European Breast Cancer Conference, Vienna, March 2012
Advanced breast cancer consensus and the latest on triple negative breast cancer
Professor Eric Winer - Dana-Farber Cancer Institute, Boston, USA
I was part of the ABC 1 conference which was advanced breast cancer, which was focused on advanced breast cancer, in Lisbon in November. And the purpose of that conference was both to review the status of the treatment of advanced breast cancer and to develop some consensus guidelines to help practising physicians care for patients who have advanced breast cancer.
At that meeting I specifically spoke about triple negative breast cancer, and I summarised what had been discussed at that meeting on triple negative breast cancer in my talk here at EBCC. And in particular I focused on how some of the guidelines that had been developed would play out for patients who have triple negative breast cancer. And to put it in a few minutes, I think what we can say is that patients who have metastatic triple negative breast cancer usually have developed their disease after having had a course of adjuvant therapy, oftentimes a relatively recently administered course of adjutant therapy, so many patients with metastatic triple negative breast cancer have been pre-treated with anthracyclines and with taxanes. At this point in time the treatment that we have is unfortunately largely limited to chemotherapy, there are many chemotherapy regimens. In someone who has never received any chemotherapy, for some reason didn’t receive adjuvant therapy, or is presenting with stage four disease de novo, then an anthracycline or taxane can be used in a first line setting. Taxanes can often be used in the first line setting if they were used before, as long as it was a reasonable disease-free interval.
But when those agents aren’t available, we turn to many of the other drugs that we have, including drugs like capecitabine, and vinorelbine, and eribulin and, increasingly over the past few years, the platinum salts which have been used in triple negative breast cancer in clinical trials with some success but which, in fairness, have a role that has yet to be fully defined. We know that they have some activity in the setting of triple negative breast cancer; we don’t know that they’re necessarily better than other agents.
A few other features of triple negative breast cancer that are worth noting. One, that about half of these patients unfortunately will develop CNS involvement during the course of their disease and while the ABC consensus recommendations are that we do not proceed with screening of asymptomatic patients, one has to have a low threshold in the setting of a symptom to obtain imaging studies of the brain and to look for brain metastases in a patient with triple negative breast cancer. Unlike the situation with HER2 positive breast cancer, however, patients with triple negative breast cancer develop brain metastases when their systemic disease is also progressing, most of the time, it’s not occurring when they’re doing well otherwise. And, fortunately or unfortunately, depending on the way you want to look at it, women with CNS involvement from triple negative breast cancer don’t die of that CNS involvement. It would be unfortunate if they were to die of that involvement no matter what, but in the setting of HER2 positive breast cancer, we see women dying of CNS involvement at times, not in every one, but at times, because there is such good systemic control of the disease. And the unfortunate part of triple negative breast cancer is usually the extra CNS control of disease is poor enough that long before patients can develop progressive CNS problems, they unfortunately will have already succumbed to their liver or lung metastatic disease, or disease in other parts of the body.
And then finally in terms of other agents, there was hope that bevacizumab or Avastin would be an important drug for triple negative breast cancer. It seems to work about as well in triple negative breast cancer as in ER-positive breast cancer, and it does prolong progression free survival but, at least in my view, doesn’t convincingly prolong overall survival. There has been one sub-group analysis that has suggested that perhaps there is some small improvement in survival in a sub-subset of patients with triple negative breast cancer, but I think it’s hard to make too much of that at this point in time. And then one hopes of course that eventually we will have predictors of benefit for bevacizumab but to date we have failed to do so both in the triple negative setting and in the ER-positive setting.
And then finally the PARP inhibitors which were thought to be the great hope. Unfortunately at this point in time pretty clearly work in women who have BRCA mutations but their role in patients with sporadic triple negative breast cancer remains unclear; as single agents they don’t seem to be effective there. And whether or not, in combination with chemotherapy, some of the PARP inhibitors will add to our presently available therapies remains to be seen.
But no question, we need new therapies, we need to understand the biology of triple negative breast cancer which is far from simple and far from uniform because there are many sub-classes of triple negative breast cancer. We need to understand this biology better, and then we need to just keep working hard to develop better therapies.
Where might these new therapy areas be?
A subset of patients with triple negative breast cancer, a small subset, appeared to have tumours that appeared to express the androgen receptors, so androgen receptor antagonists for a very small minority of patients with triple negative breast cancer may be useful. There are patients with triple negative breast cancer whose tumours appear to have a very prominent immunologic component, or there are immunomodulatory cells that have infiltrated the tumour, and that at least raises the possibility that immune-based therapies might possibly be useful there.
As we better understand more classical triple negative breast cancer, that is the basal-like phenotype, we may identify, and certainly hope that we identify new targets that can be tested in the clinic. Many of these tumours have lost p10 or a related protein INPP4B, and it is thought that in those patients, that PI3 kinase inhibitors, or PI3 kinase inhibitors in combination with either chemotherapy or other biologic agents, may be useful and that’s being tested. So I think it’s really a situation where rather than empirically testing a variety of new agents, we need to go back to the biology, we need to better understand the biology of triple negative breast cancer, we need to better understand the heterogeneity of triple negative breast cancer, and building upon pre-clinical work, we have to move in to the clinic.
Will we find more and more subtypes of triple negative breast cancer?
You know, there are those who believe that of the, for example in the United States, the 180,000 cases of breast cancer each year, that that represents 180,000 different diseases. I’m not convinced of that by any means. I think that there is a limit in general to the number of different major sub-types that we will see and I do think that even within these subtypes that originally we thought were more uniform, like triple negative, HER2 positive, what have you, there is going to be a fair amount of heterogeneity, but how exactly that will play out remains to be seen. As many people have been talking about, there was a very interesting paper in the New England Journal of Medicine within the past two weeks that looked at intratumoral heterogeneity. So it’s not only that one woman’s tumour is different from another but that within an individual woman’s tumour there’s a lot of diversity. And as one is able to effectively target one’s sub-population of tumour cells, there may be others that can cause additional problems.
So for at least some patients, the task of finding curative therapies may be very, very difficult. But it is worth remembering that somewhere in the range of 75% of women with breast cancer treated in developed countries actually go on and never have any recurrence of their cancer, so it’s not as if breast cancer is by any means or even closer to an entirely fatal illness. For the most part it is an entirely curable illness. But it’s this sub-group of women who develop recurrences and who ultimately die of breast cancer for whom we need to come up with better therapies both to prevent that and then to treat it.
