The Need for a Clinical Trials Group in the Late 1970’s

“At the time, all sorts of people had individual ideas about how to treat a patient with cancer, but there wasn’t a lot of evidence about which was a better way to go. An individual experience of two or three cases often changed a treating doctor’s opinion.”

“That’s not scientific, and the trouble is that you get different answers for different smaller experiences. The way to get around that is to do proper, clinical trials, which compare policies that are, that give you an answer, as to how you apply them next.”

“And so, by the time I got back from training overseas in the late 1970s, there were quite a number of people who had experience of doing clinical trials, in various parts of the world. UK, United States, particularly, and we’re setting up to do them here. The breast cancer group was the first organized group to do trials in any particular cancer in this country, with a possible exception of the pediatricians who’d done a few things in childhood leukemia, a few years earlier.”

The Introduction of ANZ-8101

“You know, ANZ-8101 was an important trial. It was a successful trial that the group ran, but it wasn’t the first trial the group ran. And to put it into context, our first generation of trials compared policies in treating women with metastatic breast cancer.”

“Should they start with a hormone treatment? Should they start straight into chemotherapy? Or is it better to use both together? And we’ve got a clear answer from that first generation of trials, ANZ-7802 and ANZ-7801, that starting with endocrine treatment was just as good and put off the day when you had to give what was then very unpleasant chemotherapy.

“ANZ-8101 was a separate trial for the woman who had already required chemotherapy and was asking questions, again, trying to make life easier for women because in those days, the side effects of chemotherapy were even worse than they are now.”

“We didn’t have the ability to control, particularly nausea and vomiting, which was a major problem with all of the drugs we used and particularly some of the newer ones we were beginning to use in the 1980s.”

“So, ANZ-8101 compared different policies of using chemotherapy, and then asked questions about ‘can you give the patient a bit of a break and then go back to treatment only when you need to.’ That was a great idea. It sounded good. It worked in lymphomas and other types of cancer. It didn’t work in breast cancer, but we needed a trial to find that out, and the trial asked the question, do we start and keep going, or do we start and then give three cycles, stop and wait, and only treat if we need to.”

“The bottom line was that both from the control of the tumour, response of the treatment, how long the patient lived, and also from the point of view of the patient’s own symptoms, it was better to keep going. And the reason we know that is that this is the first trial in which patients gave their own assessment of outcomes.”

“That is what we now call patient reported outcomes or quality of life measures, which were incorporated into ANZ-8101 for the first time in ancient clinical trials in Australia. We used techniques that had been developed, particularly in the UK and by a visiting scientist from Canada who was on sabbatical, in Sydney.”

“But we used things that were simple and could be applied to hundreds of women in busy clinics and get a real measure of what those women thought about the quality of life during treatment, and the answer was very clear that in this particular comparison, the quality of life of patients who continued treatment, continued to improve. Whereas when we stopped treatment, tried to give the patient a break, quality of life deteriorated.

Improving Chemotherapy and Existing Treatments

“We needed to make the best use of the available chemotherapies, and in those days, there weren’t a lot of drugs available to choose from. One of the newer drugs was a drug called Doxorubicin or Adriamycin, and it was touted as a real improvement.”

“In fact, we used it and we used the older combination of three drugs with some cortisone drugs as well, and we compared those, one or the other, in the trial as well as the policy of stopping or continuing. It turned out that the distinction between the two types of chemotherapy wasn’t important, but the distinction of keeping going was important in terms of patient outcomes.”

The Development of the BIG 1-98 Clinical Trial

“Okay, so in BIG 1-98, we are moving in two important different ways. One, we’re talking about patients with early breast cancer that it has not yet come back. And two, because we need very large, much larger numbers to get answers in this group, we had to offer an international collaboration.”

“All of these treatments are in the endocrine treatment phase, the hormone type treatments. The mainstay that the established drug was a drug called Tamoxifen, which is undoubtedly the best drug I saw in all the years I was practicing. It made a fundamental difference to women with breast cancer.”

“A new class of drugs had come along, which was also designed to reduce the impact of endocrine treatment and endocrine agents on the tumour. That is, some tumours, most of them the tumour is driven to some extent by, estrogen in the woman’s body.”

“If you can turn that off with aromatase inhibitors or block its action with Tamoxifen, then many of the tumours will respond, and the use of those same drugs early after surgery for breast cancer, it was hoped, was going to reduce the chances of the tumour coming back, and in fact both of those work.”

“When we were starting BIG 1-98, we were trying to work out where the new drugs fitted into the sequence, and whether they should be used upfront or only if an older treatment such as Tamoxifen had failed.”

“We took a trial design that has been started by a drug company as a two-arm study comparing Tamoxifen with an aromatase inhibitor, and we designed it instead to answer academically important questions, including the sequence of starting with one and switching to the other, or starting with one and keeping it going for the whole of the treatment, which was a five-year treatment in those days.”

“So BIG 1-98 had four arms by the time we were running it and that was continuous aromatase inhibitor, a drug called Letrozole, continuous Tamoxifen, we’ll start with Tamoxifen and switch after two to three years to Letrozole or start with Letrozole and switch to Tamoxifen.”

“All of those arm’s work. They all reduce the chance of the tumour coming back on average across all patients. The arms that included Letrozole did slightly better, but what we found out by the analysis of all the patients taking part was that that benefit didn’t apply uniformly to all women.”

“Women at average or less risk did just as well with Tamoxifen alone. The sequence of starting with Tamoxifen and switching, which was being used in another trial at the same time, in the UK, was as good for most patients, except for the very high-risk ones where it was better to start with the newer drug.”

BCT’s Involvement In Other More Recent Major Breakthroughs

“I think the next important group was to look at the premenopausal adjuvant studies. This is the group of studies called SOFT and TEXT, that Prue Francis has led for our group. And that’s asking the same sort of questions about the treatment of women before the menopause. Tamoxifen again was the mainstay of treatment. Is it better to use one of these new drugs?”

“The problem is that you can’t just give a premenopausal woman Letrozole. It would be swamped by the estrogen that her body makes. And so, as part of that treatment, you have to turn off estrogen production with another sort of drug.”

So, there’s an LHRH agonist drug that’s used triptorelin or gooseling, which turns off the body’s ability to make estrogen. And then you can use a drug like letrozole. Stopping the estrogen production in and of itself was another possibility. So, some of the arms that were used in these studies were Tamoxifen alone, Tamoxifen plus the blocker, or the blocker making it possible to use Letrozole.”

“And again, it depends on the degree of risk, and Dr Francis will tell you more about the details of this, but it seems to me the complicated treatments, the ones that involve stopping estrogen production and then using, a drug like Letrozole are beneficial, but they’re beneficial, particularly for women at higher risk. Whereas for women at low risk, a simple treatment like Tamoxifen might be quite adequate.”

Looking Towards the Future of Breast Cancer Research

“The game is changing. When we did trials like BIG 1-98, or ANZ-8101, almost all the patients who came to your clinic would be eligible for that question because it, as far as we knew, the question applied to all of them. Nowadays we are finding out so much more about the subgroups within breast cancer, that the group of patients for whom any treatment question applies is smaller and smaller.”

“So, it’s getting harder to find questions that have enough patients to be answered reliably. And that’s requiring a great deal of collaboration internationally to get the numbers required for the statistics to work, on groups of patients that are increasingly defined by molecular subtypes that we now understand in breast cancer.”

“I think that the clinical research gives us reliable information so we can advise patients not on the basis of whim and personal experience, but on solid science. And that’s what the last 50-years of clinical trials have contributed to the wellbeing of the next woman who comes through the door.”

What is Invasive Lobular Carcinoma?

Invasive Lobular Carcinoma (ILC) is a breast cancer that begins in the milk glands of the breast and has spread beyond the lobules, potentially spreading to the lymph nodes and other parts of the body.

“So Invasive Lobular Carcinoma is a special breast cancer subtype. It’s the second most common breast cancer subtype, and it accounts for around 10 to 15% of all breast cancer cases. So that is around 2,400 new breast cancer diagnoses per year in Australia.”

“Invasive Lobular Carcinoma is also unique in terms of its pathology and clinical behaviour. And patients with Invasive Lobular Carcinoma show worse long term prognostic outcomes compared to patients who are diagnosed with the most common breast cancer subtype.”

What are the Current Treatments for this Type of Breast Cancer?

“So, in terms of treatment, patients with Invasive Lobular Carcinoma do not have a specific targeted treatment strategy that is unique to their clinical needs. So, patients with Invasive Lobular Carcinoma are treated in the same way as other breast cancer patients using standard treatment protocols that include surgery, radiotherapy, and chemotherapy.”

Is there Potential for a Clinical Trial down the Track?

“So lobular breast cancer patients are not well represented in clinical trials, and they do not have specific treatment options available. So, there is an unmet need for this patient group to have trials that are specifically devoted to their disease process.”

“There are two clinical trials that are currently being established, in Europe, and there’s potential to expand these clinical trials to Australian and New Zealand patients in the future.”

Dr Sokolova’s Hope for the Future

“I hope that this research will identify a clinically useful biomarker that will help to identify patients who may benefit from new targeted treatment approaches in Invasive Lobular breast cancer. So, there are two early clinical trials that have been established overseas looking at ROS1 targeted treatment in these patients.”

“Depending on the results of these trials, they may be offered overseas to other countries, and that may include Australian and New Zealand patients.”

What is a Fear of Recurrence?

The fear of breast cancer coming back is a very real and common concern for many people diagnosed with breast cancer.

“So, after a breast cancer diagnosis, it’s really understandable that women will have a concern about the cancer returning or progressing. So, a fear of cancer recurrence is essentially a fear about cancer recurring or coming back in the breast or in another part of the body.”

“It really entails a worry or concern, and it can range from a normal level of concern to quite significant, persistent thoughts and anxiety. So, women tell us that managing a fear of cancer recurrence is one of their most significant unmet needs and  around 40-70% of those women, the concern is so severe that it impacts their daily quality of life.”

“So, this is a really important area of research for us to better understand.”

What are the Side Effects of Having a Fear of Recurrence?

“Fear of recurrence ranges from no concern at all, where the thought doesn’t enter the woman’s mind, to quite severe debilitating anxiety. And for women who have the more severe fear cancer recurrence, they describe that they’re unable to plan for the future, that their enjoyment is really impacted, they’re hypervigilant to signs of recurrence in their bodies. And so, it really can impact their quality of life in a significant way.”

“So, this is really important, as fear of cancer recurrence is unlikely to reduce without interventional treatment, so it can last for years into survivorship.”

How can People with this Fear be Supported?

“When this fear and this concern impacts all aspects of someone’s life and is persistent and really distressing for them, and they can’t plan holidays for the future, and they really are noticing that they are concerned about any change in their body for a sign of recurrence, that’s when intervention and treatment can really assist these women to live with a fear of cancer recurrence in a better way and to reduce the impacts that it has on their lives.”

“So, treatments are quite effective and there’s a broad range of treatments that are available, the most common of which is cognitive behavioral therapy, which is an umbrella term to refer to several different therapies that really build coping strategies and skills for women. They have been shown to reduce the frequency and intensity of fear of cancer recurrence thoughts, and really improve quality of life into survivorship for breast cancer patients.”

What does your Research Project Involve?

“We need to be aware of different treatments and how they impact the levels of fear so that we can be more attuned to those patients who might be more vulnerable and who we intervene with or provide better support for sooner.”

“So, the project I’m working on is looking at three treatment pathways, with early breast cancer that have been recommended. We’re then comparing the level of fear of cancer recurrence between these women to better understand how the fear of cancer recurrence may be influenced by their recommended treatment pathway.”

Why are you Investigating Data of the PROSPECT Trial and De-escalation of Treatment?

“So, there’s a growing amount of evidence that de-escalation is an appropriate treatment pathway for some women with early breast cancer, and therefore this might become a more common treatment pathway. But we don’t understand how de-escalation can impact psychological wellbeing or fear of cancer recurrence in these women.”

“And so that’s really important for us to understand if this is to become a usual care pathway or a more common form of treatment. So, we want to understand if de-escalation is associated with increased fear of cancer recurrence. So, we’re asking the question, ‘does receiving less treatment increase the amount of fear of cancer recurrence women have?”

“PROSPECT involves screening women with early breast cancer via MRI to assess suitability for de-escalation. And we’ll be exploring levels of fear of cancer recurrence in the women on the PROSPECT trial, but also in another sample of women who had usual care, so they weren’t on a clinical trial.”

“And this way we’re able to compare the level of fear of cancer recurrence across different treatment pathways and better understand how their treatment may have impacted their quality of life and their levels of fear.”

Is this a New Area of Research?

“Our understanding of fear of cancer recurrence in breast cancer patients is quite well established, but as de-escalation of radiation therapy as a potential treatment pathway is a relatively new area, understanding how fear of cancer occurrence in, women who undergo de-escalation is definitely a new area and we don’t know enough about it at all.”

What are CDK4/6 Inhibitors?

CDK4/6 inhibitors are a class of drugs that are being given to patients in order to treat certain types of breast cancer and have been proven to help stop the division of cancer cells.

Breast Cancer Trials has been directly involved with research into CDK4/6 inhibitors since they were introduced in 2015. With Palbociclib being the first drug. These trials include Penelope B, PALLAS, PATINA, and the Paloma 2 trial which led to the registration and PBS listing of Palbociclib.

Dr Shom Goel is a clinician-scientist at the University of Melbourne and Peter MacCallum Cancer Centre, with a strong interest in translational breast cancer research. He was a guest speaker at the 2022 Breast Cancer Trials Annual Scientific Meeting. And we asked Dr Goel to explain his research into CDK4/6 inhibitors and where research is going in the future.

“CDK4/6 is a long-winded name, but essentially these are tablets that people can take at home that have been shown to help stop cancer cells from dividing. That’s the primary way that they work.”

“And at the moment we have found that if we combine those CDK4/6 inhibitors with hormonal therapy, this is for patients who have breast cancer that’s called hormone receptor positive (HR+), it significantly improves outcomes for patients compared to giving hormone therapy alone.”

“So, in that subgroup of patients, these drugs have really been a game changer. At the moment we use them mainly for patients with what we call advanced hormone receptor positive breast cancer. That means cancer that spread to other parts of the body. But we are looking to see whether they could also be useful in early-stage disease.”

‘Making the Most of a Good Thing’

“So, my presentation is called ‘CDK4/6 Inhibitors – Making the Most of a Good Thing’. I’m talking about that topic because that is what my laboratory research is all about. I say ‘a good thing’ because I think these drugs really have dramatically improved outcomes for many women with breast cancer.”

“And I say, ‘making the most of’ because I think there’s still a lot more we can do to bring these treatments to more women and see better outcomes for patients in different settings, or even with different subtypes of breast cancer.”

Where is Research Going in the Future with CDK4/6 Inhibitors?

“It’s a really exciting time for this class of drugs. They’re clearly here to stay which is great. And so now it’s upon us as researchers to find out how we can use them better. I’d say the first thing that’s coming, is the introduction of these drugs in what we call the early-stage breast cancer setting. So, this is not only about treating patients with advanced disease but now using these drugs to try and prevent breast cancer recurrence and increase people’s chances of a long-term cure.”

“And the second thing that I think is really exciting, are attempts to bring these drugs to patients with other subtypes of breast cancer. So, we talk about another subtype called HER2-positive breast cancer.”

“There have already been clinical trials looking at CDK4/6 inhibitors in that patient group, some of which Breast Cancer Trials was heavily involved with. And we’re just waiting to see if those trials look good, and we’re optimistic.”

“There are even trials which I’m involved with seeing whether we might be able to use these drugs for patients with what’s called triple-negative breast cancer.”

What Challenges Do Young Women with Breast Cancer Face?

When a young woman is diagnosed with breast cancer, she will face a whole range of unique and often confronting challenges that differ considerably to women who are diagnosed when they are older. Premature menopause, fertility and parenting issues, sexuality and body image difficulties, career disruption, and high levels of psychosocial stress are just some of the factors that affect young women.

Associate Professor Lesley Stafford is a clinical psychologist in psycho-oncology and women’s health, with a specific interest in women with, or at risk of breast cancer. Lesley consults in the Breast Service and Familial Cancer Centre at the Royal Melbourne Hospital, as well as in private practice. She is an Associate Professor at the University of Melbourne.

She was a guest speaker at the 2022 Breast Cancer Trials Annual Scientific Meeting, and we asked Professor Stafford to explain the definition of a young woman when receiving a breast cancer diagnosis.

“So, it’s a good question. I think for a long time the view was that young women are premenopausal women. But increasingly I think when we talk about women who are young with breast cancer, we’re talking about women who are 40 at most or even 35 in some groups, but certainly not older than 45.”

How Can Breast Cancer Affect a Young Woman’s Fertility?

“Well, there are the main ways that breast cancer affects fertility, which is through chemotherapy and some of the hormone blocking drugs they reduce the amount of oestrogen produced in the ovaries. This can mean that it is more difficult to get pregnant after treatment is over. And obviously for a young person who perhaps hasn’t had a baby yet or who hasn’t completed their family, this would be a major issue.”

How Does Breast Cancer Impact a Young Woman’s Sexuality and Body Image?

“I think the impact of breast cancer on sexuality and body image is felt across the trajectory of age. So sometimes from the side effects of chemotherapy or hormone blocking drugs, you’ll find women have weight gain and loss of sexual functioning and feel less like themselves.”

“And you know that this affects body confidence and sexuality, but for young women it’s tough because you’re often at that age where you are, seeking out relationships and or consolidating a relationship in the prime of your youth. So  that can be quite difficult, those weight related changes and so on.”

“But also for young women, the loss of hair potentially with treatment, or scars if you’ve had a mastectomy, plus or minus reconstruction, those are sort of daily reminders as well and can really affect your perception of your attractiveness to a partner.”

Can the Psychological Distress of Young Women Differ to that of Postmenopausal Women?

“I think that women who are younger do have higher levels of distress. I think the severity of their distress is higher and the prevalence or the rates of distress are also higher, and I think that’s for a number of reasons. So, some of those reasons are because they’re young and the side effects impact them. The effects from treatment that we’ve talked about, like changes to body integrity and the way we look, but also the impact of fertility, and those sorts of things.”

“I think parenting is a big factor in this. So, when you’re young, if you do have children, they are probably young, and young children are often demanding of our time, their care is more intensive, and they’re more reliant on parents for their daily needs. When you’re young, it’s natural to worry that you may not survive your breast cancer and that you wouldn’t be around to see your kids growing up. That can be a big driver of psychological distress.”

“I guess also to put into the mix is that when you’re a young person who’s sick, you’re out of step with your peers. Cancer particularly  is a disease of old age. And so, when you’re young, your friends are making career moves, they’re studying, they’re traveling, they maybe having a family and you’re sort of in a forced holding pattern while you complete your treatment.”

“So that’s really hard. It’s not like you have a whole life that you’ve lived behind you already. Your life lies ahead of you still. And just on the back of that, sometimes young women may experience early menopause as a result of breast cancer treatment.”

How Can this Affect a Young Woman and Her Life Plans?

“So, I think that with the early menopause issue, of course early menopause can be temporary, and a period can come back, but it can be permanent. And again, I think the main issue here is around fertility and disrupted plans to either starting a family or completing a family. And there will be a lot of grief in the long-term potentially associated with those menopausal symptoms, there’s a long-standing impact from that.”

“The other impact is in terms of the changes treatment has to weight gain, and sometimes sleep disruption. Women can have problems with libido, with sexual functioning, because they become dry and there are some remedies for some of these things. But these are bigger issues that you’re not necessarily wanting to be dealing with as a younger person.”

How Should People Approach Their Children in Discussing Breast Cancer?

“I get asked this a lot from parents around their children because I think it’s quite normal when you’re told that you have cancer, no matter how old or young you are, for your mind to sort of go, am I going to die? And what would that mean for my children?”

“So, before I say anything else, I want to preface this by saying that women know their children best and they will know what is right for their child and within every family, if you’ve got more than one child, you’ll know that your children differ, and their needs differ. So, having said that, my general suggestion is that you do tell your children when you know enough to tell them something that makes a difference.”

“What you tell them depends on their developmental age and their maturity. I often remind my patients that children are not small versions of adults, they’re children. Their worries are not the same as our worries. They’re concerned about routine; they’re concerned about how whatever is happening to you will impact on their day-to-day life.”

“So, when you tell them what’s going on for you, you tell them with a view to say something like ‘I’m going to go to the hospital for a few days, I’m going to have an operation, but nana will take you to school’. Or ‘Daddy will be here at night’, or something along those lines.”

“I also encourage parents to tell their children little bits of information. You don’t want to overwhelm them; you just want to give them a little bit of simple information and give them an opportunity to come back to you if there’s more that they want to know.”

“I think probably a good point to make is that I do encourage the use of the word cancer. Many parents are afraid of telling their children that they have cancer. And for very young children, it’s probably not that important. But for an older child who is aware of the concept of cancer, the very worst way to hear that mum has cancer is to hear it on the playground or two overhear, mum on the phone with someone else.”

“So, I just want to reassure people that the data shows if you have a loving and open relationship with your child, and you keep kind of the lines of communication open, then outcomes for these kids are very good. Children can be very resilient. This is an opportunity for you to model to them how one manages in a very difficult situation, and children are not left, generally speaking, traumatically scarred by my mum’s cancer.”

How Can You Best Support a Young Woman Going Through Breast Cancer?

“I think that if you’re a friend of a young woman with breast cancer, what she’d probably really like is for you to listen to her. When someone we love or someone we care about is going through a hard time, I think we have a tendency to want to make that better too and we often do that by saying, ‘don’t worry, it’ll be fine’ and trying to sort of replicate and reassure them in that way.”

“But the problem with doing that is it can make the person feel that their concerns are diminished, and that they’re not really being listened to. So, I think really speaking with people, in a way where you’re listening and containing is important.”

“So, if you are able to do things like pick up kids from school or take your friend to appointments or even sit in appointments with her, or do up a food roster, those sorts of things are great.”

“Another thing to keep in mind with your friend, is that this diagnosis of cancer, is something that’s happened to her, not who she is. So, she will have a whole range of interests and activities that she’s enjoyed beforehand, and as a friend you can keep her engaged and interested in those things. You can remind her of some of those aspects of her life.”

“So, you know encourage her to go on walks with you, encourage her to meet you for coffee. I guess the final point I would make is keep up the support. So very often the support that people receive is right at the intense stage, either at diagnosis or when treatment is at its height, and then it kind of tapers off. But what we know from our patients is that their needs don’t necessarily diminish even though the intensity of the treatment is not as great.”

“So, survivorship when treatment is over is also very tough and just because treatment is over it doesn’t mean they still don’t need to be listened to that, or that they still don’t need food rosters, or help with lifts and things like that.”

If a Young Woman is Struggling and Seeking Help, what Resources are Available?

“So, if a young woman is seeking help, if she’s still part of a hospital treating team, she can hopefully speak with the nurses and doctors in the treating team and they may be able to support her, or they may be able to refer her to a social worker or psychologist. If they have those resources at their hospital.”

“If the young woman is not under the care of a hospital anymore and the distress is severe or not necessarily even severe but interrupting with her quality of life and her ability to live a good life, I would suggest she speak with her GP. And GPs can make referrals to community-based psychologists.”

“Currently you’re eligible for 20 Medicare-available sessions in the calendar year. Not all women need formal clinical support though and there are lots of resources out in the community that can be very helpful.”

“So, in addition to speaking to family and friends, Breast Cancer Network Australia (BCNA) has wonderful support, online webcasts, podcasts, and links to all sorts of fact sheets. Counterpart is another community-based advocacy organisation. They have a patient navigator system. So, if you can log on there, they also have wonderful resources for patients. Then also the Cancer Council has a telephone support service that you can access and like BCNA, that service can also link you in with support groups and so on. If that’s something that you think you would find helpful.”

What is Metastatic Breast Cancer?

Metastatic breast cancer, also known as advanced, secondary or stage four breast cancer, occurs when cancer cells break away from the cancer in the breast and move through the blood vessels or lymphatic vessels and form a new cancer growth in other parts of the body.

Dr David Okonji is a medical oncologist at Wellington Hospital in New Zealand, who is researching  metastatic breast cancer, asking the question, are we curing HER-positive metastatic breast cancer? He was a guest speaker at the 2022 Breast Cancer Trials Annual Scientific Meeting, and we asked Dr Okonji to explain his research on this topic.

“I think we’re making huge leaps and bounds, and the prospect of a cure is becoming more of a reality in today’s age. Whether we’ve achieved that just yet is a matter of debate. But having said that, there’s very different ways that people view cure. If you ask a patient what cure means, it might be very different from what an oncologist thinks cure is.”

Are We Curing HER+ Metastatic Breast Cancer?

“I think most patients look at cure as ‘have I lived longer than I expected to and is my quality of life great’? So, in their mind, if they thought they were going to live, say three months and 10 years later, they’re still alive often they will compute that in their mind as being cured. They might not use those words, they might say the cancer is in remission, but in effect the way they’re living their lives and the fact that they are devoid of same major symptoms, would be tantamount to saying cure.”

“On the other hand, if you’re using an academic description of ‘cure’ or definition for that matter, you’d probably want to say that ‘cure’ is not having any cancer in your body whatsoever and being able to live your life as if this had never happened in the first place. That reality is unlikely to be the case.”

“But in many respects, that might be a redundant thing to think about if the patient lives beyond the expectations and  dies or something else totally unrelated to cancer or the treatment they’re receiving.”

“It is possible that one day we could cure metastatic breast cancer. Metastatic breast cancer means many things and there are very many sub definitions of what metastatic disease might be.”

“I think it depends on the extent and burden of the disease. Say, for example, we have a patient with only one single metastatic lesion in the body, that can be amenable to a reception surgically or even high dose radio belated doses of treatment. And in so doing, we rid them of the disease in effect if there’s no sign of cancer in the body. Then you can say that they’ve been cured of it.”

“Now, the real strength of courage here would be whether we could then choose not to give them any treatment thereafter. In such a case, if the disease was not to come back and the patient was to live without any symptoms, they would effectively to be cured.”

“On the other hand, if have someone has disease right throughout the body involving multiple organs, and then again you start treatment, and without treatment, whether that be with anti-HER2 therapy as we have today, you’re able to render them rid of the disease to the extent that there is nothing that you can find when you scan them, when you examine them and when you do relevant blood tests to monitor the tumour activity. In many respects, they are free of the cancer.”

“The question is whether the threshold has been reached within the bloodstream to say that there’s no cancer whatsoever. In many ways, that’s an academic question because as they live their lives and how they look, they’re free of cancer.”

How is Treatment for HER+ Different to Other Types of Breast Cancer?

“As we know, there are various subtypes of breast cancer, broadly speaking, we have oestrogen-receptor positive breast cancer, triple-receptor negative breast cancer, and HER2-positive breast cancer. Even within those subtypes, there are further subtypes in each one of those groups.”

“If we broadly look at HER2-positive breast cancer, the biggest change that we’ve seen over the last 20-25 years is the explosion of different systemic therapy available for HER2-positive breast cancer. Some of it involves chemotherapy, others involve HER2-directed antibodies. And more recently we’ve got antibody directed drug conjugates.”

“These are different ways of delivering treatment. But I think what remains the significant factor in all these treatments is the fact that there is one target that remains relatively conserved, and that’s the HER2-receptor. Provided the cancer remains HER2-receptor addicted, there’s a target that we can treat with various iterations of different drugs with different mechanisms of action.”

Unfortunately, in the other subtypes of breast cancer there isn’t one particular receptor, so to speak, that we can target repeatedly and see such dramatic responses. Say for example, oestrogen-receptor positive breast cancer. At some point the cancer becomes resistant to oestrogen-receptor directed therapy, and one has a segue to use chemotherapy.”

“This seems less so with HER2-positive breast cancer, where you can give various iterations of HER2 directed therapy, and then paradoxically get amazing responses reproduced time and time again, even the first, second, third and sometimes sixth line and beyond. And I think that’s what makes the difference in HER2-positive breast cancer. The number of treatments made available that are effective that result in long term durable responses and sustained survival.”

Dr Okonji’s Hope for the Future

“The question is whether we can improve those numbers from being 10% in 10-years, to say 50% in 10-years. That is the ontological leap that we must try to achieve and reach out for. And that is where most of the study I believe will be going into.”

“In summary, identifying who those long-term responders are, recognising there are very few, and then developing more treatments that will target the vast majority who at some point appear to become resistant to treatment, so that we can put them into the group of the long-term responders.”

What is Endocrine Therapy?

Endocrine therapy, or hormone therapy, is treatment that tries to block or reduce circulating oestrogens which is what drives the majority of breast cancers. These drugs block or reduce the ability for the body to produce oestrogen which can reduce the risk of breast cancer returning.

Dr Belinda Yeo is a medical oncologist at the Olivia Newton-John Cancer Wellness and Research Centre in Melbourne, who is researching the level of therapy that breast cancer patients require to minimize toxicity and treatment. She was a guest speaker at the 2022 Breast Cancer Trials Annual Scientific Meeting, and we asked Dr Yeo to explain her research project on endocrine therapy.

“My research is predominantly in trying to better work out which patients need what therapy in breast cancer to try and minimize the toxicity that we give with our treatments.”

“Today’s talk was about looking at the data with regards to endocrine therapy in oestrogen driven breast cancers, and comparing the various drugs that we have, how long patients need to take them, their benefit, and of course what the cost for these treatments that actually go for many years.”

“So endocrine therapy, often people use this term interchangeably with hormone therapy, is treatment that tries to either block or reduce circulating oestrogens because the vast majority of breast cancer that we see is driven by oestrogen. So, these drugs actually either block or reduce the ability for the body to produce oestrogen, and both of those strategies reduce the risk of the cancer coming back.”

“Most women who are diagnosed with an ER-positive breast cancer, even if it’s a low risk one, will be offered a form of endocrine therapy, which are usually tablets, for many years.”

“How intensive that needs to be, and how long that needs to go for depends on their risk and most importantly depends on their tolerance to the drugs.”

How Much Endocrine Therapy is Enough?

“That was the topic of my talk but I’m not sure I quite got there. I think if I’m honest if I could answer that in one line, it’s whatever is enough for the patient. So, the data for endocrine therapy is probably best sitting at five years for most patients. But five years is still quite a long time to take these medications.”

“There’s certainly benefit even if they only take it for one year. One year is better than none. Two years are better than one and five years are in fact better than two. The question is beyond five years, the data gets a little bit less strong and there will be some women, particularly those at high risk of the cancer coming back, where longer therapy makes a difference.”

Rate of Toxicity vs Benefits of Treatment?

“I mean this is something that we discuss with patients every day and I’m sure that if you discussed this with patients, this is something that they’re dealing with on a day-to-day basis. So ideally what we would love is to be able to give a treatment that has minimal toxicity and massive benefit.”

“And in the case of endocrine therapy, there’s quite a substantial benefit. But I do believe that there is a quite substantial toxicity. Some of our drugs are better tolerated than others, but it’s up to I guess the individual patient because some side effects are felt by more patients and some patients remarkably can take these medications and go completely unscathed.”

“I think it really is an individual decision with the patient you have in front of you. For example, some patients will be very concerned about hot flushes, other patients might be very concerned about the risk of their bones thinning and the risk of fractures. And we all perceive these risks very differently. We do that day-to-day.”

“So, I think you have to have the discussion with the patient that’s in front of you to make the best decision.”

What Research and Clinical Trials are Happening in Endocrine Therapy?

“Yes, so, we’re still debating how long you need to go and how intensive you need to go. I guess one of the things we’ve recently seen in the last few years is, for young women, being more aggressive, so blocking virtually as much oestrogen as you can, does seem to make quite a substantial difference to their outcome.”

“The problem is that young women have a lot of oestrogen and of course blocking a lot of oestrogen means that you’re almost certainly going to get side effects. So, I think the research where we’re going now is to try and work out which women need that more intensive treatment, and of course then for how long? Because maybe you only need to do it for a few years and then you could stop or do something a little bit easier.”

“So, there’s some research in that capacity. I guess some of the other research that we still don’t quite know the answer to is when we’re looking at endocrine therapy and chemotherapy, it’s working out are the benefits with endocrine therapy above chemotherapy, and vice versa. Are the benefits of chemotherapy above endocrine therapy?”

“So that’s something that our trials are still looking at, particularly for young women, which is the theme of our meeting.”

Dr Yeo’s Hope for the Future

“Well, obviously I would love to not have to give any of this, and the drugs that we spoke about today are also very good at preventing breast cancer in the first place. Of course, prevention is always better than having to treat cancers, but most of us don’t really want to take a tablet for a disease that we haven’t had yet.”

“You know, we tend to only take something if we really need it and that’s the kind of the scenario of being diagnosed with breast cancer.”