Overcoming implementation challenges of personalised cancer therapy
Advances in high-throughput technologies to characterise tumours and the expanding repertoire of molecularly targeted therapies will make it increasingly achievable
- Date : 19 Sep 2012
- Topic : Cancer prevention
Personalised cancer therapy is based on the perception that detailed molecular characterisation of the patient's tumour and its microenvironment will enable tailored therapies to improve outcomes and decrease toxicity. The goal of personalised therapy is to target aberrations that drive tumour growth and survival, by administering the right drug combination for the right person. The time seems right for finally delivering personalised cancer therapy as standard of care, thanks to the increasing understanding of the mechanisms underlying tumour progression and drug sensitivity, and the increasing availability of targeted therapies and cost-effective multiplex testing. However, there are numerous challenges that need to be overcome to successfully implement personalised cancer therapy. In the Perspectives article published in the September issue of Nature Reviews Clinical Oncology, Funda Meric-Bernstam who is a Medical Director of the Institute for Personalised Cancer Therapy and Gordon Mills, a professor with joint appointments in Systems Biology, Breast Medical Oncology and Immunology units of The University of Texas MD Anderson Cancer Centre, analyse these challenges in the hope of understanding what still needs to be done to make personalised cancer therapy happen. In their article, Drs Meric-Bernstam and Mills discuss that until the clinical utility of personalised cancer therapy is not demonstrated broadly, it will not be considered as a standard of practice and thus not billable and payable.
- Tumour heterogeneity
Over the past several years, there has been increasing recognition that tumours are heterogeneous. First, there is significant intertumoral heterogeneity, but cancer cells within the tumour may have also functional heterogeneity. Furthermore, tumours may differ in their ability to migrate and invade, and, at the same time, cancer cells that do disseminate can survive, remain dormant, or develop metastases.
- Molecular evolution and resistance
The array of clones with particular aberrations can change under both the selective pressure of a targeted therapy and as a result of the mutagenic activity of radiation and chemotherapy. Resistance to therapy can be pre-existing due to the presence of concurrent aberrations, can arise through adaptive responses induced by the targeted therapeutic or can appear by acquisition of novel mutations that activate signalling pathways necessary for tumour cell survival. There are two general conceptual approaches to deal with intratumoral heterogeneity and emergence of resistance: in-depth characterisation of tumours and recurrence to identify rare and dominant clones, and low-depth sequential characterisation of tumours to identify dominant clones. As obtaining multiple biopsies is costly and associated with potential morbidity, surrogates such as molecular imaging, or analysis of circulating tumour cells or circulating free DNA, are also being pursued in ongoing studies.
- Undruggable targets
To date, most of the effective targeted therapies have targeted gain-of-function mutations in oncogenes. However, many proteins are currently 'undruggable', and loss-of-function mutations in many tumour suppressor genes are currently not actionable.Technical challenges Identification and validation of markers of sensitivity and resistance is a key step in the implementation of personalised cancer therapy. Nevertheless, due to the potential gains from increased understanding of mechanisms of treatment sensitivity and resistance, molecular analysis of unusual responders should be integral to all personalised cancer therapy programmes. Comprehensive analysis of not only alterations in the genome but also the epigenome, transcriptome, proteome, and gene–gene, protein–protein and genome–environment interactions is likely to have important clinical implications in biomarker development.
- Need for new trial designs
Biomarker discovery and validation must be integrated into all aspects of drug development, from discovery through to clinical trials. However, current clinical trial designs are often not optimal for biomarker discovery and validation. Novel clinical trial designs to identify and validate biomarkers and targeted therapeutics require special approaches such as mandatory research biopsies, and comprehensive tumour and germline characterisation. When research biopsies are optional rather than mandatory, the biopsies often are not obtained. In many trials the scientific information to be gained by the research biopsies outweigh the biopsy risks, as research biopsy-related complications are relatively rare (about 1.4%).
- Multiplexed marker analysis
Currently, individual assays of relevant biomarkers are often carried out before starting the treatment with standard therapy or before enrolling the patient in a clinical trial. This approach would help in reducing testing costs overall. However, it can introduce delays in treatment initiation, require large amounts of precious tissue and, for patients whose tumours are negative for tested biomarkers, this approach can potentially delay implementation of an effective therapy. The retrieval of archival tissue blocks can take days to weeks, especially if they are stored in a different institution. This potential delay in therapy implementation could be accentuated with whole-exome sequencing (WES) and whole-genome sequencing (WGS), in which testing and analysis can take several weeks, extending the testing process beyond a clinically acceptable window for many patients. One option to avoid delays in biomarker turnaround is to carry out comprehensive multiplexed tumour testing when the patient is first diagnosed, particularly for patients at high risk of progression or recurrence. However, until the impact of this approach on benefiting patient care is proven, how to cover costs of early testing is problematic, particularly because many of these patients will not have targetable mutations and only a portion of patients are likely to have disease recurrence. Further, up-front testing does not account for tumour evolution or alterations induced by therapy. Alternatively, on disease recurrence or progression, new biopsies could be obtained, eliminating the time for archival tissue retrieval, and allowing analysis of molecular evolution. However, this approach engenders cost and morbidity because of the biopsy. Quality of biopsies and whether they are representative are also a significant concern as, even with dedicated radiologists and pathologists, a significant proportion of biopsies are inadequate for biomarker assessment. Three different conceptual approaches to multiplexed testing are under evaluation: first 'hot spot' analysis of recurrent mutations; second, evaluation of open-reading frames of the many identified cancer genes; and, third, WES and WGS. It will soon be less expensive to sequence whole genomes than to store, manipulate and analyse data.
- Target and therapy prioritisation
High-quality bioinformatics are needed to use data generated from molecular profiling for decision making. Today, only a few dozen aberrations are truly targetable with high-quality data indicating that targeted therapies are likely to benefit the patient with those mutations.
It is not yet known what degree and duration of target inhibition is necessary to develop optimal outcomes. Would short-term, high level inhibition of the target be more effective or less toxic than chronic inhibition? This is particularly challenging with combination therapy due to additive toxicities and needs for appropriate dosing and sequencing of both drugs. A major preclinical efforts linking systems biology approaches to animal models and clinical trials are needed.
- Clinical laboratory certification
Biomarkers used for clinical decision-making (including patient selection or stratification for clinical trials) need to be identified in a certified laboratory. This can add significant costs and delays to biomarker implementation. The spectrum of 'actionable' events is rapidly evolving with the emergence of new drugs and biomarker-drug pairs. Thus, there needs to be a prospective plan in place to determine which targets and assays should be performed in a certified laboratory.
In this early stage of genomic testing, it has remained unclear which tests will be reimbursable, and what level of evidence is needed to consider a test a 'standard of care' test, rather than research in intent. This is an area of significant activity and controversy, and guidelines for utilisation and reimbursement of molecular diagnostics are needed.
Patient willingness for participating in study-required tests is high, especially for less–invasive tests such as urine, blood, and imaging with CT and ultrasound, whereas patients are less willing to undergo tumour and skin biopsies. However, most patients are willing to undergo at least one tumour biopsy. The new era of genomic diagnostics will also have unique challenges due to patient demands for molecular testing as well as unrealistic expectations of patients. WES and WGS will bring unique challenges about return of incidental research findings, as will biospecimen and data-sharing for genomic research.
The full perspective you can read through the ESMO Scientific Journal Access programme.
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