In an interview with <em>Targeted Oncology</em>, Susan Branford, PhD discussed the current role of NGS testing in hematologic malignancies. Following her presentation at the 2019 EHA Congress, she addressed how NGS can be incorporated more into the community practice and what challenges must be overcome in order to make this happen.
Susan Branford, PhD
Next-generation sequencing (NGS) testing provides both clinicians and patients with a greater understanding of the disease biology, particularly in hematologic malignancies. By understanding the mutations that are present in the patient’s tumor, clinicians can make more well-informed treatment decisions for each individual patient.
Tyrosine kinase inhibitor (TKI) therapy has been a standard treatment option for patients with chronic myeloid leukemia (CML), and TKIs have been able to induce deep and durable responses in these patients. However, a major challenge that has developed with these agents is the emergence of TKI resistance. Mutations are frequently found in the BCR-ABL kinase domain in patients with CML, for example. These mutations can be detected by NGS testing to understand how a patient’s response to TKI therapy might be impacted.
NGS testing can detect a number of mutations to help predict outcome in patients across many hematologic malignancies, though more research must be done to understand how mutations can help make treatment decisions. BCR-ABL is only 1 of many mutations in CML that can help predict response to therapy.
“I think BCR-ABL remains the single most mutated gene, but we are now discovering that there are other mutations,” said Susan Branford, PhD. “Some of them may even be present at the time of diagnosis, so they actually contribute to primary resistance, which is something we haven’t understood previously.”
Incorporating these tests into clinical practice in the community setting remains a challenge. However, as research continues, the tests become more easily understood which will make moving them to the community much easier.
“I think there are so much data out there now showing a clinical need and how important it is to know the patient’s genomics so that they get the right drug,” said Branford, “and this will lead to so many more benefits, like cost savings, overall, in terms of hospital stays.”
In an interview withTargeted Oncology, Branford, an associate professor at the Centre for Cancer Biology, SA Pathology, in Adelaide, Australia, discussed the current role of NGS testing in hematologic malignancies. Following her presentation at the 2019 European Hematology Association (EHA) Congress, she addressed how NGS can be incorporated more into the community practice and what challenges must be overcome in order to make this happen.
TARGETED ONCOLOGY: How can we reduce barriers to access genomic technology in areas that have resource short falls?
Branford:This is a difficult question to answer at this stage, and I don’t think we fully understand the role of genomics in CML at this stage. There is still a lot of work to be done before we can make sense of all these data, then put out some recommendations and perhaps guidelines. What does it mean if you find a mutation? What do you do if you find a mutation? I think a lot of those types of questions need to be answered first, then this is the type of thing that needs to be tackled.
If we find that there is a clinical benefit to doing this testing, how can we get that out there, particularly in regions of poor resource? We [also] need to ensure that patients can benefit from this. That’s going to be another stage and the next battle; it’s taken us many years to get molecular monitoring for CML, and there has been a lot of work done to get that out in resource-poor areas, so there are now some techniques available so patients can receive good-quality monitoring. However, it took us a long time to get there.
TARGETED ONCOLOGY: What have you found about characteristics of leukemic cells that persist after treatment with TKIs?
Branford:Again, I think we are still trying to learn what’s going on there. There’s about 10% to 20% of patients that don’t respond optimally [to TKI therapy], so we do see persistence of leukemic stem cells or their progeny, and this contributes to lack of response to targeted TKI therapy. I think what we are starting to learn is that there are a number of mechanisms of resistance.
For many years, we’ve known of mutations within the BCR-ABL kinase domain, the main mechanism. I think BCR-ABL remains the single most mutated gene, but we are now discovering that there are other mutations. Some of them may even be present at the time of diagnosis, so they actually contribute to primary resistance, which is something we haven’t understood previously.
TARGETED ONCOLOGY: How frequently in clinical practice have you found NGS is actually used as a diagnostic tool for patients with hematologic malignancies?
Branford:For hematologic malignancies, I think it is moving into the mainstream, particularly for diseases like acute myeloid leukemia where there are some prognostic markers that can establish risk and assign therapy. They’re very important and the same with myeloproliferative neoplasms (MPNs)there are some recurrent mutations that are very important [in MPNs], likeJAK2,CALR, so they have been in the mainstream for many years.
For CML, it’s a different story. We still don’t understand, but we hope that once we have a better understanding that we will be able to do some additional testing, perhaps just in some patients who meet certain criteria such as high-risk scores, other factorsthe ones we can pinpoint that may benefit from additional mutation screening. These patients may benefit in terms of clinical decisions, like whether patients should have accommodation therapy or a more potent inhibitor. There’s still a lot of work to do in CML.
TARGETED ONCOLOGY: How have you seen genomics improve to make a real impact on patients and the treatment decisions?
Branford:It certainly has [improved]. There’s a lot of things that have improved, both in the technology like the availability of kits, off-the-shelf kits, but also the bioinformatics have improved and the instruments have improved as well. There are some techniques where it will do everything; it will extract the DNA through the NGS, it will run and do the bioinformatics, and it will give you a list of mutations at the end. It’s a fantastic improvement, so I think it means a lot of labs without NGS experience in the coming years will have lots of options to readily introduce it into their hospitals.
TARGETED ONCOLOGY: What steps can we take as a community to make NGS more widespread for community practice?
Branford:It may differ country to country; we currently don’t have much funding in Australia to perform these tests. This year, the government has recognized the need for this type of testing, so we will get some funding. Funding is an important issue, and you can understand that if the hospital doesn’t have any support to do this testing, then it’s not going to be done. There’s a lot of issues like that that need to be sorted out.