New therapeutic approaches in breast cancer

Maturitas 68 (2011) 121–128

Contents lists available at ScienceDirect

Maturitas journal homepage: www.elsevier.com/locate/maturitas

Review

New therapeutic approaches in breast cancer Eleri Davies a , Stephen Hiscox b,∗ a b

Surgical Breast Centre, Singleton Hospital, Swansea SA2 8QA, United Kingdom Welsh School of Pharmacy, Redwood Building, Cardiff University, Cardiff CF10 3NB, United Kingdom

a r t i c l e

i n f o

Article history: Received 29 October 2010 Received in revised form 29 October 2010 Accepted 29 October 2010

Keywords: Breast cancer Targeted therapy HER2 EGFR mTOR

a b s t r a c t Breast cancer is the most common cancer among women in the UK, with 46,000 new cases and 12,000 deaths due to this disease estimated to have occurred in 2008. Around three-quarters of breast cancers express the estrogen receptor and are therefore presumed to be hormone-responsive and potentially treatable or preventable by anti-estrogenic agents. Expression of the HER2 receptor occurs in a fifth of breast cancers and is associated with limited endocrine response in hormone receptor-positive tumours and directs treatment with HER2-targeted agents. Despite improvements in the clinical outcome of breast cancer patients through the development of endocrine and targeted agents, overcoming de novo or acquired resistance remains a considerable therapeutic hurdle. In addition, as our understanding of the complexity of breast cancer biology increases, it is clear that existing therapies will fall short of offering an effective treatment solution to many patients. The ability to profile molecular pathways in drugresponsive and drug-resistant tumours has provided an important step in identifying novel targets in breast cancer. To this end, a number of new targeted therapeutics are currently being investigated both as single agents and as a means to improve existing therapeutic regimens. © 2010 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2.

3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ER+ disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Endocrine therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Emerging therapeutic strategies in ER+ breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Growth factor inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Farnesyl transferase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3. mTOR inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HER2+ disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Targeted therapy in HER+ disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Trastuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Lapatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. New therapeutic strategies in HER2+ disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. mTOR inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Heat shock protein 90 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Antibody-based strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Basal/triple-negative breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. PARP inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. EGFR inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. VEGF inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. mTOR inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Src inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Tel.: +44 02920 870107; fax: +44 02920 875157. E-mail address: [email protected] (S. Hiscox). 0378-5122/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2010.10.012

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Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Breast cancer represents a major cause of death for women in the Western world with a 10% lifetime risk of the disease and over 1 million new cases annually. The majority of breast cancers express the estrogen receptor (ER) and are thus potentially sensitive to the growth-promoting effects of circulatory oestrogens. As such, therapies targeted at abrogating oestrogen-dependence represent the standard form of treatment for ER-positive breast cancers and have been employed successfully for decades. The selective ER modulator tamoxifen, in particular, has been widely used for its excellent efficacy as well as its favourable side effect profile in the adjuvant endocrine treatment of post-menopausal women or alongside ovarian suppression in a pre-menopausal context [1]. More recently, aromatase inhibitors have demonstrated excellent performance in several large international trials and are emerging as a new standard therapy for estrogen-dependent breast cancers [2]. Over the last two decades, our understanding of the complexity of breast cancer biology has increased and we now consider breast cancer to encompass a range of diseases with different behaviours, which require different treatments. The development and application of array-based technologies has revealed a number of intrinsic molecular subtypes: the luminal A and B subtypes are mostly ER+ tumours which are of histological low and high grade respectively; the HER2+ subtype, characterized by amplification and overexpression of the human epidermal growth factor receptor-2 (HER2) gene, and the basal-like subtype, which are mostly ER, progesterone receptor (PR) and HER2 negative and therefore at present lack any specific therapeutic target [3,4]. Our knowledge of breast cancer molecular biology has led to the development of a number of targeted therapies with proven effectiveness clinically. However, a significant proportion of patients with early-stage breast cancer will have recurrent disease as will almost all patients in the metastatic setting, clearly demonstrating the need for better treatments, tailored to specific cancer subtypes, which will improve existing outcomes and circumvent the problem of therapeutic resistance. Our increasing understanding of the molecular biology underlying breast cancer subtypes and therapeutic response/resistance mechanisms will continue to reveal potential drug targets that will result in a wider range of therapeutic options. This review will focus on new targeted therapies that are either currently under pre-clinical and/or clinical development in addition to discussing novel targeted therapies that have already become the standard of care for specific breast cancer types. 2. ER+ disease 2.1. Endocrine therapy Breast cancers positive for the ER are potentially sensitive to the growth-promoting effects of estrogens. Subsequently, the development and clinical application of a number of various steroid receptor modulators has provided a great opportunity to effectively manage ER+ breast disease. Although endocrine therapies with tamoxifen have proved beneficial in these tumours, the estrogenic effects of tamoxifen in other tissues and organs can increase the risk of endometrial cancer [5], thromboembolic events and stroke [6].

126 126 126 126 126

Furthermore, the benefits of adjuvant tamoxifen are limited to the first 5 years of treatment since extending tamoxifen for longer than this does not improve survival [7]. The development of aromatase inhibitors (AIs) represents a new strategy in the treatment of breast cancer; these agents abrogate estrogen-induced ER activation but do not possess estrogenic effects associated with tamoxifen. Consequently, AIs have a much improved side effect profile compared with tamoxifen [8] and appear superior in limiting disease recurrence [9]. Fulvestrant was developed as a novel type of ER antagonist and prevents ER dimerization resulting in rapid degradation and loss of cellular ER. In hormone-sensitive xenografts models, fulvestrant delayed the emergence of acquired resistance compared with tamoxifen although it has been shown to be no more effective than either tamoxifen or aromatase inhibitors as a first-line agent in advanced breast cancer. However, fulvestrant displays an efficacy similar to that of AI when used as a second- and/or third-line agent [10,11]. Importantly, xenograft models suggest that combination treatment using AIs alongside fulvestrant are significantly more effective at delaying resistance compared to each as a single agent [12]. Consequently, the use of fulvestrant in combination with AIs is currently being investigated through a number of phase III clinical trials [13]. Despite the undoubted benefits for breast cancer patients achieved with these treatments, their effectiveness is limited by the phenomenon of hormone resistance. Clinically, around 50% of metastatic breast cancers will display an intrinsic resistance to hormone therapies despite being hormone receptor positive (de novo resistance) whilst more than a third of patients with endocrineresponsive, early stage breast cancer and almost all of those with metastatic disease will acquire resistance during the course of their disease [14,15] despite an initial response to the therapy, resulting in disease relapse and progression. An understanding of the cellular processed that underlie endocrine insensitivity has been central to the identification of alternative therapeutic targets through which the effectiveness of existing endocrine therapies may be enhanced in order to overcome de novo or acquired resistance. 2.2. Emerging therapeutic strategies in ER+ breast cancer 2.2.1. Growth factor inhibitors It is now clear that cross-talk between the ER and growth factor signalling pathways plays a key role in promoting a resistant phenotype [16]. Acquired tamoxifen-resistant breast cancer cell lines over-express the epidermal growth factor receptor (EGFR) which plays a dominant role in sustaining the growth of these cells in the presence of tamoxifen. Consequently, these cells are highly sensitive to the EGFR small molecule inhibitor, gefitinib. Clinically, the EGFR is over-expressed in many breast cancers and is associated with poor response to tamoxifen suggesting that EGFR inhibitors may have a role as clinical agents (see below). Over-expression and activation of growth factor receptors results in activation of downstream signalling pathways that include MAPK and PI3K/AKT and may contribute to an endocrine resistant state though promoting ER loss [17,18] or acting as the dominant growth-signal input for the cell, circumventing the ER. Moreover, bi-directional interactions have been described for the ER and these growth factor signalling pathways. For

E. Davies, S. Hiscox / Maturitas 68 (2011) 121–128

123

Table 1 Selected recent clinical trials of key targeted agents for ER+ breast cancer. Mechanism of action of targeted therapy EGFR inhibition

Therapeutic agent Gefitinib

Erlotinib

Farnesyl transferase inhibition

mTOR inhibition

Tipifarnib

Disease context

Treatment regimen

Ref.

Notes

Heavily pre-treated MBC Post-menopausal MBC

Single agent Combined with anastrozole

20 21

EBC

Combined with anastrozole

22

ER+, tamoxifen-resistant and ER-, hormone insensitive disease ER+, ABC with progression on tamoxifen and AI and ER-, hormone insensitive disease Operable, untreated breast cancer including ER+, HER2+ and TNBC ABC, progression on chemotherapy MBC

Single agent

23

Modest clinical response addition of gefitinib improved PFS no clinical benefit from addition of gefitinib Clinical benefit seen in a third of patients overall

Single agent

24

Low CBR and no tumour response

Single agent

25

Single agent

26

In combination with bevacizumab Single agent

27

Tipifarnib + tamoxifen

36

Letrazole ± tipifarnib

37

Single agent

40

Letrazole ± temsirolimus

39

Evaluation in pre-surgical setting. Suppression of proliferation in ER+ tumours minimal activity in unselected ABCs combination well-tolerated but limited benefit clinical activity reported in ABC patients primary end point of efficacy (three objective responses) not achieved Addition of tipifarnib to letrozole did not improve objective response rate Anti-tumour activity demonstrated No added benefit from mTOR inhibitor

ABC

Hormone-receptor+, post-menopausal MBC with progression on tamoxifen Hormone-receptor+, post-menopausal ABC with progression on tamoxifen Temsirolimus Locally advanced/MBC Locally advanced breast cancer and MBC

34

EBC: early breast cancer; ABC: advanced breast cancer; MBC: metastatic breast cancer. PFS: progression-free survival; CBR: clinical benefit rate. All trials were conducted as Phase II unless otherwise stated.

example, growth factor-induced MAPK and AKT activation can potentiate estrogen-mediated ER transcriptional activity and ligand-independent ER activation through their ability to phosphorylate the ER; conversely, non-genomic activity of the ER may result in activation of growth factor receptors at the membrane, potentiating the activity of pro-proliferation/survival mechanisms. The ability to therapeutically exploit this dynamic relationship between the ER and growth factor signalling networks has been demonstrated in preclinical models, where small molecule inhibitors of growth factor receptors improve the action of endocrine treatments [19]. Based on this pre-clinical data, a number of treatment regimens have been investigated in the clinic in both the early and advanced setting (Table 1). The use of the small molecule EGFR tyrosine kinase inhibitor, gefitinib, in advanced breast cancer failed to provide significant improvement when used as a single agent [20], although combining gefitinib with anastrozole was effective in postmenopausal women with MBC versus anastrozole plus placebo [21]. Interestingly, a phase II trial of neoadjuvant anastrozole alone or with gefitinib in early breast cancer demonstrated that addition of gefitinib to neoadjuvant anastrozole had no additional clinical or biologic effect [22]. Recently, a small phase II trial has also shown that gefitinib as a single agent is effective in ER+, tamoxifen-resistant tumours [23] in contrast to previous similar trials which have failed to show any significant benefit [24]. Erlotinib, another EGFR tyrosine kinase inhibitor, when used preoperatively in ER+, untreated early breast cancers, resulted in a reduction in tumour cell proliferation as revealed by Ki67 staining [25]. In contrast, studies of erlotinib as a single agent in pre-treated MBC failed to show any significant benefit [26]. Similarly, when combined with the VEGF inhibitor, bevacizumab, erlotinib had limited activity in unselected, pre-treated MBC patients [27]. Overall, these conflicting study results likely reflect the fact that the ideal clinical setting for the use of anti-EGFR therapies has not

yet been fully identified and highlight the need for reliable predictive biomarkers to determine tumours most likely to respond to such treatments. Thus although preclinical data have suggested a rational for the clinical application of therapies targeted to growth factor receptors as a means to improve endocrine therapy and delay resistance, this does not translate straightforwardly into the clinic. 2.2.2. Farnesyl transferase inhibitors Activation of the RAS pathway is critical for tumour growth [28] and aberrant activation of the RAS signal transduction pathway thought to be common in breast cancers. Several mechanisms may contribute to this including RAS point mutations, although the incidence of this is low in breast cancer specifically [29], and activation of RAS proteins by upstream growth factor receptors including the EGFR [30]. RAS proteins play an important role in signal transduction and cellular transformation [31]; to function in this context, RAS must attach to the plasma membrane where it can interact with membrane receptors and downstream effectors such as RAF and PI3K which in turn promote cell survival and proliferation [32]. Farnesylation of RAS makes the protein more hydrophobic and enables it to attach to the plasma membrane [33]. As such, inhibitors of farnesyl transferase, the enzyme responsible for this process, have been developed with a view to inhibiting cellular process which rely on RAS-mediated signalling. Tipifarnib and lonafarnib are two potent farnesyl transferase inhibitors (FTIs) developed to prevent farnesylation of a variety of intracellular targets in solid tumours and are currently in clinical development. Tipifarnib was shown to be effective in endocrineresistant MBC as a single agent [34]. Although tipifarnib synergises with tamoxifen to suppress tumour proliferation in vitro and in vivo [35], subsequent investigation of this combination in the clinic in ER+, tamoxifen-resistant MBC failed to demonstrate effectiveness [36]. Tipifarnib has also been studied in combination with letrozole in tamoxifen-resistant disease however these studies also demon-

combination clinically effective in trastuzumab-resistant disease Treatment with ertumaxomab yielded strong immunologic response Clinical benefit in 11/15 patients 54

56

59

50

48

Single agent

Single agent

Trastuzumab and tanespimycin

In combination with trastuzumab an dpaclitaxel

Inhibition of HER2-refractory tumour growth Addition of everolimus may overcome resistance to trastuzumab

Lapatinib equally effective in HER2+ and p95HER2+ tumours 41

Lapatinib (as first line intervention) or lapatinib + capecitabine (as second line therapy) Pertuzumab and trastuzumab

strated no added benefit of the combination compared to letrozole alone [37]. Lonafarnib has been shown to improve the anti-tumour activity of aromatase inhibitors in xenografts models [38] and is currently under investigation alongside anastrozole in a phase II study [39]. Given that FTIs likely inhibit a range of intracellular targets, a better defining of these targets may aid in determining the most appropriate clinical context for their use. 2.2.3. mTOR inhibitors The PI3K/Akt pathway interacts with the ER and is its activity is frequently up-regulated in breast cancer. Mammalian target of rapamycin (mTOR) kinases alter and regulate PTEN and are important mediators of the pro-proliferative PI3K/AkT pathway to promote progression through the cell cycle via transcriptional activation of cell-cycle regulatory genes including c-myc and cyclin D1. Thus blocking mTOR function may present a promising therapeutic strategy in breast cancer. Although rapamycin was the first mTOR inhibitor developed, its instability and poor solubility lead to the development of the rapamycin analogues, temsirolimus and everolimus. When used as a single agent, temsirolimus demonstrated antitumour activity in patients with heavily-pretreated, locally advanced/MBC in a phase II study [40]. However, a large randomized phase III trial of temsirolimus plus letrozole versus letrozole alone in ER+ postmenopausal women with advanced breast cancer was halted early because of lack of benefit [39]. Everolimus, is currently undergoing evaluation in a phase II study in combination with letrozole as preoperative therapy of primary breast cancer in postmenopausal women and also in a phase III trial as first-line therapeutic regimen for advanced breast cancer.

ABC: advanced breast cancer; MBC: metastatic breast cancer.

Everolimus mTOR inhibition

HSP90 inhibitor

Tanespimycin

Phase I in HER2+ MBC progressing on trastuzumab HER2+ ABC progressing on trastuzumab HER2+, trastuzumab-resistant MBC Trastuzumab–DM1

Ertumaxomab

HER2+ breast cancer

advanced HER2+ breast cancer progressing on trastuzumab Phase I in HER2+ MBC Pertuzumab Antibody-based therapeutics

Therapeutic agent

lapatinib HER2 inhibition Tyrosine kinase inhibitors

Disease context

3. HER2+ disease

Mechanism of action of targeted therapy

Table 2 Selected recent clinical trials of targeted therapies under investigation in HER2+ trastuzumab-responsive and -resistant breast cancer.

Notes Ref.

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Treatment regimen

124

Approximately 20% of breast cancers over-express the human epidermal growth factor receptor-2 (HER2), a receptor tyrosine kinase of the EGFR family, primarily as a result of gene amplification. Clinically, HER2 over-expression correlates with endocrine insensitivity, aggressive disease and decreased survival. In these tumours, HER2 becomes activated through the formation of homodimers with other HER2 receptors in a ligand-independent fashion or by heterodimerization with other members of the EGFR receptor family as a result of ligand binding. Both result in HER2 activation with resultant signalling through RAS-MAPK and PI3K/AKT/mTOR pathways to promote cell proliferation, survival and angiogenesis. Currently the only licensed targeted therapies for HER2+ breast cancer are trastuzumab and lapatinib, agents whose action are predominantly directed at inhibition of HER2-mediated signalling. However, a number of new therapies are currently under development, either as first-line therapies for HER2+ tumours or for HER2+ tumours that progress on trastuzumab and lapatinib. 3.1. Targeted therapy in HER+ disease 3.1.1. Trastuzumab The treatment of HER2+ breast cancer has been significantly improved with the relatively recent development of trastuzumab (Herceptin), a recombinant humanized monoclonal antibody which targets the extracellular domain of HER2. Binding of trastuzumab to the extracellular, juxtamembrane portion of the HER2 receptor suppresses HER2-mediated signalling resulting in cell cycle arrest and inhibition of angiogenesis. In addition, trastuzumab binding to HER2 leads to antibody-dependent cell-mediated cytotoxicity (ADCC). In the metastatic setting, the addition of trastuzumab to standard chemotherapy improves survival in patients with HER2+ tumours [41]. The administration of trastuzumab in the adjuvant (i.e. initial postoperative) setting, in

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combination with, or sequentially after chemotherapy, results in an improvement in disease-free survival, with a 50% reduction in the risk of relapse, as well as improving the overall survival of patients with HER2-positive advanced and early-stage breast cancer [41]. 3.1.2. Lapatinib Lapatinib is an orally active small molecule tyrosine kinase inhibitor that targets both HER2 and the EGFR. Lapatinib competes with ATP for binding sites in the kinase domain of both HER2 and EGFR resulting in inhibition of downstream signalling intermediates ERK1/2 and PI3K/AKT which regulate cell proliferation and survival respectively. Thus in pre-clinical models, lapatinib treatment blocked cellular proliferation and promoted an increase in apoptosis [42]. Clinical trials of lapatinib and trastuzumab combined demonstrated a significant survival benefit whilst synergism between lapatinib and capecitabine has been reported in patients with HER2+, locally advanced, or metastatic breast cancer refractory to chemotherapy and trastuzumab [43] leading to the licensing of lapatinib in combination with capecitabine in this context. 3.2. New therapeutic strategies in HER2+ disease Despite the benefits of trastuzumab, therapeutic resistance to this approach remains a considerable problem in the treatment of both early and advanced stage HER2+ breast cancer. However, our improved understanding of mechanisms of resistance to trastuzumab have facilitated the development of novel agents for HER2+ breast cancer and also resulted in superior outcomes when added to chemotherapy in the adjuvant setting (Table 2). Several mechanisms have been identified that underlie resistance in HER2+ cells. One such mechanism is the shedding of the extracellular domain of HER2 leaving behind a truncated form (p95HER2) that retains kinase activity. Although truncation of HER2 results in a receptor inaccessible to antibody-based therapy, tumour cells expressing p95HER2 remain sensitive to lapatinib which binds the intracellular kinase domain of the receptor [44]. Other forms of trastuzumab resistance may occur through cross-talk between HER2 and the insulin-like growth factor receptor (IGF-1R) and/or EGFR family members [45] and the aberrant activation of signalling pathways downstream of such receptors, such as the presence of activating PI3K mutations or loss of function of the phosphatase PTEN [46]. 3.2.1. mTOR inhibitors As mentioned above, the rapamycin analogues temsirolimus and everolimus may represent effective therapeutic agents in ER+ breast cancer. However, their use is now being explores in HER2+ disease also given that HER2 signals through the PI3K/Akt/mTOR pathway. Preclinical data have demonstrated that the addition of PI3K and/or mTOR inhibitors can restore sensitivity to anti-HER2 agents [47]. Moreover, results from two phase I trials in which the mTOR inhibitor everolimus was combined with trastuzumab and chemotherapy suggest that the addition of everolimus may overcome resistance to trastuzumab [48]. Clinical assessment is now underway to determine the effectiveness of mTOR inhibitorcontaining, trastuzumab-based combination treatment regimens at circumventing resistance in HER2+ cancers. 3.2.2. Heat shock protein 90 inhibitors Heat shock protein 90 is a ubiquitous molecular chaperone that regulates the stability, turnover and function of many oncogenic signalling proteins. In vitro models demonstrate that inhibition of HSP90 leads to the degradation of Her2 and the simultaneous blockade of multiple intercellular signal transduction pathways. The HSP90 inhibitor tanespimycin, a derivative of the antineoplastic antibiotic geldanamycin, decreases HER2 expression and

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inhibits breast-cancer growth in cell lines and in animal studies [49]. Subsequently, phase I clinical trials have shown a response to tanespimycin in trastuzumab-resistant disease [50]. Alvespimycin, a second-generation HSP90 inhibitor with higher potency than tanespimycin, is currently being assessed in combination with trastuzumab in early phase trials [51]. Interestingly, tumours in which HER2 is truncated remain sensitive to HSP90 inhibitors and thus this therapeutic strategy may represent a novel strategy in the treatment of breast cancers with p95HER2-mediated trastuzumabresistance mechanisms. 3.2.3. Antibody-based strategies 3.2.3.1. Pertuzumab. Pertuzumab is a humanized monoclonal antibody that binds to an extracellular domain of the HER2 receptor distinct from that to which trastuzumab binds. Binding of pertuzumab to HER2 sterically prevents HER2 dimerization. Pertuzumab has demonstrated potent activity in pre-clinical cell and animal models as a single agent [52] whilst the combination of pertuzumab with trastuzumab has been shown to synergistically inhibit the survival of breast tumour cells [53]. Importantly, pertuzumab appears to be effective clinically in patients with HER2+, trastuzumab-refractory disease when given alongside trastuzumab [54]. Given the association between trastuzumab and enhanced cardiotoxicity it is interesting to note that this combination treatment regimen of pertuzumab and trastuzumab was not associated with an increased risk of adverse cardiac effects [55]. 3.2.3.2. Ertumaxomab. Ertumaxomab is a bi-specific monoclonal antibody targeting HER2 and the CD3 receptor. This enables the antibody to simultaneously bind both HER2+ tumour cells and CD3-expressing T-cells. In addition, ertumaxomab simultaneously binds Fc␥ receptor expressing accessory cells via its Fc domain [56]. Interactions with these cell types results in activation of T-cells, which can destroy the HER2+ tumour cells through release of lytic enzymes, and stimulation of phagocytosis via the activity of Fc␥ receptor-positive cells such as macrophages. In phase I clinical trials, ertumaxomab treatment resulted in antitumour responses in patients with MBC. Recent reports have demonstrated that ertumaxomab is also able to induce cytotoxicity in various tumour cell lines, including those with low HER2 antigen density [57] and thus may provide a novel therapeutic option for breast cancer patients not eligible for trastuzumab. A recent phase I study in 17 HER2+ metastatic breast cancer patients demonstrated that ertumaxomab treatment induced a strong immunogenic response and resulted in tumour response in a third of patients [56]. To this end, ertumaxomab is currently under investigation in phase II studies in MBC patients irrespective of HER2 gene amplification [58]. 3.2.3.3. Antibody conjugates. Trastuzumab–DM1 (T–DM1) is a conjugate of trastuzumab and the potent anti-microtubule agent, maytansince DM1 and represents a method of delivering active chemotherapeutic agents selectively to tumour cells. T–DM1 binds to, and is internalised by, HER2+ cells whereupon the highly potent DM1 is released. T–DM1 has demonstrated encouraging anti-tumour activity in both preclinical and early-phase clinical studies and with very limited toxic effects [59]. Currently, T–DM1 is being assessed as a first-line and second-line therapeutic in comparison with lapatinib and capecitabine combined. 4. Basal/triple-negative breast cancer The basal-like subtype of breast cancer accounts for around 15% of all breast cancers [60] and is generally characterised by the socalled ‘triple-negative’ phenotype (ER, PgR and HER2 negative). Although there is some controversy as to whether the basal phenotype consists only of triple negative breast cancer (TNBC) [61,62],

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it is likely that TNBC certainly forms the greater component of this breast cancer subtype. TNBCs are particularly problematic as they are characterized by an aggressive behaviour and distinct pattern of metastasis, frequently involving the brain. Although a subset of early stage TNBCs respond well to chemotherapy [63] remaining patients usually experience early metastatic relapse with very poor outcome [64]. Moreover, their triple negativity means that this form of breast disease presently lacks effective targeted treatment options. Because of this, TNBCs have become a key topic of clinical and research interest; although clinical trials of targeted therapeutics remain in a relative infancy in the setting of TNBC as compared to other subtypes of the disease, molecular profiling of this disease subtype has led to the identification of a number of potential therapeutic targets. 4.1. PARP inhibitors Such studies have revealed that TNBCs can be characterized by a deficiency in the DNA repair machinery, similar to that observed for BRCA1-associated breast cancers. BRCA1 cancers are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors and thus it has been hypothesized that these agents may useful in TNBC. In vitro data suggests that TNBC cell lines are more sensitive to the PARP inhibitor PJ34 whilst PARP inhibition also synergises with chemotherapy in TNBC [65]. Importantly, this therapeutic strategy appears to translate into the clinic as recent phase II studies on the PARP inhibitor, iniparib, in TNBC have also shown promising results with a phase III trial to test the survival benefit of iniparib in combination with chemotherapy in metastatic TNBC now underway [66]. 4.2. EGFR inhibitors A subset of TNBCs possess activated EGFR and thus may be amenable to EGFR inhibitors. However, data to date suggest that EGFR inhibition is not associated with a major improvement in the outcome of TNBC [67]. However, it is not yet clear if stratification of TNBCs into EGFR-over-expressing groups would present a group of tumours more likely to derive benefit from such interventions. 4.3. VEGF inhibitors The VEGF-tageting monoclonal antibody, bevacizumab, is effective in a variety of solid tumours including breast cancer. In TNBC, bevacizumab has been shown to improve progression-free survival when given alongside chemotherapy versus chemotherapy alone [68]. 4.4. mTOR inhibitors The high frequency of PTEN loss and mTOR activation reported in TNBC suggests that these tumours may be susceptible to mTOR inhibition. In preclinical cell models of basal breast cancer, combination of the mTOR inhibitor rapamycin and cisplatin was synergistic in contrast to cell models of luminal breast cancer where there was limited effect [69]. These data suggest that there is a rationale to combine cisplatin and mTOR inhibitors in patients with TNBC. 4.5. Src inhibitors Recent preclinical studies have suggested that inhibitors of the intracellular Src family of kinases may possess activity in TNBC. Gene microarray analysis of a panel of 39 human breast cancer cell lines representing both luminal and basal subtypes identified that

basal-type breast cancer cell lines were most sensitive to growth inhibition by dasatinib, an oral small molecule inhibitor of BCRAbl and Src kinase [70]. Further data suggest a significant level of synergy upon combining dasatinib with chemotherapy in TNBC cells. Encouragingly, phase I studies of dasatinib and capecitabine have shown moderate efficacy [71] and further studies will reveal whether the application of this treatment strategy in TNBC represents an effective option. 5. Conclusions Our increased understanding of the molecular basis of breast cancer has led to the identification of a number of novel targets, some of which are currently being tested in the clinical setting. However, despite the undoubted improvements already seen in the treatment of breast cancer, there still remain significant challenges to overcome. Judicious selection of patient populations for clinical trials of novel agents may help avoid seemingly disappointing outcomes; underlying this is a need for predictive biomarkers to identify such potentially responsive populations. Continued use of molecular profiling will undoubtedly reveal a greater complexity to breast cancer, unveiling more subdivisions in this disease. However, such information may be employed effectively to identify predictive and prognostic biomarkers to direct these novel therapies appropriately. Whilst novel therapies for breast cancer continue to be discovered and applied, it is important to elucidate the mechanisms of resistance to these agents. Understanding molecular pathways utilised by the cell to circumvent these targeted therapies will help inform rational combinations of therapies to evade these processes. Contributors SH drafted the initial version and subsequently contributed to the revised manuscript. ELD contributed to the revision of the draft manuscript. Competing interest The authors declare no competing interests. Provenance and peer review Commissioned and externally peer reviewed. References [1] Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365(9472):1687–717. [2] Howell A. The endocrine prevention of breast cancer. Best Pract Res Clin Endocrinol Metab 2008;22(4):615–23. [3] Cianfrocca M, Gradishar W. New molecular classifications of breast cancer. CA Cancer J Clin 2009;59(5):303–13. [4] Weigelt B, Mackay A, A’Hern R, et al. Breast cancer molecular profiling with single sample predictors: a retrospective analysis. Lancet Oncol 2010;11(4):339–49. [5] Cohen I. Endometrial pathologies associated with postmenopausal tamoxifen treatment. Gynecol Oncol 2004;94(2):256–66. [6] Venturini M, Del Mastro L. Safety of adjuvant aromatase inhibitor therapy. Cancer Treat Rev 2006;32(7):548–56. [7] Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 2001;93(9):684–90. [8] Buzdar A, Howell A, Cuzick J, et al. Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncol 2006;7(8):633–43. [9] Gligorov J, Pritchard K, Goss P. Adjuvant and extended adjuvant use of aromatase inhibitors: reducing the risk of recurrence and distant metastasis. Breast 2007;16(Suppl. 3):S1–9.

E. Davies, S. Hiscox / Maturitas 68 (2011) 121–128 [10] Perey L, Paridaens R, Hawle H, et al. Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00). Ann Oncol 2007;18(1):64–9. [11] Mauriac L, Romieu G, Bines J. Activity of fulvestrant versus exemestane in advanced breast cancer patients with or without visceral metastases: data from the EFECT trial. Breast Cancer Res Treat 2009;117(1):69–75. [12] Macedo LF, Sabnis GJ, Goloubeva OG, Brodie A. Combination of anastrozole with fulvestrant in the intratumoral aromatase xenograft model. Cancer Res 2008;68(9):3516–22. [13] Johnston SR. New strategies in estrogen receptor-positive breast cancer. Clin Cancer Res 2010;16(7):1979–87. [14] Nicholson RI, Johnston SR. Endocrine therapy – current benefits and limitations. Breast Cancer Res Treat 2005;93(Suppl. 1):S3–10. [15] Howell A, Bundred NJ, Cuzick J, Allred DC, Clarke R. Response and resistance to the endocrine prevention of breast cancer. Adv Exp Med Biol 2008;617:201–11. [16] Shou J, Massarweh S, Osborne CK, et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 2004;96(12):926–35. [17] Oh AS, Lorant LA, Holloway JN, Miller DL, Kern FG, El-Ashry D. Hyperactivation of MAPK induces loss of ERalpha expression in breast cancer cells. Mol Endocrinol 2001;15(8):1344–59. [18] Massarweh S, Osborne CK, Creighton CJ, et al. Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res 2008;68(3):826–33. [19] Gee JM, Harper ME, Hutcheson IR, et al. The antiepidermal growth factor receptor agent gefitinib (ZD1839/Iressa) improves antihormone response and prevents development of resistance in breast cancer in vitro. Endocrinology 2003;144(11):5105–17. [20] Arteaga CL, Truica CI. Challenges in the development of anti-epidermal growth factor receptor therapies in breast cancer. Semin Oncol 2004;31(Suppl. 3):3–8. [21] Cristofanilli M, Valero V, Mangalik A, et al. Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer. Clin Cancer Res 2010;16(6):1904–14. [22] Smith IE, Walsh G, Skene A, et al. A phase II placebo-controlled trial of neoadjuvant anastrozole alone or with gefitinib in early breast cancer. J Clin Oncol 2007;25(25):3816–22. [23] Gutteridge E, Agrawal A, Nicholson R, Leung Cheung K, Robertson J, Gee J. The effects of gefitinib in tamoxifen-resistant and hormone-insensitive breast cancer: a phase II study. Int J Cancer 2010;126(8):1806–16. [24] Green MD, Francis PA, Gebski V, et al. Gefitinib treatment in hormoneresistant and hormone receptor-negative advanced breast cancer. Ann Oncol 2009;20(11):1813–7. [25] Guix M, Granja Nde M, Meszoely I, et al. Short preoperative treatment with erlotinib inhibits tumor cell proliferation in hormone receptor-positive breast cancers. J Clin Oncol 2008;26(6):897–906. [26] Dickler MN, Cobleigh MA, Miller KD, Klein PM, Winer EP. Efficacy and safety of erlotinib in patients with locally advanced or metastatic breast cancer. Breast Cancer Res Treat 2009;115(1):115–21. [27] Dickler MN, Rugo HS, Eberle CA, et al. A phase II trial of erlotinib in combination with bevacizumab in patients with metastatic breast cancer. Clin Cancer Res 2008;14(23):7878–83. [28] McCubrey JA, Steelman LS, Chappell WH, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 2007;1773(8):1263–84. [29] Miyakis S, Sourvinos G, Spandidos DA. Differential expression and mutation of the ras family genes in human breast cancer. Biochem Biophys Res Commun 1998;251(2):609–12. [30] Clark GJ, Der CJ. Aberrant function of the ras signal transduction pathway in human breast cancer. Breast Cancer Res Treat 1995;35(1):133–44. [31] Malaney S, Daly RJ. The ras signaling pathway in mammary tumorigenesis and metastasis. J Mammary Gland Biol Neoplasia 2001;6(1):101–13. [32] Grant S, Qiao L, Dent P. Roles of ERBB family receptor tyrosine kinases, and downstream signaling pathways, in the control of cell growth and survival. Front Biosci 2002;7:d376–89. [33] Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003;3(1):11–22. [34] Johnston SRD, Hickish T, Ellis P, et al. Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer. J Clin Oncol 2003;21(13):2492–9. [35] Martin LA, Head JE, Pancholi S, et al. The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in vitro and in vivo. Mol Cancer Ther 2007;6(9):2458–67. [36] Dalenc F, Doisneau-Sixou SF, Allal BC, et al. Tipifarnib plus tamoxifen in tamoxifen-resistant metastatic breast cancer: a negative phase II and screening of potential therapeutic markers by proteomic analysis. Clin Cancer Res 2010;16(4):1264–71. [37] Johnston SR, Semiglazov VF, Manikhas GM, et al. A phase II, randomized, blinded study of the farnesyltransferase inhibitor tipifarnib combined with letrozole in the treatment of advanced breast cancer after antiestrogen therapy. Breast Cancer Res Treat 2008;110(2):327–35. [38] Liu G, Marrinan CH, Taylor SA, et al. Enhancement of the antitumor activity of tamoxifen and anastrozole by the farnesyltransferase inhibitor lonafarnib (SCH66336). Anticancer Drugs 2007;18(8):923–31.

127

[39] Gligorov J, Azria D, Namer M, Khayat D, Spano JP. Novel therapeutic strategies combining antihormonal and biological targeted therapies in breast cancer: focus on clinical trials and perspectives. Crit Rev Oncol Hematol 2007;64(2):115–28. [40] Chan S, Scheulen ME, Johnston S, et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 2005;23(23):5314–22. [41] Valabrega G, Montemurro F, Aglietta M. Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann Oncol 2007;18(6):977–84. [42] Xia W, Mullin RJ, Keith BR, et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 2002;21(41):6255–63. [43] Bauerfeind I, Elling D, Heinemann V. Lapatinib in the treatment of hormone receptor-positive/ErbB2-positive breast cancer. Breast Care (Basel) 2010;5(s1):13–5. [44] Scaltriti M, Chandarlapaty S, Prudkin L, et al. Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor. Clin Cancer Res 2010;16(9):2688–95. [45] Bischoff J, Ignatov A. The role of targeted agents in the treatment of metastatic breast cancer. Breast Care (Basel) 2010;5(3):134–41. [46] Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007;12(4):395–402. [47] Serra V, Markman B, Scaltriti M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Research 2008:8022–30. [48] Baselga J. Treatment of HER2-overexpressing breast cancer. Ann Oncol 2010;21(Suppl. 7):vii36–40. [49] Di Cosimo S, Baselga J. Targeted therapies in breast cancer: where are we now? Eur J Cancer 2008;44(18):2781–90. [50] Modi S, Stopeck AT, Gordon MS, et al. Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study. J Clin Oncol 2007;25(34):5410–7. [51] Jones KL, Buzdar AU. Evolving novel anti-HER2 strategies. Lancet Oncol 2009;10(12):1179–87. [52] Brockhoff G, Heckel B, Schmidt-Bruecken E, et al. Differential impact of cetuximab, pertuzumab and trastuzumab on BT474 and SK-BR-3 breast cancer cell proliferation. Cell Prolif 2007;40(4):488–507. [53] Pal SK, Pegram M. Targeting HER2 Epitopes. Semin Oncol 2006;33(4):386– 91. [54] Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 2010;28(7):1138–44. [55] Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer. Semin Oncol 1999;26(4 Suppl. 12):78–83. [56] Kiewe P, Hasmuller S, Kahlert S, et al. Phase I trial of the trifunctional antiHER2 × anti-CD3 antibody ertumaxomab in metastatic breast cancer. Clin Cancer Res 2006;12(10):3085–91. [57] Jager M, Schoberth A, Ruf P, Hess J, Lindhofer H. The trifunctional antibody ertumaxomab destroys tumor cells that express low levels of human epidermal growth factor receptor 2. Cancer Res 2009;69(10):4270–6. [58] Kiewe P, Thiel E. Ertumaxomab: a trifunctional antibody for breast cancer treatment. Expert Opin Investig Drugs 2008;17(10):1553–8. [59] Krop IE, Beeram M, Modi S, et al. Phase I study of trastuzumab–DM1, an HER2 antibody–drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol 2010;28(16):2698–704. [60] Anders CK, Carey LA. Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer. Clin Breast Cancer 2009;9(Suppl. 2):S73– 81. [61] Bidard FC, Conforti R, Boulet T, Michiels S, Delaloge S, Andre F. Does triple-negative phenotype accurately identify basal-like tumour? An immunohistochemical analysis based on 143 ‘triple-negative’ breast cancers. Ann Oncol 2007;18(7):1285–6. [62] Seal MD, Chia SK. What is the difference between triple-negative and basal breast cancers? Cancer J 2010;16(1):12–6. [63] Rouzier R, Perou CM, Symmans WF, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 2005;11(16):5678–85. [64] Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 2008;26(8):1275–81. [65] Hastak K, Alli E, Ford JM. Synergistic chemosensitivity of triple-negative breast cancer cell lines to poly(ADP-Ribose) polymerase inhibition, gemcitabine, and cisplatin. Cancer Res 2010;70(20):7970–80. [66] Liang H, Tan AR, Iniparib. a PARP1 inhibitor for the potential treatment of cancer, including triple-negative breast cancer. IDrugs 2010;13(9):646–56. [67] Berrada N, Delaloge S, Andre F. Treatment of triple-negative metastatic breast cancer: toward individualized targeted treatments or chemosensitization? Ann Oncol 2010;21(Suppl. 7):vii30–5. [68] Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357(26):2666–76.

128

E. Davies, S. Hiscox / Maturitas 68 (2011) 121–128

[69] Wong SW, Tiong KH, Kong WY, et al. Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through up-regulation of p73. Breast Cancer Res Treat 2010. [70] Finn RS, Dering J, Ginther C, et al. Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-

type/“triple-negative” breast cancer cell lines growing in vitro. Breast Cancer Res Treat 2007;105(3):319–26. [71] Pal SK, Mortimer J. Triple-negative breast cancer: novel therapies and new directions. Maturitas 2009;63(4):269–74.