Consensus on the clinical use of CDK4/6 inhibitors for the treatment of hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer (2023 edition) / 中华肿瘤杂志

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have led transformative breakthrough of clinical therapy for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER-2)-negative breast cancer patients. CDK4/6 inhibitors that have been marketed in China include Ribociclib, Palbociclib, Abemaciclib and Dalpiciclib. For HR-positive HER-2-negative locally advanced and metastatic breast cancer, CDK4/6 inhibitors combined with endocrine therapy have become standard regimen, which can prolong the survival of patients. In the adjuvant treatment stage of early breast cancer, CDK4/6 inhibitors have also achieved positive results and been approved for indications. At present, CDK4/6 inhibitors have been widely used in clinical practice in China. In order to further improve the standardized application of CDK4/6 inhibitors in China, the Breast Cancer Expert Committee of the National Center for Cancer Quality Control and the Professional Committee of Clinical Research of Cancer Drugs of the Chinese Anti-Cancer Association organized the related expert to update the consensus based on the "CDK4/6 inhibitor consensus on clinical application of in the treatment of hormone receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer (2021 edition)" . The updated consensus systematically introduces the pharmacological characteristics, drug monitoring and adverse event management, etc., of CDK4/6 inhibitors to promote the accuracy of clinical decision-making with the ultimate goal to prolong the overall survival of patients and improve the quality of life.

Guidelines for pharmaceutical care of endocrine therapeutics for breast cancer(2023 edition) / 中华肿瘤杂志

Endocrine therapy is one of the primary treatment methods for hormone receptor-positive breast cancer patients. As of June 1 2023, the National Medical Product Administration has approved 56 drugs related to endocrine therapy in patients with HR+ /HER-2- breast cancer (including generic drugs that have passed the consistency evaluation), including 44 endocrine drugs which can be categorized according to their mechanisms of action into selective estrogen receptor modulators, selective estrogen receptor down-regulators, aromatase inhibitors, luteinizing hormone-releasing hormone analogs, and progestogens and 12 targeted drugs for combined with endocrine therapy, including CDK4/6 inhibitors, mTOR inhibitors, and HDAC inhibitors. The different pharmacological characteristics, mechanisms of action, and long-term medication factors of breast cancer endocrine therapy-related drugs can directly affect patients' medication adherence and medication safety. To standardize the pharmaceutical care of endocrine therapy drugs for breast cancer and promote rational use in clinical settings, the Oncology Specialty Pharmacist Subcommittee, in conjunction with multidisciplinary experts nationwide, has developed the "Guidelines for pharmaceutical care of endocrine therapy drugs for breast cancer (2023 edition)". The guidelines is based on clinical evidence-based evidence, relevant regulations of pharmaceutical management, and pharmaceutical care practices. The Delphi method and expert interviews were used to formulate the guidelines. The GRADE approach was used for assessing the certainty of evidence. This guideline mainly focuses on endocrine therapy for HR+ /HER-2- breast cancer patients. Due to space constraints, HER-2 positive targeted drugs were not included in the guideline. It covers 6 dimensions and 22 key problems of pharmaceutical care in the whole process of drug therapy, providing a scientific basis for pharmacists to carry out pharmaceutical care of such drugs.

Treatment of palbociclib in hormone receptor positive breast cancer: a real-world study and efficacy prediction model / 中华肿瘤杂志

Objective: To summarize the clinical use of palbociclib and evaluate its efficacy and safety in hormone-receptor (HR)-positive advanced breast cancer patients. Methods: We retrospectively analyzed data from 66 HR-positive metastatic breast cancer patients treated with palbociclib and endocrine therapy at the Department of Oncology in the First Affiliated Hospital with Nanjing Medical University between 2018 and 2020. We evaluated the factors affecting the efficacy of palbociclib using Kaplan-Meier method and Log-rank test for survival analysis and Cox regressions for multivariate analysis. Nomogram model was built for predicting prognosis among HR-positive breast cancer patients who received palbociclib. Concordance index (C-index) and calibration curve were used for internal validation to assess the predictive ability and conformity of the model. Results: Of the 66 patients treated with palbociclib, 33.3%(22), 42.4%(28) and 24.2%(16) patients were treated without endocrine therapy, first-line endocrine therapy, second-line or above endocrine therapy after recurrence, respectively. 36.4%(24) patients had hepatic metastasis, 16.7% (11) patients were sensitive to previous endocrine therapy, 27.3%(18/66) patients had primary resistance to endocrine therapy, while 56.1% (37) patients had secondary resistance to endocrine therapy. The overall response rate was 14.3% (95% CI: 6.7%, 25.4%) and clinical benefit rate was 58.7% (95% CI: 45.6%, 71.0%). Better clinical outcomes were associated with non-hepatic metastasis (P=0.001), sensitive/secondary resistant to previous endocrine therapy (P=0.004), no or only one line of chemotherapy for metastatic breast cancer (P=0.004), recent pathological confirmation of immunohistochemical analysis (P=0.025). Hepatic metastasis (P=0.005) and primary resistance to endocrine therapy (P=0.016) were the independent risk factors of progression free survival. The C-index of predictive probability for the nomogram constructed from the patient clinical characteristics (whether liver metastasis, whether primary endocrine resistance, lines of chemotherapy after metastasis, lines of endocrine therapy, number of metastatic sites, and time to last immunohistochemistry) to predict the progression-free survival at 6 and 12 months for patients was 69.7% and 72.1%, respectively. The most common adverse events were hematologic toxicities. Conclusions: Our report indicates that palbociclib combined with endocrine therapy for HR-positive recurrent metastatic breast cancer is effective and safe; patients with hepatic metastases and primary resistance to endocrine therapy have worse prognoses and are independent risk factors for progression after palbociclib therapy. The constructed nomogram could help predict the survival and guide the use of palbociclib.

Study on the modification and anti-tumor activity of silybin derivatives for CDK4/6 targeted / 药学学报

By using computer-aided drug design, the activities group model which CDK4/6 inhibitors on the market were introduced to silybin C-7, and a series of silybin derivatives were designed and synthesized, and the structure was confirmed by MS, 13C NMR and 1H NMR. The in vitro antitumor activity evaluation of the target compound was carried out by MTT method, and the in vitro anti-tumor activity was carried out in human hepatocellular carcinoma cells (HepG-2). Experimental results show that all compounds are higher than the activity of the parent silybin, of which compound I1 has a certain inhibitory effect on human HepG-2 cells, which is worth further study.

Complete response in metastatic breast cancer with visceral crisis using a combination of cyclin-dependent kinase 4/6 inhibitor and aromatase inhibitor: A case report from the eastern region of India

Patients with metastatic breast cancer (MBC) in visceral crisis require systemic chemotherapy. However, a coexisting cardiac failure that contradicts the use of systemic chemotherapy often demands an alternative treatment. Here, we report a case of hormone-receptor-positive MBC with cardiological comorbidities. She was treated with a combination treatment of tablet Ribociclib (600 mg once daily for 21 days followed by 7 days gap) and tablet Letrozole (2.5 mg once daily). The patient had a complete metabolic response in 18-Fluorodeoxyglucose Positron Emission tomography-Computed Tomography (18F-FDG PET/CT), after 6 months of treatment. Combination treatment with Ribociclib and Letrozole is beneficial in postmenopausal females with hormone receptor-positive and human epidermal growth factor receptor 2 neu-negative MBC in visceral crisis who have a contraindication to chemotherapy.

Expert consensus on the management of adverse events of CDK4/6 inhibitors in breast cancer / 中华肿瘤杂志

Cyclin-dependent kinases 4/6 (CDK4/6) inhibitors are anti-tumor agents for the treatment of hormone receptor-positive breast cancer. Palbociclib, abemaciclib and dalpiciclib have been approved for the treatment of breast cancer in China. Common adverse effects of CDK4/6 inhibitors include bone marrow suppression, gastrointestinal toxicities, liver dysfunction, and skin or subcutaneous tissue adverse reactions (AEs). The Breast Cancer Expert Group of Chinese Society of Clinical Oncology (CSCO) summarized the incidence, clinical manifestations, and grading of the AEs. This expert consensus reports measures of AE management on the basis of experience of clinical practice and the latest advances worldwide, aiming to guide clinical practice by the way of managing AE and help to choose the best treatment regimen.

CDK4/6 signaling pathway and its targeted therapeutic agents in cancer therapy: a review / 生物工程学报

The development and progression of most cancers have been well recognized as the result of highly activated cell cycle. Cyclin dependent kinase 4/6 plays important roles not only in mitosis, but also in multiple biological processes that contribute to cancer development, such as aging, apoptosis and histone modification. Three FDA approved CDK4/6 inhibitors, Palbociclib, Ribociclib and Abemaciclib, have been used as targeted cancer therapeutic agents to benefit patients with endocrine therapy-resistant breast cancer and other types of cancer, prolonging their survival. However, the clinical application of these inhibitors also leads to acquired drug resistance and other problems. This paper reviews the regulatory roles of CDK4/6, the application of CDK4/6 inhibitors in cancer and the challenge of drug resistance.

Selective inhibition of CDK4/6: A safe and effective strategy for developing anticancer drugs

The sustained cell proliferation resulting from dysregulation of the cell cycle and activation of cyclin-dependent kinases (CDKs) is a hallmark of cancer. The inhibition of CDKs is a highly promising and attractive strategy for the development of anticancer drugs. In particular, third-generation CDK inhibitors can selectively inhibit CDK4/6 and regulate the cell cycle by suppressing the G1 to S phase transition, exhibiting a perfect balance between anticancer efficacy and general toxicity. To date, three selective CDK4/6 inhibitors have received approval from the U.S. Food and Drug Administration (FDA), and 15 CDK4/6 inhibitors are in clinical trials for the treatment of cancers. In this perspective, we discuss the crucial roles of CDK4/6 in regulating the cell cycle and cancer cells, analyze the rationale for selectively inhibiting CDK4/6 for cancer treatment, review the latest advances in highly selective CDK4/6 inhibitors with different chemical scaffolds, explain the mechanisms associated with CDK4/6 inhibitor resistance and describe solutions to overcome this issue, and briefly introduce proteolysis targeting chimera (PROTAC), a new and revolutionary technique used to degrade CDK4/6.

Tratamiento del Cáncer de Mama Metastásico, Receptor Hormonal Positivo, Her 2 Negativo: Enfoque actual a Dianas Terapéuticas / Treatment of Metastatic Breast Cancer, Hormone Receptor Positive, Her 2 Negative: Current Approach to Therapeutic Targets

En el cáncer de mama luminal, la terapia hormonal está indicada en adyuvancia y neoadyuvancia. El estadio metastásico incluye un grupo heterogéneo de tumores que varían de acuerdo con el sitio de metástasis, tiempo de aparición, condición general de las pacientes, entre otras características intrínsecas del tumor. Esto establece tiempos de sobrevida con rangos variables de meses a muchos años. Los estrógenos actúan en receptores de membrana citoplasmática y nuclear: en las células neoplásicas estimulan la transcripción del ARN, con persistencia de la proliferación. El bloqueo de la acción hormonal en el cáncer avanzado encuentra mecanismos de resistencia con el uso de vías de señalización paralelas, este conocimiento ha permitido el desarrollo de inhibidores de CDK 4/6, mTOR y PIK3-CA, que se recomiendan en enfermedad metastásica, con prolongación significativa de la supervivencia global. En crisis visceral aún se mantiene el uso de quimioterapia sistémica secuencial o combinada

For a patient with estrogen receptor positivebreast cancer, the adjuvant and neoadjuvant endocrine therapy has an absolute benefit. The metastatic stage includes a diverse group of tumors that vary according to the site of metastasis, time of appear, general condition of the patients, and other intrinsic characteristics of the tumor. survival in cancer varies according these features, from a few months to many years. Estrogen hormones stimulate nuclear and cytoplasmic receptors. In neoplastic cells, estrogen regulate RNA transcription, with persistence of proliferation. The blocking of hormonal action in metastatic cancer, has resistance mechanisms with the use of parallel signaling pathways, this knowledge has allowed the development of inhibitors of CDK 4/6, mTOR and PIK3-CA, which are recommended in metastatic disease. with significant prolongation of overall survival. In visceral crisis, the use of sequential or combined systemic chemotherapy is still maintained

Ribociclib: new antitumor drug of cyclindependent kinase 4/6 inhibitor / 药物评价研究

Ribociclib is an oral small molecule cyclindependent kinase 4/6 inhibitor,which inhibits tumor progression by inhibiting the conversion of tumor cells from G1 phase to S phase.The combination ofribociclib and letrozole was approved in the United States on March 13,2017 as a treatment for HR+/HER2-advanced and metastatic breast cancer patients.Clinical results showed that the drug on advanced and metastatic tumors had a significant inhibitory effect and could extend the survival of patients without deterioration compared with using letrozole alone.The incidence of adverse drug reactions is higher,but the tolerance is better.This article focuses on pharmacodynamics,pharmacokinetic,clinical results and adverse effects of this drug.