Targeted therapies for breast cancer (original) (raw)
ER- and PR-positive breast cancer has, for more than three decades, been the prime example of cancer amenable to targeted drug approaches. Estrogen-focused therapies remain pivotal to the treatment of this disease, with the ER modulator tamoxifen improving survival among women with early and advanced breast cancer and further improvements provided by aromatase inhibitors (AIs) and the ER-degrading agent fulvestrant (15–18). Their long-term efficacy, however, is limited by relapse of disease and development of resistance. Despite continuous expression of ER at relapse in either locally recurrent or secondary metastatic tumors, up to 50% of patients with HR-positive primary breast cancer who develop metastatic disease do not respond to first-line endocrine treatment (de novo resistance), and the remainder will eventually relapse despite an initial response (acquired resistance) (19).
The HER family of proteins comprises 4 receptors (EGFR/HER1 and HER2–4) activated by numerous extracellular ligands. Upon ligand binding the receptors dimerize, become phosphorylated, and transduce intracellular signals that regulate a variety of cellular processes including proliferation and survival. Resistance to therapy can occur as a result of cross-talk between the ER and HER themselves or between signaling pathways downstream of these receptors, such as PI3K/Akt/mTOR (ref. 20 and Figure 2). HER2 overexpression confers intrinsic or primary resistance to hormone-based therapy despite the presence of HRs. Within tumors that are both HER2 and ER positive, HER2 signaling is dominant, as demonstrated by the poor response of such tumors to endocrine therapy alone (21–24). This resistance can be partially overcome by combining anti-estrogen and anti-HER2 therapies. The addition of the anti-HER2 monoclonal antibody trastuzumab to an AI improved outcomes for patients with metastatic breast tumors that co-expressed both ER and HER2 (24). Likewise, in a large cohort of patients with known ER- and HER2-positive tumors, the addition of lapatinib, an anti-HER2 TKI, to an AI also significantly reduced the risk of progression (25). In contrast to HER2 and despite supportive preclinical data, observed clinical success with anti-HER1 inhibitors and endocrine therapy combinations has been limited (26–28).
The activation of compensatory pathways may contribute to the development of resistance to targeted therapies in HER2-positive breast cancer. Inhibition of PI3K results in the release of a negative feedback loop and activation of HER2 and, in turn, activation of ERK, a potentially detrimental effect. Strategies to prevent the compensatory pathway include intervention at different levels, i.e., at the receptor level or by blocking ERK.
In addition to HER1 and HER2, there is growing interest in HER3 as a potential therapeutic target (29). Recently, HER3 and its physiologic ligand heregulin (HRG) have been implicated in the development of resistance to anti-estrogen therapies (30). There are now a number of anti-HER3 monoclonal antibodies in development, including MM-121, a fully humanized monoclonal antibody that binds to HER3 and prevents the HRG- and betacellulin-induced phosphorylation of HER3 and also effectively inhibits the HER2/HER3 heterodimer (31). This compound is in Phase II studies, in combination with the nonsteroidal AI exemestane, in patients with advanced breast cancer that had previously progressed on endocrine therapies (32).
The PI3Ks phosphorylate the 3-hydroxyl group of phosphoinositides to activate second messenger molecules and set in motion a variety of physiological cellular metabolic and survival functions. Class IA PI3K molecules are heterodimers composed of a regulatory subunit (p85) and a catalytic subunit (p110), the α isoform of which is widely mutated or amplified in human cancer (33). The PI3K signaling pathway is critical for the growth and survival of cancer cells in many human tumors including breast (34–36). For this reason, multiple PI3K inhibitors are currently in clinical development (33). These agents display variable specificity to the different PI3K subunits and an ability to inhibit other targets such as mTOR. It is likely, but yet unproven, that these agents will be of most benefit in breast tumors harboring a somatic mutation in PIK3CA (the gene encoding p110α) or in those with nonfunctioning or absent PTEN protein. Although PIK3CA mutations are found in all breast cancer subtypes (at a frequency of approximately 30%), they are most frequently identified in HR-positive or HER2-overexpressing tumors (36, 37). Although rarely mutated in breast cancer, diminished levels of PTEN expression through loss of heterozygosity and/or epigenetic silencing mechanisms are observed in up to 48% of breast tumors (38, 39). Interestingly, loss of PTEN has been shown to be more prevalent in triple-negative breast tumors and results in preferential activation of the PI3Kβ subunit, an observation that suggests PI3Kβ-specific inhibitors could be effective in this setting (40, 41). More advanced is the clinical development of rapalogs to inhibit mTOR. One of these agents, everolimus, has shown signs of improving the effects of AIs in a large presurgical study in patients with HR-positive breast cancer (42), and a randomized, placebo-controlled, Phase III study of everolimus in combination with exemestane is currently ongoing in the advanced disease setting (43).
As mentioned in the Introduction, inhibition of the PI3K/AKT/mTOR pathway elicits compensatory activation of multiple survival routes (13, 14). For example, it has been shown in tumors that inhibition of mTOR with rapalogs releases a negative feedback loop, resulting in activation of IGF1R signaling and ultimately phosphorylation of AKT (44). This activation may be prevented if IGF1R signaling is blocked with anti-IGF1R monoclonal antibodies. This finding led to a Phase I clinical study combining ridaforolimus (a rapalog) and dalotuzumab (an antibody targeted against IGF1R) that showed remarkable clinical activity in breast cancer (45). This combination is now being explored in a larger, Phase II study restricted to women with HR-positive metastatic breast cancer (46).
Almost a decade ago it was first suggested that anti-angiogenic strategies should be combined with drugs that target the proteins needed for cell motility and invasion, including hepatocyte growth factor (HGF) and C-MET (47), the rationale being that expression of these increases under hypoxic conditions and drives tumor cell survival and invasiveness even when anti-angiogenic agents are employed (48). Dual inhibition of MET and VEGFR2 would therefore be predicted to block major escape mechanisms used by tumors to overcome hypoxia. Cabozantinib (XL184; Exelixis) is a unique oral compound that inhibits multiple tyrosine kinases including MET and VEGFR2 (49). Preliminary data from an ongoing Phase II, randomized discontinuation trial of cabozantinib suggest remarkable activity of this agent in visceral sites of solid tumors but particularly within bone metastases, perhaps because HGF is expressed by both tumor cells and bone stroma, and MET is subsequently highly activated in bone metastases (50). A Phase II study of this agent is planned in patients with metastatic HR-positive breast cancer to bone.