The PI3K pathway is the most frequently altered pathway in breast cancer: the
PIK3CA gene (encoding the catalytic isoform p110α) is the second most frequently mutated oncogene, and
PTEN (encoding the phosphatase and tensin homolog) is among the most mutated tumor suppressor genes [
24,
25]. In addition, many other molecular alterations within different components of the pathway, including
PIK3CA amplifications,
AKT1 mutations, and
PTEN loss, have been observed in ER+ breast cancer [
16,
25]. Moreover, the PI3K/Akt/mTOR pathway has been described as potentially intervening in secondary endocrine resistance in ER+ breast cancer [
16,
26,
27]. In preclinical models, long-term estrogen-deprived breast cancer cells show an up-regulation of the PI3K pathway leading to a ligand-independent activation of ER by its phosphorylation through the mTOR complex 1 (mTORC1)/S6K1 axis [
26,
28]. A series of first-generation mTOR inhibitors have been developed including everolimus (Afinitor, Novartis) [
29] and temsirolimus (Torisel, Wyeth) [
30] as rapamycin derivatives that inhibit mTOR through allosteric binding to mTORC1. In preclinical models, the use of everolimus in combination with aromatase inhibitors (AIs) results in synergistic inhibition of proliferation and induction of apoptosis [
31]. In a randomized, phase II study comparing neoadjuvant everolimus plus letrozole with letrozole alone in patients with newly diagnosed ER-positive breast cancer, the response rate for the combination was higher than that for letrozole alone [
32]. Several phase II and III studies including an mTOR inhibitor have been completed in patients with advanced hormone receptor (HR)+ breast cancer, and so far three major randomized trials have reported consistent data in efficacy [
33‐
35] (Table
1). The phase III trial BOLERO (Breast cancer trials of oral everolimus)-2 enrolled 724 patients who were randomized to receive everolimus combined with exemestane (a steroidal AI) versus exemestane plus placebo in postmenopausal patients with HR+ advanced breast cancer previously treated with a non-steroidal AI (letrozole or anastrozole). At the time of the pre-planned analysis, median progression-free survival (PFS) was significantly better for the everolimus plus exemestane arm compared to the control arm (6.9 versus 2.8 months, HR 0.43, 95 % CI 0.35 to 0.54,
P < 0.001 according to local assessment) [
34]. The results of this study led to the approval by the FDA and EMA of everolimus in combination with exemestane in postmenopausal patients with advanced HR+ breast cancer previously exposed to letrozole or anastrozole. Final study results with median 18-month follow-up show that median PFS remained significantly longer with everolimus plus exemestane versus placebo plus exemestane in the overall population [investigator review: 7.8 versus 3.2 months, respectively; HR = 0.45 (95 % CI 0.38 to 0.54);
P < 0.0001; central review: 11.0 versus 4.1 months, respectively; HR = 0.38 (95 % CI 0.31 to 0.48);
P < 0.0001] [
36]. Updated results have not found a significant benefit for overall survival (OS) with the combination arm, although a trend was observed, with a median OS of 31 months versus 27 months for everolimus versus the placebo arm, respectively; (HR = 0.89; 95 % CI 0.73 to 1.10;
P = 0.14) [
37]. Similarly, the French phase II study TAMRAD (tamoxifen plus everolimus) randomized endocrine therapy alone (in this case tamoxifen) versus tamoxifen plus everolimus in patients again with metastatic ER+ breast cancer previously treated with endocrine therapy [
33]. In this trial including a total of 111 patients, clinical benefit rate (CBR) at 6 months (the primary endpoint) was clearly superior for the combination arm as compared with tamoxifen alone (61 % versus 42 % for combined therapy versus tamoxifen alone, respectively (exploratory
P = 0.045). Time to progression (TTP) was also favorable in the combination arm (8.6 versus 4.5 months; HR 0.54, 95 % CI 0.36 to 0.81,
P = 0.0021). There was also a benefit in OS for the mTOR-inhibitor arm (not reached versus 32.9 months, HR 0.45, 95 % CI 0.24 to 0.81,
P = 0.007) [
33]. Interestingly, the HORIZON trial, a phase III study in postmenopausal women with HR+ breast cancer that randomized 1,112 patients to receive the mTOR inhibitor temsirolimus in combination with letrozole versus letrozole plus placebo as first-line endocrine treatment, was closed prematurely following an intermediate analysis due to futility [
35]. The analysis showed no difference in PFS, the primary endpoint, between the two arms (median PFS of 9 months; HR 0.90, 95 % CI 0.76 to 1.07,
P = 0.25). There are several ongoing major randomized trials with everolimus in HR-positive advanced breast cancer including BOLERO-4, which will evaluate the benefit from the combination of everolimus and letrozole as first-line treatment (NCT01698918) and might be able to determine if the lack of benefit observed with temsirolimus in the HORIZON study was related to patient population, as preclinical studies have observed that the PI3K/Akt/mTOR pathway is mostly activated after previous endocrine therapy exposure. Finally, the BOLERO-6 trial is an ongoing three-arm phase II randomized study comparing everolimus plus exemestane, exemestane alone, and capecitabine (NCT01783444) in postmenopausal patients with HR+ breast cancer already exposed to endocrine therapy.
Table 1
Main clinical trials with targeted agents for ER+/HER2- advanced/metastatic breast cancer: mTOR inhibitors, PI3K inhibitors, and Akt inhibitors
mTOR | mTOR inhibitor | Evelorimus | | III | nsAI failure | EXE + evelorimus vs. EXE | | | 10.6 mo vs. 4.1 mo | n.s. |
BOLERO-4 NCT01698918 | II | First line | LET + evelorimus vs. LET | Ongoing |
BOLERO-6 NCT01783444 | II | nsAI failure | EXE + evelorimus vs. EXE vs. capecitabine | Ongoing |
| II | First line | TAM + evelorimus vs. TAM | 61 % vs. 42 % | 8.5mo vs. 4.5mo | | Not reached vs. 32.9mo |
Tensirolimus | | III | First line | LET + tensirolimus vs. LET | Terminated | n.s. | |
mTORC | mTORC dual TORC1/2 inhibitor | MLN0128 | NCT02049957 | I/II | | MLN0128 + EXE vs. MLN0128 + FUL | Ongoing |
PI3K | Pan-PI3 K inhibitor | BKM120 | BELLE-2 NCT01610284 | III | AI failure | Fulvestrant + BKM120 vs. fulvestrant | Ongoing |
BELLE-3 NCT01633060 | III | mTOR inhibitor resisetance | Fulvestrant + BKM120 vs. fulvestrant | Ongoing |
BELLE-4 NCT01572727 | III | First line | BKM120 vs. BKM120 + PTX | Terminated | n.s. | |
PI3K-α inhibitor | BYL719 | NCT02058381 | II | Premenopausal patients | BYL719 + TAM + Gos vs. BKM120 + TAM + Gos vs. TAM + Gos | Ongoing |
Pan-PI3K inhibitor/dual PI3K/mTOR inhibitor | XL147/XL765 | NCT01082068 | I/II | nsAI failure | XL147 + LET vs. XL765 + LET | Completed |
dual PI3K/mTOR inhibitor | GDC0941/GDC0980 | NCT01437566 | II | AI failure | Fulvestrant + GDC0941 vs. fulvestrant + GDC0980 vs. fulvestrant | ORR 7.9 % vs. unknown vs. 6.3 % | | 6.6mo vs. unknown vs. 5.1mo | |
Akt | Akt inhibitor | AZD2014 | MANTA NCT02216786 | II | AI failure | AZD2014 + FUL vs. everolimus + FUL vs. FUL | Ongoing |
AZD5363 | BEECH NCT01625286 | I/II | Part B: PI3CA mut | AZD5363 + wPTX vs. wPTX | Ongoing |
MK2206 | NCT01277757 | II | PIK3CA mut AKT mut PTEN loss/mut | Monotherapy | Terminated |
Many efforts have been performed in order to identify potential biomarkers of benefit from mTOR inhibition in patients with breast cancer. Immunohistochemistry (IHC) studies conducted on 55 formalin-fixed paraffin-embedded primary samples from the TAMRAD trial suggested that everolimus is more effective for tumors presenting with high levels of p4EBP1 (a downstream effector of the mTOR pathway), suggesting that baseline mTOR activation might be associated with sensitivity to mTOR inhibition [
38]. In parallel, next-generation sequencing studies performed in 309 samples from the BOLERO-2 trial found that the presence of more than one molecular alteration (from four key pathways including
FGFR1/2 amplification,
PIK3CA mutation,
PTEN loss, or
CCDN1 amplification) was associated with a lack of benefit from everolimus treatment (HR = 0.78; 95 % CI 0.39-1.54) [
17]. These findings suggest that primary resistance to mTOR inhibition might depend on the coexistence of mutations or amplifications in other pathways; therefore, combination therapy with other target agents should be considered for this population. Interestingly, the presence of a
PIK3CA mutation was not predictive of benefit from everolimus treatment.