How Do Research Results Help Create New Clinical Trials

Individual trials are important for two reasons: one is that the evolution of treatment has been incremental and each trial builds on the results of the previous trial. The other aspect is that this is very complex and we need to be very sure that what we believe is right, that it is the truth.

Often it’s important to do a trial to replicate previously published results and possibly to address any weaknesses that have become apparent in the previous study.

A good example of that is the ACOSOG Z11 trial which was the trial that suggested that patients who have a small amount of disease in their lymph gland, in their sentinel node, do not need any further surgery or radiation in the armpit. That’s a very provocative trial.

If it’s right, it’s going to save a lot of people from a lot of side effects but there are clearly some weaknesses in the trial design and the way it was carried out, so one of our trials known as POSNOC is attempting to replicate to Z11 trial but addressing the weaknesses that became apparent.

If it does replicate the results, that is going to be really good news. But if it doesn’t, it’s not so good news but it’s really going to be very important information.

How Clinical Trial Research Has Evolved

Breast cancer surgery is a fantastic example of the benefits that come from clinical trials. The evolution of breast cancer surgery is really quite a journey.

In the early 20th century the standard treatment was a radical mastectomy. That involved the routine removal of the entire breast, the skin over the breast, the muscle underneath and all the associated lymph nodes. It was thought at the time that that was the only way to control the disease. Since then, a lot’s changed and clinical trials have been central to the evolution.

The initial trials compared that radical mastectomy to what’s called a modified radical or a simple mastectomy where the underlying muscle was left behind. That showed no difference, so the removal of the muscle made no difference to the long-term outcome.

After that, trials were done comparing the removal of the total breast, so total mastectomy, to breast conservation which was removal of the cancer with a little bit of surrounding tissue, and then delivery of radiation. Again, that showed that breast conservation was safe.

It’s not suitable for everyone, but most people have the opportunity, the option of breast conservation. Again, it was a clinical trial comparing those two that led us to reduce the amount of surgery.

With respect to the lymph nodes, because breast cancer if it spreads is found in the lymph nodes most often – these are the glands under the armpit – it was thought that all of the lymph nodes need to be removed.

A clinical trial showed that sentinel node biopsy which is the procedure by where we find a single lymph node, or one or two lymph nodes, by doing sentinel node biopsy if the sentinel node was clear, there’s no need to take all the lymph nodes. Again, the outcomes, the chance of curing the cancer was just the same but the impact on the patient, the side effects, are far less.

That leads us to the current stage. Currently it’s believed that if some cancer is found in that sentinel node that it’s important to remove all of the other lymph nodes in the area. The reason for that is that when those nodes are removed, some more cancer is found in about 25-30% of cases.

The interesting thing is that in people who do not have the other lymph nodes removed, the rate of recurrence in the armpit – the cancer coming back in the armpit – is far less than we expected. Now there’s a lot of reasons for that but one of them is that we have other effective treatments that patients generally receive, things like chemotherapy or hormonal treatment.

A large trial was done in the United States where women who had a small amount of disease in the sentinel node were randomised to either have the rest of the lymph nodes removed – that’s the standard treatment, or no further surgery. Now a lot of people thought that this was crazy, that clearly if there was cancer in 25 or 30% of cases, it would be essential to remove the glands.

Very surprisingly, the difference in outcome between the two groups – those who had the surgery and those who didn’t – was minimal. Essentially, there was no difference. This was quite radical and suggested that a lot of unnecessary surgery is being done.

Building On Previous Clinical Trial Results

With many trials, what happens is the result comes out, the trial is looked at very carefully and there are issues with the trial. There are reasons why the result may not be reliable. This is unfortunate that this happens, but it does.

It’s a fact. What that has meant is that most people consider those trials to be suggestive and very interesting, but not definitive. Not enough or solid enough information for us to tell our patients that no further surgery is needed.

That’s where our POSNOC trial comes in. POSNOC is attempting to replicate the results of that American trial that is known colloquially as Z11. We are trying to replicate the study but addressing the shortfalls in the study, and there were some important shortcomings.

POSNOC is a trial that is being led by Dr Amit Goyal, an academic breast surgeon from the UK. Breast Cancer Trials are leading the Australian and New Zealand contribution and we’re making a very important contribution to that trial.

Already we have about 800 patients have been randomised, we’re aiming to get 1900 because it’s been assessed that if we can get 1900 patients we’re going to be able to either provide solid endorsement of the findings from Z11 and thereby save a lot of people from unnecessary extra axillary treatment.

Alternatively, it may be that we find out that the findings of Z11 were not true and that the treatment should be done.

Obviously, I’m trying to do less treatment. It’s really a very important aim. If we can get equal outcomes with less treatment, then we are sparing a lot of women unnecessary side effects.

But on the other hand, we’re here to treat the cancer and we don’t want to reduce treatment too fast so that we compromise safety.

Why Participate In A Breast Cancer Clinical Trial?

There are two main paths to clinical trials: the first is where the treating doctor is aware of the trial, looking for participants. In that situation, where there is potentially eligible patient, the doctor will explain the standard treatment and then explain the trial, and then it’s up to the individual whether she would like to participate.

The second group may be more difficult. For those that are searching for a trial that either they or a loved one may be eligible, that will require a little bit of research.

Fortunately, we have made this easy – has a list of all available trials, details about the trials and where they are open.

Alternatively, there’s a national website anzctr.org.au and going to that website one is also able to find open trials.

We’ve developed a brand new app – ClinTrial Refer app – it’s available wherever you get your apps.

• Apple App Store
• Google Play

That is a simple way to find sites and identify relevant trials.

What Happens On A Breast Cancer Clinical Trial?

A lot of people want to know what’s involved in a clinical trial, ie. what happens. The answer to that depends on the type of trial.

Many trials are randomised control trials. What that means is that if someone meets the eligibility criteria for the trial and agrees to take part, then which treatment they will receive – whether they receive standard treatment or often standard treatment plus an experimental extra treatment – is a randomised process and neither the doctor nor the patient has control over which treatment the patient is allocated to.

That’s very important because that’s the way that we can absolutely identify the benefit or the difference between standard arm and the new arm.

Other trials are not randomised. Other trials are single arm trials where patients who are eligible and who consent agree to have a treatment that is somewhat different from standard treatment – the experimental treatment.

In that trial what would happen is someone who is willing to take part, who understands the process and consents, would then be registered and would receive a treatment other than standard treatment.

Once the treatment is decided and delivered, usually follow-up is fairly standard. We attempt to minimise the inconvenience associated with trials but often there are extra blood tests or extra imaging or extra visits that are necessary so that we can collect the information necessary to assess the new treatment.

So the answer to the question ‘what happens’ very much depends on the specifics of the trial, and that’s something that is always explained to the patient while they are considering, and before giving consent to take part in a trial.

What Is Personalised Medicine?

Personalised medicine means treatment that is designed to be tailored to the unique characteristics of the person and the unique characteristics of their particular condition.

Each person would have particular features, for example; their age, their physiology, their genetics and then their disease would also have its particular characteristics. Illnesses and diseases manifest differently in different people and have different characteristics.

Personalised medicine aims to tailor the therapy for a condition to the specific unique characteristics for the person.

The way we treat breast cancer has changed. Previously, breast cancer was really considered to be one condition, and there was a standard way to manage it. For example, all women with node-positive breast cancer had a particular treatment recommended.

Nowadays, we are looking much more at the specific characteristics of the person who has the breast cancer and the specific characteristics of their breast tumour before we decide how they should be approached from a treatment perspective. So, we would categorise women according to their age, and their menopausal status and their treatment would be personalised according to those factors.

We would also be looking at their health status, their other medical conditions or things they might be at risk for, we would be looking at their personal and family medical history. We would be having a look at the specific characteristics of their tumour.

Previously, breast cancer was more or less considered to be one type of cancer, but now we know there are specific sub-groups of tumours that have quite different behaviours, so we’re dividing breast cancers by hormone receptors – so oestrogen or progesterone receptors, the presence or absence of those.

We’re also looking at how much of the cancer actually expresses the hormone receptor because not everybody with oestrogen-receptor positive breast cancer will have exactly the same type of cancer.

Some oestrogen receptor-positive breast cancers will have a lot of oestrogen receptors; some will only have a few. We’ll also be looking at the HER2 status of a tumour to see whether a tumour is HER2-positive or HER2-negative.

Then we’ll be looking at other characteristics that might be involved; the grade of the tumour, other features to do with the extent of lymph node involvement or the absence of lymph node involvement, and we’re going to be trying to craft a specific program for that woman that is based on a number of features we’ve looked at.

Going forward there are going to be more and more specific pathology tests that may go into even more detail for tumours so that personalising the treatment may be possible above and beyond what I’ve talked about.

Clinical Trials Which Use Personalised Medicine

Personalised medicine has really changed the nature of the breast cancer trials that we do. When I was first involved in trials with the trials group, there were large trials that enrolled many thousands of women who had quite differing characteristics of their cancer – women with oestrogen receptor-positive cancers were mixed together with women who were oestrogen receptor-negative, or sometimes we didn’t even know the oestrogen receptor status in the earlier years, we didn’t know the HER2 status before that was known to be important, and sometimes women of different menopausal status were all mixed together.

Nowadays we’re increasingly looking at niche trials, and this makes the research more useful because ultimately we can answer questions better if we have a trial that’s tailored to women with a particular type of cancer. It also makes it more challenging because for each individual trial, not every woman would be eligible for it. So it’s trying to find the patients – not always women – that would be suited for a particular trial, and it’s more niche trials rather than across-the-board trials.

An example of personalised medicine in relation to breast cancer trials would be the OlympiA trial. The OlympiA trial is testing whether the addition of an oral tablet after other therapies have been completed would be helpful in reducing breast cancer recurrence; however, the patients that would be suitable for the OlympiA trial would be those who had breast cancer and those who also carry a BRCA gene mutation. So it’s a particularly niche trial because the drug that is being tested, the tablet, is something that is likely to be helpful potentially in women that carry this mutation but is not likely to be helpful in women generally with breast cancer. So, it’s a particular trial that is personalised medicine.

We’re also due to embark on a trial later this year called EXPERT. EXPERT is a trial where routinely women who’ve had surgery where they’ve conserved the breast – it’s standard for those women to be recommended to receive radiation – and in the EXPERT trial we’re looking for women who are 50 years of age or older and we are going to be studying the particular characteristics of their tumour by a multi-gene assay.

So depending on the exact genetic makeup of their tumour we will decide whether women would be suitable for an approach in this trial where women might be randomised to not receive radiation or to receive radiation. So, again, not all women 50 years of age or older could participate in the trial, but women whose particular characteristics of their tumour appear suitable by a personalised test will be the women who’ll be eligible to participate.

I think the future of personalised medicine is to try to tailor treatments appropriately to avoid over-treating people and to avoid under-treating people. I think at the moment we are getting quite good outcomes in breast cancer but there probably are people who are being over-treated because we haven’t yet worked out all the answers to personalised treatment, and there are some who are being under-treated in the sense that we know some women still have a recurrence of their breast cancer, so trying to continue to tailor our trials and our therapies to try to get that balance perfect is a goal of personalised medicine in terms of breast cancer trials.

Are There Different Types of Breast Cancer Clinical Trials?

There are a number of different types of breast cancer clinical trials. Many breast cancer clinical trials are looking at new treatments for breast cancer; other trials are looking at new prevention strategies whether they be medications or alterations in lifestyle, such as exercise and reducing body weight.

There are also trials that are looking at the best way to deliver the interventions that we already have. Other trials are focused on women with advanced breast cancer and how we might support them.

So there’s a whole different array of types of breast cancer clinical trials that we do.

The Different Phases of a Breast Cancer Clinical Trial

Once a new treatment has been studied extensively in the laboratory, the next step is to start testing that on people. This testing in people is usually done in a series of clinical trials that we call ‘phases‘.

A Phase 1 clinical trial is often the first time that a drug will have been used in humans. It’s aimed at looking at what the side effects are of that drug, and also trying to work out what the best dose of that drug would be and also the best scheduling of the drug.

It’s really about finding out what’s the best way to give the drug to minimise side effects.

At the end of a Phase 1 clinical trial, we know the optimal dose and dosing regimen for the drug of interest, and we then move into a Phase 2 clinical trial.

This is really designed to look at how active the new drug is, what proportion of people with breast cancer who get that new drug will actually benefit from it, to give us an idea of whether it’s likely to be more beneficial that the standard treatment.

When things look good in a Phase 2 clinical trial, and we’re seeing quite a bit of activity, we then move drugs into Phase 3 clinical trials.

That’s generally when we’re comparing directly the new agent with the current standard treatment, and we’re looking to see if the new agent is better – so if it improves the breast cancer outcomes – and also whether it has fewer side effects than the current standard treatment.

Once new drugs prove to be better than the current standard treatment in a Phase 3 clinical trial, this is when we’re then able to move them into the clinic to become the next new standard of care.

This is how we incrementally improve things in clinical trials – the old standard of care is replaced by a new standard of care that’s informed by Phase 3 clinical trials.

In general, there’s a step-by-step process through the different phases of clinical trials, but in some trials, the phases are merged together so we have some trials with slightly more complex designs that might be combining Phase 1 and Phase 2, or Phase 2 and Phase 3.

Who Is Involved In A Breast Cancer Clinical Trial?

The research team behind a clinical trial is really pretty comprehensive and large. There are the people the clinical trial patients would see in the clinic – the doctors and clinicians looking after them, the research nurses, the research coordinators and data managers who are helping to collect the information in the clinical trial. In the background, there are a large number of other people, too.

In the trials group, we have our trials department where our staff are working on the data that’s coming in, looking at it, making sure it’s correct and increasing the robustness and integrity of the clinical trial.

Clinical trials are like a great big machine. The patient is really only seeing one tiny little piece of that machine. There’s a whole other great big piece of machinery behind it that’s not seen face-to-face by the patient, but it’s all there, and it’s all really important.

Why Do We Need Breast Cancer Clinical Trials?

A breast cancer clinical trial is really the action end of the development of new treatments and interventions for breast cancer. This is where we’re trying to work out if the new treatment works, how well it works, whether it works better than the current standard treatments, what the side effects are and what the costs are.

In the development of new drugs for breast cancer a lot of work has gone on in the laboratory for many, many years before new treatments are trialled in women. Those laboratory experiments would be going on with cells, cancer cells in the lab, and subsequently very often with laboratory animals and there’s a lot already known about the drug before that drug enters clinical trials in people.

Before a clinical trial is approved there has to be a very comprehensive protocol written for the clinical trial. The protocol is like a handbook, if you like, although it’s a very detailed handbook, of how the trial will be conducted and it contains information about things like the rationale or the reason why the trial needs to be conducted, what the main questions are that we’re trying to answer with the clinical trial, who are the participants and what sort of participants would be suitable for the clinical trial, and exactly step by step how the trial will be conducted, what drugs will be given, in what doses and on what schedule.

In addition to that, there’s also a lot of information about exactly what information is to be collected on participants who are in the clinical trial. That protocol then gets very detailed peer review, so there are many scientists and clinicians who would look at the protocol and fine tune it, as well as lay people.

At Breast Cancer Trials we’re very lucky because we have our own Consumer Advisory Panel, these are people who are dedicated to helping us to make sure that we do the best research that we can from a consumer perspective. They’re very helpful for clinicians and researchers in helping us to ground our research, making sure that the questions that we’re asking are the ones that are really important to people with the disease, and making sure that the trials we conduct are conducted in a way that would be thought to be reasonable by the ordinary person in the community.

That’s another step in the development of a clinical trial. Once the protocol for a clinical trial is finalised and finished, it then gets completely independent ethical peer review at the various institutions at which the trial will be conducted. It’s only after all of those steps have occurred that the clinical trial would be open and start to recruit patients.

A specific trial that I’m involved in is the OlympiA clinical trial. This is looking at a new treatment for breast cancer that’s occurring in the setting of inherited gene mutations. Some women inherit a gene mutation that predisposes them to developing breast cancer and this trial is looking at if you get breast cancer in the setting of one of those inherited gene mutations, does this new drug add to the current standard of treatment that we have. It’s really asking the question, ‘We have all these standard treatments for breast cancer, and they work quite well in quite a lot of people, but there’s more we can do. This drug is targeted to work particularly in people with these gene abnormalities. If we add that to the standard treatment, will people get better outcomes?’ So that trial is designed so that it is comparing standard treatment versus standard treatment with the additional drug.

I think there are a couple of motivations for people to go on clinical trials. Sometimes the main motivation is because the clinical trial might offer access to a promising new drug that the patient might otherwise not have access to, so there’s a sense that, ‘If I go on the clinical trial I might have a better outcome from my cancer than I might have had had I not been on the clinical trial’. That’s certainly a strong motivator both for women and also for their clinicians because clinicians are very motivated to do the best thing for their patients.

Another motivator is altruism. The idea that, ‘Well, it might help me, but even if it doesn’t help me it’s going to help people in the future who might have this disease’. Sometimes, with the trial that I was talking about before which is for people who have inherited gene mutations that other people in their family might also have, and those other people might also be at risk of cancer, there’s this sense that ‘I might be helping other people in my family who might develop cancer’. Sometimes when people are hearing about clinical trials for the first time – because I guess when people are diagnosed with breast cancer they come from a variety of backgrounds. We have women who come from very scientific backgrounds who might be in healthcare themselves who already know quite a lot about clinical trials before they’re in the situation of considering one for themselves, but we also have a lot of people who come from non-scientific backgrounds, and this is really the first time they’re hearing about a clinical trial.

I think those words ‘clinical trial’ can be quite frightening for people; it sounds cold and somewhat scary. I think the experience of being on a clinical trial is really the opposite of that for most people. Most people find that when they’re on a clinical trial, they’re getting an incredibly high level of support from the whole trials team. Rather than just seeing their doctors regularly and getting support from their doctors, there’s a whole range of clinical trials staff that they have access to and that are seeing them on a regular basis. People often find that very comforting and reassuring.

Over the decades we’ve seen multiple improvements in treatments for breast cancer. Many of these improvements have been incremental, step-by-step improvements each time improving the outcomes a little bit. Each clinical trial really builds on what’s gone before. What we’ve seen since the 1980s is a major improvement in survival rates from breast cancer. In the 1980s, only about 72% of women who were diagnosed with breast cancer would survive for five years. Now that statistic is well over 90%, and much of that comes down to new treatments that have been developed in clinical trials. The work that’s done in clinical trials goes even beyond that because we’re not only interested in improving survival, although obviously, that’s a major priority, we’re also very interested in improving quality of life of women living with breast cancer. So that’s another focus of Breast Cancer Trials.

The number of women that will be diagnosed with breast cancer during their lifetime, depending on whether you cut that at age 70 or age 80, it’s somewhere around 1 in 10 – is pretty phenomenal when you think about it. It remains an important issue. Apart from that, breast cancer remains the greatest burden of disease from cancer, and that’s because it affects women’s lives so dramatically, it often affects young women, and the treatments can go on sometimes for many years when women are living with breast cancer. So the burden of disease is high even though the cure rates are relatively high.