What is targeted therapy for breast cancer? It means blocking the growth of breast cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth. A greater understanding of the underlying biology of breast cancer has resulted in the identification of a number of molecular targets. Among them are tyrosine kinase inhibitors (TKIs) directed at a number of targets (HER1, HER2, HER3, IGF receptor [IGFR], C-MET, FGF receptor [FGFR]), inhibitors of intracellular signaling pathways (PI3K, AKT, mammalian target of rapamycin [mTOR], ERK), angiogenesis inhibitors, and agents that interfere with DNA repair. Some of these agents have shown remarkable activity and have already become part of the standard of care in patients with breast cancer (exemplified by the anti-HER2 agents trastuzumab and lapatinib). Others have shown clinical activity but are not yet approved for clinical practice. In this group are novel anti-HER2 agents as well as rapamycin analogs ("rapalogs," or inhibitors of mTOR) and the poly(ADP-ribose) polymerase (PARP) inhibitors for BRCA-deficient tumors. The third (and clearly the largest) group of compounds are still in an early phase of development, but in some cases, indications of clinical responses have already been observed.
Triple-negative breast cancer is a phenotypic description of breast cancers that do not express ER and progesterone receptor and are also without HER2 overexpression or amplification. Unlike ER positive or HER2 positive breast cancers, there is no approved targeted therapy for triple-negative breast cancer.
Angiogenesis is an essential step for tumor growth and metastasis, and vascular endothelial growth factors (VEGFs), particularly VEGF-A, are among the most prominent factors in inducing pathological angiogenesis. Compared with other breast cancer subtypes, triple-negative breast cancer has been associated with significantly higher levels of intratumor VEGF-A expression, which provides a rationale for evaluation of anti-VEGF agents in the treatment of triple-negative breast cancer. Bevacizumab (Avastin; Genentech) is a humanized monoclonal antibody directed against VEGF-A. In initial studies of bevacizumab in breast cancer, performed in unselected patients with metastatic HER2 negative disease, the addition of bevacizumab to standard chemotherapy improved overall response rate (ORR) and progression-free survival (PFS), but not overall survival (OS).
Most basal-like breast cancers, the major molecular subtype of triple-negative breast cancer, overexpress EGFR, raising the possibility of targeting EGFR in triple-negative breast cancer. However, limited phase II trials of EGFR-targeted agents in triple-negative breast cancer have not demonstrated significant effect. In a phase II study that evaluated weekly irinotecan plus carboplatin with or without cetuximab as firstor second-line therapy in patients with metastatic breast cancer, the addition of cetuximab led to an improved response rate (30% versus 49%), but without any benefit in PFS and OS among patients with triple-negative breast cancer.
The poly(ADP-ribose) polymerases (PARPs) are a group of enzymes important in many cellular processes, including base excision repair of single-strand DNA breaks, a vital mechanism for DNA damage repair when homologous recombination repair mechanisms such as BRCA1/2 are deficient. PARP inhibitors induced synthetic lethality in BRCA1- and BRCA2-related tumors in preclinical studies. In a phase II trial of olaparib (AZD2281; AstraZeneca) in metastatic breast cancers in carriers of BRCA mutations, an ORR of 41% was observed with a 400 mg b.i.d. dose.
Overexpression of HER2 as a result of gene amplification occurs in 18% to 20% of human breast cancers and is associated with a more aggressive phenotype. Introduction of the monoclonal antibody trastuzumab has led to significant improvement in the outcome of this disease. In addition to trastuzumab, several HER2-targeted agents, including laptinib, pertuzumab, and trastuzumab emtansine have been approved for treatment of advanced HER2 positive disease.
Trastuzumab (Herceptin; Genentech), a fully humanized monoclonal antibody against HER2 extracellular domain, is approved for both metastatic and adjuvant therapy for HER2 positive breast cancer. The mechanisms of action of trastuzumab are not fully understood, but studies have shown that trastuzumab functions by antibody-dependent cellular cytotoxicity, inhibition of the cleavage of the HER2 extracellular domain, inhibition of signaling mediated by HER2 through PI3K, and MAPK cascades. The activities of trastuzumab in combination with various chemotherapy agents have been demonstrated in multiple clinical trials. In the pivotal phase III trial, the addition of trastuzumab to chemotherapy in the first-line setting for metastatic HER2þ breast cancer resulted in a significant improvements in overall response rate.
Lapatinib is an orally available small-molecule inhibitor effective against both HER1 and HER2, although its use has been limited largely to HER2 positive breast cancer. In a randomized phase III study of capecitabine with or without lapatinib in patients with HER2 positive locally advanced or metastatic breast cancer who had previously received anthracycline, taxane, and trastuzumab, the combination therapy was superior in median time to progression.
Pertuzumab is an anti-HER2 humanized monoclonal antibody that binds to subdomain II of the extracellular domain of HER2, in contrast to trastuzumab, which binds to subdomain IV. Binding of pertuzumab inhibits the dimerization of HER2 with other HER family members (most notably HER3) and synergizes with trastuzumab in treating HER2 positive breast cancer in both preclinical and clinical studies.
Trastuzumab emtansine (T-DM1) (Kadcyla; Genentech) is an antibodyedrug conjugate in which trastuzumab is linked to the microtubule-inhibitory agent mertansine (DM1). Based on the results of the EMILIA trial, T-DM1 was approved by the FDA in February 2013 for the treatment of patients with HER2 positive metastatic breast cancer who had previously received trastuzumab and a taxane, separately or in combination.
Hormone receptor positive breast cancers are largely driven by the estrogen/ER pathway, and endocrine therapy targeting this pathway has been most successful. However, resistance to endocrine therapy, either de novo or acquired, is a common phenomenon and a significant clinical challenge. The mechanisms of endocrine resistance are complex and not fully understood.
Experimental models indicate that endocrine resistance is accompanied by activation of estrogen-independent growth and survival signaling pathways as a result of genomic or epigenetic alterations; these pathways could be targeted for therapeutic interventions.
The HER2 gene, ERBB2, is amplified in approximately 10% of ERþ breast cancer. Compared with ER positive, HER2 negative disease, ER positive, HER2 negative breast cancer is associated with a higher risk of relapse on adjuvant endocrine therapy. This is explained by the finding of incomplete cell-cycle arrest under treatment with endocrine agents alone in the neoadjuvant setting.The benefit of adding HER2-targeted agents in this patient population was demonstrated in studies of adjuvant trastuzumab in HER2 positive breast cancer; the ER positive HER2 positive subset derived a significant benefit from trastuzumab in reducing relapse.
The PI3K-AKT-mTOR pathway is a cardinal nodal point in the transduction of extracellular and intracellular growth and survival signals. Deregulation of this pathway is an important mechanism of endocrine resistance. In addition, the development of acquired endocrine resistance was accompanied by activation of the PI3K pathway in studies of long-term estradiol-deprived breast cancer cell lines, and inhibition of PI3K pathway signaling reduced cancer cell growth and survival.
The rapamycin analogs, which are allosteric inhibitors of mTOR complex 1 through its interaction with FKBP12, were among the first evaluated in clinical trials. The Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) trial, a randomized, double-blind, placebo-controlled phase III study of exemestane with or without the rapamycin analog everolimus (Afinitor; Novartis) in postmenopausal women with ER positive HER2 negative advanced breast cancer refractory to nonsteroidal AIs, demonstrated a median PFS of 10.6 months with combination therapy, compared with 4.1 months with exemestane alone (HR Z 0.36; 95% CI Z 0.27e0.47; P < 0.001), leading to U.S. Food and Drug Administration (FDA) approval for its application in the AI-resistant population.
The G1-to-S phase transition is controlled by CDKs 4 and 6. These are activated on binding to D-type cyclins, leading to phosphorylation of the retinoblastoma susceptibility gene (RB1) product (Rb), which releases the E2F and DP transcription factors to drive expression from genes promoting S-phase entry (Figure 3). There is a strong link between the action of estrogen and CDK4/6 activity, through the transcriptional regulation of cyclin D1 by ER. That is related with resistance to endocrine therapy in ER positive breast cancer. Thus, CDK4/6 inhibitors are particularly attractive agents for ER posotive disease. PD 0332991 is a first-in-class, oral, highly selective inhibitor of CDK4/6 kinase. In a panel of breast cancer cell lines, PD 0332991 was found to be preferentially effective in ER positive cancer cells, including those that are resistant to antiestrogen.
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2. Mohamed A, Krajewski K, Cakar B, et al. Targeted therapy for breast cancer[J]. The American journal of pathology, 2013, 183(4): 1096-1112.