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Weight Loss WINS in Breast Cancer

31 diciembre, 2014

Weight Loss WINS in Breast Cancer

Kathy D. Miller, MD, Jennifer A. Ligibel, MD

December 24, 2014

Obesity, Recurrence, and Mortality

Kathy D. Miller, MD: I’m Kathy Miller, professor of medicine at the Indiana University School of Medicine in Indianapolis. Welcome to this edition of Medscape Oncology Insights, coming to you from the 2014 San Antonio Breast Cancer Symposium. More and more we are finding that exercise and a healthy diet improve the outcomes for our patients with breast cancer, and we have seen more data at this meeting. To help us sort through the most important information, I have invited my next guest, Dr Jennifer Ligibel, associate professor in the Department of Medicine at the Harvard Medical School, and senior physician in adult oncology at the Dana-Farber Cancer Institute in Boston. Welcome, Jennifer.
Take us back to some of the earlier observational data we saw that suggested how our patients live is important in their risk for recurrence of breast cancer.
Jennifer A. Ligibel, MD: It is interesting that the first study that looked at the relationship between a woman’s weight at the time she is diagnosed with breast cancer and risk for recurrence and mortality was published in the 1970s.[1] This was a long time ago. That study showed that women who were heavier when they were diagnosed with breast cancer had a higher risk of developing recurrent disease and succumbing to breast cancer mortality. Since that time, there have been more than 100 similar studies looking at the links between weight at diagnosis or a few months or years before or immediately after diagnosis, and the risk for cancer occurrence and mortality.
In the past year, two large studies have looked at meta-analyses of these data.[2,3] One was presented at the American Society of Clinical Oncology annual meeting, looking at data from the Early Breast Cancer Trialist group,[2] so it took data from many large-scale adjuvant trials and looked at the relationship between weight at the time of enrollment in the study, which was generally very soon after cancer diagnosis and before treatment, and the risk for cancer-related mortality. It showed that the risk for breast cancer mortality in premenopausal women with hormone receptor-positive disease was an absolute 5% higher in obese vs nonobese women. Of interest, that study did not show differences in postmenopausal women or in women with hormone receptor-negative disease.
Another meta-analysis[3] that was recently published looked at data not only from clinical trials, but also from prospective observational cohorts (and this was 82 studies—about 200,000 women). It showed a relationship between poor outcomes and weight at diagnosis in both pre- and postmenopausal women. Another analysis[4] looked at both hormone receptor–negative and hormone receptor–positive groups of women, all showing that being obese at the time of breast cancer diagnosis is linked to a higher risk for cancer-related mortality.

Does Obesity Contribute to Undertreatment?

Dr Miller: That is always difficult, because how do we separate out the fact that breast cancer might develop differently in women who are obese? Maybe it is more aggressive at diagnosis. We have seen some studies suggesting that obese women are undertreated; there is a tendency to nudge their chemotherapy doses down or use ideal body weight, which undertreats them, so maybe they don’t get the full benefit of our systemic therapies. Would changing weight really help?
Dr Ligibel: Those are a lot of questions, and we don’t have answers to some of them. However, the question about whether it is obesity or the way that we treat people who are obese is something that we do have some answers for; the data that come from the clinical trials are able to look at that. In early trials, a lot of women received lower doses of effective chemotherapy if they were obese, using, as you suggest, ideal body weight to cap total doses of chemotherapy. More recent clinical trials have not done those things, yet the relationship between poor outcomes and weight has persisted.
The E1199 study,[5] which was updated today,[6] showed poor outcomes in women with hormone receptor–positive cancers who were obese at the time of diagnosis. The initial analysis of that study showed that women had received appropriate doses of chemotherapy regardless of body weight.
Our group did a similar analysis of the CALBG 9741 study, which established dose-dense treatment.[7] We found the exact same thing: that ideal doses of chemotherapy did not change the relationship between poor outcomes and weight.[8] In that study we saw poor outcomes in both hormone receptor–positive and hormone receptor–negative women who were obese at the time of diagnosis. So there is more going on than just weight and treatment relationships.
Dr Miller: What about the question of the milieu at diagnosis predisposing the breast cancer to be worse? By changing a woman’s habits and reducing her body size, could we change her outcome?
Dr Ligibel: That is a good question. Studies have looked at the characteristics of cancer in obese vs nonobese women, and they haven’t shown a lot of consistent patterns. Sometimes obese women have larger tumors at the time of diagnosis because diagnosis can be complicated by obesity. Conversely, obese women can have breasts that are less dense; that should make diagnosis easier. Tumor sizes vary. Biologically, we haven’t seen a lot of consistent differences between obese and nonobese women.
We did a study[8] in the setting of CALBG 9741 in which we looked at PAM50 in tumors from obese and nonobese women to see whether there was a difference in the distribution of biologic subtypes. We found identical prevalence of triple-negative, HER2-positive subtypes. The only slight difference was that luminal cancers were distributed somewhat differently in obese vs nonobese patients, with obese patients having a slightly higher risk of developing a luminal B cancer vs luminal A. It was not a large enough difference to explain the differences in outcomes seen in other studies that looked at clinical characteristics—such as grade and ER status—and didn’t see differences between obese and nonobese women. Your question about whether changing weight after diagnosis would change outcomes is a harder one to answer.

Change Behavior, Change Outcomes

Dr Miller: And it is harder to do. In some ways we focused on those other questions, hoping to get us out of this bind, because we don’t know how to help our patients lose weight in the real world.
Dr Ligibel: An enormous amount of work has been done in the past few years on how to help our patients lose weight and exercise more after diagnosis. One study that tells us a little bit about the relationship between weight change and outcomes is a large-scale randomized trial, the Women’s Interventional Nutrition Study (WINS). It was not a weight loss trial; it was a dietary intervention study in the 1990s that enrolled women who had completed their therapy for early-stage breast cancer (surgery, chemotherapy, radiation, and endocrine therapy, which they could still be taking) and randomly assigned them to a low-fat dietary intervention or to a usual-care control group.
The results of this study were presented 8 years ago,[9] and it showed that women who took part in the dietary intervention, lowered their dietary fat from about 30% of calories to 20%, and maintained that for 5 years lost an average of 6 lb, which was maintained for the 5-year duration of the intervention. The intervention group had a 24% reduction in the risk for cancer recurrence in the initial reports of the study. We are going to hear more about this trial tomorrow when they present a long-term survival analysis.[10]
Dr Miller: It’s an interesting study—our first hint that changing behavior would change outcomes, but it raised a lot of questions. The amount of weight the women lost was not a lot. Six pounds is not a huge amount, although perhaps maintaining it over a long time was more important than the actual amount. Also, the benefit was seen mostly in the ER-negative patients, and I was perhaps naively expecting that if this was going to have a benefit, it would be in the ER-positive patients.
Dr Ligibel: I think that was actually the hypothesis when the study was designed. At that point we thought that all of the relationships between weight and physical activity were mediated by estrogen. Since that time there has been an enormous growth in the translational science looking at energy balance, weight, physical activity, and diet and how they affect cancer. There has been a lot of interest in such factors as metabolism, insulin levels, and inflammation, which can be seen in both ER-positive and ER-negative patients, and they could have stronger effects in patients who are not using endocrine therapies. There are a lot of theories. Everyone is eagerly awaiting the results from the study tomorrow to see whether the findings in ER-negative patients have held up over time and whether with longer-term follow-up we start to see changes in the hormone receptor–positive population as well.

A Coach to Avoid Getting Sidelined

Dr Miller: Let’s talk about the actual intervention in the WINS and other studies, because a healthy diet, a healthy lifestyle, and more exercise are important for our patients. I am not sure we know how to help our patients make those changes. Convincing adults to change their behavior is not easy. What do we know about what works?
Dr Ligibel: We can learn a lot from the obesity, endocrinology, and cardiovascular literature, because large-scale studies have been done in individuals with diabetes and risk for diabetes and heart disease, looking at how to change behaviors in large groups of patients. We see certain things over and over. It is important to focus on behavior change and how to motivate people. It’s not about giving information on the importance of diet, or saying, “Here are a lot of studies that show you that diet is important or that physical activity is something you should do.” It boils down to how to get people to be ready to make a change. How do you support them through that? Many studies have suggested that having a coach—someone who is able to break the information down and provide motivation—is important.
Another thing that has come out of the diabetes literature, especially a study called Look AHEAD,[11] is the toolbox approach. You develop a generalized strategy for how to help people and what the goals are, but then you individualize the approach for each person. If a person isn’t interested in the low-fat diet used in WINS, it’s important to have alternatives—for example, a vegetarian diet or a Mediterranean diet—allowing the approach to be tailored to the individual. With physical activity, people are starting from many different places, and if you give people, right off the bat, a goal that they can’t attain, they become frustrated and drop out. It is very important to meet people where they are at the start and then work with them to build up gradually.
We have done a number of physical activity studies at Dana-Farber, and our eligibility criteria for many of them have said that people can’t be doing more than an hour of any kind of physical activity in aggregate in a week. In the first study, the women who were enrolled performed an average of 10 minutes of physical activity over the course of a week, which is a very inactive group. At the end of the 16-week intervention, they were doing 220 minutes of physical activity a week, some of it working with a trainer, and the rest was home-based walking. It really changed those women’s lives. I remember meeting with one of the patients, a 76-year-old woman who had never exercised in her life. By the end of the study, she was volunteering to be in all of our pictures doing weight training at the gym. It was the funniest thing; she was this tiny woman and she talked about how the study had changed her life and shown her that she could do things she never thought she would be able to do.

Technology to Push Your Buttons

Dr Miller: Do we know about the persistence of those changed behaviors? In many of the intervention studies that I have seen, they are 8, 12, or 16 weeks. I wonder whether that is long enough for the behaviors to stick or whether, when the intervention ends and the coach isn’t there, there is backsliding.
Dr Ligibel: There is, but there is also very interesting science coming—not out of the oncology world, but from the endocrinology and the behavior-change world—looking at using remote technology to extend interventions. Most interventions have an intensive phase and a maintenance phase during which the patient still has contact with the coach or whatever the mechanism was to cause their behavior change. A man named Gary Bennett has been doing a lot of work looking at whether we can extend that further by using chat groups or automated text messages[12,13] to keep patients feeling that they have some connection and that somebody is looking over their shoulder and seeing whether they are continuing these behaviors. The results have been amazing.
The other interesting this is that some of it depends on how the behavior change was implemented in the first place. If you have a very intensive intervention where people come into your center three or four times a week and work one-on-one with a counselor or in a group, that isn’t something you can sustain forever. But a telephone-based intervention sometimes can be more durable because that intervention lends itself to less frequent calls and to automated telephone reminders, so there isn’t the dramatic fall-off that you see when you go from an in-person intervention to something that is less intensive over time.
Dr Miller: You pointed out when we sat down that I am wearing a Fitbit. There are an increasing number of wearable devices that monitor heart rate, sleep, and level of physical activity. There are devices that will nudge you if you have been sedentary for a certain amount of time. I am addicted to getting my daily buzz, signaling that I have met my goal. Have these devices been studied? Do we know whether they could help as part of the ongoing intervention?
Dr Ligibel: Those have been studied. What have been best studied are the older versions of technology—pedometers—which have been studied in many large-scale trials. These show that writing down the number of steps people take each day is motivational.
Fitbits and similar devices are newer, and larger studies are looking at them, but short-term studies show that they are great motivational devices.[14,15] If people are competing with each other, that can be used to increase physical activity. There is a social element that is helpful for some people in maintaining behavior change over time. There are things that are still being looked at, but these are great additions to trying to get people to become more active, and different things work for different people. For some people, a device like that is great. Other people find that it becomes a chore or something that they have to do. Individualization, again, is important.
Dr Miller: Thank you again, Jennifer, for coming in to review this really important area for us, and thank you to our listening audience for joining us for this edition of Medscape Oncology Insights. This is Kathy Miller, reporting from the San Antonio Breast Cancer Symposium 2014.

References

  1. Donegan WL, Hartz AJ, Rimm AA. The association of body weight with recurrent cancer of the breast. Cancer. 1978;41:1590-1594. Abstract
  2. Pan H, Gray RG, on behalf of the Early Breast Cancer Trialists’ Collaborative Group; Effect of obesity in premenopausal ER+ early breast cancer: EBCTCG data on 80,000 patients in 70 trials. Program and abstracts of the 2014 American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2014; Chicago, Illinois. Abstract 503.
  3. Chan DS, Vieira AR, Aune D, et al. Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol. 2014;25:1901-1914. Abstract>
  4. Niraula S, Ocana A, Ennis M, Goodwin PJ. Body size and breast cancer prognosis in relation to hormone receptor and menopausal status: a meta-analysis. Breast Cancer Res Treat. 2012;134:769-781. Abstract
  5. Sparano JA, Wang M, Zhao F, et al. Obesity at diagnosis is associated with inferior outcomes in hormone receptor-positive operable breast cancer. Cancer. 2012;118:5937-5946. Abstract
  6. Sparano JA, Zhao F, Martino S, et al. Ten year update of E1199 Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in patients with axillary node-positive or high-risk node-negative breast cancer. Program and abstracts of the San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract S3-08.
  7. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of intergroup trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21:1431-1419. Abstract
  8. Ligibel JA, Cirrincione C, Liu MC, et al. Body mass index (BMI), tumor subtype, and relapse-free survival (RFS) in CALBG 9741 (Alliance). Program and abstracts of the 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, Illinois. Abstract 1032.
  9. Chlebowski RT, Blackburn GL, Thomson CA, et al. Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study (WINS). J Natl Cancer Inst. 2006;98:1767-1776. Abstract
  10. Chlebowski RT, Blackburn GL. Final survival analysis from the randomized Women’s Intervention Nutrition Study (WINS) evaluating dietary intervention as adjuvant breast cancer therapy. Program and abstracts of the San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract S5-08.
  11. Williamson DA, Rejeski J, Lang W, et al, for the Look AHEAD Research Group. Impact of a weight management program on health-related quality of life in overweight adults with type 2 diabetes. Arch Intern Med. 2009;169:163-171. Abstract
  12. Bennett GG, Foley P, Levine E, et al. Behavioral treatment for weight gain prevention among black women in primary care practice: a randomized clinical trial. JAMA Intern Med. 2013;173:1770-1777.
  13. Bennett GG, Warner ET, Glasgow RE, et al. Obesity treatment for socioeconomically disadvantaged patients in primary care practice. Arch Intern Med. 2012;172:565-574. Abstract
  14. Spring B, Duncan JM, Janke EA, et al. Integrating technology into standard weight loss treatment: a randomized controlled trial. JAMA Intern Med. 2013;173:105-111.
  15. Burke LE, Styn MA, Sereika SM, et al. Using mHealth technology to enhance self-monitoring for weight loss: a randomized trial. Am J Prev Med. 2012;43:20-26. Abstract

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