Clinical development of mTOR inhibitors in breast cancer
- 6.4k Downloads
The mammalian target of rapamycin (mTOR) pathway is a central pathway that regulates mRNA translation, protein synthesis, glucose metabolism, lipid synthesis and autophagy, and is involved in malignant transformation. Several randomized trials have shown that the use of mTOR inhibitors could improve patient outcome with hormone receptor-positive or human epidermal growth factor receptor-2-positive breast cancer. This review analyzes new perspectives from these trials. Preclinical studies have suggested that the mTOR pathway may play a role in the resistance to hormone therapy, trastuzumab and chemotherapy for breast cancer. This concept has been tested in clinical trials for neoadjuvant treatment and for metastatic breast cancer patients. Also, much effort has gone into the identification of biomarkers that will allow for more precise stratification of patients. Findings from these studies will provide indispensable tools for the design of future clinical trials and identify new perspectives and challenges for researchers and clinicians.
KeywordsBreast Cancer Paclitaxel Trastuzumab Everolimus Advanced Breast Cancer
eIF4E binding protein 1
Protein kinase B
Adenosine monophosphate-activated protein kinase
Human epidermal growth factor receptor-2
Insulin growth factor 1-receptor
Liver kinase B1
mammalian target of rapamycin
non-steroidal aromatase inhibitor
Regulatory associated protein of mTOR
Rapamycin insensitive companion of mTOR
ribosomal protein S6 kinase
Triple-negative breast cancer
Tuberous sclerosis 1/2.
The mammalian target of rapamycin pathway
As a serine/threonine kinase and downstream member of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) and adenosine monophosphate-activated protein kinase (AMPK) pathways, mammalian target of rapamycin (mTOR) is a key regulator of cell growth and metabolism. In cells, mTOR is a component of two structurally similar complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Both complexes contain mTOR, the DEP-domain containing mTOR interacting protein and mLST8 (mTOR associated protein); mTORC1 also includes the regulatory associated protein of mTOR (RAPTOR) and a 40 kDa proline-rich AKT substrate, while mTORC2 contains the rapamycin insensitive companion of mTOR (RICTOR), the mammalian stress activated map kinase interacting protein 1 and protein observed with RICTOR.
Interestingly, a large panel of activating mutations is found in the mTOR pathway, including PI3KCA (the PI3K catalytic subunit alpha isoform), AKT1 and mTOR mutations, as well as PTEN loss. Drugs targeting various levels of the mTOR pathway have been developed, including PI3K, AKT and mTOR inhibitors. mTORC1 is the biological target for rapalogs such as everolimus and temsirolimus, whereas other inhibitors are capable of simultaneously targeting both mTOR complexes.
Clinical development of rapalogs in breast cancer
Estrogen receptor-positive breast cancer
Endocrine manipulation is the principal treatment for ER + breast cancer patients, both in the early and advanced phases of the disease. However, not all patients with ER + tumors are sensitive to endocrine treatment (primary resistance) and a proportion of initially sensitive patients may develop a secondary resistance during or after treatment. Multiple mechanisms of resistance to anti-endocrine agents have been described. mTOR activation was shown to mediate resistance to endocrine therapy in preclinical models . Furthermore, mTOR inhibitors such as everolimus synergized with letrozole in preclinical models  and mTOR was described as a mechanism facilitating escape of long-term estrogen deprivation . The addition of mTOR inhibitors to endocrine treatment has been investigated in phase II and III studies, including patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor-2-negative (HER2-) breast cancer. Three major randomized trials have reported consistent data on everolimus efficacy in ER + breast cancer. In a randomized phase II neoadjuvant trial including 270 patients, everolimus in addition to letrozole was compared against letrozole plus placebo . The clinical response rate by palpation was higher in the everolimus arm (68 versus 59%, P = 0.06, prespecified cutoff for significance <0.1), suggesting everolimus increased letrozole efficacy in the neoadjuvant setting . Interestingly, Ki67 expression was evaluated at baseline and after 15 days of treatment, in 91 tumors for the everolimus arm and 82 tumors for the placebo arm, and the evaluation was based on the reduction in Ki67 expression to natural logarithm of percentage positive Ki67 of less than 1 at day 15. The results show a greater antiproliferative response for the everolimus treated patients (57% of patients with everolimus responded versus 25% of patients with placebo, P < 0.01). TAMRAD was a phase II randomized trial of tamoxifen plus everolimus versus tamoxifen alone in patients with HR+, HER2- advanced breast cancer and previous exposure to an aromatase inhibitor (AI) . The primary end point was the clinical benefit rate of tamoxifen plus everolimus and was estimated as 61% (compared to 42% with tamoxifen alone). Otherwise, time to progression appeared to be more prolonged with the combination compared to tamoxifen alone (8.6 months versus 4.5 months, hazard ratio 0.54, 95% CI 0.36 to 0.). At the last update of overall survival in September 2011, only 16 patients were dead in the combination group versus 31 with tamoxifen alone. Median overall survival was not available for the combination group while it was 32.9 months for tamoxifen alone. The phase III trial BOLERO-2 enrolled 724 patients with HR + advanced breast cancer who experienced a recurrence during or within 12 months after the end of adjuvant non-steroidal aromatase inhibitor (nsAI) treatment or progression during or within 1 month after the end of nsAI treatment for advanced disease . Patients were randomized to receive everolimus combined with exemestane versus exemestane plus placebo. At the time of the pre-planned interim analysis, the median progression-free survival (PFS) was significantly better for the everolimus plus exemestane arm compared to the control arm, for both local investigator and central assessment analyses (6.9 months versus 2.8 months, hazard ratio 0.43, 95% CI 0.35 to 0.54, P < 0.001; 10.6 versus 4.1 months, hazard ratio 0.36, 95% CI 0.27 to 0.47, P < 0.001) . At a median follow-up of 18 months, the addition of everolimus to exemestane was confirmed to significantly improve patient outcome over exemestane alone (median PFS 7.8 versus 3.2 months, hazard ratio 0.45, 95% CI 0.38 to 0.54, P < 0.0001) . Everolimus has since received approval from the Food and Drug Administration and the European Medicines Agency in combination with exemestane for HR+/HER2- advanced breast cancer patients after failure of a nsAI [13, 14].
However, many questions remain to be addressed. For example, the role of everolimus in premenopausal women and endocrine sensitive patients has yet to be established. Other schedules, such as everolimus alone or in combination with chemotherapy, need to be evaluated and compared to the approved treatments. Ongoing trials are beginning to address some of these issues. BOLERO-6 is a three-arm phase II randomized trial comparing everolimus plus exemestane, exemestane alone and capecitabine for patients with HR+/HER2- advanced breast cancer refractory to nsAI (ClinicalTrials.gov number NCT01783444), while BOLERO-4 (single-arm, phase II) is evaluating the combination of everolimus and letrozole as a first-line treatment for patients with ER + advanced breast cancer (endocrine treatment for early breast cancer is allowed, if completed 1 year before enrollment) (ClinicalTrials.gov number NCT01698918).
A broad clinical development program for everolimus in early breast cancer is being pursued, with two investigator-initiated studies evaluating everolimus in the adjuvant setting in patients with high-risk disease.
An ongoing American study is planning to enroll up to 3,400 premenopausal and postmenopausal women with HR+/HER2- breast cancer who have received prior standard neoadjuvant or adjuvant chemotherapy. Patients will be randomized to receive everolimus 10 mg/day or placebo for the first year of 5 years of adjuvant endocrine therapy (ClinicalTrials.gov number NCT01674140). A phase III French-UK study will evaluate the addition of everolimus to adjuvant endocrine treatment for patients with HR+/HER2- breast cancer who remain disease-free following 2 to 3 years of adjuvant endocrine therapy (ClinicalTrials.gov number NCT01805271). These studies have a different design and will hopefully provide clarifications on two different points. The American one will test the efficacy of adjuvant everolimus upfront for all subjects; therefore, the biologic background refers mainly to baseline mTOR activation. In contrast, the European study plans the introduction of everolimus after 2 to 3 years of adjuvant endocrine therapy, and will mainly focus on the hypothesis of induced mTOR activation occurring during anti-endocrine treatment. The results are expected to shed light on the underlying disease mechanisms.
Despite these interesting findings, one phase III randomized trial appeared to be negative: the HORIZON trial enrolled 1,112 AI naïve patients to evaluate the efficacy and safety of a letrozole and temsirolimus combination daily versus letrozole and placebo in patients with advanced HR + breast cancer. Unfortunately, HORIZON was stopped for futility as the letrozole-temsirolimus combination did not lead to an improvement in PFS, which was the primary end point, and more grade 3 or 4 adverse events (AEs) were noticed (median PFS of 9 months, hazard ratio 0.90, 95% CI 0.76 to 1.07, P = 0.25). This trial was especially conducted with AI naïve patients and only 40% received adjuvant endocrine therapy, testing the primary resistance and possibly explaining the negative results compared to the BOLERO-2 trial .
Human epidermal growth factor receptor-2-positive breast cancer
HER2 overexpression/amplification leads to an aggressive breast cancer phenotype and poor prognosis . The introduction of the recombinant humanized anti-HER2 monoclonal antibody trastuzumab in the management of this breast cancer subtype has dramatically improved patient outcome . However, many patients develop resistance to this therapy. PTEN loss or PI3K mutation have been shown to induce mTOR activation and mediate trastuzumab resistance . Other preclinical studies have shown that rapalogs overcome resistance to trastuzumab , suggesting that mTOR inhibitors could potentially delay or reverse trastuzumab resistance.
Early-phase trials (phase Ib-II) have evaluated the efficacy of the addition of everolimus to trastuzumab plus paclitaxel or vinorelbine for patients with HER2+ advanced breast cancer who progressed after trastuzumab. These studies reported overall response rates in the range of 19 to 44%, indicating that mTOR inhibitors can overcome resistance to trastuzumab [20, 21, 22].
BOLERO-1 and BOLERO-3 are randomized phase III trials addressing HER2+ advanced breast cancer. BOLERO-3 has tested the hypothesis that addition of everolimus could overcome an acquired resistance to anti-HER2 therapy . Patients (n = 572) have been receiving vinorelbine, trastuzumab with everolimus (5 mg/day) or placebo, and initial results indicate that everolimus is able to improve PFS in trastuzumab-resistant patients (hazard ratio 0.78, 0.95% CI 0.65 to 0.95). Interestingly, PFS subgroup analyses determined more benefit for patients with prior adjuvant or neoadjuvant trastuzumab treatment and who were HR- (hazard ratio 0.65, 95% CI 0.48 to 0.87).
BOLERO-1 is an ongoing phase III randomized trial involving patients with HER2+ advanced breast cancer who have not received trastuzumab in the metastatic setting, thus testing the potential for everolimus to overcome baseline trastuzumab resistance. Patients will be randomized to receive paclitaxel plus trastuzumab and the same combination plus everolimus (10 mg/day). The primary end point will be PFS (ClinicalTrials.gov number NCT00876395).
Considering the research efforts currently being applied to the development of HER2 drugs, it will be important to identify patients that are highly sensitive to everolimus. Indeed, the results of BOLERO-3 should have particular relevance for this issue.
Triple-negative breast cancer
The rationale for developing rapalogs for treatment of triple-negative breast cancer (TNBC) is based on the recent detection of a high frequency of PTEN loss, which is known to correlate with AKT activation, in array comparative genomic hybridization studies [24, 25]. A recent gene expression analysis of TNBC identified at least six tumor molecular subtypes, including a mesenchymal-like subset that was highly sensitive to PI3K/mTOR inhibitors in vitro and in vivo. Additionally, everolimus has been shown to sensitize basal-like breast cancer to DNA damaging agents, including cisplatinum [27, 28]. These preclinical findings have led to clinical evaluation of everolimus in TNBC. In a phase II neoadjuvant study including 50 TNBC patients, everolimus has been tested in addition to 12 weekly administrations of paclitaxel followed by fluorouracil, epirubicin and cyclophosphamide every 3 weeks for four cycles . There was a higher clinical response rate in the everolimus treatment compared to chemotherapy alone (48% versus 30%), but this did not reach statistical significance (P = 0.075). Another phase II randomized study comparing neoadjuvant cisplatin and paclitaxel with or without everolimus (Clinicaltrials.gov number NCT00930930) is ongoing.
Critical points for future research will be to define, if possible, a subgroup of TNBC patients most likely to benefit from the addition of everolimus to chemotherapy and to define the potential predictive role of PTEN loss.
Preclinical studies have suggested that rapalogs could synergize with taxanes  and this has been addressed in a recent neoadjuvant phase III study . Patients with HER2- breast cancer (n = 403) were enrolled. Patients showing no response after four cycles of preoperative epirubicin and cyclophosphamide (with or without bevacizumab) were randomized to receive paclitaxel or paclitaxel plus everolimus (starting at 2.5 mg every other day and escalating to 5 mg per day). The pathologic complete response was 3.6% in the paclitaxel group, compared with 5.6% in the paclitaxel plus everolimus group (P = 0.476). Moreover, the clinical response rate was 52% and 62% in the paclitaxel alone and everolimus groups, respectively. Although there is currently no evidence to suggest everolimus may be able to overcome chemoresistance in these patients, the appropriateness of pathologic complete response as the optimal end point for the efficacy of new targeted agents is questionable. Furthermore, everolimus and chemotherapy dose intensities may require optimization for best results. Other studies, such as a randomized phase II trial evaluating a combination of paclitaxel and bevacizumab with or without everolimus (10 mg/day) for patients with HER2- metastatic breast cancer (Clinicaltrials.gov number NCT00915603) are ongoing.
Mammalian target of rapamycin inhibitor toxicities
In the everolimus trials, the most common AEs are fatigue, stomatitis, anorexia, diarrhea, metabolic disorders with hyperglycemia, noninfectious pneumonitis and hematologic disorders. These AEs were noticed in the TAMRAD study, mostly grade 1 to 2 in severity , as well as in the BOLERO-2 trial, in which 23% of patients in the combination treatment had serious AEs versus 12% in the exemestane group . In a phase 1 study, stomatitis was the most common AE, occurring in 27 of the 33 patients enrolled at any grade, 7 of which were grade 3 . They also observed one interstitial pneumonitis. Everolimus is usually relatively tolerated but sometimes needs to be adapted with dose reduction and a perfect knowledge of AEs is required for treating patients.
Similar AEs were observed in the temsirolimus trial, with some cases of headache and fever; most grade 3 AEs were hyperglycemia, hyperlipemia, dyspnea and asthenia .
Moving beyond rapalogs: how to prepare second generation trials?
Biomarkers for patient stratification
Secondly, it will be important to identify patients that are hypersensitive to mTOR inhibitors. Analysis of such a subgroup could lead to the identification of genetic drivers of mTOR-activation. GOLPH3 amplifications and PTEN, STK11 and TSC1 mutations have all been described as outlier responders to everolimus [33, 34, 35, 36].
Sensitive patients can then be further classified on the basis of the pathway responsible for everolimus efficacy (for example, the PI3K-dependent ‘classic’ pathway or the LKB1/AMPK metabolic pathway). Preclinical findings suggest that PI3K mutation is a predictor of mTOR inhibition efficacy ; however, recent next-generation sequencing results of 309 samples from the BOLERO-2 trial failed to confirm this. Indeed, neither PIK3CA mutation nor PI3K pathway alteration by mutations in other pathway members were predictive of everolimus benefit . Interestingly, results from the TAMRAD study suggest that mTOR activation by the LKB1/AMPK pathway predicts everolimus efficacy .
Finally, research efforts should focus on patients with primary or acquired resistance to mTOR inhibition. Some markers of intrinsic resistance have already been proposed in preclinical models, such as KRAS mutations or a high 4EBP1/elF4E expression ratio [39, 40].
Next-generation sequencing from the BOLERO-2 trial has demonstrated that patients with a minimal number of genetic alterations derived the greatest benefit from everolimus, suggesting that concomitant mutations in other oncogenic pathways might mediate resistance or attenuate everolimus efficacy . Interestingly, this study found that FGFR1 amplification was associated with reduced sensitivity to mTOR inhibitors.
In this review we have highlighted the importance of integrating biologic and clinical data for the clinical development of mTOR inhibitors. Indeed, a molecular stratification of breast cancer patients based on mTOR-related factors may be key for future research in the field. Overall, various ongoing phase III clinical trials are testing the efficacy of everolimus according to the hypothesized timing of mTOR activation, for both HR + and HER2+ breast cancer. This reflects the proposed classification into ‘baseline’ and ‘during treatment’ mTOR activation. Furthermore, biomarker studies in the metastatic setting and new tools for molecular diagnosis (such as phosphoprotein quantification and polysome profiling) should be conducted and developed in the proposed patients groups. These will help answer some of the major unanswered questions. In addition, studies in the post-everolimus setting will be required for the second wave of rapalogs.
This article is part of a series on “Recent advances in breast cancer treatment”, edited by Jenny Chang. Other articles in this series can be found at http://breast-cancer-research.com/series/treatment.
- 7.Miller TW, Hennessy BT, González-Angulo AM, Fox EM, Mills GB, Chen H, Higham C, García-Echeverría C, Shyr Y, Arteaga CL: Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010, 120: 2406-2413. 10.1172/JCI41680.CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, Campone M, Kubista E, Greil R, Bianchi G, Steinseifer J, Molloy B, Tokaji E, Gardner H, Phillips P, Stumm M, Lane HA, Dixon JM, Jonat W, Rugo HS: Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009, 27: 2630-2637. 10.1200/JCO.2008.18.8391.CrossRefPubMedGoogle Scholar
- 10.Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaëth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E: Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012, 30: 2718-2724. 10.1200/JCO.2011.39.0708.CrossRefPubMedGoogle Scholar
- 11.Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012, 366: 520-529. 10.1056/NEJMoa1109653.CrossRefPubMedGoogle Scholar
- 12.Piccart M, Baselga J, Noguchi S, Burris H, Gnant M, Hortobagyi G, Mukhopadhyay P, Taran T, Sahmoud T, Rugo H: Final progression-free survival analysis of BOLERO-2: a phase III trial of everolimus for postmenopausal women with advanced breast cancer. Cancer Res. 2012, 72: 492s-493s. 10.1158/1538-7445.AM2012-492.CrossRefGoogle Scholar
- 13.Afinitor: Highlights of Prescribing Information. [http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022334s016lbl.pdf]
- 14.EPAR: Product Information. [http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Product_Information/human/001038/WC500022814.pdf]
- 15.Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L, Sun Y, Neskovic-Konstantinovic Z, Guimaraes RC, Fumoleau P, Chan A, Hachemi S, Strahs A, Cincotta M, Berkenblit A, Krygowski M, Kang LL, Moore L, Hayes DF: Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol. 2013, 31: 195-202. 10.1200/JCO.2011.38.3331.CrossRefPubMedGoogle Scholar
- 17.Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001, 344: 783-792. 10.1056/NEJM200103153441101.CrossRefPubMedGoogle Scholar
- 18.Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D: PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004, 6: 117-127. 10.1016/j.ccr.2004.06.022.CrossRefPubMedGoogle Scholar
- 19.Miller TW, Forbes JT, Shah C, Wyatt SK, Manning HC, Olivares MG, Sanchez V, Dugger TC, de Matos Granja N, Narasanna A, Cook RS, Kennedy JP, Lindsley CW, Arteaga CL: Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells. Clin Cancer Res. 2009, 15: 7266-7276. 10.1158/1078-0432.CCR-09-1665.CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Morrow PK, Wulf GM, Ensor J, Booser DJ, Moore JA, Flores PR, Xiong Y, Zhang S, Krop IE, Winer EP, Kindelberger DW, Coviello J, Sahin AA, Nuñez R, Hortobagyi GN, Yu D, Esteva FJ: Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol. 2011, 29: 3126-3132. 10.1200/JCO.2010.32.2321.CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Andre F, Campone M, O’Regan R, Manlius C, Massacesi C, Sahmoud T, Mukhopadhyay P, Soria JC, Naughton M, Hurvitz SA: Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol. 2010, 28: 5110-5115. 10.1200/JCO.2009.27.8549.CrossRefPubMedGoogle Scholar
- 22.Jerusalem G, Fasolo A, Dieras V, Cardoso F, Bergh J, Vittori L, Zhang Y, Massacesi C, Sahmoud T, Gianni L: Phase I trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat. 2011, 125: 447-455. 10.1007/s10549-010-1260-x.CrossRefPubMedGoogle Scholar
- 23.O’Regan R, Ozguroglu M, Andre F, Toi M, Jerusalem GHM, Wilks S, Isaacs C, Xu B, Masuda N, Arena FP, Yardley AD, Yap YS, Mukhopadhyay P, Douma S, El-Hashimy M, Taran T, Sahmoud T, Lebwohl DE, Gianni L: Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab-resistant, advanced breast cancer (BOLERO-3). J Clin Oncol. 2013, 31 (suppl): Abstract 505-Google Scholar
- 24.Andre F, Job B, Dessen P, Tordai A, Michiels S, Liedtke C, Richon C, Yan K, Wang B, Vassal G, Delaloge S, Hortobagyi GN, Symmans WF, Lazar V, Pusztai L: Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array. Clin Cancer Res. 2009, 15: 441-451. 10.1158/1078-0432.CCR-08-1791.CrossRefPubMedGoogle Scholar
- 25.Marty B, Maire V, Gravier E, Rigaill G, Vincent-Salomon A, Kappler M, Lebigot I, Djelti F, Tourdès A, Gestraud P, Hupé P, Barillot E, Cruzalegui F, Tucker GC, Stern MH, Thiery JP, Hickman JA, Dubois T: Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basal-like breast cancer cells. Breast Cancer Res. 2008, 10: R101-10.1186/bcr2204.CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Beuvink I, Boulay A, Fumagalli S, Zilbermann F, Ruetz S, O’Reilly T, Natt F, Hall J, Lane HA, Thomas G: The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell. 2005, 120: 747-759. 10.1016/j.cell.2004.12.040.CrossRefPubMedGoogle Scholar
- 28.Wong SW, Tiong KH, Kong WY, Yue YC, Chua CH, Lim JY, Lee CY, Quah SI, Fow C, Chung C, So I, Tan BS, Choo HL, Rosli R, Cheong SK, Leong CO: Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through up-regulation of p73. Breast Cancer Res Treat. 2011, 128: 301-313. 10.1007/s10549-010-1055-0.CrossRefPubMedGoogle Scholar
- 29.Gonzalez-Angulo A, Green MC, Murray JL, Palla SL, Koenig KH, Brewster AM, Valero V, Ibrahim NK, Moulder SL, Litton JK, Crawford DJ, Flores PR, Dryden MJ, Symmans WF, Giordano SH, Pusztai L, Buzdar A, Mills GB, Hortobagyi GN, Meric-Bernstam F: Open label, randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC (T-FEC) versus the combination of paclitaxel and RAD001 followed by FEC (TR-FEC) in women with triple receptor-negative breast cancer (TNBC). J Clin Oncol. 2011, 29 (suppl): Abstract 1016-Google Scholar
- 31.Huober J, Fasching PA, Hanusch C, Rezai M, Eidtmann H, Kittel K, Hilfrich J, Schwedler K, Blohmer JU, Tesch H, Gerber B, Höß C, Kümmel S, Mau C, Jackisch C, Khandan F, Costa SD, Krabisch P, Loibl S, Nekljudova V, Untch M, Minckwitz G: Neoadjuvant chemotherapy with paclitaxel and everolimus in breast cancer patients with non-responsive tumours to epirubicin/cyclophosphamide (EC)±bevacizumab - results of the randomised GeparQuinto study (GBG 44). Eur J Cancer. 2013, 49: 2284-2293. 10.1016/j.ejca.2013.02.027.CrossRefPubMedGoogle Scholar
- 32.Treilleux I, Arnedos M, Cropet C, Ferrero JM, Abadie Lacourtoisie S, Spaeth D, Levy C, Legouffe E, Pujade-Lauraine E, Wang Q, Bachelot T: Predictive markers of everolimus efficacy in hormone receptor positive (HR+) metastatic breast cancer (MBC): final results of the TAMRAD trial translational study. J Clin Oncol. 2013, 31 (suppl): Abstract 510-Google Scholar
- 33.Scott KL, Kabbarah O, Liang MC, Ivanova E, Anagnostou V, Wu J, Dhakal S, Wu M, Chen S, Feinberg T, Huang J, Saci A, Widlund HR, Fisher DE, Xiao Y, Rimm DL, Protopopov A, Wong KK, Chin L: GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer. Nature. 2009, 459: 1085-1090. 10.1038/nature08109.CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Klümpen HJ, Queiroz KC, Spek CA, van Noesel CJ, Brink HC, de Leng WW, de Wilde RF, Mathus-Vliegen EM, Offerhaus GJ, Alleman MA, Westermann AM, Richel DJ: mTOR inhibitor treatment of pancreatic cancer in a patient with Peutz-Jeghers syndrome. J Clin Oncol. 2011, 29: e150-e153. 10.1200/JCO.2010.32.7825.CrossRefPubMedGoogle Scholar
- 36.Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, Ostrovnaya I, Viale A, Heguy A, Peng L, Chan TA, Bochner B, Bajorin DF, Berger MF, Taylor BS, Solit DB: Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012, 338: 221-10.1126/science.1226344.CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Loi S, Haibe-Kains B, Majjaj S, Lallemand F, Durbecq V, Larsimont D, Gonzalez-Angulo AM, Pusztai L, Symmans WF, Bardelli A, Ellis P, Tutt AN, Gillett CE, Hennessy BT, Mills GB, Phillips WA, Piccart MJ, Speed TP, McArthur GA, Sotiriou C: PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci U S A. 2010, 107: 10208-10213. 10.1073/pnas.0907011107.CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS, Burris HA, Campone M, Noguchi S, Perez AT, Deleu I, Shtivelband M, Provencher L, Masuda N, Dakhil SR, Anderson I, Chen D, Damask A, Huang A, McDonald R, Taran T, Sahmoud T, Baselga J: Correlation of molecular alterations with efficacy of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer: results from BOLERO-2. J Clin Oncol. 2013, 31 (suppl): Abstract LBA509-Google Scholar
- 39.Janku F, Wheler JJ, Westin SN, Moulder SL, Naing A, Tsimberidou AM, Fu S, Falchook GS, Hong DS, Garrido-Laguna I, Luthra R, Lee JJ, Lu KH, Kurzrock R: PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol. 2012, 30: 777-782. 10.1200/JCO.2011.36.1196.CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Alain T, Morita M, Fonseca BD, Yanagiya A, Siddiqui N, Bhat M, Zammit D, Marcus V, Metrakos P, Voyer LA, Gandin V, Liu Y, Topisirovic I, Sonenberg N: eIF4E/4E-BP ratio predicts the efficacy of mTOR targeted therapies. Cancer Res. 2012, 72: 6468-6476. 10.1158/0008-5472.CAN-12-2395.CrossRefPubMedGoogle Scholar
- 41.O’Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N: mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006, 66: 1500-1508. 10.1158/0008-5472.CAN-05-2925.CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP: Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008, 118: 3065-3074.PubMedPubMedCentralGoogle Scholar
- 43.Naing A, Kurzrock R, Burger A, Gupta S, Lei X, Busaidy N, Hong D, Chen HX, Doyle LA, Heilbrun LK, Rohren E, Ng C, Chandhasin C, LoRusso P: Phase I trial of cixutumumab combined with temsirolimus in patients with advanced cancer. Clin Cancer Res. 2011, 17: 6052-6060. 10.1158/1078-0432.CCR-10-2979.CrossRefPubMedPubMedCentralGoogle Scholar
- 44.Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, Shi EY, Stumpf CR, Christensen C, Bonham MJ, Wang S, Ren P, Martin M, Jessen K, Feldman ME, Weissman JS, Shokat KM, Rommel C, Ruggero D: The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature. 2012, 485: 55-61. 10.1038/nature10912.CrossRefPubMedPubMedCentralGoogle Scholar
- 45.Tabernero J, Cervantes A, Gordon MS, Chiorean EG, Burris HA, Macarulla T, Perez-Fidalgo A, Martin M, Jessen K, Liu Y, Le T, Rommel C, Berk GI, Bui LA, Infante JR: A phase I, open label, dose escalation study of oral mammalian target of rapamycin inhibitor INK128 administered by intermittent dosing regimens in patients with advanced malignancies. Cancer Res. 2012, 72: Abstract CT-02-CrossRefGoogle Scholar