Mechanism of action of trastuzumab and scientific update (2023)

  • Local immunotherapy of cancer and metastasis

    2021, Systemic Drug Delivery Strategies: Volume 2 of Delivery Strategies and Engineering Technologies in Cancer Immunotherapy

    Cancer immunotherapy has improved the clinical outcomes of cancer treatment. In the context of immunotherapy, traditional chemotherapy also sees a new opportunity as a companion treatment. However, their optimal and safe delivery remains a challenge due to the systemic adverse effects. Local drug delivery systems can help reduce the systemic toxicity of immunotherapy by confining the immunostimulatory effects on tumors. Introducing immunoactive biomaterials and combinations of supporting agents, drug delivery systems further enhance the efficacy of local antitumor immunity and enable its translation to systemic effects against metastatic tumors. This chapter summarizes different types of cancer immunotherapy and introduces various drug delivery systems used for their local delivery, focusing on intervention therapies using immunostimulators and chemotherapy. We discuss the rationales, outcomes, and remaining challenges of current delivery approaches.

  • A new anti-HER2 antibody that enhances the anti-tumor efficacy of trastuzumab and pertuzumab with a distinct mechanism of action

    2020, Molecular Immunology

    The majority of patients with metastatic breast cancer who are treated with the anti-HER2 monoclonal antibody, trastuzumab, generally develop resistance to the drug within a year after initiation of the treatment. Here we describe a new anti-HER2 humanized monoclonal antibody, 19H6-Hu, which binds to HER2 extracellular domain (ECD) with high affinity and inhibits proliferation of multiple HER2-overexpressing cancer cell lines as a single agent or in combination with trastuzumab. 19H6-Hu binds to the domain III in proximity to the domain IV of HER2 ECD, which differs from trastuzumab and pertuzumab. 19H6-Hu in combination with trastuzumab was more effective at blocking phosphorylation of ERK1/2, AKT(S473)and HER2 (Y1248) in HER2-positive cancer cells compared to trastuzumab alone or in combination with pertuzumab. Combination of three antibodies, 19H6-Hu, inetetamab (a trastuzumab analog) and pertuzumab exhibited much stronger inhibition of large NCI-N87 tumor xenografts (>400mm3) than the current standard of care, inetetamab (trastuzumab) plus Docetaxel (DTX), as well as the combination of 19H6-Hu, inetetamab and DTX. Our results highlight the functional variability of HER2 domains and provide a new insight into the design of HER2-targeting agents.

  • Novel flexible heteroarotinoid, SL-1-39, inhibits HER2-positive breast cancer cell proliferation by promoting lysosomal degradation of HER2

    2019, Cancer Letters

    SL-1-39 [1-(4-chloro-3-methylphenyl)-3-(4-nitrophenyl)thiourea] is a new flexible heteroarotinoid (Flex-Het) analog derived from the parental compound, SHetA2, previously shown to inhibit cell growth across multiple cancer types. The current study aims to determine growth inhibitory effects of SL-1-39 across the different subtypes of breast cancer cells and delineate its molecular mechanism. Our results demonstrate that while SL-1-39 blocks cell proliferation of all breast cancer subtypes tested, it has the highest efficacy against HER2+ breast cancer cells. Molecular analyses suggest that SL-1-39 prevents S phase progression of HER2+ breast cancer cells (SKBR3 and MDA-MB-453), which is consistent with reduced expression of key cell-cycle regulators at both the protein and transcriptional levels. SL-1-39 treatment also decreases the protein levels of HER2 and pHER2 as well as its downstream effectors, pMAPK and pAKT. Reduction of HER2 and pHER2 at the protein level is attributed to increased lysosomal degradation of total HER2 levels. This is the first study to show that a flexible heteroarotinoid analog modulates the HER2 signaling pathway through lysosomal degradation, and thus further warrants the development of SL-1-39 as a therapeutic option for HER2+ breast cancer.

    (Video) Trastuzumab Deruxtecan for Breast Cancer | NEJM

  • Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial

    2018, The Lancet Oncology

    ABP 980 (Amgen Inc, Thousand Oaks, CA, USA) is a biosimilar of trastuzumab, with analytical, functional, and pharmacokinetic similarities. We compared the clinical safety and efficacy of ABP 980 with that of trastuzumab in women with HER2-positive early breast cancer.

    We did a randomised, multicentre, double-blind, active-controlled equivalence trial at 97 study centres in 20 countries, mainly in Europe and South America. Eligible women were aged 18 years or older, had histologically confirmed HER2-positive invasive early breast cancer, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and were planning to have surgical resection of the breast tumour with sentinel or axillary lymph node dissection and neoadjuvant chemotherapy. After four cycles of run-in anthracycline-based chemotherapy, patients were assigned 1:1 to receive ABP 980 or trastuzumab with a permuted block design (blocks of four) computer-generated randomisation schedule. Patients received neoadjuvant therapy with a loading dose (8 mg/kg) of ABP 980 or trastuzumab plus paclitaxel 175 mg/m2 in a 90 min intravenous infusion, followed by three cycles of 6 mg/kg intravenous ABP 980 or trastuzumab plus paclitaxel 175 mg/m2 every 3 weeks in 30 min intravenous infusions (or 80 mg/m2 paclitaxel once per week for 12 cycles if that was the local standard of care). Randomisation was stratified by T stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographical region. Surgery was completed 3–7 weeks after the last dose of neoadjuvant treatment, after which adjuvant treatment with ABP 980 or trastuzumab was given every 3 weeks for up to 1 year after the first dose in the study. Patients had been randomly assigned at baseline to continue APB 980, continue trastuzumab, or switch from trastuzumab to APB 980 as their adjuvant treatment. The co-primary efficacy endpoints were risk difference and risk ratio (RR) of pathological complete response in breast tissue and axillary lymph nodes assessed at a local laboratory in all patients who were randomly assigned and received any amount of neoadjuvant investigational product and underwent surgery. We assessed safety in all patients who were randomly assigned and received any amount of investigational product. This trial is registered with, number NCT01901146 and Eudra, number CT 2012-004319-29.

    Of 827 patients enrolled, 725 were randomly assigned to receive ABP 980 (n=364) or trastuzumab (n=361). The primary endpoint was assessable in 696 patients (358 who received ABP 980 and 338 who received trastuzumab). Pathological complete response was recorded in 172 (48%, 95% CI 43–53) of 358 patients in the ABP 980 group and 137 (41%, 35–46) of 338 in the trastuzumab group (risk difference 7·3%, 90% CI 1·2–13·4; RR 1·188, 90% CI 1·033–1·366), with the upper bounds of the CIs exceeding the predefined equivalence margins of 13% and 1·318, respectively. Pathological complete response in the central laboratory assessment was seen in 162 (48%) of 339 patients assigned to ABP 980 at baseline and 138 (42%) of 330 assigned to trastuzumab at baseline (risk difference 5·8%, 90% CI −0·5 to 12·0, and RR 1·142, 90% CI 0·993 to 1·312). Grade 3 or worse adverse events during the neoadjuvant phase occurred in 54 (15%) of 364 patients in the ABP 980 group and 51 (14%) of 361 patients in the trastuzumab group, of which the most frequent grade 3 or worse event of interest was neutropenia, occurring in 21 (6%) patients in both groups. In the adjuvant phase, grade 3 or worse adverse events occurred in 30 (9%) of 349 patients continuing ABP 980, 11 (6%) of 171 continuing trastuzumab, and 13 (8%) of 171 who switched from trastuzumab to ABP 980, the most frequent grade 3 or worse events of interest were infections and infestations (four [1%], two [1%], and two [1%]), neutropenia (three [1%], two [1%], and one [1%]), and infusion reactions (two [1%], two [1%], and three [2%]). Two patients died from adverse events judged to be unrelated to the investigational products: one died from pneumonia while receiving neoadjuvant ABP 980 and one died from septic shock while receiving adjuvant ABP 980 after trastuzumab.

    Although the lower bounds of the 90% CIs for RR and risk difference showed non-inferiority, the upper bounds exceeded the predefined equivalence margins when based on local laboratory review of tumour samples, meaning that non-superiority was non-conclusive. In our sensitivity analyses based on central laboratory evaluation of tumour samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study.


  • HER2-positive early breast cancer: Affordable risks, affordable therapies, and new developments

    2018, Oncogenomics: From Basic Research to Precision Medicine

    Since the introduction of trastuzumab, the outcome of HER2-positive breast cancer patients has significantly improved. Nevertheless, some patients experience relapse despite optimal treatment. On the other hand, the current standard may be an overtreatment for patients at lower risk of relapse (small, node-negative tumors). In order to personalize treatment, there are two major directions: improve the prognosis of high-risk patients through more effective treatment strategies and improve the risk–benefit balance of anti-HER2 strategies for low-risk or frail patients. At the core of this research effort lies the identification of reliable prognostic and predictive biomarkers beyond stage, HER2, and hormone-receptors status.

  • The Role of MicroRNAs in HER2-Positive Breast Cancer: Where We Are and Future Prospective

    2022, Cancers

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  • Research article

    Trastuzumab-induced cardiotoxicity and role of mitochondrial connexin43 in the adaptive response

    Toxicology in Vitro, Volume 67, 2020, Article 104926

    Trastuzumab, the humanized monoclonal antibody specific for HER2 receptor, is the gold standard in the treatment of HER2+ breast cancer. Despite its high therapeutic efficacy, cardiotoxicity has emerged as a significant side effect. The molecular mechanisms involved are not well understood, but all converge on mitochondria. Mitochondrial Cx43 can confer cardioprotection by regulating mitochondrial calcium homeostasis, ROS production and propagation of apoptotic signals, and studies report that it is overexpressed both in ischemic preconditioning and in Doxorubicin-induced cardiotoxicity. This study was designed to evaluate whether mitochondrial Cx43 (mCx43) is also involved in Trastuzumab-induced cardiotoxicity. Here we demonstrated that mCx43 is overexpressed in Trastuzumab-treated H9c2 cells. Our data showed that inhibition of Cx43 translocation to mitochondria, obtained by radicicol pre-treatment, significantly increases cytosolic and mitochondrial superoxide formation, mitochondrial membrane depolarization and the consequent apoptosis induced by Trastuzumab. Our results support the hypothesis that disruption of mitochondrial function is the principal mechanism by which Trastuzumab elicits its cardiotoxicity and mCx43 appears to counteract the Trastuzumab-induced mitochondrial damage.

  • Research article

    The HER2 amplicon in breast cancer: Topoisomerase IIA and beyond

    Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1836, Issue 1, 2013, pp. 146-157

    HER2 gene amplification is observed in about 15% of breast cancers. The subgroup of HER2-positive breast cancers appears to be heterogeneous and presents complex patterns of gene amplification at the locus on chromosome 17q12-21. The molecular variations within the chromosome 17q amplicon and their clinical implications remain largely unknown. Besides the well-known TOP2A gene encoding Topoisomerase IIA, other genes might also be amplified and could play functional roles in breast cancer development and progression. This review will focus on the current knowledge concerning the HER2 amplicon heterogeneity, its clinical and biological impact and the pitfalls associated with the evaluation of gene amplifications at this locus, with particular attention to TOP2A and the link between TOP2A and anthracycline benefit. In addition it will discuss the clinical and biological implications of the amplification of ten other genes at this locus (MED1, STARD3, GRB7, THRA, RARA, IGFPB4, CCR7, KRT20, KRT19 and GAST) in breast cancer.

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  • Research article

    Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNγ secretion

    Cancer Letters, Volume 430, 2018, pp. 47-56

    Here, we report that treatment of syngeneic mouse tumors transduced to overexpress human epidermal growth factor receptor-2 (HER2) with the anti-human HER2 antibody trastuzumab upregulated the level of programmed death-ligand 1 (PD-L1), an important negative regulator of T-cell response, in a transgenic mouse model immune-tolerant to human HER2. We further found that trastuzumab alone had no detectable effect on the level of PD-L1 expression in monocultures of HER2-overexpressing human breast cancer cells but upregulated PD-L1 in the same panel of HER2-overexpressing breast cancer cells when they were co-cultured with human peripheral blood mononuclear cells, and the upregulation of PD-L1 could be blocked by an IFNγ-neutralizing antibody. Inhibition of HER2 intrinsic signaling via HER2 expression knockdown or kinase inhibition had variable and cell-context-specific effects on downregulating the PD-L1 level. Analysis of The Cancer Genome Atlas database showed no direct correlation between HER2 and PD-L1 at the messenger RNA level. Trastuzumab-mediated upregulation of PD-L1 through engagement of immune effector cells may function as a potential mechanism of trastuzumab resistance. Our data justify further investigation of the value of adding anti-PD-1 or anti-PD-L1 therapy to trastuzumab-based treatment.

  • Research article

    A systematic review of dual targeting in HER2-positive breast cancer

    Cancer Treatment Reviews, Volume 40, Issue 2, 2014, pp. 259-270

    Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15–20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both the adjuvant and metastatic settings. However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. The present review addresses efficacy and toxicity of dual targeting in HER2-positive breast cancer.

    A computer-based literature search was carried out using PubMed; data reported at international meetings and was included.

    (Video) Research Update for HER2-Positive MBC | 2021-2022 EMBRACE MBC Virtual Forum Series

    This paper describes efficacy and safety of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described.

    Dual blockade is likely to represent a substantial advance for patients with HER2-positive breast cancer. However, the relevant subpopulation remains to be defined and side effects including cardiotoxicity might be a limiting factor to the use. There is an urgent need for prospective biomarker-driven trials to identify patients for whom dual targeting is cost-effective.

  • Research article

    HER2-positive breast cancer: Current and new therapeutic strategies

    The Breast, Volume 39, 2018, pp. 80-88

    Since the identification of the HER2 receptor amplification as an adverse prognostic factor that defined a special subtype of metastatic breast cancer, there has been a substantial improvement in survival of patients affected with this disease due to the development of anti-HER2 targeted therapies. The approval of trastuzumab and pertuzumab associated to a taxane in first line and subsequent treatment with the antibody-drug conjugate T-DM1 has certainly contributed to achieve these outcomes. The Tyrosine Kinase Inhibitor lapatinib was also approved in the basis of an improvement in progression free survival, becoming another commonly used treatment in combination with capecitabine. Inevitably, despite these therapeutic advances most patients progress on therapy due to primary or acquired resistance or because of an incorrect HER2 positivity assessment. Hence, it is crucial to correctly categorize HER2 amplified tumors and define mechanisms of resistance to design effective new treatment approaches. In addition, identifying biomarkers of response or resistance permits to tailor the therapeutic options for each patient sparing them from unnecessary toxicity as well as improving their outcomes. The aim of this review is to examine new strategies in development to treat HER2-positive metastatic breast cancer referring to the mechanisms of action of new drugs and new combinations including results reported so far.

  • Research article

    Treatment of advanced HER2-positive breast cancer: 2018 and beyond

    Cancer Treatment Reviews, Volume 67, 2018, pp. 10-20

    In the 1980s the importance of HER2 signalling to the aberrant behaviour of a subset of breast cancer cells was recognized for the first time and, consequently, a hitherto unknown subtype of breast cancer – HER2-positive (HER2+) breast cancer was identified. The development of the anti-HER2 class of drugs, first with trastuzumab, followed closely by lapatinib, pertuzumab, and T-DM1, has improved outcomes dramatically. Nevertheless, metastatic HER2+ breast cancer remains an incurable disease and new therapeutic options are needed. Additionally, the rapid changes in treatment standards 5 years ago have left unanswered numerous questions, including the “real-life” benefit of pertuzumab and T-DM1, since both the CLEOPATRA and EMILIA trials were conducted in populations that no longer exist in practice and, moreover, on the role of endocrine therapy in HER2+ disease. Furthermore, despite significant research efforts, including translational efforts and new imaging techniques, no predictive biomarkers have been clinically validated and therefore a more refined approach to treatment tailoring remains beyond our reach. Finally, a better understanding of resistance to currently existing anti-HER2 agents and of the role played by the microenvironment (e.g. immune system) and of interconnected signalling pathways (e.g. PI3K-mTOR-AKT) is at the core of clinical trials exploring new drugs and new regimens. These include the combination of anti-HER2 agents and anti-PD-1/PDL-1, PI3K inhibitors and CDK 4/6 inhibitors, as well as a host of new panHER inhibitors, drug antibody conjugates and anti-HER antibodies, which may, in coming years further push the boundaries of what we can do for our patients.

Copyright © 2001 Published by Elsevier Inc.

(Video) Breast Cancer Breakout: Rapid research developments and new treatment combinations


1. Research Update for HER2-Positive MBC | 2022-2023 EMBRACE MBC Virtual Forum Series
(Dana-Farber Cancer Institute)
2. Research Update for Triple Negative MBC | 2022-2023 EMBRACE MBC Virtual Forum Series
(Dana-Farber Cancer Institute)
3. Title: Update on Breast Cancer Therapeutics and Biomarkers
(Innovinc Conferences)
4. Dr. Hamilton Discusses Trastuzumab deruxtecan - NBCLX
(Sarah Cannon Research Institute)
5. Metastatic HER2-Positive Breast Cancer: Newer and Emerging Treatment Considerations
(HMP Education)
6. Herceptin (trastuzumab) for HER2-Positive Breast and Stomach Cancer
(Oncology Associates)
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