bims-cyhorp 2022-10-23 papers

Issue of 2022–10–23
four papers selected by
Piotr Okupski,

Crit Rev Oncol Hematol. 2022 Oct 15. pii: S1040-8428(22)00272-4. [Epub ahead of print] 103848

Optimizing CDK4/6 inhibitors in advanced HR+/HER2- breast cancer: a personalized approach.

Caterina Fontanella, Carlo Alberto Giorgi, Stefania Russo, Silvia Angelini, Linda Nicolardi, Tommaso Giarratano, Simona Frezzini, Marta Pestrin, Dario Palleschi, Silvia Bolzonello, Veronica Parolin, Eva R Haspinger, Costanza De Rossi, Filippo Greco, Lorenzo Gerratana.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are now a backbone of treatment for hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. CDK4/6i plus ET is more effective than ET alone in this setting; however, the risk of grade 3-4 adverse events also increases. Approved agents in this class have similar efficacies, but important differences due to their structural and pharmacological properties. We review biomarkers and discuss determinants to inform a rational approach to therapy choice when selecting the most appropriate ET and CDK4/6i partners. We also identify subgroups that may benefit from specific ET-CDK4/6i combinations and discuss strategies to overcome resistance. This personalized approach aims to minimize treatment-related toxicities that may affect patient QoL and compliance, and ultimately therapy efficacy.

Keywords: CDK4/6 inhibitor; HR-positive/HER2-negative; advanced breast cancer; biomarkers; personalized medicine

DOI: https://doi.org/10.1016/j.critrevonc.2022.103848

Support Care Cancer. 2022 Oct 19.

Risk factors associated with palbociclib-induced neutropenia in patients with metastatic breast cancer.

Lesli Lavery, Kristyn DiSogra, Julia Lea, Sally J Trufan, James T Symanowski, Ashley Roberts, Donald C Moore, Arielle Heeke, Sridhar Pal.

BACKGROUND: Neutropenia is the most common adverse event with palbociclib, an oral cyclin-dependent kinase 4/6 inhibitor, with grade 3/4 neutropenia occurring in up to 67% of patients in phase III trials evaluating this agent in metastatic breast cancer. This retrospective chart review assessed characteristics of patients on palbociclib to evaluate for risk factors in the development of grade 3/4 neutropenia.
PATIENTS AND METHODS: Patients with metastatic breast cancer who received palbociclib were included. Patient demographics collected included age, gender, race, body mass index, breast cancer treatment history, palbociclib starting dose, baseline absolute neutrophil count, baseline platelet count, concomitant hormonal therapy, concomitant use of denosumab, and use of concomitant strong CYP3A4 inhibitors/inducers. Events of interest occurring within 30 days of initiation of palbociclib were also noted including antibiotic and corticosteroid use, mucosal conditions, open wounds, or surgery. The incidence and potential risk factors for grade 3/4 neutropenia in the first 6 months of treatment were analyzed.
RESULTS: A total of 257 patients were included in the analysis with 206 patients (80.2%) and 139 patients (54.1%) experiencing all-grade neutropenia and grade 3/4 neutropenia, respectively. Multivariate analysis found baseline myelosuppression and recent antibiotic use to be independent predictors of grade 3/4 neutropenia. Normal weight patients had an increased risk for grade 3/4 neutropenia compared to obese patients by multivariate analysis.
CONCLUSION: The results of this study showed baseline myelosuppression and recent antibiotic use within 30 days of palbociclib initiation were predictive of a higher incidence of grade 3/4 neutropenia. Obese patients were less likely to develop grade 3/4 neutropenia compared to normal weight patients.

Keywords: Breast cancer; CDK4/6 inhibitor; Neutropenia; Palbociclib

DOI: https://doi.org/10.1007/s00520-022-07400-z

Cancer Chemother Pharmacol. 2022 Oct 22.

Starting dose selection of palbociclib in Chinese patients with breast cancer based on population kinetic-pharmacodynamic model of neutropenia.

Weizhe Jian, Junsheng Xue, Qingyu Yao, Rong Chen, Ye Yao, Mopei Wang, Tianyan Zhou.

Neutropenia is the most common adverse event (AE) of palbociclib, an oral CDK4/6 inhibitor for breast cancer. Neutropenia increases the risk of infection and is even life threatening. Asian patients generally suffer more severe neutropenia from palbociclib treatment, but the label does not recommend a reduction in the starting dose for Asian patients. Therefore, the study aimed to explore the exposure-response (E-R) relationship in Chinese patients and preliminarily generate a scale for starting dose selection of palbociclib in Chinese patients. After comparing the kinetic-pharmacodynamic (K-PD) and the pharmacokinetic/pharmacodynamic (PK/PD) model, a semi-mechanistic K-PD model was selected and developed on the basis of real-world data from 28 patients with breast cancer to describe the time course of longitudinal absolute neutrophil counts (ANC). The longitudinal ANC data were well described by the population K-PD model with reasonable parameters: mean transit time (MTT) of 198 h, feedback parameter (γ) of 0.317, baseline ANC level (Circ0) of 3.36 × 109 L-1, drug effect coefficient (kd) of 0.0349, and drug effect power (β) of 0.383. No covariate was included in the final model. The model showed that palbociclib dose-dependently reduced ANC levels in a Chinese population, and lower baseline ANC level was associated with more severe neutropenia. The dose selection scale suggested that palbociclib 125 mg daily was appropriate for Chinese patients with Circ0 higher than 3.75 × 109 L-1. In summary, the K-PD model of palbociclib well described the longitudinal ANC in Chinese patients. Besides, the starting dose selection scale may provide reference for clinicians during individualized therapy.

Keywords: Model-based simulation; Neutropenia; Palbociclib; Population kinetic–pharmacodynamic model

DOI: https://doi.org/10.1007/s00280-022-04484-6

Breast Cancer (Dove Med Press). 2022 ;14 351-362

Ribociclib Plus Letrozole in Italian Male Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Case Studies of Phase 3b CompLEEment-1 Trial.

Roberta Caputo, Alessandra Fabi, Emanuela Romagnoli, Editta Baldini, Donatella Grasso, Nicola Fenderico, Andrea Michelotti.

Abstract: Male breast cancer (BC) is rare, globally constituting only 0.5-1% of all patients with BC. In Italy, more than 2000 new male BC cases were registered between 2000 and 2014. The survival rate was lower in males than in females. Delayed diagnosis may be the reason for poorer outcome observed in male BC patients compared with female patients. Due to lack of substantial evidence and low availability of published data on male BC, the current treatment recommendations are based on evidence derived from trials on female patients. In Italy, most of the male BC patients are estrogen and progesterone receptor-positive. Targeted therapy in combination with endocrine therapy provides a clinically meaningful outcome in patients with hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) advanced BC. CompLEEment-1 is a single-arm, open-label, multicenter, phase 3b trial investigating the safety and efficacy of a CDK4/6 inhibitor, ribociclib, in combination with letrozole in men and women. Herein, we report the results from a retrospective analysis of five Italian male patients who completed the core phase. In this case series, the combination of ribociclib and letrozole was well tolerated and appeared to be effective in the male cohort with HR-positive, HER2-negative advanced BC in Italy. CompLEEment-1 trial representative of a real-world setting would add value by supporting the existing efficacy and safety profile of ribociclib in combination with letrozole in male patients with HR-positive, HER2-negative advanced BC.
ClinicalTrialsgov Registration Number: NCT02941926.

Keywords: CDK4/6 inhibitor; case report; male breast cancer; progression-free survival; targeted therapy

DOI: https://doi.org/10.2147/BCTT.S376902