ROGER EXPLORES… Whole Genome Sequencing: Hopes are high, but limitations (still) a reality

by Roger Wilson

When newly diagnosed it is quite natural for patients to want to know everything they can about their sarcoma. New technology seems to hold a host of opportunities for better treatment. Among them is genomic analysis.

Requests for Whole Genome Sequencing (WGS) are becoming more common and are putting a pressure on clinical diagnostics. These are usually services provided by academic units, which have limited capacity, or by commercial scientific organisations.

The wish to have the full genome of your sarcoma available for analysis, even if you do not understand it yourself, is understandable.  And while the costs fifteen years ago were in millions, it has come down in recent years to  600-1000 Euros or US dollars, and will fall further. However, having WGS at first diagnosis has many issues which need to be considered.

Whole genome sequencing has still many issues

The first challenge is whether WGS can be handled by your clinical team – laboratories have a particular approach to how samples are taken and stored. Their protocols must be met by the doctors taking the samples and the staff submitting them or analysis can be refused. Close working is required.

Then there is the timing. A decision to seek WGS should never delay standard of care treatment. If a specialist surgeon thinks that prompt excision of a tumour is necessary, or that neo-adjuvant therapy should begin, it should not be delayed.  Surgery is the primary treatment for almost every sarcoma, and surgery will rarely be affected by genetic information. Specialist pathology giving accurate histology information and good quality scans - usually MRI - are what is necessary for a surgeon’s planning.

Following curative surgery, genetics currently play no part in any decision-making. Adjuvant therapy is determined by the histology information, staging and grade of the tumour, and the reports from surgeon and pathologist following the surgery. Whether genetics will play a role at this stage in treatment in the future is an open question, which will only be answered by research. We hope for maintenance therapies for sarcoma that would be applicable when specific biomarkers are present. But there is little research on this at present.

The diagnostic capabilities of WGS are growing with experience but, as with any test, it has its limitations. Clinicians and patients should be aware that WGS is extremely reliable in some areas, but in others it still needs improvement and may miss or misinterpret a variant where signals are low. Bioinformatic technology is constantly evolving and improving, and it is important that doctors know what genes and what types of variants are being looked for and to keep up to date with these requirements

Recent studies underline its usefulness for diagnosis

A study published in 2024 by Cambridge University Hospitals (a long-standing leader in genomics) used WGS at diagnosis for a group of 73 patients. For 6 of them insufficient tissue was taken at biopsy to allow WGS, although they all had a full diagnosis. For the remaining 67 Sequencing was done to look for diagnostic clarification and for treatment targets. The study reports that 25 of the patients received an altered diagnosis, with ten either being confirmed as benign (non-sarcoma) or changed to benign. One case was described pathologically as an angiosarcoma but WGS revealed a gene fusion unique to epithelioid haemangioendothelioma(an even rarer sarcoma). One patient with metastatic sarcoma, having failed two lines of chemotherapy, was sequenced and indicated for an anti-PD1 immunotherapy. Such treatment is not authorized by regulators for sarcoma, but an exceptional treatment request was agreed for the drug pembrolizumab and the patient has survived three years so far. The paper has a full description of each of the 67 patients’ analyses. [i]

The European Society for Medical Oncology (ESMO) reported in 2024 the results of an international Working Party reviewing WGS in cancer. Their comments on sarcoma reinforce the results from the Cambridge study describing Sequencing as “an essential tool for identifying the histological sub-type of soft-tissue sarcomas and improving diagnosis.” [ii]

We are still far from routine WGS, but we should push

We are at the early stages of dawn for a new day in sarcoma diagnosis. It is currently being defined by limited access to sequencing, the costs involved, and developing the knowledge and skills which allow analysis to benefit patients. Where histological variants of uncertain significance are found, WGS data may be key to an accurate diagnosis but moving to the situation where this can be routine is a big step which has yet to start.[iii]

So, if you are diagnosed with sarcoma, discuss with your medical team before asking for your biopsy to be sequenced. Ask if it will take a long time to be completed, ask if it will help decisions about your primary treatment. Even if it does not help initially, it may give you prognostic information which is valuable to you. But, agree immediately if your doctor suggests that it is a valid approach and available.

However, if disease advances, it may be the route to an effective treatment and knowing what it reveals may open up access to innovative treatment quicker. To ensure value, there must be discussion. If WGS is taken into account when treatment decisions are being made, it should be discussed by a multidisciplinary team meeting which includes the genetics laboratory experts.

 

[i] Cambridge study of WGS at diagnosis: British Journal of Cancer 2024,Introduction and impact of routine whole genome Sequencing in the diagnosis and management of sarcoma, Dr J. Watkins and colleagues, Cambridge University Hospitals, https://doi.org/10.1038/s41416-024-02721-8

[ii] Report from European Society for Medical Oncology (ESMO), Annals of Oncology, Recommendations for the use of next-generation Sequencing (NGS) for patients with advanced cancer in 2024: a report from the ESMO Precision Medicine Working Group, https://doi.org/10.1016/j.annonc.2024.04.005

[iii] Further reading can be found in: Comments on WGS from a different disease perspective: British Medical Journal, Lessons and pitfalls of whole genome Sequencing, Dr Christopher J Record, Professor Mary M Reilly, University College London https://doi.org/10.1136/pn-2023-004083

 

Credits:  Graphic design by Karl Berger