scholarly journals CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 332
Author(s):  
Michela Roberto ◽  
Antonio Astone ◽  
Andrea Botticelli ◽  
Luisa Carbognin ◽  
Alessandra Cassano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Hormone Receptor ◽  
Molecular Mechanisms ◽  
Breast Cancer Subtype ◽  
Endocrine Resistance ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Disease Recurrence ◽  
Advanced Breast

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common breast cancer subtype, and endocrine therapy (ET) remains its therapeutic backbone. Although anti-estrogen therapies are usually effective initially, approximately 50% of HR+ patients develop resistance to ET within their lifetime, ultimately leading to disease recurrence and limited clinical benefit. The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) to ET have remarkably improved the outcome of patients with HR+ advanced breast cancer (ABC) compared with anti-estrogens alone, by targeting the cell-cycle machinery and overcoming some aspects of endocrine resistance. However, which patients are the better candidates for these drugs, which are the main characteristics for a better selection of patients or if there are predictive biomarkers of response, is still unknown. In this review we reported the mechanism of action of CDK4/6 inhibitors as well as their potential mechanism of resistance, their implications in clinical practice and the forthcoming strategies to enhance their efficacy in improving survival and quality of life of patients affected with HR+, HER2−, ABC.

scholarly journals Systemic treatment approaches in her2-negative advanced breast cancer—guidance on the guidelines

2015 ◽  
Vol 22 ◽  
pp. 29 ◽  
Author(s):  
A.A. Joy ◽  
M. Ghosh ◽  
R. Fernandes ◽  
M.J. Clemons
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
De Novo ◽  
Treatment Guidelines ◽  
Early Stage ◽  
Symptom Control ◽  
Growth Factor Receptor ◽  
Disease Recurrence ◽  
Primary Treatment ◽  
Advanced Breast

Despite advancements in the treatment of early-stage breast cancer, many patients still develop disease recurrence; others present with de novo metastatic disease. For most patients with advanced breast cancer, the primary treatment intent is noncurative—that is, palliative—in nature. The goals of treatment should therefore focus on maximizing symptom control and extending survival. Treatments should be evaluated on an individualized basis in terms of evidence, but also with full respect for the wishes of the patient in terms of acceptable toxicity. Given the availability of extensive reviews on the roles of endocrine therapy and her2 (human epidermal growth factor receptor 2)–targeted therapies for advanced disease, we focus here mainly on treatment guidelines for the non-endocrine management of her2-negative advanced breast cancer in a Canadian health care context.

scholarly journals The role of abemaciclib in treatment of advanced breast cancer

2018 ◽  
Vol 10 ◽  
pp. 175883591877692 ◽  
Author(s):  
Amelia McCartney ◽  
Erica Moretti ◽  
Giuseppina Sanna ◽  
Marta Pestrin ◽  
Emanuela Risi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Single Agent ◽  
Endocrine Resistance ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Advanced Breast ◽  
Significant Activity ◽  
Epidermal Growth

Until recently, the mainstay of treatment in the majority of hormone receptor (HR)-positive, human epidermal growth factor 2 receptor (HER2)-negative advanced breast cancer (ABC) has consisted of single-agent endocrine therapy (ET). However, as understanding of endocrine resistance has grown, newer targeted agents have come to the fore. Inhibition of cyclin-dependent kinase complexes 4 and 6 (CDK4/6) combined with ET has shown significant activity in HR+ HER2− ABC, with impressive results in terms of progression-free survival (PFS) when compared with ET alone. This review summarizes the seminal findings pertaining to CDK4/6 inhibition in this population, specifically focusing on abemaciclib, contrasted with palbociclib and ribociclib. Potential directions for future studies are discussed, as a way of addressing outstanding issues such as establishing optimal treatment sequencing and agent combinations, appropriate patient selection to derive maximal benefits, predictive biomarkers and the employment of CDK4/6 inhibition beyond the ABC setting.

Correlation of molecular alterations with efficacy of everolimus in hormone-receptor–positive, HER2-negative advanced breast cancer: Results from BOLERO-2.

2013 ◽  
Vol 31 (26_suppl) ◽  
pp. 142-142
Author(s):  
Hope S. Rugo ◽  
Gabriel N. Hortobagyi ◽  
Martine J. Piccart-Gebhart ◽  
Howard A. Burris ◽  
Mario Campone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Hormone Receptor ◽  
Predictive Biomarkers ◽  
Copy Number Variations ◽  
Genetic Variations ◽  
Advanced Breast ◽  
Phase Iii ◽  
Gene Copy ◽  
Hormone Receptor Positive

142 Background: Everolimus (EVE) plus exemestane (EXE) more than doubled progression-free survival (PFS) while maintaining quality of life vs EXE alone in postmenopausal women with hormone receptor–positive (HR+), HER2-negative (HER2–) advanced breast cancer (BOLERO-2 phase III; NCT00863655). PFS benefit was seen in all clinically defined subgroups. We evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with EVE benefit. Methods: Exon sequence and gene copy number variations were analyzed in 182 cancer-related genes by next-generation sequencing (NGS). Correlations with PFS were evaluated using univariate and multivariate Cox models. Results: NGS data (>250x coverage) were successfully generated from archival tumor specimens from 227 patients (NGS population, 157 in EVE + EXE arm and 70 in EXE arm) whose baseline characteristics and clinical outcome were comparable to the trial population (PFS HR = 0.40 and 0.45, respectively). The treatment benefit of EVE + EXE over EXE was maintained in the subgroups defined by each of the 9 genes with a mutation rate >10% (e.g., PIK3CA, FGFR1, CCND1) or when less frequently mutated genes (e.g., PTEN, AKT1) were included in their respective pathways. Patients with 0 or 1 genetic alteration in PI3K or FGFR pathways or CCND1 had a greater treatment effect from EVE (HR = 0.27, 95% CI 0.18-0.41, adjusted by covariates, in 76% of the NGS population), indicating the value of these pathways for predicting sensitivity to EVE in this setting. Conclusions: This is the first global registration trial in which efficacy-predictive biomarkers were explored by correlating broad genetic variations with clinical efficacy. The preliminary results suggest that a large subgroup of patients (76%), defined by minimal genetic variations in the PI3K or FGFR pathways or CCND1, derives the most benefit from EVE therapy (HR = 0.27 vs 0.40 for the full NGS population). These exploratory results and their implication in understanding the interplay of multiple pathways in tumor cells and testing new hypotheses for targeted combination therapies in HR+/HER2– BC will be further investigated. Clinical trial information: NCT00863655.

scholarly journals Optimising endocrine therapy in postmenopausal women with advanced breast cancer

2018 ◽  
Vol 25 (7) ◽  
pp. 705-721 ◽  
Author(s):  
Thomas Ho Lai Yau ◽  
Kwok-Leung Cheung
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Combination Therapy ◽  
Advanced Breast Cancer ◽  
Hormone Receptor ◽  
Endocrine Resistance ◽  
Growth Factor Receptor ◽  
Sequential Therapy ◽  
Hormone Receptor Positive ◽  
Endothelial Growth Factor

Hormone receptor-positive breast cancer is commonly treated with endocrine therapy (ET); however, over time, cancer cells can develop endocrine resistance. This review aims to document combination therapy and sequential therapy in the use of endocrine agents and targeted agents, by conducting two systematic searches using four databases: Cochrane Library, MEDLINE, EMBASE and Web of Science. A total of 26 studies that covered combination therapy were obtained and included for the review. Fourteen were phase III documenting combinations of mechanistic target of rapamycin (mTOR), phosphoinositide-3-kinase (PI3K), vascular endothelial growth factor receptor, human epidermal growth factor receptor 2 and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. The remaining studies were of phase II nature that reported combinations involving inhibitors in mTOR, endothelial growth factor receptor, CDK4/6 and TKI. Interesting findings in inhibitor combinations involving CDK4/6, mTOR and PI3K suggest clinical activity that can overcome endocrine resistance. On the other hand, there were 0 studies that covered sequential therapy. Overall findings showed that combination therapy improved treatment efficacy over monotherapy in postmenopausal patients with hormone receptor-positive advanced breast cancer. Inevitably, the benefits are accompanied with increased toxicity. To optimise ET, further research into combinations and effective patient selection will need to be defined. Additionally, this review warrants future studies to explore sequential therapy.

Correlation of molecular alterations with efficacy of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer: Results from BOLERO-2.

2013 ◽  
Vol 31 (18_suppl) ◽  
pp. LBA509-LBA509 ◽  
Author(s):  
Gabriel N. Hortobagyi ◽  
Martine J. Piccart-Gebhart ◽  
Hope S. Rugo ◽  
Howard A. Burris ◽  
Mario Campone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Hormone Receptor ◽  
Predictive Biomarkers ◽  
Copy Number Variations ◽  
Genetic Variations ◽  
Advanced Breast ◽  
Phase Iii ◽  
Gene Copy ◽  
Hormone Receptor Positive

LBA509 Background: Everolimus (EVE) plus exemestane (EXE) more than doubled progression-free survival (PFS) while maintaining quality of life vs EXE alone in postmenopausal women with hormone-receptor positive (HR+), HER2-negative (HER2-) advanced breast cancer (BOLERO-2 phase III; NCT00863655). PFS benefit was seen in all clinically defined subgroups. We evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with EVE benefit. Methods: Exon sequence and gene copy number variations were analyzed in 182 cancer-related genes by next-generation sequencing (NGS). Correlations with PFS were evaluated using both univariate and multivariate Cox models. Results: NGS data (>250x coverage) were successfully generated from archival tumor specimens from 227 patients (NGS population, 157 and 70 in EVE+EXE and EXE arms, respectively) whose baseline characteristics and clinical outcome were comparable with the trial population (PFS HR = 0.40 and 0.45, respectively). The treatment benefit of EVE+EXE over EXE is maintained in the subgroups defined by each of the nine genes with a mutation rate >10% (eg, PIK3CA, FGFR1, and CCND1), or when less frequently mutated genes (eg, PTEN, AKT1) were included in their respective pathways. Patients with no or only 1 genetic alteration in PI3K or FGFR pathways, or CCND1, had a greater treatment effect from EVE (HR = 0.27, 95% CI 0.18-0.41, adjusted by covariates, in 76% of the NGS population), indicating the value of these pathways for predicting sensitivity/resistance to EVE in this setting. Conclusions: This is the first global registration trial in which efficacy-predictive biomarkers were explored by correlating broad genetic variations with clinical efficacy. It demonstrated the feasibility of applying large-scale NGS and subsequent correlative analysis to such trials. The observations suggest that a large subgroup of patients (76%), defined by minimal genetic variations in the PI3K or FGFR pathways, or CCND1, derives the most benefit from EVE therapy (HR = 0.27 vs 0.40 for the full NGS population). These exploratory results and their implication in understanding the interplay of multiple pathways in tumor cells and testing new hypotheses for targeted combination therapies in HR+/HER2- BC will be further investigated. Clinical trial information: NCT00863655.

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