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Incorporating CDK4/6 Inhibitors in the Treatment of Advanced Luminal Breast Cancer.

ABSTRACT: After optimizing endocrine monotherapy modalities in the setting of advanced luminal breast cancer (BC), dual endocrine/targeted therapy combinations have been tested with positive results, and are transforming this BC subtype treatment landscape. Cell cycle deregulation is a hallmark of cancer that has become a key druggable target in hormone receptor (HR)-positive BC due to its role in endocrine resistance mechanisms. Cyclin dependent kinase (CDK)4/6 inhibitors have experienced a fast development in combination with endocrine therapy and have already been commercialized in some countries. In this review, we will summarize the development of these CDK4/6 inhibitors in luminal BC, from the preclinical data to the pivotal phase III trials that led to their approval, focusing on the efficacy and safety data for each of the treatment settings. Moreover, we will consider the challenges CDK4/6 inhibitors face in their positioning in the algorithm of treatment for advanced luminal BC and the considerations physicians should take into account when selecting these therapies for their patients. However, we are still in need of reliable predictive biomarkers in order to identify patients who will derive the greatest benefit from these drug combinations that are not exempt from toxicity.

SUBMITTER: Echavarria I

PROVIDER: S-EPMC5704690 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Incorporating CDK4/6 Inhibitors in the Treatment of Advanced Luminal Breast Cancer.

Echavarria Isabel I Jerez Yolanda Y Martin Miguel M López-Tarruella Sara S

Breast care (Basel, Switzerland) 20171019 5

After optimizing endocrine monotherapy modalities in the setting of advanced luminal breast cancer (BC), dual endocrine/targeted therapy combinations have been tested with positive results, and are transforming this BC subtype treatment landscape. Cell cycle deregulation is a hallmark of cancer that has become a key druggable target in hormone receptor (HR)-positive BC due to its role in endocrine resistance mechanisms. Cyclin dependent kinase (CDK)4/6 inhibitors have experienced a fast developm ...[more]

PMID: 29234248

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Project description:BackgroundRecent evidence indicates that a dysregulated host metabolism influences treatment outcomes in patients with breast cancer. We investigated the association of computed tomography (CT)-derived body composition indices with therapeutic responses in patients with hormone receptor-positive, HER2-negative advanced breast cancer (ABC) on endocrine plus CDK4/6 inhibitor (CDK4/6i) treatment.MethodsThe study involved a retrospective cohort of patients with ABC at the Yonsei Cancer Center who received CDK4/6i and aromatase inhibitors as first-line therapy between January 2017 and October 2020. Body composition parameters were estimated from the non-enhanced CT images of the third lumbar spine by commercialized deep learning software. Patients with low skeletal muscle radiodensity (SMD) were defined as patients with SMD of low tertile (≤ 28.7 Hounsfield Units). The primary outcome was progression-free survival (PFS).ResultsAmong the 247 female participants (median age, 53 years; mean body mass index [BMI], 23.7 kg/m2), 45.7% had disease progression or death during a median follow-up of 36.4 months. After adjusting for age and visceral metastasis, SMD was the only independent predictor among body composition parameters for worse PFS (adjusted hazard ratio [HR] = 1.20 per standard deviation decrement, 95% CI: 1.01-1.42, p = 0.041), whereas BMI, muscle area, and fat area were not. Participants with low SMD had a higher risk of progression than those without (PFS, 27.2 vs. 51.1 months, p = 0.009; adjusted HR 1.84, 95% CI: 1.22-2.76, p = 0.003). Strong associations between low SMD and poor PFS were observed in groups with pre-menopause status (HR, 3.04 vs. 1.19 in post-menopause; 95% CI: 1.54-5.99, p for interaction < 0.05) and without visceral metastases (HR, 2.95 vs. 1.19 in with visceral metastases; 95% CI: 1.59-5.49, p for interaction < 0.05).ConclusionsCT-defined low SMD predicts poor treatment outcomes in patients with ABC undergoing first-line treatment with aromatase inhibitors and CDK4/6i.

Project description:PurposeCDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy are considered standard-of-care for first-line therapy of patients with hormone receptor positive, HER2 negative, advanced breast cancer (HR+/HER2- ABC). Superiority of combination therapy over endocrine monotherapy has been demonstrated in a multitude of randomized controlled trials (RCTs) in phase III and IV. However, RCTs reflect clinical reality only to a limited extent, as narrow inclusion criteria lead to a selected patient collective. Here, we present real-world data (RWD) on CDK4/6i treatment in patients with HR+/HER2- ABC at four certified German university breast cancer centers.MethodsPatients diagnosed with HR+/HER2- ABC who were treated in clinical routine with CDK4/6i between November 2016 and December 2020 at four certified German university breast cancer centers (Saarland University Medical Center, University Medical Center Charité Berlin, University Medical Center Bonn, and University Medical Center Hospital Schleswig-Holstein, Campus Kiel) were identified and enrolled in this retrospective study. Clinicopathological characteristics and clinical outcomes were recorded with particular emphasis on CDK4/6i therapy course [progression-free survival (PFS) following treatment initiation, toxicity, dose reduction, therapy discontinuation, prior and subsequent therapy line].ResultsData from n = 448 patients were evaluated. The mean patient age was 63 (±12) years. Of these patients, n = 165 (36.8%) were primarily metastasized, and n = 283 (63.2%) had secondary metastatic disease. N = 319 patients (71.3%) received palbociclib, n = 114 patients (25.4%) received ribociclib, and n = 15 patients (3.3%) received abemaciclib, respectively. Dose reduction was performed in n = 132 cases (29.5%). N = 57 patients (12.7%) discontinued the treatment with CDK4/6i due to side effects. N = 196 patients (43.8%) experienced disease progression under CDK4/6i treatment. The median PFS was 17 months. Presence of hepatic metastases and prior therapy lines were associated with shorter PFS, whereas estrogen positivity and dose reduction due to toxicity were positively associated with PFS. Presence of bone and lung metastases, progesterone positivity, Ki67 index, grading, BRCA1/2 and PIK3CA mutation status, adjuvant endocrine resistance, and age did not significantly impact on PFS.ConclusionOur RWD analysis on CDK4/6i treatment in Germany supports data from RCTs regarding both treatment efficacy and safety of CDK4/6i for treatment of patients with HR+/HER2- ABC. In comparison to data from the pivotal RCTs, median PFS was lower but within the expected range for RWD, which could result from inclusion of patients with more advanced diseases (i.e., higher therapy lines) to our dataset.

Dataset Information

Incorporating CDK4/6 Inhibitors in the Treatment of Advanced Luminal Breast Cancer.

Publications

Incorporating CDK4/6 Inhibitors in the Treatment of Advanced Luminal Breast Cancer.

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