Initiative Aims to Increase Use of Next-Generation Sequencing in Canadian Clinics for Multiple Cancers

John Bartlett, MD

John Bartlett, PhD

A 3-year initiative to improve the management of pancreatic, prostate, and breast cancer is underway, as the Ontario Institute for Cancer Research (OICR), Thermo Fisher Scientific, and Genome Canada collaborate to develop next-generation sequencing assays and analysis software to specifically target these cancer types.

The solution will reportedly provide more insight into driver mutations by assessing DNA, like most assays, but also by determining expression signatures from RNA. To accomplish this, translational researchers from OICR will supplement the newly developed assays with new DNA and RNA biomarkers with which they can better classify patients with the various subtypes of pancreatic, prostate, and breast cancer, and guide in treatment decisions.

This collaborative project may solve existing challenges with these cancers, including, identifying patients with breast cancer who do not benefit from chemotherapy, determining which patients with prostate cancer require surgery or aggressive therapy, and bringing molecular testing for pancreatic cancer out of the research development phase and into clinical practice. Although the short-term objective is bringing solutions to Canada, the team hopes that eventually, these practices are picked up around the world.

In an interview withTargeted Oncology, John Bartlett, PhD, program director, Diagnostic Development, Ontario Institute for Cancer Research, explained the standardized cancer testing project, its relevance, and how it could be used to improve the treatment of patients with pancreatic, prostate, breast cancer. 

TARGETED ONCOLOGY: Can you briefly discuss the testing landscape and frequency for pancreatic, prostate, and breast cancer in Canada? What are some of the challenges?

Bartlett: In the routine setting, molecular testing for breast cancer is established primarily to assess a patient’s risk of recurrence in the 5- to 10-year period after diagnosis, using RNA signatures. More recently, some of those signatures, particularly the Oncotype DX signature, has been used to select those patients who do not benefit from chemotherapy even though they may have moderately high-risk cancers. That's where we are with breast cancer in terms of molecular testing.

For prostate cancers, there are few emerging tests, but none that are globally accepted for use in either prognostication or prediction of outcome. And in pancreatic cancer at the moment, we're still in the research development phase. None of these 3 cancer types use molecular testing, genomic or transcriptomic, to direct therapeutic choices.

In breast cancer, there is a safe assay for the HER2 oncogene which is used for HER2-directed therapies. Although in the metastatic setting, and possibly increasing in the adjuvant setting, we may use targeted therapies to signal pathways in particular gene drivers, we don't currently have evidence to support stratifying patients by molecular testing in any of these disease settings.

TARGETED ONCOLOGY: Can you provide some background on the development project? 

Bartlett: The project that we're involved in seeks to transit research or discovery programs into clinical management by identifying different tensions in these 3 disease settings.

Pancreatic cancer is an aggressive cancer, and time is limited for us to intervene for patients' benefit. As we try to evaluate and implement new therapies targeted against particular gene drivers, time is of the essence. What we're doing there is, we're trying to use existing research evidence in pancreatic cancer, and use a much more accelerated diagnostic program, getting results in days rather than weeks for patients who don't have a lot of time to spare, if we're going to be successful.

In breast cancer, we're addressing a slightly different challenge to ask: With a large number of patients who are diagnosed with the HER2-positive breast cancer, and have a long-term risk of relapse, how do we identify those subgroups who will benefit from particular molecular therapies? How do we match the driver pathways in those cancers specifically to the drugs that these patients will likely benefit from? That's much more of a targeted therapeutics or targeted genomics approach.

In prostate cancer, we're now asking much earlier questions which are, who needs aggressive therapy, who need surgery following a diagnosis of low-risk prostate cancer, or who might be able to avoid the morbidity associated with surgical intervention or even with active surveillance to repeat biopsies? By being told that the disease is relatively low-risk and benign, they can just wait until something happens, if it were to happen, and have a good outcome.

TARGETED ONCOLOGY: Why do you think this is especially needed in Canada? And why specifically for these 3 cancer types?

Bartlett: I think Canada is a good proving ground for these types of technologies because there is a much more flexible and evidence-led approach to interventions like these. I think there is a groundswell in Canada that allows us to adopt new molecular technologies more rapidly. However, that said, this kind of approach is needed globally. Wherever these diseases are present, what we will test and prove in Canada will be pertinent to other jurisdictions.

These 3 cancer types illustrate the 3 different challenges that we have in the broader context of molecular diagnostic medicine. It's fast and accurate testing, where time is limited in a setting like pancreatic cancer where patients don't have as good of an outcome and interventions need to be assigned rapidly. Can we produce a paradigm for accelerated diagnostics? That again will reach into other cancer types where a fast diagnosis is important.

For breast cancer, when does one size no longer fit all? When do we start to personal treatment on the basis of molecular evidence of different cancers for different patients? We've gotten past the situation where we think breast cancer is one disease. Molecularly, it's probably somewhere between 20 and 30 subtypes of the disease. How do we exploit that information so that new targeted therapies can be implemented?

For prostate cancer, as I said, it's risk. It's how do we ensure that patients aren't being over-treated. How do we use molecular testing to give patients the reassurance that their disease is low-risk or that they can survive their cancer and not have to go through aggressive treatment with all the mortality and morbidity associated with that? [They could] simply live with their cancer rather than have it aggressively managed just because they've heard the "c" word.

TARGETED ONCOLOGY: What ongoing need will the development of these assays serve in the pancreatic, prostate, and breast cancer patient populations? How do you believe this will improve care in these patient populations?

Bartlett: It's different for each setting. For pancreatic cancer, I think what we will be able to do is accelerate the testing of new therapeutic options and deliver a targeted therapeutic approach toward this aggressive cancer much more rapidly. [This will enable us to] test drug molecular combinations much more rapidly and intervene for more patients, because the diagnosis will reach them more rapidly.

In breast cancer, again, I think it's going to be that tailored approach. [Physicians] are able to say, with this particular molecular driver, this is the type of family of drugs that should be tested in that group of cancer as opposed to the current approach, which is just to pick a drug and a pathway and see how many patients benefit and hope that you can refine therapy that way.

As for prostate cancer, the benefit will be reduced morbidity. Many patients with low-risk prostate cancer who come forward will experience multiple biopsies just to make sure that their disease is not high-risk. If we can implement molecular tests at that stage, we can avoid those biopsies, which carry a significant risk of infection. In the year of Methicillin-resistant staphylococcus aureus (MRSA) bacteria, those infections can be life-threatening.

TARGETED ONCOLOGY: What specific driver mutations are you hope to pick up and how will this improve physician treatment decision making and patient outcomes?

Bartlett: The cancer [that we understand the most clearly] is breast cancer. We know that a portion of breast cancers are driven by CDK4/6 signaling, and we know we have therapeutic options for those patients. One of the things we can do is start to refine testing to ensure that those patients get appropriate treatment. Also, breast cancers are driven by PI3K/AKTsignaling pathway. [That's] different signaling and different targets and drugs that would be used in that population. Another subgroup is driven by the fibroblast growth receptor family and signaling pathways related to that. Then we have breast cancer subgroup of cases that are driven by MDM2/p53. As we've mapped it to those groups of treatments, we can see that those patients [had] greater benefit [from those treatment].