HER2-targeted therapies — a role beyond breast cancer

Published on Jan 1, 2020in Nature Reviews Clinical Oncology53.276
· DOI :10.1038/S41571-019-0268-3
Do Youn Oh (SNU: Seoul National University), Do-Youn Oh30
Estimated H-index: 30
(New Generation University College),
Yung-Jue Bang107
Estimated H-index: 107
(SNU: Seoul National University)
Sources
Abstract
HER2 is an established therapeutic target in a large subset of women with breast cancer; a variety of agents including trastuzumab, pertuzumab, lapatinib, neratinib and trastuzumab emtansine (T-DM1) have been approved for the treatment of HER2-positive breast cancer. HER2 is also overexpressed in subsets of patients with other solid tumours. Notably, the addition of trastuzumab to first-line chemotherapy has improved the overall survival of patients with HER2-positive gastric cancer, and has become the standard-of-care treatment for this group of patients. However, trials involving pertuzumab, lapatinib and T-DM1 have failed to provide significant improvements in the outcomes of patients with HER2-positive gastric cancer. HER2-targeted therapies are also being tested in patients with other solid tumours harbouring HER2 overexpression, and/or amplifications or other mutations of the gene encoding HER2 (ERBB2), including biliary tract, colorectal, non-small-cell lung and bladder cancers. The experience with gastric cancer suggests that the successes observed in HER2-positive breast cancer might not be replicated in these other tumour types, owing to differences in the level of HER2 overexpression and other aspects of disease biology. In this Review, we describe the current role of HER2-targeted therapies beyond breast cancer and also highlight the potential of novel HER2-targeted agents that are currently in clinical development. HER2-targeted therapies have dramatically improved the outcomes in women with HER2-positive breast cancer. Furthermore, genetic sequencing studies have revealed HER2 alterations in a range of other cancers, including gastric cancer, colorectal cancer and non-small-cell lung cancer. In this Review the authors describe the available data on HER2-targeted therapies beyond breast cancer.
📖 Papers frequently viewed together
47 Citations
43 Citations
2012
1 Author (Rita Nahta)
14 Citations
References139
Newest
#2Joseph C. GonzalezH-Index: 5
Last. Michael N. AlonsoH-Index: 10
view all 19 authors...
Deficient anti-tumor immunity often results from an immunosuppressive tumor microenvironment (TME) that renders antigen presenting cells (APCs) unable to effectively stimulate T cells. Recent studies indicate that local delivery of immunostimulatory adjuvants can activate tumor resident APCs, driving uptake, processing and presentation of tumor neoantigens to T cells that mediate anti-tumor immunity. To overcome challenges associated with intratumoral delivery of such adjuvants, we developed a n...
5 CitationsSource
#1Kenji TamuraH-Index: 35
#2Junji Tsurutani (Kindai University)H-Index: 34
Last. Shanu Modi (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 46
view all 17 authors...
Summary Background Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody–drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and potent topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing, advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansio...
102 CitationsSource
#1Kohei ShitaraH-Index: 46
#2Hiroji IwataH-Index: 72
Last. Toshihiko DoiH-Index: 61
view all 15 authors...
Summary Background Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody–drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5·4...
67 CitationsSource
#1Anna Dorothea Wagner (UNIL: University of Lausanne)H-Index: 16
#2Heike I. Grabsch (UM: Maastricht University)H-Index: 34
Last. Florian LordickH-Index: 72
view all 15 authors...
10–20% of patients with gastric cancer (GC) have HER2+ tumors. Addition of trastuzumab (T) to cisplatin/fluoropyrimidine-based chemotherapy (CT) improved survival in metastatic, HER2+ GC. When pertuzumab (P) was added to neoadjuvant T and CT, a significant increase in histopathological complete response rate was observed in HER2+ breast cancer. This study aims to investigate the added benefit of using both HER2 targeting drugs (T alone or the combination of T + P), in combination with perioperat...
30 CitationsSource
#1Funda Meric-Bernstam (University of Texas MD Anderson Cancer Center)H-Index: 108
#2Amber Johnson (University of Texas MD Anderson Cancer Center)H-Index: 14
Last. Sarina Anne Piha-Paul (University of Texas MD Anderson Cancer Center)H-Index: 56
view all 9 authors...
The introduction of HER2-targeted therapy for breast and gastric patients with ERBB2 (HER2) amplification/overexpression has led to dramatic improvements in oncologic outcomes. In the past 20 years, five HER2-targeted therapies have been FDA approved, with four approved in the past 8 years. HER2-targeted therapy similarly was found to improve outcomes in HER2-positive gastric cancer. Over the past decade, with the introduction of next-generation sequencing into clinical practice, our understandi...
76 CitationsSource
#1Gabriel Rinnerthaler (Salk Institute for Biological Studies)H-Index: 13
#1Gabriel Rinnerthaler (Salk Institute for Biological Studies)H-Index: 1
Last. Richard Greil (Salk Institute for Biological Studies)H-Index: 13
view all 3 authors...
Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed therapies, the prognosis of HER2 amplified breast cancers has improved meaningfully. Next to monoclonal anti-HER2 antibodies and tyrosine kinase inhibitors, the antibody-drug conjugate T-DM1 is a pillar of targeted treatment of advanced HER2-positive breast cancers. Currently, several HER2 directed antibody-drug conjugates are under ...
53 CitationsSource
#1Yan Wang (Tongji University)H-Index: 9
#2Tao Jiang (Tongji University)H-Index: 27
Last. Fred R. Hirsch (Anschutz Medical Campus)H-Index: 88
view all 19 authors...
ABSTRACT Background Effective targeted therapy for non-small-cell lung cancer (NSCLC) patients with human epidermal growth factor receptor 2 (HER2) mutations remains an unmet need. This study investigated the antitumor effect of an irreversible pan-HER receptor tyrosine kinase inhibitor, pyrotinib. Patients and methods Using patient-derived organoids and xenografts established from an HER2-A775_G776YVMA-inserted advanced lung adenocarcinoma patient sample, we investigated the antitumor activity ...
66 CitationsSource
#1Sherene Loi (Peter MacCallum Cancer Centre)H-Index: 85
#2Anita Giobbie-Hurder (Harvard University)H-Index: 59
Last. Patrick SchneierH-Index: 1
view all 58 authors...
Summary Background HER2-positive breast cancers usually contain large amounts of T-cell infiltrate. We hypothesised that trastuzumab resistance in HER2-positive breast cancer could be mediated by immune mechanisms. We assessed the safety and anti-tumour activity of pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, added to trastuzumab in trastuzumab-resistant, advanced HER2-positive breast cancer. Methods We did this single-arm, multicentre, phase 1b–2 trial in 11 centres based ...
144 CitationsSource
#1Tanja Ignatov (Otto-von-Guericke University Magdeburg)H-Index: 16
#2Franceska Gorbunow (Otto-von-Guericke University Magdeburg)H-Index: 1
Last. Atanas Ignatov (Otto-von-Guericke University Magdeburg)H-Index: 18
view all 5 authors...
Purpose HER2 expression has been reported to be discordant between primary tumor and metastatic tissue.
10 CitationsSource
#1Shanu ModiH-Index: 46
#2Junji TsurutaniH-Index: 34
Last. S. TakahashiH-Index: 9
view all 16 authors...
Background: HER2-targeted therapies have improved survival for advanced HER2-positive breast cancers (BC), but none have been approved for tumors with low levels of HER2 expression (ie, HER2 IHC 1+ or 2+/ISH-negative). Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody attached to a potent topoisomerase I inhibitor payload by a cleavable peptide-based linker, which is designed to have broad antitumor activity in HER2-expressing tumor...
12 CitationsSource
Cited By126
Newest
Last. Gang Du (Guangxi Medical University)
view all 4 authors...
Abstract Breast cancer (BC) is considered as one the most prevalent cancers worldwide. Due to its high resistance to chemotherapy and high probability of metastasis, BC is one of the leading causes of cancer-related deaths. The controlled release of chemotherapy drugs to the precise site of the tumor tissue will increase the therapeutic efficacy and decrease side effects of systemic administration. Among various drug delivery systems, natural polymers-based drug carriers have gained significant ...
2 CitationsSource
#1Hester A. Doyle (Yale University)H-Index: 16
#2Renelle J. Gee (Yale University)H-Index: 14
view all 0 authors...
Epidermal Growth Factor Receptor (EGFR) is overexpressed on a number of human cancers, and often is indicative of a poor outcome. Treatment of EGFR/HER2 overexpressing cancers includes monoclonal antibody therapy (cetuximab/trastuzumab) either alone or in conjunction with other standard cancer therapies. While monoclonal antibody therapy has been proven to be efficacious in the treatment of EGFR/HER2 overexpressing tumors, drawbacks include the lack of long-lasting immunity and acquired resistan...
Source
#1Tianyou Chen (China University of Geosciences (Beijing))H-Index: 1
#2Chunxia Huang (China University of Geosciences (Beijing))H-Index: 1
Last. Jing Wu (China University of Geosciences (Beijing))H-Index: 5
view all 4 authors...
Abstract null null Cell is the most basic unit of the morphological structure and life activity of an organism. Learning the composition, structure and function of cells, exploring the life activities of cells and studying the interaction between cells are of great significance for human cognition and control of the life activities of organisms. Therefore, rapid, convenient, inexpensive, high-precision and reliable methods of cell separation and analysis are being developed to obtain accurate in...
Source
#1Tianqi Xu (Uppsala University)H-Index: 2
#2Anzhelika Vorobyeva (Uppsala University)H-Index: 11
Last. Vladimir Tolmachev (Uppsala University)H-Index: 61
view all 11 authors...
Efficient treatment of disseminated ovarian cancer (OC) is challenging due to its heterogeneity and chemoresistance. Overexpression of human epidermal growth factor receptor 2 (HER2) and epithelial cell adhesion molecule (EpCAM) in approx. 30% and 70% of ovarian cancers, respectively, allows for co-targeted treatment. The clinical efficacy of the monoclonal antibody trastuzumab in patients with HER2-positive breast, gastric and gastroesophageal cancers makes it readily available as the HER2-targ...
Source
#1Yu Hua (PRC: China Medical University (PRC))
#2Lihong Gao (PRC: China Medical University (PRC))
Last. Xiaobo Li (PRC: China Medical University (PRC))
view all 3 authors...
Background: Reprogramming of cell metabolism is one of the most important hallmark of breast cancer. This study aimed to comprehensively analyze metabolic genes in the initiation, progression and prognosis of breast cancer. Materials and Methods: Data from TCGA in breast cancer were downloaded including RNA-seq, copy number variation, mutation and DNA methylation. Gene co-expression network was constructed by the WGCNA package in R. Association of metabolic genes with tumor related immune cells ...
Source
#1Lingzhou Zhao (SJTU: Shanghai Jiao Tong University)H-Index: 15
#2Changcun Liu (SJTU: Shanghai Jiao Tong University)H-Index: 6
Last. Jinhua Zhao (SJTU: Shanghai Jiao Tong University)H-Index: 18
view all 7 authors...
Accurate determination of human epidermal growth factor receptor 2 (HER2) expression is essential for HER2-targeted therapy in patients with cancer. HER2 expression in a complex environment, such as in a heterogeneous tumor, makes the precise assessment of the HER2 status difficult using current methods. In this study, we developed a novel 99mTc-labeled anti-HER2 single-domain antibody (99mTc-NM-02) as a molecular imaging tracer for the noninvasive detection of HER2 expression and investigated i...
Source
#1Yasuhiro Maruoka (NIH: National Institutes of Health)H-Index: 13
#2Hiroaki Wakiyama (NIH: National Institutes of Health)H-Index: 4
Last. Hisataka Kobayashi (NIH: National Institutes of Health)H-Index: 80
view all 4 authors...
Near-infrared photoimmunotherapy (NIR-PIT) is a newly-developed, highly-selective cancer treatment, which utilizes a monoclonal antibody conjugated to a photoabsorbing dye, IRDye700DX (IR700). The antibody conjugate is injected into the patient and accumulates in the tumour. Within 24 h of injection the tumour is exposed to NIR light which activates the conjugate and causes rapid, selective cancer cell death. A global phase III clinical trial of NIR-PIT in recurrent head and neck squamous cell c...
Source
#1Yaakov E. Stern (McGill University)
#2Stephanie Duhamel (McGill University)H-Index: 2
Last. Morag ParkH-Index: 68
view all 10 authors...
Receptor tyrosine kinases (RTKs) are recognized as targets of precision medicine in human cancer upon their gene amplification or constitutive activation, resulting in increased downstream signal complexity including heterotypic crosstalk with other RTKs. The Met RTK exhibits such reciprocal crosstalk with several members of the human EGFR (HER) family of RTKs when amplified in cancer cells. We show that Met signaling converges on HER3 tyrosine phosphorylation across a panel of seven MET-amplifi...
Source
#1Carla De Giovanni (UNIBO: University of Bologna)H-Index: 34
#2Lorena LanduzziH-Index: 36
Last. Pier Luigi Lollini (UNIBO: University of Bologna)H-Index: 67
view all 6 authors...
Rhabdomyosarcomas (RMS) are tumors of the skeletal muscle lineage. Two main features allow for distinction between subtypes: morphology and presence/absence of a translocation between the PAX3 (or PAX7) and FOXO1 genes. The two main subtypes are fusion-positive alveolar RMS (ARMS) and fusion-negative embryonal RMS (ERMS). This review will focus on the role of receptor tyrosine kinases of the human epidermal growth factor receptor (EGFR) family that is comprised EGFR itself, HER2, HER3 and HER4 i...
Source
#1Masuko KatohH-Index: 30
#2Masaru KatohH-Index: 69
Source