bims-cyhorp 2022-08-14 papers

Issue of 2022–08–14
four papers selected by
Piotr Okupski,

Front Pharmacol. 2022 ;13 897951

An Integrated Pharmacological Counselling Approach to Guide Decision-Making in the Treatment with CDK4/6 Inhibitors for Metastatic Breast Cancer.

Rossana Roncato, Lorenzo Gerratana, Lorenza Palmero, Sara Gagno, Ariana Soledad Poetto, Elena Peruzzi, Martina Zanchetta, Bianca Posocco, Elena De Mattia, Giovanni Canil, Martina Alberti, Marco Orleni, Giuseppe Toffoli, Fabio Puglisi, Erika Cecchin.

A wide inter-individual variability in the therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) has been reported. We herein present a case series of five patients treated with either palbociclib or ribociclib referred to our clinical pharmacological counselling, including therapeutic drug monitoring (TDM), pharmacogenetics, and drug-drug interaction analysis to support clinicians in the management of CDKis treatment for metastatic breast cancer. Patients' plasma samples for TDM analysis were collected at steady state and analyzed by an LC-MS/MS method for minimum plasma concentration (Cmin) evaluation. Under and overexposure to the drug were defined based on the mean Cmin values observed in population pharmacokinetic studies. Polymorphisms in selected genes encoding for proteins involved in drug absorption, distribution, metabolism, and elimination were analyzed (CYP3A4, CYP3A5, ABCB1, SLCO1B1, and ABCG2). Three of the five reported cases presented a CDKi plasma level above the population mean value and were referred for toxicity. One of them presented a low function ABCB1 haplotype (ABCB1-rs1128503, rs1045642, and rs2032582), possibly causative of both increased drug oral absorption and plasmatic concentration. Two patients showed underexposure to CDKis, and one of them was referred for early progression. In one patient, a CYP3A5*1/*3 genotype was found to be potentially responsible for more efficient drug metabolism and lower drug plasma concentration. This intensified pharmacological approach in clinical practice has been shown to be potentially effective in supporting prescribing oncologists with dose and drug selection and could be ultimately useful for increasing both the safety and efficacy profiles of CDKi treatment.

Keywords: CDK4/6 inhibitors; TDM; breast cancer; personalized medicine; pharmacological counselling; polymorphisms

DOI: https://doi.org/10.3389/fphar.2022.897951

Breast Care (Basel). 2022 Jun;17(3): 330-335

Second-Degree Type 2 Atrioventricular Block Requiring Permanent Cardiac Pacing in Patients on CDK4/6 Inhibitors: Report of Two Cases.

Maria Paola Cicini, Gianluigi Ferretti, Nicola Morace, Cecilia Nisticò, Francesco Cognetti, Francesco Rulli.

Introduction: A wide spectrum of cardiovascular (CV) toxicity is associated with anticancer treatment, and nearly all chemotherapeutic agents can elicit CV toxicity. Inhibitors of cyclin-dependent kinases 4/6 (CDK4/6Is) have become standard of care in the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC). CV side effects are uncommon with CDK4/6Is and only include QT prolongation, with a low incidence rate.
Case Presentation: This paper describes 2 cases of new-onset second-degree type 2 atrioventricular (AV) blocks requiring permanent cardiac pacing involving 2 women with MBC receiving ribociclib or abemaciclib. Both our patients had no known history or risk factors of cardiac disease and a normal 12-lead resting electrocardiogram (ECG) when diagnosed with breast adenocarcinoma. Both patients have been subjected to surveillance for cardiotoxicity with serial ECG and echocardiography. No left ventricular dysfunction or arrhythmia was found during the follow-up, and cardiac biomarkers were normal.
Conclusion: To our knowledge, these are the first cases reported in the literature of new-onset advanced AV blocks in patients under treatment with CDK4/6Is, suggesting the clinical relevance of a more frequent ECG monitoring, besides the QT interval, in these patients.

Keywords: 4/6 inhibitors; Atrioventricular block; Case report; Metastatic breast cancer

DOI: https://doi.org/10.1159/000519728

Int J Retina Vitreous. 2022 Aug 12. 8(1): 54

Regression of choroidal metastasis from breast carcinoma with palbociclib.

Shweta Parakh, Shrutanjoy Das, Shrey Maheshwari, Vinita Gupta, Gaurav Luthra, Saurabh Luthra.

BACKGROUND: Uveal metastasis is reported to be the most common intraocular malignancy. The most common site of origin of ocular metastases in females is the breast. In some cases, uveal metastatic lesions respond to systemic chemotherapy. We report a case of a patient who developed choroidal metastasis, while on endocrine therapy with selective estrogen receptor modulator (SERM), tamoxifen, for estrogen receptor (ER) positive, progesterone receptor (PR) positive and (human epidermal growth factor receptor 2) HER2 negative primary breast carcinoma, which then regressed following systemic chemotherapy with palbociclib.
CASE DESCRIPTION: An 83-year-old female, with a history of modified radical mastectomy, chemotherapy and radiation therapy for infiltrating duct carcinoma of the breast, presented with a choroidal metastatic lesion in the left eye along with liver and lung metastases, 3 years after the primary carcinoma was treated. At the time of presentation, she was on tamoxifen. The choroidal tumor showed regression after the introduction of palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor.
CONCLUSION: This report highlights the use of palbociclib, in the palliative treatment of choroidal metastasis from primary breast cancer. The use of chemotherapy for choroidal metastasis can help avoid external beam radiation therapy and its concurrent side effects. Although there are a few reports involving the use of palbociclib for metastatic breast carcinoma, all of those have been in conjunction with and/or following non-response to other treatment modalities. Ours is the first report wherein palbociclib has been used as the first-line palliative chemotherapy and helped in regression of choroidal metastasis.

Keywords: Breast carcinoma; Choroidal metastasis; Cyclin-dependent kinase 4/6 (CDK4/6) inhibitor; Palbociclib; Palliative chemotherapy

DOI: https://doi.org/10.1186/s40942-022-00398-w

Nat Commun. 2022 Aug 10. 13(1): 4689

Targeting the Retinoblastoma/E2F repressive complex by CDK4/6 inhibitors amplifies oncolytic potency of an oncolytic adenovirus.

Jana Koch, Sebastian J Schober, Sruthi V Hindupur, Caroline Schöning, Florian G Klein, Klaus Mantwill, Maximilian Ehrenfeld, Ulrike Schillinger, Timmy Hohnecker, Pan Qi, Katja Steiger, Michaela Aichler, Jürgen E Gschwend, Roman Nawroth, Per Sonne Holm.

CDK4/6 inhibitors (CDK4/6i) and oncolytic viruses are promising therapeutic agents for the treatment of various cancers. As single agents, CDK4/6 inhibitors that are approved for the treatment of breast cancer in combination with endocrine therapy cause G1 cell cycle arrest, whereas adenoviruses induce progression into S-phase in infected cells as an integral part of the their life cycle. Both CDK4/6 inhibitors and adenovirus replication target the Retinoblastoma protein albeit for different purposes. Here we show that in combination CDK4/6 inhibitors potentiate the anti-tumor effect of the oncolytic adenovirus XVir-N-31 in bladder cancer and murine Ewing sarcoma xenograft models. This increase in oncolytic potency correlates with an increase in virus-producing cancer cells, enhanced viral genome replication, particle formation and consequently cancer cell killing. The molecular mechanism that regulates this response is fundamentally based on the reduction of Retinoblastoma protein expression levels by CDK4/6 inhibitors.

DOI: https://doi.org/10.1038/s41467-022-32087-5