CDK4/6 Inhibition - Therapy Sequences and the Quest to Find the Best Biomarkers - an Overview of Current Programs

Abstract

In recent years, new targeted therapies have been developed to treat patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer. Some of these therapies have not just become the new therapy standard but also led to significantly longer overall survival rates. The cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the therapeutic standard for first-line therapy. Around 70 - 80% of patients are treated with a CDK4/6i. In recent years, a number of biomarkers associated with progression, clonal selection or evolution have been reported for CDK4/6i and their endocrine combination partners. Understanding the mechanisms behind treatment efficacy and resistance is important. A better understanding could contribute to planning the most effective therapeutic sequences and utilizing basic molecular information to overcome endocrine resistance. One study with large numbers of patients which aims to elucidate these mechanisms is the Comprehensive Analysis of sPatial, TempORal and molecular patterns of ribociclib efficacy and resistance in advanced Breast Cancer patients (CAPTOR BC) trial. This overview summarizes the latest clinical research on resistance to endocrine therapies, focusing on CDK4/6 inhibitors and discussing current study concepts.

Keywords: CDK4/6; breast cancer; therapy.

Fig. 1

Concentrations of palbociclib required to inhibit 50% of cell growth .

Fig. 2

Use of different therapeutic options as first-line therapy in patients with advanced HR+/HER2− breast cancer .

Fig. 3

Treatment algorithm of the Breast Commission of the AGO outlining sequential therapies for patients with HR+/HER2− breast cancer in an advanced therapy setting.

Fig. 4

Possible course and clinical application of ctDNA analysis.

Fig. 5

Progression-free survival (PFS) in the BioItaLEE trial depending on changes in ctDNA between the start of therapy (BL) and 15 days after the start of therapy (D15) . Mut = mutated, WT = wildtype.

Fig. 6

Progression-free survival in the BioItaLEE trial depending on the changes in serum thymidine kinase activity under therapy with ribociclib . HR = hazard ratio, mPFS = median progression-free survival, sTKa = serum thymidine kinase activity

Fig. 7

Effect of ESR1 mutation on the function of the estrogen receptor (Creative Commons Licence 4.0, 59 ). LBD: ligand-binding domain, AF-2: activating factor-2 domain, DBD: DNA-binding domain, AF-1: activating factor 1 domain, E2: estradiol, SERM: selective estrogen receptor modulator, SERD: selective estrogen receptor degrader, WT: wildtype, MUT: mutated (Source: Brett JO, Spring LM, Bardia A et al. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res 2021; 23: 85. doi:10.1186/s13058-021-01462-3.) © 2021. The Author(s). Licensed under a Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ). Changes: Addition of explanations for WT and MUT in the image.

Fig. 8

Study design of the CAPTOR BC trial and planned molecular analyses. ET = endocrine therapy, FFPE = formalin-fixed, paraffin-embedded tissues, HR = homologous recombination, OS = overall survival, PFS = progression-free survival, SNP = single-nucleotide polymorphism

Fig. 9

Technical procedure used for molecular characterization in the CATCH program.

Fig. 10

Therapy allocation based on molecular characteristics in the CATCH program.

Abb. 1

Konzentrationen von Palbociclib, die notwendig waren, um 50% des Zellwachstums zu hemmen .

Abb. 2

Nutzung der verschiedenen Therapieoptionen in der ersten Therapielinien bei Patientinnen mit fortgeschrittenem HRpos/HER2neg Mammakarzinom .

Abb. 3

Therapiealgorithmus der Kommission Mamma der AGO e. V. für die Sequenztherapie von Patientinnen in der fortgeschrittenen Therapiesituation mit HRpos/HER2neg Mammakarzinom.

Abb. 4

Möglicher Ablauf und klinische Anwendungen einer ctDNA-Analyse.

Abb. 5

Progressionsfreies Überleben (PFÜ) in der BioItaLEE-Studie in Abhängigkeit von ctDNA-Veränderungen zwischen Therapiebeginn (BT) und 15 Tage nach Therapiestart (D15) . MUT = mutiert, WT = Wildtyp.

Abb. 6

Progressionsfreies Überleben in der BioItaLEE-Studie in Abhängigkeit vom Verlauf der Serum-Thymidinkinase-Aktivität unter einer Therapie mit Ribociclib . HR = Hazard Ratio, mPFÜ = medianes progressionsfreies Überleben, sTKa = Thymidinkinase-Aktivität im Serum.

Abb. 7

Effekt einer ESR1 -Mutation auf die Funktionsweise des Östrogenrezeptors (unter Creative Commons Lizenz 4.0, 59 ). LBD: ligandenbindende Domäne, AF-2: Activating Factor-2 Domäne, DBD: DNA-bindende Domäne, AF-1: Activating Factor 1-Domäne, E2: Östradiol, SERM: selektiver Östrogenrezeptor-Modulator, SERD: selektiver Östrogenrezeptor-Degradierer, WT: Wildtyp, MUT: mutiert (Quelle: Brett JO, Spring LM, Bardia A et al. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res 2021; 23: 85. doi:10.1186/s13058-021-01462-3 . © 2021. The Author(s). Licensed under a Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ). Changes: Addition of explanations for WT and MUT in the image.

Abb. 8

Studiendesign der CAPTOR BC-Studie und geplante molekulare Analysen. ET = endokrine Therapie, FFPE = formalin-fixiertes Paraffin-eingebettetes Gewebe, HR = homologe Rekombination, OS = Gesamtüberleben, PFS = progressionsfreies Überleben, SNP = Einzelnukleotid-Polymorphismus.

Abb. 9

Technischer Ablauf der molekularen Charakterisierung im Rahmen des CATCH-Programms.

Abb. 10

Therapiezuordnung anhand molekularer Charakteristika im Rahmen des CATCH-Programms.