- Email: [email protected]
One step forward, two steps back: The story of everolimus in advanced breast cancer
The Breast xxx (2015) 1e3
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Viewpoints and debate
One step forward, two steps back: The story of everolimus in advanced breast cancer Saroj Niraula a, *, Alberto Ocana b, Eitan Amir c a
Department of Medical Oncology and Hematology, CancerCare Manitoba and University of Manitoba, Winnipeg, MB, R3E 0V9, Canada Medical Oncology Department, Albacete University Hospital and AECC Unit, Albacete, Spain c Division of Medical Oncology and Hematology, Princess Margaret Cancer Center and University of Toronto, Toronto, Canada b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 November 2014 Accepted 16 April 2015 Available online xxx
There has been a substantial surge of ‘targeted agents’ in contemporary anticancer drug armamentarium and some of these agents have revolutionized the outcome of cancer patients. However, on contrary to the nomenclature, not all new targeted agents are selected based on presence of target molecules on the cancer cells. Drugs are typically approved based on demonstration of benefit in randomized controlled trials with regards to efficacy outcomes although both the ‘benefits’ and ‘outcomes’ are defined inconsistently. Surrogates that are not validated properly are often used as endpoints. Furthermore, new anticancer drugs are frequently associated with increased inconvenience to the patients and/or to the society due to added toxicity and cost. In this perspective article, emphasis is given to the above problems focusing on room for improvement in anticancer drug development. An illustration of a recently approved drug to treat advanced breast cancer, everolimus and a previously revoked drug bevacizumab is given. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Everolimus Breast cancer mTOR Biomarkers Randomized controlled trial
Normal cells transform into cancer cells as a result of aberrant changes of physiological functions that are involved in cell survival, proliferation, migration and angiogenesis, among others [1]. These alterations can be due to modifications of the genome or posttranscriptional changes. With increasing recognition of these oncogenic pathways, the contemporary cancer arena has experienced a surge in new anticancer drugs against druggable proteins. Ironically, when these ‘targeted’ drugs are evaluated in definitive randomized controlled clinical trials (RCTs), the participants are not necessarily selected based on the presence or absence of the proposed targets in their tumors. Identification of biomarkers predictive of treatment response is the backbone of personalized medicine but recognition of such marker has unfortunately been one of the most elusive tasks in modern drug development armamentarium. Targeted agents have unpleasant toxicities that are costly so treating untargeted population with such drugs can result in serious harms to the patients and augment costs to the healthcare system [2].
* Corresponding author. CancerCare Manitoba and University of Manitoba, ON2068 e 675 McDermot Avenue, Winnipeg, MB, R3E 0V9, Canada. Tel.: þ1 204 787 1992; fax: þ1 204 786 0196. E-mail address: [email protected] (S. Niraula).
The ultimate goals of any medical intervention particularly that of the treatment of advanced cancers, are to improve duration and/ or quality of survival of the patients. Therefore, recommendations for use of new anticancer drugs should be based on demonstration of benefit in overall survival (OS), or a relevant measure of the quality of life (QoL). Other clinical outcomes may be useful intermediates but may not represent the outcomes that are most valuable to the patients. Drug development should benefit from the inherent advantages of intermediate endpoints, but use of such endpoints should not eliminate or diminish the need to establish their surrogacy for definitive clinical outcomes. Arguments have been made that delaying progression of cancer is associated with better quality of life but that largely depends on the magnitude of adverse events which result from new treatment. To put this in context, BOLERO-2, a 724 patient RCT reported initially in 2012 compared the combination of an aromatase inhibitor, exemestane and the inhibitor of the mammalian target of rapamycin (mTOR), Everolimus (Afinitor; Novartis, Basel, Switzerland) to exemestane alone in women with advanced breast cancer who had progressed after previous hormonal therapy [3]. Everolimus received FDA approval based on a significant improvement in progression free survival (PFS) in BOLERO-2 with a Hazard Ratio (HR) of 0$43, 95% Confidence Interval (CI): 0$35e0$54, p < 0$001. Although this result is impressive, it is
http://dx.doi.org/10.1016/j.breast.2015.04.006 0960-9776/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Niraula S, et al., One step forward, two steps back: The story of everolimus in advanced breast cancer, The Breast (2015), http://dx.doi.org/10.1016/j.breast.2015.04.006
2
S. Niraula et al. / The Breast xxx (2015) 1e3
important to recognize the limitations in the analysis of the trial. There was a substantially imbalanced rate of informative censoring between the arms, therefore inflating the effect of PFS due to increased withdrawal in the experimental arm. Furthermore, approximately 40% of events that were deemed to be related to progression by local review were subsequently reclassified as ‘nonevents’ upon central review. Overall survival was a secondary endpoint in BOLERO-2. The trial possessed 80% power to detect an HR of 0$74 for OS and required 398 events to demonstrate that difference. After a median follow-up of 39 months, and 410 survival events, recently reported mature OS data from BOLERO-2 at the 9th European breast cancer conference failed to show a significant difference in OS between the arms (HR 0$89, 95% CI 0$73 to 1$10, p ¼ 0$14) [4]. There were 7 deaths attributed to the study drug in the experimental arm of the BOLERO-2 trial, compared to one death in the exemestane arm. Serious adverse events related to the treatment occurred in 11% versus in 1% of the patients, respectively. About a quarter (24%) of patients randomized to the experimental arm discontinued the treatment early because of side effects or withdrawal of consent, versus only 6% in the control arm. Treatment discontinuation is usually not expected in the absence of progression or intolerable toxicity. Furthermore, patients who withdrew from BOLERO-2 prior to documentation of disease progression were censored likely inflating the magnitude of difference in PFS between the arms and favoring the experimental arm. Previous report of the health-related quality of life from BOLERO-2 indicates that deterioration in QoL symptoms was delayed with everolimus but again, the analysis suffered from the informative censoring bias described above [5]. Data on toxicity of everolimus are also reflected in other clinical trials-when tested in combination with tamoxifen compared to tamoxifen alone in a phase II trial in advanced breast cancer, everolimus met its primary endpoint of improvement in clinical benefit rate but there were similar differences in toxicities and treatment discontinuation as seen in BOLERO-2 [6]. When combined with vinorelbine and trastuzumab in HER-2 positive breast cancer, everolimus demonstrated a significant improvement in PFS of 1$3 months, and with similar increase in toxicity [7]. Despite these results, this study also advocated the use of everolimus for that indication. The assessment of regulators regarding the approval of everolimus in HER2 positive breast cancer is eagerly awaited. The difference in PFS demonstrated by BOLERO-2 and other everolimus studies signifies the fact that everolimus does have biologic activity in a subset of patients with advanced breast cancer. Therefore, identification of patients most likely to benefit from everolimus is important, particularly because of the concerns with toxicity. BOLERO-2 was designed based on reasonable evidence that aberrant signaling through phosphatidylinositol 3-kinase (PI3K)-Akt-mTOR pathway is key to endocrine resistance in breast cancer. There have been high-level, intensive efforts trying to identify biomarker(s) predicting for benefit from everolimus but apart from a few associations of less clear significance, the search for clinically useful markers has not materialized clinically [8,9]. In metastatic breast cancer, individual data meta-analysis of 4000 patients from 11 RCTs has shown no association of any intermediate endpoints, including PFS, with OS [10]. When a tested therapeutic intervention prolongs PFS, has no effect on overall survival, and adds serious toxicities on substantial number of patients, critical questions regarding therapeutic value of such intervention are obvious to follow. Signals of initial efficacy of a new intervention leading to widespread use, followed by confirmation of ineffectiveness, or sometimes harm, has been a recurring phenomenon in several medical specialties. These experiences have not sensitized us to
recognize potentially harmful interventions. A relevant example is the use of bevacizumab (Avastin; Genentech, South San Francisco, CA), a monoclonal antibody against vascular endothelial growth factor, in advanced breast cancer. This agent received an accelerated approval by FDA in 2008 for treatment of metastatic breast cancer based on an improvement in median PFS of 5$9 months. Subsequently, a meta-analysis that included the initial registration trial, and two other trials, showed less impressive improvements in PFS (2e5 months) with addition of Bevacizumab [11]. Furthermore, there was no improvement in either OS or QoL and bevacizumab increased incidence of serious toxicities. In 2010, FDA revoked its decision to license bevacizumab in metastatic breast cancer. The story of everolimus is similar. Both everolimus and bevacizumab were tested for treatment of incurable breast cancer where maintaining the quality of life is important. The underlying hypothesis of both drugs is to target important proteins in cellular survival pathways, but neither has validated predictive biomarkers. Both drugs have a demonstrated advantage of extending PFS in women with metastatic breast cancer compared to the control treatment but neither has an effect in OS. The risk of serious toxicities that can substantially impact patients' QoL, including risk of treatment-related death, is increased substantially with the use of both drugs. Bevacizumab and everolimus are only examples. They represent the tip of the iceberg of trends in licensing and marketing modern cancer therapeutics. Despite decades of experience in drug regulations, improvements in clinical trial qualities, and well-formed guidelines in several aspects of drug development process, we are still inconsistent about type and magnitude of benefits that are acceptable for introducing a new drug into the market. Extent of acceptable trade-offs in exchange of desired benefit is even less clear. Policy decisions about new medical interventions based on intermediate outcomes or on premature data may cause harm to patients, and to society. Setting a relatively low threshold to introduce a promising intervention based conditionally on exceptionally good early results may be useful for the general public and might be justified on a temporary basis as long as definitive assessment is completed and reassessed by regulatory agencies. However, a high threshold should be applied for maintaining such interventions in the market. Consistency in the decision about accelerated approvals, regular approvals and revoking of approvals is an integral part of the trust that the physicians, patients and other stakeholders require for regulatory agencies. Conflict of interest statement There is no conflict of interest of any authors that is directly or indirectly relevent to this manuscript. Acknowledgment We would like to thank Dr. Ian Tannock, Toronto for his constructive remarks on previous version of this manuscript. References [1] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646e74. [2] Niraula S, Amir E, Vera-Badillo F, Seruga B, Ocana A, Tannock IF. risk of incremental toxicities and associated costs of new anticancer drugs: a metaanalysis. J Clin Oncol 2014 Nov 10;32(32):3634e42. [3] Baselga J, Campone M, Piccart M, Burris 3rd HA, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl J Med 2012;366:520e9. [4] Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Noguchi S, Rugo H, et al. Everolimus plus exemestane for hormone receptor-positive (hrþ), human epidermal growth factor receptor-2enegative (HER2e) advanced breast
Please cite this article in press as: Niraula S, et al., One step forward, two steps back: The story of everolimus in advanced breast cancer, The Breast (2015), http://dx.doi.org/10.1016/j.breast.2015.04.006
S. Niraula et al. / The Breast xxx (2015) 1e3 cancer (BC): overall survival results from BOLERO-2. EBCC-9; 19e21. March 2014. Glasgow, Scotland. Abstract 1LBA. [5] Burris 3rd HA, Lebrun F, Rugo HS, Beck JT, Piccart M, Neven P, et al. Healthrelated quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3, randomized, controlled, BOLERO-2 trial. Cancer 2013;119:1908e15. [6] Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, et al. 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 Off J Am Soc Clin Oncol 2012;30:2718e24. [7] Andre F, O'Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 2014;15:580e91.
3
[8] Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS, Burris HA, Campone M, Noguchi S, et al. Correlation of molecular alterations with efficacy of everolimus in hormone receptorepositive, HER2-negative advanced breast cancer: results from BOLERO-2. J Clin Oncol 2013;31. suppl; abstr LBA509. F, Chen D, Robinson D, Ozguroglu M, Lang I, et al. & L., G. [9] Jerusalem G, Andre Evaluation of everolimus (EVE) in HER2þ advanced breast cancer (BC) with activated PI3K/mTOR pathway: exploratory biomarker observations from the BOLERO-3 trial. Eur J Cancer September 2013;49(3). European Cancer Congress 2013, Abstract #16. [10] Burzykowski T, Buyse M, Piccart-Gebhart MJ, Sledge G, Carmichael J, Luck HJ, et al. Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 2008;26:1987e92. [11] Rossari JR, Metzger-Filho O, Paesmans M, Saini KS, Gennari A, de Azambuja E, et al. Bevacizumab and breast cancer: a meta-analysis of first-line phase iii studies and a critical reappraisal of available evidence. J Oncol 2012;2012:417673.
Please cite this article in press as: Niraula S, et al., One step forward, two steps back: The story of everolimus in advanced breast cancer, The Breast (2015), http://dx.doi.org/10.1016/j.breast.2015.04.006
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Viewpoints and debate
One step forward, two steps back: The story of everolimus in advanced breast cancer Saroj Niraula a, *, Alberto Ocana b, Eitan Amir c a
Department of Medical Oncology and Hematology, CancerCare Manitoba and University of Manitoba, Winnipeg, MB, R3E 0V9, Canada Medical Oncology Department, Albacete University Hospital and AECC Unit, Albacete, Spain c Division of Medical Oncology and Hematology, Princess Margaret Cancer Center and University of Toronto, Toronto, Canada b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 November 2014 Accepted 16 April 2015 Available online xxx
There has been a substantial surge of ‘targeted agents’ in contemporary anticancer drug armamentarium and some of these agents have revolutionized the outcome of cancer patients. However, on contrary to the nomenclature, not all new targeted agents are selected based on presence of target molecules on the cancer cells. Drugs are typically approved based on demonstration of benefit in randomized controlled trials with regards to efficacy outcomes although both the ‘benefits’ and ‘outcomes’ are defined inconsistently. Surrogates that are not validated properly are often used as endpoints. Furthermore, new anticancer drugs are frequently associated with increased inconvenience to the patients and/or to the society due to added toxicity and cost. In this perspective article, emphasis is given to the above problems focusing on room for improvement in anticancer drug development. An illustration of a recently approved drug to treat advanced breast cancer, everolimus and a previously revoked drug bevacizumab is given. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Everolimus Breast cancer mTOR Biomarkers Randomized controlled trial
Normal cells transform into cancer cells as a result of aberrant changes of physiological functions that are involved in cell survival, proliferation, migration and angiogenesis, among others [1]. These alterations can be due to modifications of the genome or posttranscriptional changes. With increasing recognition of these oncogenic pathways, the contemporary cancer arena has experienced a surge in new anticancer drugs against druggable proteins. Ironically, when these ‘targeted’ drugs are evaluated in definitive randomized controlled clinical trials (RCTs), the participants are not necessarily selected based on the presence or absence of the proposed targets in their tumors. Identification of biomarkers predictive of treatment response is the backbone of personalized medicine but recognition of such marker has unfortunately been one of the most elusive tasks in modern drug development armamentarium. Targeted agents have unpleasant toxicities that are costly so treating untargeted population with such drugs can result in serious harms to the patients and augment costs to the healthcare system [2].
* Corresponding author. CancerCare Manitoba and University of Manitoba, ON2068 e 675 McDermot Avenue, Winnipeg, MB, R3E 0V9, Canada. Tel.: þ1 204 787 1992; fax: þ1 204 786 0196. E-mail address: [email protected] (S. Niraula).
The ultimate goals of any medical intervention particularly that of the treatment of advanced cancers, are to improve duration and/ or quality of survival of the patients. Therefore, recommendations for use of new anticancer drugs should be based on demonstration of benefit in overall survival (OS), or a relevant measure of the quality of life (QoL). Other clinical outcomes may be useful intermediates but may not represent the outcomes that are most valuable to the patients. Drug development should benefit from the inherent advantages of intermediate endpoints, but use of such endpoints should not eliminate or diminish the need to establish their surrogacy for definitive clinical outcomes. Arguments have been made that delaying progression of cancer is associated with better quality of life but that largely depends on the magnitude of adverse events which result from new treatment. To put this in context, BOLERO-2, a 724 patient RCT reported initially in 2012 compared the combination of an aromatase inhibitor, exemestane and the inhibitor of the mammalian target of rapamycin (mTOR), Everolimus (Afinitor; Novartis, Basel, Switzerland) to exemestane alone in women with advanced breast cancer who had progressed after previous hormonal therapy [3]. Everolimus received FDA approval based on a significant improvement in progression free survival (PFS) in BOLERO-2 with a Hazard Ratio (HR) of 0$43, 95% Confidence Interval (CI): 0$35e0$54, p < 0$001. Although this result is impressive, it is
http://dx.doi.org/10.1016/j.breast.2015.04.006 0960-9776/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Niraula S, et al., One step forward, two steps back: The story of everolimus in advanced breast cancer, The Breast (2015), http://dx.doi.org/10.1016/j.breast.2015.04.006
2
S. Niraula et al. / The Breast xxx (2015) 1e3
important to recognize the limitations in the analysis of the trial. There was a substantially imbalanced rate of informative censoring between the arms, therefore inflating the effect of PFS due to increased withdrawal in the experimental arm. Furthermore, approximately 40% of events that were deemed to be related to progression by local review were subsequently reclassified as ‘nonevents’ upon central review. Overall survival was a secondary endpoint in BOLERO-2. The trial possessed 80% power to detect an HR of 0$74 for OS and required 398 events to demonstrate that difference. After a median follow-up of 39 months, and 410 survival events, recently reported mature OS data from BOLERO-2 at the 9th European breast cancer conference failed to show a significant difference in OS between the arms (HR 0$89, 95% CI 0$73 to 1$10, p ¼ 0$14) [4]. There were 7 deaths attributed to the study drug in the experimental arm of the BOLERO-2 trial, compared to one death in the exemestane arm. Serious adverse events related to the treatment occurred in 11% versus in 1% of the patients, respectively. About a quarter (24%) of patients randomized to the experimental arm discontinued the treatment early because of side effects or withdrawal of consent, versus only 6% in the control arm. Treatment discontinuation is usually not expected in the absence of progression or intolerable toxicity. Furthermore, patients who withdrew from BOLERO-2 prior to documentation of disease progression were censored likely inflating the magnitude of difference in PFS between the arms and favoring the experimental arm. Previous report of the health-related quality of life from BOLERO-2 indicates that deterioration in QoL symptoms was delayed with everolimus but again, the analysis suffered from the informative censoring bias described above [5]. Data on toxicity of everolimus are also reflected in other clinical trials-when tested in combination with tamoxifen compared to tamoxifen alone in a phase II trial in advanced breast cancer, everolimus met its primary endpoint of improvement in clinical benefit rate but there were similar differences in toxicities and treatment discontinuation as seen in BOLERO-2 [6]. When combined with vinorelbine and trastuzumab in HER-2 positive breast cancer, everolimus demonstrated a significant improvement in PFS of 1$3 months, and with similar increase in toxicity [7]. Despite these results, this study also advocated the use of everolimus for that indication. The assessment of regulators regarding the approval of everolimus in HER2 positive breast cancer is eagerly awaited. The difference in PFS demonstrated by BOLERO-2 and other everolimus studies signifies the fact that everolimus does have biologic activity in a subset of patients with advanced breast cancer. Therefore, identification of patients most likely to benefit from everolimus is important, particularly because of the concerns with toxicity. BOLERO-2 was designed based on reasonable evidence that aberrant signaling through phosphatidylinositol 3-kinase (PI3K)-Akt-mTOR pathway is key to endocrine resistance in breast cancer. There have been high-level, intensive efforts trying to identify biomarker(s) predicting for benefit from everolimus but apart from a few associations of less clear significance, the search for clinically useful markers has not materialized clinically [8,9]. In metastatic breast cancer, individual data meta-analysis of 4000 patients from 11 RCTs has shown no association of any intermediate endpoints, including PFS, with OS [10]. When a tested therapeutic intervention prolongs PFS, has no effect on overall survival, and adds serious toxicities on substantial number of patients, critical questions regarding therapeutic value of such intervention are obvious to follow. Signals of initial efficacy of a new intervention leading to widespread use, followed by confirmation of ineffectiveness, or sometimes harm, has been a recurring phenomenon in several medical specialties. These experiences have not sensitized us to
recognize potentially harmful interventions. A relevant example is the use of bevacizumab (Avastin; Genentech, South San Francisco, CA), a monoclonal antibody against vascular endothelial growth factor, in advanced breast cancer. This agent received an accelerated approval by FDA in 2008 for treatment of metastatic breast cancer based on an improvement in median PFS of 5$9 months. Subsequently, a meta-analysis that included the initial registration trial, and two other trials, showed less impressive improvements in PFS (2e5 months) with addition of Bevacizumab [11]. Furthermore, there was no improvement in either OS or QoL and bevacizumab increased incidence of serious toxicities. In 2010, FDA revoked its decision to license bevacizumab in metastatic breast cancer. The story of everolimus is similar. Both everolimus and bevacizumab were tested for treatment of incurable breast cancer where maintaining the quality of life is important. The underlying hypothesis of both drugs is to target important proteins in cellular survival pathways, but neither has validated predictive biomarkers. Both drugs have a demonstrated advantage of extending PFS in women with metastatic breast cancer compared to the control treatment but neither has an effect in OS. The risk of serious toxicities that can substantially impact patients' QoL, including risk of treatment-related death, is increased substantially with the use of both drugs. Bevacizumab and everolimus are only examples. They represent the tip of the iceberg of trends in licensing and marketing modern cancer therapeutics. Despite decades of experience in drug regulations, improvements in clinical trial qualities, and well-formed guidelines in several aspects of drug development process, we are still inconsistent about type and magnitude of benefits that are acceptable for introducing a new drug into the market. Extent of acceptable trade-offs in exchange of desired benefit is even less clear. Policy decisions about new medical interventions based on intermediate outcomes or on premature data may cause harm to patients, and to society. Setting a relatively low threshold to introduce a promising intervention based conditionally on exceptionally good early results may be useful for the general public and might be justified on a temporary basis as long as definitive assessment is completed and reassessed by regulatory agencies. However, a high threshold should be applied for maintaining such interventions in the market. Consistency in the decision about accelerated approvals, regular approvals and revoking of approvals is an integral part of the trust that the physicians, patients and other stakeholders require for regulatory agencies. Conflict of interest statement There is no conflict of interest of any authors that is directly or indirectly relevent to this manuscript. Acknowledgment We would like to thank Dr. Ian Tannock, Toronto for his constructive remarks on previous version of this manuscript. References [1] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646e74. [2] Niraula S, Amir E, Vera-Badillo F, Seruga B, Ocana A, Tannock IF. risk of incremental toxicities and associated costs of new anticancer drugs: a metaanalysis. J Clin Oncol 2014 Nov 10;32(32):3634e42. [3] Baselga J, Campone M, Piccart M, Burris 3rd HA, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl J Med 2012;366:520e9. [4] Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Noguchi S, Rugo H, et al. Everolimus plus exemestane for hormone receptor-positive (hrþ), human epidermal growth factor receptor-2enegative (HER2e) advanced breast
Please cite this article in press as: Niraula S, et al., One step forward, two steps back: The story of everolimus in advanced breast cancer, The Breast (2015), http://dx.doi.org/10.1016/j.breast.2015.04.006
S. Niraula et al. / The Breast xxx (2015) 1e3 cancer (BC): overall survival results from BOLERO-2. EBCC-9; 19e21. March 2014. Glasgow, Scotland. Abstract 1LBA. [5] Burris 3rd HA, Lebrun F, Rugo HS, Beck JT, Piccart M, Neven P, et al. Healthrelated quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3, randomized, controlled, BOLERO-2 trial. Cancer 2013;119:1908e15. [6] Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, et al. 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 Off J Am Soc Clin Oncol 2012;30:2718e24. [7] Andre F, O'Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 2014;15:580e91.
3
[8] Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS, Burris HA, Campone M, Noguchi S, et al. Correlation of molecular alterations with efficacy of everolimus in hormone receptorepositive, HER2-negative advanced breast cancer: results from BOLERO-2. J Clin Oncol 2013;31. suppl; abstr LBA509. F, Chen D, Robinson D, Ozguroglu M, Lang I, et al. & L., G. [9] Jerusalem G, Andre Evaluation of everolimus (EVE) in HER2þ advanced breast cancer (BC) with activated PI3K/mTOR pathway: exploratory biomarker observations from the BOLERO-3 trial. Eur J Cancer September 2013;49(3). European Cancer Congress 2013, Abstract #16. [10] Burzykowski T, Buyse M, Piccart-Gebhart MJ, Sledge G, Carmichael J, Luck HJ, et al. Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 2008;26:1987e92. [11] Rossari JR, Metzger-Filho O, Paesmans M, Saini KS, Gennari A, de Azambuja E, et al. Bevacizumab and breast cancer: a meta-analysis of first-line phase iii studies and a critical reappraisal of available evidence. J Oncol 2012;2012:417673.
Please cite this article in press as: Niraula S, et al., One step forward, two steps back: The story of everolimus in advanced breast cancer, The Breast (2015), http://dx.doi.org/10.1016/j.breast.2015.04.006