Review of precision cancer medicine: Evolution of the treatment paradigm

Abstract

In recent years, biotechnological breakthroughs have led to identification of complex and unique biologic features associated with carcinogenesis. Tumor and cell-free DNA profiling, immune markers, and proteomic and RNA analyses are used to identify these characteristics for optimization of anticancer therapy in individual patients. Consequently, clinical trials have evolved, shifting from tumor type-centered to gene-directed, histology-agnostic, with innovative adaptive design tailored to biomarker profiling with the goal to improve treatment outcomes. A plethora of precision medicine trials have been conducted. The majority of these trials demonstrated that matched therapy is associated with superior outcomes compared to nonmatched therapy across tumor types and in specific cancers. To improve the implementation of precision medicine, this approach should be used early in the course of the disease, and patients should have complete tumor profiling and access to effective matched therapy. To overcome the complexity of tumor biology, clinical trials with combinations of gene-targeted therapy with immune-targeted approaches (e.g., checkpoint blockade, personalized vaccines and/or chimeric antigen receptor T-cells), hormonal therapy, chemotherapy and/or novel agents should be considered. These studies should target dynamic changes in tumor biologic abnormalities, eliminating minimal residual disease, and eradicating significant subclones that confer resistance to treatment. Mining and expansion of real-world data, facilitated by the use of advanced computer data processing capabilities, may contribute to validation of information to predict new applications for medicines. In this review, we summarize the clinical trials and discuss challenges and opportunities to accelerate the implementation of precision oncology.

BAP1: Not just a BRCA1-associated protein

“…[40,48] Recent studies suggest that genomic selection of patients for clinical trials can be a useful approach for treatment. [77][78][79][80][81][82][83][84] In the case of malignancies harboring aberrant BAP1, directly targeting BAP1 functions using HDAC inhibitors and EZH2 inhibitors, as well as targeting DNA damage repair mechanisms with the use of platinums or PARP inhibitors may be a viable approach. Additionally, augmenting the immune response via checkpoint blockade and/or other modalities of immunotherapy are strategies that merit further investigation.…”

“…Recent studies suggest that personalized combination therapies may be a more optimal approach, particularly for molecularly complex tumors. [78,83] Given that BAP1 is involved in a number of biological pathways and interacts with an array of cancer-associated genes, this type of combinatorial approach may be necessary. One strategy may be to binds to ASXL to form the PR-DUB complex, responsible for regulation of chromatin through Histone H2A deubiquitination.…”

Biomarker-guided targeted and immunotherapies in malignant pleural mesothelioma

“…Precision oncology, a strive for personalized medicine that targets unique molecular aberrations in patients, has made tremendous progress in the last decade in various cancers, 7 but is lagging far behind in MPM. 8 Comprehensive genomic studies have shown a rarity of oncogenic driver mutations in MPM, 9,10 while inactivating mutations [e.g.…”

Tumor-Infiltrating Immune Cell Signature Predicts the Prognosis and Chemosensitivity of Patients With Pancreatic Ductal Adenocarcinoma

“…Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related deaths worldwide and it consists of almost 90% pancreatic cancers (1,2). Although in recent years significant improvements have been achieved in the diagnosis and treatment of different kinds of cancers (3), the mortality rate of PDAC has not experienced substantial changes during the past decades. This is because PDAC is a highly destructive cancer with an extraordinarily high malignancy and a particularly poor prognosis (4).…”