December 24, 2014
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. 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, 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 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 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.
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, which was updated today, 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. We found the exact same thing: that ideal doses of chemotherapy did not change the relationship between poor outcomes and weight. 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 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.
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, 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.
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.
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, 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.
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.
December 15, 2014Long-awaited survival data from the Women’s Intervention Nutrition Study (WINS), which began in 1994 and evaluated a low-fat diet intervention as an adjuvant breast cancer therapy, show that there was no statistically significant reduction in mortality in the overall study population.
However, there was a significant effect seen in a small subgroup of patients with hormone receptor (HR)-negative disease, where there was a 2.2-year benefit in median overall survival in the women who were in the diet intervention group, compared with control subjects.
Although this finding comes from an exploratory post hoc analysis, this is “the most intriguing part of the results,” said lead researcher Rowan Chlebowski, MD, PhD, medical oncologist at the Los Angeles Biomedical Research Institute at the Harbor-UCLA Medical Center.
However, he described the results overall as being “mixed”.
“I wonder if you shouldn’t be stronger in your conclusions,” commented Kent Osborne, MD, director of the Dan L. Duncan Cancer Center at the Baylor College of Medicine in Houston, who moderated the press briefing at which the study was highlighted here at the San Antonio Breast Cancer Symposium (SABCS) 2014.
Although taking on board the caveat that this was a result from a post hoc analysis, Dr Osborne said the result in the hormone-negative population was “pretty remarkable,” and the effect is “as good as or even greater than we see with our best treatments.”
“All of us, as oncologists, should take dietary intervention more seriously,” Dr Osborne said. “Oncologists should have a mechanism for referring patients to a nutritionist who can counsel them about diet. I think we need to take this far more seriously that we have in the past,” Dr Osborne told Medscape Medical News.
Dietary Intervention Targeted Fat Intake
The WINS trial enrolled 2437 women (48 to 79 years) with early-stage breast cancer who received standard care (surgery ± chemotherapy). In addition, tamoxifen was used in women with estrogen receptor (ER)-positive tumors, present in 1597 women (65% of the total).
The dietary intervention specifically targeted fat intake reduction through regular individual counseling sessions with dieticians. Dr Chlebowski said that this involved cutting out butter and margarine, cream and oils (e.g., from salad dressings), and avoiding fatty meat, such as sausages, etc.
Women in the intervention group were given a fat-gram goal by centrally trained, registered dieticians implementing a low-fat eating plan, explained Dr. Chlebowski. The women underwent eight biweekly individual counselling sessions with subsequent contacts every 3 months. The women self-monitored their fat/gram intake using a “keeping score” book, and fat intake was externally monitored by unannounced 24-hour telephone recalls performed annually, he said.
After a median of 5 years on this low-fat eating plan, the women in this intervention group had significantly reduced fat intake (from 29.2% to 20.3% of calories; P < .0001) and had significant weight loss of about 5 to 6 lbs (2.7 kg) (P = .005), whereas the women in the control group showed no change.
However, there was some overlap between the 2 groups, Dr Chlebowski noted, with about a third of women in the control group showing similar weight loss to those in the intervention group. If this was a drug vs placebo trial, it would be equivalent to more than 30% of the control group actually taking the active drug instead of the placebo.
Dr Chlebowski noted that that since the trial was started, it has emerged that it is weight loss rather than fat intake that is important for breast cancer risk reduction.
An earlier report from the WINS study, at 5-year follow-up, showed a significant effect on breast cancer recurrence, as reported by Medscape Medical News at the time and subsequently published (J Natl Cancer Inst. 2006;98:1767).
This 5-year follow-up showed that the breast cancer recurrence rate was 24% lower in the dietary intervention group than in the control group (hazard ratio [HR], 0.76; P = .03).
Dr Chlebowski noted that funding for the study finished in 2004, and since then there had been no contact with individuals. Further follow-up has been only through death registry data, which was continued until 2013 (with a follow-up of up to 19.4 years).
The survival data at this 19-year follow-up show that in the overall population there was no significant effect on mortality (13.6% in intervention group vs 17% in control group; HR, 0.82; P = .146).
The result was similar in the large subgroup of women with ER-positive disease, with no significant effect on mortality. Dr Chlebowski noted that these women were taking tamoxifen, and speculated that tamoxifen may have interfered with the weight loss from the dietary intervention.
However, in the small subgroup of women with ER-negative tumors (n = 478; 19.6% of total), there was a 36% reduction in deaths (all-cause mortality) in the intervention group, compared with the control group (HR, 0.64; P = .045). Median survival was 1.9 years greater for the intervention group than the control group (13.6 vs 11.7 years).
The reduction was even more significant for women with cancers that were both ER- and progesterone-receptor-negative (n = 362; 15% of total), Dr Chlebowski said, with a 56% reduction in death (P = .006). Here, median survival was 2.2 years longer in the intervention group, compared with the control group (14.0 vs 11.7 years).
Although testing for HER2 was not available at the time this trial was started, he suspects that many of these women (over 70%) would also be HER2-negative and have triple-negative breast cancer. These patients generally have a poor prognosis, so a signal here of a substantial effect on survival is of interest, he said.
This is of interest, said Beverly Moy, MD, clinical director at the Massachusetts General Hospital Cancer Clinic in Boston. “This is an important study with potentially important clinical implications,” she told Medscape Medical News. “We have seen previously from this study a significant effect from the low-fat diet on disease progression, and these new data on survival, although they are not significant for the population overall, they are statistically significant in the subgroup of women with ER-negative disease.”
This is important because these patients have fewer therapeutic options, and these patients tend to have more aggressive disease, she told Medscape Medical News.
Really good studies on lifestyle intervention are lacking, but this study shows clearly that a low-fat diet resulting in weight loss really can improve outcomes. This is something we can discuss with our patients, and this is something that they can do, she added.
“We hear all the time from our patients, what can I do to give myself the best chance of cure?” she commented. “Now we can say that a low-fat diet with weight loss can improve your outcome, and this is fantastic,” she added. “I’m delighted that there is real evidence from a randomized trial to show that there is benefit.”
Although this study didn’t show a specific effect on survival in the overall population of breast cancer patients, there are other studies that have shown benefits from exercise and weight loss, and there is also evidence from subgroup analyses of large adjuvant studies that show clearly that women who have ER-positive disease who are obese have a significantly worse outcome. “So I think that you can generalize and say that it’s never a bad idea to live a good lifestyle,” she said, adding that it also has benefits for overall health, reducing cardiovascular, and diabetes risks.
The WNIS study was funded by the National Cancer Institute and the American Institute of Cancer Research. Dr Chlebowski reports receiving consulting support from Pfizer, Novartis, Amgen, Genomic Health, and Novo Nordisk, and honorarium from Novartis.
San Antonio Breast Cancer Symposium (SABCS) 2014: Abstract S5-08. Presented December 12, 2014.
La obesidad aumenta el riesgo de desarrollar hasta 10 tipos de cáncer
Ago 2014. Hace más de una década que la Medicina empezó a mirar con atención la relación entre la obesidad y cáncer. Y se sabe que tener unos kilos de más es un factor de riesgo importante. Pero ahora un grupo de expertos de la Escuela de Medicina Tropical e Higiene de Londres realizó un estudio inédito –el mayor hasta hoy por su extensión y tamaño– que demostró que la obesidad y el sobrepeso aumentan el riesgo de padecer diez de los cánceres más comunes.
La investigación, que se publicó recientemente en la prestigiosa revista científica The Lancet, se extendió siete años y medio y abarcó a 5,2 millones de británicos mayores de 16 años. Permitió calcular, entre otras cosas, que el sobrepeso entre los adultos contribuye anualmente en más de 12 mil casos de la enfermedad en el Reino Unido. Y si siguen aumentando habrá otros 3.700 casos diagnosticados cada año.
Los especialistas calcularon que por cada subida de peso de entre 13 y 16 kilos aumenta el riesgo de afrontar seis tipos distintos de cáncer. La propensión a padecer cáncer de útero sube un 62%; el de vesícula 31%; el de hígado 25%; el de cérvix 10%; el de tiroides 9%; y, finalmente, el riesgo de padecer leucemia aumenta también un 9%.
Además, las personas con un mayor índice de masa corporal –la relación entre el peso y la altura– tienen más riesgos de desarrollar cáncer de hígado (19%), de colon (10%), de ovarios (9%), y de mama en la post-menopausia (5%). Un índice de masa corporal superior a 30 es considerado como una señal de obesidad en los adultos; quienes tienen entre 25 y 30 padecen sobrepeso.
Krishnan Bhaskaran, un graduado de la Universidad de Sheffield y especialista en estadísticas epidemiológicas que lideró el equipo que realizó el estudio, explicó que hay muchas variaciones en los efectos que tiene la masa corporal en los distintos tipos de cáncer. “Por ejemplo, el riesgo de sufrir cáncer de útero aumenta sustancialmente con un mayor índice de masa corporal, mientras que para otros tipos de la enfermedad se registró un aumento más modesto en los riesgos, o en algunos casos ningún efecto”. Y agregó: “Esta variación nos dice que el índice de masa corporal debe afectar el riesgo de padecer cáncer a través de un número de diferentes procesos, dependiendo del tipo que se padezca”.
En declaraciones al canal de televisión británico BBC, Tom Stansfeld, integrante de la organización benéfica para la lucha contra esa enfermedad Cancer Research UK, opinó que aunque la relación entre el cáncer y obesidad “es compleja”, está claro que los kilos de más “incrementan el riesgo de desarrollar ciertos tipos de la enfermedad”. Además, recomendó “mantener un peso saludable” porque “reduce el riesgo”, y dijo que “la mejor manera de lograrlo es con una dieta sana y equilibrada y haciendo ejercicio de forma regular”.
De acuerdo a cifras de la Organización Mundial de la Salud (OMS), el cáncer es una de las primeras causas de muerte a nivel mundial y en 2012 se le atribuyeron 8,2 millones de decesos. La entidad mundial concluyó que los tipos de cáncer que causan un mayor número anual de muertes son los de pulmón, hígado, estómago, colon y mama. El 70% de las muertes registradas en los últimos años se produjeron en África, Asia, América Central y América del Sur, y advirtió que los casos anuales aumentarán de 14 millones en 2012 a 22 millones en las próximas dos décadas.
La obesidad, en tanto, también es un problema que crece y preocupa: se calcula que casi un tercio de la población mundial tiene sobrepeso o es obesa.