Use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in older patients with ER-positive HER2-negative breast cancer: Young International Society of Geriatric Oncology review paper

Abstract

The current standard of care for the management of estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer has been redefined by the introduction of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Although adults aged 65 years and older account for the majority of patients with breast cancer, limited data are available about the age-specific dosing, tolerability, and benefit of CDK4/6 inhibitors in this growing population. Older adults are under-represented in clinical trials and as a result, clinicians are forced to extrapolate from findings in younger and healthier patients when making treatment decisions for older patients. In this article, we review the limited age-specific evidence on the efficacy, toxicity, and quality of life (QoL) outcomes associated with the use of CDK4/6 inhibitors in older adults. We also describe ongoing trials evaluating CDK4/6 inhibitors in the older population and highlight that only a minority of adjuvant and metastatic trials of CDK4/6 inhibitors in the general breast cancer population includes geriatric assessments. Finally, we propose potential strategies to help guide decision making for fit and unfit older patients based on disease endocrine sensitivity, the need for rapid response and geriatric assessment.

Safety and efficacy of abemaciclib plus endocrine therapy in older patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: an age-specific subgroup analysis of MONARCH 2 and 3 trials

“…More recently, the use of geriatric assessments in clinical trials enrolling older patients as standard practice has been suggested [21,22]. The relevance of comprehensive geriatric assessments to guide CDK4 and 6 inhibitor treatment plans in older patients with breast cancer has also been noted [2]. There are also some limitations due to study differences: MONARCH 2 enrolled a more pretreated study population [16], and each study incorporated different ETs.…”

“…Subjects enrolled in clinical trials may not be representative of the general population seen in clinical practice [ 5 ]. This is particularly true in the case of older patient populations, where narrow eligibility criteria often exclude all but the healthiest older patients [ 2 ]. MONARCH 2 and 3 studies were designed to explore safety in a broad age population; thus, the protocols did not include a comprehensive geriatric assessment for older patients.…”

“…More recently, the use of geriatric assessments in clinical trials enrolling older patients as standard practice has been suggested [ 21 , 22 ]. The relevance of comprehensive geriatric assessments to guide CDK4 and 6 inhibitor treatment plans in older patients with breast cancer has also been noted [ 2 ].…”

“…Breast cancer is the leading cancer diagnosis in women, and a significant proportion of these patients are 65 years of age or older [ 1 , 2 ]. In the United States from 2013 to 2017, the ≥65 age group accounted for almost 45% of all new breast cancer diagnoses (age 65–74, 25.5%; 75–84, 13.6%; >84, 5.4%) and two-thirds of breast cancer deaths (age 65–74, 23.4%; 75–84, 19.7%; >84, 17.2%) [ 3 ].…”

“…Specifically, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) breast cancer subtype has the highest incidence rate per 100,000 across age groups [ 4 ], and the majority of HR+, HER2− subtypes occur in older women [ 5 ]. Older patients tend to have a higher incidence of comorbidities, including vascular, gastrointestinal, metabolic, nutritional, and renal disorders, and increased risk for treatment-related toxicities like gastrointestinal and renal toxicities, which has relevance for quality of life [ 2 , 6 , 7 ]. The underrepresentation of older patients in clinical trials may reflect lower enrollment due to perceived risk increase for treatment-related adverse events (TEAEs), and/or limitations placed on eligibility due to comorbidities or prior concomitant medications and potential for drug–drug interactions [ 8 ].…”