Deep proteomic analysis of plasma exosomes in patients with advanced, hormone receptor-positive breast cancer treated with palbociclib and tamoxifen.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1030-1030
Author(s):  
Xiuyuan Ma ◽  
Yu Gao ◽  
Gayatry Mohapatra ◽  
Louis Coleman ◽  
Yael Simons ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Disease Progression ◽  
Hormone Receptor ◽  
Proteomic Analysis ◽  
Progression Free Survival ◽  
Mechanisms Of Resistance ◽  
First Line Therapy ◽  
Hormone Receptor Positive ◽  
Best Response ◽  
Extraction And Purification

1030 Background: Combining a CDK4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) in advanced, hormone receptor (HR)-positive, HER2-negative breast cancer (BC) doubles median progression-free survival, but eventually drug resistance and disease progression occur. For most patients, the mechanism of resistance is unknown. Exosomes are membrane-bound extracellular vesicles that contain lipids, proteins, and nucleic acids, and are released from tumors as a form of intercellular communication. Exosomes can be recovered from plasma, and analysis of their cargo provides a dynamic read-out of biological pathways that are activated in cancer cells. Proteomic analysis of plasma exosomes may provide insight into mechanisms of resistance that emerge during treatment with CDK4/6i-ET. Methods: The Big Ten Cancer Research Consortium conducted a single arm, phase II trial of palbociclib plus tamoxifen as first line therapy for advanced, HR+/HER2- BC (NCT02668666). Whole blood was collected in Streck tubes from study participants (n = 49) at baseline, at disease progression, and at time points during study treatment. Plasma was separated and stored at -80C within 48 hours of collection. Exosomes were isolated from thawed plasma using commercially available kits and ultracentrifugation. Exosome extraction and purification was optimized for protein recovery. Purified exosomes were processed for proteomic analysis and labeled with TMT10 (tandem mass tag 10plex) and quantified with the QExactive HF mass spectrometer. Ultrasensitive mass spectrometry provided deep proteomic coverage of exosomal proteins and detected various post-translational modifications (PTM). Data were analyzed with a pipeline developed in our lab using an improved SEQUEST/ProLuCID database search engine and Percolator data filtering toolchain. Exosome protein expression was determined at baseline, at best response and at the time of progression. Results: With our ultrasensitive proteomic method, we detected more than 500 exosome proteins from as little as 100 ng of purified exosomes. A significant enrichment of exosome specific markers was observed when comparing patient samples with healthy donor samples. Enrichment of surface glycoproteins (e.g. CD44) was seen in BC patient samples, as in previous reports. Ultrasensitive proteomics also detected PTM including phosphorylation, methylation, oxidation, deamidation, and glycosylation. Differential proteomic and PTM profiles comparing samples collected from responding patients at baseline vs. at progression will be presented. Conclusions: Our innovative method provided an unparalleled portrait of the proteomic landscape of plasma exosomes during treatment with CDK4/6i-ET. This powerful approach may provide novel insights into mechanisms of resistance that emerge during treatment. This study was funded by Pfizer. Clinical trial information: NCT02668666 .

scholarly journals Patterns of treatment and outcome of palbociclib plus endocrine therapy in hormone receptor-positive/HER2 receptor-negative metastatic breast cancer: a real-world multicentre Italian study

2021 ◽  
Vol 13 ◽  
pp. 175883592098765
Author(s):  
Raffaella Palumbo ◽  
Rosalba Torrisi ◽  
Federico Sottotetti ◽  
Daniele Presti ◽  
Anna Rita Gambaro ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Endocrine Therapy ◽  
Real World ◽  
Hormone Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Her2 Receptor ◽  
Treatment Line ◽  
Hormone Receptor Positive

Background: The CDK4/6 inhibitor palbociclib combined with endocrine therapy (ET) has proven to prolong progression-free survival (PFS) in women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC). Few data are available regarding the efficacy of such a regimen outside the clinical trials. Patients and methods: This is a multicentre prospective real-world experience aimed at verifying the outcome of palbociclib plus ET in an unselected population of MBC patients. The primary aim was the clinical benefit rate (CBR); secondary aims were the median PFS, overall survival (OS) and safety. Patients received palbociclib plus letrozole 2.5 mg (cohort A) or fulvestrant 500 mg (cohort B). Results: In total, 191 patients (92 in cohort A, 99 in cohort B) were enrolled and treated, and 182 were evaluable for the analysis. Median age was 62 years (range 47–79); 54% had visceral involvement; 28% of patients had previously performed one treatment line (including chemotherapy and ET), 22.6% two lines and 15.9% three. An overall response rate of 34.6% was observed with 11 (6.0%) complete responses and 52 (28.6%) partial responses. Stable disease was achieved by 78 patients (42.9%) with an overall CBR of 59.8%. At a median follow-up of 24 months (range 6–32), median PFS was 13 months without significant differences between the cohorts. When analysed according to treatment line, PFS values were significantly prolonged when palbociclib-based therapy was administered as first-line treatment (14.0 months), to decrease progressively in second and subsequent lines (11.7 and 6.7 months, respectively). Median OS was 25 months, ranging from 28.0 months in 1st line to 18.0 and 13.0 months in 2nd and subsequent lines, respectively. Conclusions: Our data indicate that palbociclib plus ET is active and safe in HR+/HER2− MBC, also suggesting a better performance of the combinations in earlier treatment lines.

scholarly journals Epirubicin and docetaxel as neoadjuvant treatment of hormone receptor positive, HER-2 negative breast cancer: findings from two successive phase II studies

2013 ◽  
Vol 47 (1) ◽  
pp. 57-62
Author(s):  
Alessandro Tuzi ◽  
Davide Lombardi ◽  
Diana Crivellari ◽  
Loredana Militello ◽  
Tiziana Perin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Progression Free Survival ◽  
Preoperative Treatment ◽  
Free Survival ◽  
Hormone Receptor Positive ◽  
In Series ◽  
Her 2

Abstract Background. We report on the activity of the combination of epirubicin and docetaxel given in neoadjuvant setting for 4 and 8 cycles respectively in 2 successive series of patients with large operable or locally advanced, hormone receptor positive, HER-2 negative breast cancer. Patients and methods. Patients were treated from 2002 to 2006 with epirubicin 90 mg/m2 and docetaxel 75 mg/ m2 intravenously, every 3 weeks for 4 cycles before and 4 cycles after surgery (Series I - 13 patients), and from 2006 to 2010 with the same regimen administered for 8 cycles preoperatively (Series II - 37 patients), plus hormonal therapy for 5 years and radiation therapy if indicated. All Series I and 32 Series II patients were able to complete the preoperative chemotherapy. Results. A complete response was found in 1 patient from Series I and 13 patients from Series II and the partial remission in 10 patients from Series I and 21 patients from Series II. Two Series I and 3 Series II patients did not respond clinically. Response rate (Series I/Series II) was 84/92%. All 50 patients underwent surgery. In Series I patients, 3 pCR occurred in the breast and the axilla was histologically negative in 2 cases. No evidence of disease both in the breast and in the axilla was achieved in 7.6% (1/13) of patients. In Series II patients, 8 pCR occurred in the breast and axilla was histologically negative in 15 patients. No evidence of disease both in the breast and in the axilla occurred in 10.8% (4/37) of patients. G3-G4 toxicity included myelosuppression in 3 patients from Series I and all patients from Series II, and mucositis in 1 patient from Series I and 4 patients from series II. No other G3-4 toxicities or toxic deaths occurred. Five-year progression free survival was 38% and 90% in Series I and Series II patients respectively. Conclusions. The incidence of pathologic complete remissions was lower in our patient population, compared to reported data. A longer duration of the preoperative treatment might be associated with a longer progression-free survival.

scholarly journals CDK4/6 inhibitors in breast cancer: beyond hormone receptor-positive HER2-negative disease

2018 ◽  
Vol 10 ◽  
pp. 175883591881834 ◽  
Author(s):  
Adriana Matutino ◽  
Carla Amaro ◽  
Sunil Verma
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Breast Cancers ◽  
Cyclin Dependent Kinase ◽  
Her2 Positive ◽  
Hormone Receptor Positive ◽  
Epidermal Growth

The development of cyclin-dependent kinase (CDK) 4/6 inhibitors has been more prominent in hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancers, with a significant improvement in progression-free survival (PFS) in first and later lines of metastatic breast cancer (MBC) therapy. Preclinical evidence suggests that there is activity of CDK4/6 inhibitors in nonluminal cell lines. Here, we present a review of the current preclinical and clinical data on the use of CDK inhibitors in HER2-positive and triple-negative breast cancer (TNBC).

Progression-Free Survival for Real-World Use of Palbociclib in Hormone Receptor-Positive Metastatic Breast Cancer

2020 ◽  
Vol 20 (1) ◽  
pp. 33-40 ◽  
Author(s):  
Jonathan Wilkie ◽  
M. Alexandra Schickli ◽  
Michael J. Berger ◽  
Maryam Lustberg ◽  
Raquel Reinbolt ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Real World ◽  
Hormone Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Free Survival ◽  
Hormone Receptor Positive

Review of Cyclin-Dependent Kinase 4/6 Inhibitors for the Treatment of Hormone Receptor–Positive Advanced Breast Cancer

2018 ◽  
Vol 53 (2) ◽  
pp. 195-203
Author(s):  
Keith A. Hecht ◽  
Christopher Selby
Keyword(s):  
Breast Cancer ◽  
Adverse Effects ◽  
Advanced Breast Cancer ◽  
Hormone Receptor ◽  
Progression Free Survival ◽  
Advanced Breast ◽  
Cdk Inhibitors ◽  
Cyclin Dependent Kinase ◽  
Hormone Receptor Positive ◽  
Positive Breast Cancer

Objective: To evaluate the existing literature regarding the use of cyclin-dependent kinase (CDK) 4/6 inhibitors in the treatment of hormone receptor–positive advanced breast cancer (ABC). Data Sources: A search of the medical literature was performed using PubMed (2014 to June 2018). Search terms included cyclin-dependent kinase, CDK, breast cancer, palbociclib, ribociclib, abemaciclib, PD0332991, LEE011, and LY2835219. Clinicaltrials.gov was also searched. Study Selection and Data Extraction: Trials with clinical efficacy outcomes evaluating CDK 4/6 inhibitors in the treatment of advanced hormone-positive breast cancer were considered. Data Synthesis: Palbociclib, abemaciclib, and ribociclib each demonstrated significant benefit when combined with an aromatase inhibitor, the benefit to patients was similar for each, with an improvement of 42% to 51% in median progression-free survival (PFS). In combination with fulvestrant, CDK 4/6 inhibitors used for the treatment of hormone receptor–positive ABC resulted in a 43% to 58% improvement in median PFS versus fulvestrant alone. CDK inhibitors are relatively well tolerated; however, discontinuation as a result of adverse effects was highest with abemaciclib. Relevance to Patient Care and Clinical Practice: This review considers the use of the 3 commercially available CDK 4/6 inhibitors for treatment of hormone receptor–positive breast cancer, including data on each of the 3 agents in newly advanced and treatment refractory disease. Conclusions: The CDK inhibitors should be used in combination with endocrine therapies for the treatment of ABC. Efficacy of the 3 agents is similar. Selection within the class should include consideration of adverse effects and drug interactions.

scholarly journals Treatment of Advanced Hormone Receptor-Positive (HR+) HER2-negative Breast Cancer

2019 ◽  
Vol 79 (12) ◽  
pp. 1328-1335
Author(s):  
Nina Ditsch ◽  
Marcus Schmidt
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Treatment Options ◽  
Clinical Status ◽  
Progression Free Survival ◽  
Current Treatment ◽  
Free Survival ◽  
Cyclin Dependent Kinases ◽  
Hormone Receptor Positive ◽  
Study Results

AbstractThe article gives an overview of current treatment options for metastatic hormone receptor-positive and HER2-negative breast cancer. The focus is on combined therapies, e.g., with CDK4/6 inhibition compared with purely endocrine-based therapies in the pre- and postmenopause, presenting the latest study results. The addition of a CDK4/6 inhibitor to endocrine-based therapy with an aromatase inhibitor or fulvestrant leads to a marked improvement in progression-free survival and is independently beneficial whether palbociclib, ribociclib or abemaciclib is involved. The particular clinical status of inhibition of cyclin-dependent kinases argues for its use in the first-line treatment of women with metastatic, hormone receptor-positive and HER2-negative breast cancer compared with the available purely endocrine-based therapies.

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