Palbociclib: A Review in HR-Positive, HER2-Negative, Advanced or Metastatic Breast Cancer

Kim, Esther; Scott, Lesley J.

doi:10.1007/s11523-017-0492-7

Cited by 39 publications

(27 citation statements)

References 41 publications

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“…Abnormal cell cycle is a hallmark of cancer. Targeting this pathway has already shown a promise in treating breast cancer, and several drugs targeting cell cycle have been approved by FDA 42 , 43 . Recent studies in cell cycle indicated that the interaction among cyclins, CDKs and cyclin-dependent kinase inhibitors (CKIs) plays a fundamental role in cell cycle progression 13 , 44 , 45 .…”

Section: Discussionmentioning

confidence: 99%

The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0/G1 arrest and apoptosis

et al. 2018

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Women with aggressive triple-negative breast cancer (TNBC) are at high risk of brain metastasis, which has no effective therapeutic option partially due to the poor penetration of drugs across the blood−brain barrier. Trifluoperazine (TFP) is an approved antipsychotic drug with good bioavailability in brain and had shown anticancer effect in several types of cancer. It drives us to investigate its activities to suppress TNBC, especially the brain metastasis. In this study, we chose three TNBC cell lines MDA-MB-468, MDA-MB-231, and 4T1 to assess its anticancer activities along with the possible mechanisms. In vitro, it induced G0/G1 cell cycle arrest via decreasing the expression of both cyclinD1/CDK4 and cyclinE/CDK2, and stimulated mitochondria-mediated apoptosis. In vivo, TFP suppressed the growth of subcutaneous xenograft tumor and brain metastasis without causing detectable side effects. Importantly, it prolonged the survival of mice bearing brain metastasis. Immunohistochemical analysis of Ki67 and cleaved caspase-3 indicated TFP could suppress the growth and induce apoptosis of cancer cells in vivo. Taken together, TFP might be a potential available drug for treating TNBC with brain metastasis, which urgently needs novel treatment options.

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Section: Discussionmentioning

confidence: 99%

The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0/G1 arrest and apoptosis

et al. 2018

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“…Palbociclib (IBRANCE â ) is a first-in-class, orally bioavailable inhibitor of CDK4/6 approved for the treatment of HRþ/ HER2À metastatic breast cancer (MBC) in combination with fulvestrant in pre/perimenopausal and postmenopausal women with disease progression after ET and in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women [10]. In the phase 3, randomised, double-blind PALOMA-3 study, palbociclib plus fulvestrant demonstrated significantly improved efficacy versus placebo plus fulvestrant in patients with endocrine-resistant HRþ/HER2À MBC, with median progression-free survival (PFS) of 11.2 versus 4.6 months, respectively (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.40e0.62; one-sided P < 0.0001) [11,12]. Although ET is more effective overall when combined with a CDK4/6 inhibitor [13e16], prolonged responses have been observed in subsets of patients with breast cancer receiving ET alone [17].…”

Section: Introductionmentioning

confidence: 99%

Predictors of prolonged benefit from palbociclib plus fulvestrant in women with endocrine-resistant hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer in PALOMA-3

Cristofanilli¹,

DeMichele

Giorgetti

et al. 2018

European Journal of Cancer

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Background: The addition of palbociclib to fulvestrant improved clinical outcomes over placebo-fulvestrant in endocrine-pretreated metastatic breast cancer (MBC) patients in PALOMA-3. Here, we examined factors predictive of long-term benefit. Methods: Premenopausal-peri/postmenopausal patients with endocrine-resistant, hormone receptorepositive (HRþ)/human epidermal growth factor receptor 2enegative MBC were randomised 2:1 to fulvestrant (500 mg) and either palbociclib (125 mg/d; 3/1 schedule; n Z 347) or placebo (n Z 174). Baseline characteristics, mutation status and HR expression levels were compared in patients with and without prolonged benefit (treatment duration !18 months). Results: By August 2016, 100 patients (29%) on palbociclib-fulvestrant and 26 (15%) on placebo-fulvestrant demonstrated prolonged benefit, with long-term responders in both arms sharing common clinical characteristics. They usually had less disease burden at baseline versus those treated <18 months, such as having one disease site (40% vs 29% on palbociclib-fulvestrant and 69% vs 29% on placebo-fulvestrant), bone-only disease (32% vs 22% and 46% vs 17%) and were less heavily pretreated (69% vs 56% and 73% vs 60% had 2 prior therapies). Baseline tumour ESR1 and PIK3CA mutation rates were lower among long-term responders in both arms; median oestrogen receptor H-scores were similar, whereas progesterone receptor H-scores were higher among long-term responders. Conclusions: This exploratory analysis demonstrates that some patients with endocrineresistant MBC derive significant and prolonged benefit when treated with palbociclibfulvestrant, with fewer patients experiencing similar efficacy with placebo-fulvestrant. The current analysis did not identify specific molecular or clinical factors prognostic of long-term benefit with palbociclib-fulvestrant (ClinicalTrials.gov, NCT01942135).

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“…Patient 16 received anti-CTLA4 immunotherapy, which resulted in a stable disease. In case of disease progression the SwissMTB report recommends off-label treatment with palbociclib to target the observed loss-of-function variant R80* in CDKN2A [ 85 , 86 ].…”

Section: Resultsmentioning

confidence: 99%

SwissMTB: establishing comprehensive molecular cancer diagnostics in Swiss clinics

Singer

Irmisch

Toussaint

et al. 2018

BMC Med Inform Decis Mak

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BackgroundMolecular precision oncology is an emerging practice to improve cancer therapy by decreasing the risk of choosing treatments that lack efficacy or cause adverse events. However, the challenges of integrating molecular profiling into routine clinical care are manifold. From a computational perspective these include the importance of a short analysis turnaround time, the interpretation of complex drug-gene and gene-gene interactions, and the necessity of standardized high-quality workflows. In addition, difficulties faced when integrating molecular diagnostics into clinical practice are ethical concerns, legal requirements, and limited availability of treatment options beyond standard of care as well as the overall lack of awareness of their existence.MethodsTo the best of our knowledge, we are the first group in Switzerland that established a workflow for personalized diagnostics based on comprehensive high-throughput sequencing of tumors at the clinic. Our workflow, named SwissMTB (Swiss Molecular Tumor Board), links genetic tumor alterations and gene expression to therapeutic options and clinical trial opportunities. The resulting treatment recommendations are summarized in a clinical report and discussed in a molecular tumor board at the clinic to support therapy decisions.ResultsHere we present results from an observational pilot study including 22 late-stage cancer patients. In this study we were able to identify actionable variants and corresponding therapies for 19 patients. Half of the patients were analyzed retrospectively. In two patients we identified resistance-associated variants explaining lack of therapy response. For five out of eleven patients analyzed before treatment the SwissMTB diagnostic influenced treatment decision.ConclusionsSwissMTB enables the analysis and clinical interpretation of large numbers of potentially actionable molecular targets. Thus, our workflow paves the way towards a more frequent use of comprehensive molecular diagnostics in Swiss hospitals.Electronic supplementary materialThe online version of this article (10.1186/s12911-018-0680-0) contains supplementary material, which is available to authorized users.

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Palbociclib: A Review in HR-Positive, HER2-Negative, Advanced or Metastatic Breast Cancer

Cited by 39 publications

References 41 publications

The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0/G1 arrest and apoptosis

The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0/G1 arrest and apoptosis

Predictors of prolonged benefit from palbociclib plus fulvestrant in women with endocrine-resistant hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer in PALOMA-3

SwissMTB: establishing comprehensive molecular cancer diagnostics in Swiss clinics

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