A Phase II Open Label Study of Everolimus in Combination With Endocrine Therapy in Resistant Hormone Receptor-Positive HER2-Negative Advanced Breast Cancer

Yardley, Denise A.; Liggett, William H.; Mainwaring, Mark G.; Castrellon, Aurelio; Blakely, L. Johnetta; Hemphill, Brian; Anz, Bertrand; Young, Robyn R.; Shastry, Mythili; DeBusk, Laura M.; Hainsworth, John D.; Burris, Howard A.

doi:10.1016/j.clbc.2019.06.005

Cited by 6 publications

(7 citation statements)

References 22 publications

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“…Addressing this issue, clinical trials have been started and are ongoing. Although side-effects are relatively frequent, they seem to be manageable, and the results are promising [ 36 , 37 , 38 ]. All these studies emphasise the importance of finding appropriate biomarkers and developing up-to-date combination therapies [ 36 , 37 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

In Situ Metabolic Characterisation of Breast Cancer and Its Potential Impact on Therapy

Petővári

Dankó

Tőkés

et al. 2020

Cancers

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In spite of tremendous developments in breast cancer treatment, the relatively high incidence of relapsing cases indicates a great need to find new therapeutic strategies in recurrent, metastatic and advanced cases. The bioenergetic needs of growing tumours at the primary site or in metastases—accumulating genomic alterations and further heterogeneity—are supported by metabolic rewiring, an important hallmark of cancer. Adaptation mechanisms as well as altered anabolic and catabolic processes balance according to available nutrients, energy, oxygen demand and overgrowth or therapeutic resistance. Mammalian target of rapamycin (mTOR) hyperactivity may contribute to this metabolic plasticity and progression in breast carcinomas. We set out to assess the metabolic complexity in breast cancer cell lines and primary breast cancer cases. Cellular metabolism and mTOR-related protein expression were characterised in ten cell lines, along with their sensitivity to specific mTOR and other metabolic inhibitors. Selected immunohistochemical reactions were performed on ~100 surgically removed breast cancer specimens. The obtained protein expression scores were correlated with survival and other clinicopathological data. Metabolic and mTOR inhibitor mono-treatments had moderate antiproliferative effects in the studied cell lines in a subtype-independent manner, revealing their high adaptive capacity and survival/growth potential. Immunohistochemical analysis of p-S6, Rictor, lactate dehydrogenase A, glutaminase, fatty acid synthase and carnitine palmitoyltransferase 1A in human samples identified high mTOR activity and potential metabolic plasticity as negative prognostic factors for breast cancer patients, even in subtypes generally considered as low-risk. According to our results, breast cancer is characterised by considerable metabolic diversity, which can be targeted by combining antimetabolic treatments and recent therapies. Alterations in these pathways may provide novel targets for future drug development in breast cancer. We also propose a set of immunostainings for scoring metabolic heterogeneity in individual cases in order to select patients who may benefit from more accurate follow-up and specific therapies.

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Section: Discussionmentioning

confidence: 99%

In Situ Metabolic Characterisation of Breast Cancer and Its Potential Impact on Therapy

Petővári

Dankó

Tőkés

et al. 2020

Cancers

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“…In a systematic meta-analysis that used statistical analyses to rank the efficacy of therapy options for patients with MBC whose disease had progressed on a prior endocrine therapy (maximum efficacy score of 100), everolimus plus exemestane had an efficacy score of 95.0, palbociclib plus fulvestrant had an efficacy score of 93.9, and various endocrine monotherapies had efficacy scores below 70.0 [74]. These and the results of NCT02291913, where patients initiated everolimus but remained on the same endocrine therapy after disease progression [39], support the use of everolimus combination therapy as one option after disease progression on endocrine monotherapy. Everolimus plus fulvestrant or tamoxifen are also supported by phase II data [35][36][37].…”

Section: The Role Of Everolimus Within the Mbc Treatment Algorithmmentioning

confidence: 83%

“…Patients whose disease had progressed on endocrine therapy continued on this same endocrine therapy and, in addition, initiated treatment with everolimus. Median PFS in the intentto-treat population was 6.6 months, which was substantially longer than placebo plus exemestane in BOLERO-2 [39].…”

Section: Everolimus Plus Exemestanementioning

confidence: 89%

“…Investigator-assessed median PFS was 5.4 months in the fulvestrant arm, 12.3 months in the everolimus plus fulvestrant arm, and 7.6 and 8.0 months in the vistusertib plus fulvestrant arms, at the vistusertib continuous or intermittent dose, respectively [37]. As mTOR inhibitors can reverse endocrine therapy resistance in preclinical models [38], a phase II, single-arm, open-label trial (NCT02291913) evaluated whether the addition of everolimus could overcome resistance to standard endocrine therapy in 47 postmenopausal women with HR+, HER2− MBC [39]. Patients whose disease had progressed on endocrine therapy continued on this same endocrine therapy and, in addition, initiated treatment with everolimus.…”

Section: Everolimus Plus Exemestanementioning

confidence: 99%

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Everolimus-based combination therapies for HR+, HER2− metastatic breast cancer

O’Shaughnessy

Beck

Royce

2018

Cancer Treatment Reviews

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Metastatic breast cancer (MBC) is the leading cause of cancer-related morbidity and mortality among women worldwide. Endocrine therapy is the standard of care for the most common subtype of MBC, hormone-receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) disease. Advances in treating this type of MBC have focused on improving the efficacy of endocrine therapy by adding agents that target specific molecular pathways of breast cancer cell growth and survival. The combination of the aromatase inhibitor exemestane and the mammalian target of rapamycin inhibitor, everolimus, more than doubled median progression-free survival compared with exemestane alone (7.8 vs 3.2 months, respectively; hazard ratio 0.45 [95% confidence interval 0.38-0.54]; log rank P < 0.0001) in the BOLERO-2 study in postmenopausal women with HR+, HER2- locally advanced or metastatic breast cancer that had recurred or progressed on prior non-steroidal aromatase inhibitor therapy. In addition, everolimus plus exemestane was associated with a manageable safety profile. The results of BOLERO-2 led to regulatory approval of everolimus plus exemestane. Additional everolimus-based combinations have been or are under investigation in the HR+, HER2- MBC setting, including combinations with letrozole, fulvestrant, ribociclib, tamoxifen, and chemotherapy. This review summarizes key data on everolimus-based combinations focusing on efficacy, safety, biomarkers, quality of life, and health economic outcomes. These data are discussed in the context of the changing MBC treatment algorithm to provide insights into the clinical relevance of everolimus-based combinations.

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“…While these data indicate that Eve/Let is an effective first-line combination treatment, they also show that Eve continuation after disease progression is a poorly effective therapeutic strategy. Other phase II studies evaluating Eve in combination with Let, Fulv, Exe, or TAM in patients with mBC progressing on/after prior NSAI therapy showed interesting activity and efficacy, in the absence of relevant unforetold toxicities [44][45][46][47][48][49].…”

Section: Other Prospective Studies Investigating Eve or Alpmentioning

confidence: 99%

Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications

et al. 2020

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Background: The PI3K/AKT/mTORC1 axis is implicated in hormone receptor-positive HER2-negative metastatic breast cancer (HR+ HER2− mBC) resistance to anti-estrogen treatments. Based on results of the BOLERO-2 trial, the mTORC1 inhibitor everolimus in combination with the steroidal aromatase inhibitor (AI) exemestane has become a standard treatment for patients with HR+ HER2− mBC resistant to prior non-steroidal AI therapy. In the recent SOLAR-1 trial, the inhibitor of the PI3K alpha subunit (p110α) alpelisib in combination with fulvestrant prolonged progression-free survival (PFS) when compared to fulvestrant alone in patients with PIK3CA-mutated HR+ HER2− mBC that progressed after/on previous AI treatment. Therefore, two different molecules targeting the PI3K/AKT/ mTORC1 axis, namely everolimus and alpelisib, are available for patients progressing on/after previous AI treatment, but it is unclear how to optimize their use in the clinical practice. Main body of the abstract: Here, we reviewed the available clinical evidence deriving from the BOLERO-2 and SOLAR-1 trials to compare efficacy and safety profiles of everolimus and alpelisib in advanced HR+ HER2− BC treatment. Adding either compound to standard endocrine therapy provided similar absolute and relative PFS advantage. In the SOLAR-1 trial, a 76% incidence of grade (G) 3 or 4 (G3/G4) adverse events was reported, while G3/G4 toxicities occurred in 42% of patients in the BOLERO-2 trial. While alpelisib was only effective in patients with PIK3CA-mutated neoplasms, retrospective analyses indicate that everolimus improves exemestane efficacy independently of PIK3CA mutational status. (Continued on next page)Conclusions: Based on the available efficacy and safety data, the "new" alpelisib may be burdened by higher incidence of severe adverse events, higher costs, and anticancer efficacy that is limited to PIK3CA-mutated tumors when compared to the "old" everolimus. Therefore, the everolimus-exemestane combination remains an effective and reasonably well-tolerated therapeutic option for HR+ HER2− mBC patients progressing after/on previous AI treatment, independently of PIK3CA mutational status. BackgroundEndocrine therapy (ET) is the mainstay of treatment for patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (mBC) [1]. However, tumors initially responding to ET, including the most recent ET-Cyclin-Dependent Kinase 4/6 (CDK4/6) inhibitor combinations, almost invariably develop resistance [2][3][4]. Hence, the identification of targeted therapies that are able to revert or delay endocrine resistance is a clinically relevant issue.Aberrant signaling through the phosphatidylinositol 3kinase/protein kinase B (AKT)/mechanistic target of rapamycin complex 1 (PI3K/AKT/mTORC1) cascade is clearly implicated in endocrine resistance, thus providing the rationale for combining inhibitors of this pathway with currently available ET [5][6][7]. Based on the results of the BOLERO-2 trial, the mTORC1 inh...

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A Phase II Open Label Study of Everolimus in Combination With Endocrine Therapy in Resistant Hormone Receptor-Positive HER2-Negative Advanced Breast Cancer

Cited by 6 publications

References 22 publications

In Situ Metabolic Characterisation of Breast Cancer and Its Potential Impact on Therapy

In Situ Metabolic Characterisation of Breast Cancer and Its Potential Impact on Therapy

Everolimus-based combination therapies for HR+, HER2− metastatic breast cancer

Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications

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