Living the Molecular Revolution

What have been the biggest molecular pathology game-changers?

The fact that we now have molecular alterations that we can target is game-changing in itself. The tyrosine kinase (TK) story is a good example of how molecular pathology changed our life and our way of thinking. After its approval in 2001, the tyrosine kinase inhibitor (TKI) therapy imatinib caused an almost doubling of survival rate in people with chronic myeloid leukemia and gastrointestinal stromal tumors.

Diagnostic technologies have also undergone a substantial evolution; we now have reliable, sensitive tools that can identify mutations. We realize that low levels of targetable mutant cells in tumors matter, and these technologies allow us to find them.

As the importance of molecular diagnostics increases, what difficulties might pathologists face?

Education is a big challenge. Pathologists are under constant pressure to keep track of developments and we are only just starting to address this knowledge gap. I’m president of the newly formed Belgian molecular pathology working group and we’re aiming to remedy the situation in my home country by uniting academic and clinical pathologists to share knowledge, which we’ll do through regular meetings, newsletters and journal publications. Unfortunately, pathology residents are not well-trained in molecular pathology. How can we expect full-time pathologists to keep on top of the latest developments in this area if they have no foundation from their initial training? So as part of the working group, we will look to introduce molecular education into residents’ training programs.

And in spite of many pathologists’ and oncologists’ concerns about the changes that will inevitably be accompanied by the rising importance of molecular pathology, the thirst for the knowledge is there. For instance, we are running an educational workshop in Brussels this month on immuno-oncology. We expected 50 people to attend, but we have 170 registered! Pathologists and oncologists understand that if they don’t learn about these new advances, they’ll be left behind.

Another key challenge for pathologists is the need to understand new technology platforms. Even if they are sending material to another lab to be tested, it’s so important that pathologists understand the technology that’s used in testing their material; in particular how reliable it is, how sensitive it is, and what the detection limits are.

Though many pathologists have been reluctant to adopt these new techniques and technologies, they need to be assured that molecular pathology is becoming part of their job.

How have the technologies and techniques that you use changed in the last few years?

We started out using Sanger sequencing and polymerase chain reaction (PCR). But now we work with next-generation sequencing (NGS), liquid biopsy, and digital automated PCR technologies, such as Idylla (Biocartis). Our needs have changed a lot over the years; we need speed, reliability, sensitivity, high-quality. Newer technologies are giving us that, allowing us to make better diagnoses than ever before.

In our lab we currently receive around 2,500 cases per year, 80 percent of which are from other hospitals. We run a lot of HER2 FISH tests for breast, RAS tests for colon, and EGFR and ALK tests for lung cancers. We also conduct a lot of BRAF testing for melanoma and identify rarer forms of cancer, such as Ewing’s sarcoma. I’m very excited about the advances in molecular pathology – they are allowing us to play a central role in improving patient survival! Having said that, our increasing knowledge and capabilities have their downsides too.

Downsides, such as…?

The volume of data generated by NGS. Our problem is having too much of it; we are overwhelmed. Also, our understanding of disease has advanced so much that we are now expected to run regular molecular tests for cancer patients not only for diagnostic purposes but also for follow-up. For example, in NSCLC, I receive plasma samples from lung cancer patients receiving TKI’s every three months to look for T790M resistance mutations. It’s great, in that we can identify the 50 percent of patients affected by resistance but it is important that new drugs can be used to treat these resistant mutation. In the future, this kind of monitoring testing will become increasingly important and will account for much more work. These patients can have survival rates of three to four years, so it goes without saying that the huge burden on molecular pathology services will only worsen.

How will pathology services cope?

This is a difficult question to answer – I don’t know. I’m hoping that more hospitals will conduct molecular testing with a short turnaround time. Turnaround times for these tests are so important, and waiting for one month or more for a result is unacceptable.

Molecular tumor boards are also very important. We already run these in our hospital; we meet weekly to discuss cases, in particular when non-classical mutations are found, and work to find solutions and treatment pathways. More hospitals need to run similar tumor boards, but for them to be truly effective, the pathologists and oncologists need to be kept updated of developments, otherwise they won’t work.

Where will the money come from to expand molecular services?

Governments. I can’t deny it won’t be easy though. When I speak with government officials about the advances in molecular diagnostic technologies and what installing them will mean for patient outcomes, they’re enthusiastic. But when we come to the issue of cost, the conversation ends. We are in hard financial times and every idea that costs more to healthcare services is not an easy sell. I do think that governments will back these technologies once they become cheaper. Remember when PCR was first introduced? Only academic institutes had a PCR because they were viewed as expensive and complex; I believe there were only around five or six systems in Belgium. Nowadays you can get a PCR for next to nothing. If these new platforms start to reduce in price, prove themselves reliable, easy to handle, and sensitive, why wouldn’t almost every hospital have one? I believe this is the only way that we will be able to cope with the continuously expanding demands on molecular services.

I am very happy that I am not the Minister of Health – that must be such a tough job!

What technological improvements are still needed?

Fluids that can stabilize DNA so that it is easier to transport sample materials would be very helpful to us. If we consider the current process with plasma samples. First you have to take a 10 ml blood sample, then you have to centrifuge it within 1.5 hours, then you have to transport it immediately (or in dry ice), and it needs to make it to the testing lab as soon as possible. Improvements in stability to make all of these factors less critical would be ideal. Also, you need a lot of DNA to have a reliable test result and it would be helpful if analytical equipment could test DNA with lower blood volumes.

Manufacturers are making good progress, though. This is a commercially-competitive field and we can only benefit from that.

What are your predictions for the future of molecular pathology?

Follow-up testing of patients will become more important than ever. Also, our approach to diagnosis will need to change. For example, in the past, we would use traditional methods to diagnose lung cancer and this would be followed by molecular techniques to identify EGFR mutations. In the future, I believe we will look immediately for targetable mutations in a tumor.

One thing we can’t predict though is the future influence of immuno-modulatory therapy on oncology. Advances in this field will change things for us. Currently I know of five firms that are trialing PD-1/PDL-1 antibodies, but they are being developed with their own partnered diagnostic assay. The fact that we may only be able to recommend new treatments with a specific companion diagnostic test result is a catastrophe for those of us who run the tests.

We are in need of new biomarkers too. I was speaking with someone at the recent ESMO congress in Vienna who said that, PDL-1 immunohistochemical tests “were the best of a bad bunch.” We know they’re not optimal predictive tests for PD-1 immunomodulatory therapy, but we currently have no alternatives.

Are you optimistic?

Always! When I was a resident, the impact of the pathologist on treatment decisions was sometimes limited. Nowadays, oncologists can do absolutely nothing without the pathologist. They don’t know how to treat their patients unless they have all of the molecular information from us. So we are moving from the periphery of the clinical field to the central part of it. But we are not used to that. Pathologists are starting to understand though that, in order to progress in this field, they have to embrace this central role. Pathologists know it’s time to change and I’m very optimistic about the future of our profession.