Targeted therapies in breast cancer: Where are we now?
Introduction
In recent years, improvements in the understanding of the altered molecular events leading to breast cancer have led to the identification of new molecular targets and the development of targeted therapy. One of the earliest validations to this approach has been observed with the anti-HER2 monoclonal antibody (MAb) trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing tumours and with the anti-angiogenesis MAb bevacizumab, respectively.1, 2 In the case of patients with HER2 amplified breast tumours, a group of tumours with poor prognosis, trastuzumab has markedly improved the survival of this subgroup of patients and has markedly changed the outcome of HER2 positive breast cancer.
Other potential hallmarks of malignancy that represent a new opportunity for therapeutic targeting include evasion of apoptosis, lack of senescence, invasion and metastasis and genomic elasticity.3 Therefore, new compounds are being developed that may interfere with these hallmarks and that may prove to be effective in monotherapy or in combination with cytotoxic therapy or other targeted therapies. This review highlights targeted agents that are furthest along in their clinical development as novel breast cancer therapeutics.
The development of these agents will require a new set of skills. First, these agents, unlike chemotherapy, will only work in the subset of tumours that show dependency on the target that the therapy is being directed to. This is again well exemplified by the anti-HER2 agent trastuzumab that is only active against tumour with high level of expression and/or amplification of the HER2 gene. Taking into account that HER2 is overexpressed in only 25% of breast tumours and that the single agent activity of trastuzumab is modest, if trastuzumab would have been developed in an unselected patient population, its antitumour activity would have been missed due to a dilutional effect brought in by the non-HER2-overexpressing population. This principle probably applies to the majority of classes of agents under study. The implication of this principle is that patient selection strategies will be of paramount importance in the development of these agents. Second, in early clinical studies with these agents in addition to establish their safety and optimal doses and schedules, it may prove to be instrumental to also check for the presence of the target in the studied tumours and to seek for indications of target engagement with the study agent. A debate, heated at times, is underway among the proposers of careful analysis of markers of target engagement – also known as pharmacodynamic studies (reviewed in [4]) – and those who are supporters of a more classical drug development process based on maximally tolerated doses. This review will not solve this discussion topic, but suffice to say that the need to determine target engagement is currently being taken into account with the majority of clinical trials with novel agents that are moved into the clinic. Third, the therapy end-points with these agents also need to be revisited. Some of these agents are not expected to result in tumour shrinkage (or response), and therefore we cannot propose a unified definition of clinical benefit as it has been done with chemotherapy in the past. Fourth, some of these agents will have limited activity by themselves and yet have the capacity to markedly enhance the antitumour activity of conventional agents like chemotherapy or even other biological agents. This later point is well exemplified by the anti-angiogenesis MAb bevacizumab that has no activity as a single agent and yet is clinically active when combined with chemotherapy. Lastly, with the increase in the number of available lines of therapy in breast cancer, there is a danger that novel agents will be tested in a heavily pre-treated patient population. While there is little debate that for early clinical studies patients with advanced disease that have received multiple lines of therapy may be appropriate study participants, there is also a growing concern that patients with advanced disease may not be the ideal population to detect the antitumour activity of novel agents since their tumours may have become highly resistant to any type of therapy. In addition, the drive to identify new biomarkers of target engagement and sensitivity with these novel agents is also promoting the search for new clinical study designs in a minimally pre-treated population. Studies of novel agents in the neo-adjuvant setting in breast cancer are therefore being incorporated with targeted therapeutics.
Section snippets
HER2 receptor inhibitors
The epidermal growth factor receptor (EGFR) family is composed of cell surface tyrosine kinase receptors that are involved in the regulation of cellular proliferation and survival of epithelial cells. The EGFR family includes four receptors: EGFR/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4. These receptors have an extracellular domain (ECD), a transmembrane region and an intracellular domain with tyrosine kinase activity. Except for HER2, binding of receptor-specific ligands to the ectodomain
Inhibitors of the PI3K/Akt/mTOR pathway
The PI3K/Akt pathway plays a central role in diverse cellular functions including proliferation, growth, survival and metabolism. In addition to their physiological role, several isoforms of the PI3K family are implicated in disease. In particular, members of class 1A PI3Ks, which are heterodimers comprising a p85 regulatory and a p110 catalytic subunit, are often mutated in human cancer.27, 28, 29, 30, 31, 32 As a result of receptor tyrosine kinase activation and phosphorylation, PI3K
Src-family tyrosine kinases inhibitors
The v-Src (Rous sarcoma virus) tyrosine kinase was the first oncogenic gene discovered.53 The corresponding cellular gene, c-Src, is a non-receptor signalling kinase that functions as a hub of a vast array of signal transduction pathways that influence cellular proliferation, differentiation, motility and survival.54
Several mechanisms lead to increased Src activity in tumours. Src is downstream in signalling from a number of growth factor receptors including PDGF receptor (PDGFR), epidermal
PARP inhibitors
Poly(ADP-ribose) polymerase 1 (PARP-1) is the initial and best characterised member of a family of enzymes largely associated with the maintenance of genomic stability. Activation of PARP-1 is part of the immediate cellular response to DNA strand breaks, converting them into an intracellular signal via poly(ADP-ribosylation) of nuclear proteins.71, 72 This results in a highly negatively charged target, which in turn leads to the unwinding and repair of the damaged DNA through the base excision
HSP90 inhibitors
Heat shock protein 90 (HSP90) is a molecular chaperone required for the stability and function of several conditionally activated and/or expressed signalling proteins.79 Many of these client proteins such as Akt, HER2, Bcr-Abl, c-Kit, EGFR and PDGFR-α are oncoproteins and important cell-signalling proteins.80, 81 As signal transducers and molecular switches, these client proteins are inherently unstable. HSP90 keeps unstable signalling proteins poised for activation until they are stabilised by
Targeted therapies in breast cancer: the way forward
We have reviewed some of the most promising new targeted agents in breast cancer. This list, however, is far from complete. Additional classes of agents in clinical development in breast cancer include inhibitors of angiogenesis, anti-IGF-1R MAbs and TKI’s, other tyrosine kinase inhibitors and also enhancers of apoptosis. We all hope that this list will keep enlarging.
As mentioned in the introduction, the clinical development of these agents will require a new set of skills and a greater degree
Conflict of interest statement
None declared.
References (90)
- et al.
The hallmarks of cancer
Cell
(2000) - et al.
Pharmacodynamic endpoints in primary breast cancer
Ann Oncol
(2007) - et al.
2-Year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial
Lancet
(2007) - et al.
Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth
Cancer Cell
(2002) - et al.
Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex
Cancer Cell
(2004) - et al.
Mutant PIK3CA promotes cell growth and invasion of human cancer cells
Cancer cell
(2005) - et al.
PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients
Cancer Cell
(2004) - et al.
A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer
Mol Cell
(2007) - et al.
Src and FAK signalling controls adhesion fate and the epithelial-to-mesenchymal transition
Curr Opin Cell Biol
(2005) - et al.
Analysis of pp60c-src protein kinase activity in human tumor cell lines and tissues
J Biol Chem
(1986)
PARP-2, a novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase
J Biol Chem
Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1
J Biol Chem
Clinical perspectives of PARP inhibitors
Pharmacol Res
Hsp90 inhibitors disrupt mitochondrial homeostasis in cancer cells
Chem Biol
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2
New Engl J Med
Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer
New Engl J Med
Untangling the ErbB signalling network
Nat Rev Mol Cell Biol
Common and distinct elements in cellular signaling via EGF and FGF receptors
Science
Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells
Proc Natl Acad Sci USA
Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer
Science
Overexpression of ErbB2 in cancer and ErbB2-targeting strategies
Oncogene
Humanization of an anti-p185HER2 antibody for human cancer therapy
PNAS
In vitro and in vivo anti-tumour effects of a humanised monoclonal antibody against c-erbB-2 product
Br J Cancer
Recombinant humanized anti-HER2 antibody (herceptinTM) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts
Cancer Res
Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group
J Clin Oncol
Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer
N Engl J Med
Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer
N Engl J Med
Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer
N Engl J Med
Lapatinib plus capecitabine for HER2-positive advanced breast cancer
New Engl J Med
EGF105084, a phase II study of lapatinib for brain metastases in patients (pts) with HER2+ breast cancer following trastuzumab (H) based systemic therapy and cranial radiotherapy (RT)
J Clin Oncol
Targeting HER2 in brain metastases from breast cancer
Clin Cancer Res
A phase II combination study of lapatinib (TYKERB) and paclitaxel as neoadjuvant therapy in patients with newly diagnosed inflammatory breast cancer (IBC)
Breast Cancer Res Treat
HKI-272, an irreversible pan erbB receptor tyrosine kinase inhibitor: Preliminary phase 1 results in patients with solid tumors
J Clin Oncol.
Phase 1 study with BIBW 2992, an irreversible dual tyrosine kinase inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) in a 2 week on 2 week off schedule
J Clin Oncol
Objective response rate in a Phase II multicenter trial of pertuzumab (P), a HER2 dimerization inhibiting monoclonal antibody, in combination with trastuzumab (T) in patients (Pts) with HER2 positive metastatic breast cancer (MBC) which had progressed during trastuzumab therapy
J Clin Oncol
High frequency of mutations of the PIK3CA gene in human cancers
Science
The PIK3CA gene is mutated with high frequency in human breast cancers
Cancer Biol Ther
PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas
Oncogene
Mutation of the PIK3CA gene in ovarian and breast cancer
Cancer Res
Frequent mutation of the PIK3CA gene in ovarian and breast cancers
Clin Cancer Res
The phosphatidylinositol 3′-kinase p85alpha gene is an oncogene in human ovarian and colon tumors
Cancer Res
New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway
Proc Nat Acad Sci
The phosphoinositide 3-kinase pathway
Science
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Science
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Nat Cell Biol
Cited by (79)
Effects of rapamycin on the mechanistic target of rapamycin (mTOR) pathway and telomerase in breast cancer cells
2018, Mutation Research - Genetic Toxicology and Environmental MutagenesisTherapeutic Use of Estrogen Receptor β Agonists in Prevention and Treatment of Endocrine Therapy Resistant Breast Cancers: Observations From Preclinical Models
2017, Progress in Molecular Biology and Translational ScienceRecent advances in the field of anti-cancer immunotherapy
2015, BBA ClinicalHormonal receptor positive breast cancer: Adjuvant treatment, first line inmetastatic cancer and new strategies (mTOR inhibition)
2015, Gaceta Mexicana de OncologiaReceptor-mediated endocytosis for drug delivery in African trypanosomes: Fulfilling Paul Ehrlich's vision of chemotherapy
2013, Trends in ParasitologyCitation Excerpt :Regardless of the precise cellular mechanisms behind the role of ISG75 in suramin accumulation by T. brucei, these data indicate that ISG75 (and ISG65) represents a novel means to access the parasite and deliver trypanocides. This has appeal, as the ISGs are specific to the parasite, and also is conceptually related to oncology therapies exploiting similarly novel or overexpressed antigens for clinical gain [40]. Most obviously, the design of compounds related to suramin or screened for binding to ISG75 (or even ISG65) may represent a targeted route by which novel trypanocidal drug entities can be identified.
Plant cyclopeptide RA-V kills human breast cancer cells by inducing mitochondria-mediated apoptosis through blocking PDK1-AKT interaction
2013, Toxicology and Applied Pharmacology