bims-cyhorp 2022-01-09 papers

Issue of 2022‒01‒09
five papers selected by
Piotr Okupski

Breast Cancer Res Treat. 2022 Jan 07.

Barriers and facilitators to taking CDK4/6 inhibitors among patients with metastatic breast cancer: a qualitative study.

Claire C Conley, McKenzie McIntyre, Nicole A Pensak, Filipa Lynce, Deena Graham, Roohi Ismail-Khan, Katherine Lopez, Susan T Vadaparampil, Suzanne C O'Neill.

PURPOSE: Most studies of adherence to treatment for breast cancer have focused on early-stage patients. Findings from these studies may not generalize to patients with metastatic breast cancer (MBC). The objective of this study was to identify barriers and facilitators of adherence to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors among patients with MBC, guided by the social ecologic model (SEM).METHODS: Patients with MBC (N = 25), their caregivers (N = 9), and oncology providers (N = 13) completed semi-structured qualitative interviews exploring their experiences with CDK4/6 inhibitors. Interviews were audio-recorded, transcribed verbatim, and analyzed by three raters using a combined deductive and inductive approach.
RESULTS: Qualitative analysis identified barriers and facilitators of adherence at each SEM level. Intrapersonal and interpersonal factors were most frequently discussed. Intrapersonal factors included knowledge/beliefs about CDK4/6 inhibitors, side effects, and establishing a routine. Interpersonal factors included effective communication with/coordination by the care team, support from family and friends, and information from other patients with MBC. Although less frequently discussed, policy factors (i.e., cost of CDK4/6 inhibitors) were of great concern to patients, caregivers, and providers.
CONCLUSION: Barriers to adherence to CDK4/6 inhibitors exist at multiple levels. Our results underscore the potential value of a multilevel intervention (e.g., patient education, evidence-based strategies for symptom management, tips for open and assertive communication with providers, information about financial resources/support available, and so on) to support adherence in this population.

Keywords: Breast cancer; CDK4/6 inhibitors; Medication adherence; Metastatic breast cancer; Oral medication; Social ecologic model

DOI: https://doi.org/10.1007/s10549-022-06518-2

Can J Hosp Pharm. 2022 ;75(1): 26-33

Effectiveness and Safety of Palbociclib plus Endocrine Therapy in Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: Real-World Results.

Cristina Fernández-Cuerva, Juan Carlos Del Rio Valencia, Rocio Tamayo Bermejo.

Background: Real-world data are critical to demonstrate the reproducibility of evidence and the external generalizability of randomized clinical trials. Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4/6 that has been shown to improve progression-free survival when combined with letrozole or fulvestrant in phase 3 clinical trials.Objective: To evaluate real-world outcomes in patients with metastatic breast cancer who received palbociclib in combination with endocrine therapy in routine clinical practice.
Methods: In this retrospective observational multicentre study, data were evaluated for all women with metastatic breast cancer who were treated with palbociclib from April 2017 to September 2019. Treatment response was assessed through progression-free survival according to the Response Evaluation Criteria in Solid Tumors, version 1.1.
Results: Fifty-three patients were included in the study, with median age 57 years (range 31-87 years). For all patients treated with palbociclib, median progression-free survival by the end of the study period was 14.4 months (95% confidence interval [CI] 6.2-22.2 months). Twenty-three women who received palbociclib as a first-line treatment did not experience progression-free survival; for these patients, the median treatment duration was 12.1 months (95% CI 1.4-28.0 months). For the 23 patients who received palbociclib as second-line therapy for metastatic breast cancer, median progression-free survival was 13.3 months (95% CI 4.1-22.4 months). Among the 7 women who received palbociclib as third-line therapy, median progression-free survival was 6.0 months (95% CI 0.9-11.1 months). The most common adverse events were hematologic, with grade 3 or 4 neutropenia occurring in 20 (38%) of the 53 patients.
Conclusions: This study provides data from a real-world setting that match the results of previous studies in terms of effectiveness (i.e., progression-free survival) when palbociclib plus endocrine therapy was used as second- or third-line treatment. Palbociclib had appropriate tolerability and a profile of easily manageable adverse effects, with none of the patients suspending their treatment because of toxic effects.

Keywords: cancer du sein métastatique; cyclin-dependent kinase inhibitor; fulvestrant; inhibiteur des kinases dépendantes des cyclines; letrozole; létrozole; metastatic breast cancer; palbociclib

DOI: https://doi.org/10.4212/cjhp.v75i1.3252

J Clin Oncol. 2022 Jan 07. JCO2101918

Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib With Adjuvant Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03).

PURPOSE: The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS.METHODS: Patients with stage II-III HR+, HER2- disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS.
RESULTS: Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non-protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11).
CONCLUSION: Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.

DOI: https://doi.org/10.1200/JCO.21.01918

MedComm (2020). 2021 Dec;2(4): 514-530

CDK4/6 inhibitors: A potential therapeutic approach for triple negative breast cancer.

Lubaid Saleh, Caroline Wilson, Ingunn Holen.

Triple negative breast cancer (TNBC) cells lack expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2). Thus, TNBC does not respond to hormone-based therapy. TNBC is also an aggressive subtype associated with poorer prognoses compared to other breast cancers. Conventional chemotherapeutics are used to manage TNBC although systemic relapse is common with limited benefits being reported as well as adverse events being documented. Here, we discuss current therapies for TNBC in the neo- and adjuvant settings, as well as recent advancements in the targeting of PD-L1-positive tumors and inclusion of PARP inhibitors for TNBC patients with BRCA mutations. The recent development of cyclin-dependent kinase (CDK) 4/6 inhibitors in ER-positive breast cancers has demonstrated significant improvements in progression free survival in patients. Here, we review preclinical data of CDK 4/6 inhibitors and describe current clinical trials assessing these in TNBC disease.

Keywords: CDK/4/6 inhibitors; metastatic; triple negative breast cancer

DOI: https://doi.org/10.1002/mco2.97

EMBO J. 2022 Jan 05. e108946

Pharmacological CDK4/6 inhibition reveals a p53-dependent senescent state with restricted toxicity.

Boshi Wang, Marta Varela-Eirin, Simone M Brandenburg, Alejandra Hernandez-Segura, Thijmen van Vliet, Elisabeth M Jongbloed, Saskia M Wilting, Naoko Ohtani, Agnes Jager, Marco Demaria.

Cellular senescence is a state of stable growth arrest and a desired outcome of tumor suppressive interventions. Treatment with many anti-cancer drugs can cause premature senescence of non-malignant cells. These therapy-induced senescent cells can have pro-tumorigenic and pro-disease functions via activation of an inflammatory secretory phenotype (SASP). Inhibitors of cyclin-dependent kinases 4/6 (CDK4/6i) have recently proven to restrain tumor growth by activating a senescence-like program in cancer cells. However, the physiological consequence of exposing the whole organism to pharmacological CDK4/6i remains poorly characterized. Here, we show that exposure to CDK4/6i induces non-malignant cells to enter a premature state of senescence dependent on p53. We observe in mice and breast cancer patients that the CDK4/6i-induced senescent program activates only a partial SASP enriched in p53 targets but lacking pro-inflammatory and NF-κB-driven components. We find that CDK4/6i-induced senescent cells do not acquire pro-tumorigenic and detrimental properties but retain the ability to promote paracrine senescence and undergo clearance. Our results demonstrate that SASP composition is exquisitely stress-dependent and a predictor for the biological functions of different senescence subsets.

Keywords: CDK4/6 inhibitors; SASP; cellular senescence; chemotherapy; p53

DOI: https://doi.org/10.15252/embj.2021108946