(monotherapy,w/chemo,w/Sorafenib,w/Avastin,w/Curcumin, w/IGFR-1 inhib, w/Zol, w/Cy=PI3k/Akt, in er-, immuno-synergy, intermittent resensitizes, Cdk2 inhib roscovitine, Soy warning)
Breast Cancer Res Treat. 2007 October; 105(Suppl 1): 105–115.
Published online 2007 October 3. doi: 10.1007/s10549-007-9697-2.
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Copyright © Springer Science+Business Media, LLC 2007
Femara® and the future: tailoring treatment and combination therapies with Femara
FULL TEXT HERE
Matthew Ellis
and Cynthia Ma
Medical Oncology, Washington University, 660 Euclid Ave, Campus Box 8056, St Louis, MO 63110 USA
Matthew Ellis, Phone: +1-314-3623774, Fax: +1-314-3627086, Email:
mellis@wustl.edu.
Corresponding author.
Received January 3, 2007; Accepted July 17, 2007.
Abstract
Long-term estrogen deprivation treatment for breast cancer can, in some patients, lead to the activation of alternate cellular pathways, resulting in the re-emergence of the disease. This is a distressing scenario for oncologists and patients, but recent intensive molecular and biochemical
studies are beginning to unravel these pathways, revealing opportunities for new targeted treatments. Far from making present therapies redundant, these new discoveries open the door to novel combination therapies that promise to provide enhanced efficacy or overcome treatment resistance.
Letrozole, one of the most potent aromatase inhibitors, is the ideal candidate for combination therapy; indeed, it is one of the most intensively studied aromatase inhibitors in the evolving combinatorial setting. Complementary to the use of combination therapy is the development of molecular tools to identify patients who will benefit the most from these new treatments. Microarray gene profiling studies, designed to detect letrozole-responsive targets, are currently under way to understand how the use of the drug can be tailored more efficiently to specific patient needs.
Quote:
Hormone-sensitive breast cancer can be regarded as a chronic disease with a persistent risk of escape from effective endocrine control. Activation of growth factor signaling pathways has been implicated in progression of HR+ breast cancer to an estrogen-independent phenotype and the development of resistance to endocrine therapy, particularly tamoxifen. It has been hypothesized that combining endocrine therapy with targeted signal transduction inhibitors may circumvent hormone-independent signaling pathways, so that patients may experience prolonged disease control.
Letrozole is one of the most potent AIs. As such, it may be more effective than tamoxifen for patients with tumor profiles associated with a high risk of developing hormone resistance (e.g., tumors with HER2 gene amplification) and represents an ideal combination partner for agents that inhibit growth signaling pathways implicated in hormone resistance. The efficacy of letrozole is currently being investigated with a variety of signal transduction inhibitors with different mechanisms of action, including monoclonal antibodies against HER family receptors, receptor tyrosine kinase inhibitors, and downstream signaling pathway inhibitors.
Gene expression profiling has been validated as a useful new tool to predict risk of relapse in patients treated with hormone therapy and chemotherapy. This approach will help physicians to identify which patient will likely benefit from specific therapies, such as letrozole. Tailoring therapy to individual patient profiles (clinical, histologic, pathologic, and genetic) will become more sophisticated in the future, helping to maximize the benefits of endocrine therapy throughout the breast cancer continuum; letrozole will undoubtedly become an integral part of the next generation of tailored combination regimens for the treatment of breast cancer.
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Ai Zheng. 2010 Jan;29(1):9-14.
The aromatase inhibitor letrozole combined with curcumin in the inhibition of xenografted endometrial carcinoma growth.
Liang YJ,
Zhang HM,
Wu YZ,
Hao Q,
Wang JD,
Hu YL.
Department of Obstetrics and Gynecology, Jinling Hospital, Nanjing University School of Medicine,Nanjing, Jiangsu 210002, P. R. China.
yuanjiao1965@126.com.
Background and Objective: Letrozole is an aromatase inhibitor that is used in the treatment of estrogen-sensitive tumors such as endometrial carcinoma. Tumor inhibition to a certain extent has been demonstrated, however, the therapeutic effects need improvement.
Curcumin is reported to have antitumor capabilities and can enhance the sensitivity of tumor cells to anticancer agents. The present study promoted the inhibitory effect on implanted endometrial tumor growth by combining letrozole and curcumin. Methods:
Endometrial carcinoma was implanted into nude mice. Tumor-laden mice were treated with the aromatase inhibitor letrozole (Let), curcumin (Cur), or both. The tumor growth was monitored. Tumor cell apoptosis was detected in both the control and treated groups. The expression of bcl-2 mRNA and Bcl-2 protein was detected with reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Results: A total of 50 mice successfully received implants of endometrial tumors. Treatment with letrozole markedly inhibited tumor growth, and the inhibitory effect was enhanced by the combination of letrozole and curcumin.
The inhibitory rates in the Let(1), Let(10), Cur, and Let+Cur groups were 15.95%, 22.49%, 21.57%, and 35.89%, respectively. Treatment with curcumin inhibited the expression of Bcl-2 in tumor cells at the mRNA and protein levels.
The rates of apoptosis in the control group and the above-mentioned groups were 16.97%, 32.90%, 35.80%, 34.16%, and 47.24%, respectively. Tumor cell apoptosis was observed in mice treated with either letrozole or curcumin; however, the combination of letrozole and curcumin enhanced the inhibition rate in tumor growth. Conclusions: Treatment with either letrozole or curcumin could inhibit xenografted endometrial tumor growth by inducing apoptosis in tumor cells. The combination of letrozole and curcumin enhanced the inhibitory effect.
PMID: 20038303 [PubMed - in process]
Low Forms of Cyclin E Reduce Breast Cancer Drug's Effectiveness
ScienceDaily (Feb. 9, 2010) —
Overexpression of low-molecular-weight (LMW-E) forms of the protein cyclin E renders the aromatase inhibitor letrozole ineffective among women with estrogen-receptor-positive (ER+) breast cancers, researchers from The University of Texas M. D. Anderson Cancer Center report in
Clinical Cancer Research.
The M. D. Anderson research, led by Khandan Keyomarsi, Ph.D., professor in M. D. Anderson's Department of Experimental Radiation Oncology and the Hubert L. and Olive Stringer Professor in Medical Oncology, found evidence that women whose cancers express the LMW-E are more likely to develop resistance to letrozole. However, their research also showed that
treating breast cancer cells with a cyclin-dependent kinase 2 (CDK2) inhibitor can reverse letrozole resistance.
Cyclin E is one of the proteins that regulates the cell cycle, influencing how rapidly a cell passes through the four phases and divides. In tumor cells, cyclin E is converted to low-molecular weight forms, an event that does not occur in normal cells. High levels of LMW-E accelerate the cell's transition through the G1phase, an important checkpoint that can arrest the cell cycle if DNA damage is detected. Elevated levels of LMW-E have been linked to uncontrolled cell proliferation and a poor outcome in breast cancer patients.
Outwitting Drug Resistance
Keyomarsi estimated that approximately 70 percent of all breast cancer patients are estrogen receptor positive (ER+), of which a large percentage are post-menopausal, and would thereby be a candidate to receive an aromatase inhibitor as maintenance therapy. Aromatase inhibitors can reduce the risk of early metastasis among postmenopausal women with ER+ breast cancer. However,
not every patient responds to aromatase inhibitors, and those who do will develop resistance to the drugs over time, explained Keyomarsi. Understanding the mechanisms behind this resistance has been a long-standing goal in breast cancer research.
The M. D. Anderson team hypothesized that ER+ breast cancer patients whose tumors express the LMW forms of cyclin E would be less responsive to treatment with an aromatase inhibitor. To test their hypothesis, the researchers exposed aromatase-overexpressing MCF-7/Ac1 breast cancer cells to the full-length form of cyclin E or to the LMW-E forms ("low forms").
"We found that we could negate the growth inhibitory effects of letrozole with the low forms of cyclin E but not with the wild-type cyclin E," said Keyomarsi, the study's senior author. "The mechanism behind this is that the
low forms of cyclin E increase the activity of the cyclin E complex, and this complex is what mediates the negative effects."
CDK2 Inhibitor Restores Letrozole's Growth Inhibition
After confirming that the LMW forms of cyclin E suppress the anti-proliferative effects of letrozole, the researchers examined whether a CDK2 inhibitor could reverse the drug resistance in the unresponsive breast cancer cells.
"We challenged the aromatase-overexpressing cells with either the wild-type or the low forms of cyclin E and then treated them with the CDK2 inhibitor roscovitine," Keyomarsi said. "When we did that, we could kill all the cells."
The researchers also looked back at the results of another ongoing study from their group in which 128 ER+ breast cancer patients were treated with an aromatase inhibitor. "Of those, 100 expressed normal levels of wild-type cyclin E, and 28 overexpressed the low forms," Keyomarsi said. "When we looked at recurrence, three of the hundred with wild-type cyclin E had experienced a recurrence compared to four of the twenty-eight with the low forms. That in itself tells us there is a huge difference between the two groups of patients based on the pattern of expression of normal versus low forms of cyclin E."
Of the seven patients who had a recurrence, six had high levels of cyclin E activity. Keyomarsi noted that these patients can be treated with a CDK2 inhibitor, which is now clinically available.
"I believe that in the very near future we will be able to take advantage of the knowledge we now have about the low forms of cyclin E, and identify the patients who have these forms and devise a personalized treatment," Keyomarsi added.
This research was supported by National Institutes of Health grant CA87458 and National Cancer Institute grant P50CA116199, as well as funds from the Clayton Foundation.
Keyomarsi's co-authors on the all-M. D. Anderson study include: Said Akli, Ph.D., Tuyen Bui, Anna Biernacka, M.D. all of the Department of Experimental Radiation Oncology; Kelly K. Hunt, M.D.; and Hannah Wingate, Ph.D., Department of Surgical Oncology; Stacy Moulder, M.D., Department of Breast Medical Oncology; and Susan L. Tucker, Ph.D., Department of Bioinformatics and Computational Biology.
Breast Cancer Res Treat. 2010 Jan 7. [Epub ahead of print]
Synergistic activity of letrozole and sorafenib (Nexavar) on breast cancer cells.
FULL TEXT purchase
Bonelli MA,
Fumarola C,
Alfieri RR,
La Monica S,
Cavazzoni A,
Galetti M,
Gatti R,
Belletti S,
Harris AL,
Fox SB,
Evans DB,
Dowsett M,
Martin LA,
Bottini A,
Generali D,
Petronini PG.
Department of Experimental Medicine, University of Parma, Via Volturno, 39, 43100, Parma, Italy.
Estrogens induce breast tumor cell proliferation by directly regulating gene expression via the estrogen receptor (ER) transcriptional activity and by affecting growth factor signaling pathways such as mitogen-activated protein kinase (MAPK) and AKT/mammalian target of rapamycin Complex1 (mTORC1) cascades. In this study we demonstrated the preclinical therapeutic efficacy of combining the aromatase inhibitor letrozole with the multi-kinase inhibitor sorafenib in aromatase-expressing breast cancer cell lines.
Treatment with letrozole reduced testosterone-driven cell proliferation, by inhibiting the synthesis of estrogens. Sorafenib inhibited cell proliferation in a concentration-dependent manner; this effect was not dependent on sorafenib-mediated inhibition of Raf1, but involved the down-regulation of mTORC1 and its targets p70S6K and 4E-binding protein 1 (4E-BP1). At concentrations of 5-10 muM the growth-inhibitory effect of sorafenib was associated with the induction of apoptosis, as indicated by release of cytochrome c and Apoptosis-Inducing Factor into the cytosol, activation of caspase-9 and caspase-7, and PARP-1 cleavage.
Combination of letrozole and sorafenib produced a synergistic inhibition of cell proliferation associated with an enhanced accumulation of cells in the G(0)/G(1) phase of the cell cycle and with a down-regulation of the cell cycle regulatory proteins c-myc, cyclin D1, and phospho-Rb. In addition, longer experiments (12 weeks) demonstrated that sorafenib may be effective in preventing the acquisition of resistance towards letrozole. Together, these results indicate that combination of letrozole and sorafenib might constitute a promising approach to the treatment of hormone-dependent breast cancer.
PMID: 20054642 [PubMed - as supplied by publisher]
Br J Cancer. 2008 Nov 18;99(10):1564-71. Epub 2008 Oct 21.
Preoperative bevacizumab combined with letrozole and chemotherapy in locally advanced ER- and/or PgR-positive breast cancer: clinical and biological activity.
Torrisi R,
Bagnardi V,
Cardillo A,
Bertolini F,
Scarano E,
Orlando L,
Mancuso P,
Luini A,
Calleri A,
Viale G,
Goldhirsch A,
Colleoni M.
Department of Medicine, Research Unit of Medical Senology, European Institute of Oncology Milan, Milan, Italy.
rosalba.torrisi@ieo.it
The antiangiogenic agent bevacizumab showed synergistic effects when combined with chemotherapy in advanced breast cancer.
We presently investigated the activity of bevacizumab in combination with chemotherapy, including capecitabine and vinorelbine, and endocrine therapy, including letrozole (+triptorelin in premenopausal women), as primary therapy for patients with ER and/or PgR > or =10% T2-T4a-c, N0-N2, M0 breast cancer. Biological end point included the proliferative activity (Ki67), whereas clinical end points were clinical response rate, pathological complete response (pCR) and tolerability. Circulating endothelial cells (CECs) and their progenitors, as surrogate markers of antiangiogenic activity, were measured at baseline and at surgery.Thirty-six women are evaluable. A clinical response rate of 86% (95% CI, 70-95) and no pCR were observed; Ki67 was significantly decreased by 71% (interquartile range, -82%, -62%). Toxicity was manageable: two grade 3 hypertension, four grade 3 deep venous thrombosis and no grade >2 proteinuria were observed.
Treatment significantly decreased the percentage of viable CECs and prevented the chemotherapy-induced mobilisation of circulating progenitors. Basal circulating progenitors were positively associated with clinical response. In conclusion,
bevacizumab is feasible and active in association with primary chemoendocrine therapy for ER-positive tumours in terms of proliferation inhibition, clinical response and antiangiogenic activity.
PMID: 18941458 [PubMed - indexed for MEDLINE]
J Clin Oncol. 2006 Aug 1;24(22):3623-8.
Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients.
FULL TEXT HERE
Bottini A,
Generali D,
Brizzi MP,
Fox SB,
Bersiga A,
Bonardi S,
Allevi G,
Aguggini S,
Bodini G,
Milani M,
Dionisio R,
Bernardi C,
Montruccoli A,
Bruzzi P,
Harris AL,
Dogliotti L,
Berruti A.
Breast Unit and Anatomia Patologica, Azienda Ospedaliera Istituti Ospitalieri Cremona, Italy.
PURPOSE: To investigate the activity of letrozole plus/minus oral metronomic cyclophosphamide as primary systemic treatment (PST) in elderly breast cancer patients. METHODS: One hundred fourteen consecutive elderly women with T2-4 N0-1 and estrogen receptor-positive breast cancer were randomly assigned to
primary letrozole therapy (2.5 mg daily for 6 months) or a combination of letrozole plus oral cyclophosphamide (50 mg/daily for 6 months) in an open-labeled, randomized phase II trial. Tumor response was assessed clinically, and tumor Ki67 index and vascular endothelial growth factor (VEGF) -A levels were measured before and after treatment. RESULTS: Overall response rate was 71.9% (95% CI, 60.0 to 83.8) in the 57 patients randomly assigned to receive primary letrozole and 87.7% (95% CI, 78.6 to 96.2) in the 57 patients randomly assigned to receive letrozole plus cyclophosphamide. The difference in activity between treatment arms was predominantly confined to patients with ductal histology.
There was a significantly greater suppression of Ki67 and VEGF-A expression in the letrozole/cyclophosphamide-treated group than in the letrozole-treated group, leading to lower Ki67 and VEGF expression at post-treatment residual histology (P = .03 and P = .002, respectively). CONCLUSION: Both letrozole and letrozole plus cyclophosphamide treatments appeared active as PST in elderly breast cancer patients.
Metronomic scheduling of cyclophosphamide may have an antiangiogenic effect and the combination of letrozole plus cyclophosphamide warrants testing in a randomized phase III trial.
PMID: 16877730 [PubMed - indexed for MEDLINE]
Quote:
Chemotherapy efficacy is dependent mainly on proliferative activity, whereas endocrine therapies are cytostatic, so that an antagonistic interaction between the two treatment modalities is expected when they are administered concomitantly.14 The results of a large randomized clinical trial published recently are in line
with these assumptions.15
Because the target of the metronomic chemotherapy is not the proliferating cancer cells, this treatment modality could potentiate the efficacy of endocrine therapy.
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Quote:
In this article, we explored the activity of the combination of LET-CYC administration as PST in elderly breast cancer patients as compared to standard LET. The response rate of 72% in patients randomly assigned to the LET arm was higher than the 60% obtained in a previous randomized trial with primary LET therapy.2 The different patient population and the longer exposure of our patients to LET (6 months v 4 months) can account for the observed difference.
The response rate obtained in the LET-CYCarm(88%) was high.
The study design was not aimed at testing the difference in response rates in the two treatment arms, and both passed the test of activity. However, the comparison with the randomized control arm indicates that the high activity of the experimental arm was not caused by a biased sample,22 and suggests that the addition of CYC is associated with an increase in the activity of LET in this patient population (OR, 2.79). Although these results are encouraging, they failed to be confirmed by pathCR, a known predictor of long-term outcome. pathCR was observed in two patients (3.5%), one in each arm. A very low pathCR with primary LET therapy (1.7%) was obtained in the randomized trial comparing LET versus tamoxifen,2 suggesting that this condition is not a sensitive end point for primary endocrine therapy. The addition of metronomic CYC failed to increase the pathCR rate. Others have also found that patients with ER tumors have a low propensity to obtain pathCR after chemotherapy.23,24
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Clin Cancer Res. 2008 May 1;14(9):2673-80.
Down-regulation of phosphatidylinositol 3'-kinase/AKT/molecular target of rapamycin metabolic pathway by primary letrozole-based therapy in human breast cancer.
Generali D,
Fox SB,
Brizzi MP,
Allevi G,
Bonardi S,
Aguggini S,
Milani M,
Bersiga A,
Campo L,
Dionisio R,
Vergoni F,
Giardini R,
Dogliotti L,
Bottini A,
Harris AL,
Berruti A.
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Abstract 
PURPOSE: The
phosphatidylinositol 3'-kinase (PI3K)/AKT/molecular target of rapamycin (mTOR) pathway is involved in the development of tumor resistance to endocrine therapy in breast cancer cell lines and represents an attractive target for pharmacologic intervention. However, the effects of endocrine therapy with aromatase inhibitors on in vivo expression of this signaling cascade, and its relation to tumor response and patient outcome, is unknown. EXPERIMENTAL DESIGN: PI3K, phospho-AKT (pAKT) and phospho-mTOR were assessed by immunohistochemistry on tumor specimens collected at baseline and after 6 months of treatment in 113 elderly breast cancer patients consecutively enrolled in a randomized phase II trial of primary letrozole therapy and letrozole associated with metronomic cyclophosphamide. RESULTS: Basal expression of the pathway was not significantly correlated with response or patient outcome.
Both letrozole alone and letrozole with cyclophosphamide resulted in a significant reduction of PI3K expression (P = 0.02 and P < 0.005, respectively) and phospho-mTOR expression (P = 0.0001 and P = 0.0001, respectively). pAKT showed no change in the letrozole arm, whereas it was significantly decreased in the letrozole plus cyclophosphamide arm (P < 0.005). pAKT expression reduction was associated with a greater response rate (P = 0.05) and greater reduction in Ki67 expression (P = 0.05). Phospho-mTOR expression reduction was associated with a significantly longer disease-free survival in a multivariate analysis (P = 0.02). CONCLUSIONS:
Letrozole inhibits key molecules in the PI3K pathway that are important targets of new drugs being developed to overcome resistance. Changes in these molecules may have prognostic significance. These results should be taken into account when planning prospective trials testing up-front aromatase inhibitor with drugs targeting the PI3K/AKT/mTOR signaling pathway.
PMID: 18451231 [PubMed - indexed for MEDLINE]Free Article
Stopping Treatment Can Reverse Acquired Resistance to Letrozole
Gauri J. Sabnis1, Luciana F. Macedo1, Olga Goloubeva2, Adam Schayowitz1 and Angela M.H. Brodie1,2
1 Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine and 2 University of Maryland Greenebaum Cancer Center, Baltimore, Maryland
Requests for reprints: Angela M.H. Brodie, Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Health Science Facility I, Room 580G, 685 West Baltimore Street, Baltimore, MD 21201. Phone: 410-706-3137; Fax: 410-706-0032; E-mail: abrodie@umaryland.edu .
Using the intratumoral aromatase xenograft model, we have observed that despite long-lasting growth inhibition, tumors eventually begin to grow during continued letrozole treatment. In cells isolated from these long-term letrozole-treated tumors (LTLT-Ca), estrogen receptor-
(ER) levels were decreased, whereas signaling proteins in the mitogen-activated protein kinase cascade were up-regulated along with human epidermal growth factor receptor 2 (Her-2). In the current study, we evaluated the effect of discontinuing letrozole treatment on the growth of letrozole-resistant cells and tumors. The cells formed tumors equally well in the absence or presence of letrozole and had similar growth rates. After treatment was discontinued for 6 weeks, letrozole was administered again. Marked tumor regression was observed with this second course of letrozole treatment. Similarly, in MCF-7Ca xenografts, a 6-week break in letrozole treatment prolonged the responsiveness of the tumors to letrozole. To understand the mechanisms of this effect, LTLT-Ca cells were cultured in the absence of letrozole for 16 weeks. The resulting cell line (RLT-Ca) exhibited properties similar to MCF-7Ca cells. The cell growth was inhibited by letrozole and stimulated by estradiol. The expression of phosphorylated mitogen-activated protein kinase (MAPK) was reduced and ER and aromatase levels increased compared with LTLT-Ca cells and were similar to levels in MCF-7Ca cells. These results indicate that discontinuing treatment can reverse letrozole resistance. This could be a beneficial strategy to prolong responsiveness to aromatase inhibitors for patients with breast cancer. [Cancer Res 2008;68(12):4518–24]
letrozole and IGF-IR inhibitors synergistically induce apoptosis in lab models of bc
http://breast-cancer-research.com/co...df/bcr2113.pdf
Breast Cancer Res. 2008;10(4):R56. Epub 2008 Jul 8.
The aromatase inhibitor letrozole and inhibitors of insulin-like growth factor I receptor synergistically induce apoptosis in in vitro models of estrogen-dependent breast cancer.
Lisztwan J,
Pornon A,
Chen B,
Chen S,
Evans DB.
Novartis Institutes of BioMedical Research Basel, Oncology Research, Klybeckstrasse 141, CH-4057, Basel, Switzerland.
joanna.lisztwan@novartis.com
INTRODUCTION: Endocrine-dependent, estrogen receptor positive breast cancer cells proliferate in response to estrogens, synthesized by the cytochrome p450 aromatase enzyme. Letrozole is a potent nonsteroidal aromatase inhibitor that is registered for the treatment of postmenopausal women with advanced metastatic breast cancers and in the neoadjuvant, early, and extended adjuvant indications.
Because crosstalk exists between estrogen receptor and insulin-like growth factor I receptor (IGF-IR), the effect of combining a selective IGF-IR inhibitor (NVP-AEW541) with letrozole was assessed in two independent in vitro models of estrogen-dependent breast cancer. METHODS: MCF7 and T47D cells stably expressing aromatase (MCF7/Aro and T47D/Aro) were used as in vitro models of aromatase-driven breast cancer. The role of the IGF-IR pathway in breast cancer cells stimulated only by 17beta-estradiol or androstenedione was assessed by proliferation assays. The combination of letrozole and NVP-AEW541 was assessed for synergy in inhibiting cell proliferation using Chou-Talalay derived equations. Finally, combination or single agent effects on proliferation and apoptosis were assessed using proliferation assays, flow cytometry, and immunoblotting. RESULTS: Both MCF7 and T47D cells, as well as MCF7/Aro and T47D/Aro, exhibited sensitivity to inhibition of 17beta-estradiol dependent proliferation by NVP-AEW541.
Letrozole combined with NVP-AEW541 synergistically inhibited androstenedione-dependent proliferation in aromatase-expressing cells with combination index values of 0.6 or less. Synergistic combination effects correlated with higher levels of apoptosis as compared with cells treated with the single agent alone. Treatment with either agent also appeared to inhibit IGF-IR signalling via phosphoinositide 3-kinase. Notably,
IGF-IR inhibition had limited effect on estrogen-dependent proliferation in the cell lines, but was clearly required for survival, suggesting that the combination of letrozole and IGF-IR inhibition sensitizes cells to apoptosis. CONCLUSION:
Inhibition of the IGF-IR pathway and aromatase was synergistic in two independent estrogen-dependent in vitro models of breast cancer. Moreover, synergism of NVP-AEW541 and letrozole correlated with induction of apoptosis, but not cell cycle arrest, in the cell lines tested. Combination of IGF-IR inhibitors and letrozole may hold promise for the treatment of patients with estrogen-dependent breast cancers.
PMID: 18611244 [PubMed - indexed for MEDLINE]
Br J Cancer. 2010 Feb 16. [Epub ahead of print]
Combined effects of the bisphosphonate, zoledronic acid and the aromatase inhibitor letrozole on breast cancer cells in vitro: evidence of synergistic interaction.
Neville-Webbe HL,
Coleman RE,
Holen I.
Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield S10 2SJ, UK.
Background:Aromatase inhibitors are widely used in the treatment of oestrogen receptor-positive post-menopausal breast cancer. These patients may also be receiving the bisphosphonate, zoledronic acid (ZA) to prevent bone loss or reduce skeletal morbidity in the setting of advanced disease. The potential biological interaction of these two drugs in breast cancer has not been assessed.Methods:Aromatase-expressing breast cancer cells were treated with letrozole and ZA either simultaneously or in sequence, and the resulting apoptosis was assessed by staining with Hoechst 33342 and propidium iodide and examined using a fluorescent inverted Leica DMIRB microscope and a UV filter.Results:
We found that letrozole and ZA induce levels of apoptosis in breast cancer cells in vitro that are significantly greater compared with treatment with each drug alone. However, this potentially, synergistic relationship is drug-sequence dependent, occurring only when cells are treated with letrozole, followed by ZA. The converse sequence, or administering drugs simultaneously, induces levels of apoptosis no greater than each drug alone.Conclusion:Owing to the enhanced anti-tumour efficacy of sequential drug administration, our findings may indicate that, for post-menopausal women who require treatment with letrozole, ZA should also be considered.British Journal of Cancer advance online publication, 16 February 2010; doi:10.1038/sj.bjc.6605579
www.bjcancer.com.
PMID: 20160726 [PubMed - as supplied by publisher]
Letrozole (Femara) alone or with Cyclophosphamide decrease Tregs, possibly helpful to Crotherapy, even in ER- tumors:
Clin Cancer Res. 2009 Feb 1;15(3):1046-51.
Immunomodulation of FOXP3+ regulatory T cells by the aromatase inhibitor letrozole in breast cancer patients.
Generali D, Bates G, Berruti A, Brizzi MP, Campo L, Bonardi S, Bersiga A, Allevi G, Milani M, Aguggini S, Dogliotti L, Banham AH, Harris AL, Bottini A, Fox SB.
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
FREE TEXT
Abstract
PURPOSE: We have shown previously that tumor infiltration by FOXP3+ regulatory T cells (Treg) is associated with increased relapse and shorter survival of patients with both in situ and invasive breast cancer. Because estrogen regulates Treg numbers in mice and promotes the proliferation of human Tregs, we hypothesized that blocking estrogen receptor-alpha signaling would abrogate Tregs and be associated with response to hormonal therapy and increased survival. EXPERIMENTAL DESIGN: FOXP3+ Tregs were quantified in tumor samples collected at baseline by incisional biopsy and after 6 months at definitive surgery in 83 elderly breast cancer patients (T2-4 N0-1) enrolled in a randomized phase II trial based on 6 months of primary letrozole (2.5 mg/d) or 6 months of letrozole plus oral "metronomic" cyclophosphamide (50 mg/d). RESULTS: Treg number ranged from 0 to 380 (median, 30) before treatment and from 0 to 300 (median, 8) after treatment. There was a significant reduction in Tregs in letrozole and letrozole-cyclophosphamide patients (P < 0.0001 and P < 0.002, respectively) after treatment. Treg number at residual histology was inversely related with response (P < 0.03 and P = 0.50, respectively) and a greater Treg reduction was observed in responding patients (P < 0.03). CONCLUSION: This study suggests that aromatase inhibitors may have an indirect antitumor mechanism of action through reducing Tregs in breast tumors and may be of use in estrogen receptor-alpha-negative tumors in combination with immunotherapy approaches.
PMID: 19188178 [PubMed - indexed for MEDLINE]Free Article
Quote:
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Translational Relevance We have shown recently that high numbers of Tregs in in situ and invasive breast carcinomas give independent prognostic information even beyond 5 years when conventional pathologic factors lose their power. Because Tregs play a pivotal role in immunosuppression and tumor emergence, we performed a phase II randomized controlled trial of letrozole ± the immunomodulatory agent cyclophosphamide in breast cancer patients to assess the clinical utility of the number of Tregs in predicting the response to therapy. This question addresses second of the top 15 breast cancer research priorities determined by registrants at the San Antonio Breast and St Gallen meetings in 2005. We show a significant reduction in the numbers of Tregs in the primary tumor after treatment with an aromatase inhibitor but not by the addition of cyclophosphamide, showing that the effect is largely due to the aromatase inhibitor. Importantly, this reduction in Tregs is inversely related to the response. These novel findings suggest that letrozole has a significant immunomodulatory role and that aromatase inhibitors could be used in the future in combination with other immunotherapeutic approaches not only in patients with ER-positive but also in ER-negative tumors.
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J Clin Oncol. 2009 Jun 1;27(16):2630-7. Epub 2009 Apr 20.
Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer.
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.
Medical Oncology Department, Vall d'Hebron University Hospital, P Vall d'Hebron, Barcelona, Spain.
jbaselga@vhebron.net
Comment in:
PURPOSE:
Cross-talk between the estrogen receptor (ER) and the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways is a mechanism of resistance to endocrine therapy, and blockade of both pathways enhances antitumor activity in preclinical models. This study explored whether sensitivity to letrozole was enhanced with the oral mTOR inhibitor, everolimus (RAD001). PATIENTS AND METHODS:
Two hundred seventy postmenopausal women with operable ER-positive breast cancer were randomly assigned to receive 4 months of neoadjuvant treatment with letrozole (2.5 mg/day) and either everolimus (10 mg/day) or placebo. The primary end point was clinical response by palpation. Mandatory biopsies were obtained at baseline and after 2 weeks of treatment (ie, day 15). Samples were assessed for PI3K mutation status (PIK3CA) and for pharmacodynamic changes of Ki67, phospho-S6, cyclin D1, and progesterone receptor (PgR) by immunohistochemistry. RESULTS:
Response rate by clinical palpation in the everolimus arm was higher than that with letrozole alone (ie, placebo; 68.1% v 59.1%), which was statistically significant at the preplanned, one-sided, alpha = 0.1 level (P = .062).
Marked reductions in progesterone receptor and cyclin D1 expression occurred in both treatment arms, and dramatic downregulation of phospho-S6 occurred only in the everolimus arm.
An antiproliferative response, as defined by a reduction in Ki67 expression to natural logarithm of percentage positive Ki67 of less than 1 at day 15, occurred in 52 (57%) of 91 patients in the everolimus arm and in 25 (30%) of 82 patients in the placebo arm (P < .01). The safety profile was consistent with historical results of everolimus monotherapy; grades 3 to 4 adverse events occurred in 22.6% of patients who received everolimus and in 3.8% of patients who received placebo. CONCLUSION:
Everolimus significantly increased letrozole efficacy in neoadjuvant therapy of patients with ER-positive breast cancer.
PMID: 19380449 [PubMed - indexed for MEDLINE]
Previous preclinical of above:
Semin Oncol. 2006 Apr;33(2 Suppl 7):S18-25.
Future directions in the treatment of hormone-sensitive advanced breast cancer: the RAD001 (Everolimus)-letrozole clinical program.
Lane HA,
Lebwohl D.
Novartis Institutes For BioMedical Research, Oncology Basel, Novartis Pharma AG, Switzerland.
Therapeutics that interfere with estrogen receptor function (antiestrogens, eg, tamoxifen; aromatase inhibitors, eg, letrozole) have contributed to a dramatic reduction in breast cancer mortality; however, not all estrogen-receptor-positive breast cancers respond. The mammalian target-of-rapamycin (mTOR) is emerging as an important target molecule in the treatment of breast cancer. Furthermore,
activation of growth-factor signaling pathways that involve mTOR may contribute to both the failure of endocrine therapy as well as the development of resistance. RAD001 (everolimus) is a potent, orally bioavailable inhibitor of the mTOR pathway. Preclinical data show that RAD001 effectively inhibits the proliferation and growth of a number of cancer cell lines in vitro and a range of tumor types in experimental animal models of cancer. Moreover,
RAD001 exhibits an antiangiogenic activity, which may also contribute to its anticancer activity. The aromatase inhibitor letrozole is a potent endocrine therapy for breast cancer that acts to inhibit the aromatization of androgens, thereby reducing plasma and tumor estrogen levels.
Combining RAD001 with letrozole is a rational approach to the treatment of advanced breast cancer, offering the potential for inhibition of tumor cell growth/proliferation and angiogenesis while at the same time potentially preventing the development of letrozole resistance. Preclinical data, derived from aromatase-expressing, estrogen-receptor-positive breast tumor models, suggest a synergistic interaction between RAD001 and letrozole that results in more profound effects on proliferation and the induction of tumor cell death. Importantly, early clinical data show no pharmacokinetic interaction or increase in toxicity with combined treatment, as compared with treatment with RAD001 alone, and there is evidence of antitumor activity. Enrollment into phase II studies is presently underway.
PMID: 16730273 [PubMed - indexed for MEDLINE]
Clin Cancer Res. 2005 Jul 15;11(14):5319-28.
Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer.
Boulay A,
Rudloff J,
Ye J,
Zumstein-Mecker S,
O'Reilly T,
Evans DB,
Chen S,
Lane HA.
Novartis Institutes for BioMedical Research Basel, Oncology Research, Novartis Pharma AG, Basel, Switzerland.
PURPOSE: RAD001 (everolimus), a mammalian target of rapamycin (mTOR) pathway inhibitor in phase II clinical trials in oncology, exerts potent antiproliferative/antitumor activities. Many breast cancers are dependent for proliferation on estrogens synthesized from androgens (i.e., androstenedione) by aromatase. Letrozole (Femara) is an aromatase inhibitor used for treatment of postmenopausal women with hormone-dependent breast cancers. The role of the mTOR pathway in estrogen-driven proliferation and effects of combining RAD001 and letrozole were examined in vitro in two breast cancer models. EXPERIMENTAL DESIGN: The role of the mTOR pathway in estrogen response was evaluated in aromatase-expressing MCF7/Aro breast cancer cells by immunoblotting. Effects of RAD001 and letrozole (alone and in combination) on the proliferation and survival of MCF7/Aro and T47D/Aro cells were evaluated using proliferation assays, flow cytometry, immunoblotting, and apoptosis analyses. RESULTS:
Treatment of MCF7/Aro cells with estradiol or androstenedione caused modulation of the mTOR pathway, a phenomenon reversed by letrozole or RAD001. In MCF7/Aro and T47D/Aro cells, both agents inhibited androstenedione-induced proliferation; however, in combination, this was significantly augmented (P < 0.001, two-way ANOVA, synergy by isobologram analysis). Increased activity of the combination correlated with more profound effects on G1 progression and a significant decrease in cell viability (P < 0.01, two-way ANOVA) defined as apoptosis (P < 0.05, Friedman test). Increased cell death was particularly evident with optimal drug concentrations.
CONCLUSION: mTOR signaling is required for estrogen-induced breast tumor cell proliferation. Moreover, RAD001-letrozole combinations can act in a synergistic manner to inhibit proliferation and trigger apoptotic cell death. This combination holds promise for the treatment of hormone-dependent breast cancers.
PMID: 16033851 [PubMed - indexed for MEDLINE]
Carcinogenesis. 2008 Nov;29(11):2162-8. Epub 2008 Jul 16.
Dietary genistein negates the inhibitory effect of letrozole on the growth of aromatase-expressing estrogen-dependent human breast cancer cells (MCF-7Ca) in vivo.
Ju YH,
Doerge DR,
Woodling KA,
Hartman JA,
Kwak J,
Helferich WG.
Department of Food Science and Human Nutrition, University of Illinois, 905 S Goodwin Avenue, Room 580 Bevier Hall, Urbana, IL 61801, USA.
Genistein (GEN), a soy isoflavone, stimulates growth of estrogen-dependent human tumor cells (MCF-7) in a preclinical mouse model for postmenopausal breast cancer. Antiestrogens and aromatase inhibitors are frontline therapies for estrogen-dependent breast cancer. We have demonstrated that dietary GEN can negate the inhibitory effect of tamoxifen.
In this study, we evaluated the interaction of dietary GEN (at 250-1000 p.p.m. in the American Institute of Nutrition 93 growth diet) and an aromatase inhibitor, letrozole (LET), on the growth of tumors in an aromatase-expressing breast cancer xenograft model (MCF-7Ca) in the presence and absence of the substrate androstenedione (AD). Dietary GEN (250 and 500 p.p.m.) or implanted AD stimulated MCF-7Ca tumor growth. Implanted LET inhibited AD-stimulated MCF-7Ca tumor growth. In the presence of AD and LET, dietary GEN (250, 500 and 1000 p.p.m.) reversed the inhibitory effect of LET in a dose-dependent manner. Uterine wet weight, plasma estradiol (E(2)) levels (enzyme-linked immunosorbent assay) and total plasma GEN and LET levels (liquid chromatography-electrospray/tandem mass spectrometry) were measured. Ki-67 (cellular proliferation), aromatase and pS2 protein expression in tumors were evaluated using immunohistochemical (IHC) analysis.
In conclusion, dietary GEN increased the growth of MCF-7Ca tumors implanted in ovariectomized mice and could also negate the inhibitory effect of LET on MCF-7Ca tumor growth. These findings are significant because tumors, which express aromatase and synthesize estrogen, are good candidates for aromatase therapy dietary and GEN can reverse the inhibitory effect of LET on tumor growth and adversely impact breast cancer therapy. Caution is warranted for consumption of dietary GEN by postmenopausal women with estrogen-dependent breast cancer taking LET treatment.
PMID: 18632754 [PubMed - indexed for MEDLINE]
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