Kathy D. Miller, MD; George W. Sledge, Jr., MD


December 19, 2011

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Kathy D. Miller, MD: Hello. I am Kathy Miller, Associate Professor of Medicine at the Indiana University School of Medicine, in Indianapolis. This is the Medscape Oncology Wrap-up of the 2011 San Antonio Breast Cancer Symposium.

Joining me today is Dr. George Sledge, Professor of Medicine and Pathology, and Co-Director of the Simon Cancer Center Breast Program at Indiana University. He is also the past President of American Society of Clinical Oncology. Welcome.

George W. Sledge, Jr., MD: I am glad to be here.

Two Winners Hands Down

Dr. Miller: As the 2011 San Antonio meeting is winding down, what are you going to remember as most important from this meeting?

Dr. Sledge: I am going to remember this as the year when we took the next step in terms of applying breast cancer biology to the clinic. In particular, what we have learned from this year is that the combination of biologic therapies can have potent effects for patients with metastatic breast cancer. I'll remember 2 large phase 3 trials, the BOLERO-2 trial,[1] looking at the question of estrogen resistance to estrogen receptor-targeted therapy, and a genuinely wonderful trial, the CLEOPATRA trial,[2] that looks at the question of trastuzumab resistance in the front-line metastatic setting. Both of these trials used a combinatorial approach to the biology, respectively, of the estrogen receptor and the HER2 target, and both trials show that combinatorial therapy has significant effects.

BOLERO-2: Huge Results, Huge!

Dr. Miller: Let's talk about the BOLERO-2 trial first. This was a trial for women with ER-positive disease who had received previous nonsteroidal aromatase inhibitor therapy, looking at either the steroidal aromatase inhibitor exemestane with placebo, or exemestane with the mTOR inhibitor everolimus, hoping to reverse resistance and further extend the benefits of hormone therapy. You said that these were huge results. How huge, in numerical terms?

Dr. Sledge: In numerical terms, BOLERO-2 showed an approximately 4-month improvement in progression-free survival in the metastatic breast cancer setting. The study is immature in terms of overall survival results, so we don't know whether this will translate to an improvement in overall survival, but this has been a tough area in which to show improvements, particularly tough for women on hormonal therapy alone. To show that adding anything has ever benefited these patients has been very difficult.

Dr. Miller: Whenever we think about adding something to hormone therapy, the toxicity becomes an even bigger component than chemotherapy, because the hormones are reasonably devoid of chemotherapy-related toxicity. Does everolimus fit in that hormonal mindset when you think about the toxicities?

Dr. Sledge: Nothing that we deal with is as nontoxic as hormonal therapy, and everolimus certainly has some toxicities, particularly some issues related to mucositis. But in comparison with chemotherapeutics, for example, this is certainly far below that level of toxicity. I would put this somewhere between hormonal therapy and chemotherapy in terms of toxicity. At the end of the day the tradeoff is going to be important if we see an improvement in survival; if, à la antiangiogenic therapy, we see an improvement in progression-free survival without an improvement in overall survival, then these risk-benefit analyses for toxicity will become very important.

Dr. Miller: I have to challenge you on something you said a little earlier. You said that it has been hard to show that adding anything provides benefit in this situation, yet the results of a SWOG study[3] looking at combined antiestrogen therapy caught everyone by surprise.

Dr. Sledge: This is another very interesting trial, asking whether, if we add something to fulvestrant, we will get additional benefit. The answer was, if you added an aromatase inhibitor to fulvestrant, you appeared to get a significant improvement in terms of progression-free survival. This was a somewhat odd study, so I don't view this as having quite the same value or interest as the BOLERO-2 study. It's "odd" because in contrast to what I see in clinic, and what I think most American physicians see in clinic, 40% of the patients in this trial had truly hormone therapy-naive metastatic breast cancer. Among my patients, 40% are not hormone therapy-naive. Furthermore -- and subset analyses are always dangerous -- all of the benefit appeared to be focused in that population of hormone therapy-naive metastatic breast cancer, so I don't quite know what to make of those data.

Dr. Miller: Maybe not an "odd" study, because the study was well done, but certainly a strange patient population. Having spoken to the SWOG investigators, they had the same thoughts. When they first saw those data, they actually sent them back to their coordinating office and said, "No, you need to go look at this again," so they rechecked all of the charts to verify that 40% of the patients were truly hormone therapy-naive.

Dr. Sledge: That probably suggests, at least in part, that there was a fair amount of selection bias going on with the physicians who were entering the patients into the trial. Something like that was at play.


Dr. Miller: We have to switch to the CLEOPATRA trial[2]and the HER2-positive patients. This is another area where we have wondered whether we might be nearing the top in the benefits that we could accrue for patients with metastatic disease. If your response rates are 70%-80% or upwards, you don't have a lot of room to improve.

Dr. Sledge: It has been a very exciting area, and it has been exciting in part because we have a whole bunch of new agents coming down the pike that we can combine with trastuzumab. Previous studies combined the receptor tyrosine kinase inhibitor, lapatinib, with trastuzumab and showed benefit -- indeed an overall survival benefit in a fairly far advanced population of patients. We are now seeing newer agents, such as T-DM1 or, as in the CLEOPATRA study, pertuzumab, which when combined with chemotherapy (in this case docetaxel), along with trastuzumab, showed a very impressive 6-month improvement in progression-free survival. This is a pretty large improvement in progression-free survival, attended by a lot of zeroes in the P value, so this has the smell of reality about it. The early analysis suggests that we will eventually see an improvement in overall survival. It didn't quite cross the O'Brien-Fleming boundary yet, but it certainly looks like it is headed in that direction. If that is the case, then this will be a real survival advantage for patients with metastatic HER2-positive disease.

The tough issue going forward is that if the ALTTO trial, combining trastuzumab and lapatinib, turns out to be positive in the adjuvant setting, and if we shift things up, somewhere above 90% disease-free survival, how are we going to bring all of these wonderful new agents, such as pertuzumab, T-DM1, neratinib, etc., into the adjuvant setting? This could be very tough.

Dr. Miller: You could also imagine it changing the questions that we would want to ask.

Dr. Sledge: Indeed.

Dr. Miller: Most of our adjuvant studies have looked at adding more cycles, adding new drugs, increasing the doses, and in some way doing more.

Dr. Sledge: Yes.

Dr. Miller: You can imagine that this almost becoming a bit like testis cancer, where the questions start to become, what do we not need to do to still preserve the results but minimize toxicity and exposure to therapies?

Dr. Sledge: Inevitably, and eventually, the question is going to be, can we get away without chemotherapy? If we reach a point of significantly high response rate in this population with combined HER2 targeting, or targeting multiple aspects of the HER2 pathway or HER2 resistance mechanisms, will we even need chemotherapy? That is what excites investigators. We are a long way off from knowing the answer, but it is certainly something that we are all headed towards.

Bisphosphonates: A Confused Picture

Dr. Miller: We have made that leap into thinking about adjuvant therapy studies in the future, but we should think first about some of the adjuvant studies that we heard about at this meeting. Perhaps some of the biggest news was 2 more bisphosphonate studies, for which we have awaited results for a long time. Finally we have results. In your mind, are we at the point with enough cumulative evidence that we should start using bisphosphonates in the adjuvant setting, outside of a protocol?

Dr. Sledge: This will be a question for the US Food and Drug Administration in the near future. I came away more confused than enlightened this year. Indeed, 4 bisphosphonate randomized trials were presented this year. Certainly the one that we were all waiting for was the National Surgical Adjuvant Breast and Bowel Project clodronate trial.[4] This trial summarizes the confusion that we feel in this field, because the overall disease-free survival endpoint (the primary endpoint of the trial) did not show benefit for the addition of clodronate in the adjuvant setting, but a subset analysis in the postmenopausal population did suggest a benefit. I have always felt that we should judge studies by their primary endpoints, because that is the most statistically rigorous. At this meeting we heard other data suggesting that perhaps older patients or hormone-deprived patients might get the greatest benefit from bisphosphonate therapy. That is an interesting hypothesis. I don't consider it proven yet, but it is certainly interesting.

Dr. Miller: So, on Monday, when you are seeing a 65-year-old, clearly postmenopausal woman in the adjuvant setting, who is going to be starting an aromatase inhibitor, are you handing her another prescription or appointment for bisphosphonate?

Dr. Sledge: I might get a bone mineral density test and see if she has a significant degree of osteopenia.

Dr. Miller: You are going to take the sneaky way out and look for a reason to do it without saying that that is what you are going to do.

Dr. Sledge: Indeed.

Dr. Miller: I like that approach. That is probably what I would do as well.

Disappointing Results

Dr. Miller: Any disappointments from this year's meeting, or things that we had all hoped would pan out?

Dr. Sledge: We saw a trial that looked at late adjuvant lapatinib for patients with early-stage HER2-positive breast cancer.[5] Although this trial bordered on a positive P value, the results were somewhat disappointing -- they were not the striking "knock your socks off" results that we saw in some of the other trials. In the metastatic setting, the disappointment was the AVEREL trial,[6] which looked at the addition of antiangiogenic therapy with bevacizumab to trastuzumab in the setting of front-line metastatic breast cancer. In that trial, although there was a small improvement in terms of progression-free survival, there was certainly no indication of an improvement in overall survival, and it confirms the larger picture that we have seen with antiangiogenic therapy in metastatic disease: advantages in progression-free survival, but no overall survival advantage. That is certainly a disappointment.

Other trials may have disappointed certain parts of the oncology community. One of these was an analysis of local therapy results, with a brachytherapy approach with MammoSite, suggesting significantly worse cosmesis with a partial breast irradiation approach.[7] That was a major disappointment to many, I am sure.

Dr. Miller: Just to be clear for our listeners, these are not results from one of the randomized trials, but from a database approach -- they used claims data to look at women who had received radiation with either a brachytherapy approach or traditional whole-breast external beam radiation. They then looked at claims data that would suggest complications -- infections, additional surgeries, and ultimately mastectomy which, to me, was the most damning. We do breast-conserving surgery to preserve the breast.

Dr. Sledge: Absolutely, and this is certainly a disappointment to the many people who thought that this would be a less invasive attack on breast cancer than whole-breast radiation therapy. This demonstrates, as we have seen over and over, that we need real data rather than to rely on our assumptions.


Dr. Miller: That is a perfect place to wrap up this Wrap-up, so thank you for joining us, George.

Dr. Sledge: Thank you.

Dr. Miller: And thank you to our audience for joining us for this edition of Medscape Oncology Insights. This is Kathy Miller at the 2011 San Antonio Breast Cancer Symposium.


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