2024-02-12 03:00:09
This approach should be used early in the disease course, and patients should have a complete tumor profile and access to effective compatible therapy.
The rapidly expanding body of 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 characteristics, such as those involved in immune suppression. However, genomics has also revealed a complicated reality regarding malignancies that requires a major shift in the therapy paradigm: away from treatment focused on tumor type and toward gene-directed, histology-independent treatment, which It is individualized for each patient based on biomarker analysis.
This paradigm shift is reflected in the emergence of precision medicine trials with innovative designs. Next-generation sequencing (NGS) of advanced cancers has shown that genomic alterations do not fall neatly into categories defined by the organ of origin of the tumor. Furthermore, metastatic tumors harbor tremendously complex and individually unique genomic and immunological landscapes. Therefore, to attack malignant neoplasms with “precision”, treatment must be personalized.
In this article, the authors review the rapid evolution 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 designs for precision medicine
Traditionally, oncology trials are drug-focused and aim to identify common attributes among patients (e.g., their tumor type or, more recently, a shared genomic abnormality) and enroll them in a trial with a specific drug regimen. . The large variability in genomic subgroups, microenvironment, baseline characteristics, comorbidities, and other covariates resulted in tumor-specific clinical studies encompassing a tremendously heterogeneous population in histology-specific independent gene assays.
Randomized phase III trials were often critical for regulatory approval of a new agent/regimen, especially because the antitumor activity of a new drug/regimen was frequently only better than that of the comparison group (usually conventional therapy), as perhaps because the regimen was effective only in a small subgroup of the diverse population represented by a specific histology.
The ultimate goal of precision medicine is an individualized, patient-centered (rather than drug-centered) trial based on the best available biomarkers. In “N of 1” trials, treatment of each patient is considered separately based on their molecular, immunological, and other biological characteristics. These trials involve personalized drug combinations tailored to individual patients. To determine efficacy in “N of 1” trials it is necessary to evaluate the strategy of matching patients to medications, rather than treatments, which differ from patient to patient.
Genomics and other biomarkers
Genomics has been the cornerstone of precision medicine studies. Beyond genomics, RNA and protein profiles, with proteins being the effectors of signaling, also appear to be important in mediating biological impact. Interestingly, comparing patients to drugs on the basis of genomics has been shown to be more effective in improving outcomes than comparison on the basis of protein assays, perhaps for technical reasons.
Despite current practical limitations, protein and transcript assays can provide essential information when integrated with genomics. Recently, panels incorporating immune signatures, based on DNA, RNA and/or proteins, have also gained clinical importance.
> Analysis of cell-free DNA derived from blood.
Clinical-grade ctDNA testing, which is noninvasive and reflects tumor heterogeneity (because tumor DNA can leak into the bloodstream from multiple metastatic lesions), is increasingly used to select cancer therapies and monitor the dynamics of subclones during treatment. The discordance observed in some cases between the results of ctDNA testing and genotyping analysis of tumor tissue might reflect technical problems, but might be attributable to the following biological reasons: (1) tumor NGS measures genomics in the small portion of biopsied tissue, while ctDNA evaluates DNA shed from multiple sites; (2) ctDNA is associated with tumor burden and can be detected at low levels.
> Analysis of circulating tumor cells (CTCs) derived from blood
The presence of CTCs, which are epithelial tumor cells, has been 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 CTC in clinical practice has not been fully established.
Finally, serial CTC analyzes might enable real-time disease surveillance. A Comparative Study of Five Prospective Randomized Phase III Trials in 6,081 Patients With Metastatic Castration-Resistant Prostate Cancer
evaluated the prognostic value of CTCs in comparison with prostate-specific antigen. CTC ≥ 0 at baseline and at week 13 from 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 great advance in oncology. Several novel approaches are currently being explored: checkpoint blockade, oncolytic viruses, cellular products, engineered cytokines, CD3 bispecific antibodies, vaccine platforms, and adoptive cell therapy.
> Blockade of checkpoints
There are seven FDA-approved checkpoint inhibitors: ipilimumab, pembrolizumab, nivolumab, avelumab, cemiplimab, durvalumab, and atezolizumab. Selected patients with advanced disease have a notable response, including durable complete remission (CR).
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