“Overcoming breast cancer drug resistance with mTOR inhibitors”. Could it be a myth or a real possibility in the short-term future?

Margariti, Nadia; Fox, Stephen B.; Bottini, Alberto; Generali, Daniele

doi:10.1007/s10549-010-0986-9

Cited by 50 publications

(35 citation statements)

References 28 publications

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“…These findings provide clinical rationale for enhancing or extending endocrine sensitivity by combining endocrine therapy with a targeted agent against compensatory pathways. The PI3K/AKT/mTOR pathway is a crucial mediator of tumor progression [5,6,7]. As the PI3K/Akt/mTOR pathway is heavily deregulated in breast cancer [8,9], inhibitors of mTOR are of interest as potential therapeutic agents for breast cancer patients, with everolimus and temsirolimus being the key drugs considered (S1 Table).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer

et al. 2017

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PurposeMetastatic breast cancer (MBC) progressing after endocrine therapy frequently activates PI3K/AKT/mTOR pathway. The BOLERO-2 trial showed that everolimus-exemestane achieves increased progression free survival (PFS) compared with exemestane. However, there is great inter-patient variability in toxicity and response to exemestane-everolimus treatment. The objective of this study was to perform an exploratory study analyzing the implication of single nucleotide polymorphisms (SNPs) on outcomes from this treatment through a pharmacogenetic analysis.Patients and methodsBlood was collected from 90 postmenopausal women with hormone receptor-positive, HER2-negative MBC treated with exemestane-everolimus following progression after prior treatment with a non-steroidal aromatase inhibitor. Everolimus pharmacokinetics was measured in 37 patients. Twelve SNPs in genes involved in everolimus pharmacokinetics and pharmacodynamics were genotyped and associations assessed with drug plasma levels, clinically relevant toxicities (non-infectious pneumonitis, mucositis, hyperglycemia and hematological toxicities), dose reductions or treatment suspensions due to toxicity, progression free survival (PFS) and overall survival.ResultsWe found that CYP3A4 rs35599367 variant (CYP3A4*22 allele) carriers had higher everolimus blood concentration compared to wild type patients (P = 0.019). ABCB1 rs1045642 was associated with risk of mucositis (P = 0.031), while PIK3R1 rs10515074 and RAPTOR rs9906827 were associated with hyperglycemia and non-infectious pneumonitis (P = 0.016 and 0.024, respectively). Furthermore, RAPTOR rs9906827 was associated with PFS (P = 0.006).ConclusionsCYP3A4*22 allele influenced plasma concentration of everolimus and several SNPs in PI3K/AKT/mTOR pathway genes were associated with treatment toxicities and prognosis. These results require replication, but suggest that germline variation could influence everolimus outcomes in MBC.

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Section: Introductionmentioning

confidence: 99%

Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer

et al. 2017

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“…An improvement in OS (30.9 vs. 25.1 months) for patients receiving TDM-1 was also detected [24]. One of the mechanisms of resistance to trastuzumab is an increase in activation of the PI3K/AKT/mTOR pathway [25]. In vitro studies showed that mTOR activation was related to HER2 overexpression and responsible for HER2-positive breast cancer progression.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Therapeutic Efficacy of the Early and the Delayed Use of Vinorelbine-Based Regimens for Patients with Advanced Breast Cancer

Wang

Liu²,

Jia³

et al. 2016

Chemotherapy

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Background: The aim of this study was to evaluate the efficacy of vinorelbine-based regimens as first-, second- and more-line therapies in advanced breast cancer (ABC) and to analyze the best timing of vinorelbine treatment. Methods: A total of 71 ABC patients were retrospectively reviewed. Of these, 35 patients were treated with vinorelbine-based regimens as first-line chemotherapy, and 36 patients were treated with vinorelbine-based regimens as second-line or more-line therapy. The primary end point of the study was progression-free survival (PFS). Results: No difference was found in baseline characteristics between the two groups (p > 0.1 for all comparisons). There was a significant difference in the objective response rate (ORR; p = 0.006) and clinical benefit rate (CBR; p = 0.013) between the first-line group and the second- or more-line groups. In the vinorelbine first-line group, the ORR was 68.6% (24 patients), and in the second-line or more-line groups the ORR was 36.1% (13 patients). A significant difference in PFS between the first-line group and the second-line or more-line groups was also observed (p = 0.030). The median PFS in the overall population was 6.3 ± 1.32 months (95% CI 3.69-8.90). The median PFS was 11.1 ± 3.76 months (95% CI 3.73-18.47) in the first-line group compared with 5.2 ± 1.35 months (95% CI 2.54-7.85) in the second-line or more-line groups. In patients treated with vinorelbine-trastuzumab combination as the first-line therapy, a complete response was observed in 1 patient (12.5%) and partial response in 5 patients (62.5%), giving an ORR of 75.0%. Progressive disease was observed in 1 patient (12.5%), and stable disease in 1 patient (12.5%), leading to a CBR of 87.5%. The median PFS was 13.8 ± 2.75 months (95% CI 8.42-19.18), and median OS was 37.0 ± 11.6 months (95% CI 14.18-59.82). No significant difference was found in overall survival (OS) between the groups (p = 0.612). Conclusion: For ABC patients, no significant difference in median OS was found between the early use and delayed use of vinorelbine-based regimens, but the short-term efficacy and PFS of vinorelbine-based regimens were significantly better in the early use group than in the delayed use group.

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“…2) [8]. It has been postulated that the use of mTOR inhibitors in breast cancer may be twofold: in patients with acquired resistance, they could be used to partially restore sensitivity and provide an additional treatment period for drugs such as trastuzumab or aromatase inhibitors, whereas in patients who have not previously been treated with endocrine therapies, they could be used in combination with hormonal treatments to delay the onset of resistance and prolong treatment [5,9]. …”

Section: Rationale For Using Mtor Inhibitors In Breast Cancermentioning

confidence: 99%

Mammalian Target of Rapamycin as a Rational Therapeutic Target for Breast Cancer Treatment

LoRusso¹

2012

Oncology

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Therapies directed at endocrine receptors and human epidermal growth factor receptor 2 are important treatment options for patients with breast cancer; however, drug resistance and subsequent disease progression in patients with advanced disease is inevitable. The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and proliferation implicated in the cellular processes that lead to the uncontrolled growth of cancer cells. Hence, overactivation of the mTOR pathway may also represent a key process in the development of resistance to these therapies, and interrupting this signaling cascade may alleviate resistance and help restore drug sensitivity. A number of agents that target the mTOR pathway have shown potent antitumorigenic effects in vitro, and several agents have also shown promise in treating patients with breast cancer. Everolimus and temsirolimus are the most clinically advanced agents in this class, with recent data from the BOLERO-2 study indicating significant benefit associated with everolimus when added to endocrine therapy in patients with endocrine therapy-resistant disease. In this review, we consider the translation of mTOR inhibitors from laboratory studies to large clinical trials, driven by a rational understanding of the role of mTOR in the processes that underlie breast cancer tumorigenesis.

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“Overcoming breast cancer drug resistance with mTOR inhibitors”. Could it be a myth or a real possibility in the short-term future?

Cited by 50 publications

References 28 publications

Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer

Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer

Comparison of the Therapeutic Efficacy of the Early and the Delayed Use of Vinorelbine-Based Regimens for Patients with Advanced Breast Cancer

Mammalian Target of Rapamycin as a Rational Therapeutic Target for Breast Cancer Treatment

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