Results Flat in ALTTO Breast Cancer Trial

Kathy D. Miller, MD: Hi. I am Kathy Miller, Associate Professor of Medicine at the Indiana University School of Medicine in Indianapolis, Indiana. Welcome to Medscape Oncology Insights on Breast Cancer, coming to you from the 2014 annual meeting of the American Society of Clinical Oncology (ASCO®). Joining me today is Dr. Karen Gelmon, Professor of Medicine at the University of British Columbia and Head of the Division of Medical Oncology of the British Columbia Cancer Agency in Vancouver. Welcome, Karen.

Karen A. Gelmon, MD: Thank you. It's nice to be here.

Surprising Results: The ALTTO Trial

Dr. Miller: Two breast cancer abstracts were presented at the plenary session this year. Let's start at the top and talk about the largest study, maybe one of the largest studies in history -- the ALTTO trial.^[1] We have been awaiting these results for a long time. What have we learned?

Dr. Gelmon: The ALTTO trial is very interesting. More than 8000 women were randomly assigned, so it was a huge study. We had NeoALTTO^[2] in which we looked at the combination of lapatinib and trastuzumab, and it showed that the combination was superior, so we have all been waiting for the ALTTO study. We have all become more excited about neoadjuvant treatment, including the US Food and Drug Administration (FDA), and many people have been surprised by the ALTTO results, which didn't show any difference for the combination of trastuzumab and lapatinib vs trastuzumab alone, except in the realm of toxicity.

Dr. Miller: That is surprising to many people. At its initiation, ALTTO had 4 groups: a control group (trastuzumab alone); a lapatinib-alone arm that fell out a couple of years ago when those patients clearly were not going to fare as well; a combination arm; and a sequential arm. The biggest hopes were pinned on the combination group and the sequential arm, thinking that maybe an early switch might avoid resistance. The NeoALTTO study fueled enthusiasm for the combination. Are there any hints, trends, or any prayer that this could be resurrected?

Dr. Gelmon: It is always interesting when looking at results before all of the events are reported. At this presentation, they said that they didn't have all of the events that they were planning for. Having the lapatinib arm fall out in August 2011 was disappointing, but we all thought that the combination would be superior. Dual blockage of the targeted therapy is our mantra now, so we were shocked at the results.

Does Surgery Affect Adjuvant Therapy Response?

Dr. Miller: We had seen improvements in the metastatic setting with dual blockade, using trastuzumab and lapatinib^[3] or trastuzumab and pertuzumab.^[4] Both of those combinations led to improvements in pathologic complete response (PCR) in the neoadjuvant setting, and in comparison, lapatinib monotherapy in the neoadjuvant setting didn't fare as well. So until these results dropped on us, we were marching along quite beautifully, thinking that neoadjuvant therapy would predict what we would see with adjuvant therapy.

There is an adjuvant pertuzumab trial going on. Pertuzumab is the first of the drugs with accelerated approval for neoadjuvant therapy. Would you care to bet on the APHINITY trial,^[5] or if you are at the FDA, are you having a few sleepless nights?

Dr. Gelmon: You bring up a few points. We have only seen the first results [of the ALTTO trial], and until we pore over all the data, we don't have an idea about compliance and dose, or the full results. This is a first look at a whole year of the combination therapy, and with the toxicity being so remarkably different (the rate of diarrhea, for example, was 75% vs 20%). We have to see the full results.

But in terms of the prediction for the approval of [therapies from the] neoadjuvant to adjuvant setting -- what the FDA is thinking now -- makes us pause. The question is whether the old studies that looked at the effects of disrupting a tumor by removing it might be relevant. Is there something there? Are we doing something with our surgery?

Dr. Miller: Bernie Fisher^[6] might have another life?

Dr. Gelmon: Yes, exactly. The other question is predictability. We had thought that particularly with HER2 and triple-negative breast cancers, there was a predictability from the neoadjuvant to adjuvant setting. Yet we saw the findings with bevacizumab,^[7,8] so we might need to go back to the drawing board. Predicting for APHINITY is going to be difficult because these are 2 different drugs, representing different types of dual blockade. APHINITY might reach its endpoint, but it might not; we have certainly seen that with ALTTO.

Dr. Miller: The other area where neoadjuvant therapy results have some centers rushing to change both neoadjuvant and adjuvant therapy is in triple-negative disease with platinums.^[9] The improvements in PCR rates in those studies seemed fairly similar to the improvements in PCR with lapatinib in NeoALTTO. Should that have us rethinking triple-negative settings as well?

Dr. Gelmon: We might need to rethink. If only we could do that great trial that looks at neoadjuvant vs adjuvant, platinum vs no platinum, we would get these answers, but we won't necessarily conduct those trials.

If we go back to the B18 trial,^[10] age was a factor. In the subset analysis, younger women fared better with neoadjuvant treatment. We had assumed that this was a consequence of biology. We assumed that it was the triple-negative and HER2 cancers. Maybe it wasn't. Maybe we need to look at age again. Yet again, we are surprised in the breast cancer world. It demonstrates the power of clinical studies.

Dr. Miller: Of phase 3 studies.

Dr. Gelmon: We have to do phase 3 trials or we are not going to have the answers. Remember, some of the platinum neoadjuvant studies are phase 2 studies. Maybe we shouldn't be too quick to jump to conclusions.

Dr. Miller: Like with lapatinib, adding platinum resulted in some real toxicity issues.

Dr. Gelmon: Exactly.

SOFT Answers to Hard Questions

Dr. Miller: The other plenary presentation^[11] provided results for which we have been waiting a long time. This is treatment for our youngest patients, the premenopausal women who have estrogen-positive tumors. What is the optimal hormone therapy for those women? We have tried to answer that question in some old studies that essentially ignored the impact of chemotherapy on ovarian function.

We heard some sobering results from the ABCSG (Austrian Breast and Colorectal Cancer Study Group)-12 trial^[12] several years ago, suggesting that maybe an aromatase inhibitor (AI) or tamoxifen in the setting of ovarian suppression were equivalent. We now have the combined analysis of the TEXT and SOFT trials.^[11] TEXT (what I used to call the "true believer trial," for people who were positive that ovarian suppression was useful) compares tamoxifen and an AI in that setting. SOFT has those 2 arms plus a tamoxifen-alone group. Do we know what the optimal therapy is yet or are we getting closer?

Dr. Gelmon: We all want to see the SOFT question answered -- tamoxifen vs tamoxifen plus ovarian suppression, or exemestane vs ovarian suppression. We don't have that answer yet.

The SOFT data, showing that exemestane plus ovarian suppression was superior in many of the 4600 women in that analysis, are of interest. This finding fits with some of our prejudices about postmenopausal women.

Dr. Miller: Certainly -- it's ATAC [anastrozole and tamoxifen, alone or in combination] with ovarian suppression.

Dr. Gelmon: Exactly, but it might not be the whole story. In the ABCSG trial,there were women who hadn't had chemotherapy, and increased numbers of women in this analysis have had chemotherapy. Is this the same population? That is one issue.

The disease-free survival results are extremely good, but they are not as good as those from the ABCSG trial. Another question is whether this is a higher-risk group of women. Are Austrian women different? We don't have an answer.

Dr. Miller: Women do well if they are premenopausal with an ER-positive tumor in Austria. Here, in the United States, these women all had undergone chemotherapy to be eligible to enter these studies. They had to have had ongoing or resumption of ovarian function after chemotherapy, so at least we know that when they entered the studies, their ovaries were functioning.

Dr. Gelmon: As we use aromatase inhibitors more, we are increasingly understanding toxicity. I am concerned about compliance. With the recent ATLAS^[13] and aTTom^[14] studies, we are talking about 10 years of tamoxifen treatment or 10 years of therapy [eg, AI for 5 years and tamoxifen for 5 years] for premenopausal women. Exemestane plus ovarian suppression is going to be quite difficult. The menopausal side effects, and the impact on sexual function, are difficult, so we will have to look at this more carefully.

A question that comes up is whether to start with exemestane, and if women aren't tolerating it, have them go on to something else -- similar to the BIG 1-98^[15] question. This is extrapolating in ways that we probably shouldn't, but it raises a very important question, and I suspect that the results that we heard today will be practice-changing.

Dr. Miller: Certainly for patients who want ovarian suppression, for whom that has been recommended, these results should influence practice.

I still want to know whether I should ablate the ovaries. In addition to all of our other therapies, toxicity is added with ovarian suppression. I would like to know whether it helps those women.

Dr. Gelmon: Exactly, so we need the SOFT data. We need the results of that tamoxifen-alone arm. Many people say, "If ovarian suppression with exemestane looks better than ovarian suppression with tamoxifen, how can we even expect tamoxifen to look as good?" We have to use caution until we get the data.

Dr. Miller: Compliance and toxicity could be the reasons that tamoxifen looks as good.

Dr. Gelmon: Until we get the data, we can't extrapolate.

POEMS: An Ode to Fertility

Dr. Miller: On the flipside of the hormone therapy question are the youngest patients, who have concerns about fertility and menopausal symptoms. Many of them don't wish to become a menopausal woman at such an early age. For patients whose tumors are estrogen-negative, and there isn't a good rationale for hormone therapy as a component of their treatment, we have had questions about what we could do to preserve their fertility. We finally have a randomized trial that includes outcome pregnancy data, which we have never had before. The POEMS study,^[16] which closed early, was a tour de force in ever being conducted at all.

Dr. Gelmon: The POEMS study is interesting. We had several single-arm studies that gave contradictory results about doing ovarian suppression to preserve fertility. The power of a randomized trial is once again demonstrated.

This study was very hopeful for our young women because it showed preservation of fertility using a very short-term course of ovarian suppression in estrogen-receptor negative patients, without any negative effect on outcomes, which is important.

This is practice-changing. We now have to think about offering this to women who are young and who want to preserve their fertility. It also is interesting because there is a study coming up called the POSITIVE study, which is going to be run in the United States, Canada, and Europe -- around the world -- and is headed by the International Breast Cancer Study Group and the Alliance of North America. This study is going to look at tamoxifen interruption to allow women to become pregnant. We are talking more about understanding the need for many of our patients to have their reproductive potential fulfilled. We still need to improve outcomes, but we are looking more at survivorship issues.

Dr. Miller: Many patients with ER-negative tumors, to whom the POEMS study findings apply, are not enthusiastic about in vitro fertilization, preserving oocytes, or freezing parts of their ovaries. It is quite expensive and may not be covered by insurance. It is also quite time-consuming. This gives women an option that is much less expensive and can be started immediately. It addresses a major concern.

Dr. Gelmon: It does. I would also like to draw your attention to some data^[17] that we presented from British Columbia at this meeting, which shows that after about 4 years, the risk for systemic recurrence in ER-negative cancer is low. In the context of preserving fertility and being able to reassure our patients that maybe in 5 years (or even earlier) they might be able to have a child, it's very important.

Dr. Miller: Thank you, Karen. It was a pleasure having you here today with some practice-changing data for our patients with breast cancer. Thank you for joining us on this edition of Medscape Oncology Insights. This is Kathy Miller, reporting from ASCO 2014.