The ability to predict the future behavior of an individual cancer is crucial for precision cancer medicine. The discovery of extensive intratumor heterogeneity and ongoing clonal adaptation in human ...tumors substantiated the notion of cancer as an evolutionary process. Random events are inherent in evolution and tumor spatial structures hinder the efficacy of selection, which is the only deterministic evolutionary force. This review outlines how the interaction of these stochastic and deterministic processes, which have been extensively studied in evolutionary biology, limits cancer predictability and develops evolutionary strategies to improve predictions. Understanding and advancing the cancer predictability horizon is crucial to improve precision medicine outcomes.
Large-scale genomic cancer medicine initiatives are under way in several countries across the globe.
However, it remains a major challenge to use genomic information to make accurate predictions for individual cancer patients.
Multiple genomic studies substantiated the notion of cancer as an evolutionary process that can readily adapt within the lifetime of a patient.
Evolutionary adaptation results from the interplay of mutation generation and genetic drift, which are both stochastic processes, and clonal selection, which is deterministic in nature.
The influence of stochastic factors fundamentally limits the predictability of cancer evolution.
Understanding the limits of predictability and the development of more accurate prediction algorithms using evolutionary models is key to improving outcomes through genomic cancer medicine.
Precision diagnostics is one of the two pillars of precision medicine. Sequencing efforts in the past decade have firmly established cancer as a primarily genetically driven disease. This concept is ...supported by therapeutic successes aimed at particular pathways that are perturbed by specific driver mutations in protein-coding domains and reflected in three recent FDA tissue agnostic cancer drug approvals. In addition, there is increasing evidence from studies that interrogate the entire genome by whole-genome sequencing that acquired global and complex genomic aberrations including those in non-coding regions of the genome might also reflect clinical outcome. After addressing technical, logistical, financial and ethical challenges, national initiatives now aim to introduce clinical whole-genome sequencing into real-world diagnostics as a rational and potentially cost-effective tool for response prediction in cancer and to identify patients who would benefit most from ‘expensive’ targeted therapies and recruitment into clinical trials. However, so far, this has not been accompanied by a systematic and prospective evaluation of the clinical utility of whole-genome sequencing within clinical trials of uniformly treated patients of defined clinical outcome. This approach would also greatly facilitate novel predictive biomarker discovery and validation, ultimately reducing size and duration of clinical trials and cost of drug development.
This manuscript is the third in a series of three to review and critically appraise the potential and challenges of clinical whole-genome sequencing in solid tumors and hematological malignancies.
Precision cancer medicine (PCM), frequently used for the expensive and often modestly efficacious off-label treatment with medications matched to the tumour genome of end-stage cancer, challenges ...healthcare resources. We compared the health effects, costs and cost-effectiveness of our MetAction PCM study with corresponding data from comparator populations given best supportive care (BSC) in two external randomised controlled trials.
We designed three partitioned survival models to evaluate the healthcare costs and quality-adjusted life years (QALYs) as the main outcomes. Cost-effectiveness was calculated as the incremental cost-effectiveness ratio (ICER) of PCM relative to BSC with an annual willingness-to-pay (WTP) threshold of EUR 56,384 (NOK 605,000). One-way and probabilistic sensitivity analyses addressed uncertainty.
We estimated total healthcare costs (relating to next-generation sequencing (NGS) equipment and personnel wages, molecularly matched medications to the patients with an actionable tumour target and follow-up of the responding patients) and the health outcomes for the MetAction patients versus costs (relating to estimated hospital admission) and outcomes for the BSC cases. The ICERs for incremental QALYs were twice or more as high as the WTP threshold and relatively insensitive to cost decrease of the NGS procedures, while reduction of medication prices would contribute significantly towards a cost-effective PCM strategy.
The models suggested that the high ICERs of PCM were driven by costs of the NGS diagnostics and molecularly matched medications, with a likelihood for the strategy to be cost-effective defying WTP constraints. Reducing drug expenses to half the list price would likely result in an ICER at the WTP threshold. This can be an incentive for a public-private partnership for sharing drug costs in PCM, exemplified by ongoing European initiatives.
NCT02142036
Precision cancer medicine promises to tailor clinical decisions to patients using genomic information. Indeed, successes of drugs targeting genetic alterations in tumors, such as imatinib that ...targets BCR–ABL in chronic myelogenous leukemia, have demonstrated the power of this approach. However, biological systems are complex, and patients may differ not only by the specific genetic alterations in their tumor, but also by more subtle interactions among such alterations. Systems biology and more specifically, network analysis, provides a framework for advancing precision medicine beyond clinical actionability of individual mutations. Here we discuss applications of network analysis to study tumor biology, early methods for N-of-1 tumor genome analysis, and the path for such tools to the clinic.
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•Networks provide a platform for inference from 'omic data.•Many network-based methods have been developed around cancer 'omic data analysis.•Most tumor network analyses rely on cohorts, but some N-of-1 methods exist.•Many challenges remain for applying network-based analysis in clinical settings.
Precision cancer medicine brought the promise of improving outcomes for patients with cancer. High-throughput molecular profiling of tumors at treatment failure aims to direct a patient to a ...treatment matched to the tumor profile. In this way, improved outcome has been achieved in a small number of patients whose tumors exhibit unique targetable oncogenic drivers. Most cancers, however, contain multiple genetic alterations belonging to and of various hallmarks of cancer; for most of these alterations, there is limited knowledge on the level of evidence, their hierarchical roles in oncogenicity, and utility as biomarkers for response to targeted treatment(s). We developed a proof-of-concept trial that explores new treatment strategies in a molecularly-enriched tumor-agnostic, pediatric population. The evaluation of novel agents, including first-in-child molecules, alone or in combination, is guided by the available understanding of or hypotheses for the mechanisms of action of the diverse cancer events. Main objectives are: to determine 1) recommended phase 2 doses, 2) activity signals to provide the basis for disease specific development, and 3) to define new predictive biomarkers. Here we outline concepts, rationales and designs applied in the European AcSé‐ESMART trial and highlight the feasibility but also complexity and challenges of such innovative platform trials.
•ESMART explores targeted agents in a molecularly enriched childhood cancer cohort.•ESMART confronts limitations in access to innovative therapies and trial designs.•More than 250 patients in 16 arms from 6 countries have been included since 2016.•ESMART reflects the strong families’, patients’, citizens’ desire and commitment.•It brings drug development and translating biology into new therapeutic strategies.
Next generation sequencing (NGS) has been an invaluable tool to put genomic sequencing into clinical practice. The incorporation of clinically relevant target sequences into NGS‐based gene panel ...tests has generated practical diagnostic tools that enable individualized cancer‐patient care. The clinical utility of gene panel testing includes investigation of the genetic basis for an individual's response to therapy, such as signaling pathways associated with a response to specific therapies, microsatellite instability and a hypermutated phenotype, and deficiency in the DNA double‐strand break repair pathway. In this review, we describe the concept of precision cancer medicine using target sequences in gene panel tests as well as the importance of the control of sample quality in routine NGS‐based genomic testing. We describe geographic and ethnic differences in cancer genomes, and discuss issues that need to be addressed in the future based on our experiences in Japan.
The incorporation of clinically relevant target sequences into next generation sequencing (NGS)‐based gene panel tests has generated practical diagnostic tools that enable individualized cancer‐patient care. In this review, we describe the concept of precision cancer medicine using target sequences in gene panel tests as well as the importance of the control of sample quality in routine NGS‐based genomic testing. We describe geographic and ethnic differences in cancer genomes, and discuss issues that need to be addressed in the future based on our experiences in Japan.
Two recent policy documents by the European Union, ‘Europe's Beating Cancer Plan’ and its accompanying ‘Conquering Cancer: Mission Possible’ (CCMP), articulate broad policies aimed at reducing cancer ...mortality across Europe, for example, by promoting prevention and early detection. The focus for cancer treatment in these manifestos is the expansion of personalised cancer medicine (PCM). However, the CCMP document suggests that the uptake of PCM is “hampered by uncertainty about its outcomes”. What are these outcomes and why this uncertainty? We address the limits of PCM in pathology-driven and pathology-agnostic PCM, briefly discussing the results of umbrella and basket trials. We suggest that the complexity, plasticity and genetic heterogeneity of advanced cancers will continue to thwart the impact of PCM, limiting it to specific pathologies, or rare subsets of them. Caution regarding the advancement of PCM is justified, and policymakers should be wary of the hype of lobbyists, who do not acknowledge the limits of PCM.
•This current perspective comments on recent cancer policy statements from the European Union regarding the persuit of personalised cancer medicine.•The complex biology of advanced cancers, particularly their genetic evolution in space and time, limits the impact of personalised cancer medicine.•Caution regarding the advancement of personalised cancer medicine is justified.
Cancer is often driven by the accumulation of genetic alterations, including single nucleotide variants, small insertions or deletions, gene fusions, copy-number variations, and large chromosomal ...rearrangements. Recent advances in next-generation sequencing technologies have helped investigators generate massive amounts of cancer genomic data and catalog somatic mutations in both common and rare cancer types. So far, the somatic mutation landscapes and signatures of >10 major cancer types have been reported; however, pinpointing driver mutations and cancer genes from millions of available cancer somatic mutations remains a monumental challenge. To tackle this important task, many methods and computational tools have been developed during the past several years and, thus, a review of its advances is urgently needed. Here, we first summarize the main features of these methods and tools for whole-exome, whole-genome and whole-transcriptome sequencing data. Then, we discuss major challenges like tumor intra-heterogeneity, tumor sample saturation and functionality of synonymous mutations in cancer, all of which may result in false-positive discoveries. Finally, we highlight new directions in studying regulatory roles of noncoding somatic mutations and quantitatively measuring circulating tumor DNA in cancer. This review may help investigators find an appropriate tool for detecting potential driver or actionable mutations in rapidly emerging precision cancer medicine.
Background
Precision cancer medicine-related rashes are a kind of skin and mucous lesions caused by precision therapy. More and more evidences indicated that such events should not be ignored in the ...course of anti-tumor therapy. Since cancer treatment entered the “Precision Era”, there has been a rapid increase in this field. However, there was few bibliometric studies to provide an overall review of this field. This study aims to evaluate the literature output and trends in researches on precision cancer medicine-related rashes from a global perspective.
Methods
Collected publications on precision cancer medicine-related rashes from the Web of Science Core Collection database, which were limited to articles and reviews in English. Microsoft Excel, VOS viewer and CiteSpace V were used for quantitative and visual analysis.
Results
A total of 1,229 papers were identified. From 2008 to 2021, annual publications increased year by year. The United States published the most papers in this field (44.9%) and ranking first in citation frequency (19,854 times) and H-index (69). The University of Texas system ranks first with 98 papers published. Lacouture M.E and Robert C were the principal investigators. Cancers has the largest number of articles published, with 70 articles. In recent years, there have been research hotspots related to immunotherapy, including ipilimumab, immunotherapy, tumor microenvironment, association, checkpoint inhibitor, and cutaneous adverse event.
Conclusion
Precision cancer medicine-related rashes are a hot research topic in oncology. The number of relevant publications will increase dramatically. “Checkpoint inhibitors”, “skin adverse events”, “associations” and “tumor microenvironment” may become research hotspots in the future.
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