THE ROLE OF GENOMIC TESTING AND THERAPEUTIC TARGETS IN BREAST CANCER

Dr Stephen Luen is a Medical Oncologist and Translational Researcher at the Peter MacCallum Cancer Centre in Melbourne. His current research interests include the study of genomic and immune biomarkers in breast cancer, with a particular focus on investigating biological characteristics and developing clinical trials for high-risk subgroups of patients.

We spoke to Dr Luen about the role of genomic testing in breast cancer treatment.

“At the heart of it, there’s two main components of genomic testing as we call it, and it’s becoming much more common as our standard approach to breast cancer. So, one is what we call germline testing, which is essentially testing and looking at the DNA in normal cells in an individual.”

“Usually that’s from a blood sample or from a mouth swab or something. And many people will understand that sometimes we’re looking for mutations in certain genes that might be inherited, that increase your lifetime risk of breast cancer. But increasingly we’ve recognized we can also use that to predict benefit from certain drugs.”

“So, the classic example is with a BRCA1 or BRCA2 gene mutation, where we can use PARP inhibitors. But moving beyond that, we’ve also looked at doing genomic testing on the tumour itself. And by doing that we start to understand what changes in the DNA are driving the cancer to grow and propagating that cancer’s growth.”

“Sometimes we’re able to identify those alterations and target them with specific drugs. Now, in the old days, these drugs were only partly effective, and they were pretty toxic. So, they caused lots of side effects, but the newer generation of drugs are certainly becoming cleaner, they have less side effects and they’re more potent so they’re potentially more effective.”

“And so, in my talk, I would like to sort of present some data and discuss some of the themes that are coming about with the development of these drugs.”

How does genomic testing contribute to personalised treatment approaches for breast cancer patients?

“The whole premise of the genomic testing is to understand what is driving this individual cancer, because every cancer is unique. And in that way, you can really personalise the treatment for each patient. So, if there’s a change in one of the BRCA genes, you can then use a PARP inhibitor. If there’s a change in PIK3CA, you can use a PI3 kinase inhibitor, and it sort of pushes away from that concept of everyone having the same treatment.”

“They all come in trials where they use things like chemotherapy and endocrine therapy. So, it’s the idea of personalising treatments so that you can better target the individual cancer.”

What are some potential benefits of undergoing genomic testing for breast cancer patients?

“From my perspective as a clinician the most common reason we’re doing genomic testing is to identify, ideally, a change that results in a new drug target, and that means we can potentially use a drug that has improved efficacy and really good effectiveness in an individual’s tumour to be able to control the cancer better or even increase the chance of cure.”

“And I think this allows patients to have more choices in terms of therapy. Of course, there’s nuances in how you use those drugs. Are they used in combination with other drugs? Are they used at certain times? Are there particular what we call lines of therapy? Are they used in early breast cancer or advanced breast cancer? But it gives us more choices and helps us understand how to best manage a cancer, optimise patient outcomes, as well as improve quality of life.”

“We’ve fortunately just had approval of Olaparib in the neoadjuvant setting. This was from a clinical trial called OlympiA. There will be some discussion about that trial at the symposium. But there are a multitude of other clinical trials that are coming about, and in my presentation today, I’m just going to highlight a few clinical trials in those fields.”

“There are a number of clinical trials using these drugs called Selective Estrogen Receptor Degraders (SERD), which target the oestrogen receptor, and they actually degrade the oestrogen receptor. And these are proven to be more effective in patients with these mutations in a gene called ESR1.”

“And this is an acquired resistance mechanism, so it gives us an opportunity to treat a cancer that is developing resistance to our standard hormonal therapies. Another example is the INAVO120 clinical trial, where they’ve really introduced a PI3 kinase inhibitor early on in the piece, and that’s shown effectiveness in phase III data in combination with the current standard treatment.”

“However, we always need to balance this with the side effect profile that adds when you add it in combination. And finally, I did also want to talk a bit about new strategies. I’ve mentioned a drug called Saruparib, which is a new next generation PARP inhibitor, which will be tested in a new clinical trial that’s upcoming called EVOPAR-BREST01.”

“So, just a few clinical trials on the horizon and there are many more with new drugs coming through.”

What advice would you give breast cancer patients who might be considering genomic testing?

“So I think the first thing you should do is have a discussion with your medical oncologist. Genomic testing is something that is relatively new, but I’d expect most oncologists to have some literacy around this and be able to discuss it with you. There are a few ways to get genomic testing. Of course, some of them are reimbursed. And most of that is germline testing.”

“At the moment, there is also a national program where we’re able to perform a comprehensive genomic test on a tumour, and I’d encourage people and clinicians to consider using those tests to be able to springboard our patients on to give them opportunities in clinical trials and access to novel drugs, which hopefully will improve their outcomes.”

“So, in the context of genomic testing and targeted therapies, I think this is definitely one way forward, and the way I think it’s going to happen is through one of the themes that I’m going to talk about, which is bringing in these drugs early and in combination, bearing in mind that there may be some increased toxicities or side effects that are associated with that approach.”

“But what’s happening in drug design now with targeted therapies, is that there’s a real focus on two things. One, to make the drugs more potent and hopefully therefore more effective, but also to make them more selective, which means they hit a target very selectively and they result in much fewer side effects.”

“The ideal situation here is to be able to target resistance mechanisms all in that first line of therapy, to really give you the best duration of response as well as quality of life in that first line setting, which I think will be the way forward with targeted therapies in breast cancer.”