scholarly journals Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

2020 ◽  
Vol 21 (18) ◽  
pp. 6479 ◽  
Author(s):  
Michela Piezzo ◽  
Stefania Cocco ◽  
Roberta Caputo ◽  
Daniela Cianniello ◽  
Germira Di Gioia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Clinical Outcomes ◽  
Cell Cycle Control ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
New Combination ◽  
Hormone Receptor Positive ◽  
Combination Strategies ◽  
New Biomarkers

Deregulation of cell cycle, via cyclin D/CDK/pRb pathway, is frequently observed in breast cancer lending support to the development of drugs targeting the cell cycle control machinery, like the inhibitors of the cycline-dependent kinases (CDK) 4 and 6. Up to now, three CDK4/6 inhibitors have been approved by FDA for the treatment of hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. These agents have been effective in improving the clinical outcomes, but the development of intrinsic or acquired resistance can limit the efficacy of these treatments. Clinical and translational research is now focused on investigation of the mechanism of sensitivity/resistance to CDK4/6 inhibition and novel therapeutic strategies aimed to improve clinical outcomes. This review summarizes the available knowledge regarding CDK4/6 inhibitor, the discovery of new biomarkers of response, and the biological rationale for new combination strategies of treatment.

scholarly journals The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer

2019 ◽  
Author(s):  
Seth A. Wander ◽  
Ofir Cohen ◽  
Xueqian Gong ◽  
Gabriela N. Johnson ◽  
Jorge Buendia-Buendia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
Resistance Mechanisms ◽  
Akt Activation ◽  
Hormone Receptor Positive ◽  
Ras Activation ◽  
Whole Exome ◽  
Clinical Resistance

AbstractClinical resistance mechanisms to CDK4/6 inhibitors in HR+ breast cancer have not been clearly defined. Whole exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of ER expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Besides inactivation of RB1, which accounts for ∼5% of resistance, seven of these mechanisms have not been previously identified as clinical mediators of resistance to CDK4/6 inhibitors in patients. Three of these—RAS activation, AKT activation, and AURKA activation—have not to our knowledge been previously demonstrated preclinically. Together, these eight mechanisms were present in 80% of resistant tumors profiled and may define therapeutic opportunities in patients.SignificanceWe identified eight distinct mechanisms of resistance to CDK4/6 inhibitors present in 80% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ MBC.

Polymorphisms in XRCC1, XRCC3, and CCND1 and Survival After Treatment for Metastatic Breast Cancer

2006 ◽  
Vol 24 (36) ◽  
pp. 5645-5651 ◽  
Author(s):  
Mary A. Bewick ◽  
Michael S.C. Conlon ◽  
Robert M. Lafrenie
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Dna Repair ◽  
Metastatic Breast Cancer ◽  
Bone Metastases ◽  
Cell Cycle Control ◽  
Multivariable Analysis ◽  
Metastatic Breast ◽  
High Dose ◽  
Cancer Specific Survival

Purpose Single nucleotide polymorphisms (SNPs) in DNA repair and cell cycle control genes may alter protein function and therefore the efficacy of DNA damaging chemotherapy. We retrospectively evaluated the association of SNPs in DNA repair genes, XRCC1-01 (Arg399Gln) and XRCC3-01 (Thr241Met), and a cell cycle control gene, CCND1-02 (A870G), with progression-free survival (PFS) and breast cancer specific survival (BCSS) in patients with metastatic breast cancer (MBC). Patients and Methods SNPs in 95 patients with MBC enrolled onto one of five prospective clinical trials of high-dose chemotherapy and autologous stem-cell transplantation were evaluated using genotyping assays. Results For XRCC1-01, the hazard ratio (HR) for BCSS was 2.8 (95% CI, 1.60 to 5.00) and the HR for PFS was 2.0 (95%CI, 1.12 to 3.43). For XRCC3-01, the HR for BCSS was 2.0 (95%CI, 1.12 to 3.70) and the HR for PFS was 2.0 (95%CI, 1.09 to 3.59). For CCND1-02, the HR for BCSS was 1.8 (95%CI, 1.12 to 2.78) and the HR for PFS was 1.8 (95%CI, 1.15 to 2.85). Patients carrying one variant genotype (HR, 1.7; 95%CI, 1.07 to 2.82) or combinations of any two variant genotypes (HR, 4.7; 95% CI, 2.41 to 8.94) had significantly poorer BCSS compared with patients carrying zero variants. In multivariable analysis, XRCC1-01, presence of liver metastases, and bone metastases independently predicted BCSS. Combinations of any two variant genotypes were stronger independent predictors of BCSS and PFS than the presence of liver or bone metastases. Conclusion XRCC1-01, XRCC3-01, and CCND1-01 may be predictive of survival outcome in patients with MBC treated with DNA damaging chemotherapy.

EPR19-73: Risk of Gastrointestinal and Hepatic Toxicities in Patients With Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer Treated With CDK4/6 Inhibitors

2019 ◽  
Vol 17 (3.5) ◽  
pp. EPR19-73
Author(s):  
Anita Sultan ◽  
Sriman Swarup ◽  
Somedeb Ball ◽  
Miguel Quirch ◽  
Meily Arevalo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Side Effects ◽  
Cell Cycle Progression ◽  
Meta Analysis ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Hormone Receptor Positive ◽  
Genes Encoding ◽  
Grade 3

Background: CDK4 and CDK6 are cyclin-dependent kinases that control transition between G1 and S phases of the cell cycle, hence controlling cell cycle progression by reversible combination with cyclin D1. In cancer cell, CDK4/6 activity is overexpressed, which can lead to amplification or overexpression of the genes encoding for CDK 4/6 or the cyclin D. Additionally, loss of endogenous INK4 inhibitors can also lead to over activity of CDK4 and CDK6. We undertook a meta-analysis of randomized controlled trials (RCT) to determine the risk of gastrointestinal (GI) and hepatic toxicities associated with CDK 4/6 inhibitors. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts from inception through September 2018. In our analysis, we incorporated RCTs that mention GI toxicities and elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) as adverse effects. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% CI. Random effects model was applied. Results: A total of 4,557 patients with advanced breast cancer from 7 phase III and 1 phase II RCTs were eligible. The study arms used were palbociclib/ribociclib/abemaciclib or placebo in combination with letrozole or anastrozole or fulvestrant or other hormonal agents. The RR of all-grade side effects were as follows: diarrhea, 1.691 (95% CI: 1.220–2.345; P=.002); nausea, 1.632 (95% CI: 1.447–1.840; P<.001); vomiting, 1.684 (95% CI: 1.256–2.259, P=.001); stomatitis, 2.160 (95% CI: 1.332–3.503; P=.002); elevated AST, 1.832 (95% CI: 1.312–2.558; P<.001); and elevated ALT, 2.150 (95% CI: 1.649–2.803; P<.001). The RR of high-grade side effects were as follows: diarrhea, 2.592 (95% CI: 0.853–7.877; P=.093); nausea, 1.326 (95% CI: 0.589–2.988; P=.496); vomiting, 1.089 (95% CI: 0.479–2.476; P=.839); stomatitis, 2.097 (95% CI: 0.502–0.753; P=.310); elevated AST, 2.274 (95% CI: 1.173–4.410; P=.015); and elevated ALT, 3.988 (95% CI: 2.387–6.663; P<.001). Conclusions: Our study demonstrated that the risk of developing all grade GI toxicities and all grades of hepatic side effects including grade 3 and 4, was high in CDK 4/6 inhibitors group, compared to control arm, and prompt intervention with good supportive care is required.

Real world clinical outcomes of palbociclib in hormone receptor positive (HR+) metastatic breast cancer (MBC) patients.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e13034-e13034 ◽  
Author(s):  
Akaolisa Samuel Eziokwu ◽  
Leticia Varella ◽  
Megan Lynn Kruse ◽  
Xuefei Jia ◽  
Halle C. F. Moore ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Clinical Outcomes ◽  
Real World ◽  
Hormone Receptor ◽  
Metastatic Breast ◽  
Hormone Receptor Positive

Treatment Algorithms for Hormone Receptor-Positive Advanced Breast Cancer: Applying the Results from Recent Clinical Trials into Daily Practice—Insights, Limitations, and Moving Forward

2013 ◽  
pp. e20-e27
Author(s):  
Sheridan Wilson ◽  
Stephen K. Chia
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Acquired Resistance ◽  
Mammalian Target Of Rapamycin ◽  
Real Life ◽  
Metastatic Breast ◽  
Predictive Biomarkers ◽  
Endocrine Treatment ◽  
First Line ◽  
Hormone Receptor Positive

Hormone receptor–positive (HR+) breast cancer is the most prevalent subtype of breast cancer in both early- and advanced-stage disease. Thus, the treatment of HR+ breast cancer has had the greatest global influence in improving clinical outcomes overall. Although the first-line metastatic breast cancer (MBC) trials comparing a third-generation aromatase inhibitor (AI) to tamoxifen have favored the AI, one of the challenges in translating these findings into clinical practice stems from the influence of prior adjuvant endocrine therapy, particularly the increasing use of adjuvant AIs today, on the choice of endocrine agent in the advanced setting because of the development of acquired resistance. Because the majority of patients enrolled into these studies were either endocrine-treatment naïve or exposed to tamoxifen only, the “real-life” applicability of the evidence is unclear. Because a superior dose of the selective estrogen receptor (ER) downregulator fulvestrant has now been established, its role as first-line therapy is being re-established. We are now starting to see the promise realized with blocking cross-talking growth factor pathways in addition to the ER pathway. The greatest efficacy is seen with the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with exemestane and, perhaps to a lesser extent, anti-HER2–directed therapy in combination with an AI. Future gains will likely involve a greater understanding of the redundancy and compensation induced by blocking these pathways, trials involving blocking multiple pathways in addition to hormonal agents, and the molecular interrogation of the individual's tumor in search of predictive biomarkers and “actionable” genomic aberrations.

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