Cyclin-Dependent Kinase 4/6 Inhibitors as Neoadjuvant Therapy of Hormone Receptor-Positive/HER2-Negative Early Breast Cancer: What do we Know so Far?

The introduction of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors to the treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer is regarded as one of the greatest achievements of the last decades in breast oncology. To date, palbociclib, abemaciclib and ribociclib are the 3 approved CDK4/6 inhibitors that combined with endocrine therapy are now considered as the standard first-line treatment of metastatic HR+/HER2- breast cancer. The great success of these drugs in the setting of metastatic disease and the need to combat the high risk of recurrence have paved the way for a number of clinical trials to explore the use of CDK4/6 inhibitors in the neoadjuvant treatment of early breast cancer. In this review, we summarize the main findings of clinical trials that examined the use of CDK4/6 inhibitors in combination with hormone therapy or chemotherapy as neoadjuvant treatment of hormone receptor-positive and HER2-negative breast cancer. Active clinical trials that investigate different treatment schemes are also briefly presented and current limitations and future goals are discussed.

Estrogen-Receptor-Low-Positive Breast Cancer: Pathological and Clinical Perspectives.

The expression of estrogen receptors (ERs) in breast cancer (BC) represents a strong prognostic and predictive biomarker and directs therapeutic decisions in early and advanced stages. ER-low-positive BC, defined by the immunohistochemical (IHC) expression of ERs from 1% to 9%, constitutes a distinct subset of total BC cases. Guidelines recommend that a low expression of ERs be reported in pathology reports since the benefit of endocrine therapy in patients with ER-low-positive BC is uncertain. Recently, several cohorts, mostly of a retrospective nature, have been published, reporting the clinicopathological characteristics and outcomes of ER-low-positive BC. However, the majority of the data focus on early-stage BC and the use of (neo)adjuvant therapy, and there is a significant lack of data regarding metastatic ER-low-positive BC. Further factors, including tumor heterogeneity as well as the potential loss of ER expression due to endocrine resistance, should be considered. Including patients with ER-low-positive BC in clinical trials for triple-negative breast cancer (TNBC) might improve the understanding of this entity and allow novel therapeutic approaches. The design and conduction of randomized clinical trials regarding this subgroup of patients are greatly anticipated.

Bcl-2 pathway inhibition in solid tumors: a review of clinical trials

Due to their key role in the pathogenesis of cancer through the regulation of apoptosis, the B-cell leukemia/lymphoma-2 (BCL-2) family proteins have been an attractive target for cancer therapy for the past decades. Throughout the years, many Bcl-2 family inhibitors have been developed, with Venetoclax being now successfully used in treating hematological malignancies. Although their effectiveness in the treatment of solid tumors is yet to be established, some preclinical evidence indicates their possible clinical application. This review aims to summarize current data from completed clinical trials that used Bcl-2 protein family inhibitors as monotherapy or in combination with other agents for the treatment of solid malignancies. We managed to include clinical trials of various phases which analyze the pharmacokinetics and pharmacodynamics of the drugs, as well as the effectiveness and adverse effects. Active and recruiting clinical trials are also briefly presented and future prospects and challenges are discussed (AU)

Bcl-2 pathway inhibition in solid tumors: a review of clinical trials.

Due to their key role in the pathogenesis of cancer through the regulation of apoptosis, the B-cell leukemia/lymphoma-2 (BCL-2) family proteins have been an attractive target for cancer therapy for the past decades. Throughout the years, many Bcl-2 family inhibitors have been developed, with Venetoclax being now successfully used in treating hematological malignancies. Although their effectiveness in the treatment of solid tumors is yet to be established, some preclinical evidence indicates their possible clinical application. This review aims to summarize current data from completed clinical trials that used Bcl-2 protein family inhibitors as monotherapy or in combination with other agents for the treatment of solid malignancies. We managed to include clinical trials of various phases which analyze the pharmacokinetics and pharmacodynamics of the drugs, as well as the effectiveness and adverse effects. Active and recruiting clinical trials are also briefly presented and future prospects and challenges are discussed.

Comprehensive clinical evaluation of CAR-T cell immunotherapy for solid tumors: a path moving forward or a dead end?

INTRODUCTION: Chimeric Antigen Receptor (CAR)-T cell therapy is a form of adoptive cell therapy that has demonstrated tremendous results in the treatment of hematopoietic malignancies, leading to the US Food and Drug Administration (FDA) approval of four CD19-targeted CAR-T cell products. With the unprecedented success of CAR-T cell therapy in hematological malignancies, hundreds of preclinical studies and clinical trials are currently undergoing to explore the translation of this treatment to solid tumors. However, the clinical experience in non-hematologic malignancies has been less encouraging, with only a few patients achieving complete responses. Tumor-associated antigen heterogeneity, inefficient CAR-T cell trafficking and the immunosuppressive tumor microenvironment are considered as the most pivotal roadblocks in solid tumor CAR-T cell therapy. MATERIALS AND METHODS: We reviewed the relevant literature/clinical trials for CAR-T cell immunotherapy for solid tumors from Pubmed and ClinicalTrials.gov. CONCLUSION: Herein, we provide an update on solid tumor CAR-T cell clinical trials, focusing on the studies with published results. We further discuss some of the key hurdles that CAR-T cell therapy is encountering for solid tumor treatment as well as the strategies that are exploited to overcome these obstacles.