Fabrice André , MD, PhD; Ian E. Smith, MD


October 08, 2012

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Fabrice André, MD, PhD: Hello. I am Fabrice André, Associate Professor in the Department of Medical Oncology at Institut Gustave Roussy in Villejuif, France. Welcome to this edition of Medscape Oncology Insights on Breast Cancer. Today we will highlight several of the significant studies in breast cancer presented at the 2012 European Society for Medical Oncology (ESMO), being held in Vienna, Austria.

Joining me is Dr. Ian Smith, Professor of Cancer Medicine at the Institute of Cancer Research and Head of the Breast Unit at the Royal Marsden Hospital in London. England. Welcome, Ian. You are the Chair of the ESMO Early Breast Cancer Track. What study do you want to emphasize?

HERA Weighs in on Trastuzumab Duration

Ian E. Smith, MD: There were 2 or 3 interesting studies at ESMO. Probably the most eagerly awaited was the HERA trial[1] update of the 1-year vs 2-year treatment with trastuzumab. Trastuzumab has been standard of care for a long time in HER2-positive breast cancer, and 1 year has been the empirically defined duration of treatment. The HERA trial is the only one of the large initial trials that looked at the duration question. Patients were randomly assigned to 1 year or 2 years. The results show that there is no gain in continuing treatment beyond 1 year. There is no statistical improvement in time to relapse or in survival.

It's interesting, because the curves separate slightly between 1 and 2 years. Furthermore, there is the suggestion that there may be a small group of patients who biologically have continuously active HER2 and who probably would benefit from long-term suppression. But this separation is not statistically significant, and there isn't any way that we are ever going to be able tease out who these patients are. However, the message is that giving trastuzumab for more than 2 years is actually not necessary, and there is no additional gain. This is in early breast cancer. Of course, the situation may be very different in metastatic disease.

NeoALTTO Finds Mastectomy Rate High

Another very important presentation was from the NeoALTTO group.[2] NeoALTTO is a large trial [randomly assigning patients either to trastuzumab, lapatinib, or their combination given concomitantly with chemotherapy prior to surgery] for early HER2-positive breast cancer. The group has already shown that the combination of trastuzumab and lapatinib gives a higher pathologic complete remission (PCR) in neoadjuvant treatment. But what is disappointing in the trial is that a large number of patients still get mastectomies. The mastectomy rate was not in any way reduced in the group who had combination treatment, who had a higher PCR rate. This is a shame for women, because you obviously don't need a mastectomy if you have a PCR.

Various reasons for that came forward. One was that if the surgeons had predefined in advance what the surgery was going to be, they tended not to change their minds. They tended to do mastectomies in patients who were ER-negative, which is completely the wrong way around, because the ER-negative, HER2-positive patients have the highest chance of PCR.

In discussing that study, I pointed out that another very large study from the German neoadjuvant group (GeparQuattro)[3] had a much lower incidence of mastectomies after neoadjuvant treatment in this group of patients. The difference is that the German group worked with surgeons who were very experienced in neoadjuvant treatment and who worked together in multidisciplinary units. This is an important message for medical oncologists treating breast cancer. The neoadjuvant approach to large HER2-positive breast cancers is very important, and it very greatly reduces the need to do mastectomies. Oncologists have to work very carefully with their surgeons at multidisciplinary team meetings to get this message across.

Can Gene Array Identify the Right Chemotherapy?

Dr. André: What do you think about this study in the neoadjuvant setting, giving chemotherapy according to the old genome profiling?

Dr. Smith: Another very interesting study[4] came from your part of the world, from Paris and looked at whether you could predict response using the gene expression array -- this is one I wasn't aware of, the DLD-30 -- perhaps you know more about it than me. They looked at whether topoisomerase-2 status was positive or not. They tried to see whether these parameters would define which chemotherapy we could select that would be useful. They showed that both DLD-30 and topoisomerase-2 were very good at predicting who was going to respond to neoadjuvant chemotherapy. But they did not, unfortunately, give any indication about which particular type of chemotherapy should be used. It didn't tell whether this patient would benefit more from taxanes or anthracyclines. We still do not have a solid marker that tells us which chemotherapy to select.

Dr. André: An interesting point of this trial is the fact that at this group of academic centers, it was feasible to do the genome array in the context of daily practice. They show that if you run the gene expression array, you can easily determine receptor expression, HER2 status, and so on. We are moving step by step to an all-in-one approach where we could do all genome array for our patients.

Molecular Predictors Fine-Tune Therapy

Dr. Smith: The other point that comes out of the NeoALTTO study is that mastectomies are not the way to go. We need to be treating a lot more breast cancer by starting medical treatment, and then doing a second core-biopsy before surgery, looking both at the original parameters and the change in parameters. These are molecular predictors. We can do this. Everyone says, "Oh, it's very difficult, we can't get the results back in time." The French group showed that you can.[4]You can do these tests, and you can have all the results back in 2 weeks, ready for planning treatment. It has to be the way that we go forward, and it's a very important message. It isn't acceptable anymore for people to say, "It's all very well, but these are very sophisticated studies, and we can't do them; it takes too long and the women can't wait." The Paris group demonstrated that it is feasible.

Dr. André: In fact, in the metastatic setting, there will be some similar studies.

Dr. Smith: What did you find interesting?

Dr. André: In the metastatic setting, there is a similar study from France,[5] where 18 centers ran all genome profiling for 400 metastatic breast cancer patients. They used the results to identify the target and then treated the patient according to this approach. Of interest, 50% of the patients presented with targetable genomic aberration, suggesting that this approach was a way to select patients for a target agent. Several of these patients were treated with a target agent, and some of them had some benefit. So, during this ESMO, we are seeing the beginning of the era of personalized medicine using all of these genomic approaches.

Novel Agent Shows Promise in Metastatic Disease

In the metastatic session, 3 randomized trials were presented. One was a direct comparison between trastuzumab and lapatinib in patients who were resistant to trastuzumab.[6] It is going to validate the concept that you can continue trastuzumab after progressive disease.

From my perspective, the most important data are coming from the phase 1 study[7] that will be presented at the very end of the session, where they will show very impressive results with a new compound, E-3810, which is a fibroblast growth factor receptor (FGFR)-1 plus a vascular endothelial growth factor (VEGF) inhibitor. The study showed a high rate of response when the drug is used as a single agent in patients who present with FGFR mutation. They had a very high level of response. This study paves the way for further development of this compound in breast cancer. It's a very exciting compound.

Dr. Smith: It also emphasizes the crucial importance of getting these gene expression markers right at the start, before you start planning your therapy.

Four Take-Home Messages in Breast Cancer

Dr. André: Overall, there are 4 main messages from this ESMO. The first is that large academic studies are needed to fine-tune how to use adjuvant treatment, as illustrated by the HERA trial as well as the PHARE trial from France.[8]On the basis of these studies, we are not going to change the duration of trastuzumab treatment in the adjuvant setting.

The second message is the use of the neoadjuvant setting to develop drugs and to find new biomarkers. That is really important.

Message number 3 is the development now of personalized medicine, with plenty of new technologies that are being implemented in daily practice.

Message number 4 is the arrival of all of these new compounds that are very exciting but that work only in a small subset of patients. This is the example of this very impressive FGFR-1 inhibitor and the results of PI3K inhibitors in breast cancer patients,[9]which will be presented at the same session.

Weight Maintenance Lowers Risk for Recurrence

Dr. Smith: I would like to finish with a very different study, which came from colleagues in southern Italy.[10] They looked at the role of obesity in early breast cancer. They showed that having a body mass index of over 30 kg/m2 at the start of treatment didn't have any effect on outcomes, although a lot of other studies show that if a woman is obese when she develops breast cancer, the prognosis is worse. They showed that women who gained weight after their treatment began had worse outcomes than women who did not gain weight. Other data have shown the same thing. In fact, randomized trial data suggest that if a woman loses weight, her prognosis may be better. This is a very important point. We are talking about all of these new drugs, and they are very exciting. They are also very expensive. We have to make it very clear to women that they must not gain weight after they have had breast cancer, and that they can reduce their risk for recurrence almost as much by not gaining weight as provided by all of our expensive adjuvant treatments. It is a very important message.

Closing Remarks

Dr. André: Ian, thank you for sharing your insights.

Dr. Smith: It's a pleasure.

Dr. André: Thank you for joining us for Medscape Oncology Insights on Breast Cancer. This is Fabrice André, signing off from ESMO 2012 in Vienna.