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Long term side-effects of chemotherapy in early breast cancer -

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Norman Swan: While chemo generally isn't given for ductal carcinoma in situ, it is for early breast cancers which have started to invade the tissues around them. While most people are focussed on the short term side effects of chemotherapy, it's becoming clear that for a small number of women there are long term problems, in particular the risk of leukaemia.

That's what Kala Visvanathan has been investigating. Kala is a Sydney trained cancer specialist and researcher based at Johns Hopkins School of Medicine in Baltimore. As you'll hear, she is also interested in ways of preventing breast cancer in the first place.

Kala Visvanathan: There have been a number of studies, and the earliest ones were in the 1980s showing that leukaemia can follow a diagnosis of breast cancer.

Norman Swan: Why?

Kala Visvanathan: The thought is twofold, that it is somehow related to either some of the chemotherapy agents and possibly radiation as well.

Norman Swan: So you set out to find out whether the finding was real and how big it was.

Kala Visvanathan: Not so much that it was real…

Norman Swan: You were pretty convinced of that.

Kala Visvanathan: People were convinced of that. What we tried to do in a very large dataset was to actually try to clarify the association between a treatment for early stage breast cancer and the development of leukaemia over a 10-year follow-up period.

Norman Swan: So tell me about the woman you followed, how many, what sort of stage of cancer, what sort of treatment they got.

Kala Visvanathan: The results of the study come from what we call the NCCN, so this is a database of 18 comprehensive cancer centres here in the US. We actually only used invasive breast cancer in stage 1 to 3, so it's not ductal carcinoma in situ, it's what we call early stage breast cancer where the standard practice is that women have surgery to remove the cancer, followed either by hormone therapy, chemotherapy or both and, depending on whether they have a lumpectomy or mastectomy they will have radiation.

Norman Swan: But in many of these women the prognosis is pretty good.

Kala Visvanathan: Correct, in the majority of these women the prognosis is really good, so even in this study, which was 20,000 patients who had early stage breast cancer. So then what we did is we follow these women over time to identify how many of them developed what we call a myelodysplastic syndrome, which is sort of an early leukaemia, pre-leukaemia would be a better way, or leukaemia itself. And only a small number of women who had treatment ended up getting leukaemia. So of the 20,063 women, only 50 got any sort of leukaemia.

Norman Swan: And some of those who got leukaemia would have been nothing to do with their breast cancer. So what was the excess over what you would have expected in 20,000 women?

Kala Visvanathan: The way that we got out that question, which is an important one, is we compared all the women in this database, so all these women who had already had breast cancer, to the general population in the US. What we found is that the risk of getting leukaemia was higher in breast cancer survivors than the general population, and it was approximately about three-fold higher.

Norman Swan: And is there a date beyond which you say, well, you are safe now, you haven't got leukaemia by now, you're never going to get it?

Kala Visvanathan: That's a very good question. The answer is no. But it is interesting to note that we found that the median follow-up time of developing leukaemia was 4.9 years.

Norman Swan: But did the risk go down after that?

Kala Visvanathan: So the risk persisted over time.

Norman Swan: So the risk is low, but significant. What's the message from this? Because you could scare women.

Kala Visvanathan: The first important thing to say is the message is not to scare women. It's actually for oncologists and women to be aware that there are toxicities that are associated with chemotherapy, and therefore when making the decision of whether a woman should get chemotherapy we should take this into consideration, meaning that if we don't think that the benefit of chemotherapy does not outweigh the risks, then we should not give them chemotherapy.

Norman Swan: And do we know who those women are?

Kala Visvanathan: We do. For example, someone with a very small tumour where you think the benefit of chemotherapy in that woman is very small, less than 1% or 2%. You have to really start to think about also the risks.

Norman Swan: And is there anything in a woman that might predict an increased risk of leukaemia?

Kala Visvanathan: Another good question. What we found is that the women who did get leukaemia in this study were slightly older, but I don't think that's necessarily on its own a great indicator. There is a lot of research going on to try to understand the types of leukaemia, and the thought is that there is certain types of chemotherapy that make you more susceptible.

Norman Swan: The Holy Grail here with breast cancer is prevention. It's a difficult area. You've looked at aspirin and you've looked at statins. What have you found?

Kala Visvanathan: I was going to add there definitely exercise and optimising weight would be two things that I think would be very important.

Norman Swan: And of course your family history.

Kala Visvanathan: And acting on your family history, being proactive to see whether increased screening or other preventative options might be helpful. On the breast cancer prevention angle there is the proven preventive agents such as tamoxifen, raloxifene and the aromatase inhibitors now which block oestrogen. What we've been interested to look at is whether some of the other common medications that are being used for other indications, for example aspirin in individuals who have already had heart disease, or statins are used to reduce cholesterol.

Norman Swan: And why would you think that would be the case? Well, there is good evidence with aspirin.

Kala Visvanathan: So the reason that we think so is that a lot of these agents have multiple mechanisms by which they work, and so we've been very interested both to look at these agents in breast cancer as well as in terms of ovarian cancer. We started to look at them first in individuals with cancer. And what we're finding is very interesting. We are finding first of all in terms of breast cancer we are finding that statin use is associated with a reduction in disease progression. We particularly have found a reduction in mortality.

Norman Swan: This is not a randomised trial, this is just…

Kala Visvanathan: This is not randomised. We looked at a group in Finland where they are looking at a national database, sir this means that they have data on everyone in Finland, and one of the strengths of these European databases is that they actually have prescription data on everyone. We basically looked at statin use in women with breast cancer and breast cancer mortality and showed a significant reduction. We're not advocating that women with breast cancer all go and have statins now, we are saying that the data looks very promising and supports the use of a randomised trial to confirm our findings.

Norman Swan: And aspirin, where the evidence is quite strong in bowel cancer prevention, what's the story with aspirin and breast cancer?

Kala Visvanathan: In breast it's been interesting. Long-term aspirin use and breast cancer risk has not shown a strong association, but aspirin use and cancer mortality for multiple cancers have, and what we are seeing is that some of this effect in women with breast cancer, some of the effect of reduction in mortality may in fact be a few years prior to diagnosis. And so we are following up on that now to look at early stage cancers, like DCIS, to see if we see the same effect. But we think that some of the benefit from aspirin in reduction in mortality is related to having taken the aspirin close to when they are diagnosed, so when cells are already abnormal but initiating and starting to grow. And we are seeing similar effects with statins.

Norman Swan: Kala Visvanathan is Associate Professor of Oncology and Epidemiology and director of the Clinical Cancer Genetics and Prevention Service at Johns Hopkins in Baltimore.