Precision oncology: origins, optimism, and potential

Prasad, Vinay; Fojo, Tito; Brada, Michael

doi:10.1016/s1470-2045(15)00620-8

Cited by 207 publications

(150 citation statements)

References 33 publications

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“…Although the precision oncology approach still remains an unproven hypothesis [11] , existing data suggest that benefits can definitely be achieved for a subset of patients. Since this proof-of-principle has been conducted, the extension of these benefits to a larger population still remains to be achieved, but as we argue here, deeper molecular analyses will have to be part of this process.…”

Section: Introductionmentioning

confidence: 99%

Cancer Precision Medicine: Why More Is More and DNA Is Not Enough

Schütte

Ogilvie

Rieke

et al. 2017

Public Health Genomics

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Every tumour is different. They arise in patients with different genomes, from cells with different epigenetic modifications, and by random processes affecting the genome and/or epigenome of a somatic cell, allowing it to escape the usual controls on its growth. Tumours and patients therefore often respond very differently to the drugs they receive. Cancer precision medicine aims to characterise the tumour (and often also the patient) to be able to predict, with high accuracy, its response to different treatments, with options ranging from the selective characterisation of a few genomic variants considered particularly important to predict the response of the tumour to specific drugs, to deep genome analysis of both tumour and patient, combined with deep transcriptome analysis of the tumour. Here, we compare the expected results of carrying out such analyses at different levels, from different size panels to a comprehensive analysis incorporating both patient and tumour at the DNA and RNA levels. In doing so, we illustrate the additional power gained by this unusually deep analysis strategy, a potential basis for a future precision medicine first strategy in cancer drug therapy. However, this is only a step along the way of increasingly detailed molecular characterisation, which in our view will, in the future, introduce additional molecular characterisation techniques, including systematic analysis of proteins and protein modification states and different types of metabolites in the tumour, systematic analysis of circulating tumour cells and nucleic acids, the use of spatially resolved analysis techniques to address the problem of tumour heterogeneity as well as the deep analyses of the immune system of the patient to, e.g., predict the response of the patient to different types of immunotherapy. Such analyses will generate data sets of even greater complexity, requiring mechanistic modelling approaches to capture enough of the complex situation in the real patient to be able to accurately predict his/her responses to all available therapies.

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Section: Introductionmentioning

confidence: 99%

Cancer Precision Medicine: Why More Is More and DNA Is Not Enough

Schütte

Ogilvie

Rieke

et al. 2017

Public Health Genomics

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“…6,7 The only prospective, randomized study evaluating the role of molecular profiling in informing treatment strategy…”

Section: Discussionmentioning

confidence: 99%

“…These programs must balance concerns regarding cost and clinical benefit. 6,7 Commercial molecular testing using large gene panels can cost upwards of US$5000 and current data suggests that molecular profiling results in only 4% of patients receiving a matched treatment. 8,9 Prior to merging with the Peter MacCallum Cancer Centre in To keep costs low, custom panels only included genes of interest and cost approximately US$300 per patient, which is an order of magnitude lower than commercial panels.…”

Section: Introductionmentioning

confidence: 99%

Precision oncology using a clinician‐directed, tailored approach to molecular profiling

Lam

Beck

Tie

et al. 2017

Asia-Pac J Clncl Oncology

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Aim: Precision oncology involves molecularly matching patients to targeted agents usually in early drug development (EDD) programs. Molecular profiling (MP) identifies actionable targets. Comprehensive commercial MP platforms are costly and in resource limited environments, a more practical approach to MP is necessary to support EDD and precision oncology. We adopted a clinician-directed, tailored approach to MP to enrol patients onto molecularly targeted trials. We report the feasibility of this approach. Results:We identified 377 patients referred to RMH EDD. A total of 216 (57%) had MP ordered.The remainder had known actionable targets (19%), or were inappropriate for clinical trials (24%).In those undergoing MP, 187 genetic aberrations were found in 113 patients with 98 considered actionable targets in 86 patients. Ninety-eight (25%) patients were enrolled onto a clinical trial, including 40 (11%) receiving molecularly matched treatments. Median progression-free survival was improved in patients enrolled onto molecularly matched trials compared to those on unmatched trials (3.6 months vs 1.9 months, HR 0.58 [0.38-0.89], P = 0.013). Conclusion:A clinician-directed, tailored approach to the use of MP is feasible, resulting in 11% of patients enrolled onto molecularly matched trials.

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“…Recent advances in genomic technologies and bioinformatics analyses have significantly reduced the cost of sequencing tumor samples and, in few cases, have altered treatment strategies 51 . Precision therapeutics programs in many institutions rely on sequencing of genes frequently mutated/amplified/deleted in cancer and believed to be associated with cancer progression 17, 55 .…”

Section: Introductionmentioning

confidence: 99%

A system for detecting high impact-low frequency mutations in primary tumors and metastases

et al. 2017

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Tumor complexity and intratumor heterogeneity contribute to subclonal diversity. Despite advances in next-generation sequencing (NGS) and bioinformatics, detecting rare mutations in primary tumors and metastases contributing to subclonal diversity is a challenge for precision genomics. Here, in order to identify rare mutations, we adapted a recently described epithelial reprograming assay for short-term propagation of epithelial cells from primary and metastatic tumors. Using this approach, we expanded minor clones and obtained epithelial cell-specific DNA/RNA for quantitative NGS analysis. Comparative Ampliseq Comprehensive Cancer Panel sequence analyses were performed on DNA from unprocessed breast tumor and tumor cells propagated from the same tumor. We identified previously uncharacterized mutations present only in the cultured tumor cells, a subset of which has been reported in brain metastatic but not primary breast tumors. In addition, whole-genome sequencing identified mutations enriched in liver metastases of various cancers, including Notch pathway mutations/chromosomal inversions in 5/5 liver metastases, irrespective of cancer types. Mutations/rearrangements in FHIT, involved in purine metabolism, were detected in 4/5 liver metastases, and the same four liver metastases shared mutations in 32 genes, including mutations of different HLA-DR family members affecting OX40 signaling pathway, which could impact the immune response to metastatic cells. Pathway analyses of all mutated genes in liver metastases showed aberrant tumor necrosis factor and transforming growth factor signaling in metastatic cells. Epigenetic regulators including KMT2C/MLL3 and ARID1B, which are mutated in >50% of hepatocellular carcinomas, were also mutated in liver metastases. Thus, irrespective of cancer types, organ-specific metastases may share common genomic aberrations. Since recent studies show independent evolution of primary tumors and metastases and in most cases mutation burden is higher in metastases than primary tumors, the method described here may allow early detection of subclonal somatic alterations associated with metastatic progression and potentially identify therapeutically actionable, metastasis-specific genomic aberrations.

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Precision oncology: origins, optimism, and potential

Cited by 207 publications

References 33 publications

Cancer Precision Medicine: Why More Is More and DNA Is Not Enough

Cancer Precision Medicine: Why More Is More and DNA Is Not Enough

Precision oncology using a clinician‐directed, tailored approach to molecular profiling

A system for detecting high impact-low frequency mutations in primary tumors and metastases

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