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Cancer Therapy in the Genomic Era: Barriers and Distractions

Recent step change advances in sequencing technologies have delivered a near-complete lexicon of genomic cancer drivers. In parallel, progress in synthetic chemistry has facilitated the assembly of a broad armamentarium of molecularly-targeted therapies. However, whilst immunotherapy agents have produced notable benefits for subgroups of patients, the impact of molecularly-targeted therapies have been relatively modest.

Further unlocking the undeniable power of genomics in cancer will involve both the systematic removal of barriers and the avoidance of distractions that obscure progress. Both of which are discussed here.

Current barriers to progress

1. Availability and affordability of genomic testing
Access to clinical grade sequencing remains out of reach for most patients.

2. Quality and standardisation
Clinical offerings vary in their quality, partly related to the lack of appropriately applied standards. Key issues include poor regulation of laboratory developed tests (LDTs) in the US and over-reliance on the ISO15189 quality standard in Europe, which does not provide sufficient rigour to cover the development of the complex informatic pipelines required for variant calling.

3. Genomic scope
Cancer genomic research to date has been skewed towards analysis of DNA mutations (substitutions and small insertions/deletions) with less attention paid to structural variants such as copy number changes. This is also reflected in clinical genomic offerings, but does not mirror the biology of the disease, where copy number changes are key cancer drivers and underlie the majority of targetable events in tumour types such as sarcoma and ovarian cancer.

4. Identification of biologically significant (‘driver’) mutations
At the level of DNA substitutions, biologically important (‘driver’) mutations are significantly out-numbered by inconsequential collateral damage (‘passenger mutations’), yet processes to assign driver status are lacking. Failure to distinguish drivers from passengers risks contaminating molecularly stratified trials with false positive patients, with the attendant risk of abandoning effective therapies. Conversely, overly parsimonious allocation of driver status may deprive patients of beneficial therapy.

5. Reporting and interpretation of genomic data
The rapid emergence of sequencing technologies has out-paced the development of expertise in clinical interpretation. Unresolved issues include where to target training (oncologists versus pathologists) and how to represent complex genomic data so that it can be digested and understood rapidly in the context of a pressurised clinical practice.

6. Clinical trial design
Perhaps most importantly of all, the full realisation of the power of genomics in cancer requires significant changes in the way clinical trials are designed. Positive steps would include the inclusion of high-quality biomarker studies in all trials of targeted therapies, a move away from single agent therapy to combination approaches as routine, and a move away from the paradigm of iterative drug development based on specific resistance mutations (as exemplified by EGFR inhibitors in lung cancer).

Distractions to progress

1. Expecting a revolution
Precision oncology in the genomics era represents an evolution of current practice, not a revolution. Talk of a revolution has resulted in unrealistic expectations and led some to prematurely question the utility of precision oncology.

2. Whole genome sequencing in cancer
The rapid pace of change in genomic technologies has led some to recommend a move to clinical whole genome sequencing in cancer. Whilst it is likely that whole genome sequencing will eventually become the platform of choice, now is not the time, particularly for resource-stretched public healthcare providers.

3. Tumour heterogeneity and drug resistance
Tumour heterogeneity continues to be cited as a barrier to the full realisation of precision oncology. In the context of emerging drug resistance, it is now appreciated that by the time of presentation, cancers already contain collections of cells harbouring all possible genomic mutations, such that resistance to single agent therapy is pre-existing and thus inevitable. Solutions lie in the development of effective multi-drug therapy. A slightly different flavour of heterogeneity involves the presence of targetable mutations in a subset of cancer cells. However, this phenomenon is not universal and appears to be gene and cancer-type specific; for example, PIK3CA mutations are often sublonal in colorectal cancer whereas EGFR mutations are almost invariably clonal in lung cancer.

4. Circulating tumour DNA
The notion that analysis of circulating tumour DNA (ctDNA) can capture the entirety of the cancer genomic landscape across the primary and metastatic sites is appealing but unproven. Current techniques are also limited in their ability to capture the full spectrum of driver events, particularly copy number alterations. Of particular concern is the implication that ctDNA can be used to detect emerging drug resistance and guide therapy change prior to clinically overt disease progression; such an approach needs to be tested in properly controlled trials, as the concertinaing of sequential therapies into a smaller time window runs the risk of reducing overall patient survival. Whilst ctDNA holds promise, it is not a panacea and clinical applications need to be better understood and more rigorously tested before this approach represents a standard of care.

In conclusion, the full potential of cancer genomics to improve patient outcomes has yet to be fully realised. Whilst barriers exist, they are not insurmountable; however, progress will take time and expectations need to be realistic.

Philip Beer260

Philip Beer
is a Consultant Haematopathologist at the HMDS, St James’ Hospital in Leeds and a Visiting Scientist at the Sanger Institute in Hinxton. Philip will be leading a roundtable and speaking at the NGS and Clinical Applications Strand of the 4Bio Summit next month.

Click here to find out more about the 4Bio Summit.

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