study. Ann Oncol. 2018. doi:10.1093/annonc/mdy424.063
74. Xu CWW, Zhu Y, Yu Z, Zhang H, Wang H. Potential resistance mechanisms using next generation sequencing from Chinese EGFR T790M+ nonsmall cell lung cancer patients with primary resistance to osimertinib: a multicenter study. Ann Oncol. 2019;30:ii48.
75. Martin V, Landi L, Molinari F, et al. HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer patients. Br J Cancer. 2013;108(3):668–675. doi:10.1038/bjc.2013.4
76. Hotta K, Yanai H, Ohashi K, et al. Pilot evaluation of a HER2 testing in non-small-cell lung cancer. J Clin Pathol. 2020;73(6):353–357. doi:10.1136/jclinpath-2019-206204
77. Kuyama S, Hotta K, Tabata M, et al. Impact of HER2 gene and protein status on the treatment outcome of cisplatin-based chemoradiotherapy for locally advanced non-small cell lung cancer. J Thorac Oncol. 2008;3(5):477–482. doi:10.1097/JTO.0b013e31816e2ea3
78. Ninomiya K, Hata T, Yoshioka H, et al. A Prospective Cohort Study to define the clinical features and outcome of lung cancers harboring HER2 aberration in Japan (HER2-CS STUDY). Chest. 2019;156(2):357–366. doi:10.1016/j.chest.2019.01.011
79. Bunn PA
80. Langer CJ, Stephenson P, Thor A, Vangel M, Johnson DH; Eastern Cooperative Oncology Group S. Trastuzumab in the treatment of advanced non-small-cell lung cancer: is there a role? Focus on Eastern Cooperative Oncology Group study 2598. J Clin Oncol. 2004;22(7):1180–1187. doi:10.1200/JCO.2004.04.105
81. Herbst RS, Davies AM, Natale RB, et al. Efficacy and safety of single-agent pertuzumab, a human epidermal receptor dimerization inhibitor, in patients with non small cell lung cancer. Clin Cancer Res. 2007;13(20):6175–6181. doi:10.1158/1078-0432.CCR-07-0460
82. Johnson BE, Janne PA. Rationale for a phase II trial of pertuzumab, a HER-2 dimerization inhibitor, in patients with non-small cell lung cancer. Clin Cancer Res. 2006;12(14 Pt 2):4436s–4440s. doi:10.1158/1078-0432.CCR-06-0629
83. de Langen AJ, Jebbink M, Hashemi SMS, et al. Trastuzumab and paclitaxel in patients with EGFR mutated NSCLC that express HER2 after progression on EGFR TKI treatment. Br J Cancer. 2018;119(5):558–564. doi:10.1038/s41416-018-0194-7
84. Cretella D, Saccani F, Quaini F, et al. Trastuzumab emtansine is active on HER-2 overexpressing NSCLC cell lines and overcomes gefitinib resistance. Mol Cancer. 2014;13:143. doi:10.1186/1476-4598-13-143
85. Jamal-Hanjani M, Hackshaw A, Ngai Y, et al. Tracking genomic cancer evolution for precision medicine: the lung TRACERx study. PLoS Biol. 2014;12(7):e1001906. doi:10.1371/journal.pbio.1001906
86. La Monica S, Cretella D, Bonelli M, et al. Trastuzumab emtansine delays and overcomes resistance to the third-generation EGFR-TKI osimertinib in NSCLC EGFR mutated cell lines. J Exp Clin Cancer Res. 2017;36(1):174. doi:10.1186/s13046-017-0653-7
87. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a Phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–697. doi:10.1016/S0140-6736(10)61121-X
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