15th Milan Breast Cancer Conference
Gene activation in breast cancer subtypes
Dr Alan Coates - University of Sydney, Australia
Breast cancer used to be regarded as one disease, you’ve either got it or you haven’t. What has become very clear over the last couple of decades is that breast cancer is really many different diseases and there are various ways of dividing that up but one particularly important way that developed about twelve years ago was to look at the genes that are activated within different types of breast cancer. There are ways of shuffling those around to work out what patterns are common and it turns out that there are at least several types of breast cancer that can be detected by that assay and we call them luminal A, luminal B, HER2 and basal. There are probably more within that but the area I’m particularly interested in is the luminal cancers because they’re the ones where there is likely to be a benefit of giving some form of hormonal manipulation, either the addition of a drug like tamoxifen or using a drug which will turn off the body’s own female hormones like the aromatase inhibitors. Those have been by far the most effective drugs for breast cancer treatment over my practising lifetime, the last forty years. Tamoxifen has to be the number one drug that has ever come out for breast cancer and it remains a very important drug in the treatment of women today.
What is clear is that for these luminal types of breast cancer all patients will need some form of endocrine treatment to reduce their risk of the cancer coming back and that works. The question that arises and that has been most difficult to tease out is which, if any of them, need additional treatment with drugs called cytotoxic drugs, that is commonly called chemotherapy. The problem is that for some people it may not be necessary, for some it may not even be effective and for anyone who does receive it it can be quite toxic. So we try to be more specific about who might benefit from the addition of chemotherapy and a lot of the debate around the treatment of so-called luminal A breast cancer is who, if anybody, needs chemotherapy as well as the appropriate hormone treatment.
The appropriate hormone treatment is fairly well developed but there are a few trials going on to refine that as well. I mentioned a drug called tamoxifen, that is a class of drugs of which it’s really the only successful one for breast cancer treatment. That can be used for women of any age. Another more recent approach has been to use drugs that turn off the residual ability that a woman has to make oestrogen and that actually comes mainly from the body fat after the ovaries stop at menopause. You can turn that off fairly effectively with a class of drugs called aromatase inhibitors and there are a few of them. So by and large, comparing those with tamoxifen, they were slightly better on average. But what has become evident is that that doesn’t apply to all women and there are quite a number of women with lower risk disease for whom tamoxifen alone is quite adequate and you’d get no additional benefit from substituting or adding the aromatase inhibitors to the treatment sequence. That’s important because tamoxifen is off patent and is relatively cheap and available to women all over the world. The aromatase inhibitors have been very expensive although they are now coming off patent as well and I guess they’ll be cheaper, but they have their own particular side effects. It’s nice to see that for a large number of women you may not need them.
For the younger women we’ve got an additional benefit to be had perhaps by stopping the ovary function. Tamoxifen doesn’t do that but you can stop ovarian function with a number of drugs and of course in the older days it was done by surgically removing the ovaries and that goes all the way back to Sir George Beatson in the late 19th century who first discovered that that was a way of controlling breast cancer. Why it works is that it turns off the main source of oestrogen in a younger woman which comes from the ovaries and that change in the oestrogen has a beneficial effect. Now we don’t yet know whether you need to do that as well as tamoxifen in younger women but that trial is well advanced and we hope to have the results of it sometime next year. So that’s a watch this space for young women. I think we’ve also got increasing evidence that longer durations of treatment, either with tamoxifen or by adding an aromatase inhibitor after tamoxifen can improve on the outcome for women in the hormone treatment.
So there’s progress within the hormone sector, the difficulty is defining who needs something more than just the hormones. That has been the most controversial area over years and each successive panel at St Gallen has wrestled with that question – what’s the threshold at which we should be advising women that they need chemotherapy as well as the hormones. For the last couple of St Gallen meetings the panel has been willing to adopt the classification into luminal types of breast cancer, as best you can measure it without the complicated genetic tests, by using commonly available pathology measures of things like the oestrogen receptor, the progesterone receptor, a measure of the HER2 oncogene, sometimes just with immunohistochemistry, sometimes it needs a slightly different test, and a measure of the proliferative capacity of the tumour which turns out to be quite important. That’s done by the pathologist with a test called Ki-67. Now Ki-67 has been very controversial, it’s not clear quite why because it has been around and used for thirty years and we’ve known for many, many years that it’s a reliable way of predicting what’s likely to happen to a woman, that high values of this test go along with a poorer outcome and that’s one of the reasons we should be thinking about giving something over and above just endocrine treatment.
In the United States the test never really caught on because they’ve got enough money to do the fancy genetic tests on almost everybody and so they were very sceptical about the use of the Ki-67 test. I think the wisdom of the panel, which is a large international panel, was that Ki-67 is very good, thank you, and we’ll continue to use it. So that’s what the panel has decided and that will be coming out as a paper reporting the St Gallen meeting in a journal called The Annals of Oncology and it will be coming out, at least online, very soon we understand.
So, yes, we’ve refined things a bit this time at St Gallen but the basic message has been, yes, we can get a good enough approximation of the breast cancer subtypes by commonly available pathological tests. Yes, that’s enough to help guide treatment and help select the women who need more than just endocrine therapy and I think that’s a service that we can offer the world as a consensus opinion of a large group of people who’ve got an enormous amount of experience in the treatment of breast cancer and that will last us for a couple of years. Over the next two years more evidence will accumulate and another panel will probably convene in much the same sort of sequence as the St Gallen meeting that’s just finished and it may come to different conclusions with different evidence because that has been the evolution of treatment recommendations over the years from St Gallen, that the panel tries to bring together the best of the new evidence and make sense of its recommendations for the average treatment of people around the world.
About two-thirds of breast cancer happens in older women, post-menopausally and it is true that the oestrogen receptor positive types, that is the hormonally responsive types, are more common as you get older but you get quite a number of younger women, before menopause, who still have endocrine responsive cancers and they’re the group in whom we’re doing the big trial to see whether you get additional benefit over and above the tamoxifen, which we know works, can you get even better benefit by turning the function of the ovaries off for a period of time in those younger women.
Is there a difference between the oestrogen produced in the ovaries compared to in fat?
The molecule is oestrogen, or oestradiol to be precise, and it can be produced from either source. But in the younger woman the amount produced by the ovaries just swamps anything that’s coming from the adipose tissue whereas when the ovaries stop the adipose tissue continues to do much the same as it’s always done and that is then the major source of the remaining oestrogen in a post-menopausal woman.
The circulating hormone is different from the presence or absence of the oestrogen receptor in the tumour. The oestrogen receptor was discovered in the 1950s by Elwood Jensen and was the first target for molecularly targeted therapy. We’ve actually been treating it unknowingly ever since George Beatson started taking ovaries out but the oestrogen receptor is a manifestation of the fact that the tumour is still responsive to oestrogenic manipulations and that just happens to be more common as women age, the tumours that they get are more commonly done that way. Now why that should be we don’t know.