>> GOOD AFTERNOON AND WELCOME TO THE ANNUAL ADVANCES IN CANCER PREVENTION LECTURE. I'M DAVE NELSON, I DIRECT THE CANCER PRESENSION FELLOWSHIP HERE AT NCI. BEFORE I INTRODUCE OUR SPEAKER I'VE BEEN TOLD THERE'S ANNOUNCEMENTS WE NEED TO MAKE SURE THAT YOU GET. SO FIRST OF ALL IF YOU HAVE YOUR CELL PHONES WITH YOU, MAKE SURE THEY ARE ON MUTE OR TURNED OFF ALTOGETHER. SECOND OF ALL, THERE IS NO FOOD OR DRINK ALOUD IN THE AUDITORIUM, THIS INCLUDES WATER AND WATER BOTTLES AND THEY'RE VERY SERIOUS ABOUT ENFORCING THAT POLICY FOR THOSE WHO WERE HERE EARLIER, YOU WILL KNOW ABOUT THAT. SO WITH THAT SAID I'M GOING TO GO AHEAD AND INTRODUCE OUR SPEAKER IS DR. WALTER WILLIS, DETAILS ABOUT HIS BACKGROUND ARE IN THE PROGRAM YOU RECEIVED, I WOULD HIGHLIGHT A COUPLE OF THINGS. HE'S THE PROFESSOR OF PUBLIC AND BACKGROUND IN TRAINING IS PRIMARILY THE STATE OF MICHIGAN, THE DEGREE OF MICHIGAN STATE UNIVERSITY, AND UNIVERSITY OF STATE MICHIGAN, HE ALSO ATTENDED THE HARVARD SCHOOL OF PUBLIC HEALTH WHERE HE GOT A DOCTORAL DEGREE, HE IS PROBABLY 1 OF THE MOST NOTED NUTRITIONISTS IN THE WORLD AS WELL AS IN THE COUNTRY. WITH THAT I WILL STOP TALKING, SO I WILL INTRODUCE HIM TO YOU NOW. THANK YOU. [ APPLAUSE ] >> THANK YOU VERY MUCH, I AM GLAD TO SEE THAT AFTER ALL THE BUDGET CUTS, NIH IS STILL STANDING. I'M GOING TO GIVE AN OVERVIEW OF WHAT I SEE IN THE AREA OF DIET AND CANCER OVER THE LAST 40 YEARS AND END UP WITH A LITTLE DISCUSSION WHERE I THINK SOME OF THE MOST IMPORTANT AREAS TO LOOK MIGHT BE. AND PRESENT THIS AS 4 PARADIGMS I THINK WE TRAMPED THROUGH OVER THIS PERIOD OF TIME. THE FIRST IS THE CARCINOGEN AND FOODS PARADIGM. WHEN I STARTED HEARING ABOUT DIET AND CANCER, BACK IN THE 1960S, THIS IS PRETTY MUCH ALL WE HEARD ABOUT, THOSE CHEMICALS IN GRILLED FOODS, BARBEQUED FOODS THAT ARE CARCINOGENS AND LIKELY TO CAUSE CANCER, CARCINOGENS AND HUMAN CARCINOGENS, I'M NOT GOING TO SAY MUCH MORE ABOUT THIS PERIOD. IT'S PRETTY INTERESTING, THOUGH THAT I DON'T THINK WE'VE TOTALLY RESOLVED THIS QUESTION IN PART BECAUSE WE DON'T HAVE A GOOD BIOMARKER OF LONG-TERM EXPOSURE TO FIT--AND SOME OF THESE OTHER COMPOUNDS THAT ARE OF CONCERN, BUT STILL, IF THIS WAS A MAJOR CAUSE OF HUMAN CANCER, PROBABLY WE WOULD HAVE SEEN IT BY NOW, BECAUSE A LOT OF PEOPLE HAVE LOOKED AND MOST OF THE STUDIES HAVE NOT SEEN CLEAR ASSOCIATIONS BETWEEN CALCULATED INTAKE AND RISK OF VARIOUS HUMAN CANCERS. THE WHOLE ISSUE OF DIET AND CANCER REALLY CAME TO THE ATTENTION OF THE BIOMEDICAL COMMUNITY IN THE EARLY 1980S A REPORT BY DOLL AND PITO, ON THE CAUSES OF CANCER DEATHS IN THE UNITED STATES. IT WAS NO SURPRISE TO ANYONE THAT TOBACCO WAS REALLY HIGH, NEAR THE TOP OF THE LIST, IF NOT AT THE TOP OF THE LIST, BUT WHAT SURPRISED A LOT OF PEOPLE WAS THAT DOLL AND PATENTSER ATTRIBUTED--PETER ATTRIBUTED 30% TO DIETARY FACTORS, THAT WAS NEWS TO PEOPLE BUT THEY WERE UNCLEAR ABOUT THE MAGNITUDE OF THAT ESTIMATE AND THEY WERE MORE UNCLEAR ABOUT WHAT IT WAS ABOUT DIET THAT MIGHT BE RELATED TO CANCER, PROTECTIVE OR CAUSAL AND THIS OF COURSE RAISED LOTS OF QUESTIONS, AND GREATLY STIMULATED RESEARCH IN THE DIET AND CANCER AREA. MUCH OF THIS CONCLUSION OF DOLL AND PETER THAT DIET IS IMPORTANT CAME FROM ECOLOGICAL STUDIES COMPARING CANCER INCIDENTS AND MORTALITY RATES IN VARIOUS COUNTRIES AROUND THE WORLD AND FINDING VERY LARGE DIFFERENCES ALMOST ALL THE CANCERS COMMON IN WESTERN COUNTRIES AND ALSO ALONG WITH THIS, OTHER EPIDEMIOLOGIST FOR LOOKING AT MIGRANT WHO IS CAME FROM LOW INCIDENCE AREAS LIKE JAPAN TO THE U.S., AND WITHIN, EITHER THE SAME GENERATION OR 1 OR 2, GENERATIONS, THE--THE INDIVIDUALS ADOPTED THE RATES OF CANCER IN THEIR NEW ENVIRONMENT, AND SOME CASES LIKE BREAST CANCER AND COLORECTAL CANCER PERHAPS OVERSHOOTING THE RATES OF CANCER IN THE UNITED STATES. AND THIS OF COURSE IS CRITICAL EVIDENCE THAT SAYS IN A VERY BROADWAY THAT GENETIC FACTORS ARE NOT THE MAJOR CAUSES OF THE HIGH RATES OF COLORECTAL CANCER, BREAST CANCER, ENDOMEETRIAL CANCER OR SRORBGS VALID AND RELIABLIAN CANCER THAT WE'RE ASSUMING HERE AND THAT'S IMPORTANT TO UNDERSTAND BECAUSE OF THE ENTHUSIASM THAT WE WOULD UNDERSTAND AND PREDICT CANCER IF WE COULD ANALYZE THE HUMAN GENOME. I THINK EPIDEMIOLOGIST UNDERSTOOD LONG AGO THAT WE WERE ON SOMETHING BUT NOT ACCOUNT FOR MOST OF THE CANCERS IN THIS COUNTRY BY GENETIC FACTORS. BUT IT DIDN'T GO UMKC UP IN THE QUESTION, WHAT IS IT THAT IS CAUSING THESE HUGE RATES, AND HUGE DIFFERENCES IN CANCER RATES AMONG MIGRANTS AND HUGE VARIATION AMONG COUNTRIES AND THAT AGAIN WAS HUGE STIMULUS TO DO MORE DETAILED STUDIES. THERE WERE HYPOTHESIS FROM THESE ECOLOGICAL STUDIES AND MAINLY, PEOPLE CONCLUDED THAT IT WAS FAT IN THE DIET OR ANIMAL FAT THAT WERE--WAS THE MAJOR CAUSES OF BREAST COLORECTAL PROSTATE AND ENDOMEETRIAL CANCER, ESSENTIALLY BECAUSE OF THESE LARGE--VERY STRONG CORRELATIONS. BUT I THINK EPIDEMIOLOGISTS ALSO APPRECIATED THAT THERE WAS PLENTY OF OPPORTUNITY FOR CONFOUNDING HERE BY PHYSICAL ACTIVITY, SMOKING, OTHER LIFESTYLE FACTORS, REPRODUCTIVE FACTORS, ENERGY BALANCE AND THAT IT MIGHT NOT BE FAT PER SE IN A DIET, AND THAT INITIATED THEN A SERIES OF LARGE COHORT STUDIES, WE'VE BEEN CONDUCTING SEVERAL OF THEM IN OUR OWN GROUP, THE NURSES HEALTH STUDIES AND PROFESSIONAL FOLLOW UP STUDIES BUT THERE ARE NOW SEVERAL DOZEN LARGE COHORT STUDIES THAT ARE ESTABLISH INDEED IN COUNTRY AND AROUND THE WORLD. AND WHEN WE FIRST LOOKED AT FAT INTAKE AND BREAST CANCER, IN OUR COHORT STUDY, THE NURSES HEALTH STUDY WE FOUND NO RELATIONSHIP AND THAT OF COURSE STIMULATED A LOT OF OF CONTROVERSY BECAUSE OF BELIEVE THAT FAT WAS THE MAJOR CAUSE OF CANCERS IN WESTERN COUNTRIES WAS VERY STRONG AND ISSUES WERE RAISED ABOUT ABILITY TO MEASURE FAT INTAKE AND DOSE RESPONSE RELATIONSHIPS, BUT A LOT OF THIS DID CENTER AROUND THE MEASURE FOR DIETARY EXPOSURES IT WAS NOT JUST OUR OWN GROUP THAT DID NOT FIND RELATIONSHIPS BETWEEN FAT INTAKE AND BREAST CANCER RISK THIS, IS A--THIS IS A POOLED ANALYSIS OF COHORT STUDIES THAT DAVID HUNTER CONDUCT INDEED THE MID1990S WHERE 7 LARGE COHORT STUDIES ABOUT 7000 INCIDENCE OF BREAST CANCER AND IT'S VERY FLAT, EXCEPT FOR YOU LOOK AT THE LOWEST FAT INTAKE, THERE WAS AN INKRES RATHER THAN DECREASE IN RISK OF BREAST CANCER. NOW EVEN THOUGH THIS WAS STATISTICALLY SIGNIFICANT, NOT REALLY SURE THIS IS TRUE BUT THERE ARE SOME POSSIBLE CAUSAL MECHANISMS, BUT, THE POINT IS IT MAKES IT QUITE UNLIKELY THERE'S AN IMPORTANT REDUCTION IN RISK OR BREAST CANCER WITH VERY LOW FAT INTAKE. AND EMPHASIZE THAT THIS IS FAT INTAKE DURING MIDLIFE AND LATER. THE WOMAN'S HEALTH INITIATIVE WAS LAUNCH INDEED THE EARLY 1990S TO TEST THE HYPOTHESIS IN A RANDOMIZED TRIAL WHERE FAT REDUCTION WOULD REDUCE BREAST CANCER RISK, THIS WAS THE BIGGEST MOST EXPENSIVE STUDY OVER DONE AND INVOLVED RANDOMIZATION OF ABOUT 48,000 WOMAN TO A LOW FAT DIET OR REGULAR DIET AND THE STUDY LASTED FOR AN AVERAGE OF ABOUT 7 YEARS OF FOLLOW UP OF THE WOMEN WHO HAD BEEN RANDOMIZED. THE RELATIVE RISK, MOST OF YOU ARE FAMILIAR WITH THIS, IS .91 WAS NOT STATISTICALLY SIGNIFICANT. ONE WOULD HOPE WITH THIS HUGE INVESTMENT, THIS WOULD HAVE PROVIDED A DEFINITIVE ANSWER TO THE QUESTION ABOUT FAT REDUCTION, BUT THOSE WHO WERE ENTHUSIASTIC ABOUT THE HYPOTHESIS, ARGUED THAT FAT REDUCTION HAD BEEN GREATER, THIS MIGHT HAVE BEEN STATISTICALLY SIGNIFICANT, ON THE OTHER HAND WE DID CALCULATIONS AND ESTIMATED THAT EVEN SEVERAL KILOGRAM WEIGHT DIFFERENCE IN THE GROUPS COULD HAVE ACCOUNTED FOR THIS RELATIVE RISK OF .91. BUT IT DIDN'T MEET THE FORM AT TEST OF TAFTISTICAL SIGNIFICANCE. FAT REDUCTION ARE EXPERIENCED FOR ANY MAJOR OUTCOME, BREAST CANCER INDENSE OR MORTALITY, TOTAL MORTALITY OR GLOBAL INDEX COMBINED CANCER AND OTHER MAJOR OUTCOMES. THE MOST SOBERING ASPECT OF THE WOMEN'S HEALTH STUDY, WOMEN'S HEALTH INITIATIVE WAS PUBLISHED JUST A COUPLE OF YEARS AGO, IN THE AMERICAN JOURNAL OF CLINICAL NUTRITION LOOKING AT THE CHANGES IN BLOOD LIPIDS THAT OCCURRED IN THE LOW FAT GROUP VERSES THE CONTROL GROUP OVER TIME AND AS YOU CAN SEE, THERE WAS ABSOLUTELY NO EFFECT OF THE LOW FAT DIET ON HDL CHOLESTEROL OVER THE SECURE PERIOD, OR NO EFFECT OF THE LOW FAT DIET ON TRIGLYCERIDES. AND WE KNOW FROM MANY CONTROLLED FEEDING STUDIES THAT IF THE PERCENTAGE OF THE CALORIES IS REDUCED, HDL CHOLESTEROL GOES DOWN AND TRIGLYCERIDES GO UP, SO THIS PROVES, I THINK DEFINITIVELY THAT WOMEN'S HEALTH INITIATIVE DID NOT ACTUALLY TEST THE HYPOTHESIS. THAT DIETARY FAT IS RELATED TO BREAST CANCER OR ANY OUTCOME AND THAT'S PRETTY SOBERING, AGAIN BECAUSE OF THE RESOURCES THAT WERE PUT INTO THIS AND REALLY THE TOP PEOPLE WORKED HARD ON THIS. I CAN'T THINK THAT I WOULD HAVE DONE ANY BETTER. THIS WAS THE BEST RYE WE COULD DO AND WE JUST DID NOT MANAGE TO CREATE ENOUGH DIETARY CHANGE TO EVALUATE THE HYPOTHESIS. WHICH I THINK IS A MAJOR CONCERN IN TRYING TO DEVELOP A STRATEGY FOR HOW WE LEARN ABOUT DIET AND CANCER. ONE OF THE LIMITATIONS AND OTHER LIMITATION OF THE WOMEN'S HEALTH INITIATIVE THAT IT WENT JUST 7 YEAR WHICH IS IS PRETTY LONG IN TERMS OF DIETARY INTERVENTION BUT IT'S A SHORT PERIOD OF TIME IN THE DEVELOPMENT OF HUMAN CANCER WHICH FROM OTHER EVIDENCE WE KNOW CAN TAKE DECADES TO DEVELOP AND I'LL COME BACK AND TALK ABOUT THAT MORE. SO WE DID--WE HAVE LOOKED IN THE NURSES HEALTH STUDY AT LONGER TERM FOLLOW UP. THIS IS OVER A PERIOD OF 20 YEARS NOW AND STILL ABNORMALITIES EVACUATELY NO RELATIONSHIP BETWEEN FAT INTAKE OVER WIDE RANGE AND RISK OF OF POST MENOPAUSAL BREAST CANCER. I WOULD ADD THAT USING OUR QUESTIONNAIRE, WE SEE STRONG CORRELATIONS BETWEEN HDL CHOLESTEROL AND TRIGLYCERIDES AS A FUNCTION OF PERCENTAGE OF CALORIES FROM DIETARY FAT WHICH DOES VALIDATE OUR DIETARY ASSESSMENT AND WE SAW THAT WITH THE FOOD FREQUENCY QUESTIONNAIRE IN THE WOMEN'S HEALTH INITIATIVE TOO, SO THE QUIETARY QUESTIONNAIRES CAN DISCRIMINATE AMONG DIFFERENT LEVELS OF FAT INTAKE BUT THE INTERVENTION DID NOT--WAS NOT SUFFICIENT TO EVALUATE THE HYPOTHESIS. ONE OF THE OTHER LESSONS WE'VE LEARNED IN THE EXPERIENCE WE'VE HAD LOOKING AT DIET AND CANCER IS THE CASE CONTROL STUDIES ARE JUST VERY PRONE TO BIASES AND I THINK CANNOT REALLY RELIAISONNABLY PROVIDE INFORMATION ON DIET AND CANCER AND WE SHOULD IN GENERAL AVOID THEM WITH VERY FEW MAYBE SPECIAL EXCEPTIONS WHERE WE CAN'T DO A PROSPECTIVE STUDY. THIS IS--THIS SAY SUMMARY OF CASE CONTROL STUDIES THAT JEFF HOWE PUT TOGETHER SOME YEARS AGO. AND YOU CAN SEE IF YOU LOOK AT CASE CONTROL STUDIES, ABOUT HALF OF THEM ARE SIGNIFICANTLY POSITIVE IN EXAMINING THE RELATIONSHIP BETWEEN FAT INTAKE AND BREAST CANCER, BUT--IN THE SUMMARY RELATIVE RISK IS HERE, IT'S VERY FIGHT CONFIDENCE AND HIGHLY STATISTICALLY SIGNIFICANT AND LARGE HETEROGENEOUS ROW GENERATED AITY AMONG THESE STUDIES WHERE THE PROSPECTIVE STUDIES ARE MUCH MORE CONSISTENT, SO NIG CAVE CANT HETEROGENEOUS ROW GENERATED AITY AND OVERALL SUMMARY IS ABSOLUTELY DEAD-ON, NO. SO I THINK THERE'S OBVIOUSLY MANY POTENTIAL SOURCES OF BIAS AND CASE CONTROL STUDIES, RECALL BIAS IS USUALLY RAISED AS A PROBLEM BECAUSE PEOPLE WITH DISEASE MAY RECALL THEIR DIET DIFFERENTLY THAN THOSE WITHOUT THE DISEASE BUT ACTUALLY THINK THAT SELECTION BIAS IS PROBABLY A BIGGER PROBLEM BECAUSE IN TODAY'S WORLD, NOT EVERYBODY PARTICIPATES IN--IN CONTROLS IN CONTROL STUDIES AND THOSE WHO PARTICIPATE ARE MUCH MORE LIKELY TO BE HEALTH CONSCIOUS AND DO WHAT THEY'RE BEING TOLD. IN OTHER WORDS EAT LOW FAT DIETS AND EAT MORE FRUITS FRUITS AND VEGETABLES AND EAT MORE AND SMOKE ESZ, SO YOU KNOW WHAT THE RESULT OF A CASE CONTROL STUDY WILL BE THE 1 OF THE STUDIES THAT WAS HELD UP AS AN ARGUMENT WHY WE WERE NOT MEASURING GIVING--YOUETARY FAT ADEQUATELY TO DETECT AN ASSOCIATION IN THE COHORT STUDIES WAS THIS VERY SMALL COHORT, CONDUCTED BY SHEILA BIG HAM, IT ONLY INCLUDED 160-SOMETHING CASES OF BREAST CANCER AND SHE REPORTED THAT IF YOU USE--IN THEIR ANALYSIS, DIET RECORD, 1 WEEK DIET RECORD THAT THEY COLLECTED AT BASELINE, THEY FOUND A VERY STRONG RELATIONSHIP BETWEEN FAT INTAKE AND BREAST CANCER, ABOUT A 2 FOLD HIGHER RISK AMONG WOMEN IN THE HIGHEST WENTILE OF DIETARY FACT BUT IF YOU USE THE FREQUENCY IN THE SAME POPULATION COMPLETED BY THE SAME WOMEN, YOU DID FOCUS ON THE FIND AN ASSOCIATION. THIS WAS--I THOUGHT SOMETHING WAS SORT OF FISHY ABOUT THESE DATA FROM THE BEGINNING BECAUSE WE JUST COULD NOT HAVE MISSED AN ASSOCIATION THAT STRONG OR 2 FOLD ELEVATION AND RISK OF BREAST CANCER WITH THE CROSS QUI NTEX, LLA FAT INTAKE. AND ALSO IN THE STUDY, THE ASSOCIATION WITH THE FOOD FREQUENCY QUESTIONNAIRE WAS QUITE A BIT STRONGER THAN WE HAD SEEN IN ANY OF THE COHORT STUDIES SO FAR. AMONG SOME THINGS THEY ACTUALLY DIDN'T ADJUST CORRECTLY FOR TOTAL ENERGY INTAKE BUT SOMEHOW THE DATA JUST DIDN'T MAKE SENSE. FORTUNATELY, TIM KEYS AND OTHERS IN UK HAVE GONE ON TO CONTINUE TO FOLLOW UP THAT STUDY AND ALSO ADD 3 OTHER STUDIES IN THE UK THAT USE BOTH A DIET RECORD AND A FOOD FREQUENCY QUESTIONNAIRE AND THEY'VE JUST RECENTLY PUBLISHED THIS ANALYSIS, 4 TIMES AS MANY CASES, AS SHEILA HAD IN HER ORIGINAL REPORT AND WHAT THEY FIND IS THAT BOTH WITH DIET RECORDS AND FOOD FREQUENCY QUESTIONNAIRE, THERE'S ACTUALLY A WEAK, NONSIGNIFICANT INVERSE RELATIONSHIP WITH BREAST CANCER RISK AND NO REAL DIFFERENCE AT ALL BETWEEN THE METHODS. SO I THINK THIS--THIS REAL LE TOTALLY ENDS THE ARGUMENT THAT HAD BEEN PUT FORTH BY DR. BING HAM. AND ALSO, SINCE THE WOMEN'S HEALTH INITIATIVE, NORM BOYD'S GROUP PUBLISHED A RANDOMIZED TRIAL LOOKING AT FAT AND BREAST CANCER RISK. THESE WERE WOMEN WHO WERE AT SOMEWHAT HIGHER RISK BECAUSE OF THEIR MAMMOGRAMS, BUT RANDOMIZED TO LOW FAT DIET OR CONTROL DIET, AND INTERESTINGLY THERE, THE LOW FAT GROUP, ACTUALLY HAD A NONSIGNIFICANTLY HIGHER RISK OF BREAST CANCER COMPARED TO THE CONTROLLED GROUP, BUT WHAT WAS ALSO PRETTY INTERESTING IN THIS STUDY, THAT THERE WERE DIFFERENCES IN HDL CHOLESTEROL BETWEEN THE INTERVENTION AND THE CONTROL GROUP, MEANING THEY ACTUALLY DID TEST THE HYPOTHESIS IN THIS ANALYSIS AND I THINK IT'S PRETTY IMPORTANT TO UNDERSTAND WHY THIS STUDY ACTUALLY DID MANAGE TO INDUCE SUSTAINED DIETARY CHANGE AND THEIR INTERVENTION GROUP AND THE WOMEN'S HEALTH INITIATIVE DID NOT. ONE IMPORTANT DIFFERENCE IS THAT, THEY SCREENED WOMAN, A LARGE NUMBER OF WOMEN TO IDEBTIFY WOMEN WHO THEY THOUGHT WOULD BE MOST LIKELY TO COMPLY WITH AN INTERVENTION, NOT TRY TO BE REPRESENTATIVE THAT THEY WERE LOOKING FOR VALIDITY, NOT REPRESENTATIVENESS AND I THINK THAT'S REALLY AN IMPORTANT POINT, THEY WANT TO TEST THE HYPOTHESIS, TO REPRESENT THIS AND IT'S PRETTY MUCH IRRELEVANT. NOW 1 OF THE LAST STANDS OF THE LOW FAT ENTHUSIANTS THAT OVERWEIGHT AND OBESITY ARE RESPECTERS FOR PWRAFT CANCER AND LOW FAT DISCIPLINARYYS REDUCE WEIGHT AND HIGH FAT DIETS CAUSE OVERWEIGHT. AND THAT WAS REALLY FIRMLY IN THE BELIEF OF MAIN STREAM NUTRITION A FEW YEARS AGO BUT I ACTUALLY--I THINK WHAT HAPPENED, WHAT I REALIZED WAS HAPPENING WAS THAT IF YOU DO A LITTLE TRIAL, OF WEIGHT LOSS WITH LOW FAT DIETS, PEOPLE LOSE WEIGHT FOR THE FIRST 2 OR 3 MONTHS BUT THEN THEY REGAIN IT. AND IN FACT, IT LOOKS LIKE, NO MATTER WHAT DIET YOU PUT PEOPLE ON FOR A FEW MONTHS THEY LOSE WEIGHT AND TEND TO REGAIN IT SO I TRY TO DIG OUT ALL STUDIES I COULD FIND OF LOW FAT DIETS THAT LASTED 1 YEAR OR MORE, AND THIS IS THE SUMMARY OF THE RESULTS IF YOU DO A--DID A META-ANALYSIS, THERE WAS ABSOLUTELY NO IMPACT OF LOW FAT DIETS ON WEIGHT LOSS, AT 1 YEAR AND THIS HAS BEEN CONFIRMED BY MANY OTHER STUDIES. IN FACT IT LOOKS--THE OVERALL EVIDENCE SUGGESTS MORE THAT LOW FAT DIETS ARE LESS SUCCESSFUL IN MAINTAINING WEIGHT LOSS IF ANYTHING. SO I THINK WE REALLY DID, I THINK BURRY THE LOW FAT PARADIGM AND WHAT EMERGED NEXT WAS THE FOOD AND VEGETABLE PARADIGM AND I THINK MANY PEOPLE HERE ARE FAMILIAR WITH MANY THINGS THAT WERE SAID. IF YOU EAT 5 SERVINGS A DAY OF FRUITS AND VEGETABLES, IT WILL REDUCE YOUR CANCER RISK, 40 OR 50%, THERE WAS A BIG PROMISE POULT OUT THERE AND THIS WAS REPRESENTED IN THIS REPORT BY THE WORLD CANCER RESEARCH PUBLISHED IN 1997, I WAS PART OF THAT COMMITTEE, TOO AND TAKING THE BLAME FOR SOME OF THIS, THAT THE NUMBER 1 RECOMMENDATION WAS CHOOSE PREDOMINANTLY PLANT BASED DIETS THAT WAS RICH IN VEGETABLES THAT WAS THE NUMBER 1 ADVISE FOR KANSASER PREVENTION AND THIS WAS AN EXTENSIVE REVIEW ASK THERE WAS THOUGHT TO BE EVIDENCE AS YOU CAN SEE FOR MANY DIFFERENT CANCER SITES, OF REDUCTION AND RISK FOR VEGETABLES AND FRUITS BUT THE PROBLEM WAS, ALMOST ALL OF THOSE STUDIES THAT WE REVIEWED AT THAT TIME WERE CASE CONTROL STUDIES THAT IN FACT, DID QUITE CONSISTENTLY SHOW LOWER RISK WITH HIGHER FRUITS AND VEGETABLES, BUT IT'S THE PROSPECTIVE STUDIES HAVE COME IN, THEY REALLY HAVE NOT SUPPORTED, I THINK THE BENEFITS HAD BEEN SUGGESTED BY CASE CONTROL STUDIES AND I THINK THIS IS ANOTHER PLACE WHERE THERE IS A LOT OF BIAS, THIS IS LOOKING AT POOL ANALYSIS OF COURT STUDIES THAT WE DID A FEW YEARS AGO, AND STEPHANIE SMITH WARNER LED THIS, OVER 3000 CASES OF LUNG CANCER AND MAYBE A LITTLE BLIP UP THE LOWEST INTAKE AND BASICALLY FLAT FAT DOSE RESPONSE RELATIONSHIP FOR LUNG CANCER. THIS IS COMBINING OUR CORES, FRUITS AND VEGETABLES IN CORRELATION TO COLORECTAL CANCER THIS, IS COMPLETELY FLAT. PULLING FROM THE PROJECT, LOOKING AT FRUITS AND VEGETABLES FOR BREAST CANCER AND YOU CAN SEE MAYBE SLIGHT INVERSE RELATIONSHIPS BUT TRENDS AREN'T SIGNIFICANT AND THIS IS AN ANALYSIS WE DID A FEW YEARS AGO, LOOKING AT ALL CANCER SITES COMBINED AND TOTALLY FLAT ACROSS INCREASING CATEGORIES FROM EVEN 8 SERVINGS A DAY VERSES LESS THAN 1 AND HALF SERVINGS A DAY. NOW, THIS DOESN'T--I JUST WOULD ADD THAT IN THE SAME POPULATION WE DID SEE'S HIGHLY SIGNIFICANT INVERSE TREND WITH CARDIOVASCULAR DISEASE SO THERE ARE DEFINITE MECHANISMS AND BENEFITS ARE WHAT ARE DESCRIBED FOR CARDIOVASCULAR DISEASE, SO THERE'S--DON'T OPEN UP YOUR REFRIGERATORS THROW AWAY THE SAGEITABLES AND LOAD UP WITH TWINKIES, FRUITS AND VEGETABLES ARE GOOD FOR US BUT THE BENEFIT WILL BE PRIMARILY CARDIOVASCULAR DISEASE. NOW IT DOESN'T MEAN THERE'S ABSOLUTELY NO BENEFIT OF FRUITS AND VEGETABLES FOR CANCER RISK. WHEN WE DIG DOWN DEEPLY WE DO FIND SOME--SOME POTENTIAL BENEFIT FIST WE LOOK AT SPECIFIC FRUITS AND VEGETABLES, OR VERY SPECIFIC SUBSETS OF CANCER. FOR EXAMPLE, THIS IS LOOKING AT ESTROGEN RECEPTOR NEGATIVE POST MENOPAUSAL BREAST CANCER AND WE SEE AN INVERSE RELATIONSHIP WHERE THE PRUDENT DIETARY SCORE AND WHEN WE DELVE IN DEEPLY INTO THAT, IT'S MOSTLY FROM FRUITS AND VEGETABLES AND THAT'S BEEN SEEN IN SEVERAL DATA SETS, NOW I THINK THAT'S PROBABLY CONSIDERED CONFIRMED RELATIONSHIP, BUT WHEN YOU COMBINE ALL BREAST CANCERS TOGETHER, THERE'S NO SIGNIFICANT RELATIONSHIP SINCE ESTROGEN RECEPTOR NEGATIVE IS A FAIRLY MODEST SUBSET OF THE TOTAL AND WHEN WE'VE LOOKED AT PROSTATE CANCER WE DO SEE AN INVERSE RELATIONSHIP WITH LIKE O PENE INTAKE OR TOMATO PRODUCTS AND THAT'S BEEN SEEN IN A NUMBER OF STUDIES NOW, USING EITHER INTAKE OF TOMATO PRODUCTS OR BLOOD LEVELS OF LIKE O PENE. SO IT LOOKS LIKE THERE ARE SOME RELATIONSHIPS THERE, BENEFITS AGAIN, BUT THEY'RE MODEST IN THE BIG PICTURE THEY GET LOST. SO I THINK WE'VE THERE'S STILL MORE DETAILS TO LOOK AT WITH FRUITS AND VEGETABLES BUT IT'S NOTICE CLOSED DOOR BUT IT'S NOT A MAJOR SOLUTION TO CANCER PREVENTION. THAT TAKES US TO THE FOURTH PARADIGM WHICH IS THE ENERGY OR OBESITY PARADIGM. THIS 1 IS HERE TO STAY. FOR SOMETIME WE WERE A LITTLE BIT I THINK MISLED OR DIDN'T APPRECIATE WHAT WAS GOING ON OR FOR EXAMPLE, FOR PWRAFT CANCER WE'VE SEEN IN THE NURSES HEALTH STUDY, IF WE LOOKED OVERALL, THE RELATIONSHIP BETWEEN BMI AND INCIDENCE OF BREAST CANCER IS ACTUALLY VERY WEAK AND PART OF THAT IS BECAUSE OF--THAT THERE'S AN INSRERZ RELATIONSHIP BETWEEN BMI AND BREAST CANCER BEFORE MENOPAUSE AND AFTER MENOPAUSE, THERE'S POST MENOPAUSAL BREAST CANCER, THE RELATIONSHIP WAS SURPRISINGLY WEAK, AND I SAY SURPRISINGLY BECAUSE OBESE WOMEN HAVE ABOUT 3 TIMES THE PLASMA LEVELS OF ESTRO DIAL COMPARED TO LEEWOMAN, BUT WE WOULD EXPECT MORE OF A ASSOCIATION. BUT WHEN WE STRATIFIED AND LOOK AT WEIGHT CHANGE DURING ADULT LIFE WE SAW A MUCH--VERY CLEAR RELATIONSHIP AMONG WOMEN WHO NEVER USED HORMONE REPLACEMENT THERAPY. SO THERE WAS ABOUT A DOUBLING OF RISK IN THE WOMEN WHO GAINED THE MOST WEIGHT COMPARED TO WOMEN WITH STABLE WEIGHTS AND AMONG CURRENT HORMONE REPLACEMENT USER THERE IS WAS NO RELATIONSHIP, THESE WOMEN WERE HIGH PRESUMABLY DUE TO PHARMACOLOGIC LEVELS OF ESTROGEN AND PROGESTERONE AND ESTROGEN AT THIS TIME BUT ONLY THE VERY OBESE WOMEN, THE WOMEN WHO GAINED A LOT OF WEIGHT GOT UP TO THAT LEVEL. AND THIS IS ACTUALLY PRETTY IMPORTANT FIGURE I THINK BECAUSE IN OUR POPULATION, WOMEN WHO DID NOT GAIN WEIGHT DURING ADULT LIFE AND NEVER USED HORMONE REPLACEMENT THERAPY WHERE ONLY ABOUT 5% OF THE TOTAL POPULATION BUT IN JAPAN THIS GROUP WAS ALMOST A HUNDRED% OF THE POPULATION, SO, THIS ACTUALLY ACCOUNTS, THESE 2 FACTORS ADULT WEIGHT GAIN AND HORMONE REPLACEMENT THERAPY ACCOUNT FOR ABOUT A THIRD OF BREAST CANCER INCIDENCE, MOST MENOPAUSAL BREAST CANCER INCIDENCE IN BREAST MORTALITY. SO THIS IS A BIG CHUNK OF THE INTERNATIONAL DIFFERENCES. FOR MEN, WE SAW AN ASSOCIATION WITH BMI, AND WOMEN AS WELL IN RELATION TO COLORECTAL CANCER RISK, BUT IT WAS ACTUALLY STRONGER IF WE LOOKED AT WAIST CIRCUMFERENCE, WHICH IS IN MEN, BETTER CAPTURES OBESITY IN OLDER MEN. THIS RELATIONSHIP BETWEEN OTOPACKITY AND CANCER INCIDENT WAS BROUGHT TO THE PUBLIC'S ATTENTION MOST CLEARLY FROM THE STUDY FROM THE CANCER SOCIETY, PUBLISHED IN THE NEW ENGLAND JOURNAL OF MEDS, THIS WAS BASED ON SEVERAL MEN AND WOMEN AND DOCUMENTED VERY CLEAR DOSE RESPONSE RELATIONSHIP WITH ELEVATED RISK IT IS EVEN IN THE OVERWEIGHT NOT YET OBESE RANGE, BUT STEADY ILLEGALSEE INCREASING WITH INCREASING BODY MASS INDEX AND THE RISK WERE ELEVATED FOR COLORECTAL CANCER, GAL BLADDER, UTERINE CERVICAL AND OTHER CANCER SOCIETIES HAVE BEEN ADDED TO THIS, ADENO CARCINOMA OF THE ESOPHAGUS AND SOME OF THE LYMPHATIC CANCERS AND LEUKEMIAS AS WELL. SO THERE HAS BEEN STUDIES DONE IN DOZENS AND DONES OF STUDIES AND THIS IS NOT TOTALLY NEW IF WE LOOK BACK AT DIET AND CANCER STUDIES, BACK IN THE 1930S IT WAS APPRECIATED THAT WEIGHT GAIN WAS OR DID INCREASE RISK OF TUMORS IN THOSE ANIMALS AND THAT WAS THOUGHT OF MORE AS A NUISANCE ASK IGNORED BUT IT IS A MAJOR FACTOR IN HUMAN CANCER. I DID A CALCULATION A WHILE AGO, LOOKING AT THE POPULATION ATTRIBUTABLE RISK OF OVERWEIGHT AND BMI, COMPARED TO SMOKING. AND AT THIS POINT IN TIME, BECAUSE SMOKING RISKS HAD GONE DOWN AND OBESITY HAS GONE UP, IT LOOKS LIKE THE NUMBER OF CANCERS ATTRIBUTABLE TO OVERWEIGHT AND OBESITY ARE PRETTY SIMILAR TO THE NUMBER OF CANCERS ACCOUNTED FOR BY CURRENT SMOKING IN THE UNITED STATES, YOU CAN ARGUE A LITTLE BIT WHICH WAY IT IS BUT THEY'RE IN THE SAME BALL PARK. SO THIS, I THINK IS AN IMPORTANT DISCOVERY. IT WASN'T--A LOT OF DISCOVERIES CAME OUT, THE CASE REALLY BUILT UP OVER A PERIOD OF YEARS BUT IT'S OF IMPORTANCE IN MAGNITUDE SIMILAR TO SMOKING. I JUST WANT TO ADD THOUGH, IF YOU LOOK, ON THE POPULATION LEVEL FOR AN INDIVIDUAL, THE RELATIVE RISK IS MUCH HIGHER FOR SMOKING THAN IT IS FOR OVERWEIGHT BECAUSE THE NUMBER OF SMOKER SYSTEM MUCH FEWER THAN OVERWEIGHT AND OBESE PEOPLE. SO THOSE ARE THE 4 PARADIGMS I'VE IDENTIFIED BUT THERE'S--I THINK A LOT MORE TO DIET AND CANCER THAT HOPEFULLY WILL WILL TAKE A SIGN TO ADDITIONAL PARADIGMS. THIS THE REPORT THAT IT CONTRIBUTED TO, ACTUALLY IT WAS A SUBCOMMITTEE IN REALITY, THERE WERE JUST 3 OF US, ARTHUR AND TIM KEITH THAT TRIED TO PUT TOGETHER IN A NONSYSTEMATIC LITERATURE REVIEW, BUT IT WAS OUR SUMMARY AND IT WOULD BE THE SAME SUMMARY IF YOU DID A SYSTEMATIC REVIEW, OF WHAT'S IMPORTANT AND WHAT WE COULD SAY ABOUT PREVENTION OF CANCER BY DIET AND NUTRITION IN 2003 AND IT REALLY DID PUT AT THE TOP ENERGY BALANCE, MAINTAINING A BMI AND HEALTHY RANGE, REGULAR PHYSICAL ACTIVITY, ALCOHOLIC BEVERAGES, IDENTIFIED TAXINS IN FOODS BUT THEY WERE TALKING ABOUT LIVER CANCER AND DEVELOPING COUNSEL COUNTRIES AND CHINESE SALTED FISH WHICH IS A SOUTHEAST ASIAN ISSUE, WE STILL MENTION FRUITS AND VEGETABLES BUT THAT WAS MAINLY BASED ON VERY SHAKY CASE CONTROL STUDY SYSTEM THAT WAS NOT VERY SUBSTANTIALLY SUPPORTED ACTUALLY AND MORE FOR HISTORICAL REASONS PER--PERHAPS AND REIDENTIFY PRESERVED MEETS IN PARTICULAR AND POULTRY AND FISH WERE NOT ASSOCIATED WITH CANCER RISK EVEN THOUGH THEY HAD BEEN EXAMINED QUITE A BIT AND VERY HOT FOODS WHICH COMES FROM THE MATAE SOUTH AMERICAN HABIT AND ORAL AND PHARYNGEAL CANCER, VERY LOCAL ISSUE. SO THAT SEEMED LIKE A PRETTY SMALL LIST, BUT AGAIN, THERE WAS A LOT MORE THAT I THINK IS LIKELY TO BE ADDED TO THAT LIST. AND 1 OF THOSE IS POLLATE AND IT'S BEEN A TOPIC OF A LOT OF INTEREST AND CONTROVERSY, THIS IS OUR MOST RECENT ANALYSIS LOOKING AT FOALATE INTAKE INTO THE--IN RELATION TO COLORECTAL CANCER IN OUR COHORTS, AND THIS ANALYSIS, WE USE THE MANY REPEATED MEASURES OF DIET THAT WE HAVE, WE HAVE 8 DIFFERENT MEASURES EVERY 4 YEARS NOW IN THE NURSES HEALTH STUDY WHICH WAS START INDEED 1980 AND WE COULD THEN LOOK AT A LOT OF POWER AND LATENCY PERIODS AND I THINK THIS IS AN IMPORTANT POINT THAT IF WE LOOK AT JUST 0 TO 4 YEARS OF FOLLOW UP, THERE WAS ABSOLUTELY NO SUGGESTION OF BENEFIT. THIS LINE IS NOT SHOWING IN THE RIGHT PLACE, IT'S A BIT TOO HIGH. JUST SOME PROBLEM WITH WORD PROCESSING BUT THESE ARE NONSIGNIFICANT REDUCTIONS HERE HERE AT 8 TO 12 YEARS AND INVERSE REDUCTION BUTTA AT THE TIME WE GET OUT TO 12 OR 16 YEARS, THERE'S A FAIRLY ROBUST SIGNIFICANT INVERSE RELATIONSHIP BETWEEN FULLY INTAKE AND COLORECTAL RISK WHICH SUGGESTS THAT THIS IS OPERATING PERHAPS AT A TIME OF INITIATION OR AT LEAST WITH ALARM LATENCY AND THAT WOULD BE MISS IF WE DON'T PAY ATTENTION TO LATENCY. NOW 1 OF THE REASONS WHY I THINK THIS IS VERY STRONGLY AND LIKELY TO BE A REAL PREVENTIVE FACTOR IS THE ESSENTIAL USE OF MENTORSHIP SKILLELIAN RANDOMIZATION AND VERY FEW EXAMPLES THAT WE HAVE THAT I THINK HAS BEEN ROBUSTLY CONFIRMED AND THAT'S THE POLYMORPHISM AND THE MTH FR GENE WHERE THE HOMOZYGOTE VARIANT WHICH HAS A PREVALENCE OF ABOUT 15%, HAS A SIGNIFICANTLY LOWER RISK OF COLORECTAL CANCER AND SINCE THIS VARIANT, THIS ENZYME IS SPECIFICALLY INVOLVED IN FOALATE METABOLISM, THIS MAKE ITS VERY LIKELY THAT FOALIC ACID IS INVOLVED IN THE ETIOLOGY OF COLORECTAL CANCER. OF COURSE IF YOU ONLY HAD THIS, IT DOESN'T SAY WHICH DIRECTION THE RELATIONSHIP BETWEEN FOALATE AND RISK OF CANCER WOULD BE BUT OF COURSE, THE EPIDEMIOLOGIC EVIDENCE POINTS TO BENEFIT OR REDUCTION IN COLORECTAL CANCER RISK AND THIS IS--REALLY 1 OF THE FIRST GENOTYPES THAT WAS LOOKED AT WHEN WE WERE JUST DOING 1 SNIP AT A TIME BUT IT STOOD THE TEST OF TIME. IT'S BEEN HELD UP AND REPLICATED MANY, MANY TIMES AND IT WAS NOT REPORTED WAS NOT, BUT THAT DOES MAKE A STRONG CASE, THAT COMBINATION OF EVIDENCE. THERE HAVE BEEN CONCERNS THAT MANY PEOPLE WERE--THAT HIGH FOALIC INTAKE MIGHT INCREASE COLORECTAL CANCER RISK TRANSIENTLY, AND IT'S POSSIBLE THAT SOME THINGS THAT MIGHT IN THE LONG-TERM BE PREVENTED AND TRANSIENTLY INCREASE RISK WHEN THERE WAS INITIAL INCREASE IN INTAKE. AND THIS WAS A PAPER THAT GOT A LOT OF ATTENTION OR RISK BY DR. JOEL MASON AND OTHERS AT TUSTS UNIVERSITY AND THEY LOOKED AT CANCER INCIDENCE IN THE UNITED STATES REPORTED IN A SEER DATA AND ESSENTIALLY SAID THERE WAS A BLIP IN INDENSE OCCURRING IN THE LATE 1990S, BUT AT THE END, THIS WAS THE SAID IN RESPONSE TO THE HYPOTHESIS, TO THE FOALIC FORTIFICATION WHICH OCCURRED IN THIS TIME AROUND 1998 IT HAD--THERE HAD TO BE FORTIFICATION SOME OF THE FOOD INDUSTRY WAS PUTTING FOALATE IN THE A FOR A FEW YEARS BEFORE IT WAS REQUIRED BUT IT'S IMPORTANT TO ELECTRIC AT THE SCALE HERE. THIS IS ONLY--THIS IS NATIONAL DATA, THE INCIDENCE IS ONLY ABOUT--YOU KNOW 2% INCREASE, THERE, IT'S QUITE SMALL. AND, OF COURSE 1 OF THE PROBLEMS WAS THIS WAS AT THE TIME THAT THIS WAS A BIG BURST IN COLONOSCOPY SCREENING AND SO THIS COULD HAVE BEEN DUE TO--FOR MANY PEOPLE THE RIGHT SIDE OF THEIR COLON BEING VISUALIZED FOR THE FIRST TIME. SO HOW DO WE DISTINGUISH BETWEEN A SCREENING ARTIFACT AND OUR TRUE INCIDENCE OF CANCER AND I WOULDN'T KNOW THAT EVEN IF THERE WAS A BLIP, THE RATES CONTINUED TO DECLINE EVEN AFTER THAT TIME OF PARALLEL, WHATEVER IT WAS, IT WAS DEFINITELY TRANSIENT. THE WAY TO MAKE IT DISTINCTION CLEARLY IS TO LOOK AT WHAT HAPPENED TO MORTALITY AND I LOOKED AT THAT PRETTY CAREFULLY TO SEE IF THERE WAS A CORSPOBDING BLIP IN MORTALITY, AND THERE ACTUALLY IS NO HINT OF AN INCREASE IN MORTALITY, I THINK MANY OF YOU ARE AWARE OF CANCER MORTALITY HAS BEEN FALLING STEADY ILLEGALSY IN THE UNITED STATES AND AFTER THAT, IS WHERE THEY WERE DESCRIBING A BLIP UP, THERE WAS A SHARP--STEEPER DECLINE IN MORTALITY RATES FROM COLORECTAL CANCER AND THIS WAS ALMOST FOR SURE SOME OF THIS WAS DUE TO THE SCREENING, INCREASE IN SCREENING, POSSIBLY DUE TO THE ADDITIONAL FOALATE AS L. IT'S HARD TO MAKE THAT DISTINCTION. TO COVER A FEW OTHER TOPICS WHICH I THINK ARE IMPORTANT TO POTENTIALLY IMPORTANT, ALCOHOL AND BREAST CANCER, WE KNOW ALCOHOL IS RELATE INDEED HIGH DOSES TO A NUMBER OF CANCER SITES, PARTICULARLY UPPER GI AND ESOPHAGEAL CANCER, BUT WE'VE ALSO COME TO APPRECIATE THE FACT THAT ALCOHOL CAN ALSO CAUSE OTHER CANCERS. AND WE CAN SEE EVEN AT 5 TO 9-GRAMS PER DAY, THAT'S ABOUT A HALF A DRINK A DAY, IT'S LOW DOSE, THERE'S--EVEN THERE'S A SIGNATURES THEUF CANT INCREASE ABOUT A 15% INCREASE IN LINEAR DOSE RESPONSE RELATIONSHIP, UP TO ABOUT AT LEAST ABOUT 40-GRAMS OF ALCOHOL PERDAY. ANOTHER TOPIC WHERE I THINK THE EVIDENCE IS QUITE STRONG IS A BENEFIT OF CALCIUM INTAKE, THESE ARE DATA FROM THE POOLED ANALYSIS OF PROTECTIVE STUDIES, AND DO SHOW A SIGNIFICANT INVERSE TREND, BUT IT LOOKS LIKE IT'S NOT REALLY LINEAR THAT IT PLATEAUS OFF ABOUT A THOUSAND MILLIGRAMS OF CALCIUM PER DAY. AND IN THAT EXAMPLE, WE ALSO HAVE DATA FROM THE CONTROLLED TRIALS OF SUPPLEMENTING CALCIUM AMONG INDIVIDUALS WHO HAVE ALREADY BEEN DIAGNOSED WITH COLORECTAL ADENOMA AND I THEN IS AN EXAMPLE OF PROBABLY THE LEVEL OF EVIDENCE THAT WE WILL BE ABLE TO GET ON DIET AND CANCER, I THINK GIVEN WITH WOMEN'S HEALTH INITIATIVE AND OTHER EXPERIENCES IN LONG-TERM INTERVENTION TRIALS WITH THE INTERVENTION IS DIETARY CHANGE, IT'S--IT'S EXTRAORDINARILY DIFFICULT TO DO THOSE STUDIES BECAUSE OF ADHERENCE AND THE DURATION THAT'S NECESSARY. SO PROBABLY IN MOST INSTANCES IT WILL--THE BEST WE'LL BE ABLE TO DO IS A COMBINATION OF DATA USING LARGE PROSPECTIVE STUDIES OBVIOUSLY REPLICATED AND SHORTER TERM CONTROLLED STUDIES WITH INTERMEDIATE END POINTS AND ADENOMA AND IT MIGHT BE 1 BUT HORMONE LEVELS IN BLOOD WHICH COULD BE JUST FOR A FEW WEEKS. I THINK WE'RE GOING TO NEED TO BE CREATIVE AND THEN OF COURSE THE POSSIBLE EDITION IN SOME INSTANCES OF OF MENDELIAN RANDOMIZATION USE OF GENETIC INFORMATION TO SUPPORT OR REFUTE ETIOLOGIC HYPOTHESIS. ANOTHER TOPIC THAT IS I THINK POTENTIALLY IMPORTANT, NOT OATALLY RESOLVED AND MILK AND DAIRY CONSUFPGZ SUFPLGZ IN RELATION TO FATAL PROSTATE CANCER. NOW THIS FIRST REPORT WAS FROM A SEVENTH DAY ADVENTIST STUDY WITH A 2 AND HALF FOLD INCREASE WITH 3 OR MORE GLASSES PER DAY, IF THAT'S REAL, THAT'S A BIG ISSUE BECAUSE THAT'S THE NATIONAL DIETARY RECOMMENDATION IS 3 SERVES OF MILK A DAY, NOW IF IT HAS THAT MUCH OF AN INCREASE IN PROSTATE CANCER RISK, IT WOULD INDUCE MANY MEN TO THINK ABOUT THEIR DAIRY COMSUMPTION, WE CONFIRMED THAT IN THE HEALTH OFFICS STUDY WE SEE IN RISK OF FATAL PROSTATE CANCER OR OR DAIRY COMSUMPTION BUT NOTHING FOR THE NONADVANCED PSA DETECTED CASES. AND THERE'S ACTUALLY PRETTY GOOD BIOLOGICAL BASIS FOR THAT THAT I THINK THE EVIDENCE IS CLEAR, THAT HIGH MILK COMSUMPTION DOES INCREASE BLOOD LEVELS OF IGF 1, RANDOMIZED TRIAL OF FEEDING 3 GLASSES OF LOW FAT MILK A DAY, A 10% INCREASE IN BLOOD IGP LEVELS AND A REDUCTION IN IGP BINDING PROTEIN AND IGP LEVELS HAVE BEEN REPEATEDLY SHOWN TO PRODICK PROSTATE CANCER INCIDENCE---PREDICT PROSTATE CANC INCIDENCE. SOY COMSUMPTION WAS ALSO PUBLISHED BY THE 70th DAY ADVENTIST STUDY AND HERE THERE WAS A STRONG INVERSE RELATIONSHIP BUT AS YOU CAN SEE, BASED ON VERY SMALL NUMBERS AND NOT VERY ROBUSTLY SIGNATURES THEUF CANT, NOT MANY OTHER POPULATIONS HAVE ENOUGH SOY COMSUMPTION AND ENOUGH PROSTATE CANC TORE LOOK AT THIS SO THIS I THINK REMAINS UNRESOLVED. ANOTHER AREA WHERE THERE'S QUITE A BIT OF LITERATURE IS MEAT COMSUMPTION IN COLORECTAL CANCER RISK AND HERE FOR OVERALL RED MEET, THIS IS A META-ANALYSIS DONE A FEW YEARS AGO, THERE IS A POSITIVE ASSOCIATION AND IT'S STRONGER FOR PROCESSED MEAT AND I'VE SEEN IN OTHER STUDIES SINCE THAT TIME. OF COURSE, I THINK ALMOST EVERYONE IS AWARE HERE THAT 1 OF THE HOTTEST TOPICS IN NUTRITION AND CANC SER VITAMIN D AND THE EVIDENCE IS PROBABLY STRONGEST FOR RISK OF COLORECTAL CANCER IN THE NURSES HEALTH STUDY, WE FOUND ABOUT A 50% RISK IN WOMEN WITH THE HIGHEST LEVELS OF PLASMA VITAMIN D AND THAT'S REPLICATE INDEED THE WOMEN'S HEALTH INITIATIVE, OBSERVATIONAL STUDY AND OTHER STUDIES. IT'S NOT YET DEFINITIVE AND THERE'S IN FACT A POOLED ANALYSIS GOING ON RIGHT NOW. WE'LL HAVE A LOT BETTER DATA ON THAT RELATIONSHIP, HOPEFULLY IN A MATTER OF A YEAR OR SO. NOW, FOR PROSTATE CANCER THERE'S ALSO BEEN A HYPOTHESIS BASED ON ECOLOGICAL DATA THAT VITAMIN D MAY BE PROTECTIVE, PARTICULARLY AGAINST FATAL PROSTATE CANCER AND OUR GROUP RECENTLY PUBLISHED THIS ANALYSIS SHOWING A STRONG INVERSE RELATIONSHIP BETWEEN PLASMA VITAMIN D AND LETHAL PROSTATE CANCER, NO RELATIONSHIP WITH THE INDOLENT FORM OF PROSTATE CANCER. AND IN THIS INSTANCE WE USE--THIS WAS DR. SHIED'S WORK. ANOTHER USE OF GENETIC AT THAT DAT TO EVALUATE THE HYPOTHESIS, WE DID NOT FIND ANY SIGNIFICANT INTERACTIONS OR ASSOCIATIONS WITH INDIVIDUALS SNIPS IN THE VITAMIN D PATHWAY BUT THIS YEAR'S IS THE LOGISTIC COLONEL MACHINE TEST TO ASSESS MULTIPLE SNIPS AT THE SAME TIME. ACTUALLY 97 SELECTED SNIPS IN THE VITAMIN D METABOLISM PATHWAY AND THIS TEST USES JUST 1 DEGREE OF FREEDOM TO EVALUATE WHETHER THERE IS A DIFFERENCE IN THE DISTRIBUTION OF SNIPS IN IN PATHWAY BETWEEN CASES OF PROSTATE CANCER AND THEN WHO DID NOT DEVELOP PROSTATE CANCER SO I THINK IT'S AN EFFICIENT WAY OF DEALING WITH THESE LARGE NUMBER OF SNIPS WHICH FAIRLY MODEST ASSOCIATIONS AND THIS TEST WAS STATISTICALLY SIGNIFICANT. EVERYTHING NEEDS TO BE REPLICATED, IF HAD IS REPLICATED IT WOULD PROVIDE STRONG SUPPORT FOR A BENEFIT OF VITAMIN D IN SUSPENDING LETHAL PROSTATE CANCER. AND THIS KIND OF COMBINATION IS WHAT WE'LL HAVE TO HAVE TO LOOK AT THIS. THERE WILL NEVER BE A RANDOMIZED TRIAL BIG ENOUGH TO LOOK AT LETHAL PROSTATE CANCER, THIS TOOK ABOUT 25 YEARS FOR US TO ACCUMULATE ENOUGH CASES OF LETHAL PROSTATE CANCER IN OUR COHORT TO BE ABLE TO LOOK AT THIS OBSERVATION. SO IT'S SOMETHING SORT OF BEYOND THE REACH OF RANDOMIZED TRIAL AND YOU'LL HAVE TO AGAIN USE COMBINATIONS OF DATA TO EVALUATE THIS RELATIONSHIP. NOW 1 OF THE IMPORTANT POINTS I WANT TO END WITH IS TO EMPHASIZE THAT WHAT WE'VE LOOKED AT SO FAR IN THE WHOLE LITERATURE AND DIET AND CANCER IS ALMOST ENTIRELY DIET IN MIDLIFE AND LATER IN RELATION TO FUTURE RISK OF CANCER AND WE KNOW TRUSTEES FOR MANY OTHER EPIDEMIOLOGIC OBSERVATIONS THAT FACTORS ACTING EARLY IN LIFE ARE VERY IMPORTANT FOR BREAST CANCER, REPRODUCTIVE FACTORS ARE IMPORTANT, SO THAT WEIGHT AT 5 AND 10 ARE IMPORTANT IN PREDICTING FUTURE CANCER, WE KNOW THAT WHEN WE DROPPED BOMBS ON JAPAN THAT WOMEN WHO WERE OLDER THAN 40, ATOMIC BOMBS THAT THEY DID NOT DEVELOP BREAST CANCER. AFTERWARDS BUT IF THERE WERE CHILDREN OR YOUNG ADULTS THEY DEVELOPED DIFFERENT BREAST CANCER O ALL THIS POINTS TO EARLY LIFE BEING SUSEPTIBLE PERIOD AND IF DIET WERE ACTING DURING THAT PERIOD, WE WOULD HAVE MISSED IT IN ALMOST ALL THE PUBLISHED LITERATURE, UP UNTIL THIS IT TIME. SO THAT WAS THE RATIONAL FOR STARTING NURSES HEALTH STUDY, TOO, THESE WOMEN WERE BOTH 25 TO 42 YEARS OF AGE SO ALL MEN ARE PREMENOPAUSAL AND THEN WE ALSO COLLECTED DATA FROM THEM ABOUT WHAT THEY WERE CONSUMING DURING HIGH SCHOOL AND SHOWING THAT THAT HAS GOOD VALIDITY AND ALSO COLLECTED DATA FROM THEIR MOTHERS ABOUT THEIR MOTHERS MEG NANCY WITH OUR PARTICIPANT, AND BREAST FEEDING AND WEANING, FOODS, GIVEN TO HER PARTICIPANT WHO'S NOW IN THE NURSES HEALTH STUDY, TOO SO WE PIECE MEALED THE COURSE TOGETHER THAT YOU WOULD LIKE TO LOOK PROGRESSIVELY BUT NO 1 WOULD GET A GRANT FOR THAT AND WHAT EPIDEMIOLOGIST WOULD WANT TO DO THAT IF THEY CAN'T SEE THE RESULTS EITHER. WE ARE SEE MATH NURSE'S HEALTH STUDY TOO, DIFFERENT RELATIONSHIPS AND LOOKING AT FAT INTAKE AND BREAST CANCER RISK AND WE DO SEE ANIMAL FAT, THIS IS DURING EARLY ADULT LIFE, THERE IS A POSITIVE ASSOCIATION WITH ANIMAL FAT BUT NOT WITH VEGETABLE FAT WHICH SUGGESTS IT'S NOT FAT PER SE, BUT MAYBE SOMETHING ABOUT EITHER THE FATTY ACIDS OR OTHER CONSTITUENTS OF FOODS HIGH IN ANIMAL FAT THAT ARE RELATED TO BREAST CANCER RISK. AND THEN WE'VE ALSO LOOKED AT DIET DURING HIGH SCHOOL AND THERE'S AN ASSOCIATION BETWEEN RED MEAT COMSUMPTION AND BREAST CANCER AND THE NUMBERS ARE FAIRLY MODEST HERE ABOUT 400 IN SEVERAL CASES AND IT WOULD BE A BIG [INDISCERNIBLE] MORE BUT THIS IS SOMETHING WE DIDN'T SEE WHEN WE LOOK AT RED MEAT IN RELATION TO BREAST CANCER AT MIDLIFE OR LATER. AND THEN, JUST TO POINT OUT THAT THERE'S STILL SOME PROVOCATIVE FINDINGS THAT COME ALONG THAT WE'LL NEED FURTHER CONFIRMATION, WE RAOEBTLY PUBLISHED A PAPER LOOKING AT SOURCES OF PROTEIN AND RISK OF PROSTATE CANCER IN MEN AND THIS IS FOCUSING AGAIN ON LETHAL PROSTATE CANCER WHICH IS A MINORITY BUT THE MOST IMPORTANT MINORITY OF PROSTATE CANCER AND WE FOUND A QUITE STRONG POSITIVE ASSOCIATION BETWEEN EGG CONSKPUFPLGZ LETHAL PROSTATE CANCER SO WE'RE LOOKING TO SEE IF THAT WILL BE CONFIRMED IN OTHER DATA SETS AND OFF THE RECORD, IT LOOKS LIKE IT MAY. SO TO CONCLUDE, DOLLS ESTIMATE, BACK IN 1982, OF 30-35% OF CANCER DUE TO NUTRITIONAL FACTORS IT'S STILL REASONABLE BUT MUCH OF THIS WE NOW KNOW IS RELATED TO OVERWEIGHT AND INACTIVITY, AND ALCOHOL COMSUMPTION DOES CLEARLY INCREASE THE RISK OF BREAST AND OTHER CANCERS BEFORE IT LIKELY CONTRIBUTES TO A RISK OF COLON AND POSSIBLE OTHER CANCERS. I ARE CONSIDERABLE EVIDENCE SUPPORTS THE ROLE OF HIGH DAIRY COMSUMPTION AND LOWER INTAKES OF CALCIUM, LIKE O PENE AND VITA MINE D IN HUMAN CANCER BUT FINALLY WE STILL HAVE MUCH TO LEARN AND STUDY STUDIES DONE DURING CHILDHOOD AND LUNG STUDIES WOULD BE CRITICAL. THANK YOU. [ APPLAUSE ] >> ONE QUESTION I'VE BEEN WONDER BEING MYSELF FROM THE STUDIES I LOOK AT IN LUNG CANCER, WITH REGUARD TO THE THE OBESITY ASSOCIATED CANCERS IF YOU LOOK AT LUNG CANCER AND ESOPHAGEAL CANCER, OFF THE TOP, SPECIFICALLY, ESOPHAGEAL SQUEAMISH CANCER, THEY'RE BOTH INVERSELY ASSOCIATED WITH BMI, BUT IF YOU DIG DEEPER AND LOOK AT WAIST SER CUM FERENCE, IT'S POSITIVELY ASSOCIATE WIDE RISK AND LUNG AND I'M WONDER FIGURE YOU HAD THE IDEAS ABOUT THIS AND WHAT YOUR THOUGHTS WERE. >> YEAH, I THINK LUNG CANCER OBVIOUSLY IS OVERWHELMINGLY CAUSED BY CIGARETTE SMOKING AND IT'S VERY COMPLICATED BECAUSE SMOKING ITSELF CAUSES WEIGHT AND LUNG CANCER ALSO DOES NOT DEVELOP IN HEALTHY LUNGS. IF YOU LOOK LUNGS OF PEOPLE--SMOKERS WHO DEVELOP LUNG CANCER THEY'RE DAMAGED, INFLAMED--OOPS, EXCUSE ME. THESE PEOPLE HAVE BEEN DISEASED FOR LONG, MANY YEARS, DECADES USUALLY AND SO THAT I THINK WE'RE SEEING A LOT OF REVERSE CAUSATION. WHEN WE LOOK AT LUNG CANCER, IT'S A VERY COMPLICATED RELATIONSHIP TO PULL A PART. >> I HAVE A FEW QUESTIONS FOR YOU. ONE OF THEM WITH CLARIFICATION, YOU SAID THAT FAT OR ANIMAL FAT WAS NOT NECESSARILY CORRELATED HOWEVER INCREASE IN WEIGHT AND MOST OF THE TIME WHEN IS WE THINK OF INCREASE IN WEIGHT, WE THINK OF INCREASING FAT SO I WASN'T SURE IF YOU COULD CLARIFY SOME OF THAT AND THEN AGAIN I WANTED TO KNOW ABOUT SUGARS BECAUSE LIKE, IN CANCERS, WAY BACK IN THE 50S THEY SHOWED THAT YOU KNOW CANCERS TEND--A LOT OF CANCER CELLS OR CANCER ENVIRONMENT, THEY SEEM TO METRICS TAB METABOLIZE AND STUFF LIKE THAT SO I WAS WONDERING IF THAT COULD--IF YOU EVER LOOK AT THAT AND THEN THE THIRD WAS YOU TALKED ABOUT ALCOHOL, BUT THEN THERE ARE STUDIES THAT SAYS THAT WINE IS GOOD TO SOME DEGREE SO I WAS WONDERING IF YOU LOOK ALCOHOL AND THROUGH SOME GRAPE LEAVES IN THERE IF THAT WOULD FIX THAT? [INDISCERNIBLE]. >> LOTS OF QUESTIONS THERE, THERE'S LOTS OF LITERATURE ON BOTH OF THOSE 3 TOPICS BUT FOR FAT AND BREAST CANCER THAT HAS BEEN PART OF THE BELIEF THAT FAT IN A DETAILS IS WHAT MAKES YOU FAT AND I EACH HAD COLLEAGUES SAID YOU CAN'T GET FAT EATING CARBOHYDRATE BECAUSE THE BODY CAN CONVERT KOSH O HYDRATE TO FAT AND I GREW UP IN MICHIGAN AND RURAL COMMUNITY AND FARMERS HAVE KNOWN FOR THOUSANDS OF YEARS WHAT YOU FEED THEM AND GRAINS IF YOU WANT TO FATTEN A ANIMAL UP SO YOU PUT THEM IN A PIN SO THEY CAN'T RUN AROUND AND THEY GET FAT. RESEARCH SHOWED CLEARLY THAT YOU CAN DO RANDOMIZED TRIALS LOOKING AT WEIGHT CHANGE BAH YOU NEED A NEW HUNDRED PEOPLE, YOU NEED DECADES, YOU NEED ON A YEAR OR 2, AND IT'S CLEAR FROM THOSE RANDOMIZED TRIAL RANDOMIZED TRIAL SET THAT FAT IS REALLY NOT A DETERMINANT OF BODY WEIGHT. THE PERCENTAGE OR CALORIES FROM FAT IN THE DISCIPLINARY SET NOT A DETERMINANT. A LOT OF EVIDENCE SUGGESTING IT'S EASIER FOR PEOPLE TO GET FAT ON, LOW CARBOHYDRATE DIETS. IF ANYTHING THAT'S WHAT THE LITERATURE IS SUGGESTING. SO IT IS INTERESTING THAT THE DIET, FAT IN A DIET HAS ALMOST NOTHING TO DO WITH FAT IN THE BODY, WE CAN GET VERY FAT, NONAPOPTOTIC--NOT JUST ON LOTS AND LOTS OF CARBOHYDRATES. SUGAR HYPOTHESIS, WE LOOKEDDA THE THAT AND IN OTHER PEOPLE, THERE'S NOT STRONG SUGGESTION THAT SUGAR PER SE IN A DIET, IT'S SPECIFICALLY RELATED TO CANCER INCIDENCE. BUT HIGH BLOOD GLUCOSE IS NOT RELATED TO SUGAR IN THE DIET, THOSE ARE NOT CONNECTED BUT WE GET MOST--A LARGE PART OF OUR SUGAR FROM STARCH ACTUALLY, AND THEN BLOOD SUGAR, WHICH MAY CONTRIBUTE TO CANCER IS MOSTLY DETERMINED BY INSULIN RESISTANCE, NOT BY WHAT WE'RE EATING NECESSARILY AND CONTROL AND RED WIN I DID A RED WINE IS BENEFICIAL FRENCH PROPAGANDA MACHINE. [LAUGHTER] FOR PARTICULARLY THE CASE HAS BEEN MADE THAT IT'S PARTICULARLY BENEFICIAL FOR CARDIOVASCULAR DISEASE BUT THAT'S BEEN LOOKEDDA THE FAIRLY WELL, OTHER VS LOOKED AT THAT AS WELL, ALCOHOL IS BENEFICIAL FOR HEART DISEASE AND DIABETES BUT FOR CANCER ALCOHOL IT LOOKS LIKE KEEL AND DID DOESN'T MATTER WHERE IT'S COMING FROM, WHETHER FROM--WE LOOKED THAT THE FROM RED WINE AND WHITE WINIVITY ILLEGALSED BEVERAGES AND BEER, THEY ARE SIMILARLY RELATED TO BREAST CANCER AND OTHER CANCERS SO IT'S REALLY, THE ALCOHOL PER SE. AND STUDY VS BEEN DONE ON RISK ASSESSMENTS VERTROL IN ANIMAL MODEL WHICH IS IS REPORTED BENEFICIAL FACTOR IN WHY THE DOSES WE GET IT A COUPLE GLASSES OF RED WINE ARE MINOR COMPARED TO WHAT THEY'VE BEEN USING IN THOSE STUDIES. YOU HAVE TO DRINK A COUPLE GALLONS A DAY TO GET TO THOSE KINDS OF LEVELS. >> I MISSED 1 POINT. DID YOU ALSO [INDISCERNIBLE] HYDROFOALATE, MTH PHENOTYPE, WAS THERE A PROBLEM IN TERMS OF ASSOCIATION WITH ANY [INDISCERNIBLE] CANCER. THE GENETIC ABNORMALITY IN THE FOALATE. >> TO BE CLEAR WHAT WE'RE SHOWING WAS THAT THE--WHAT WE'VE SEEN AND WHAT OTHER PEOPLE HAVE SEEN IS THAT THE HOMOZYGOUS VARIANT OR THE VAL-VAL VARIANT OF THE MTHFR GENE IS RELATED TO LOWER RISK OF COLORECTAL CANCER, I THINK THAT'S A PRETTY ESTABLISHED STRONGLY ESTABLISHED RELATIONSHIP AT THIS POINT IN TIME, AND THAT ITSELF IS BECAUSE THAT GENE ONLY HAVE A FUNCTION OF METABOLIZING FOALIC ACID THAT INDIRECTLY SAYS THAT THE SUBSTRATE FOR THAT GENE FOALATE IS IMPORTANT IN THE ETIOLOGY OF COLORECTAL CANCER, THAT'S THE ARGUMENT BASICALLY AND WE LOOK SPECIFICALLY AT FOALATE INTAKE AND COLORECTAL CANCER AND WE DO SEE QUITE A LONG LAG THAT THERE IS AN INVERSE RELATIONSHIP CONFIRM TAG AND THERE'S QUITE A FEW ANIMAL MODEL WHICH IS SUPPORT THAT. >> THANK YOU, SIR. >> THANK YOU. >> PLEASE JOIN ME IN A ROUND OF APPLAUSE FOR THE DOCTOR. >> [ APPLAUSE ]