Breast Cancer: HER2 (ERBB2) targeting therapies
HER2 (encoded by the ERBB2 gene) is a tyrosine kinase that is one of the receptors for EGF (epidermal growth factor). HER2 is often mutated in tumors (approximately one quarter of breast cancers, for example), and mutant HER2's dysregulated activity drives several pathways that promote cancer cell phenotypes. Among the most studied downstream pathways that are activated by EGF are the MAPK and PI3K/Akt pathways. Mutations in the HER2 protein (referred to has HER2v here) are associated with poor prognosis. There are essentially two approaches for targeting HER2v positive cancers
- monoclonal antibodies to inhibit receptor activation
- small-molecule inhibitors to block tyrosine kinase activity
Both of these drug categories results in a loss of activity of the tyrosine kinase and an inhibition of the oncogenic potential of EGF pathway activation. Additionally, monoclonal antibodies can elicit immunological anticancer effects, including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and complement mediated cytotoxicity (CDC).
Monoclonal antibodies:
Trastuzumab (Herceptin ®) binds directly to HER2 and induces antibody-dependent cell mediated cytotoxicity (ADCC). These agents are large protein molecules that share common IgG domains. Trastuzumab has become the standard of care for HER2v positive breast tumors with lymph node involvement. It is also approved for a subset of HER2v+ gastric tumors and can be combined with classic chemotherapeutic agents. Because it is a large IgG macromolecule, monoclonal drugs are administered via infusion and infusion-type reactions are common. Trastuzumab is teratogenic and cannot be administered to pregnant women. It also has a black box warning for heart conditions (which can be magnified if given with anthracycline chemotherapy). Therefore, patients with reduced cardiac function or heart failure (low ejection fraction less than 35%) may not be able to tolerate trastuzumab. Fatigue, nauses/vomiting, and headache are common side effects. Low white blood cell counts and lung manifestations can occur since there are tyrosine kinase receptors in the lung.
Pertuzumab is a second-generation anti-HER2 drug, but it interacts with a different binding site (epitope) on HER2. It is indicated for early and metastatic breast cancer and is often combined with other chemotherapeutic agents. It is embryo-lethal and cardiotoxic and can precipitate heart failure as demonstrated by a reduced ejection fraction.
Some of the monoclonal antibodies can be conjugated to chemotherapeutic drugs (antibody-drug conjugates, or ADCs), which allows the targeted delivery of cytotoxic agents to HER2v positive cells. The cytotoxic payloads are only released once they have been internalized by the target cells, with the aim of reducing bystander killing. Two trastuzumab ADCs that are in clinical use are trastuzumab emtansine, a.k.a. ado-trastuzumab (FDA approved in 2013), and trastuzumab deruxtecan (FDA approved in 2019). Emtansine is a β-tubulin blocker, and deruxtecan is a topoisomerase I inhibitor.
N.B. Pre-2022 the INNs for monoclonal antibodies all contained the -mab suffix (or 'stem'). However, in mid 2022, the nomenclature for monoclonal antibodies was update by the WHO, to better delineate the emerging lineages of monoclonals and their derivatives. '-mab' was discontinued, and has been replaced by four new stems -tug, -bart, --ment and -mig. See Koch et al. (2022) International nonproprietary names for monoclonal antibodies: an evolving nomenclature system for a full description of these changes doi: 10.1080/19420862.2022.2075078.
Tyrosine kinase inhibitors:
A range of small molecular weight kinase inhibitors are used in the treatment of HER2v positive cancers. Due to similarities in the structure of the drug-binding sites within the tyrosine kinases, most of theses drugs inhibit several related growth factor RTKs, in addition to the EGF receptors, including PDGFR, KIT, FLT3 and CSF1R, and so are generally viewed as 'multi kinase' inhibitors. However, their polypharmacology undoubtedly contributes to their clinical efficacy. Over the years many inhibitors with anti-angiogenic and anti-prolifertive activities have been developed and brought to the clinic, and third generation inhibitors that selectively and irreversibly target mutated versions of EGFRs (whilst sparing wild type receptors) are available.
Lapatinib is a dual tyrosine kinase inhibitor which interrupts the HER2v and epidermal growth factor receptor (EGFR) pathways. It is used in combination with other chemoterapeutics in advanced or metastatic breast cancer cases. Due to its small molecular weight the drug is capable to penetrate the blood-brain barrier and therefore can be used in the management of brain metastatsis.
Tucatinib is a selective HER2v inhibitor, it is currently used for advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.
Examples for other multi-tyrosine kinase inhibitors include those below. However, these drugs are rarely used in breast cancer.
sunitinib- targets VEGFR2, PDGFR, Kit, FGFR, and others - first approved in 2006
pazopanib - targets VEGFR1, VEGFR2, VEGFR3, PDGFRβ, FGFR1, Kit and CSF1R- first approved in 2009
cabozantinib- targets VEGFR2, MET, RET- first approved in 2012
regorafenib- targets VEGFR2, BRAF- first approved in 2012
axitinib- targets VEGFR1, VEGFR2, VEGFR3, PDGFR, Kit- first approved in
nintedanib- targets VEGFRs, PDGFR and FGFR- first approved in 2014
osimertinib - an irreversible EGFR inhibitor, with selectivity for receptors with mutations that either sensitize the receptor, or cause drug resistance (e.g., the T790M mutation). The compound is less effective against the wild-type receptor- first approved in 2015
olmutinib- an irreversible inhibitor that targets mutant EGFR selectively over wild-type- approved in South Korea in 2016