Abstract
Interview by Sophia Maprayil and Alexandra Hemsley, Commissioning Editors
Chris Twelves is a medical oncologist and leads the Section of Oncology and Clinical Research at Cancer Research UK’s Clinical Centre at St James’s Hospital, Leeds. His particular interest lies in new drug development and clinical pharmacology; his clinical practice to date has been in the field of colorectal and breast cancer. After training in London he was Senior Lecturer, then Reader, in Medical Oncology in Glasgow at the Beatson Oncology Centre before taking up his current post as Professor of Clinical Cancer Pharmacology and Oncology at the University of Leeds and St James’s Institute of Oncology. In this role, Twelves leads his team to perform hypothesis-driven studies, prioritizing therapeutics developed locally or through the Cancer Research UK New Agents Committee, of which he has been a member.
Twelves also heads the Experimental Cancer Medicine Centre in Leeds; previously he was Chair of the New Drug Development Group of the European Organisation for Research and Treatment of Cancer. He has published over 150 papers, in addition to several books, and recently presented his group’s findings from a Phase III study into the breast cancer drug eribulin.
What initially drew you towards medical oncology?
Well, 30-odd years ago, when I completed my undergraduate medical training, I was clear that I wanted to be a physician rather than a surgeon or a general practitioner. In those days, you then had to complete several years of general medical training and while doing that in the early 1980s, one of the things that struck me was that when we had patients with cancer, the practice was that they were often not told very clearly what their diagnosis was. For example, they were sometimes told they had a neoplastic growth, but the consultant might not go back and check they actually understood what that meant and what the implications were. I was very uncomfortable with the fact that we were not being frank and open with patients who had cancer. Although they were initially reassured by the limited information they given, because they did not actually understand the explanation, it later became a source of concern to them. When I started to discuss the diagnosis of cancer more openly with patients, I soon appreciated that you have to be then able to explain what it means, what the plan is, reassure them that hopefully the immediate future is not too bleak and to give them a sort of roadmap as to what will happen next. Otherwise patients swapped one worry about not knowing their diagnosis for worries about the implications of being told the bad news that they had cancer. Without training in oncology, I realized I was not able to provide that level of care, so I decided to undertake a 6-month job in medical oncology and having begun in that area, it appealed to me to get more involved, and 25 years later I am still treating patients with cancer.
You were previously a member of Cancer Research UK New Agents Committee & Chair of the New Drug Development group of the EORTC. How did you move into drug development?
When I went into medical oncology, the first job I had in the mid 1980s was at University College Hospital (UCH) in London (UK). At that time, medical oncology was a small specialty, and there were very few medical oncologists; indeed, cancer as a specialty including surgeons and radiotherapists was much less well developed than it is today. Despite this, it was an exciting time to be in medical oncology, as there were a lot of new developments with cytotoxic chemotherapy. In addition, there was very much a sense that chemotherapy might be able to cure a significant proportion of patients with cancer, based on what was the relatively recent introduction of platinum-based chemotherapy in patients with teratoma, and the emergence of new chemotherapy drugs for people with leukemias, which, in both cases, saw diseases that had previously been rapidly fatal become curable. This was particularly the case for teratoma, a testicular cancer affecting young men; once metastasized, earlier chemotherapy drugs could achieve an initial response with the cancer shrinking, but soon after the cancer would return and the patient would die. When cisplatin was introduced in the 1970s, these patients began to be cured. Therefore, in the 1980s, there was hope that if only we could find the right chemotherapy drug for breast cancer, bowel cancer or lung cancer, we might have the prospect of curing patients with these much more common cancers even once they have metastasized.
When I first went to UCH, a lot of the work that I was doing was based on clinical trials. Robert Souhami, who was a very eminent medical oncologist at that time, was leading clinical trials for lung cancer, and there was great optimism that the trials might lead to cures for these and other patients with cancer. That hope sadly has not been realized for the majority of adults with metastatic cancers, for whom chemotherapy is not curative. Nevertheless, the initial experience certainly got me interested in clinical trials, looking at new drugs, and how they might best be used. When I moved from UCH to Guy’s Hospital (London, UK) and continued my training with a focus on breast cancer, I was able to design and run clinical trials myself, and this became very much my area of interest. Later, when I moved as a consultant to the Beatson Oncology Centre (Glasgow, UK), nearly 20 years ago, that post was explicitly linked to testing new drugs during Phase I clinical trials, the first time a new drug is given to patients with cancer. This interest in early clinical trials led me to being the Chair of the EORTC New Drug Development Group and working with Cancer Research UK in a number of different ways, including through the New Agents Committee. This continues to be my main area of interest.
Can you tell us more about your current work at the Experimental Cancer Medicine Center in Leeds (UK)?
The way that cancer services are now organized in the UK is radically different compared with the ones that were around 15 or 20 years ago. Within each geographical region of the UK, we now have one major cancer center; so in central Yorkshire, we have Leeds, as you go west across the Pennines, we have one in Manchester, going south there one is Sheffield and north of us is Newcastle. Now we have a very well-defined network of these centers for the delivery of cancer care. Within most of those cancer centers, we also have academic units and many now have Cancer Research UK Clinical Centres and Experimental Cancer Medicine Centers (ECMCs). These centers provide additional funding, which we have to bid for, to provide the infrastructure we need to carry out cancer research.
There are 18 or 19 ECMCs across the country working as a network, looking into ways of treating cancer for patients with funding that comes partly from Cancer Research UK, and partly from the government and the UK taxpayer, via the National Institute for Health Research. In our own ECMC, we have people working in a wide range of areas, including Phase I clinical trials. I run a Phase I clinical trial each week where we see patients who are taking part in these first in human studies. Many are complex studies, involving patients with advanced cancer receiving an experimental drug, having additional blood tests, or scans or biopsies as part of the trial, and require quite intensive monitoring. To run these early clinical trials, we need research nurses and part of our ECMC funding contributes to that. New drug therapies also involve measuring how much of the drug gets into the patient’s blood, how long it stays there – or in other words, studying its pharmacokinetics. At the nearby laboratories of the Institute of Cancer Therapeutics (Bradford, UK) headed up by Laurence Patterson, we measured the drug levels, not only for studies we did ourselves, but also for the studies conducted elsewhere. In particular, one of the people working there, Paul Loadman, specialized in measurements of drug concentrations in the blood, tissues or tumors, which is one particular area that we are working on.
We also undertook work in molecular pathology, partly through our ECMC, where my colleague Paul Quirke (Leeds, UK) heads up the team looking at tumors to identify which patients are likely to benefit from a particular drug. This is very much a part of the concept of personalized medicine, and this work is often done in the setting of large national and international clinical trials. Many of these are for colorectal cancer with tumor samples sent to the laboratory, and a range of different histological and genetic tests are carried out on them. There is a large national trial for patients with bowel cancer that is shortly going to open, called FOCUS 4, in which a whole range of different types of bowel cancer will be identified by these complex molecular analyses, and also the different molecular subtypes with different cytotoxic or biologic agents.
A third area supported by our ECMC, continuing the theme of personalized medicine, are laboratories looking at proteomics, where blood or other tissue samples are studied and the proteins present characterized to identify biomarkers and try to identify new targets for cancer treatments or new ways of monitoring cancer. This laboratory, headed up by Roz Banks (Leeds, UK), studies kidney cancer in particular, but also other types of cancer, and their work has led us to develop a detailed system of blood and other tissue collection, processing and storage. This is a very valuable asset that we can go back to and use to try to understand cancer better.
The ECMC funding also provides some infrastructure for us to develop and evaluate novel therapies that are not part of mainstream drug development. Alan Melcher (Leeds, UK) has a laboratory-based team that looks at new biological approaches to cancer treatment, in particular using viruses, which are able to target cancer cells in the laboratory and in animal models. These are also being evaluated in experimental clinical trials, which we run through the Phase I clinic in collaboration with him. As part of these trials we have, for example, given intravenous viral therapy to patients with bowel cancer that has spread to the liver. We then collected samples from these patients when cancer in the liver was surgically removed, the sample was then examined in Melcher’s laboratory and it was shown that the viruses were able to home in on the liver. This is a very good example of translational research, another area that the ECMC funds support.
Much of your clinical practice has focused on breast cancer. What are the main challenges that this particular group of patients face with currently available therapies?
My clinical practice is divided between experimental treatments for a range of different types of cancer, and a specific focus on breast cancer; I have been treating patients with breast cancer for 25 years, since I first went to the breast unit at Guy’s Hospital. It is really very striking how things have changed. We now have the national breast cancer screening program, so we are detecting breast cancer much earlier than we were 25 years ago. Surgical treatments have changed a great deal over that time, with many fewer women having a mastectomy now, and those who require mastectomy are routinely offered breast reconstruction; fewer are also having all the lymph glands under the arm removed. These important advances in surgery have reduced the trauma and morbidity of breast cancer surgery. Radiotherapy is also much more sophisticated. At the risk of offending my radiotherapy colleagues, 25 years ago, breast radiotherapy was almost ‘point and shoot’, like with budget cameras. These days, there are very effective planning methods, so the radiotherapist can be very clear that what they are treating is the cancer, and not the heart or other normal tissues.
From my point of view, the main differences I have seen have been in drug development; we now have chemotherapy drugs, hormone treatment, or so-called targeted therapies, which we simply did not have back when I started treating breast cancer. So across the board, we have more and better drugs than we did 25 years ago. This means that many women who are diagnosed before the cancer has spread are now cured. Those women in whom the cancer comes back and spreads we are unfortunately still not able to cure, but they live longer and with a better quality of life than a generation back. So with breast cancer, the news is good, but that does not get away from the fact that breast cancer remains one of the biggest killers for women in the UK and across the world. Despite all these advances, it remains a major problem and is going to become an even bigger problem in the developing world over the next 25 years. So, I think we need to be clear that there is still a lot of work to be done. I sometimes get the sense that there may be a feeling that breast cancer has been ‘sorted’ because of the good news we hear, but unfortunately many, many women die of their disease.
So, we need progress on all those fronts that I have described; we need to see more women diagnosed earlier, more women cured before their cancer has spread, and we need more and better drugs to help women with advanced breast cancer live longer. It is very striking at the meeting I am at today in the 2012 CTRC-AACR San Antonio Breast Cancer Symposium (4–8 December 2012), that across the whole range of different types of breast cancer, we are seeing more drugs, in many cases that work better, and drugs with different or fewer side-effects compared with those that we already have in clinical use. These new drugs are going to work their way into use over the next couple of years and start making a difference to women who have breast cancer.
The results of your recent Phase III study into eribulin were recently presented at the San Antonio Breast Cancer Symposium. What were the initial aims of the trial? Can you tell us more about eribulin? How was the trial different to similar studies of its kind? What were the main findings?
We presented a large study at San Antonio this year, and a couple of years ago, we presented a similar study, which was the first big study with this new drug eribulin. Eribulin is different to many of the new drugs that we hear about these days as it is a new cytotoxic drug, rather than a targeted therapy in the way that a drug such as trastuzumab (Herceptin®) is. What is interesting about eribulin is its mechanism of action; it is similar to some of our existing chemotherapy drugs such as paclitaxel (Taxol®), in that it targets the microtubules. These microtubules have a number of roles in cancer cells, and indeed in normal cells, as they provide the cytoskeleton that holds the cell together; but when a cell divides, they also pull the chromosomes apart as we go from one cell to two cells. So, in rapidly dividing cells, such as in cancer cells, interfering with the microtubule is something that we know can be an effective way of treating cancer. Eribulin is distinctive because it is not simply a ‘me-too’ drug; it has a completely novel chemical structure compared with other microtubule-targeted drugs and is derived from a compound that was found in a marine sponge found off the coast of Japan. Eribulin also binds to the microtubules in a way that is different to existing drugs. In the laboratory, eribulin was also effective even against cancer cells that were not sensitive to the existing microtubule-targeted drugs we use. This all made eribulin an attractive drug to take into the clinic.
Having performed the initial clinical trials to establish how much of the drug to give, how often, and seen signs that it could be effective in women with breast cancer, the EMBRACE trial was carried out. A couple of years ago, we reported the results of this trial of over 700 women with heavily pretreated metastatic breast cancer who had previously received up to five different lines of chemotherapy. They were randomly assigned to either eribulin or ‘standard’ chemotherapy; two women received eribulin for every one who received the standard therapy. At the time, no individual drug was known to be better than another for these women, so standard chemotherapy was what the oncologist would have used in each particular woman had they not been on the trial and is known as ‘treatment of physician’s choice’. These women were then followed, and the main aim of the study was to see whether eribulin was able to prolong overall survival. We were delighted to see a couple of years ago that the women who were randomized to treatment with eribulin lived on average 2.5 months longer than those who were treated with the treatment of physician’s choice. This prolongation of survival was statistically significant, and the EMBRACE trial led to eribulin being approved by the regulatory authorities, and it is now increasingly used in women with heavily pretreated metastatic breast cancer.
At the same time as the EMBRACE trial was being carried out, a second study was also underway, which is the trial that was being reported for the first time this week. Currently known as Study 301, it was similar to the EMBRACE study insofar as it was for women with metastatic breast cancer who had received taxane and anthracycline chemotherapy, which are the most effective among the existing chemotherapy drugs; the trials differed in that women in Study 301 were less heavily pretreated, having received up to three lines of prior chemotherapy, compared with up to five lines in the EMBRACE trial. Patients were randomized to either eribulin or, in this case, to standard treatment with the oral drug capecitabine rather than a range of different choices; that is because for this particular group of women, capecitabine was accepted as the most effective treatment choice after a taxane and an anthracycline. The results that Peter Kaufman, (Dartmouth-Hitchcock Medical Centre, NH, USA) presented on Friday 7 December 2012 in San Antonio (TX, USA) showed that in a sense, the cup was half full and in a sense half empty. We saw in Study 301 that, on average, women treated with eribulin had better outcomes and lived approximately 6 weeks longer than those receiving capecitabine. However, this clear trend in favor of eribulin did not reach the statistical threshold for declaring it a positive study. Therefore, we are not in a position to say that eribulin is definitely better than, or should replace, capecitabine across the board. On the other hand, eribulin does look to be at least as effective as what was previously our ‘go-to’ drug for these women. This clear trend in favor of eribulin across all patients led us to then look in more detail at individual subgroups of patients, to see if there are individual subgroups of women who may benefit.
There are many ways of splitting breast cancer, which we now recognize to be not as a single disease, but as one comprising many different subtypes.
One of the easiest ways we can divide women is into those who have different types of breast cancer depending on what we call the molecular phenotype. The single biggest group of these patients are those with estrogen receptor (ER)-positive cancers. With cancer cells being derived from breast tissues, it is perhaps not surprising that approximately more than 70% of breast cancers are ER-positive and in effect able to feed off the estrogen hormones circulating in a woman’s blood. Those women with ER-positive breast cancer are often given hormonal treatment. The second subgroup of women are those who have HER2-positive breast cancer, this is another receptor sitting on the surface of normal breast cells; in approximately 20% of breast cancers, there is a huge excess of these receptors on the surface of the cells. This excess of HER2 receptors cause cancer cells to divide in excess, and these cancers carry a worse prognosis. We treat these patients with trastuzumab (Herceptin) or laptinib and other drugs targeted at the HER-2 receptor. That then leaves us with another group of patients whose cancer is not ER-positive and do not overexpress the HER-2 receptor; we call these triple-negative cancers.
In Study 301 (and in EMBRACE), patients were eligible regardless of the molecular subgroup of their cancer. When we divide them into the aforementioned molecular subgroups, we see that the trend in favor of eribulin being more effective than capecitabine is stronger in those whose cancers are HER2-negative and those with triple-negative cancers; the minority of patients with HER2-positive cancers appeared not to benefit from eribulin in Study 301.
Because this subgroup analysis was not the primary aim of the study, we cannot definitively say that this is how those particular women should be treated in the future. Nevertheless, it does give us a pointer. If I am in clinic and see a woman with metastatic breast cancer who has received an anthracycline and taxane, whereas previously the next port of call in terms of offering chemotherapy to control her disease would have been capecitabine, with this new information, I can discuss with her that there may be an alternative in the form of eribulin. We would also discuss with her the differences between the two treatments. Capecitabine is a tablet, eribulin is an injection; some women may prefer one, some may prefer the other. They have slightly different side effects; capecitabine can cause soreness of the skin on the palms of the hands and the soles of the feet, and can also cause diarrhea. Eribulin does not have those side effects, but it does cause a fall in the white blood cells, and it can cause numbness and tingling in the fingers and toes as well as thinning of the patient’s hair. We have been able to compare the different pattern of side effects in the current study.
So, although the trial would be described as ‘negative’, because it did not meet the predetermined statistical threshold, eribulin appears to be at least as effective as capecitabine. There are also pointers to suggest there may be subgroups of women with whom we should be discussing the choice between capecitabine, which has been our current treatment, and the newer option of eribulin.
What are the next steps to further study eribulin in this patient population?
Well, as I said, the current trial will help us in discussions with our patients, who we see routinely in the clinic. Eribulin has been looked at in trials in a number of different situations.
There are several studies now underway, and the preliminary results of one such study have been presented by Linda Vahdat (Weill Cornell Medical College, TX, USA), looking at giving patients with HER2-positive cancers eribulin in combination with trastuzumab, and the results looks encouraging. There are other studies, again at a very early stage, looking at whether eribulin may be a useful drug given to patients as an adjuvant therapy. Other studies are looking at giving eribulin as a first-line chemotherapy. Vahdat has presented some encouraging data with eribulin in that first-line setting, so there is some active research taking eribulin forward in breast cancer. Moreover, although they are out of my area of expertise, there are also large trials in patients with sarcoma and with lung cancer, for which we are awaiting the results.
What do you feel the impact of this research could have on women with metastatic breast cancer?
Had Study 301 crossed that magical statistical threshold, we would be discussing how, if and when eribulin should replace capecitabine in this particular group of women. Although not statistically significant, I think the results of Study 301 will have an impact. For those women that I mentioned earlier whose cancer has metastasized, and who received the most active drugs, eribulin is an alternative to capecitabine as the next therapeutic option, especially in certain subgroups; this is something we can discuss with our patients.
Most importantly, for me, taken together with the EMBRACE data presented a couple of years ago, the results of Study 301 show that eribulin is now established as part of the core armamentarium of chemotherapy drugs for women with metastatic breast cancer. As I explained earlier, we cannot cure these women; what we are aiming to do is to keep the patients well and to keep them alive as long as possible, and I think eribulin is an important additional new string to our bow that can prolong their survival.
Finally, how do you see research into metastatic breast cancer developing over the next decade?
I think we can expect to see advances across all the fronts that we discussed at the outset, some to a greater and some to a lesser extent.
I think the area of breast cancer research where we have made the least progress in the last 25 years is in preventing breast cancer in the first place. We know that there is a small proportion of patients who have inherited breast cancer, caused by the so-called BRCA gene, where they have a very strong family history of breast cancer. We can test these women, and if they do carry the BRCA1 or BRCA2 gene, we can discuss with them whether they should perhaps have a prophylactic surgery, additional screening for early detection, or perhaps hormonal treatment that appears also to reduce the risk of them developing breast cancer. However, outside the small group of women at especially high risk of developing breast cancer, we do not have proven strategies to prevent the disease developing in individual women.
I would expect refinements rather than revolution in surgery and radiotherapy, and that in the next 10 years, the major developments will be in the area of systemic therapies. Ten years ago I would not have anticipated the array of new drugs we have today, with several new chemotherapy drugs, most recently eribulin, having come to the fore over the last decade. We do not have specific treatments for patients with triple-negative cancers, although Study 301 suggests eribulin may be especially effective in those patients.
For patients with HER2-positive breast cancer, we now have new drugs such as T-DM1 and pertuzumab, whereas previously we had only trastuzumab (Herceptin) and lapatinib (Tykerb).
ER-positive cancer is the most common type; for decades, tamoxifen was essentially the only useful drug we had, but now, we have the aromatase inhibitors that are more effective than tamoxifen in postmenopausal women. There are new clinical trials and laboratory data that suggest that we may be able to reverse resistance to these hormonal drugs. The addition of everolimus to exemestane is more effective than exemestane alone in women with ER-positive cancers that have become resistant to hormone therapy.
At a more basic level, we are increasingly appreciating how heterogeneous breast cancer is, and the hope is that in the medium to longer term, we will be able to tailor the treatment to the individual woman, on the basis of a detailed analysis of the tumor, so we can match the patient and their cancer to a particular drug treatment.
Finanancial & competing interests disclosure
C Twelves is a compensated member of the speaker’s bureau for Eisai and Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.