Recent advances in advanced breast cancer

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Published: 18 Oct 2011
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Prof Stephen Johnston; Prof Johanna Mattson; Prof Ahmad Awada; Prof Rob Coleman

Prof Stephen Johnston – Royal Marsden Hospital, UK; Adjunct Prof Johanna Mattson - Helsinki University Central Hospital, Finland; Prof Ahmad Awada, Jules Bordet Institute, Belgium; Prof Rob Coleman - Weston Park Hospital, UK:


The BOLERO (Breast Cancer Trials of Oral Everolimus) clinical trial is a study which assessed the use of the mTOR inhibitor everolimus in combination with exemestane as way to overcome endocrine resistance in breast cancer patients. Early results of this trial have shown highly significant increases in the progression free survival (PFS) of patients previously treated with anastrozole or letrozole whilst not having a detrimental effect on patient quality of life.

TDM-1 is showing promise in the first line setting as a targeted therapy, combining the monoclonal antibody trastuzumab with a linked chemotherapy agent, maytansine (DM1). This method targets the DM1 specifically at the cancer cells and has been associated with significant increases in PFS whilst maintaining a low toxicity profile. The panel discuss these two advances but stress the importance of reliable HER2 testing before the use of TDM-1.

It has been shown that metastatic cancer patients can have multiple mutation profiles. The panel outline the problems this presents for the development of targeted treatments and explain what role re-biopsies can play detecting these issues. The panel conclude by talking about the surprising negative results of a recent trial investigating iniparib as a targeted therapy for triple negative breast cancer; the role of angiogenesis inhibitors such as bevacizumab; the potential role of eribulin in future chemotherapy combination treatments; and by outlining the unmet needs of patients who develop brain metastases.

This programme is made possible with an unrestricted educational grant from Eisai Ltd.
 

European Multidisciplinary Cancer Congress (EMCC) 2011, 23-27 September, Stockholm

Recent advances in advanced breast cancer

Professor Stephen Johnston – Royal Marsden Hospital, UK
Professor Johanna Mattson – Helsinki University Central Hospital, Finland
Professor Ahmad Awada – Jules Bordet Institute, Belgium
Professor Rob Coleman – Weston Park Hospital, UK


SJ:    Hello, my name is Stephen Johnston, I’m a medical oncologist and we’re here in Stockholm at the ECCO/ESMO Congress. We’re going to discuss today some of the recent advances that there have been in the management of metastatic breast cancer and I’m joined by three colleagues of mine to discuss some of the new data that we’ve seen at this meeting and recent advances over the last twelve months. So I’m going to start with you, Johanna, and talk a little bit, perhaps, first about the challenges that we face in treating our patients with metastatic disease. We clearly are in the lucky position of having a lot of new treatments but there are big challenges in how we do the clinical research to show benefit for patients. What do you think, from a patient’s perspective, a new treatment needs to offer them?

JM:    First of all I think that the patients with symptoms should get symptom relief. I think it’s very important and I think we should start to monitor that better also in trials because we don’t always get that information from the papers. Secondly, and perhaps most importantly, I think our patients want to live longer, especially the younger the patients but also everybody wants to live as long as possible, so I think it’s very important to keep that goal also in mind.

SJ:    And do you think that survival is something that is easy to demonstrate in these trials because it’s an endpoint that the regulatory authorities seem to want but, with so many treatments, it’s very difficult to prove?

JM:    Yes, of course it’s very difficult but yesterday we heard that probably it’s best to start in later lines as the EMBRACE study showed. They could show us a survival advantage in very later lines.

SJ:    When there are fewer other treatments to influence survival beyond that?

JM:    Yes.

SJ:    Yes, OK. So, with that in mind I want to discuss whether we have seen anything at this meeting that really has pushed the boundaries back by showing a quantum improvement in benefit because in early stage trials we often will measure progression free survival in metastatic disease and that’s our first signal of whether there is anything making a big benefit. Rob, is there anything that has taken your interest here in terms of something that’s making that degree of benefit?

RC:    Yes, for me the most exciting data, I think, are from the BOLERO trial. This is a study looking at whether an mTOR inhibitor, everolimus, can help overcome endocrine resistance which, as we all know, is a big problem for our patients. Endocrine therapy is the mainstay for two-thirds of our patients but it doesn’t work indefinitely so we’re looking for agents that we might add to endocrine therapy to delay or prevent drug resistance, endocrine resistance. So what the BOLERO trial has done is it randomised over 700 patients 2:1 to either exemestane plus everolimus, which is a daily tablet, or exemestane alone. And these were patients that had been previously treated with anastrozole or letrozole, typically in the metastatic setting but some in the adjuvant setting. And the data we’ve seen at this meeting show a really profound impact on progression free survival, whether that’s investigator assessed or centrally assessed, with a hazard ratio of about 0.4 and obviously hugely significant. Now we don’t have any survival data yet, it’s too early, but that’s a really impressive result. Everolimus has some side effects – mouth ulcers, fatigue, pneumonitis occasionally, but the other really nice piece of data from this study is that they looked at quality of life and there’s certainly no detriment to being on everolimus to quality of life. So you’re living longer before you progress and you’re not having a significant detriment to quality of life, so that’s very exciting.

SJ:    That’s very important for patients, isn’t it, because obviously if this is a first treatment that they would receive it has advantages of being an oral therapy and if the side effect profile is manageable and good and there is a magnitude of benefit that is significant, then that will be interesting to patients. I agree with you, I think that is perhaps the most significant data that we’ve seen at this meeting and, in my mind, it also was consistent with previous data we saw at San Antonio where everolimus was added to tamoxifen compared to tamoxifen alone and again they saw, in a very much smaller study, a magnitude of benefit, particularly in those patients with what we call acquired secondary resistance who had shown a benefit from their aromatase inhibitor but the cancer had learned to grow round it. And we might, for the very first time, be understanding resistance to aromatase inhibitors and how to overcome it. So I think this is a landmark study.

RC:    Absolutely. I guess the challenge is how do you move it forward and do you move it forward generally in hormone sensitive disease or do you have to look for a subset of ER positive disease and pick those patients?

SJ:    Yes, I think that’s absolutely right and my own view is that we have still got problems in doing clinical trials there because with other agents when we’ve taken truly endocrine sensitive disease up front and added the agent in to try and delay resistance, we haven’t always seen the benefit and if the pathway has not been activated, the targeted agent may not have a chance to work. By blocking it you just allow the cancer to develop another way of becoming resistant. So these are really challenging trials to do.

AA:    I think this is really a welcome trial and positive result because the pre-clinical data showed very strong evidence to support this kind of combination. In the same way for hormonal therapy, this follows the other combination in HER2 positive tumours which combine hormonal therapy with anti-HER2 therapy. It’s two different settings but we arrived at the combination in tumours with some aggressiveness, it could make a major difference, combination compared to single agent hormone therapy.

SJ:    So HER2 positive disease is obviously another area where we’ve had targeted agents and we’ve actually got a multitude of new agents. Is there anything you’ve seen at this meeting in HER2 positive disease that is catching your attention?

AA:    Yes, we have an update of the study comparing in the first line setting TDM-1, which is really a very important drug. This is all the dream of the oncologists to have targeted chemotherapies, this means where we have here a drug which used trastuzumab as a carrier to bring the chemotherapeutic agents, toxic chemotherapeutic agents, to the cancer cell harbouring HER2. So we have an update of this study, TDM-1, which used docetaxel and trastuzumab which showed significant advantage in terms of progression free survival with a very good response rate, around 40% and with a better safety profile, mainly in terms of alopecia and neutropenia related events which are the major toxicity of docetaxel based therapy. Clearly the study is a very interesting trial.

SJ:    I think, coming back to the point that you made, Johanna, earlier, again toxicity is an important issue and this is a drug that is just an antibody with a cytotoxic attached to it, compared to a chemotherapy targeted combination and I think that’s again quite a landmark trial to show that it’s not equivalent, it’s actually better and improved outcomes for patients in terms of toxicity.

JM:    Yes.

RC:    That’s quite a challenge, though, isn’t it? Because you have chemotherapy with maintenance Herceptin, so OK, you have short-term unpleasantness from the chemotherapy but very low side effects from maintaining the response with trastuzumab, as opposed to a conjugate which, although in the short-term is less toxic, we don’t know what it’s going to be like to stay on it for one, two, three years, which, of course, some of our patients do. So it’s a complex area.

SJ:    Early days, yes.

AA:    I think this trial raised a very important question for clinical practice that it is really important to have good quality testing of HER2 because if HER2 is not positive, this drug is not supposed to be very active because really HER2 here is driving the chemotherapeutic agent to these cells, cancer cells, harbouring HER2. So really the quality testing of HER2 here is very, very, very important.

SJ:    I think that’s actually very relevant to some new data I also saw here related to a change in receptor phenotype.

AA:    Exactly.

SJ:    From colleagues here at the Karolinska in Stockholm. Because by re-biopsying the cancer you can show that either the hormone receptor status can be lost, we’ve known that for some time, some it can be re-expressed and the HER2 status can also change. So Johanna, re-biopsying our patients, do you think this is something we should be doing more of?

JM:    Yes, definitely. But one problem, of course, is that should we biopsy all the metastases or is it enough just to biopsy one site. I do not think that it is so simple that all the metastases would then have the same profile, I think there is some data of that also. But, of course, I think it’s a start to biopsy the first site or the most easiest site to get the biopsy.

SJ:    I think you’re right because I’m aware of some data with not just the simple tests we do now but looking at more the combination of mutations that cancer cells accumulate, that if you biopsy the disease in different metastatic sites at the same time, they can all have different mutation profiles. This is going to make targeted therapy, Rob, very difficult to deliver in practice, isn’t it?

RC:    Yes, it is and these data you talk about show also that in some patients who have had three, four or five sequential biopsies, the biology is flip-flopping from one phenotype to another. So one time there’s a gain, another time there’s a loss. I think for the patient what it means is that something like an endocrine agent… it would be a great shame for a woman to die without being exposed to an endocrine agent if she’s actually got part of her disease that’s ER positive. We do make very sweeping judgements on the primary tumour and we say well this patient has got ER negative disease, endocrine therapy is irrelevant. I think what this study and others have suggested is that we need to keep a more open mind, we need to re-biopsy and perhaps there is a broader role for endocrine treatment in these patients.

SJ:    So another group of patients that have really had unmet needs are those with the so-called triple negative disease. I often call it a disease by default because you haven’t got hormone receptors, you haven’t got HER2 and triple negative breast cancer perhaps is not a single united group of diseases, it’s a more heterogeneous group. Dr Awada, we had some data at ASCO where we tried to use targeted therapies for triple negative disease and the results were not as encouraging as early results had shown. What is your view about this group of patients?

AA:    Yes, this targeted therapy studied in triple negative breast cancer, which I agree completely with you is a very, very heterogeneous disease at the molecular level as well as clinical representation. We saw this kind of patient with a very different clinical behaviour and response to therapy.  A small remark on the targeted therapy in this group of patients, at least for a group of triple negative breast cancer, is very sensitive to chemotherapy and, in particular, to anthracycline and taxane. In my opinion, it is important not to deny this group of patients this classical, well-known, active chemotherapeutic agent. We know part of them are probably cured by the adjuvant chemotherapy and will not recur. Of course, this is a heterogeneous disease, these patients recur frequently within the first three or four years and we are looking for new drugs. Of course, we have a lot of enthusiasm with one of the first targeted therapies tried in this group of patients which is iniparib…

SJ:    So these are the PARP inhibitors?

AA:    Exactly. Yes, it was supposed to be a PARP inhibitor when this drug was developed and the phase II programme showed very interesting results, very promising results, which were studied in the phase III trial and the big surprise at ASCO is that the phase III trial was clearly negative – there are no differences between chemotherapy and iniparib PARP inhibitor and chemotherapy alone. The result raised a lot of questions and there is now some doubt about, let’s say, the dose prescribed to these patients of iniparib is really a PARP inhibitor. So probably there are some problems, at least in the interpretation of the mechanism of action of this drug, at least at the dose prescribed. So we should continue research in this field. Clearly PARP inhibitors could play a role in triple negative breast cancer with the BRCA mutated tumour, there are no doubts. This is a smaller group of patients, of course, compared to the wider group.

SJ:    So I think, from my perspective, the lesson we may have learnt in that scenario is that we have to understand that the drug really is targeting the pathway and that pathway is relevant to that group of patients. But, moreover, this problem of selection of patients and grouping everybody as an all-comer group, as HER2 negative patients we’ll give angiogenesis inhibitors, for example, and expect a benefit, or triple negative PARP inhibitors, perhaps was a naïve thought that we had a few years ago. Actually, in relation to that, angiogenesis inhibitors, this last year, have had a lot of negative press; the indication has been withdrawn in the United States. Do you use these therapies? Do you think they have any benefit for patients in metastatic disease?

JM:    In fact, in Finland we never really took bevacizumab in the treatment of breast cancer, really. Probably some centres used it a little bit but the consensus among the leading clinicians in the field of breast cancer was not to take it in use. In fact, we never took it at my hospital for the therapy of metastatic breast cancer and it’s very rare that we use it because we didn’t think in the beginning that the results were so convincing.

SJ:    Yes, OK. And likewise in the UK, Rob, that’s the scenario we’ve had as well.

RC:    Yes, I mean it’s been very restricted access even through our cancer drugs fund that we have. One of the problems with bevacizumab is, of course, we don’t know what target we’re trying to treat with this, it’s not really targeted therapy, the way it’s been developed. We don’t understand why a drug that consistently, significantly improves progression free survival loses all that benefit in terms of overall survival, whether as a first line or a second line agent. There’s almost a catch-up of the tumour when you stop therapy. For me, the only area where I would consider bevacizumab at the moment is in the triple negative patient with visceral disease who has relapsed shortly after taxane-based adjuvant therapy. We know that patient is going to do very badly and it’s not that they’re more sensitive to bevacizumab but their options are so limited and that’s probably the least worst prospect for them.

SJ:    Yes, I think I agree. I think the data, perhaps, from the AVADO study that convinced me most is, and my experience is, that you can get brisker, deeper responses, you just can’t maintain that. This is, I think, one of the unmet challenges, that we can add new drugs, we watch the toxicity profile, we can get better responses but we can’t then control the disease and keep it under control for longer. This maintenance scenario is something we really don’t know how to do, particularly in hormone negative breast cancer where we haven’t got an oral therapy that we can use to maintain benefit and response. So, there are always the desires of our patients for new things that are happening, are you aware of any new cytotoxic drugs that have made an impact within the last year in the treatment of the disease? Dr Awada?

AA:    I think the best example of new cytotoxic agent active in the treatment of the disease is the drug eribulin which is a halichondrin B analogue, and a microtubule mechanism of action completely different from the mechanism of action of taxane and Vinca alkaloids. So this drug showed, in heavily pre-treated patients, very interesting anti-tumour activity and even in one phase III trial comparing this drug, eribulin, to the best choice of the investigator. This is a very interesting design of trial in heavily pre-treated patients and this drug showed a survival advantage as well as an interesting response rate even in these heavily pre-treated patients. Having participated in the phase II programme and the phase III programme of this drug, what is interesting when we look to the phase II programme, 200 patients, a little bit more than 200 patients, we have exactly the same result observed in the phase III programme in terms of anti-tumour activity - around 10% objective response rate, let’s say up to 20-25% clinical benefit rate in these heavily pre-treated patients, and this was confirmed in the phase III programme and, in addition, this survival advantage. So this is really a breakthrough in the treatment of this disease, now there are many questions - what will be the efficacy of the drug early in the metastatic setting? There are ones who are awaiting the result of one study comparing capecitabine to eribulin in patients treated with anthracycline and taxane, and I am looking to see the activity even in the first line setting because the drug has, let’s say, a good toxicity profile.

RC:    I think that’s another really important thing about eribulin is that it’s a relatively well tolerated agent, it’s a short, five minute infusion, not a lot of nausea and vomiting, the main side effect is bone marrow suppression, some neuropathy. I guess, particularly if you’ve had taxanes, that might be an issue but, other than that, very well tolerated.

SJ:    And a single agent, it’s being used on its own, highly active. So Johanna, coming back to the use of cytotoxic agents, we’ve heard that this drug may come into earlier stages of the disease. What’s your view in principle about using combinations of chemotherapy rather than monotherapy in the treatment of the disease and the discussions you have with patients, many of whom have had combination chemotherapy as their adjuvant treatment and have a view about going back on to particularly toxic combinations?

JM:    I think that it’s about the aim of the treatment so if you are in need of a quick response then it’s, of course, good to start with combination chemotherapy. But with some patients and with many patients we use a taxane signal if it’s a HER2 negative disease. It depends, with capecitabine sometimes we use as a single drug and sometimes we combine. For the first line therapy, for instance, docetaxel plus capecitabine or carboplatin might be a good choice if you really need a response.

SJ:    But again it’s about selecting the patients that you really need, either with visceral disease, a response in that first line setting, balancing the symptoms a patient has from the cancer versus the…

JM:    Yes, I think you should really tailor that therapy even though it’s not tailored therapy but also the chemotherapy should be tailored according to the patient’s status and the previous history of the cancer therapy and so on.

SJ:    I have many patients who ask whether we can test their cancer for sensitivity to cytotoxic drugs. It was something I think was done, ex vivo testing, but we are still left with chemotherapy in a sort of try it and see type scenario. I think you mentioned earlier triple negative disease, it’s not a chemoresistant disease, it can be very chemosensitive but it can relapse quite quickly despite that. Are you aware of any data that allows us to select different chemotherapy agents, depending on the types of cancer we have? Rob?

RC:    Not really in advanced disease, the only possible exception would be the use of platinum agents in triple negative, trying to exploit this concept that triple negative disease in general has a problem with DNA repair and perhaps platinum agents would be particularly effective. Of course we have a trial running in the United Kingdom specifically testing that, comparing carboplatin to a taxane. But for the majority of patients, as you say, it is very much try it and see, the decision is based on perhaps what they’ve had before, how long it is since they were exposed to those agents, what the patient’s own personal wishes are for that balance between efficacy and toxicity. So it’s very much an art form rather than an exact science.

SJ:    No, that’s right. But I think we are now, in 2011, faced with a much better set of outcomes for patients. The things that we’ve seen at this meeting about a survival advantage in third line treatment with the new chemotherapy drug eribulin; the thing that we’ve seen in combining an mTOR inhibitor, really pushing out the boundaries of response to endocrine therapy, I think we do have a lot of different options for our patients and we have to give them the information and say that there are different things that we can try but ultimately it’s still a disease that we cannot cure. I think it’s getting that balance between treatments that will provide benefit, push back the control of the disease, allow good quality survival for patients in this setting but the overall outcomes are probably now much better than they were ten years ago. Patients live with their secondary disease for longer, rather than succumbing to it quickly.

RC:    Yes, absolutely. There are some datasets to show that decade by decade improvement. On the background, of course, we mustn’t forget that fewer people are relapsing in the first place because our adjuvant therapies are better so we are creating a hard core, if you like, of difficult to treat patients and even they have more of a chronic illness now than more rapid fulminating course that we saw twenty or thirty years ago.

SJ:    With that in mind, one of the final things to cover, perhaps, is the unmet need of patients who develop brain metastases because I think, in my view, in my practice now compared to ten years ago, we do see more of this problem of brain disease, either in HER2 negative cancer where trastuzumab may not have been able to prevent it from coming back, even in triple negative disease. In your practice, Dr Awada, brain metastases – is this a problem and do you think we have any solutions in perhaps HER2 positive disease with brain metastases?

AA:    I think this is really a very important issue and, of course, the problem for brain mets is a major problem in the metastatic setting for HER2 positive tumours as well as for triple negative breast cancer. In my experience, HER2, during the evolution of the disease up to 40-50% of the patients will develop sooner or later this problem. So the attitude in our institution is to screen these patients for brain mets and the aim behind this is to intervene very quickly in terms of radiosurgery. I know there are no data to support this in terms of survival, for example, but our data and experience, by doing this we could delay the time to have neurological symptoms in these patients. So, by discovering a small lesion in the brain and to introduce, let’s say, radiosurgery which is really not toxic at all for the patient, we have the impression that we gain some months before the patient develops symptomatic…

SJ:    Is this screening of selected groups of patients when they develop metastatic disease? So taking HER2 positive breast cancer and the development of metastases and screening, and including the brain as the staging? Is that what…?

AA:    Yes, we include the brain in the staging, for example, MRI every six months. Frequently we saw this small lesion which appeared during the evolution of the disease and we go with radiosurgery and the aim here, we know there are no data to support in terms of survival, but once again by doing this the feeling is that we delay the time to have neurological symptoms in these patients. Probably in terms of quality of life could help, we tried to do a study on this way but it was difficult to recruit patients into this study. That’s one part, the other part, we saw at the last ASCO 2011, interesting, a French study in HER2 positive tumour with no symptom or asymptomatic patient with a brain met. These patients received, before radiotherapy received a combination of lapatinib and capecitabine and what is really interesting in this very selective group of patients, asymptomatic patients, they delayed the time to radiotherapy by six or seven months. I think that’s really interesting and that’s opened the door to selected patients, probably not too precipitate on the radiotherapy, at least the whole brain radiotherapy which is more toxic than we think. For patients living more than one year, two years, we see some side effects happening in terms of memory, cognitive disorders, so if we could delay the radiotherapy for several months, in terms of quality of life, once again, it could be something very important for the patient. So this study opened the door to go in this direction and try new drugs which go through the blood-brain barrier.

SJ:    Yes. Johanna, do you have a view about screening asymptomatic metastatic disease for brain metastases? Are our patients not going to be very anxious and worried about that or do you think that the point that we’re intervening early is relevant?

JM:    This is a nice idea because in fact in the area of lapatinib I have also started to think it myself, that when to start with lapatinib and when it penetrates in the brain. So I think it’s a good idea to start to screen the brains. Of course there is no data to support that, but if we think about the symptom control it’s better to give that therapy before the heavy symptoms because we don’t always know that probably with some patients the result is better if the tumour is smaller. So I think it’s a nice idea, even though, of course, it’s always bad news for the patient to have brain metastases. But still in the end I have some very good experience with patients with very, very early meningeal metastases and we have given radiotherapy and the patient has been very long progression free in the central nervous system. So I do believe that earlier therapy might be a good idea.

SJ:    I think you’re right, it has been an area where we’ve always worried that we have very few options for our patients and that the news is very bad but I agree that that approach is of benefit. We’re also doing a trial in the UK, LANTERN, where once HER2 positive brain disease has been diagnosed and you’ve used whole brain or stereotactic radiotherapy, we are going to intervene with the combination of lapatinib or capecitabine, compared to continuing trastuzumab and adding in capecitabine and seeing if we can delay the time to progression in the brain. So these sorts of clinical trials are still important to try and push the boundaries back for this group of difficult problems in metastatic disease.

OK, well thank you very much for speaking today, I think we have got quite a lot of new data to be excited about and to provide benefit for our patients so this, I think, has been a very helpful discussion about the recent advances in metastatic disease. Thank you very much.