Professor Andrew Tutt is a Consultant Clinical Oncologist in the Breast Cancer Unit at Guy’s and St Thomas’ NHS Foundation Trust in the United Kingdom. He was also a guest speaker at Breast Cancer Trial’s 45th Annual Scientific Meeting in Cairns.
We spoke to him about biomarkers for hormone therapy resistance and deficiency, and on targeting the Achilles heel in BRCA1 and BRCA2 gene mutations.
“So, it’s a great pleasure and an honour to be asked to give the Robert Sutherland Award lecture at the Breast Cancer Trials meeting this year. I am a clinician scientist, and I work in a laboratory and in the clinic looking after people with breast cancer.”
“Translational research is really this wonderful opportunity to try and take laboratory medicine, and cancer research medicine to clinical application.”
“And what I’m going to be talking about in my lecture is a long history involving many people that it’s been a pleasure to be part of, where an understanding of the causes of familial breast and ovarian cancer were really mapped out in the late 1990s as to what the genes involved were.”
“And this is a story of how understanding what these genes normally do and what happens when they don’t work properly – or the Achilles heel in breast and ovarian cancer. To develop a new treatment approach, um, that targets a deficiency that those cancers have.”
“That concept is called synthetic lethality. It’s kind of a complicated name but it essentially means targeting an Achilles heel in a strong Achilles like tumour and having a very individualised medicine way of developing a new treatment. That’s been PARP inhibitors and certain kinds of chemotherapy for that situation.”
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We spoke with Professor Andrew Tutt about biomarkers for hormone therapy resistance and deficiency, and on targeting the Achilles heel in BRCA1 and BRCA2 gene mutations.
What are biomarkers of HR deficiency in breast cancer?
“Biomarkers of homologous recombination deficiency are tests, effectively, that you can apply to a tumour or to a patient, that help us understand whether a normal process of repairing our genetic code, our DNA, is faulty in the tumour development.”
“That is used as a way of identifying if those tumours might have an Achilles heel, a particular weakness that we can target with cleverly developed individualised and targeted therapy approaches. So those biomarkers are effectively a test that can be applied for a patient on them or their cancer that help a doctor decide how best to treat them.”
How does HRD targeted therapy work?
“What ourselves and others developed some years ago was an approach whereby inhibiting an enzyme usually used by cells to repair their genetic code and stopping it working, that could critically disable cancer cells that already had a defect in another form of DNA repair, something called homologous recombination, a very accurate form of DNA repair.”
“The normal cells of the patient could tolerate that drug stopping some of their DNA repair from working because they’ve got the backup, they’ve got this homologous recombination working, but the tumour cells could not tolerate the double hit on that. That’s the synthetic lethality concept.”
“So, the targeted treatment were PARP inhibitors, developed to target, create a particular form of damage in the DNA of the tumour cell that they couldn’t survive, but that the normal cells of the body could survive.”
“Hopefully this will have a big effect on cancer, with few side effects, and that’s proven largely to be the case. So, over recent years it’s become clear that although initially it was thought that the main effects of this type of approach would be in ovarian cancer and breast cancer known to run in families, and in those that had a genetic test saying they’d inherited a faulty BRCA1 or BRCA2 gene, it now seems that this applies in other forms of cancer associated with faults in those genes, like prostate cancer and pancreatic cancer to name two.”
“But also, that people who haven’t necessarily got a damaged gene running in the family, but where the cancer itself, but not their family, the cancer’s got a damaged copy of the gene. And that means it’s potentially applicable to a larger group of patients suffering with cancer.”
“We need to develop those tests better, that tell us if that’s truly the case in the cancer. We also need tests that tell us is it not a gene that’s faulty? Is it maybe that the dimmer switch on the gene has been turned down, as it were? The gene’s just not turned up full, it’s silenced, it’s dimmed down. And whether patients with those kinds of cancers could benefit too.”
“So, it’s a work in progress.”
“My talk’s going to be about some of the tests and approaches that are asking the questions as to whether these kinds of PARP inhibitor type treatments could be helpful for a broader group of patients.”
What are some of the challenges faced by researchers in understanding a predicting the emergence of resistance to HRD targeted therapies?
“So, there are still big challenges for patients who have these kinds of cancers. I think the field has made a lot of progress and thankfully these treatments are now available for people with quite early cancers of those types like breast cancer. And that is curing patients, which is fantastic news, but sadly some patients still develop advanced forms of cancer where it’s not possible to cure or eradicate the disease. And eventually, the disease becomes used to these treatments, and it becomes resistant to them.”
“So, the challenge is working out how it becomes resistant, how it learns to cope with these apparently very targeted drugs and then realising that there’s not one way of becoming resistant, and then designing treatment approaches that deal with each of, what may be a few ways in which the cancer gets around.”
“And that’s what everyone’s trying to do at the moment, understand that. Not just what happens in the lab, what can happen for resistance, but what happens in the clinic for patients and designing the treatments that help them.”
What is the role of research in hormone therapy resistance?
“So, the role of the researcher and of research in doing this I think is manifold. We need to work with and involve our colleagues in what we call basic science. It’s not basic at all, it’s kind of fundamental science, that’s a better word for it really, to really understand the biology behind resistance and that’s often work in a lab with white benches and pipettes and clear colourless fluids and plastic dishes, but it’s very helpful.”
“It’s very contributory, connecting those with the real questions that doctors have working with patients who are, who are suffering with these diseases, so that the power is applied to real problems in the clinic. That is the opportunity for what we call translational research. And when you bring those things together, that’s why I get out of bed in the morning.”
“It’s suddenly some really meaningful conversations that happen because the fundamental scientists go, ‘I didn’t really realise that’s the problem you’re trying to solve’. And the clinicians go, ‘I didn’t realise that you could do something that could solve that problem’. And then they talk and then they redesign and then stuff happens.”
“It’s really exciting to see that happening and try and make that happen. So, what we then do is we ask our patients, would they join us in that endeavour? Which of course they do. And we can then ask if people would contribute an extra blood sample, let us study the tumour that they had removed at surgery and is sitting in a pathology department, but not being used.”
“We ask them if we can study that tumour deeply. Could they maybe have an extra biopsy? And could we take that into the lab and grow cells and do some of these very clever techniques on the living tumour, to learn how to get around the resistance and that is the research. That’s the challenge. That’s the opportunity. That’s the translational research endeavour.”
“It’s so exciting to be part of and bring everyone together. Patients, the families of the patients because they’re supporting them going through this, to give people the hope that they can improve things for others. And then the doctors and the scientists try to make it all happen. It’s a great opportunity.”
Why are the BRCA1 and BRCA2 gene mutations significant and how do they relate to targeted therapies?
“The BRCA1 and BRCA2 gene mutations, which are a large part of what I’m talking about, are very significant because they were found to be the genes that when a fault developed in them and could be inherited through generations, were responsible for the majority of the admittedly relatively small group of women who have very strong family history of breast and to some extent ovarian cancer.”
“Most breast cancers happen for reasons that we don’t fully understand. They’re more complex than just inheriting a gene or living your life in a particular way. They’re a really complex mixture of all of the genes that we might inherit and some environmental or lifestyle factors.”
“But some are due to an inherited gene fault. BRCA1 and BRCA2 were the main causes of that strong family risk. The field have identified some other genes, a gene called PALB2 being one, that are also responsible for this to a slightly lesser extent. But they all seem to operate, these strong genes, in this way in which cells keep their genetic code accurate and clean and stop it developing missed messages, that then tell the cancer cell run wild.”
“So BRCA1 and BRCA2 have been so important because they’ve led to an understanding of how breast cancer can develop and provided an opportunity to develop a targeted treatment approach, even for a rare group.”
“And I think that’s helped the whole field understand that you don’t just have to work out the common causes of cancer. You can find the rarer causes and then develop individualised approaches for them. And then find they’re actually important for a bigger group than you thought to start with. It’s taught us to care about individualised medicine. BRCA1 and BRCA2 have provided an example of that.”
What is synthetic lethality?
So, synthetic lethality is an old genetic principle, taken to an individualised medicine context, and leading to a way of identifying through a biomarker, effectively a test, a group of patients who would benefit from a targeted approach with profound effects against the cancer and few side effects in their normal self.”
“So, the excitement in the field around this are that although perhaps the poster child for synthetic lethal targeting principles has been BRCA gene faults and PARP inhibitors as the other drug partner in the synthetic lethality mix. It’s meant that cancer researchers have begun looking for other synthetic lethality opportunities, and some feature of a cancer that means that if you find the other partner, you’ll have profound effects that are restricted to the tumour.”
“And so there are other examples of that which are emerging in the field of this form of homologous recombination defective breast cancer.”
“We know that other DNA repair enzymes are being investigated. Biotech’s and drug companies are developing strategies specifically to target DNA repair enzymes in order to follow the same path that has been followed by this poster child of PARP inhibitors and BRCA. And there are a number of examples of this.”
“I won’t pick a particular one to favour any particular biotech or pharma, but there are a number, and it’s exciting. And then outside of DNA repair, there are other examples of synthetic lethal targeting as a concept.”
“I’m very passionate about the concept of team science and I think it’s a really important development in the way we all work together because the days where you could do something massively meaningful for patients as an individual or as a pair of individuals, are gone.”
What does the concept of team science mean to you, and why is it so important?
“The power is so much greater, given that we’ve got so many disciplines of science, so many different kinds of cancer that our patients are suffering from, that we have to do this as a team, in order to make a difference.”
“And our chance to make a difference is so much greater as a team. So, what does team mean? Team means communication between patients and their doctors and the scientific community, to really set out what is the problem we’re really trying to address here, not what is the sexiest piece of science, but what is the problem that we need to address and how can we bring the power of science to it?”
“It’s genome scientists, people who are using the amazing power of understanding the human genome, all the messages it creates, all the proteins that those messages lead to, the complexity of biology, which then requires you to have really highly integrated computational systems to bring that together.”
“The power of AI in enabling all of that, and then there are always new developments in how we test things in a laboratory, how we develop an idea that can test it. So, people may have heard of CRISPR/Cas-9 methodologies, where you can edit the gene. And therefore, the message and the protein that it produces in an incredibly accurate way in the genome.”
“Combine those edits to test things before they even get to needing to experiment on an animal or a patient. And the power of doing that is enormous. Bring all of those together, get people communicating and show them the problem and iterate. Bring it round in a circle and stuff happens and it’s amazing.”
What steps are taken to ensure that targeted breast cancer therapies are safe and effective for patients?
“So, there are obviously a number of steps that need to be taken to ensure that ideas around a targeted therapy are real, work, and that they’re safe and should be available to patients. Those, steps really are the validation as we call it in laboratory settings, that someone’s idea can be repeated by other people who are perhaps less invested in it having been a good idea.”
“So independent validation that what’s been found is real. And across multiple sorts of experimental systems, it’s not all just coming out of one laboratory way of asking the question. And that gives you confidence that there’s something real to take forward.”
“Then you really need to understand whether the treatment approach, or the therapy approach works in a clinical environment on patients. And before you do that, you often do need to go through testing things in patient materials. And that now can be with growing little tumours in little organoids, which are like little greenhouses of culture material. They’re more like the flat plastic things are often grown on in the lab.”
“And that is a bunch more real connection with what happens to patients’ tumours in the clinic. So that’s a step of validation in the lab, not yet in the clinic. And then they go sometimes through an experiment in a mouse to check that’s true towards clinical trials. Those are called phase one clinical trials, just checking that a drug approach is safe and what some of the side effects are that might be associated with the dose that’s actually getting to a right level in a patient and hitting the target properly, phase one.”
“And then we call phase two trials, those trials where you’re looking to get more confidence with more people, that the dose you selected in phase one is not really associated with side effects. And there some evidence it works.”
“You know, does someone’s tumour get smaller? Does it respond? And then beyond that, things that have been through that stage are really asking the question, how does it compare with the treatments that people already have available, if there is one, and how are you sure, for instance, that the effect you’re getting isn’t a placebo effect, just because someone’s reporting they feel better.”
“And that means having trials where you randomly allocate treatment, new treatment, against the best we have, and blind the doctors and the patients taking part to what they’ve had so that we can be really sure that this is going to work. And you might say, well, why be really sure? If it sounds good, just do it.”
“Well, we’ve got to be really sure because there’s always some kind of alternative that you’re taking away from someone if you’re giving them something new. So, you need to know that it’s better and the side effects you’re going to confidently tell your patient you think they might get.”
“Those phase three trials are really, really important. And the tests that you use to select patients for a targeted or individualised treatment approach need to go through that same process of validation, of checking that they work in the lab, that they’re accurate, repeatable, that they mean something clinically meaningful. That’s called clinical validity and they help a doctor advise a patient and make a better treatment choice..”
“So, it takes a while to get that right, but people expect that when a doctor sits down with them and advises them on a treatment based on a test that selects a treatment, they’re confident that it’s going to work and not cause them problems. That’s how we get there.”
“It’s important to say to your doctors looking after you, is there anything different for me because of this? Are there treatment approaches that are especially for me?”
“Because there are some. It’s difficult to summarise those here, but they apply in both the early breast cancer, the sort of curative environment in breast cancer, and also in those who’ve got secondary breast cancer, where sadly the disease is not usually considered curable, but where there still may be individual approaches for those with these mutations.”
“Also asking are there clinical trials for them? Because the trials have been developed now to take things forward specifically for this group of patients. So, it means asking the question about what may be special for you. And also, you know, considering whether if there isn’t something in your local hospital, nearby or in a more specialist hospital with a strong connection to your local hospital, there is something for you there.”
“So, I would say it means asking about individualised medicine for you. There are other things to think about, like any effects there might be on risk for the future. If you’ve just been diagnosed with an early cancer and you may be thinking about risk to your other breast. So, these are things that you need to talk to your team about and have the time to process the information and also the implications for family.”
“But I always say to people, you don’t need to make all the decisions instantly. Talk to a specialist team and take time to make the decision.”
What excites you the most about the future of breast cancer research?
“I think I’d have to say it’s the fact that there are now so many more conversations happening between patients, their doctors, and a demand to do research. To be involved in research as a patient, to be given the opportunity to consider a trial or just consider contributing maybe a little bit of extra blood or, or your previous tissue in the pathology department or have an extra biopsy to try to move things forward.”
“There are so many more opportunities for doing that. The medics are talking to the more fundamental scientists in the lab about doing that, and that there are people trained to bridge between those disciplines. Medics who’ve spent time in the lab and have learned enough to have a really good conversation about it and how much they want to be involved and help.”
“And that happens so much more now. There’s a real opportunity for us to bring this together and develop new treatments. And we do that in partnership with the biotech and pharmaceutical industry. But there’s a real contribution that patients, their doctors and the fundamental scientists can make to how biotech and pharma develop drugs. And they know that. And I think that is also changing and leading to more smart individualised medicine, and effective therapies being developed.”
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