Endocrine Treatment and Targeted Therapy for Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer: ASCO Guideline Update

Journal of Clinical Oncology, Journal Year: 2021, Volume and Issue: 39(35), P. 3959 - 3977

Published: July 29, 2021

PURPOSE To update recommendations of the ASCO systemic therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC) guideline. METHODS An Expert Panel conducted a systematic review to identify new, potentially practice-changing data. RESULTS Fifty-one articles met eligibility criteria and form evidentiary basis recommendations. RECOMMENDATIONS Alpelisib in combination with endocrine (ET) should be offered postmenopausal patients, male HR-positive, human epidermal growth factor 2 (HER2)-negative, PIK3CA-mutated, ABC, or MBC following prior without cyclin-dependent kinase (CDK) 4/6 inhibitor. Clinicians use next-generation sequencing tumor tissue cell-free DNA plasma detect PIK3CA mutations. If no mutation is found DNA, testing tissue, if available, used as this will small number additional patients There are insufficient data at present recommend routine ESR1 mutations guide HER2-negative MBC. For BRCA1 BRCA2 carriers cancer, olaparib talazoparib 1st-line through 3rd-line setting. A nonsteroidal aromatase inhibitor (AI) CDK4/6 women treatment-naïve HR-positive Fulvestrant progressive disease during treatment AIs (or who develop recurrence within 1 year adjuvant AI therapy) one line chemotherapy disease, first-line therapy. Treatment limited those exposure inhibitors Additional information can www.asco.org/breast-cancer-guidelines .

Language: Английский

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PIK3CA Mutations as a Molecular Target for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer

Frontiers in Oncology, Journal Year: 2021, Volume and Issue: 11

Published: March 25, 2021

Despite the significant achievements in diagnosis and treatment of metastatic breast cancer (MBC), this condition remains substantially an incurable disease. In recent years, several clinical studies have aimed to identify novel molecular targets, therapeutic strategies, predictive biomarkers improve outcome women with MBC. Overall, ~40% hormone receptor (HR)

Language: Английский

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Oral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Models

Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 30(16), P. 3549 - 3563

Published: May 31, 2024

Abstract Purpose: Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor 2 negative (HER2−) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become central strategy in the treatment ER+ advanced However, suboptimal ER inhibition and resistance resulting from ESR1 mutation dictates that new therapies are needed. Experimental Design: A medicinal chemistry campaign identified vepdegestrant (ARV-471), selective, orally bioavailable, potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader ER. We used biochemical intracellular target engagement assays to demonstrate mechanism action vepdegestrant, wild-type (WT) mutant preclinical cancer models degradation-mediated tumor (TGI). Results: Vepdegestrant induced ≥90% degradation ER, inhibited ER-dependent cell line proliferation vitro, achieved substantial TGI (87%–123%) MCF7 orthotopic xenograft models, better than those ET agent (31%–80% TGI). In hormone independent (HI) Y537S patient-derived (PDX) model ST941/HI, regression was similarly efficacious ST941/HI/PBR palbociclib-resistant (102% Vepdegestrant-induced robust regressions combination each CDK4/6 palbociclib, abemaciclib, ribociclib; mTOR inhibitor everolimus; alpelisib inavolisib. Conclusions: greater vivo compared fulvestrant, which correlated improved TGI, suggesting could be more effective backbone for patients ER+/HER2−

Language: Английский

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Targeting Autophagy in Breast Cancer

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(21), P. 7836 - 7836

Published: Oct. 22, 2020

Breast cancer is a heterogeneous disease consisting of different biological subtypes, with differences in terms incidence, response to diverse treatments, risk progression, and sites metastases. In the last years, several molecular targets have emerged new drugs, targeting PI3K/Akt/mTOR cyclinD/CDK/pRb pathways tumor microenvironment been integrated into clinical practice. However, it clear now that breast able develop resistance these drugs identification underlying mechanisms paramount drive further drug development. Autophagy highly conserved homeostatic process can be activated antineoplastic agents as cytoprotective mechanism. Inhibition autophagy could enhance cell death by anti-cancer therapies, representing an attractive approach control resistance. this manuscript, we present review focusing on its interplay targeted used for treatment.

Language: Английский

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CDK4/6 Inhibitors in HR+/HER2- Advanced/metastatic Breast Cancer: A Systematic Literature Review of Real-World Evidence Studies

Future Oncology, Journal Year: 2021, Volume and Issue: 17(16), P. 2107 - 2122

Published: March 5, 2021

Background: This review aims to qualitatively summarize the published real-world evidence (RWE) for CDK4/6 inhibitors (CDK4/6i) approved treating HR+, HER2-negative advanced/metastatic breast cancer (HR+/HER2- a/mBC). Materials & methods: A systematic literature was conducted identify RWE studies of CDK4/6i in HR+/HER2- a/mBC from 2015 2019. Results: identified 114 studies, which 85 were only presented at scientific conferences. Most investigated palbociclib and demonstrated improved outcomes. There are limited long-term comparative data between endocrine monotherapy, within class. Conclusion: Available suggests that associated with outcomes a/mBC, although additional longer follow-up periods needed.

Language: Английский

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Overall survival associated with CDK4/6 inhibitors in patients with HR+/HER2– metastatic breast cancer in the United States: A SEER‐Medicare population‐based study

Cancer, Journal Year: 2023, Volume and Issue: 129(7), P. 1051 - 1063

Published: Feb. 9, 2023

Evidence on overall survival (OS) with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors is generally limited to data from clinical trials or a few observational studies generalizability Medicare population. The aim of this study was determine OS benefits associated CDK4/6 in older patients hormone receptor (HR)-positive human epidermal growth factor receptor-2 overexpressing (HER2-) metastatic breast cancer (MBC).In retrospective cohort design, female aged ≥65 years diagnosis HR+/HER2- MBC 2015 2017 who initiated first-line systemic therapy within 12 months were selected the Survey Epidemiology End Results-Medicare database. effect treatment type (endocrine [ET]+CDK4/6 inhibitor vs. ET alone) analyzed using Kaplan-Meier methods multivariable Cox regression models. Adjusted hazard ratio (aHR) 95% CIs estimated.A total 630 eligible identified (169 treated ET+CDK4/6 461 alone). In analysis, rate at 3 after initiation 73.0% for versus 49.1% alone (log-rank p < .0001). 41% lower mortality (aHR, 0.590; CI, 0.423-0.823).The findings real-world demonstrate significant benefit over an population MBC, largely consistent evidence trials.

Language: Английский

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Autophagy and Breast Cancer: Connected in Growth, Progression, and Therapy

Cells, Journal Year: 2023, Volume and Issue: 12(8), P. 1156 - 1156

Published: April 14, 2023

Despite an increase in the incidence of breast cancer worldwide, overall prognosis has been consistently improving owing to development multiple targeted therapies and novel combination regimens including endocrine therapies, aromatase inhibitors, Her2-targeted cdk4/6 inhibitors. Immunotherapy is also being actively examined for some subtypes. This positive outlook marred by resistance or reduced efficacy drug combinations, but underlying mechanisms are somewhat unclear. It interesting note that cells quickly adapt evade most activating autophagy, a catabolic process designed recycle damaged cellular components provide energy. In this review, we discuss role autophagy autophagy-associated proteins growth, sensitivity, tumor dormancy, stemness, recurrence. We further explore how intersects reduces radiotherapy, chemotherapies as well immunotherapy via modulating various intermediate proteins, miRs, lncRNAs. Lastly, potential application inhibitors bioactive molecules improve anticancer effects drugs circumventing cytoprotective discussed.

Language: Английский

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The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance

Cancer Research, Journal Year: 2023, Volume and Issue: 83(23), P. 3989 - 4004

Published: Sept. 19, 2023

Abstract Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for receptor–positive (ER+) breast cancer, as they achieve greater inhibition ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated preclinical pharmacology efficacy next-generation oral SERD camizestrant (AZD9833) assessed ER–co-targeting strategies by combining with CDK4/6 inhibitors (CDK4/6i) PI3K/AKT/mTOR-targeted in models progression on CDK4/6i and/or ET. Camizestrant demonstrated robust ER degradation, modulated ER-regulated gene expression, induced complete antagonism significant antiproliferation activity ESR1 wild-type (ESR1wt) mutant (ESR1m) cancer cell lines patient-derived xenograft (PDX) models. also delivered strong antitumor fulvestrant-resistant ESR1wt ESR1m PDX Evaluation combination (palbociclib or abemaciclib) CDK4/6-naive -resistant models, well PI3Kαi (alpelisib), mTORi (everolimus), AKTi (capivasertib), indicated that was active PI3K/AKT/mTORi further increased triple combination. The response observed independently PI3K pathway mutation status. Overall, shows broad ER+ a monotherapy when combined PI3K/AKT/mTORi. Significance: Camizestrant, SERD, promise alone PI3K/AKT/mTOR to address resistance, barrier treatment.

Language: Английский

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Comparative analysis of adverse events associated with CDK4/6 inhibitors based on FDA’s adverse event reporting system: a case control pharmacovigilance study

BMC Pharmacology and Toxicology, Journal Year: 2024, Volume and Issue: 25(1)

Published: Aug. 9, 2024

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors marked a milestone in the breast cancer treatment. Due to potential impact of adverse effects on treatment decisions and patient outcomes, careful consideration varying toxicities CDK4/6 is crucial, as three inhibitors-palbociclib, abemaciclib, ribociclib-have been approved with differences event profiles. However, limitations clinical trials call for urgent real-world safety studies evaluate compare risk events (AEs) among these inhibitors. Therefore, this study aimed analyze AEs provide insights drug selection, using real world database.

Language: Английский

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Breast Cancer with Brain Metastasis: Molecular Insights and Clinical Management

Genes, Journal Year: 2023, Volume and Issue: 14(6), P. 1160 - 1160

Published: May 26, 2023

Breast cancer is the most frequently diagnosed malignancy worldwide and leading cause of cancer-related death among women. Brain metastases are a primary contributor to mortality, as they often go undetected until late stages due their dormant nature. Moreover, clinical management brain complicated by relevant issue blood-brain barrier penetration. The molecular pathways involved in formation, progression, colonization breast tumors subsequent diverse, posing significant hurdles heterogeneous nature subtypes. Despite advancements treatments, prognosis for patients with remains poor. In this review, we aim highlight biological mechanisms evaluating multi-step genetic discuss currently available emerging treatment strategies propose prospective overview complex disease.

Language: Английский

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