Hormone receptor-positive breast cancer is characterized by estrogen receptor (ER) and/or progesterone receptor (PgR) expression. About 70% of all breast cancers express hormone receptors. This breast cancer subtype is dependent on hormonal signaling for tumor growth and is commonly treated by either eliminating estrogen or inactivating the ER. Established strategies for the treatment in postmenopausal women include selective ER modulators (SERMs) such as tamoxifen, the ER downregulator (ERD) fulvestrant, and aromatase inhibitors (AIs) anastrozole, letrozole and exemestane, which decrease the synthesis of estrogen. Unfortunately, endocrine resistance is frequently observed in the treatment of ER positive breast cancer. Many patients either fail to respond to initial therapy (primary or de novo resistance) or eventually become resistant to treatment (secondary or acquired resistance).
The classic mechanism of action of the ER is its nuclear function (also referred to as the genomic activity of the ER) consisting in the regulation of the expression of genes important for normal cell function but also tumor growth and survival. In addition to ER-mediated signaling, other growth factor-mediated signaling pathways also play a role in advanced breast cancer. There is crosstalk between the ER-mediated signaling pathway and other growth factor-mediated signaling pathways. The activation of the ER by growth factor-mediated signaling pathways is referred to as ligand-independent receptor activation. Enhanced growth factor-mediated signaling pathway activation can be related to abnormalities either at the transmembrane tyrosine kinase level or at the intracellular level (second messengers). An increasing number of targeted therapies blocking this pathway activation are already available or are still under development.
Mammalian target of rapamycin (mTOR) is a highly conserved serine-threonine kinase that regulates cell growth, proliferation, motility, survival, and protein synthesis. Dysregulation of mTOR signaling occurs in various tumor types, including breast cancer, and has been associated with cancer pathogenesis, disease progression, and treatment resistance. There is growing evidence to support a close interaction between ER and PI3K/AKT/mTOR signaling. Hyperactivation of the PI3K/AKT/mTOR signaling pathway is an important mediator of endocrine resistance in hormone receptor-positive breast cancer cells. The PI3K/AKT/mTOR pathway is the most frequently mutated pathway in breast cancer, with genetic mutations and/or amplifications occurring in a very high number of patients with this disease. Therefore, combined inhibition of ER/PgR and mTOR represents a reasonable strategy for treating hormone receptor-positive disease.
BOLERO-2 is a randomized, placebo-controlled, multicenter, phase 3 study evaluating the mTOR inhibitor everolimus (10 mg/day) in combination with the steroidal AI exemestane (25 mg/day) in 724 postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer that recurred or progressed after previous nonsteroidal AI therapy. The final progression-free survival (PFS) analysis (after a median follow-up of 18 months) indicated that the median PFS by investigator assessment (primary endpoint) was 7.8 months for the combined-therapy arm compared with 3.2 months for the placebo-plus-exemestane arm. These results support the use of everolimus-based endocrine combination therapy in postmenopausal women with hormone receptor-positive advanced breast cancer that progressed after previous nonsteroidal AI therapy.
The improvement in PFS in the BOLERO-2 study was substantial and consistent across all prespecified subgroups. A major benefit was observed independently of sensitivity to prior hormonal therapy. A clinically meaningful improvement in median PFS was also seen in patients who had not yet received treatment for metastatic disease. The median PFS in these patients according to local assessment increased from 4.17 to 11.70 months.
Activation of the PI3K/AKT/mTOR signaling pathway is also observed in HER2-positive breast cancer. Amplification or overexpression of HER2 occurs in about 20% of breast cancers and is associated with more aggressive disease, shorter response duration, and reduced overall survival. Hyperactivation of the PI3K/AKT/mTOR pathway may act as a mechanism of resistance to anti-HER2 therapy. Consequently, clinical trials are also evaluating everolimus in the HER2-positive patient population. BOLERO-1 and BOLERO-3 are examples of 2 clinical trials in this patient population. Recruitment of patients has been completed, and results are awaited in the near future.
mTOR forms at least 2 functional multiprotein complexes: mTORC1 and mTORC2. First-generation mTOR inhibitors such as everolimus inhibit mTORC1 but not mTORC2, which also plays an important role in cancer growth and survival. In addition, treatment with first-generation mTOR inhibitors may also cause, at least when used as monotherapy, activation of AKT and MAPK via negative feedback loops.
First-generation mTOR inhibitors other than everolimus are currently under development. A negative phase 3 trial has been published with temsirolimus with a different patient population from BOLERO-2 and probably, most importantly, a suboptimal treatment regimen. Second-generation PI3K/AKT/mTOR pathway inhibitors are in various phases of clinical development and include: pure pan-PI3K inhibitors, dual PI3K/mTORC1/2 inhibitors, isoform-specific PI3K inhibitors, and AKT inhibitors. BKM120 is an oral inhibitor of all 4 isoforms of class I PI3K (α, β, γ, δ) that is already in 2 phase 3 trials: BELLE-2 (NCT01610284) and BELLE-3 (NCT01633060).
HER overexpression can mediate endocrine resistance and may be related to genomic dysregulation present at baseline or induced by drug exposure (acquired resistance). Clinical data indicate that patients with HER2- or epidermal growth factor receptor (EGFR)-overexpressing metastatic breast cancer (MBC) have a poorer outcome when treated with endocrine agents. It is possible to act upstream from PI3K and mTOR at the transmembrane tyrosine kinase level. EGFR, HER2, FGFR (fibroblast growth factor receptor), and (insulin-like growth factor receptor) IGFR are important potential targets for combined treatment strategies.
Clinical studies suggest that adding an HER2 inhibitor to endocrine therapy may improve outcomes. In the phase 3 randomized, double-blind, multicenter study published by Johnston and colleagues, 1286 patients with endocrine-responsive HER2-positive or -negative MBC were randomly assigned to receive letrozole plus lapatinib or letrozole plus placebo. Median PFS among the HER2-positive subgroup (219 patients) was 3 months in the letrozole-placebo group and 8.2 months in the letrozole-lapatinib group (hazard ratio: 0.71). Kaufman and colleagues observed that trastuzumab plus anastrozole improved outcomes for patients with HER2- and hormone receptor-copositive MBC compared with anastrozole alone (median PFS 4.8 v 2.4 months, hazard ratio: 0.63).
Other clinical trials evaluating the association of endocrine therapy and growth factor inhibitors have been performed. In particular, 2 randomized, placebo-controlled, phase 2 trials evaluated endocrine agents combined with gefitinib, an EGFR inhibitor, in postmenopausal women with hormone receptor-positive MBC. Cristofanilli and colleagues reported an improvement in PFS for patients receiving the combination of anastrozole and gefitinib vs patients receiving anastrozole plus placebo. Osborne and colleagues reported an improved PFS only in the subgroup of patients with de novo metastatic disease or a relapse no earlier than 1 year after stopping adjuvant tamoxifen. The IGFR inhibitor ganitumab (AMG-479) has been evaluated in a phase 2 trial and showed no improvement in median PFS with a worse overall survival in the ganitumab group than in the placebo group. Other EGFR and IGFR inhibitors are currently being evaluated in clinical trials.
Up to 8% of hormone receptor-positive, HER2-negative breast cancer patients have amplification of the FGFR1 gene, which is associated with resistance to endocrine therapy. FGFR inhibitors, including dovitinib and AZD-4547, are currently being evaluated in combination with endocrine therapy in ER-positive MBC. The study illustrated here is a multicenter, randomized, double-blind, placebo-controlled, phase 2 trial that will enroll postmenopausal hormone receptor-positive, HER2-negative locally advanced or MBC patients progressing within 12 months of completion of adjuvant endocrine therapy or after 1 prior endocrine therapy in the advanced setting. Prospective molecular screening will enrich the patient population for FGF amplification.
Aberrations in the cyclin-CDK-RB (cyclin-dependent kinase-retinoblastoma protein) pathway are common in breast cancer. Cyclin D1 is a well-characterized cell-cycle regulator with established oncogenic capabilities. Amplification of cyclin D1 has been found in 15%-20% of human breast cancers, whereas overexpression of the protein has been found at higher percentages (up to 50%). Cyclin-dependent kinases (CDKs) regulate cell proliferation and coordinate the cell-cycle checkpoint response to DNA damage. Selective CDK4/6 inhibitors have emerged as attractive antineoplastic agents because of the importance of CDK4/6 activity in regulating cell proliferation and the toxic effects associated with inhibition of other CDKs.
PD-0332991 is an oral, highly selective inhibitor of CDK4/6 kinase activity that prevents cellular DNA synthesis by prohibiting progression of the cell cycle from G1 to S phase. Preclinical studies identified luminal ER subtype as being associated with sensitivity to PD-0332991. In the second interim analysis of a phase 2 trial, the combination of PD-0332991 and letrozole compared with letrozole alone showed statistically significant improvement in median PFS. An ongoing phase 3 trial (TRIO-022, NCT01740427) will compare PD-0332991 with letrozole vs letrozole plus placebo in postmenopausal women with ER-positive, HER2-negative advanced breast cancer who have not received prior systemic anticancer therapies for their advanced/metastatic disease. Patients with prior (neo)adjuvant treatment with letrozole or anastrozole with a disease-free interval of 12 months or less from completion of treatment are excluded from the trial. Consequently, this population is different from the population studied in the BOLERO-2 trial.
A broad range of other new therapeutic strategies are being studied in clinical trials in breast cancer. Some of the new targets include: deacetylases that regulate, via protein modification, transcription and other processes involved in cell proliferation and survival; apoptosis proteins, which bind and inactivate apoptosis-inducing caspases in malignant cells; microtubules, whose stabilization suppresses tumor growth and causes cell-cycle arrest and apoptosis; HSP90, an abundant cellular chaperone responsible for the proper folding of many oncogenic proteins; PARP, an important component of DNA repair pathways whose inactivation in fast-growing tumor cells (especially those with underlying DNA repair defects such as BRCA1/2 mutant cancers) may accelerate chromosomal instability and cell death as well as potentiate the action of DNA-damaging chemotherapeutics like platinum compounds; cMET; VEGF; and IGFR-1.
Endocrine resistance is frequently observed in the treatment of ER-positive breast cancer. New treatment approaches attempt to overcome endocrine resistance by combining targeted therapies and endocrine therapy. Hyperactivation of the PI3K/AKT/mTOR pathway is frequently observed in ER-positive MBC. Everolimus combined with exemestane is the first combined treatment to outperform standard endocrine therapy alone. The BOLERO-2 trial showed similar magnitude of PFS benefit with the combined treatment of exemestane and everolimus compared with exemestane alone in all prespecified subgroups in patients with ER-positive MBC having failed prior nonsteroidal AI therapy. Current research is evaluating other targeting agents combined with endocrine therapy and in particular more potent inhibitors of the PI3K/AKT/mTOR pathway.
