ESMO -- Breast Cancer: Treatments for an Increasingly Heterogeneous Disease

Eric P. Winer, MD; Martine Piccart, MD, PhD


October 18, 2010

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Eric P. Winer, MD: Hello. I'm Eric Winer, Chief of the Division of Women's Cancers at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School in Boston, Massachusetts. I'd like to welcome you to Medscape Oncology Insights on Breast Cancer.

I'm joined today by Dr. Martine Piccart, Professor of Oncology at the Université Libre de Bruxelles and Director of the Department of Medicine at the Institute Jules Bordet in Brussels, Belgium.

For the next few minutes, we're going to highlight some of the latest data from the ESMO meeting that we're both attending, and also some recent data that have emerged over the last year, or so. Good morning.

Martine Piccart, MD, PhD: Good morning.

Dr. Winer: Nice to see you. I think we should start talking about HER2-positive disease, and perhaps HER2-positive metastatic disease. There have been a number of findings recently from studies looking at novel agents, and most notably, I think, just today we have the results of a randomized phase 2 trial being presented comparing T-DM1 and trastuzumab plus docetaxel.[1]

Dr. Piccart: Yes, Eric, I think we have been very blessed in the last decade to see so many anti-HER2 agents being developed, and being very successful. Clearly this agent, T-DM1, is particularly interesting. It links trastuzumab to a cytotoxic agent, and you know, I think that this is the drug we have been dreaming of as medical oncologists for so many years because it brings chemotherapy inside a cancer cell, and it's not supposed to affect all the cells.

So, this randomized phase 2 trial, which is going to be presented by Dr. Edith Perez, is providing very nice results. In summary, the antitumor activity seems very similar compared with the more standard treatment of docetaxel combined with trastuzumab, but toxicity is much reduced, so the incidence of grade 3 adverse events is cut back by half. This drug causes very little alopecia, which, I think, is going to be great for women.

I have, perhaps, 2 comments on this agent. The first one is that I think the drug is coming at the right time because we have made significant progress in HER2 testing. Clearly for such a drug, HER2 testing is very critical, because if we start giving such an agent to an HER2-negative patient, this will mean that we essentially give nothing to this woman.

Now, we must say that there are still problems with HER2 testing, and apparently more problems in the rest of the world, as compared with the United States. We see that in the very large ALTTO adjuvant trial,[2] where we have central pathology review, and we are still confronted with false HER2-positive cases, and this happens slightly more often in the rest of the world, as compared with the United States. So, in the rest of the world, it's in the range of 14%. That's an important message. We will have to be careful.

Dr. Winer: Even in the United States, it's still a problem. It may not be 14%, but it's probably pushing 10%.

Dr. Piccart: Exactly. So, that's the first comment. The second comment is that I hope we are going to design the right registration trials with this agent because I have seen some designs where these compounds are simply added to standard chemotherapy. I think that this is a missed opportunity.

I really think that this drug is able to markedly improve quality of life of patients and that this should be one of the major goals in these trials. I'm not too keen to see trials where patients will still get a lot of taxane plus trastuzumab and then on top of that TDM1. I think I would really like to see trials where T-DM1 replaces current treatment approaches.

Dr. Winer: I would agree, and one of the challenges in HER2-positive breast cancer is that in patients with relatively early-stage disease, such as those in the HERA trial or in the joint analysis of the US trials, the prognosis with trastuzumab and chemotherapy is really quite good.

One can't just keep adding on agent after agent to get an extra 2%-3%. We need to figure out who needs those additional drugs and which patients may do fine with far less.

Dr. Piccart: Exactly.

Dr. Winer: I should say T-DM1 isn't necessarily far less a drug, it's just far better tolerated.

Dr. Piccart: Absolutely. I think we still have a big challenge ahead of us in the tailoring of all these new anti-HER2 agents. Recently, I was impressed by some very nice preclinical work suggesting that perhaps trastuzumab has as its main mechanism of action the induction of a very robust immune response.

That surprised me a little bit because I used to look at this agent as an agent that interrupts signaling. So, if that's true, we may have to start looking a little bit more into the ability of patients to develop this immune response. These would then be strong candidates for trastuzumab-based approaches, while others would be, perhaps, candidates for the small tyrosine kinase inhibitor drugs such as lapatinib, for example. But, we don't know.

Dr. Winer: People have tried to look at this issue and have tried to identify patients who may have a more robust immune response to trastuzumab. So far, that hasn't proven very helpful, but it's something that has to be pursued, no question about it.

What about other agents? What about pertuzumab? Where does that fit into all of this? Or, for that matter, neratinib, which unlike the others is a small molecule tyrosine kinase inhibitor, but certainly on the surface appears to be more active as a single agent than lapatinib did in the initial trials.

Dr. Piccart: That's correct. We are eagerly waiting for the large randomized trials with neratinib. Pertuzumab is also a fascinating compound, and I think in San Antonio this year we are going to hear about very important randomized neoadjuvant studies.

One is going to be the NeoSphere randomized trial, which focuses on pertuzumab, in particular,[3] and the other one, of course, is the neoALTTO study,[4] which focuses on the dual HER-2targeting using trastuzumab and lapatinib. It's possible that these 2 trials will change our way of looking at treatment of HER2-positive breast cancer.

Dr. Winer: But not change our way of taking care of patients today.

Dr. Piccart: No, because these are still relatively small, neoadjuvant trials with about 400 patients, but we know that pathologic complete remission is a very good endpoint -- surrogate endpoint -- for disease-free survival. So, they are going to be influential.

Dr. Winer: Depending on what these studies show, there's going to be some temptation on the part of clinicians to adopt regimens that look more promising in terms of achieving a pathologic complete response. But I would tend to agree with you that we need larger studies to truly determine if these agents are going to play a role in preventing recurrence in women with early-stage disease.

Maybe we can spend a minute talking about a very different subtype of breast cancer -- triple-negative breast cancer -- where traditionally we have not had nearly as much success. We've had chemotherapy that works, but when women have metastatic triple-negative breast cancer, the survival is shorter than for other subtypes of the disease, and they are left, most of that time, receiving chemotherapy.

The PARP inhibitors have a lot of buzz around them. I think it remains unclear to what extent some of them will be useful in women with triple-negative breast cancer vs specifically individuals who have BRCA mutations. What are your thoughts about these agents?

Dr. Piccart: As many oncologists, I am, of course, very excited. But again, I think this triple-negative subset is incredibly heterogeneous, and unless we collaborate massively together, we are not going to be able to understand this heterogeneity.

I'm really hoping that we can collaborate, particularly in the field of biomarker research, so that we can perhaps finally understand, in a few years from now, for whom these PARP inhibitors are going to represent a clear advantage as opposed to patients where it's unlikely to be a breakthrough. That's clearly the biggest excitement today, the PARP inhibitors.

But, I think, at this meeting there are other interesting data presented. In particular, the first randomized trial comparing cisplatin alone vs cisplatin and cetuximab.[5] Again, it's a randomized phase 2 trial; it's not a phase 3. But it's interesting because I think it's clearly demonstrating synergism between the antibody and the DNA-damaging drug.

However, the control arm of this trial did not produce very exciting results, so it was a response rate of only 10%, I think, and a very short progression-free survival. I am not sure that this trial is a practice-changing study. I think that to be really excited about a randomized study, you somehow have to be convinced that the control arm is the best possible one available today.

I think cisplatin alone is working, but not in a fantastic way. And that could be because, again, the study has perhaps not been enriched with the right subset.

Dr. Winer: Right. And, then, of course, one of the big questions is, which patients in this triple-negative subset are going to be susceptible to the effects of cetuximab, because the improvement in response rate in that study was about a 10% improvement, roughly a doubling in the time of progression.

But, as you said, the time to progression for the cisplatin patients was a month and a half to 3 months, or a little bit more. Whether or not we would see a doubling of the response rate with a more effective chemotherapy regimen, I think, is unclear, or perhaps we would again see a 10% bump-up. We really need to figure out which patients are going to be susceptible to the inhibition of the EGFR pathway.

It's a challenge. For patients who have BRCA mutations, presumably BRCA1 mutations with triple-negative disease -- but, I think that this probably applies equally well to BRCA1 and BRCA2 when we talk about the PARP inhibitors -- where do you see those agents playing a role for those patients? Development has been slow of the drugs.

Dr. Piccart: I suspect these agents will be very important for these women, but the difficulty is to be able to run randomized trials in a rapid fashion. Now, I still believe that we lack very robust randomized data, so the randomized clinical trials are critical.

There is a very interesting study currently recruitingin the United Kingdom for women with advanced triple-negative breast cancer, including women with BRCA mutations. It's a study that is making a head-to-head comparison between docetaxel and carboplatin.[6] I think this study is critically important and will improve our understanding because the suspicion is, of course, that there is a subgroup of women with triple-negative breast cancer who do much better on a DNA-damaging agent than on a taxane. But this is probably not true for all of those women.

Dr. Winer: Before we close, what about the last big subgroup of breast cancer, which is ER-positive, HER2-negative disease, which, in fact, accounts for 70% of all breast cancer, maybe a slightly smaller proportion in the metastatic setting, maybe not because many of them live a long time. Physicians are certainly spending much of their time taking care of these patients.

One of the frustrations, of course, is when hormonal therapy, standard hormonal therapy, stops working in these patients. We give aromatase inhibitors, we give tamoxifen. Then, at some point in time for most patients, virtually all patients, these agents stop working. I think, for many of us, it's not entirely clear how much activity we get out of chemotherapy, although clearly some patients respond very nicely, and that is usually the approach. There have been attempts to combine targeted therapy with endocrine therapy, although most of those trials have been negative to date, as well as attempts to look at mTOR inhibition with hormonal therapy and what have you.

Where do you think that area is going, and how are we going to get smarter there? Perhaps one of the problems is we haven't selected patients and tumors very carefully for those targeted therapies.

Dr. Piccart: That's exactly the reason, I think. In fact, I think the gene expression profile studies have changed our way of looking at hormone receptor-positive breast cancer. I used to look at this disease as 2 completely different diseases. The tumors which are low proliferating, we call themluminal A, and the one that have a high proliferation.

I am convinced that we need to completely separate these 2 entities in our clinical trials. Probably the new biological agents should now be preferentially studied in the luminal B-type cancers, and I'm hoping that if we start making this selection we will see better results with drugs like, for example, mTOR inhibitors or drugs targeting the insulin growth factor receptor, PI3K inhibitors, and so on. I'm optimistic. I think that if we start separating these 2 entities, we will see progress in the community, yes.

Dr. Winer: I think that subtyping and subdividing is critical, and then within each of these subtypes of breast cancer, within the HER2-positive, triple-negative, luminal-A, luminal-B subtypes of ER-positive disease, there are almost certainly subtypes within those subtypes. They're all heterogeneous. It's ultimately by understanding, at a molecular level, what's going on in the tumor that we can match the treatment to the patient.

Dr. Piccart: Absolutely. And we should perhaps think also about the host. There are a lot of interesting things to learn about the interaction between the host and the tumor, like the story of the bisphosphonates, which is still intriguing.

Dr. Winer: But the trials become complicated, and it becomes more necessary than ever before for trials to be conducted across centers, across countries, sometimes around the world when you're talking about a phase 3 trial in a subset of a subtype.

Dr. Piccart: Exactly.

Dr. Winer: It really gets complicated. I share your optimism, though, that just because we didn't quite get it right in studies in the past doesn't mean we won't in the future. There are just so many new agents that if we do our job right, it's hard to believe there won't be a very different picture 10 years from now. But, we've got to do our job right.

With that, let me thank you for being here. On behalf of Medscape Oncology Insights, I just want to thank our viewing audience and say goodbye for now.


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