Nutrition And Quality of Health Among Older Individuals What Should We Recommend May 11 - 12, 2006 University of Pittsbu

1. I wanted to think the organizers of the meeting for the invitation to present, especially Dr.Devra Davis and Dr. Lewis Kuller. And a special apology to Ms Alice Valoski for not providing my presentation ahead of time. I am truly appreciative of the invitation because it provided with an opportunity to revise some of my work and give some thought to the relationship of diet and endocrine related factor as they pertain to the causation of breast cancer. I mentioned last night that the first grant I did not have a score to was on the role of diet and hormones in the early onset of breast cancer in young African American women. That was more than twenty years ago. The primary reason given was that everyone knew that the increase in mortality rate from breast cancer in African American women was due to a delay in seek care and/or access. Today I going to switch my presentation around to talk about the relationship between hormones, diet and breast cancer and then the potential benefits of dietary modification as it relates to the WHEL Study.I wanted to think the organizers of the meeting for the invitation to present, especially Dr.Devra Davis and Dr. Lewis Kuller. And a special apology to Ms Alice Valoski for not providing my presentation ahead of time. I am truly appreciative of the invitation because it provided with an opportunity to revise some of my work and give some thought to the relationship of diet and endocrine related factor as they pertain to the causation of breast cancer. I mentioned last night that the first grant I did not have a score to was on the role of diet and hormones in the early onset of breast cancer in young African American women. That was more than twenty years ago. The primary reason given was that everyone knew that the increase in mortality rate from breast cancer in African American women was due to a delay in seek care and/or access. Today I going to switch my presentation around to talk about the relationship between hormones, diet and breast cancer and then the potential benefits of dietary modification as it relates to the WHEL Study.

2. PROBLEMS Here are my perceptions� Health is Not a national priority, especially for the underserved of this nation. Nor is it a priority of Americans Disparities in Health in America are Real and not only affect minorities and the medically underserved, but ALL AMERICANS. They just don�t know it until it impacts them. In Houston the trauma units where on drive for four days. No on drive by for minorities and the medically underserved, but all Houstonians. The death rate in Houston went up for ALL Houstonians. Race is a social construct, but has been used as a biological one. We can avoid the involvement of gene-environment interaction in the causation of disparities along with possible solutions. But to use race as a biological classification is wrong. Americans still have not confronted the issue of racial. The recent Institute of Medicine Report on Unequal Treatment confirmed the ugly legacy of such.Here are my perceptions� Health is Not a national priority, especially for the underserved of this nation. Nor is it a priority of Americans Disparities in Health in America are Real and not only affect minorities and the medically underserved, but ALL AMERICANS. They just don�t know it until it impacts them. In Houston the trauma units where on drive for four days. No on drive by for minorities and the medically underserved, but all Houstonians. The death rate in Houston went up for ALL Houstonians. Race is a social construct, but has been used as a biological one. We can avoid the involvement of gene-environment interaction in the causation of disparities along with possible solutions. But to use race as a biological classification is wrong. Americans still have not confronted the issue of racial. The recent Institute of Medicine Report on Unequal Treatment confirmed the ugly legacy of such.

4. So here is my disclaimer, the next few minutes of my presentation will contain my perceptions. I often say in general presentations that a person�s perception is a person�s reality whether real or not. That perceptions can be true barriers to addressing health disparities and if we don�t address them we will continue to bear the blunt of health disparities, and that is if we can continue to survive as a nation with the increasing demographic and a failure to really address these issue. For If a person perceives that they can not get care from an institution, whether barriers exist or not, they will not seek care at that institution. You can say that they are not real, but to the person that believes them they are. Again to ignore them only works against you and your attempts to addressing health disparities. My perceptions is the institutions continue to talk the talk about addressing health disparities, but really don�t do all the things necessary to really walk the walk to truly address health disparities.So here is my disclaimer, the next few minutes of my presentation will contain my perceptions. I often say in general presentations that a person�s perception is a person�s reality whether real or not. That perceptions can be true barriers to addressing health disparities and if we don�t address them we will continue to bear the blunt of health disparities, and that is if we can continue to survive as a nation with the increasing demographic and a failure to really address these issue. For If a person perceives that they can not get care from an institution, whether barriers exist or not, they will not seek care at that institution. You can say that they are not real, but to the person that believes them they are. Again to ignore them only works against you and your attempts to addressing health disparities. My perceptions is the institutions continue to talk the talk about addressing health disparities, but really don�t do all the things necessary to really walk the walk to truly address health disparities.

7. First, let me admit that there are a number of endocrine related factors that have recently been shown to be related to breast cancer. However, today I am just going to focus on the ancient one, estrogens. The reason, major of all of the other factors can be traced to being influences by this category of hormones. Fact, breast cancer develops almost exclusively in females. Fact, Administration of exogenous estrogens have been associated with breast cancer in male. Fact, Early oophorectomy results in a reduction in the risk of breast cancer as well as reducing the growth of human breast cancer tumors. Fact, The plateau in the age-incidence curve for breast cancer occurs in the pre-menopausal period. These facts have not changed over the last two decades.First, let me admit that there are a number of endocrine related factors that have recently been shown to be related to breast cancer. However, today I am just going to focus on the ancient one, estrogens. The reason, major of all of the other factors can be traced to being influences by this category of hormones. Fact, breast cancer develops almost exclusively in females. Fact, Administration of exogenous estrogens have been associated with breast cancer in male. Fact, Early oophorectomy results in a reduction in the risk of breast cancer as well as reducing the growth of human breast cancer tumors. Fact, The plateau in the age-incidence curve for breast cancer occurs in the pre-menopausal period. These facts have not changed over the last two decades.

8. A known fact that approximately one third or less of all breast cancers have a know risk factor. And of all the know risk factor, almost all are associated with an increase in exposure to estrogensA known fact that approximately one third or less of all breast cancers have a know risk factor. And of all the know risk factor, almost all are associated with an increase in exposure to estrogens

9. This slide summarizing over twenty years of work in my laboratory. Most of these results first demonstrated in a mouse model system I helped to develop, has been shown in women, especially those exposed to DES in utero. First , even compounds referred to weak estrogen or those with no estrogen action, ie, 17� estradiol can result in tumor formation when administrated during critical period of development. Second, animals who are oopherectomized prior to the onset will not develop tumors. Third,perinatal estrogen treatment results in the overexpress of HER2/neu. Given the results of this model, estrogen can be both an initiator and promoter, a complete carcinogen.This slide summarizing over twenty years of work in my laboratory. Most of these results first demonstrated in a mouse model system I helped to develop, has been shown in women, especially those exposed to DES in utero. First , even compounds referred to weak estrogen or those with no estrogen action, ie, 17� estradiol can result in tumor formation when administrated during critical period of development. Second, animals who are oopherectomized prior to the onset will not develop tumors. Third,perinatal estrogen treatment results in the overexpress of HER2/neu. Given the results of this model, estrogen can be both an initiator and promoter, a complete carcinogen.

10. Over three decades ago, we first proposed the idea that the non-protein bound fraction of estradiol, along with that bound to albumin might be the key factors in determining a women�s risk of developing breast cancer; and that such a factor might be related to diet. We first published those results in 1987 in the Cancer Research. Soon after our publications came a published article by Bright- See that fit both our hypothesis and our published studies. As shown in this slide is the possible mechanism by which diet might influence the level of bioavailable estrogen, These are all endogenous ways estrogens can be increased and still does not take into account exogenous exposure.Over three decades ago, we first proposed the idea that the non-protein bound fraction of estradiol, along with that bound to albumin might be the key factors in determining a women�s risk of developing breast cancer; and that such a factor might be related to diet. We first published those results in 1987 in the Cancer Research. Soon after our publications came a published article by Bright- See that fit both our hypothesis and our published studies. As shown in this slide is the possible mechanism by which diet might influence the level of bioavailable estrogen, These are all endogenous ways estrogens can be increased and still does not take into account exogenous exposure.

11. However, more importantly is the role that a fiber rich diet might have in terms of its impact on bioavailable estrogen and therefore a women�s risk of developing breast cancer. We focus so much on Japan and other European countries, but a country to our South may have some impprtant clues to the role of fiber. However, more importantly is the role that a fiber rich diet might have in terms of its impact on bioavailable estrogen and therefore a women�s risk of developing breast cancer. We focus so much on Japan and other European countries, but a country to our South may have some impprtant clues to the role of fiber.

12. This is data from 1983 to 1987 in terms of the incidence of breast cancer in various counties. Now before you jump to the conclusion that some of this may be under reporting, we check the numbers from our own health department in Texas regarding incidence at that time and the number are about the same. And remember, people who immigrate to the US don�t have their breast cancer rate decline. The estimated fiber intake in Mexico at that time was over 26 grams per day. In Mexico City, the estimated fiber intake today is no different than that in the US, and guess what is happening with their chronic disease rates, including breast cancer. And by the way, the fat intake has not changed significantly. And before you assume that all mexican diets, especially those in the US are the same, let me just illustrate why that should not be assumed.This is data from 1983 to 1987 in terms of the incidence of breast cancer in various counties. Now before you jump to the conclusion that some of this may be under reporting, we check the numbers from our own health department in Texas regarding incidence at that time and the number are about the same. And remember, people who immigrate to the US don�t have their breast cancer rate decline. The estimated fiber intake in Mexico at that time was over 26 grams per day. In Mexico City, the estimated fiber intake today is no different than that in the US, and guess what is happening with their chronic disease rates, including breast cancer. And by the way, the fat intake has not changed significantly. And before you assume that all mexican diets, especially those in the US are the same, let me just illustrate why that should not be assumed.

16. And before you assume that I am a unideminsional person, I am aware of other factors as well as gene-environment interaction that going on in this process. But what I have wanted to see in the pass three decades is whether or not changing one factor might have a significant enough impact to effect an outcome.And before you assume that I am a unideminsional person, I am aware of other factors as well as gene-environment interaction that going on in this process. But what I have wanted to see in the pass three decades is whether or not changing one factor might have a significant enough impact to effect an outcome.

17. I should also mention these compounds, although might not be influence by diet can be inpacted when one goes on a diet. I should also mention these compounds, although might not be influence by diet can be inpacted when one goes on a diet.

18. So where does the Women Health Eating & Living Study (WHEL) come in. I was first asked to be the Endocrinologist on the WHEL, because of the above hypothesis. One of the things to be measured was a number of endocrine related factors, FSH, LH, insulin, insulin growth factors and estradiol, both total and free.So where does the Women Health Eating & Living Study (WHEL) come in. I was first asked to be the Endocrinologist on the WHEL, because of the above hypothesis. One of the things to be measured was a number of endocrine related factors, FSH, LH, insulin, insulin growth factors and estradiol, both total and free.

19. Just a little bit more reproductive endocrinology. Only 1.5% of the total circulating estrogen is free. The faction that seem to change in populations at high risk (US) and those at low risk (Japan and Mexico (unpublished) is the the albumin bound. Higher in the US and lower in the other countries.Just a little bit more reproductive endocrinology. Only 1.5% of the total circulating estrogen is free. The faction that seem to change in populations at high risk (US) and those at low risk (Japan and Mexico (unpublished) is the the albumin bound. Higher in the US and lower in the other countries.

21. WHEL Study Objective To Achieve Objectively major validated change in dietary pattern emphasizing phytochemicals in population already averaging 5 FV/day While ensuring * No Change in physical activity pattern * No Change in Weight or Body Mass Index

22. SEVEN WHEL PARTICIPATING SITES Participants UC San Diego (Hollenbach) 537 (17.3%) UC Davis (Gold) 525 (17.0%) Stanford (Stefanick) 501 (16.2%) Kaiser Oakland (Caan) 441 (14.3%) U of Arizona (Thomson) 474 (15.3%) MD Anderson (Jones) 373 (12.1%) Kaiser Portland (Karanji) 237 ( 7.7%) TOTAL PARTICIPANTS: 3088 (100%) Minority Participants: 432 (14%)

24. Study Design

29. WHEL DIETARY ASSESSMENT METHODS Set of four 24 hour recalls on random days (weekday and weekend over 3 week period) Freq = Base, 1yr, 2/3yr, 4yr, 6yr Arizona Food Frequency Questionnaire Freq = Base, 1yr, 4yr Plasma Carotenoids Freq = Base, 1yr, 2/3yr, 4yr, 6yr

30. WHEL STUDY INTERVENTION phase1: quickly get on the diet to build self- efficacy that it can be done phase 2: work on changing the daily environment to support diet phase 3: have a regular review of performance to motivate for maintenance

31. Set Daily Behavioral Targets that require major change in dietary habits 5 vegetable servings 2 cups of vegetable juice 3 Fruit servings 30g fiber 15-20% energy from fat

35. Total Plasma Carotenoids at 12 Months by Distribution at Study Baseline

36. Maintenance of WHEL Study Group Difference (24 hr recall data)

37. WHEL Study Maintenance of Plasma Carotenoid Changes (Geo. Mean, d)

45. Summary of Results from the African-American/White Population Differences in dietary intake at baseline between the two populations were found with a-carotene, total fruit servings, and dietary fiber. Baseline blood levels of lutein were also found to be significantly different between the African Americans and whites. Scatter plots and correlation coefficients showed that the only instance where the dietary intake was not significantly correlated with the blood levels was with cryptoxanthin in both the African-American and white populations.

46. Summary of the Results from AAPI/White Population The AAPI population was significantly different from the white populationin education (p-value 0.006). The AAPI population was significantly different from the white population with regard to smoking behavior (p-value <0.001). Differences in dietary intake at baseline between the two populations were found with cryptoxanthin and dietary fiber. Blood levels of cryptoxanthin and blood levels of lycopene were also found to be significantly different between AAPIs and the white population.

47. RESULTS: The intervention (but not the comparison) group reported a significantly lower intake of energy from fat (21% v 28%), and higher intake of fiber (29 g/d v 22 g/d), at 1-year follow-up (P < .001). Significant weight loss did not occur in either group. A significant difference in the change in bioavailable estradiol concentration from baseline to 1 year in the intervention (?13 pmol/L) versus the comparison (+3 pmol/L) group was observed (P < .05). Change in fiber (but not fat) intake was significantly and independently related to change in serum bioavailable estradiol (P < .01) and total estradiol (P < .05) concentrations. CONCLUSION: Results from this study indicate that a high-fiber, low-fat diet intervention is associated with reduced serum bioavailable estradiol concentration in women diagnosed with breast cancer, the majority of whom did not exhibit weight loss. Increased fiber intake was independently related to the reduction in serum estradiol concentration. RESULTS: The intervention (but not the comparison) group reported a significantly lower intake of energy from fat (21% v 28%), and higher intake of fiber (29 g/d v 22 g/d), at 1-year follow-up (P < .001). Significant weight loss did not occur in either group. A significant difference in the change in bioavailable estradiol concentration from baseline to 1 year in the intervention (?13 pmol/L) versus the comparison (+3 pmol/L) group was observed (P < .05). Change in fiber (but not fat) intake was significantly and independently related to change in serum bioavailable estradiol (P < .01) and total estradiol (P < .05) concentrations. CONCLUSION: Results from this study indicate that a high-fiber, low-fat diet intervention is associated with reduced serum bioavailable estradiol concentration in women diagnosed with breast cancer, the majority of whom did not exhibit weight loss. Increased fiber intake was independently related to the reduction in serum estradiol concentration.

49. Mean Body Weight over time and stratified by randomized status. The Women�s Healthy Eating and Living Study. (N=3088)

50. Validated WHI 9-item Physical Activity Questionnaire Sub-sample of 58 women Used accelerometer (used this as gold standard) and PAR as comparison measures Estimated whether met guideline of 30 min of moderate activity 5+ days per week

51. Mean Energy intake and Physical activity over time and stratified by randomized status. The Women�s Healthy Eating and Living Study. (N=3088)

52. BASELINE PREDICTORS OF STUDY OUTCOMES IN THE COMPARISON GROUP

53. Mortality Rates Following Breast Cancer By Lifestyle Variables

54. Mortality Rates by Interaction of Lifestyle Variables: WHEL control group

55. So where does the Women Health Eating & Living Study (WHEL) come in. I was first asked to be the Endocrinologist on the WHEL, because of the above hypothesis. One of the things to be measured was a number of endocrine related factors, FSH, LH, insulin, insulin growth factors and estradiol, both total and free.So where does the Women Health Eating & Living Study (WHEL) come in. I was first asked to be the Endocrinologist on the WHEL, because of the above hypothesis. One of the things to be measured was a number of endocrine related factors, FSH, LH, insulin, insulin growth factors and estradiol, both total and free.