Era of Hope 2011 Plenary Sessions

Session Title: Afternoon Session – Breast Cancer Prevention and Risk

Title of Presentation: Translating from Primary Prevention to Secondary Prevention

Malcolm C. Pike, PhD, Memorial Sloan-Kettering Cancer Center: The next speaker is Dr. Leslie Bernstein, who I’m very proud to say was once my student.

Leslie Bernstein, PhD, Beckman Research Institute: And I’m really proud to say I was once his student and the only person in the United States who can say that.

I want to thank you all for allowing me to present today. I’m taking liberty with the topic. I want to talk a little bit about translating from primary prevention—now I’m talking about this in the sort of sequence of what happens from the perspective of being a healthy person to developing disease to death, to secondary prevention. And the issue is can we reduce the risk of recurrence and death from breast cancer?

This actually came up in our noontime session when—when Debra [Inaudible]—and I’m going to murder the name—[Laxague], I think—I hope I got it close—actually presented her last slide. And what it said was okay, treatment is done. You’re on your own. What can you do? And so I’ve done a lot of thinking about this as I’ve been interacting with the National Breast Cancer Coalition for close to 20 years now—almost since it began. This has influenced the sort of areas of research that I’ve done and I’m going to start with risk factors.

So we’ve heard already—we heard last night; Michelle did an incredible job of reviewing these. We have non-modifiable risk factors. We have modifiable risk factors. There’s a panoply of them. As Dr. Lee’s presentation when it was presented stated, we can't add them together and give you an estimate of how much risk we could reduce; they aren't additive. They may act through similar pathways, so one is as good as another in terms of either increasing risk or decreasing risk.

There are a few factors where we have mixed results. We’ve never really been able to zero in on diet and the components; nonsteroidal anti-inflammatories, there’s still mixed results for that, and Vitamin D, the results are fairly negative. We’ve seen studies of Metformin in populations of Type 2 Diabetics, but those are special populations where Metformin has reduced the risk of breast cancer in that group. And then there’s been some suggestion that possibly bisphosphonates might work in reduction.

But I want to take this, the next step; I want to take this into the realm of what happens after treatment ends? Now just for example, we’ve worked the other way. We’ve learned how Tamoxifen reduces risk of breast cancer, second primary breast cancers and we move that into the prevention setting. We saw in a clinical trial of osteoporosis that Raloxifene that women on Raloxifene had lower risk despite both groups having osteoporosis. We moved that into a prevention setting. So can we move things that we’ve learned about in terms of risk factors into the long-term survivorship setting?

So we—what are the most important mechanisms for having better prognosis? Well we know of course it’s important what stage you are, what grade, the histology of your tumor, what its hormone receptor status and HER2-NEU status are. There are other tumor markers that appear to be important in defining what treatment you ought to get and then there are other targets as well. We’d love to have things that directly induce cell death without causing other damage. We want to reduce blood vessel formation, reduce cell grown and proliferation and motility and reduce inflammation and stimulate the immune response.

So much of this depends on the microenvironment. You’ve heard about that. Michelle mentioned that as well. Mutated cells in the microenvironment promote adverse changes; the microenvironment will produce—promote adverse changes. Cells may be recruited from the bone marrow. It’s an interactive process and there are different neighborhoods for microenvironments for preinvasive, invasive, and metastatic cancer, and we don’t understand these well yet.

But I want you to think about that as we go through some of these factors.

Now the epidemiology of breast cancer has told us that body size is important in terms—it’s actually an energy balance equation except that we’ve not been able to zero in on aspects of diet, but we know body size is important, although as I said at noontime it’s not one of the major risk factors for breast cancer and it’s only a risk factor in post-menopausal women. Physical activity in today’s Western society—much of that is a lifestyle choice of participating in exercise because jobs are far more inactive than they were in the past.

But what do we know about obesity and prognosis? There was an excellent paper just published from the Danish Breast Cancer Cooperative group study of 18,000 patients so it’s one of the largest studies ever published. Thirty-seven percent of these women received some endocrine treatment, either Tamoxifen or aromatase inhibitors; obesity had no—that’s defined as 30 kilograms per meter squared—had no impact on local or regional recurrence, but heavy women, obese women had increased risk of distant metastasis and this did not appear until 5 years of follow-up.

There was also an increased risk of breast cancer-specific mortality in obese women but this appeared 10 years after follow-up, so 10 years after diagnosis.

So the issue is it’s not immediately evident in these large series of women. We just finished a study that’s just come out in the Journal of Clinical Oncology of—from the Women’s Care Study which was a study of black women and white women; a third of the women were African American, the remainder were white. In the Danish study they’re all white and as you can see from the curves, the red line is for the African American women. That last mark is 30 kilograms per meter squared; these women had 8.6 years of follow-up so they’re getting—that’s the median follow-up, so many had more than 10 years of follow-up. And what you see is that there’s no effect of body mass index until you get to 30 kilograms per meter squared or greater which is the classification of obesity and you only see an increased risk of dying among white women.

We were quite surprised by this. We don’t still understand why but it tells us that at least the differential immortality between black and white women who have breast cancer is not because of obesity.

So what about physical activity and prognosis; there have been two kinds of studies done, those that looked post-treatment physical activity and in those studies the Nurses’ Health Study was the first to show that women who exercise nine MET hours a week, so what is nine MET hours a week? It’s moderate exercise of 2 hours okay; so women exercising at least that or more had a 35 to 50% lower risk of breast cancer. We followed up with a study called the Health Eating Activity and Lifestyle Study, the HEAL Study and found exactly the same thing. And then in another study of the California teachers, we looked at pre-diagnosis physical activity and we found that women whose lifetime activity was relatively high that on average they exercised 3 hours a week. I know that’s a lot but they did this before diagnosis. We do not know what they did after diagnosis but that was associated with a 50% lower risk of death from breast cancer.

The reason is that the physical activity carries forward—we don’t know; quite likely it is the high correlation between being active early in your life and having it continue throughout your life. And I—I can attest to that. If you don’t start your children exercising or you don’t start exercising early it’s much harder to maintain a physically active lifestyle. If you incorporate it early and I’m on my little platform right now, it works. You know you’re always going to go back to it.

Okay; the very interesting issue is in all of these studies, the effect was most apparent among heavier women, so women who were overweight or obese. So, if in fact as the Nurses’ Health Study showed that after—after diagnosis if you are overweight or obese and you exercise there is a reduction in your risk of dying.

Now this takes—this was done on a stage-by-stage basis. You can't take into account every factor. That’s the problem in these studies. Well, should we recommend weight loss to improve prognosis? Well when a woman is on aromatase inhibitors that stops the conversion of the adrenal androgen androstenedione estrogen and body fat. So while a woman is taking aromatase inhibitors weight loss isn't going to benefit the overweight woman or the obese women in the same way it would otherwise. However, we heard something last night about the fact that probably overweight and obese women are under-treated. And so if that is the case and they’re not getting the appropriate dose of aromatase inhibitors then in fact exercising or doing something to reduce their weight could improve the efficacy of the treatment they’re receiving.

So weight loss for overweight and obese women is important for other health outcomes. We cannot argue that. More than half of women with breast cancer don’t die of their disease. They die of cardiovascular disease, so in fact reducing weight and being physically active is important. And of course women aren't going to be on aromatase inhibitors forever. In fact, it’s hard sometimes to keep them on them.

So how might physical activity or weight reduction improve prognosis? Well it can change the microenvironment by reducing exposure to metabolic hormones like insulin, the sex hormones like androgens and estrogens, growth factors like IGF1, adipokines like Leptin or it might increase adiponectin which is protective if it increases. And it might decrease inflammatory factors like C-reactive protein.

So the issue with diet and cancer risk and prognosis I think this—this cartoon gives you the sense of frustration we’ve all had and I’ve had it throughout my career in defining whether diet affects breast cancer risk or breast cancer prognosis. Here I just contrast the WIN Study and the WHEL Study; both were studies, clinical trials, randomized clinical trials of diet to improve breast cancer prognosis. Both recruited women in Stage 1 to 3A; 1 took women at 12 months after surgery; the other 48 months. The age ranges weren't quite comparable; the WIN Study restricted to a much narrower age range. They—one did individual dietician visits. The other did phone calls. One did a three to two randomization; the other one to one. The WIN Study reduced women’s dietary intake from fat, the calories to 15%. That’s really restrictive. The WHEL Study restricted it to 20%, a little easier and then brought women up to eating five servings per day of vegetables and three servings a day of fruit. And the results were not comparable. The WIN Study showed a marked reduction in risk that was statistically significant. The WHEL Study showed nothing. The WIN Study looked at relapse-free survival. The WHEL Study did not. It looked at breast cancer event-free survival which includes death.

Well what about some other factors? We have to think creatively and we’ve not been thinking creatively enough. So there are a number of factors I’ve been interested in and we’re going to hear an entire talk on Metformin and I’ll just mention it briefly in a minute. And then everybody has heard me on my platform many times about aspirin and the potential that this might have because it reduces inflammation and provides a weak aromatase inhibitor. And then Vitamin D, what does it really do? I keep hearing from my advocate friends that their docs are putting them on Vitamin D. Do we know anything about it? Does it do any good?

So Metformin has been used to treat Type 2 Diabetes for more than 50 years and it can reverse many aspects of metabolic syndrome. It’s been associated as I said earlier with reduced risk in diabetic patients. The tumors that did occur in Metformin patients tend to be progesterone receptor positive; that means they can't be triple negative. But the caveat is that the evidence is limited to that sub-group right now of women with Type 2 Diabetes and we don’t know—I mean questions I might ask in this—in this area would be is treatment related—choice related to the extent of hyperinsulinemia because hyperinsulinemia is possibly associated with breast cancer risk? So there are many relevant pathways it can act through to improved prognosis, insulated-mediated, and not insulin-mediated. Users of Metformin are more likely to have a pathologic complete response to therapy and at least in one study and colleagues in Canada and one of them speaking right after me have initiated a Phase 3 clinical trial of—in early breast cancer patients randomizing them to receive Metformin versus a placebo.

Chronic inflammation in our HEAL study that I mentioned before which is a cohort of breast cancer patients we’ve followed for about 12 years now—this is a study where we drew their blood 30 months after diagnosis. The women are Stages 1 to 3A disease; they had no evidence of current disease at the time that we began following them. And we followed them to the 12-year mark. These data were presented up to 10 years and it—chronic inflammation is represented by C-reactive protein or serum Amyloid-A was associated with increased risk of breast cancer recurrence or death. And so this tells us chronic inflammation is really important. And that brings me to my little platform on aspirin or other nonsteroidal anti-inflammatories.

Aspirin acts against both the COX-1 and COX-2 pathways where Celecoxib or Celebrex operates on the COX-2 pathway. So I really am interested in trying to prove that we can use aspirin because of its lack of expense, its readily being available, so aspirin can inhibit COX pathways. It inhibits IL6, an inflammatory marker. It inhibits angiogenesis; it increases apoptosis and it activates P-Par, so there’s some very great attributes about what aspirin might do but we just don’t know.

The Nurses’ Health Study actually looked at this in terms of prognosis asking women after diagnosis how much aspirin are you using and was able to show that it reduced risk of dying of breast cancer 60 to 70% with a 40 to 60% reduction in risk of distant recurrence. The mortality data were consistent with results from the Iowa Women’s Health Study. So what the question would be—what might limit use of aspirin or nonsteroidal anti-inflammatories in women? Some people do not react well, cannot take them consistently; we don’t know what dose is the appropriate dose. And I will say the Women’s Health Study was unable to show any association of aspirin with risk of breast cancer. And this was a randomized trial where women were given aspirin or not given aspirin. The trouble is they were given on average 40 milligrams of aspirin a day. When you take a tablet it’s 325 milligrams, so it was an extremely low dose.

Well what about Vitamin D? Breast cancer patients as does a lot of the population have very high levels of Vitamin D insufficiency or frank deficiency. Now the problem is studies define deficiency at different sort of landmarks along the continuum in nanograms per milliliter. So when we did a study, the HEAL study we used deficiency to be less than 10 nanograms per milliliter and insufficiency to be 10 to 32. We found that the lowest levels, most insufficient and most deficient are African American women, followed by Hispanic women, so women of color. Levels were higher in women with in situ disease than those who had localized or regional disease. A Canadian study with different markers showed the same thing that—that a high number of women are deficient or insufficient.

It’s inversely related to markers of insulin resistance, body mass index, and higher tumor grade. So do we just give you all Vitamin D? We don’t know. Certainly the link to breast cancer is uncertain but breast cells do have Vitamin D receptors. They act as nuclear transcription factors to regulate gene activity. Low Vitamin D levels are associated with insulin resistance as I said before. And deficiency or insufficiency may be associated with worse outcomes but there isn't enough data yet to be certain. So I would say to anyone before you go on a Vitamin D supplement have a test. Find out what your Vitamin D level is. If it is low, Vitamin D supplements do work. Don’t over-supplement; taking too much can be toxic and also cause problems and that’s one of the risks about this.

So let me finish this with saying that we need some creativity in what we’re doing. We can't repeat the things we’ve been doing over and over. Breast cancer is a really complex disease. We have innumerable ways to classify the disease into smaller and smaller sub-groups. It’s not like there’s one uniform way to do it. Risk factors vary by sub-type, and the results sometimes counter our intuition about mechanisms so for example in the Teachers’ Study when I looked at physical activity I found that it worked best—it appeared to reduce the risk the most among women who had ER negative disease; total surprise to me because my hypothesis has always been hormonal than Max [Wicha] got up one day and said well, that makes sense at the stem cell level. So I was really happy.

Risk factors inform knowledge on long-term outcomes. We can go both ways—treatment trials have informed us on potential approaches for prevention. I want to emphasize that serendipity helps and that’s been sort of the story of my own career. Take advantage of opportunities and your own good luck and make it happen. Thanks.