bims-cyhorp 2021-11-07 papers

bims-cyhorp

Biomed News

on Cyclin-dependent kinases in hormone receptor positive breast cancer

Issue of 2021–11–07
eight papers selected by
Piotr Okupski,

The Association of ERBB2-Low Expression With the Efficacy of Cyclin-Dependent Kinase 4/6 Inhibitor in Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer.
Real-World Outcomes of Everolimus and Exemestane for the Treatment of Metastatic Hormone Receptor-Positive Breast Cancer in Patients Previously Treated With CDK4/6 Inhibitors.
Mechanisms of Resistance to CDK4/6 Blockade in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer and Emerging Therapeutic Opportunities.
Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial.
Lactic acidosis, a potential toxicity from drug-drug interaction related to concomitant ribociclib and metformin in preexisting renal insufficiency: A case report.
Palbociclib Induces Senescence in Melanoma and Breast Cancer Cells and Leads to Additive Growth Arrest in Combination With Irradiation.
Harmful Interference of Detoxifying Diets and Nutraceuticals with Adherence to Abemaciclib in Advanced Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor-2-Negative Breast Cancer: A Case Report.
Palbociclib in combination with aromatase inhibitors in patients ≥ 75 years with oestrogen receptor-positive, human epidermal growth factor receptor 2 negative advanced breast cancer: A real-world multicentre UK study.

JAMA Netw Open. 2021 Nov 01. 4(11): e2133132

The Association of ERBB2-Low Expression With the Efficacy of Cyclin-Dependent Kinase 4/6 Inhibitor in Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer.

Kelvin K H Bao, Leone Sutanto, Shirley S W Tse, Ka Man Cheung, Jeffrey C H Chan.

DOI: https://doi.org/10.1001/jamanetworkopen.2021.33132
Clin Breast Cancer. 2021 Oct 09. pii: S1526-8209(21)00293-7. [Epub ahead of print]

Real-World Outcomes of Everolimus and Exemestane for the Treatment of Metastatic Hormone Receptor-Positive Breast Cancer in Patients Previously Treated With CDK4/6 Inhibitors.

Hanjie Mo, Catherine E Renna, Halle C F Moore, Jame Abraham, Megan L Kruse, Alberto J Montero, Susan B LeGrand, Lu Wang, G Thomas Budd.

   PURPOSE: Everolimus with exemestane (EVE+EXE) was FDA-approved to treat metastatic hormone receptor-positive breast cancer (mHRBC) based on BOLERO-2. However, none of those patients received prior CDK4/6 inhibitors. The purpose of this study is to evaluate the efficacy of EVE+EXE in mHRBC after CDK4/6 inhibitors.
METHODS: A retrospective review of patients ≥18 years old with mHRBC treated with EVE+EXE, for ≥30 days, at our institution from January 1, 2012, to April 1, 2020 was conducted. Primary objective was to compare progression free survival (PFS) for EVE+EXE between patients with and without prior exposure to CDK4/6 inhibitors. Secondary outcomes included overall survival and safety.
RESULTS: 192 patients were included in the study (n = 79, prior CDK4/6 inhibitor use; n = 113, no prior CDK4/6 inhibitor use). Baseline patient characteristics were similar between groups. Greater number of prior therapies before EVE+EXE use increased risk of disease progression (P = .017). Patients with prior CDK4/6 inhibitor use had a lower median PFS of 3.8 months (95% CI: 3.4-4.7) vs. 5.4 months (95% CI: 3.9-6.2) for patients without prior CDK4/6 inhibitor use, with a HR for progression of 1.46 (95% CI: 1.08 to 1.97, P = .013). Overall survival between groups was not significantly different.
CONCLUSION: Patients who received a prior CDK4/6 inhibitor had a lower median PFS benefit from EVE+EXE compared to those who did not, without differences in overall survival. Although PFS is expected to decrease with subsequent lines of therapy, it is reasonable to use EVE+EXE after CDK4/6 inhibitors in selected patients, recognizing that additional benefit is modest.

Keywords:  Breast cancer; CDK4/6 inhibitor; Everolimus; Exemestane; Hormone positive

DOI:  https://doi.org/10.1016/j.clbc.2021.10.002
Clin Cancer Res. 2021 Nov 01. pii: clincanres.2947.2021. [Epub ahead of print]

Mechanisms of Resistance to CDK4/6 Blockade in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer and Emerging Therapeutic Opportunities.

Maxwell R Lloyd, Laura M Spring, Aditya Bardia, Seth A Wander.

The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have become the standard of care, in combination with anti-estrogen therapy, for patients with HR+/HER2- advanced breast cancer. Various preclinical and translational research efforts have begun to shed light on the genomic and molecular landscape of resistance to these agents. Drivers of resistance to CDK4/6i therapy can be broadly subdivided into alterations impacting cell cycle mediators and activation of oncogenic signal transduction pathways. The resistance drivers with the best translational evidence supporting their putative role have been identified via next-generation sequencing of resistant tumor biopsies in the clinic and validated in laboratory models of HR+ breast cancer. Despite the diverse landscape of resistance, several common, therapeutically actionable resistance nodes have been identified, including the mitotic spindle regulator Aurora Kinase A as well as the AKT and MAP kinase signaling pathways. Based upon these insights, precision-guided therapeutic strategies are under active clinical development. This review will highlight the emerging evidence, in the clinic and in the laboratory, implicating this diverse spectrum of molecular resistance drivers.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-2947
Nat Med. 2021 Nov 04.

Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial.

DAWNA-1 Study Consortium

Blockade of the cyclin-dependent kinase 4 and 6 pathway has been shown to be effective in the treatment of hormone receptor-positive advanced breast cancer (ABC). We report the interim results of DAWNA-1 ( NCT03927456 ), a double-blind, randomized, phase 3 trial of dalpiciclib (a new cyclin-dependent kinase 4 and 6 inhibitor) plus fulvestrant in hormone receptor-positive, HER2-negative ABC with disease progression after endocrine therapy. A total of 361 patients were randomized 2:1 to receive dalpiciclib plus fulvestrant or placebo plus fulvestrant. The study met the primary end point, showing significantly prolonged investigator-assessed progression-free survival with dalpiciclib plus fulvestrant versus placebo plus fulvestrant (median = 15.7, 95% confidence interval (CI) = 11.1-not reached versus 7.2, 95% CI = 5.6-9.2 months; hazard ratio = 0.42, 95% CI = 0.31-0.58; one-sided P < 0.0001 (boundary was P ≤ 0.008)). The most common grade 3 or 4 adverse events with dalpiciclib plus fulvestrant were neutropenia (84.2%) and leukopenia (62.1%). The incidence of serious adverse events was 5.8% with dalpiciclib plus fulvestrant versus 6.7% with placebo plus fulvestrant. Our findings support dalpiciclib plus fulvestrant as a new treatment option for pretreated hormone receptor-positive, HER2-negative ABC.

DOI: https://doi.org/10.1038/s41591-021-01562-9
Cancer Rep (Hoboken). 2021 Nov 05. e1575

Lactic acidosis, a potential toxicity from drug-drug interaction related to concomitant ribociclib and metformin in preexisting renal insufficiency: A case report.

Chalita Lagampan, Nattaya Poovorawan, Napa Parinyanitikul.

   BACKGROUND: Ribociclib, one of the cyclin-dependent kinases (CDK) 4 and 6 inhibitors, in combination with endocrine therapies has been approved in the treatment of hormonal receptor positive, HER-2 negative metastatic breast cancer worldwide. Long-term usage of ribociclib with concomitant drugs, potential drug-drug interaction may develop which can limit the therapeutic value of CDK4/6 inhibitor.
CASE: A 62-year-old with history of non-insulin dependent diabetic, dyslipidemia, and essential hypertension was diagnosed with HR-positive, HER-2 negative metastatic breast cancer and treated with fulvestrant plus ribociclib. Four weeks after administration, elevated serum creatinine was observed, and then severe lactic acidosis with acute respiratory failure was subsequently reported. Ribociclib and fulvestrant were temporarily discontinued. Three days after renal replacement therapy, her clinical was stabilized. Combination ribociclib with metformin resulted in high plasma metformin levels and dangerous consequences. Hence, special precaution should be considered during concomitant treatment with sensitive transporter substrates.
CONCLUSION: Metformin associated lactic acidosis may potentially occur after combination with ribocilib, an uncommon but lethal complication from the interaction of these drugs, especially in patients who had preexisting renal impairment.

Keywords:  concomitant; drug-drug interaction; lactic acidosis; renal insufficiency

DOI:  https://doi.org/10.1002/cnr2.1575
Front Oncol. 2021 ;11 740002

Palbociclib Induces Senescence in Melanoma and Breast Cancer Cells and Leads to Additive Growth Arrest in Combination With Irradiation.

Tina Jost, Lucie Heinzerling, Rainer Fietkau, Markus Hecht, Luitpold V Distel.

   Introduction: Several kinase inhibitors (KI) bear the potential to act as radiosensitizers. Little is known of the radiosensitizing effects of a wide range of other KI like palbociclib, which is approved in ER+/HER2- metastatic breast cancer.
Method: In our study, we used healthy donor fibroblasts and breast cancer and skin cancer cells to investigate the influence of a concomitant KI + radiation therapy. Cell death and cell cycle distribution were studied by flow cytometry after Annexin-V/7-AAD and Hoechst staining. Cellular growth arrest was studied in colony-forming assays. Furthermore, we used C12-FDG staining (senescence) and mRNA expression analysis (qPCR) to clarify cellular mechanisms.
Results: The CDK4/6 inhibitor palbociclib induced a cell cycle arrest in the G0/G1 phase. Cellular toxicity (cell death) was only slightly increased by palbociclib and not enhanced by additional radiotherapy. As the main outcome of the colony formation assays, we found that cellular growth arrest was induced by palbociclib and improved by radiotherapy in an additive manner. Noticeably, palbociclib treatment clearly induced senescence not only in breast cancer and partly in melanoma cells, but also in healthy fibroblasts. According to these findings, the downregulation of senescence-related FOXM1 might be an involved mechanism of the senescence-induction potential of palbociclib.
Conclusion: The effect on cellular growth arrest of palbociclib and radiotherapy is additive. Palbociclib induces permanent G0/G1 cell cycle arrest by inducing senescence in fibroblasts, breast cancer, and melanoma cells. Direct cell death induction is only a minor secondary mechanism of action. Concomitant KI and radiotherapy is a strategy worth studying in clinical trials.

Keywords:  breast cancer; kinase inhibitor; melanoma; palbociclib; radiotherapy; senescence

DOI:  https://doi.org/10.3389/fonc.2021.740002
Case Rep Oncol. 2021 Sep-Dec;14(3):14(3): 1399-1406

Harmful Interference of Detoxifying Diets and Nutraceuticals with Adherence to Abemaciclib in Advanced Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor-2-Negative Breast Cancer: A Case Report.

Vittorio Gebbia, Dario Piazza, Maria Rosaria Valerio.

  Many cancer patients use integrative therapies with a combination of natural products and diets. In the Western world, integrative medicine is often not shared with oncologists even during antineoplastic treatments. This behavior stems from the unmet needs of cancer patients who may feel oncologists' underestimation of their symptoms and spiritual aspects. This case report demonstrates the potential harm of inadequate diet and nutraceutical intake in a 68-year-old woman with metastatic estrogen receptor-positive, human epidermal growth factor receptor-2-negative breast cancer. Her care team recommended hormone therapy with abemaciclib plus fulvestrant. Her diarrhea started after 10 days of therapy and did not disappear, despite the use of loperamide, causing a significant reduction in adherence and dose intensity of abemaciclib. The patient finally disclosed to her oncologist she was following a detoxifying diet and taking several nutraceuticals. Her diarrhea was correlated with abemaciclib but most probably exacerbated and prolonged by the diet. Evaluation of disease after 3 months showed progressive disease. Integrative medicine should be in the multidisciplinary management of cancer patients to avoid potentially harmful events and ameliorate patients' quality of life in a holistic approach.

Keywords:  Abemaciclib; Detoxifying diet; Estrogen receptor; Metastatic breast cancer; Nutraceuticals

DOI:  https://doi.org/10.1159/000518779
Breast. 2021 Oct 28. pii: S0960-9776(21)00980-2. [Epub ahead of print]60 199-205

Palbociclib in combination with aromatase inhibitors in patients ≥ 75 years with oestrogen receptor-positive, human epidermal growth factor receptor 2 negative advanced breast cancer: A real-world multicentre UK study.

Salma El Badri, Bilal Tahir, Kirsty Balachandran, Pavel Bezecny, Fiona Britton, Mark Davies, Karen Desouza, Simon Dixon, Daniel Hills, Maung Moe, Thomas Pigott, Andrew Proctor, Yatri Shah, Richard Simcock, Anna Stansfeld, Alicja Synowiec, Marianna Theodoulou, Mark Verrill, Anshu Wadhawan, Catherine Harper-Wynne, Caroline Wilson.

   BACKGROUND: Breast cancer incidence increases with age and real-world data is essential to guide prescribing practices in the older population. The aim of this study was to collect large scale real-world data on tolerability and efficacy of palbociclib + AI in the first line treatment of ER+/HER2-advanced breast cancer in those aged ≥75 years.
METHODS: 14 cancer centres participated in this national UK retrospective study. Patients aged ≥75 years treated with palbociclib + AI in the first line setting were identified. Data included baseline demographics, disease characteristics, toxicities, dose reductions and delays, treatment response and survival data. Multivariable Cox regression was used to assess independent predictors of PFS, OS and toxicities.
RESULTS: 276 patients met the eligibility criteria. The incidence of febrile neutropenia was low (2.2%). The clinical benefit rate was 87%. 50.7% of patients had dose reductions and 59.3% had dose delays. The 12- and 24- month PFS rates were 75.9% and 64.9%, respectively. The 12- and 24- month OS rates were 85.1% and 74.0%, respectively. Multivariable analysis identified PS, Age-adjusted Charlson Comorbidity Index (ACCI) and number of metastatic sites to be independent predictors of PFS. Dose reductions and delays were not associated with adverse survival outcomes. Baseline ACCI was an independent predictor of development and severity of neutropenia.
CONCLUSION: Palbociclib is an effective therapy in the real-world older population and is well-tolerated with low levels of clinically significant toxicities. The use of geriatric and frailty assessments can help guide decision making in these patients.

Keywords:  Breast cancer; Cost analysis; Frail elderly; Palbociclib; Real-world; Toxicity; Treatment efficacy

DOI:  https://doi.org/10.1016/j.breast.2021.10.010