Molecular Evolution

When The Pathologist magazine first came into being, we spoke with Ian Cree – then Head of the World Health Organization Classification of Tumors Group, International Agency for Research on Cancer – about the best practice guidance for stellar molecular pathology results. Ten years later, we connected with Cree – now Director at CanTech Limited – to discuss advances over the past decade and to offer a glimpse into the future.

Our 2014 interview with Cree, Minimize Errors, Report with Accuracy, is available here.

A decade on, do you think molecular testing is more reliable? Is there more work to be done?
 

Yes and no! Older PCR-based technologies are now very reliable, and sequencing methods are increasingly so. However, all molecular labs need to participate in external quality assurance to ensure accuracy of results, and there are issues around those performed in single labs, with some countries limiting laboratory-developed tests. Laboratory accreditation has largely caught up, helping ensure reliability. The main issues revolve around timeliness of reporting results to patients – particularly those whose treatment requires a molecular result before starting therapy.

Have the European guidelines you mentioned in 2014 been widely adopted?
 

The basics from 2014 are still the same, but the challenges for those providing external quality assessment (EQA) services are undoubtedly greater. Obtaining or producing suitable control material to send around labs is key, and one welcome change has been the involvement of a number of companies in helping provide these controls for EQA schemes.

In your experience, is reflex testing used more widely now than in 2014? What are the implications of this?
 

Yes, reflex testing is now commonly used to efficiently utilize limited tissue samples, ensure quick results, and optimize resources. This process requires ongoing management and supervision because new drugs frequently require assay adjustments or shifts in clinical testing priorities.

What do you believe is the most important development in molecular pathology in the past decade?
 

The obvious answer here is the widespread use and capabilities of next-generation sequencing (NGS) technology, alongside decreasing costs. However, challenges remain, such as choosing the right type of NGS for specific needs and considering whether the turnaround time for centralized services could affect clinical outcomes.

A less obvious but crucial factor is the growing need for multidisciplinary collaboration to ensure optimal patient outcomes. In some countries, regular meetings (tumor boards) with all specialists involved in a patient's care are mandatory for all cancer patients and are considered best practice.

The complexity of molecular diagnosis, especially in personalized medicine, has led to the creation of molecular tumor boards, where laboratory and clinical experts meet regularly. Throughout my career, I have found these meetings invaluable for keeping the team updated on the latest treatment advances. For example, the use of simple PCR methods for assessing BRAF mutations started with melanoma. After similar mutations were identified in Langerhans cell histiocytosis, an oncologist requested testing for a case, leading to effective off-label targeted therapy with excellent results. Subsequent trials confirmed these positive outcomes.

What trends have you seen in the field in the past decade?
 

In many high-income settings, there’s a shift from PCR to next-generation sequencing (NGS), though both have their advantages. PCR offers fast results for specific sequence variants, high sensitivity, and accuracy at a lower cost. Cassette-based PCR methods reduce technical errors and allow for multiplex testing, which increases coverage. However, NGS provides broader coverage, which is crucial for some target genes. A combined approach is often used: a rapid PCR test for common variants, followed by NGS if needed. These triage strategies help pathology departments manage resources efficiently and improve cost-effectiveness.

There is an ongoing debate about using NGS panels, exome, or whole genome sequencing. The key is to carefully choose the most appropriate method for the specific need. What is effective for research may not always be the best choice for clinical services, and vice versa.

What challenges remain in molecular testing?
 

The struggles are all about resources. When I started practice in the early 1980s, medicine was a lot less complex, much less expensive, and largely ineffective. Today it is complex, expensive, but far more effective. We have the ability to treat and even cure cancers that were previously fatal. The turnaround time for diagnosis has increased, as have the number of biopsies, the number of slides, and other investigations per case, and the result is strain on healthcare systems at every level. The answer to this is not simple, and largely outside pathology laboratories control. Without reduced workload from cancer prevention and early detection, there is only so much that optimal laboratory and clinical pathway management can achieve. However, pathologists can and should be involved in decision-making outside the laboratory.

And what has improved?
 

A recent improvement is in how elevated PSA levels are managed. Previously, this often led to many prostate biopsies, which were not very cost-effective and had poor outcomes. Now, using MRI to assess patients with high PSA levels has reduced the burden on histopathologists, although it has added some pressure to radiology departments.

Looking ahead, what do you hope will happen in the next 10–20 years?
 

It’s hard to retire when the rapid pace of advancements in healthcare is so exciting! To keep up, it will be important for healthcare systems to plan better for the future. Of course, it’s essential to treat patients as they come in with disease. However, if fewer patients present with late-stage disease, it will benefit both the patients and reduce the treatment resources needed. Early cancer detection programs are promising in this regard, though they currently focus mainly on common tumors.