Peri-operative lapatinib has profound antiproliferative effect in early breast cancer

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Published: 14 Dec 2015
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Prof Nigel Bundred - University of Manchester, Manchester, United Kingdom

Prof Bundred talks to ecancertv at SABCS 2015 about early results from the UK EPHOS-B trial on the effect of peri-operative anti-HER2 therapy on cancer cell proliferation and cell survival.

The UK EPHOS-B trial is an ongoing, multicentre, two-part randomised trial in patients with operable newly diagnosed HER2 primary breast cancer. The Independent Data Monitoring Committee for the trial has agreed partial release of the data from the first part of the study only in which women about to undergo surgery were randomised to receive peri-operative treatment with lapatinib or trastuzumab alone, or to no treatment.

With approximately 11 days’ lapatinib treatment, decreased cell proliferation (defined as a ≥30% fall in Ki67, a marker of cell proliferation) was measured in 67% of women. An increase in cell death (≥30% rise in apoptosis) was measured in 30% of women.

The key point is that you need to know the HER2 status of women before undergoing surgery, Dr Bunsen suggests. This is not always done but if it is and women are positive it shows that giving them lapatinib as early as possible could significantly improve their outcome.

ecancer's filming at SABCS 2015 has been kindly supported by Novartis through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

You’ve been looking at early breast cancer and, in particular, looking at the window of opportunity between diagnosis and treatment. Can you tell me what it is you’ve been doing in this particular case with lapatinib?

This particular case was a study that was initially conceived to look at the effect of anti-HER2 therapy given peri-operatively on overall survival. The problem was there wasn’t a great deal of data of what anti-HER2 therapy did on proliferation of Ki-67 which is the main marker in the peri-operative window studies. So Cancer UK wanted us to do a trial looking at control patients, lapatinib and Herceptin to see which was the most effective to lower Ki-67 in two weeks. The aim was that we would show we could give it for a month and have an impact on overall survival, reducing the total anti-HER2 therapy you give and the morbidity such as cardiac toxicity.

So what did you do?

We did this study, we did it, halfway through we realised that the combination was becoming much more attractive so we swapped it to a comparison of combination versus Herceptin versus control. We’ve reviewed all of the data from part 1, the IDMC said we could publish lapatinib data and lapatinib is an orally given anti-HER2 drug that blocks the tyrosine kinase internally so it works differently to Herceptin. What we found was that 67% of patients had a greater than 30% reduction in Ki-67 and actually the median fall in Ki-67 was 45% so a big fall in Ki-67 and occurred in all molecular phenotypes. There was no change in apoptosis but it indicates you can see changes in HER2 positive patients within eleven days of treatment, which is a very short gap. It does give us an idea that we might be able to influence patients having surgery by using anti-HER2 therapy during surgery to improve outcome.

So in a way you’re getting a message by using the brief time, a couple of weeks or so, before the surgery takes place. What sort of advance do you think this has made for cancer doctors?

I think it’s difficult at the minute to be certain but there are a group of studies out there which suggest that you don’t need to give a year of Herceptin after surgery, that you might be better off giving your Herceptin or lapatinib before surgery because you get less cardiotoxicity. You get a bigger effect, you prevent any spread during surgery, so it will be cost effective. Actually what we’ve shown is there are no problems with undergoing surgery on anti-HER2 therapy because the whole study has shown that. So it’s well possible that that’s the way to go, to use the treatment earlier in the absence of chemotherapy. If you’ve got a major effect you might avoid chemotherapy in some patients. So I think it’s hypothesis driving; it is ideally poised if we show effects with the combination to use the combination to see if you can affect overall survival with early treatment without the use of chemotherapy. But clearly that depends on the final results.

Clearly it’s hypothesis generating but it seems there could be some practical pay-off. What message should doctors take from this now for their daily practice?

I’m not sure there is an immediate message. I think we need to complete the analysis of the whole study. There is emerging data that the sooner you put in the anti-HER2 therapy the better patients do. That’s the direction of travel. The main message would be that you have to get the HER2 measured, you have to know the HER2 status before surgery on these patients, because that’s the only way you can get them to earlier anti-HER2 therapy and chemotherapy. Still in the UK quite a lot of patients don’t get HER2 done on the core biopsy at diagnosis and that needs to change.