Abstract
Purpose
Everolimus has shown to stop formation and activity of osteoclasts. Breast cancer patients with bone metastases only are candidates for effective but low toxic treatment.
Patients and methods
We evaluated everolimus in a double-blind, placebo-controlled, phase II, randomized discontinuation study in breast cancer patients with HER2 negative breast cancer patients with bone metastases only. After being stable on 8 weeks of everolimus 10 mg/day, patients were randomized to everolimus-continuation or placebo. Primary outcome was time (from randomization) to progression (TTP). Seventy-six patients would have had to be randomized to show a hazard ration (HR) of 0.5 for everolimus-continuation.
Results
Eighty-nine patients were enrolled in 4 years. Thirty-nine patients with SD after 8 weeks on everolimus were randomized to everolimus-continuation or placebo. TTP in patients with everolimus-continuation was 37.0 (95 % CI 16.7–40.3) versus 12.6 weeks (95 % CI 7.1–17.9) with placebo [HR 0.554 (95 % CI 0.282–1.09) p = 0.0818], adjusted for endocrine therapy [HR 0.464 (95 % CI 0.226–0.954) p = 0.037]. TTP in everolimus responders (n = 6) was 86 weeks.
Conclusion
The RADAR study is mainly hypothesis generating. It suggests that everolimus has single-agent activity, and patients with bone metastases only may retrieve long-term benefit from everolimus if they do not progress within 8 weeks of treatment.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Andre F, Campone M, O’Regan R, Manlius C, Massacesi C, Sahmoud T, Mukhopadhyay P, Soria JC, Naughton M, Hurvitz SA (2010) Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol 28:5110–5115
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 (2012) 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 30:2718–2724
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 (2009) 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 27:2630–2637
Baselga J, Campone M, Piccart M, Burris HA 3rd, 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 (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520–529
Busaidy NL, Farooki A, Dowlati A, Perentesis JP, Dancey JE, Doyle LA, Brell JM, Siu LL (2012) Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J Clin Oncol 30:2919–2928
Campone M, Noguchi S, Pritchard K, Rugo H, Hortobagyi GN, Baselga J, Panneerselvam A, Taran T, Sahmoud T, Piccart M (2012) Efficacy and safety of everolimus in postmenopausal women with advanced breast cancer (BOLERO-2): effect of visceral metastases and prior endocrine therapy. Ann Oncol 23(suppl 9):ix116–ix143
Costelloe CM, Rohren EM, Madewell JE, Hamaoka T, Theriault RL, Yu TK, Lewis VO, Ma J, Stafford RJ, Tari AM, Hortobagyi GN, Ueno NT (2009) Imaging bone metastases in breast cancer: techniques and recommendations for diagnosis. Lancet Oncol 10:606–614
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revided RECIST guideline (version 1.1). Eur J Cancer 45:228–247
Ellard SL, Clemons M, Gelmon KA, Norris B, Kennecke H, Chia S, Pritchard K, Eisen A, Vandenberg T, Taylor M, Sauerbrei E, Mishaeli M, Huntsman D, Walsh W, Olivo M, McIntosh L, Seymour L (2009) Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163. J Clin Oncol 27:4536–4541
Gnant M, Balic M, Petru E, Raunik W, Singer CF, Steger GG, Watzke IM, Brodowicz T (2012) Treatment of bone metastases in patients with advanced breast cancer. Breast Care (Basel) 7:92–98
Hayashi N, Costelloe CM, Hamaoka T, Wei C, Niikura N, Theriault RL, Hortobagyi GN, Madewell JE, Ueno NT (2013) A prospective study of bone tumor response assessment in metastatic breast cancer. Clin Breast Cancer 13(1):24–30
Kneissel M, Luong-Nguyen NH, Baptist M, Cortesi R, Zumstein-Mecker S, Kossida S, O’Reilly T, Lane H, Susa M (2004) Everolimus suppresses cancellous bone loss, bone resorption, and cathepsin K expression by osteoclasts. Bone 35:1144–1156
Lipton A, Theriault RL, Hortobagyi GN, Simeone J, Knight RD, Mellars K, Reitsma DJ, Heffernan M, Seaman JJ (2000) Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer 88:1082–1090
Meric-Bernstam F, Gonzalez-Angulo AM (2009) Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 27:2278–2287
Rustin GJ, Timmers P, Nelstrop A, Shreeves G, Bentzen SM, Baron B, Piccart MJ, Bertelsen K, Stuart G, Cassidy J, Eisenhauer E (2006) Comparison of CA-125 and standard definitions of progression of ovarian cancer in the intergroup trial of cisplatin and paclitaxel versus cisplatin and cyclophosphamide. J Clin Oncol 24:45–51
Theriault RL, Lipton A, Hortobagyi GN, Leff R, Glück S, Stewart JF, Costello S, Kennedy I, Simeone J, Seaman JJ, Knight RD, Mellars K, Heffernan M, Reitsma DJ (1999) Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. J Clin Oncol 17:846–854
Conflict of interest
The following authors have declared that they have no conflict of interest: Jana Barinoff, Nicolai Maass, Christoph Mundhenke, Christian Lerchenmüller, Steffen Wagner, Bahriye Aktas, Lothar Müller, Valentina Nekljudova, Kristina Lübbe, Marcus Schmidt, and Kathrin Schwedler. Hans-Joachim Lück (Consultant/Advisory role: Roche, Celgene, Eisai, Novartis, GlaxoSmithKline), Nadia Harbeck (Remuneration: Novartis), Joachim Bischoff (Consultant/Advisory role: Roche, Eisai, Novartis, Funding: GlaxoSmithKline), Johannes Ettl (Consultant/Advisory role: Novartis), Sherko Kümmel (Consultant/Advisory role: Roche, Novartis. Genomic Health), Gunter von Minckwitz (Funding: Novartis), Dirk Bauerschlag (Remuneration: GSK, Pfizer, Consultant/Advisory role: Amgen, GlaxoSmithKline, Funding: Pfizer), and Sibylle Loibl (Consultant/Advisory role: Novartis) have declared conflict of interest.
Author information
Authors and Affiliations
Consortia
Corresponding author
Additional information
Nicolai Maass and Nadia Harbeck have contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Maass, N., Harbeck, N., Mundhenke, C. et al. Everolimus as treatment for breast cancer patients with bone metastases only: results of the phase II RADAR study. J Cancer Res Clin Oncol 139, 2047–2056 (2013). https://doi.org/10.1007/s00432-013-1518-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-013-1518-x