GOOD AFTERNOON. AND WELCOME TO THE STARS IN NUTRITION TALK. I'LL SAY A FEW WORDS ABOUT THE LECTURE SERIES, AND THEN INTRODUCE DR. GRAHAM COLDITZ FORMALLY. THESE LECTURES OCCUR EACH FALL AND SPRING, AND THEY FEATURE EXTRAORDINARY CONTRIBUTORS OR STARS IN THE FIELD OF CANCER AND NUTRITION RESEARCH. THE SPEAKERS HIGHLIGHT THE IMPORTANT ROLE NUTRITION PLAYS IN MODIFYING CANCER DEVELOPMENT, AND LECTURES AIM TO FACILITATE INTERDISCIPLINARY INTERACTIONS AMONG IS SCIENTISTS AND CLINICIANS. I'M GOING TO GIVE AN EXTREMELY ABBREVIATED SUMMARY OF HIS POSITIONS AND HIS CONTRIBUTIONS, BECAUSE TO DO OTHERWISE WOULD TAKE AWAY HALF OF HIS SPEAKING TIME AND I WANT TO LEAVE SOME TIME LEFT OVER FOR HIS ACTUAL TALK. HE'S THE PROFESSOR OF SURGERY, PROFESSOR OF MEDICINE AND ASSOCIATE DIRECTOR FOR PREVENTION AND CONTROL AT THE ALVIN J. SITEMAN CANCER CENTER. HE IS THE DEPUTY DIRECTOR FOR THE INSTITUTE FOR PUBLIC HEALTH AT WASHINGTON UNIVERSITY IN ST. LOUIS, SCHOOL OF MEDICINE, AND BARNES JEWISH HOSPITAL. HE'S THE CHIEF OF THE DIVISION OF PUBLIC HEALTH SCIENCES IN THE DEPARTMENT OF SURGERY AT WASHINGTON UNIVERSITY SCHOOL OF MEDICINE, PREVIOUSLY HE WAS A PROFESSOR OF MEDICINE AT HARVARD MEDICAL SCHOOL AND ASSOCIATE DIRECTOR OF THE CHANNING LABORATORY AT THE BRIGHAM AND WOMEN'S HOSPITAL. DR. COLDITZ WAS BORN IN AUSTRALIA, THAT YOU WOULD HAVE NOTICED ANYWAY WITHIN A MINUTE OF HIS GETTING UP TO SPEAK. BUT FOR THOSE OF YOU WHO MISS THE ACCENT, HE WAS BORN IN AUSTRALIA, AND RECEIVED HIS UNDERGRADUATE AND MEDICAL DEGREES FROM THE UNIVERSITY OF QUEENSLAND, HE COMPLETED A MASTER DEGREE IN PUBLIC HEALTH, AND DOCTORATE IN PUBLIC HEALTH FROM HARVARD. HE'S A MEMBER OF THE INSTITUTE OF MEDICINE, AMONG THE MOST HIGHLY CITED MEDICAL RESEARCHERS IN THE WORLD. AND HE'S CURRENTLY A MEMBER OF THE NATIONAL CANCER INSTITUTE, BOARD OF SCIENTIFIC ADVISORS. AT THE SITEMAN CANCER CENTER HE LEADS THE PROGRAM FOR ELIMINATION OF CANCER DISPARITIES, AND THE TRANSDISCIPLINARY RESEARCH IN ENERGETICS AND CANCER, TRAC. HE DESCRIBED THE RISK OF BREAST CANCER WITH USE OF COMBINED ESTROGEN PLUS PROGESTIN THERAPY, AND THE SIGNIFICANT INCRIES IN RISK OF BREAST CANCER WITH USE OF COMBINED THERAPIES. HE HAS MADE A HUGE PUBLIC HEALTH IMPACT IN THAT ARENA, IN ADDITION HE'S DOCUMENTED IN IT PROSPECTIVE DATA, IMPORTANCE OF RISK OF SUBSEQUENT CANCER, AND WITH THAT I WILL LEAVE THE REST OF THE TIME TO GRAHAM. I THINK YOU'LL BE DELIGHTED WITH THIS TALK. PROS APPLAUSE [APPLAUSE] >> WELL, THANK YOU. IT'S A PLEASURE TO BE HERE IN THIS STARS PROGRAM, AND I OPE I CAN DO JUSTICE TO THIS TOPIC THIS AFTERNOON TO REALLY GET AT SOME OF WHAT WE CAN CALL THE DRIVERS FOR BREAST CANCER THAT HAVE CHILDHOOANDED ED A ADOLESCENT ORIGINS, NUTRITION BEING CENTRAL, AND FINISH WITH QUESTIONS BEFORE US. I HAVE NARROW CONFLICTS OF INTEREST, AND WE'LL CONVEY THIS TALK IN THE CONTEXT, A LITTLE BACKGROUND ON WHY WE MAY BE IGNORING EVIDENCE AT THE MOMENT, BUT MOVING THROUGH THOSE BARRIERS TO LOOK AT THE DRIVERS, THE TIME IN LIFE THAT RISK ACCUMULATES, FOCUSING PARTICULARLY ON NUTRITION AND BALANCING CHILDHOOD AND ADOLESCENCE AND AS I SAY FINISH WITH OUR RESEARCH QUESTIONS. THE ISSUE FOR BREAST CANCER THAT I GET SORT OF EXCITED AND PASSIONATE ABOUT IS IN FACT THIS GROWING BURDEN. THE MAJORITY OF CANCER IS DIAGNOSED IN LOW INCOME COUNTRIES OR REALLY THE BLUE PART OF THE CIRCLE THAT THAT PROPORTION IS INCREASING AND THE KEY FACT OUT OF THE RECENT GLOBAL DATA FROM IACC 1.7 MILLION NEW BREAST CANCER CASES DIAGNOSED IN 2012 IN WORLD. SO THAT'S ONE IN FOUR CANCERS IN WOMEN, BREAST CANCER AND WE DON'T HAVE A CLEAR PREVENTION STRATEGY. WE SHOULD AND I HOPE BY THE END OF THIS TALK YOU WILL AGREE WITH ME. SO THE OBJECTIVES AS CIRCULATED REALLY TO MOVE THROUGH THIS UNDERSTANDING OF RISK ACCUMULATION, THE NATURAL HISTORY, IF YOU WILL OF BREAST CANCER DEVELOPMENT ACROSS THE LIFE COURSE, WE LOOK AT CHILDHOOD PREDICTORS AND DIG IN THERE TO UNDERSTAND INTERPLAY OF DIET, GROWTH AND RISK. SO BACK TO THE BURDEN THE OTHER PART OF THE BURDEN IF YOU FOLLOW THE NEW YORK TIMES COVERAGE OF BREAST CANCER IN INDIA, YOU WILL HAVE SEEN IN INDIA WHICH IS NOT CLASSIC LOW INCOME COUNTRY, WOMEN DO NOT HAVE ACCESS TO TREATMENT THAT WE CALL STANDARD IN THE UNITED STATES. SO THE IDEA THAT WE CAN BREATHE OUR WAY OUT OF BREAST CANCER EPIDEMIC IS A NON-STARTER ALREADY IN THE U.S. PERCENT OF TOTAL CANCER CARE IS SPENT ON BREAST CANCER AND THEN WE HAVE ON TOP OF THAT SO MAJOR BURDEN, THAT REALLY WE CAN'T SUSTAIN THIS COST GLOBALLY, SURELY WE SHOULD FOCUS ON PREVENTION. NOW, VOGELSTEIN INVITED ME TO REVIEW EVIDENCE A FEW YEARS AGO ON BARRIERS TO WHY WE'RE NOT PREVENTING CANCER AND WE CAN BOIL THE SAME BARRIERS DOWN TO THE FUNDAMENTAL FOR BREAST CANCER. THERE'S SKEPTICISM THAT CANCER IN GENERAL CAN BE PREVENTED. WE'LL LOOK AT THAT. HER STRUCTURE OF OUR RESEARCH FUNDING THE THEOLOGY OF SCIENCE IF YOU WILL AND THE WAY CONGRESS LOOKS AT THIS, GIVES US A SHORT TERM FOCUS I THINK YOU'LL AGREE CONGRESS WON'T EVEN LET YOU COST OUT BENEFITS BEYOND TEN YEARS. HOW DOES THAT CHANGE THE WAY WE LOOK AT CHILDHOOD AND ADOLESCENT RISK FACTORS. AND THE TIMES ARE WE TYING INTO THE APPROPRIATE TIME IN THE ACCUMULATION OF GENETIC DAMAGE TO ACTUALLY SUCCEED WITH PREVENTION. I HAVE NOT PAID MUST HAVE ATTENTION TO DATA ISSUES LIKE DEBATES AMONG SCIENTISTS, BUT IN THE ENERGY BALANCE WORLD YOU KNOW WE CAN HAVE FIVE EXERCISE PHYSIOLOGISTS AND GET SIX OPINIONS AS TO WHAT'S THE BEST WAY TO MEASURE ACTIVITY THAT LACK OF CONSENSUS UNDERMINES ENERGY AND ENTHUSIASM OF MOVING FORWARD WITH PREVENTION. SO LET'S LOOK AT THE SKEPTICISM. CLEARLY THERE'S DEBATE AMONG SCIENTISTS AND WE SAID DIFFERENT -- SET DIFFERENT STANDARD AS TO HOW MUCH EVIDENCE WE NEED AND DO WE NEED A PATHWAY CLEARLY DEFINED AND VALIDATED BEFORE WE ACTUALLY SAY WE HAVE A PREVENTION STRATEGY. I'LL TALK A FAIR BIT ABOUT IN OUR LESIONS CAN WE ACCEPT PRE-MALIGNANT LESIONS AS AN END POINT FOR PREVENTION TRIALS. DO WE THROW OUT ALL THAT EVIDENCE AS NOT RELEVANT, CAN WE ACCEPT THAT AND ACTUALLY MOVE FORWARD WITH THAT END POINT TO SPEED UP OUR SYNTHESIS OF EVIDENCE FOR PREVENTION PATHWAYS IF YOU START THINKING OF CHILDHOOD OBVIOUSLY PRE-MALIGNANT LESIONS HAPPEN LONG BEFORE WE GET THE CANCER AND WE LOOK AT THAT. I USE THIS SLIDE TO EXUL ACTUALLY HIGHLIGHT THAT YOU CAN GO OUT AND GET GUIDELINES FROM ASCO AND ELSEWHERE, THAT ARE BASED ON DECENT EVIDENCE AND SHOW THERE ARE RECOMMENDED PREVENTION STRATEGIES BILATERAL NEPHRECTOMY, WE MOVE OVARIES WITH BRAC 1 AND 2, WE HAVE AN ACCEPTED HIGH RISK GROUP META ANALYSIS IN JNCI OF THE FOLLOW-UP OF THESE WOMEN, 50% REDUCTION IN RISK FOLLOWING SURGICAL REMOVAL OF OVARIES. TA POSITION FAB AND -- TAMOXIFEN , RANDOMIZED TRIAL EVIDENCE THAT PREVENTION CAN WORK IN PARTICULARLY TAMOXIFEN, IN HIGH RISK WOMEN, OUR OWN DATA FROM THIS IS IT TOOK FOREVER TO GET WOMEN IN THE NURSEs HEALTH STUDY WHO LOST WEIGHT AND KEPT IT OFF. AND WHICH IS ESSENTIAL TO GET THE REDUCTION IN RISK AND WE KNOW POST WHI COMING OUT, FDA AND OTHERS HAVE DOCUMENTED PRECIPITOUS FALL IN PRESCRIBING COMBINATION ESTROGEN PLUS PRO PROPROPROGESTIN. A REDUCTION IN BREAST CANCER IN WOMEN OVER 50 AND THAT IS A SHORT FROM WHI HEARD AROUND THE WORLD, ANALYSIS IN GERMANY, AUSTRALIA, ENGLAND, ET CETERA, DOCUMENTING THE SHIFT IN PRESCRIBING AND THE REDUCTION IN BREAST CANCER INCIDENCE THAT HAPPENED IN COUNTRIES WITH NATIONAL SCREENING PROGRAMS, IT'S NOT A CHANGE IN SCREENING ITS REMOVAL OF THE CARCINOGENIC EFFECT OF COMBINATION ESTROGEN PLUS PROGESTIN. SO BREAST CANCER IS PREVENTIBLE IF WE ACCEPT THIS, BUT THERE ARE OTHER PLACES WE CAN DEBATE CAN WITH PREVENT BREAST CANCER. I WANT -- WON'T DELVE TOO FAR INTO MIGRANT STUDIES AS ONE CLASSIC EXAMPLE. WE'LL SEE LATER TODAY ACTUALLY INFORM STUDIES ON THE TIMING OF DIET AND BREAST CANCER RISK. I WANT TO LOOK WITHIN COUNTRY BECAUSE TO ME THAT IS THE MOST DRAMATIC EVIDENCE THAT ACTUALLY FEEDS TO THE PRESSING NEED TO BETTER UNDERSTAND DIET AND STRATEGIES FOR PREVENTION. I'LL USE KOREA AS AN EXAMPLE. AGE OF MONARCHY BEFORE THE SECOND WORLD WAR, 17, SECOND WORLD WAR FINISHES AND KOREA AS A NATION INDUSTRIALIZES AND NOW IS NCI INDISTINGUISHABLE FROM -- IS INDISTINGUISHABLE FROM ANY CONTIGUOUS STATES, THEY HAVE TOP SCHOOLS SENDING WOMEN TO IVY LEAGUE COLLEGES IN THE UNITED STATES AND THE SECOND MR. WARFIELD: 30 YEARS AGE OF FIRST MENSTRUAL PERIOD PLUM MET SOD IN TO YEARS THEY HAVE DONE LIT REALLY WHAT HAPPENED IN WESTERN EUROPE, THE U.S., CANADA, AUSTRALIA, NEW ZEALAND FROM THE INDUSTRIAL REVOLUTION ON 150 PLUS YEAR IN THE WESTERN WORLD AND 30 YEARS IN ASIA. NOW, THE ECONOMISTS, THE MAJOR SOURCE OF DATA FOR PUBLIC HEALTH, THEY ACTUALLY HAD A COVER STORY FOUR OR FIVE YEARS AGO ON THE FACT THAT KOREA HAD THE LOWEST REPRODUCTIVE RATE IN THE WORLD BY 2004. YES, BACK IN 1960 LIKE OTHER LOW INCOME POPULATIONS WOMEN WERE HAVING SIX BAY BUSINESS ON AVERAGE EACH THAT PLUM METED TO THIS LOW LEVEL AGAIN FASTER THAN WE HAVE SEEN ANYWHERE ELSE AND AS A CONSEQUENCE OF THIS, THE AGE SPECIFIC BREAST CANCER RATES AND I LIKE TO FOCUS ON WOMEN UNDER 50, BECAUSE THAT GETS OUTSIDE OF ANY POTENTIAL SCREENING. AND DETECTION BIAS BUT WE HAVE SEEN RATES FROM 60 TO 130 AND MORE IN A SPACE OF BIRTH COHORTS OF JUST OVER TEN YEARS APART. POWERFUL EVIDENCE WITHIN A COUNTRY WE'RE NOT CHANGING THE GENE POOL, WE CHANGED SOMETHING ABOUT LIFESTYLE AND MAYBE WE CAN BEGIN AND SEE JUST WHAT THAT IS I CONTEND REPRODUCTIVE THESIS EXPLAIN A GOOD PART OF THIS BUT NOT ALL, AND WE CAN HAVE THE EXACT SAME FOR CHINA TODAY, WHERE RURAL CHINESE WOULD HAVE BREAST CANCER INCIDENCE IN 40 TO 49 DOWN TO 60 CASES PER 100,000 AND URBAN CHINESE ARE UP OVER 120 CASES PER 100,000. THIS 134 IS NOT VERY FAR OFF OUR C RATES FOR WOMEN OF THE SAME AGE SO YOU MOVED TO OUR LIFESTYLE INCLUDING REPRODUCTIVE PATENTS AND EDUCATION LEVELS AND YOU CAN GET BREAST CANCER ANYWHERE IN THE WORLD. THE SECOND PIECE ON THE SHORT TERM FOCUS I MENTION ALREADY THE SOCIOLOGY IF YOU WILL THAT WE HAVE A DESIGN OUR STUDIES SO WE GET A SIGNIFICANT RESULT WITHIN FIVE YEARS, THAT CHANGES THE DYNAMIC HOW WE DESIGN STUDIES PREVENTION MAY TAKE MORE THAN FIVE YEARS SO HOW DO YOU THEREFORE STUDY THAT. WE DON'T HAVE A LONG TERM RANDOMIZED TRIAL OF SMOKING CESSATION IN LUNG CANCER THAT I KNOW OF. WE ACCEPT THE SMOKING CESSATION REALLY WORKS TO LOWER LUNG CANCER RISK BUT THE NATURAL HISTORY MAYBE IGNORED TO IDENTIFY A HIGH RISK SUBSET OF THE POPULATION THAT WE CAN GET A SIGNIFICANT FINDING WITHIN JUST FIVE YEARS. THAT SETS UP THE TIMING THAT MOST OF OUR EPIDEMIOLOGIC DATA OVER THE LAST 35 YEARS IF WE'RE THINKING FROM DULL AND THEO'S REPORT ON ENVIRONMENTAL CAUSES, IE NON-GENETIC CAUSES OF CANCER DOMINANT, WE HAD AN EXPLOSION IN EPIDEMIOLOGY OF DIET, NUTRITION, PHYSICAL ACTIVITY, ENERGY BALANCE, HORMONES, ORAL CONTRA SECONDTIVES, ET CETERA, BUT THE VAST MAJORITY OF IT HAS IN FACT LOOKED AT BEHAVIOR AND MEASURES NOT TOO FAR BEFORE THE ACTUAL DIAGNOSIS OF THE CANCER AND AGAIN, HAS US LOOKING UNDER THE LAMP LIGHT FOR OUR KEYS WHEN WE KNOW WE DROP THEM FURTHER BACK, IT'S THE FALLACY OF THE TIME FRAME PUSHING US TO MEASURE EARLY BEFORE THE RECENTLY BEFORE THE CANCER AND ASSUMING THAT THAT TRACKS FURTHER BACK. SO WE HAVE TO FOCUS MORE ON THE ACTUAL BIOLOGY AND PUT OUR ASSESSMENTS IN TO THAT CONTEXT. WE KNOW THE RADIATION REALLY POWERFUL EXAMPLE FOR EARLY LIFE DRIVING THE ADVERSE EFFECT OF EXPOSURE. WE KNOW FROM MORE THAN 50 YEARS OF WORKMEN MENOPAUSE HAS A DRAMATIC EFFECT ON RATE OF RISK ACUTE WE CAN LOOK AT AGE INCIDENCE CURVES TO SEE THAT DOLLAR PUBLISHED IN 1954 MORTALITY DATA FROM THE UK SHOWING THE DRAMATIC CHANGE IN MORTALITY WHEN TREATMENT WASN'T WORKING FOR BREAST AND OTHER FEMALE CANCERS. SO THERE'S SOMETHING ABOUT PRE-MENOPAUSAL YEARS THAT DRIVES RISK AND WE CAN DIG IN ON THAT. IF WE WERE LOOKING AT BREAST CELLS WE KNOW THEY WILL (INAUDIBLE) LOBULAR UNITS AND PROGRESS WITH GROWTH AND PROLIFERATION TO CELL HYPERPLASIA, MORE FOR A TYPICAL HYPERPLASIA WHICH WE'LL CALL VERY CLEAR BENIGN BREAST DISEASE THAT INCREASES RISK OF SUBSEQUENT PROGRESSION UP TO THIS H PATHWAY. WE GET MORE DIVERSITY AND DCIS, DUCTILE CARCINOMA IN SITU, (INAUDIBLE) AND COLLEAGUES AT THE UNIVERSITY OF MEL BORNE HAVE MATHEMATICALLY ESTIMATED FROM A NUMBER OF PARAMETERS THAT THE MEAN INTEGRAL FROM DCIS TO INVASIVE BREAST CANCER IS TEN YEARS SO WE'RE THINKING IF THIS IS TEN YEARS HERE WE HAVE SEVERAL MORE DECADES GOING BACK TO ACTUALLY BE STARTING DOWN THIS PATHWAY MALIGNANCY AND LOOKING AT WHAT THE DRIVERS DOWN HERE, NOT JUST WONDERING CAN WE INTERVENE AT THIS END OF THE SPECTRUM. THE ATOMIC BOMB SURVIVORS CLASSIC DATA, EVERY WOMAN IS TWO BOMBS IN JAPAN BASICALLY IDENTIFY WHERE SHE WAS, THE RADIATION DOSE ESTIMATED FOLLOWED OVER TIME, OVER A THOUSANDS CASES OF BREAST CANCER AND EXCESS RISK PER STANDARD DOSE OF RIDIATION MASSIVELY INCREASED FOR THE WOMEN WHO WERE UNDER 15 AT THE TIME. SO IT MUST BE MORE SENSITIVE TO RADIATION AT THIS STAGE THAN THE WOMEN WHO WERE 40 WHO HAD FAR LESS DRAMATIC INCREASE OR EXCESS RISK FOR THE SAME AMOUNT OF RADIATION. THIS IS OUT THERE PUBLISHED AND READ BY SCIENTISTS AT NCI, AND YET WE TAKE IT FOR GRANTED THAT SEEMS TO IGNORE ITS IMPLICATIONS FOR UNDERSTANDING BIOLOGY AND RISK ACCUMULATION AT THAT EXACT SAME TIME. THE OTHER EARLY LIFE CLUE HERE INCIDENCE FROM COUNTRIES ON THE OTHER HAND THE WORLD, NEATLY STANDARDIZED INCIDENCE AROUND THE WORLD ADJUSTING OUT OF VARYING AGE AT MONARCHY AND SEES THAT THE INCIDENCE RATE IS CLIMBING CONSTANTLY ACROSS LOW AND HIGH INCIDENCE COUNTRIES. HERE WE WE THE CHANGE MUCH SLOWER IN INCREASE AFTER MENOPAUSE THAN BEFORE, AND IMPORTANTLY BEFORE AGE 50, 22 TO 24% OF BREAST CANCER IS DIAGNOSED. NOT ONLY IS RISK ACCUMULATING HERE BUT IF WE WAIT UNTIL WOMEN GET TO 50 OR MENOPAUSE TO START THINKING ABOUT PREVENTION, WE COMMITTED THE WORLD TO SOMEWHERE NEAR A QUARTER OF BREAST CANCER IN DIAGNOSED WITHOUT ANY THOUGHT OF PREVENTION. THE PROGRESSION ACROSS THAT SEQUENCE OF PRE-MALIGNANT LESIONS THE FIRST RISING RATE OF INCIDENCE BEFORE MENOPAUSE ALL CONCURRENT ARE MENSTRUAL CYCLES CYCLING FEMALE HORMONES CELL PROLIFERATION AND EVERY MONTH, THAT IS ACCEPTABLE -- AND OTHERS THAT DESCRIBE THAT IN DETAIL, I WANT US TO TURN TO OTHER FACTORS THAT ARE HAPPENING BACK AT THE FRONT END OF THIS. FROM BIRTH TO FIRST MENSTRUAL CYCLE SO WE HAVE THE RATE OF GROWTH AND WE HAVE THE DIET AND PHYSICAL ACTIVITY AND ENERGY BALANCE IN THAT TIME PERIOD THAT MAYBE HAVING LIFE LONG IMPACT ON CANCER RISK. >> FUNDAMENTAL POINT OF THIS SLIDE IS EPIDEMIOLOGISTS WE TYPICALLY ARE USING AGE AS OUR SORT OF MARKER OF RISK. SCREEN BASED ON AGE, NOT TAKING INTO ACCOUNT ANY OTHER KNOWN RISK FACTORS EXCEPT FAMILY HISTORY. CAN WE DO A USING AGE, I GIVE YOU THE EXAMPLE ONE AGE FROM 60 TO 61, IS NOT GOING TO BE THE SAME AS ONE YEAR OF AGE FROM TEN TO 11 BUT WE SOMEHOW TAKE AGE A YEAR AS A YEAR IS A YEAR. SO THAT SORT OF SETS UP THE QUESTION OF THE PIKE MODEL WHICH HAS ITS ORIGINS IN RICHARD DAHL'S THINKING AND MALCOLM LOOKED AT THE WORLD EPIDEMIOLOGIC DATA BACK IN 1908s AND HE COINED THE TERM -- 80s AND HE COINED IT BREAST TISSUE AGING. HE DOESN'T CALL IT AGE, HE CALLS IT BREAST TISSUE AGING. AND HE SAYS THIS ACTUALLY STARTS AT MONARCHY, THE ON -- MENARCHE AND CONTINUES AT A CONSTANT LEVEL AFTER FIRST PREGNANCY, THE RATE OF TISSUE AGING SLOWS SO BREAST TISSUE ISN'T AGING A YEAR IS A YEAR BEFORE AN AFTER THAT FIRST PREGNANCY CONTINUES OUT AND THEN DROPS IN THE PERIMENOPAUSAL YEARS AND IS SLOWER AFTER MENOPAUSE. AND BECAUSE THE CASE CONTROL STUDIES AROUND THE WORLD SAY LATE AGE AT FIRST PREGNANCY HAT ADVERSE EFFECT, MALCOLM HAS THIS SENTENCE. TO ACCOMMODATE THE HIGHER INCIDENCE WITH LATE FIRST BIRTH WE ADD A CONSTANT REPRESENTING INCREASE IN RISK WITH FIRST FULL TERM PREGNANCY, A LITTLE BUMP AS WE CALL IT. VERY HIGHLY TECHNICAL TERM FROM DR. (INAUDIBLE) AND COLLEAGUE IN SOME OF THESE THINKING. THE ADVERSE EFFECT OF FIRST PREGNANCY. NICK (INAUDIBLE) ARGUED WITH US THIS SHOULDN'T BE A CONSTANT, THE LONGER THE INTERVAL FROM MENARCHE TO FIRST PREGNANCY, MORE CELL DIVISIONS SHOULDN'T PROLIFERATION BREAST AND FIRST PREGNANCY BE WORSE LATE THAN EARLY. THAT IS HIS VIEW AS A BREAST PATHOLOGIST. ACTUALLY MADE SENSE AND IN THIS CASE WAS CORRECT. WE ADJUSTED THE MAGNITUDE OF ADVERSE EFFECT OF FIRST PREGNANCY FOR LONGER THE INTERVAL FROM MENARCHE TO FIRST PREGNANCY. SO WE ACTUALLY TOOK THE MODEL APPLIED IT TO NURSES, ADDED SUBSEQUENT BIRTH, AND FAIR TO SAY THIS LOWERING RATE OF TISSUE AGING AS MALCOLM CALLED IT IS BACKED UP BY ANIMAL MODELS THAT SHOW THE CELL CYCLE IS LONGER AFTER FIRST PREGNANCY, NUMBER OF MOLECULAR CHANGES DESCRIBED IN BREAST CELL (INAUDIBLE) MICE AND ANIMAL MODELS AND WE FOUND THE ADVERSE EFFECT TO FIRST PREGNANCY ONLY AND WE CAN THINK OF THE ACCUMULATION OF THE AREA UNDER THE CURVE AS RISK AT A GIVEN AGE, RISK RISING MOST RAPIDLY FROM MENARCHE TO FIRST PREGNANCY, SLOWER AFTER EACH SUBSEQUENT PREGNANCY AND SLOWER AFTER MENOPAUSE. WE HAVE 9% PER YEAR RISING FROM MENARCHE TO FIRST PREGNANCY, 2.5% AFTER MENOPAUSE IF ANYONE FALLS OUT COLLABORATIVE REANALYSIS OF ORAL CONTRACEPTIVES IN BREAST CANCER, THE RATE OF INCREASE IN POST MENOPAUSAL WOMEN 2.5 THE SAME MENOPAUSE SO WE'RE RIGHT ON TARGET THERE. WE HAVE ALSO GOT THIS INTERVAL MENARCHE TO FIRST PREGNANCY DRIVING THE FIRST PREGNANCY LATER. THIS INTERVAL LONGER, AND THE BUMP GETTING BIGGER. THAT TO ME IS WHERE WE ASK PREVENTION. FROM CHINA TO PUT THIS IN CONTEXT AGAIN WHAT'S DRIVING RISK, WE TAKE THE COHORT STUDY THAT OXFORD HAS GOT 300 WOMEN CHINESE COLLABORATOR, BLOOD IN THE FREEZER, 300,000 WOMEN. THOSE BORN IN 1930 MEAN AGE AT MENARCHE JUST OVER 16 YEAR OF FIRST BIRTH, WOMEN HAVING BIRTH IN 1950, MEAN AGE FIRST BIRTH 19 FOR URBAN. THAT'S BASICALLY THE WOMEN BORN HERE HAVE MENARCHE AT 16, FIRST BIRTH AT 19 SO THREE YEARS TAKE OUTS NINE MONTHS FOR BEING PREGNANT, THAT'S TWO YEARS AND A FEW MONTHS OF MENSTRUAL CYCLES BETWEEN MEME FAR CAN YOU AND FIRST PREGNANCY. YOU FOLLOW -- MENARCHE. METASTASIS 1970, CHINESE NIECE AGE AT FIRST PREGNANCY IS APPROACHING 27, IT'S ALREADY PASSED THROUGH 27 TO CATCH UP WITH THE REST OF WESTERN EUROPE WITH AVERAGING APPROACHING 30 AND SO YOU HAVE EXTENDED THAT INTERVAL FROM MENARCHE TO FIRST PREGNANCY. WHO HAS DATA ON DIET LIFESTYLE ET CETERA IN THIS TIME FRAME. UNFORTUNATELY VERY FEW STUDIES. ONE FINAL PIECE OF THIS ARGUMENT, IF WE PUT ALL OUR RISK FACTORS USING THE MODEL THAT GROWS OUT OF -- AGE AT MENARCHE IS FIXED TERM, AGE FIRST BIRTH ADVERSE EFFECT OF FIRST PREGNANCY HEIGHT IS A TERM. WEIGHT AND UPDATED THROUGH ADULT LIFE. ALCOHOL MENOPAUSE, TYPE OF MENOPAUSE, AGE AT MENOPAUSE, REALLY SEPARATING THOSE FEATURES OUT. POST MEMBER PAUSAL -- BENIGN BREAST DISEASE AND FAMILY HISTORY. BASICALLY CLOSE TO THE ACCEPTED DRIVER RISK FACTORS FOR BREAST CANCER WHEN WE FIT THAT MODEL WE EXPLAIN 76% OF THE EXCESS RISK IN U.S. FIRST CHINESE DATA AND I'M ARGUING WITH YOU TODAY THE REMAINING 25% ARE DYNAMICS OF CHILDHOOD AND ADOLESCENTS THAT WE DO NOT INCLUDE IN A MODEL, MENARCHE AS A FIXED TERM HEIGHT AS A FIXED TERM. HOW BIG YOUR SPURT WAS, WHAT YOU WERE EATING IN CHILDHOOD, HOW MUCH ALCOHOL YOU MIGHT HAVE HAD BEFORE FIRST PREGNANCY, THOSE SORTS OF THINGS THAT COULD BE REALLY KEY SIGNALS TO RISK AND EXPLAIN A BIG PART OF THIS DIFFERENCE. SO LET'S LOOK AT HEIGHT, VELOCITY. CLEARLY WOMEN IN ASIA HAVE GROWN TALLER, HERE IS DATA FROM KOREA TO SHOW OVER 70 YEARS THE POPULATION AVERAGES GOING UP. BUT THINK THE DYNAMIC HERE, THIS IS NOT FIXED. STILL ATTAINING THE HEIGHT JUST BEFORE MENARCHE IS NOW FOUR OR FIVE YEARS EARLIER SO THEY'RE GROWING TALLER AND DOING IT IN A FEW YEARS. SO THE DYNAMIC PART OF THIS PROCESS THAT WE DON'T CAPTURE JUST PUTTING TWO TERMS IN A MODEL IS COMPLETELY IGNORED. FOUR OR FIVE INCHES IN HEIGHT ON AVERAGE AND LAST FOUR YEARS 17 DOWN TO 13 IN WHICH TO DO THEIR GROWING. THEY HAVE NOR CELL GROWTH, GROWING FASTER AND WE POSTULATE LESS TIME FOR ACTUAL CLEANING UP OF ANY DNA DAMAGE THAT MAYBE HAPPENING AS THEY GROW. WE DON'T HAVE A MARKER THOUGH BECAUSE NORMAL BREAST TISSUE IS NOT BIOPSIED SO THAT'S A CLEAR GAP. BUT LIKE THE PROJECT FROM AROUND THE WORLD PROSPECTIVE COHORTS HERE, PROSPECTIVE DATA FROM ONE KOREAN COHORTS CONTROL FOR BREAST CANCER RISK FACTORS, HEIGHT STILL CLEARLY RELATED TO INCREASING RISK OF BREAST CANCER ACROSS THE LIFE COURSE. SO WE HAVE DUG INTO THE HARVARD GROWTH STUDY, THE STEWART STUDY, GIRLS AND BOYS, OBVIOUSLY TODAY WE'RE FOCUSED ON GIRLS, AT THE BOSTON -- LONG WOOD AVENUE, BACK IN THE 1930s AND 1940s, EXAMINED EVERY SIX MONTHS. BIRTH AND ABDOMENS AND THEY CAME BACK EVERY SIX MONTHS AND ALL THOSE MISSION REPEATED AND WHILE THE BABY IS BEING MEASURED, THE DIETITIANS IN BOSTON WERE ACTUALLY DOING ASSESSMENT OF THE MOUSE OF WHAT THE KID HAD EATEN THE LAST SIX MONTHS. SO WE HAVE PROSPECTIVE DATA FROM LONG AGO. WE KNOW WHENEVER GIRL HIT MENARCHE BECAUSE THEY WERE COMING IN EVERY SIX MONTHS AND THEY FOLLOWED THROUGH -- 67 OF THEM BUT IT'SEN AMAZINGLY RICH DATA SET. SO WE APOLOGIZE FOR WHAT LOOKS LIKE A MATRIX THAT (INAUDIBLE) MY COLLEAGUE AND STATISTICIAN IS LOW TECH SO EVERY SIX MONTHS THIS IS (INAUDIBLE) FOR THE HEIGHT OF THE KID AND YOU GROW QUICKLY IN THE FIRST YEARS OF LIFE, SLOW DOWN, YOU HAVE A GROWTH SPURT, BEFORE YOU HIT MENARCHE AND STOP. SO SIMPLE, THIS IS ONE GIRL WE DO THESE FOR ALL 67 OF THEM. WE ALSO LOOK AT THE PEAK HEIGHT VELOCITY, SO VELOCITY IS SLOWING DOWN, THERE'S A GROWTH SPURT, A YEAR IN WHICH THEY HAVE THE GREATEST HEIGHT THEN SLOW DOWN AND STOP. WE CAN THEN USE THAT AS AN OUTCOME FIRST LET'S LOOK AT AGE AT MENARCHE POPULATION AVERAGE 12.8 YEARS, HEIGHT NEGATIVE MEANING THEY HAVE AN EARLIER MENARCHE IF TALLER AT AGE 5. PLUS THAT MEANS TWO YEARS LATER AGE AT MENARCHE FOR ONE STANDARD DEVIATION SHIFT IN PROTEIN AT AGE 3 TO 5. SO DIET AT 3 TO 5 TIME TO AGE AT MENARCHE. AND WE CAN LOOK AT THE LITERATURE SO THIS IS CONSISTENT WITH RANGE OF OTHER STUDIES A LOT OF LITERATURE ON AGE AT MENARCHE IT'S IN A PROSPECTIVE STUDY REPEATED MEASURES OF HEIGHT AND WEIGHT. THAT'S CONSISTENT WITH SUBSEQUENT STUDIES PEAK HEIGHT VELOCITY LESS RECORDED BECAUSE YOU HAVE REPEATED MEASURES OF HEIGHT. GREATEST GROWTH IN A YEAR 14-CENTIMETERS. ON AVERAGE CALORIES DRIVE FASTER GROWTH BEING PLUMPER, BMI NEGATIVE TERMS TO PLUMPER GIRLS ACTUALLY GROW MORE SLOWLY THAN LEAN GIRLS. AND ANIMAL PROTEIN STRONG POSITIVE RELATION. THIS WILL TIE TOGETHER BEFORE WE FINISH. REPEAT THOSE AT AGE TEN EXCEPT THOSE WHO HAD MENARCHE SHORTLY THEREAFTER BECAUSE WE DIDN'T WANT TO GET TO REVERSE CAUSATION WHERE WE'RE CHANGING THEIR DIET AND THE SAME PREDICTORS COME THROUGH. INDICT IN CHILDHOOD IS DRIVING SOME OF THE DYNAMIC THAT THE PACE THAT GIRLS ARE GROWING, THE HEIGHT THEY ATTAIN AND THOSE FOR INTERMEDIATE MEASURES THEMSELVES RELATE TO BREAST CANCER RISK. WHERE WE GET ANIMAL PROTEIN, MILK IS ONE CULPRIT, AND WE SORT OF SHOWN THAT PROSPECTIVELY COLLECTED AND VALIDATED DIET MEASURES ADOLESCENTS GIRLS DRINKING MORE MILK WERE GROWING TALLER. AND THEN DUTCH ECONOMISTS WANTED TO UNDERSTAND HEIGHT. THE DUTCH AT TIME SECOND WORLD WAR REPORTED THE SAME HEIGHT AS THE REST OF WESTERN EUROPE THAT'S NOT THE SAME TODAY SO HE GOT EXCITED AND ACTUALLY WEPT OUT AND DID A SYSTEMATIC REVIEW IDENTIFIED RANDOMIZED AND NON-RANDOMIZED STUDIES AND SHOWS ACROSS ALL THESE DESIGNS THAT WHOLE MILK CONSUMPTION, TALLER GIRLS. ANIMAL PROTEIN, LIKELY CULPRIT AND THERE WERE STUDIES LOOKING AT BEEF CONSUMPTION AND CHILDHOOD AND INCREASED HEIGHT GROWTH eGROWTH. THATJUST TO SUMMARIZE, GERMAN STUDIES CONTEMPORARY UK DATA, CANADIAN DATA, POINTING TO ANIMAL PROTEIN AND MILK. THE FIBER AND VEGETABLE PROTEIN, THE CANADIAN COHORT. FIBER RELATED TO AGE AT MENARCHE ACROSS ALL OF THESE. SO ACTUAL LARGE BODY OF EVIDENCE ON OBESITY LEADING TO EARLIER MENARCHE AND THEN A SMALLER SUBSET DELVING INTO DIET PROSPECTIVELY FOLLOWING GIRLS FOR MENARCHE. DOES THIS STUFF REALLY MATTER? WE TALKED FOR GROWTH VELOCITY REGRESSION CO-EFFICIENTS FROM THE HARVARD GROWTH STUDY APPLIED TO NURSES HEALTH STUDY DATA ESTIMATED FOR EACH WOMAN FOR GROWTH VELOCITY BASED ON ADIPOSITY, AGE AT MENARCHE, ATTAINED HEIGHT AND SO FORTH. AND WE CAN SEPARATE OUT THE TOP 20% OF PEAK HEIGHT VELOCITY COMPARED TO BOTTOM 20 PERSE, WE GET A SIGNIFICANT INCREASE IN PREMENOPAUSAL AND POST MENOPAUSAL BREAST CANCER. WHAT IS GROWING ON PRE-ADOLESCENTS IN GROWTH IS DRIVING RISK IN PRE- AND POST MENOPAUSAL DISEASE. AND WE HAVE SHOWN THE SAME IN THE -- DUTCH COHORT WHERE DIET IS COLLECTED PROSPECTIVELY IN THE GIRLS. THE DANISH WITH THE BEAUTIFUL ABILITY TO LINK HIGH SCHOOL RECORDS AND CANCER REGISTRIES. THEY HAVE HEIGHT AT EIGHT, HEIGHT AT EACH YEAR BUT THEY PICKED OUT EIGHT AND 14, CONTRAST FOR HOW MUCH GIRLS GREW IN THAT TIME FRAME. GIRLS WHO GREW MORE HAD HIGHER RISK OF BREAST CANCER AND THEIR REGRESSION COMES OUT THAT FOR EACH ADDITIONAL FIVE CENTNERS OF GROWTH IN THAT -- CENTIMETER'S GROWTH IN THAT SIX YEAR PERIOD SIGNIFICANT INCREASE IN BREAST CANCER BEFORE AGE 50 AND SIGNIFICANT INCREASE AFTER AGE 50. NUTRITIONAL STAGES ENERGY BALANCE FACTORS THAT WERE SERIOUSLY INTERESTED IN, NOT JUST IN NURSES BUT AS EUROPEAN DATA EARLY LIFE GROWTH DRIVING BREAST CANCER RISK. THE FLIP SIDE OF THIS IN CHILDHOOD ADIPOSITY IN BREAST CANCER THAT HAVE BEEN USED IN A NUMBER OF STUDIES CONSISTENTLY SHOW THE PLUMPER GIRLS AT FIVE AND TEN HAVE LOWER RISK OF BREAST CANCER FOR LIFE AND WE KEEP SCRATCHING OUR HEAD SAYING THAT WHAT'S THE MECHANISM, HOW DOES THIS MAKE SENSE (INAUDIBLE) LOOKED AT THIS IN PART FOR MOLECULAR SUBTYPES, DATA RECENTLY PUBLISHED IN THE SAME INCLUDING MORE MORE RECEPTOR STATUS DATA. ADIPOSITY BEFORE AGE 10 PROTECTING AGAINST ALL OF BREAST CANCER IS IT IN FACT OPERATING GROWTH VELOCITY FACTOR SINCE OBESITY SLOWS THE BRAIN WHICH GIRLS GROW THOUGH IT CLEARLY LEADS TO EARLIER MENARCHE. IF WE PUT IT IN THE MODEL WE'RE NOT CAPTURING THAT GROWTH AND IF THIS ALL HOLDS TOGETHER HOW CAN WE THINK ABOUT DIET IN CHILDHOOD CLEARLY OBESITY IS NOT A PREVENTION STRATEGY FOR DISEASES BUT WHAT IS IT TELLING US ABOUT PATHWAYS MECHANISMS AND STRATEGIES. SO WE WEPT BACK AND PUT BODY MASS INDEX REGRESSION AN INVERSELY RELATED TO PEAK HEIGHT GROWTH VELOCITY SO THERE IS POTENTIAL THAT THIS IS A PATHWAY THROUGH WHICH ADIPOSITY AT FIVE AND AT TEN LOWERING THE RISK. THESE THINGS ARE HAPPENING WAY DOWN HERE. HOW HOW ARE THEY IMPACTING THESE PRE-MALIGNANT LESIONS, WHAT ARE THE MARKERS WE MIGHT BE STUDYING HERE. UNANSWERED QUESTIONS. MY FIRST RO-1 WERE FUNDED, JOE PATEL CALLED AND MENTIONED THERE WOULD BE AN RFA, JOE WAS RIGHT. WE RESPONDED TO THE RFA AND WE WERE FUNDED BACK IN '87 TO PROSPECTIVELY IN MORPHOLOGY PRE-MALIGNANT LESIONS SUBSEQUENT RISK OF BREAST CANCER WE GET A RELATIVE RISK OF .8 FOR CHANGES AN ATIPIA, WE GET A WE GET BIG RISK OF 3 TO 5. I VIEW MAYBE THESE ARE BIG ENOUGH PREDICTORS ON THAT PATHWAY BACK HERE WE CAN USE THESE AS END POINTS OF STUDIES OF ADOLESCENT DIET RATHER THAN WAITING 40 YEARS UNTIL WOMEN GET BREAST CANCER. SO IN NURSES TOO WE GOT FUNDING TO HAVE CENTRALIZED PATHOLOGY REVIEW OF THE BENIGN LESIONS, WE HAVE WE HAVE HIGH SCHOOL DIET RECALL BY WOMEN PARTICIPATING IN NURSES TWO AND IN OUR GUTS COHORT THE DAUGHTERS OF NURSES 2 OVER 6,000 GIRLS REPORTING THEIR DIET ANNUALLY IN '96, '9 #, '98 SO AVERAGE AGE AROUND 12.8 WE VALIDATED THAT AND SO WE CAN LOOK PROSPECTIVELY HERE TO MAYBE CONFIRM OR REFUTE STUDIES BASED ON RECALL OF HIGH SCHOOL DIET EVEN IF WE'RE NOT USING THAT DATA PROSPECTIVELY. ALCOHOL. CARCINOGEN, CLASSIFIED AS SUCH BY IACC, CRITERIA ALL SET, AT LEAST THE SCIENCE IS NOT THE BEHAVIOR. SO WE HAVE LOOKED AT THE PROLIFERATIVE LESIONS. IN FACT THE BASELINE QUESTION ON THIS IS ASK WOMEN WHAT THEY WERE DRINKING AT AGE 18 TO THE 2. -- 22. SO WE HAVE PERSPECTIVE DATA, CENTRAL PATHOLOGY REVIEW, DOUBLING RISK OF SUBSEQUENT BREAST CANCER. WE THEN DEVILED FURTHER INTO THIS SAYING MAYBE JUST 18 TO 22 BUT CAN WE ACTUALLY STRATIFY BY HOW LONG THE INTERVAL IS FOR MENARCHE TO FIRST PREGNANCY. FOR PROLIFERATIVE LESIONS, THAT INTERVAL FROM MENARCHE TO FIRST PREGNANCY MORE THAN TEN YEARS, SIGNIFICANT INCREASE IN RISK SHORTER INTERVAL, ALCOHOL NO INCREASE IN RISK. SAME COHORT IN BASIC BREAST CANCER, LONGER INTERVAL MORE INCREASE IN RISK SHORTER INTERVAL NO SIGNIFICANT INCREASE IN RISK. SO THERE'S THE LENGTHENING INTERVAL, THE MORE CHANCE TO ACCUMULATE RISK IN A KNOWN CARCINOGEN IS CARRYING WHAT PARTS LIFESTYLE COULD COUNTER THIS. DIET PHYSICAL ACTIVITY, WHICH PARTS TO DIET. KEY UNANSWERED QUESTIONS BECAUSE WE'RE NOT GOING TO GO BACK TO PROHIBITION AND HAVE EVERYONE UNDER 30 STOP DRINKING LAST TIME I CHECKED, HIGH SCHOOLGIRLS ARE DRINKING MORE THAN HIGH SCHOOLBOYS. COLLEGE GIRLS ARE DRINKING AT LEAST AS MUCH AS THEIR MALE COUNTER PARTS. WHAT ARE THE PREVENTION STRATEGIES HERE AND AROUND THE WORLD AS WOMEN ARE DRINKING MORE ALCOHOL. CAN VEGETABLE, IS IT FIBER, IS IT SOY, IS IT PROTEIN, HARD TO DISENTANGLE AND DIFFERENT STUDIES REPORTED DIFFERENT FACTORS TO REMIND YOU THAT SOY INTAKE IN THE U.S. IS OFF THE SCALE, HELLO, COMPARED TO THE ASIAN INTAKE. AND SO RATHER THAN LOOKING AT U.S. DATA WE CAN LOOK AT ASIAN MIGRANTS, AND (INAUDIBLE) GOING BACK AND REALLY DELVING INTO DIET OF THE CHILDREN OF WOMEN WHO MIGRATED TO HAWAII AND THE U.S.. AND HIGH INTAKE EVEN IF I CAN'T SPELL, HIGH INTAKE IN CHILDHOOD AND POWERFULLY STRONGER PROTECTION THAN LOW INTAKE, SOME PROTECTION FOR ADOLESCENT INTAKE AND SOME FOR ADULT, THE SIGNAL LOOKS STRONGER FOR CHILDHOOD SOY INTAKE. IF WE GO TO THE SHANGHAI WOMEN'S COHORT, WE BASICALLY AGAIN SEE A STRONGER SIGNAL FOR CHILDHOOD AND ADOLESCENT PROTECTION WITH HIGH INTAKE SO ACROSS ADOLESCENT LOW AS THE REFERENCE FOR HIGH INTAKE IN ADOLESCENCE, INDEPENDENT OF ELSEWHERE BEING PROTECTIVE. SO WE ACTUALLY ABLE TO SEPARATE OUT SOY PROTEIN, FIBER THAT MAY GO INTO THAT, IN NURSES 2 WE ACTUALLY HAVE PROSPECTIVE CASES ACCRUED AFTER THE WOMEN REPORTED HIGH SCHOOL DIET. WE SEE SIGNIFICANT TRENDS LOWER RISK WITH INCREASING FIBER I HAVE BEEN TAKE, TOP 20% OF WOMEN. 29-GRAMS OF FIBER A DAY, LESS THAN 15. I CAN SHOW YOU STATIN PERSISTS WHETHER IT'S FRUIT, VEGETABLE, HOW WE DIVIDE UP FIBER WE CAN'T REALLY TEASE OUT ANYTHING OTHER THAN FIBER. SIGNIFICANT REDUCTION IN RISK OF THE PROLIFERATIVE LESIONS. SO THEN WE WENT BACK TO WHERE WE HAVE THE PROSPECTIVE COLLECTION OF DIET DURING AD LESS SENSE AND WOMEN BEING FOLLOWED INTO 20s AND 30s AND REPORT BENIGN BIOPSIES. AND BACK IN THIS ANALYSIS WE HAVE SEEN PEANUTS WERE INVERSELY RELATED, THAT DIDN'T MAKE A LOT OF SENSE. THAT WAS QUESTIONS IN OUR NEXT ANALYSIS, COULD WE ACTUALLY REPLICATE THE PEANUT FINDING. SO WE HAVE GOT PEANUT BUTTER, BAGS OF PEANUTS, THEY'RE SIGNIFICANTLY INVERSELY RELATED TEN MORE YEARS LATER TO RISK OF BENIGN BIOPSY. WE HAVE TOTAL SERVINGS OF VEGETABLES AND FIBER. THE KEY HERE, ANY WAY WE LOOK AT THESE SOURCES FOR VEGETABLES, WE GET A SUGGESTION OF INVERSE RELATION WHEN WE LOOK AT SERVINGS PER DAY OF PEANUT PEANUT BAGS OR BUTTER, BEANS LENTIL SOYBEANS AND (INAUDIBLE) SO SOURCES OF VEGETABLE PROTEEN WE GET A SIGNIFICANT REDUCTION IN BENIGN BREAST DISEASE IN THE PROSPECTIVE ANALYSIS PER SERVING. SO THIS IS INTAKE AFTER OR AT THE TIME OF MENARCHE, AVERAGE RECORDING HERE AT 12.8 SO WE'RE NOT TALKING BETWEEN AGE 5 AND 10 BUT PRETTY CLEAR HINT THAT THERE COULD BE SOMETHING SUBSTANTIAL IN THE VEGETABLE PROTEIN. PROTEIN, WHAT'S THE PROTEIN DOING, AGES MARKERS FOR MORE FIBER, HOW DO WE DISENTANGLE THAT IF WE DON'T HAVE AN INTERMEDIATE END POINT. WHAT ARE WE GOING TO LOOK FOR, IF WE DO A FIELDING STUDY TO ACTUALLY UNDERSTAND THIS PATHWAY. BUT IF WE GOT MORE THAN A 50% REDUCTION IN RISK OF BENIGN LESION SURELY THIS IS WORTH PURSUING TO REALLY UNDERSTAND HOW MODIFYING DIET MIGHT DRAMATICALLY CHANGE RISK. SO WE HAVE TO SUM UP, WORK WITH US TO SYSTEMATICALLY REVIEW AND THEN COMBINE THREE STUDIES OF OF FIBER INTAKE AND BENIGN BREAST DISEASE OR BREAST CANCER AND WHILE THERE'S VARIATION AMONG THEM THE REALITY IS WE END UP WITH SIGNIFICANT COMBINED BENEFIT. THEN WE TURN TO COLLEAGUES IN ONTARIO WHO HAVE DONE A NICE POPULATION CASE CONTROL STUDY UP IN CANADA. AND CASES AND CONTROLS AND SUPPLEMENTARY QUESTION TO RECALL THEIR ADOLESCENT DIET, DAYTIME REALLY INTERESTED IN PHYTOESTROGENS AND SO FORTH. I HAVE NEVER PUBLISHED ON ANYTHING ELSE IN THIS DATA SET ARE YOU INTERESTED IN SHARING DATA SO WE'RE GOING GET APPROVAL. WE GET THE DATA SET. HIGH PARTICIPATION. THEY WERE CONCERNED 55 FOOD ITEMS WAS A COMPLETE DATA ASSESSMENT, IT'S 55 MORE FOOD ITEMS THAN ANYONE ELSE HAS WHEN YOU LOOK AROUND THE WORLD, GUESS WHAT WE SEE, FIBER NOT A VARIABLE CONTROLLING FOR RISK FACTORS. IN PROTECTION WITH HIGH DOSE LOW QUINTILES OF FIBER VEGETABLE PROTEIN AN NUTS. WE CAN'T DISENTANGLE WHICH IT IS BUT THIS IS A SIGNAL THAT FOR INVASIVE BREAST CANCER IN A POPULATION BASED CASE CONTROL STUDY, CONFIRM IT IS CANCER WHAT WE SEE FOR PRE-MALIGNANT LEAGUES THAT THERE'S SOMETHING IN THE ADOLESCENT VEGETABLE FIBER PROTEIN THAT LOOKS POWERFULLY BENEFICIAL FOR BREAST KAREN RISK REDUCTION. AND THEN A LITTLE BIT RELATED CAROTENOIDS TO COMBINE PROSPECTIVE BLOOD SAMPLES FROM ACROSS COHORTS OF WOMEN AND SHE LOOKED AT EACH OF THE CAROTENOIDS AND I'M REALLY FOCUSED ON TOTAL CAROTENOIDS, SIGNIFICANT TREND PROTECTION WITH HIGHER TOTAL CAROTENOIDS IN THE BLOOD. WE CAN THEN GO TO GUTS AND AGAIN LOOKING IN THE ADOLESCENT FOOD BY FOOD BY FOOD REPORTING AND CALCULATE THE CAROTENOID INTAKE AND AGAIN SEE AN INVERSE RELATION. IS THIS JUST MEASURING THE SAME FOODS THAT DRIVE VEGETABLE PROTEIN AND FIBER, PROBABLY SO MAYBE IT'S NOT THE CAROTENOID BUT THERE'S A QUESTION HOW DO WE DISENTANGLE VEGETABLE PROTEIN FIBER CAROTENOIDS IN THE CHILDHOOD EARLY ADOLESCENCE IN TERMS OF CANCER RISK. AND WHILE THIS IS GOING ON IN THE U.S. AND CANADA IN TERMS OF OUR STUDIES, CHINA'S DIET IS CHANGING DRAMATICALLY. TOTAL ANIMAL SOURCE OF FOODS, ENERGY INTAKE, FROM 1991 TO 2000, 2011, NATIONAL CHINESE SURVEY DATA, CHILDREN 2 TO 18 HUGE INCREASE IN ANIMAL PROTEIN, NEW ZEALAND HAS ALMOST BUILT A PIPELINE TO SHIP MILK TO CHINA. THEY'RE SENDING CHEESE AND MINIMUMK WHEN I WAS A KID IN NEW ZEALAND SAYING MILK AND DAIRY BACK TO ENGLAND HAND REFRIGERATED SHIPPING WAS A HUGE STEP FORWARD FOR THEM. NOW, THEY'RE SENDING THAT IN AUSTRALIA'S MAJOR EXPORT FOR WINE, NO LONGER THE U.S., CHINA, THERE ARE MORE MILLIONAIRES IN CHINA THAN THERE ARE AUSTRALIANS IN AUSTRALIA. SO PEOPLE ARE RACING AFTER IT IN TIME ZONE BUT THIS IS ADOLESCENT DIET, THEY HAVE WESTERNIZED THEIR DIET. THE COURSE GRAINS FIBER PLUM MET FROM 87 TO 25-GRAMS DAILY. AND 25% REDUCTION IN LEGUMES SO VEGETABLE PROTEIN COMING DOWN AND WE'RE LEFT WITH THIS AS THEY WESTERNIZE AND REPRODUCTIVE PATENT CHANGES CANCER RATES GO UP. SO WE HAVE SOME CROSS DATA THAT IS A LITTLE BIT LATER IN PREMENOPAUSAL, I WANT TO HIGHLIGHT ONGOING ANALYSIS AND THE CHALLENGE HERE WE DEALT WITH, WE HAVE WEIGHTED AGE (INAUDIBLE) WE THEN UPDATE WEIGHT EVERY TWO YEARS IN COHORT PARTICIPANTS SO WE CAN BREAK WEIGHT GAIN INTO TWO COMPONENTS. LONG TERM WEIGHT GAIN FROM 4 YEARS AGO, SHORT TERM FROM 4 YEARS TO TODAY AND RISK OF BREAST CANCER THE NEXT TWO YEARS AND AFTER MESSAGE HERE, COMES THROUGH WEIGHT GAIN BIGGER IN PRE-MENOPAUSAL YEARS, BIG WEIGHT GAIN, SIGNIFICANT INCREASE IN RISK OF PRE-MENOPAUSAL BREAST CANCER ENERGY BALANCE IN PRE-MENOPAUSAL YEARS CAN BE DRIVING PRE-MENOPAUSAL BREAST CANCER, IT'S RAPID, IT'S NOT ESTROGEN IN MY BOOKS BUT PROBABILITY INSULIN OR OTHER PATHWAY OVERALL PRE-MENOPAUSAL POST MENOPAUSAL BREAKING IT DOWN, BMI UNDER 25 NORMAL WEIGHT CLEAREST SIGNAL FOR THIS SHORT TERM WEIGHT GAIN INCREASING RISK OF PRE-MENOPAUSAL BREAST CANCER SO ALL DAMAGES ISN'T OVER WITH, FIRST PREGNANCY, WE HAVE THIS INTERVAL FROM MENARCHE TO FIRST PREGNANCY. WE MAY TAKE THE DATA TO THINK ABOUT PLANT BASED DIET, LIMITING ALCOHOL BEFORE FIRST PREGNANCY, SOME ENERGY BALANCE ISSUE LIKE PHYSICAL ACTIVITY AND WE HAVE TO THINK OF THIS IS AVAILABLE FOR THE WHOLE WORLD, HOW DO WE MOVE FROM COVER OF SCIENCE TO PEOPLE ACTUALLY ADOPTING PLANT BASED DIET, I THINK THAT'S WIDE OUT THERE, AND THE FACT THAT TIMING MATTERS AND FRAMEWORK FOR LIFT WITH HERE ASK ME ASKING WHAT CAN INTERMEDIATE MARKERS CAN WE GET THE CONSENSUS WE CAN USE INTERMEDIATE MARKERS OR ARE WE ACTUALLY MISSING THE OPPORTUNITY TO UNDERSTAND HOW CHILDHOOD AND ADOLESCENT DIET NOT ONLY MAYBE DRIVING CURRENT RISK BUT COULD BE MODIFIED TO PROTECT AGAINST SOME OF THE NATURAL ISSUES THAT WE'RE NOT GOING TO TURN AROUND, INCREASE LENGTH OF THE INTERVAL FROM MENARCHE TO FIRST PREGNANCY IS A GOOD THING FOR WOMEN IN THE WORLD, IT'S MADE THE WORLD ACTUALLY GET TO WHERE IT IS IN TERMS OF POPULATION CONTROL AND EDUCATION FOR WOMEN. THESE ARE NOT GOING TO TURN AROUND. SO SURELY IT BEHOOVES US TO UNDERSTAND WHAT LIFESTYLE FACTORS COULD COUNTER SEEN THE ADVERSE EFFECT OF THE LATER FIRST PREGNANCY. FIRST QUESTION, CAN WE STUDY THIS IN ANIMALS OR HUMANS OR BOTH CONCURRENTLY AS TRICK IS TRYING TO DO AT THE MOMENT, ONE OF THE MARKERS -- WHAT ARE THE MARKERS GOING TO BE, IS IT DIET, IS IT PHYSICAL ACTIVITY, A COMBINATION OF BOTH WHAT CHANGES DRIVE THAT ADVERSE EFFECT OF FIRST PREGNANCY. SINCE WE'RE NOT GOING TO CHANGE THE AGE PRE-DISPOSITION TO THAT ADVERSE EFFECT. CAN WE CHANGE 9% TO 4 1/2% RATE OF INCREASE PREGNANCY BY MODIFYING DIET PEAK HEIGHT VELOCITY, IF WE BUY THAT REPLICATE IT IN EUROPE OBVIOUSLY NO RANDOMIZED CONTROL TRIAL, I DON'T THINK IT WILL BE DONE TO LOOK AT PEAK HEIGHT VELOCITY BUT MAYBE IT COULD BE. THEN ARE WE COMFORTABLE WITH THAT AS END POINT FOR INTERVENTIONS EARLIER IN LIFE AND WHAT IS IT TELLING US, IS IT RELATES TO BREAST DENSITY, OTHER MARKERS IN THE BREAST, I DON'T THINK WE HAVE MUCH CLUE AT THE MOMENT. BUT AGAIN I THINK THERE'S HUGE POTENTIAL TO UNDERSTAND RELATIONS PATHWAYS MECHANISMS AND BETTER INFORM PREVENTION STRATEGIES. AT THE MOMENT WE HAVE BEEN STUDYING THE GROSS MORPHOLOGIC FEATURE, PROLIFERATIVE BENIGN LESIONS AN ADOLESCENT DIET WE HAVE THE -- GO TO STUDIES OF CHILDHOOD DIET, PREMENARCHE, STUDIES OF 67 GIRLS AND 68 BOYS STUDYING FOR GROWTH. YOU DON'T GET ENOUGH PRE-MALIGNANT LESIONS IN 67 GIRLS TO HAVE AN END POINT. WHAT ARE THERE IMAGING WAYS NOT RADIATION RELATED, WHAT ARE THE WAYS THAT WE CAN DISEPITANGLE ENERGY BALANCE, DIET VEGETABLE PROTEIN FIBER AN THESE CHANGES THAT ARE PART OF SETTING WOMEN ON A PATH TO SUBSTANTIALLY INCREASED LIFETIME RISK OF BREAST CANCER. SO WITH THOSE QUESTION, I'LL STOP AND THANK YOU FOR YOUR ATTENTION AND TAKE QUESTIONS. PAUSE PLUS >> QUESTIONS FROM THE AID [APPLAUSE] >> QUESTIONS FROM THE AUDIENCE? FASCINATE DATA THAT YOU SHOWED, (INAUDIBLE) DISCUSSION TO NEVER SMOKERS BECAUSE THERE'S A STRONG (INAUDIBLE) AND SOME OF THEM THE RATE OF INCREASE MATCHES AND IS BETTER THAN OUR OWN RATE OF INCREASE IN LIFE EXPECTANCY. SO THE QUESTION IS, AND THOSE ARE THE COUNTRIES WITH FIRST, IS IT BECAUSE IN SPITE OF A NET HARM OF GROWTH RATE THERE'S AN IMPROVEMENT? OR IS THERE A NET BENEFIT (INAUDIBLE) >> SO THAT'S A GREAT QUESTION. AND I JUMP FIRST TO HEART DISEASE WHERE HEIGHT SEEMS TO BE RELATED TO THE SIZE OF YOUR CURRENT (INAUDIBLE) BEING TALLER WAS PROTECTIVE FOR HEART DISEASE. TRADE OFF CAUSE OF MORTALITY, I SHOW BREAST CANCER BUT HEIGHT IS RELATED TOCORON CANCER, -- TOCOLON CANCER, PROSTATE CANCER, ALL THOSE OTHER ORGANS ARE FULLY DEVELOPED, LONG BEFORE MENARCHE, WHEREAS BREAST ACTUALLY HAS FINAL MOLECULAR DIFFERENTIATION WITH THAT FIRST PREGNANCY AND LACTATION. HEIGHT RELATED TO THE CANCER AND CLEAR DATA ON HEIGHT PROTECTIVE AGAINST HEART DISEASE. SO I HAVE HAVEN'T LOOKED AT THE RISK BENEFIT TRADE OFF BUT I PREDICT THE CARDIOVASCULAR BURDEN TRUMPING CANCER, AT LEAST AS COUNTRIES MOVE FULLY THROUGH THE ECONOMIC TRANSITION AND TAKE UP SMOKING -- THE NON-SMOKER, I'M NOT SO SURE. >> GREAT QUESTION AND SOMETHING THAT COULD BE ADDRESSED WITHIN THE COHORT OF THE TRADE OFF TOTAL MORTALITY AND CAUSES OF DEATH IN MEN AND WOMEN. WHETHER IT'S AARP OR ANY OTHER COHORT, THEY ACTUALLY HAVE THE HEIGHT DATA IF NOT THE FULL TRAJECTORY. >> ARE FROM ANY DATA THAT ALLOW YOU TO SEPARATE BREAST CANCER BY TYPE WHETHER BASAL CELL OR LUMINAL IRB OR EVEN TRIPLE NEGATIVE? >> RIGHT. SO FROM THE ADOLESCENT WE'RE STRUGGLING TO HAVE ENOUGH CASES TO FULLY BREAK OUT SUBTYPES, CERTAINLY THE ADULT PREMEMBER PASTAL BREAST CANCER FRUIT AND VEGETABLE CONSUMPTION IS LOOKING PROTECTIVE AGAINST ER NEGATIVE PR NEGATIVE DISEASE. THAT I THINK IF IT HOLDS UP MIGHT FIT SEQUENCE HERE THE CHALLENGE AT THE MOMENT THAT MOST OF THESE PRE-MALIGNANT LESIONS WHEN LOOKING EVEN IN COMBINED DATA OF NURSES AND NURSES CONFIRM PROLIFERATIVE PRE-MALIGNANT LESIONS, THEY DON'T DIFFERENTIATE RISK FOR RECEPTOR STATUS. THEY ACTUALLY PREDICT BILATERAL RISK. YOU HAVE HAD A BREAST BIOPSY WHICH SORT OF IS COMPLETE TREATMENT, RIGHT? EQUAL RISK AFTER IT WHICH IS SAYING IT'S SORT OF A ROOT CAUSE OF THE DRIVER, IT'S NOT JUST AS ONE MOLECULAR CHANGE THAT WENT TO PROLIFERATIVE BENIGN BREAST DISEASE AND RISK OF PRE-IS NORMAL, LIKE THE COLON YOU TAKE OUT THE POLYP AND YOU'RE AT RISK OF POPPING ANOTHER POLYP AND GETTING COLON CANCER, NOT THE REST OF THE MUCOSA IS COMPLETELY MOLECULAR CHANGES. (OFF MIC) (INDISCERNIBLE) >> SO WHEN YOU LOOK AT THE EFFECT OF THE EARLY LIFE DIET FACTORS, BBD OR BC RISK. HOW DID YOU DISTINGUISH THE TIMING OF THE EXPOSURE AND THE LENGTH OF THE EXPOSURE BECAUSE THEORETICALLY FOR THOSE EXPOSED AT VERY EARLY AGES AND SO THEY PROBABLY WERE EXPOSED FOR LONGER PERIOD OF TIME. >> AND THAT DISENTANGLING CHILD HOOD ADOLESCENT AND ADULT, IT'S EASY FOR ALCOHOL BECAUSE IT ONLY STARTS LATER BUT THE FIBER VEGETABLE PROTEIN WE DON'T HAVE RICH ENOUGH DATA IN ANY OF THE INDIVIDUAL STUDIES TO HAVE HAD SORT OF PRE-MENARCHE DIET, HIGH SCHOOL DIET AND ADULT DIET, ALL RECORDED ON THE SAME WOMEN TO BE ABLE TO DISENTANGLE THE CORRELATION. BUT IT'S NOT GOING TO BE ABSOLUTE CORRELATION. IT'S GOING TO HAVE VARIATION. WE KNOW THAT IN THE U.S. A LOT OF GIRLS MOVE TO VEGETARIANISM IN HIGH SCHOOL WHO PROBABLY HAD A MORE TRADITIONAL DIET WITH MORE MILK AND DAIRY AND ALL THESE THINGS IN CHILDHOOD. SO THERE ARE PLACES IN THE U.S. WHERE WE MAY PICK UP SOME OF THESE GROUPS BUT TO DATE NO ONE HAS GOT A DATE SET TO REALLY DISENTANGLE IN -- WHEN WE LOOK AT ADOLESCENT WE CAN ALSO CONTROL FOR ADULT, WE KNOW TA THERE'S ONLY A CORRELATION OF .3 OR .4 BETWEEN ADOLESCENT AND ADULT, SO WE CAN DO SOME DISENTANGLE, WE DON'T HAVE IN THE COHORTS FOR THE DIET BEFORE MENARCHE AND SOME OF THE BIG STUDIES, THE UK CONTEMPORARY STUDY MAY HAVE 2,000 GIRLS FOLLOWED FROM BIRTH, 2000 GIRLS WON'T GET YOU MANY BREAST CANCERS IF YOU FOLLOW THEM UNTIL THEY'RE ALL DEAD. THE CANADIAN STUDY OF FIBER AND AGE MENARCHE HAD SOMETHING LIKE 670 GIRLS. THROUGH THE CANADIAN SYSTEM TO FIND OUT SOMEWHERE IN THE FUTURE IF ANY GET BREAST CANCER BUT THEY'RE NOT UPDATING WITH ADULT DIET TO KNOW HIGH FIBER PRE-MEN FAR CAN YOU TO LOTS OF MID LIFE DOES THAT CHANGE RISK. ISSUE OF SAMPLE SIZE AND REPEATED MEASURES. THAT WE DON'T HAVE. UNLESS WE'RE WAITING FOR LOTS OF GENERATIONS PEOPLE STARTED BIRTH COHORTS OF DIET IN FINLAND WHICH DOESN'T GET YOU MUCH. IF DIVERSITY OF COURSE, UNLESS THEY'RE USING PRE-MALIGNANT LESIONS THERE ARE FEW PEOPLE IN THIS ROOM STILL AROUND ANALYZING DATA TO HAVE BREAST CANCER CASE SORT OUT WAYS IN OUR BOOKS TO UNDERSTAND THIS ROLE OF DIET AND GET TO ENOUGH CONSENSUS ON WHAT END POINTS WE CAN USE SO WE DON'T GO BACK TO CAUSE NUMBER 6 IF THERE'S LACK OF CONSENT SO WE DON'T GO ANYWHERE WITH PREVENTION. >> THANKS, GRAHAM, THAT WAS A GREAT PRESENTATION. OFF THE WALL QUESTIONS. THE WAY WHICH PEOPLE CONSUME VEGETABLE PROTEIN OBVIOUSLY HAS CHANGED IN ANOTHER WAY. WHICH IS VEGETABLES ARE TREATED WITH PESTICIDES AND PESTICIDES OF COURSE PESTICIDE USE IS DIFFERENT ACROSS COUNTRIES AND MAKE INTERESTING COMPARISONS THERE. WE'RE IN THE ORGANIC FRUIT AND VEGETABLER RA, THERE'S CONTROVERSY ABOUT WHETHER ORGANIC FRUITS AND VEGETABLES ARE HEALTHY WHETHER THEY'RE ORGANIC. SO WHATE TENT HOW LONG WE NEED TO WAIT TO ASSESS HOW THOSE FACTORS ARE MODERATING THE EFFECTS OF EATING FRUITS AND VEGETABLES IN BREAST CANCER RISK? >> (INAUDIBLE) TALK ABOUT THE PROS AND CONS OF PESTICIDES, AND I'M NOT GOING TO GO THERE, BUT THE BOTTOM LINE IS WE HAVEN'T DONE MUCH TO DISENTANGLE THE GROWING OF OUR FRUITS AND VEGETABLES FROM ACTUALLY KNOWING WHAT WE'RE EATING. LET ALONE ANYTHING RICHER THAN THAT BECAUSE IN THIS COUNTRY AN ENORMOUS PERCENTAGE OF FOOD IS PREPARED OUTSIDE THE HOME SO PEOPLE HAVE NO IDEA, MAYBE THE PEOPLE IN THIS ROOM ACTUALLY SHOP FOR ORGANIC FOOD, IN THE REAL WORLD, IT'S A REAL HEADACHE. THE OTHER PIECE OF THIS THAT'S GOING TO HAPPEN IN OUR LIFETIME WITH ANOTHER 2 BILLION PEOPLE EXPECTED ON THE PLANET IN THE NEXT 30 YEARS, MONSANTO, UNIVERSITY OF QUEENSLAND, THE BIG EGG, PLACES LOOKING AT HOW TO MODIFY FOOD THAT WILL GROW IN A DRYER CLIMATE AND FEED 2 BILLION MORE PEOPLE ON THE PLANET. AND IT'S NOT MANY PLACES THEY CAN GO TO DO THAT. BECAUSE SOY IS ALREADY THE DNA IS OWNED. BUT RICE AND WHEAT NO ONE OWNS THE DNA. SO MY COLLEAGUES, THAT'S WHERE THE REVOLUTION IS GOING TO HAPPEN. SO THE BREAD YOU EAT IN TEN YEARS TIME MAYBE A COMPLETELY DIFFERENT WHEAT. THEY'RE SAYING IT WILL BE A BETTER GLYCEMIC LOAD, PROTECTIVE AGAINST DIABETES. BUT ARE WE GOING TO KNOW AND KNOW WHEN THE WHEAT MARKET CHANGES SO 2 BILLION MORE PEOPLE CAN BE FED. SO THERE'S GOING TO BE A LOT OF CHANGE EVEN WITHOUT GLOBAL WARMING AND IF GLOBAL WARMING WIPES OUT SOME OF OUR AGRICULTURAL PRODUCTION YOU HAVE TO PRODUTIES MORE FOOD IN DRYER -- PRODUCE MORPHED IN DRYER CLIMATES FOR MORE PEOPLE AND WHAT THE HEALTH CONSEQUENCE IS GOING TO BE WHETHER CANCER, DIABETES OR HEART DISEASE. FOOD SCIENTISTS ARE LOOKING AT FEEDING THE WORLD, THEY'RE NOT ACTUALLY LOOKING AT WHAT IS THE HEALTH CONSEQUENCE. THOUGH THEY CAN TALK GLYCEMIC LOAD. THEY'RE NOT FUNDED TO STUDY GLYCEMIC LOAD. THEY'RE FUNDED TO ENGINEER DNA IN PLANTS SO THEY CAN SELL IT. >> I THINK WE HAVE COME TO THE END. IT'S ABOUT 4:15 AND (INAUDIBLE) WE HAVE REACHED THAT TIME. THANK YOU VERY MUCH, THAT WAS A WONDERFUL TALK. [APPLAUSE]