Elsevier

European Journal of Cancer

Volume 44, Issue 18, December 2008, Pages 2781-2790
European Journal of Cancer

Targeted therapies in breast cancer: Where are we now?

https://doi.org/10.1016/j.ejca.2008.09.026Get rights and content

Abstract

Over the past several years significant advances have been made in our understanding of a growing number of critical pathways involved in breast cancer. These advances have led to the development of novel therapies that are being collectively known as molecularly targeted in order to highlight their specificity and their interference with key molecular events responsible for the malignant phenotype.

Examples of approved targeted agents in breast cancer include agents directed against the human epidermal growth factor receptor 2 (HER2) such as trastuzumab and lapatinib and the anti-VEGF bevacizumab. In addition, there are classes of therapies under evaluation including novel anti-HER2 therapies, agents against other tyrosine kinases including Src and Insulin-Like Growth Factor Receptor agents interfering with critically important signalling pathways such as the PI3K/Akt/mTOR inhibitors and agents that promote apoptosis such as Parp inhibitors and others.

The challenges that are being brought by these novel therapies are different from those being faced with conventional chemotherapy. They include the selection of appropriate dose and schedule, safety issues, selection of the patient population most likely to benefit and early readouts of clinical benefit. We will present these novel therapies and will analyse for each target the developmental status of some of the agents as well as target-specific challenges.

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.

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