Everolimus Plus Exemestane in Postmenopausal Patients with HR+ Breast Cancer: BOLERO-2 Final Progression-Free Survival Analysis

Yardley, Denise A.; Noguchi, Shinzaburo; Pritchard, Kathleen I.; Burris, Howard A.; Baselga, José; Gnant, Michael; Hortobágyi, Gabriel N.; Campone, Mario; Pistilli, Barbara; Piccart, Martine; Melichar, Bohuslav; Petráková, Katarína; Arena, Francis P.; Erdkamp, Frans; Harb, Wael A.; Feng, Wentao; Cahana, Ayelet; Taran, Tetiana; Lebwohl, David; Rugo, Hope S.

doi:10.1007/s12325-013-0060-1

Cited by 440 publications

(482 citation statements)

References 23 publications

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“…Other targets of eIFs include PI3K and mTOR inhibitors. Rapamycin and analogues, upstream signaling inhibitors of translation initiation, are now in the clinic (44)(45)(46). We assessed eIF4E and eIF5 expression in an MBC patient who was treated with agents known to impact these signaling pathways, namely the mTOR inhibitor everolimus (Afinitor/RAD001) given in combination with BEZ235, an inhibitor of class I PI3K molecules and the mTORC1 and mTORC2 complexes.…”

Section: Discussionmentioning

confidence: 99%

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

Humphries

Rajan

Droop

et al. 2017

Clinical Cancer Research

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Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar.Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico. Biomarkers were immunohistochemically assessed in 697 MBCs (n ¼ 477, training; n ¼ 220, validation set) and quantified in pre-and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor.Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P ¼ 0.013; HR ¼ 1.77, 1.12-2.8 and P ¼ 0.035; HR ¼ 1.68, 1.03-2.74, respectively), or when coexpressed (P ¼ 0.01; HR ¼ 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P ¼ 0.016; HR ¼ 2.38 (1.18-4.8), eIF5 P ¼ 0.022; HR ¼ 2.55 (1.14-5.7); coexpression P ¼ 0.001; HR ¼ 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival.Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required.

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Section: Discussionmentioning

confidence: 99%

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

Humphries

Rajan

Droop

et al. 2017

Clinical Cancer Research

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“…The most convincing argument for using PI3K pathway inhibitors as part of combination therapy comes from phase III trials with everolimus. In the BOLERO-2 trial, the combination of everolimus and exemestane significantly improved median progression-free survival (PFS) to 7.8 months compared with 3.2 months with exemestane alone, in women with advanced ERþ breast cancer (73). In BOLERO-3, the combination of everolimus, trastuzumab, and vinorelbine, improved PFS to 7.0 months, compared with 5.8 months, in patients with HER2…”

Section: Pi3k/akt/mtor Pathway Inhibitors As Combination Therapymentioning

confidence: 99%

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

Dienstmann¹,

Rodón²,

Serra³

et al. 2014

Molecular Cancer Therapeutics

387

331

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The frequent activation of the PI3K/AKT/mTOR pathway in cancer, and its crucial role in cell growth and survival, has made it a much desired target for pharmacologic intervention. Following the regulatory approval of the rapamycin analogs everolimus and temsirolimus, recent years have seen an explosion in the number of phosphoinositide 3-kinase (PI3K) pathway inhibitors under clinical investigation. These include: ATPcompetitive, dual inhibitors of class I PI3K and mTORC1/2; "pan-PI3K" inhibitors, which inhibit all four isoforms of class I PI3K (a, b, d, g); isoform-specific inhibitors of the various PI3K isoforms; allosteric and catalytic inhibitors of AKT; and ATP-competitive inhibitors of mTOR only (and thus mTORC1 and mTORC2). With so many agents in development, clinicians are currently faced with a wide array of clinical trials investigating a multitude of inhibitors with different mechanisms of action, being used both as single agents and in combination with other therapies. Here, we provide a review of the literature, with the aim of differentiating the genomic contexts in which these various types of inhibitors may potentially have superior activity.

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“…Interestingly, the PI3K/AKT/mTOR pathway seems implicated also in acquired resistance to hormone therapy in estrogen receptor (ER)-positive breast cancer [55]. In fact, in a phase 3 study, the addition of everolimus to the aromatase inhibitor exemestane, significantly prolonged progression-free survival in metastastic ER-positive, HER2-negative breast cancer patients who had had recurred or progressed while receiving previous therapy with a nonsteroidal aromatase inhibitor [56,57].Targeting mTOR in metastatic NECB may represent an intriguing therapeutic strategy that deserves specific investigation. …”

Section: Future Perspectivesmentioning

confidence: 99%

Neuroendocrine Carcinoma of the Breast: Current Evidence and Future Perspectives

et al. 2015

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Neuroendocrine carcinoma of the breast is considered a rare entity, and for this reason there are no data from prospective clinical trials on its optimal management. Early stage tumors are usually treated with the same strategy used for the other types of invasive breast cancer. Anthracycline-and taxane-based regimens represent the most frequently administered chemotherapy in neoadjuvant and adjuvant setting, as well as for metastatic disease, although combinations of platinum compounds and etoposide have been widely used, in particular for small-cell histology and tumors with a high proliferation index. For metastatic disease, a multimodality therapeutic strategy can be considered on an individual basis, with chemotherapy, endocrine therapy, peptide receptor radionuclide therapy, radiation therapy, surgery, or a combination of the above. In the near future, a better knowledge of the biology of these tumors will hopefully provide new therapeutic targets for personalized treatment. In this review, we discuss the current evidence and the future perspectives on diagnosis and treatment of neuroendocrine carcinoma of the breast. The Oncologist 2016;21:28-32 Implications for Practice: Neuroendocrine carcinoma of the breast (NECB) is a distinct entity of breast cancer. Clinical features and morphology are not helpful to distinguish NECB from other subtypes of breast cancer; therefore, immunohistochemistry markers for neuroendocrine differentiation, mainly chromogranin and synaptophysin, should be routinely used to confirm the diagnosis, especially in cases of mucinous or solid papillary carcinoma in which the suspicion of NECB may be relevant. Adjuvant treatment should be offered according to the same recommendations given for the other types of invasive breast cancer. An accurate diagnosis of NECB is also important in the metastatic setting, in which a multimodality approach including specific therapies such as peptide receptor radionuclide therapy can be considered.

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Everolimus Plus Exemestane in Postmenopausal Patients with HR+ Breast Cancer: BOLERO-2 Final Progression-Free Survival Analysis

Cited by 440 publications

References 23 publications

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

Neuroendocrine Carcinoma of the Breast: Current Evidence and Future Perspectives

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