Julie R. Gralow, MD: SWOG SO226 Trial and Bisphosphonates Update
Dr. Julie R. Gralow discusses the SWOG SO226 where postmenopausal women with metastatic breast cancer given first-line treatment of fulvestrant (Faslodex) and anastrozole (Arimidix) have a better progression-free survival (PFS) than those given anastrozole alone. She also gives an update on bisphosphonates and osteonecrosis of the jaw at the 34th Annual CTRC-AACR San Antonio Breast Cancer Symposium
Dr. Gralow is a Professor, Medical Oncology, Department of Medicine, at the University of Washington School of Medicine. She is the Director of Breast Medical Oncology at Seattle Cancer Care Alliance and Member of the Fred Hutchinson Cancer Research Center, Clinical Research Division.
The Group Room at the 34th Annual CTRC-AACR San Antonio Breast Cancer Symposium was made possible by support from:
Selma Schimmel, Founder & CEO, Vital Options International:
Hello and welcome to the Group Room where we’re at the 34th Annual CTRC-AACR San Antonio Breast Cancer Symposium. So happy to be joined again by Doctor Julie Gralow, Professor of Medical Oncology, Department of Medicine in the Division of Oncology. Doctor Gralow is the Director of Breast Medical Oncology and the member of the Fred Hutchinson Cancer Research Center Clinical Research Division.
And we get together every year at this time, and you always give us such great information and updates. And this time we’re going to talk about new treatment options for post-menopausal women, metastatic cancer and endocrine and bisphosphonates updates and recommendations.
Julie R. Gralow, MD, Director, Breast Medical Oncology, Seattle Cancer Care Alliance:
Well thank you so much for having me back again, Selma. This is always a highlight of my San Antonio Breast Cancer Symposium experience. So we had a lot of exciting data at this meeting, and some that’s really practice changing. Some years we don’t go back to the clinic again and change much but I think this year I think we got some changes.
So the first abstract I thought it would be fun to mention is called the SWOG SO226 trial. So this is looking at metastatic patients who have estrogen receptor positive breast cancer and what’s the best to treat them. In this trial we took about 700 women with newly diagnosed metastatic disease that was estrogen receptor positive and everybody got an aromatase inhibitor, which is one of the standard drugs in treating ER positive breast cancer. But we randomized half to get in combination, Fulvestrant, or Faslodex, which is another anti-estrogen treatment. Laboratory data had suggested that maybe the two together would be better than either alone. And an important part of this trial is that in the women who got only the Arimidex and Anastrozole aromatase inhibitor at the time that their tumor progressed, we actually strongly encouraged them to transition to Fulvestrant Faslodex therapy to even provide a drug to encourage the physician and the patient to do that. So it’s really more of a combination versus sequential therapy, that’s really key. We’ve really seen in combination therapies that have seen better but we don’t actually know if you need to give those drugs in combination, which is frequently more toxic, or if they could be given sequentially.
So – cut to the chase – the result was that the combination was better in terms of what we call ‘disease-free survival’, ‘progression-free survival’, the time that the patients went without the disease progressing and also overall survival. So women in the combination lived longer statistically. So we took that result, which was maybe a little surprising to us, and said ‘is there a population that seems to be doing better so that we don’t have to give everybody combination up front but we can pick out who benefits from it most’. Turns out it’s women who hadn’t had prior Tamoxifen therapy; women who really had had no prior anti-estrogen therapy seemed to do better from kind of this combination blast of estrogen targeted therapy versus giving them in sequence.
So in this day and age a lot of women who relapse in metastatic ER positive breast cancer they’ve already had prior endocrine therapy so I’m not sure it’s applicable to all of those women but the group of women who have ER positive disease that have never before seen endocrine therapy, which is the group we think this combination benefits most that’s all these women with early stage breast cancer who have never been treated. So we’re now going to design a trial looking at this combination in early stage breast cancer to see if we can reduce deaths and recurrences from the combination. Pretty exciting.
Very exciting. And also, hearing words like ‘practice-changing’ and I’ve been hearing this a lot.
Julie R. Gralow, MD:
Absolutely. This meeting had a lot of exciting practice changing data. Now, what about the bisphosphonates and the use of the bone-targeted agents in potentially reducing recurrences in early stage breast cancer? There were actually four – count them, four – oral presentations on this topic. Two of them were positive and two of them were negative so we really haven’t resolved the question of how many women, which women should be getting bisphosphonates to reduce breast cancer recurrence. But I think we did get some hints from these studies. So we saw an update of the ABCSG-12, the Austrian study of pre-menopausal ER positive breast cancer patients that not only showed reduced recurrences, which we’d seen previously but now for the first time reduction in deaths by adding Zoledronic acid, Zometa, every six months for three years. So six doses of Zometa over three years in this group of patients and the Zometa reduced deaths now. Surprised to actually really see it have that kind of strong impact.
Additionally we saw an update of a trial called Zo-fast trial. Now, instead of the Austrian trial this is post-menopausal women, about half of them got chemo, they’re all estrogen receptor positive, and they’re all starting on aromatase inhibitor for early stage breast cancer. And they were also randomized to get Zoledronic acid every six months or not, and that now has shown reduced recurrences, don’t see reduced deaths yet in that study but there’s a trend toward a reduction of deaths in that study. The good news is in both of these studies the recurrence rate and the death rates are really low. Great news for early stage patients.
So all that positive data is an ER-positive patients and a lot of them hadn’t gotten chemo. They’re just getting the endocrine therapy where we’re just seeing the benefit. Then we saw the NSABP B34 trial of an oral bisphosphonate, Clodronate, which was taken daily and it was studied for three years. And that trial was overall negative. When they tried to see, could there be a positive group it’s probably the older patients – they did a cut-point to 50 or younger, 50 or older – maybe some hints that the women 50 or older were benefiting. Remember, Clodronate trial, the B34 trial was ER positive or ER negative, lot of them got chemo, pre- or post-menopausal.
And then the last of the four bisphosphonate trial is called Gain trial. It was a German trial where everybody got really intensive anthracycline-taxane chemo, and part of the question was different chemo, but it was all aggressive chemo. And then they were randomized to get Ibandronate, oral bisphosphonate given daily or not. And that trial was also flat out negative. But again, it was a mix of ER positive, ER negative, everybody got aggressive chemo, it was a mix of pre-menopausal, post-menopausal.
So it doesn’t mean all women should be getting bisphosphonates but I do believe I’m taking home from this that in the ER positive population, especially those who aren’t given chemotherapy to, are going to be more inclined to give the bisphosphonate, not just to preserve the bone density and reduce fractures but to reduce recurrences as well.
In the research setting when you get negative results what then happens to the drug and the research?
Julie R. Gralow, MD:
Right now with Clodronate and Ibandronate at this dose we’re not going to see these drugs approved for reducing bone metastasis in early stage breast cancer. You just can’t take a negative trial, even if some women might be benefiting, and convert it into a positive trial. The interesting thing, Selma, that we’ve got an on-going trial that actually I’m the lead investigator on, we call the SWOG SO307 trial. It’s comparing the the Zoledronic acid, which is the drug that to date, we’ve really seen some positive data for, it’s comparing it with the Ibandronate at this daily dose and Clodronate at this daily dose. And this trial has met accrual couple of years ago and it will be a few years before we analyze it but this is a 6000 person trial, and we’re going to have enough data to evaluate – we’re revising our statistics to evaluate the truly post-menopausal from the pre-menopausal and we’ll have enough patients in this huge trial to try to better sort out, is one drug better than another and in which population.
So I don’t think the Clodronate, which by the way an earlier study from ten years ago was positive in this setting so that’s a little confusing as well – and I don’t think Clodronate is dead, I don’t think that the oral Ibandronate is dead. I just think that it wasn’t tested in a population that was highly likely to benefit. I’m thinking that all that chemo masked the benefit of the bisphosphonate, which is fine but I would prefer not to give chemo and to give the bisphosphonate than vice versa. So we’ve got to explore that more.
What’s the update with jaw issues?
Julie R. Gralow, MD:
Yeah, the osteonecrosis of the jaw. So we know that when we give Zoledronic acid monthly like when we do when we’re treating patients with bone mets that there’s probably a breast cancer on the order of one to two percent. Incidence over a long period of time of getting monthly Zoledronic acid in these trials were reported at this meeting the rate was reassuringly, incredibly low. Some of the trials had no ONJ, one of the trials as I recall had two or three cases but out the hundreds of women. So when we’re giving every six months Zoledronic acid but we’re giving oral bisphosphonates we’re really not seeing any substantial incidence of ONJ. It’s when we give more intensive treating for bone mets that we’re seeing some osteonecrosis of the jaw.
Thank you Doctor Gralow. In closing, I don’t know if there’s a comment that you have as to what you think is happening next – you’ve mentioned where the research is still pending, and also I know you’re heavily involved in the physical component of exercise and physical well-being of breast cancer patients, and I couldn’t help noticing the obesity studies, the question of diabetes, the nutritional studies, starch intake, carbohydrates…do you want to comment on any of those?
Julie R. Gralow, MD:
So I guess I would just summarize all of that by saying we’re finally taking a look at some of these things – the impact of physical activity and maintaining a good body weight and nutrition and mind-body, as well on outcome. A lot of women when they undergo treatment for breast cancer feel that it’s so passive, the treatments are being done to them and so I really try to encourage patients to take control of the things you can take control of, and there are some positive things you can do short of drug therapy, radiation, chemotherapy and all. And that’s try to live a healthy lifestyle, both in terms of physical as well as emotional, and it really will give you benefit in a lot of ways.
Thank you for always making time. I know you’re super busy. Doctor Julie Gralow, Professor of Medical Oncology in the Department of Medicine in the Division of Oncology. Doctor Gralow’s the Director of Breast Medical Oncology and a member of the Fred Hutchinson Cancer Research Center Clinical Research Division. Thanks, Doctor Gralow.
Julie R. Gralow, MD:
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