Precision medicine in oncology – article

This approach should be used early in the disease course, and patients should have a complete tumor profile and access to effective concomitant therapy.

Rapidly increasing knowledge on the roles of genomics and the immune system in cancer has enabled the development of therapies targeting specific molecular alterations or other biological features, such as those involved in immune suppression. However, genomics has also revealed a complex reality about malignant diseases that requires a major shift in the medical paradigm: away from treatment focused on the type of tumor and toward gene-guided, histology-independent treatment. Which is individual for each patient based on biomarker analysis. ,

This paradigm shift is reflected in the emergence of precision medicine tests with innovative designs. Next generation sequencing (NGS) of advanced cancers has revealed that genomic alterations do not fall clearly into categories defined by organ of tumor origin. Furthermore, metastatic tumors have highly complex and individually unique genomic and immunological landscapes. Therefore, to “precisely” attack the malignant neoplasm, treatment must be individualized.

In this article, the authors review the rapid development of precision medicine in oncology and, in particular, the challenge and opportunity that genomic science has revealed in the face of the need for specific treatments.

Innovative clinical trial design for precision medicine

Traditionally, oncology trials have been drug-centric and aimed at identifying common characteristics between patients (for example, their tumor type or, more recently, a shared genomic abnormality) and testing them with a specific drug regimen. To enroll in. The large variability in genomic subgroups, microenvironment, baseline characteristics, comorbidities, and other covariates resulted in tumor-specific clinical studies that included a tremendously heterogeneous population in histology-specific independent gene assays.

Randomized phase III trials were often important for regulatory approval of a new agent/regimen, particularly because the anti-tumor activity of a new drug/regimen was often superior to that of a comparison group (usually conventional therapy), Perhaps because that regimen was effective only in a small subgroup of a diverse population represented by a specific histology.

The ultimate goal of precision medicine is a personalized, patient-centered (rather than drug-centered) trial based on the best available biomarkers. In “N of 1” trials, treatment for each patient is considered separately based on their molecular, immunological, and other biological characteristics. These trials involve personalized drug combinations tailored to individual patients. “N of 1” trials need to evaluate the strategy of matching patients to drugs rather than the treatment itself to determine efficacy, which is individual for each patient.

Genomics and other biomarkers

Genomics has been the cornerstone of precision medicine studies. Beyond genomics, RNA and protein profiles, being effectors of protein signaling, also appear to be important in mediating biological effects. Interestingly, matching patients to drugs based on genomics has proven more effective in improving outcomes than comparing them based on protein testing, perhaps for technical reasons.

Despite current practical limitations, protein and transcript testing can provide essential information when integrated with genomics. Recently, panels encompassing immune signatures based on DNA, RNA and/or proteins have also gained clinical importance.

, Analysis of cell-free DNA obtained from blood.

Clinical-grade ctDNA testing, which is non-invasive and reflects tumor heterogeneity (as tumor DNA can leak into the bloodstream from many metastatic lesions), to select cancer therapies and monitor subclone dynamics during treatment. Used rapidly. The discrepancy observed in some cases between the results of ctDNA testing and genotyping analysis of tumor tissue may reflect technical problems, but may be attributable to the following biological reasons: (1) Tumor NGS measures genomics in small portions of biopsied tissue. whereas ctDNA evaluates DNA shed from multiple sites; (2) ctDNA is associated with tumor burden and can be detected at low levels.

, Analysis of blood-derived circulating tumor cells (CTCs)

The presence of CTCs, which are epithelial tumor cells, is independently associated with worse survival in several types of cancer. For example, in a prospective, multicenter, double-blind study, the number of CTCs in patients with untreated metastatic breast cancer was correlated with shorter progression-free survival (PFS) and overall survival (OS).

CTCs may also be a predictive biomarker for chemotherapy and immunotherapy. However, the use of CTCs in clinical practice has not been fully established.

Finally, serial CTC analysis can enable disease monitoring in real time. Comparative study of five prospective randomized phase III trials in 6,081 patients with metastatic castration-resistant prostate cancer.

Evaluated the predictive value of CTCs compared to prostate-specific antigen. CTC ≥ 0 at baseline and at week 13 after treatment initiation was associated with OS. The investigators demonstrated that CTC monitoring was a robust and meaningful response endpoint for early phase clinical trials in this setting.

Immunotherapy and Cell Therapy

By reactivating the innate immune antitumor response, immunotherapy has represented a major advance in oncology. Several new approaches are currently being explored: checkpoint blockade, oncolytic viruses, cellular products, engineered cytokines, CD3 specific antibodies, vaccine platforms, and adoptive cell therapy.

, blockade of posts

There are seven FDA-approved checkpoint inhibitors: ipilimumab, pembrolizumab, nivolumab, avelumab, cemiplimab, durvalumab, and atezolizumab. Selected patients with advanced disease have remarkable responses, including durable complete remission (CR).

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