Ovarian Cancer Survival

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1 Dairy Products, Calcium, Vitami D, Lactose ad Ovaria Cacer: Results from a Pooled Aalysis of Cohort Studies Stephaie Smith-Warer, PhD Departmets of Nutritio & Epidemiology Harvard School of Public Health Ovaria Cacer Survival Cacer site Case-fatality rate (%) Ovary 63 Cervix 37 Breast 1 Edometrium 18 5-year survival: overall ~44% ~70% of cases are diagosed at advaced stages I was fortuate to be asked to discuss a aalysis that I have bee directly ivolved with, so it was relatively easy to put this together. Age Stadardized Rate (/100,000) Cacer Icidece Worldwide: Wome Breast Cervix Uteri Colo Rectum Lug Stomach Ovary America Cacer Society, 2004 Most ovaria cacers are detected at advaced stages, so the case fatality rate for ovaria cacer is very high, i compariso to cervix, breast, ad edometrial cacers. So it is importat to idetify risk ad prevetive factors for ovaria cacer. Risk Factors for Ovaria Cacer Reproductive factors - decrease risk high parity oral cotraceptive use icreasig duratio of lactatio tubal ligatio Family history: first-degree relative - icrease risk GLOBOCAN, 2002 I was't sure how familiar people are with the descriptive epidemiology of cacer worldwide. I am goig to be talkig about ovaria cacer, which is the sixth leadig type of cacer i wome worldwide. To put it ito perspective, ovaria cacer icidece is about 5 times lower tha that observed for breast cacer worldwide. Ovaria Cacer Icidece Rates Some of the risk factors that have bee regularly established are reproductive factors. High parity, oral cotraceptive use, icreasig duratio of lactatio, ad tubal ligatio have bee foud to decrease the risk of ovaria cacer. Whereas, family history has bee foud to icrease the risk. Ecologic Study: Correlatio Betwee Ovaria Cacer Icidece ad Per Capita Milk Cosumptio 12 Age Stadardized Rate (/100,000) World More Developed Less Developed R 2 = 0.2, p = GLOBOCAN, 2002 There is a large geographic variatio i ovaria cacer icidece rates. The icidece rate i more developed coutries is about double that i less developed coutries. Cramer 18 Diet has also bee looked at i may studies. This is a ecologic study of milk cosumptio ad ovaria cacer icidece rates Dairy Products, Calcium, Vitami D, Lactose ad Ovaria Cacer: Results from a Pooled Aalysis of Cohort Studies Stephaie Smith-Warer 1

2 worldwide. There was a positive correlatio of.2, comparig milk cosumptio to icidece rates. Potetial Carciogeic Mechaisms Lactose galactose Icreases goadotropi levels Toxic to oocytes Vitami D decreases cell proliferatio Calcium Dowregulates vitami D absorptio Decreases parathyroid hormoe Fat icreases estroge levels There are several potetial mechaisms as to why milk may be associated with ovaria cacer risk. Milk is a rich source of lactose, which is cleaved to form galactose. Galactose has bee foud to icrease goadotropi levels, ad to be toxic to the oocytes; thereby it might icrease the risk of ovaria cacer. Dairy products are also a source of Vitami D, particularly milk. Vitami D might decrease cell proliferatio so it could decrease the risk of ovaria cacer. Calcium itake has bee foud to dow-regulate Vitami D absorptio, so it could icrease ovaria cacer risk. However, calcium also decreases parathyroid hormoe, ad by decreasig parathyroid hormoe, it could result i a decrease i ovaria cacer risk because it decreases IGF-1 levels. Diary products are also a source of fat itake ad the hypothesis with fat is that fat itake might icrease estroge levels. Poolig Project of Prospective Studies of Diet ad Cacer Iteratioal cosortium of cohort studies to evaluate diet ad cacer associatios usig stadardized aalytic criteria Meta-aalysis of idividual data Established i But whe we coducted the ovaria cacer aalyses, there were oly 12 studies that met our iclusio criteria. So the baselie cohort size is over 500,000 with over 2,000 ovaria cacer cases that were detected durig follow-up of these studies. I the Poolig Project we collect the primary data from each of the studies ad use the food data to create food groups, such as dairy products. We also collect o-dietary risk factors with which to adjust our estimates. We coduct study specific aalyses, lookig at the overall effect betwee, for example, milk ad ovaria cacer risk. Because of the large sample size with over 2,000 cases, we ca also look at associatios for tumor subtypes ad evaluate whether the associatio varies by other cacer risk factors. After we coduct the study specific aalyses, we evaluate whether there is heterogeeity betwee the study specific results ad the we pool those estimates. This is a example of a collaborative project where we have iput from the co-ivestigators at data collectio, at the aalysis of the idividual studies ad also at the poolig of the results ad i the iterpretatio of those results. We have bee meetig aually sice the project started i to discuss the results so that we have cosesus o the results that we observe ad i the writig of those mauscripts. Poolig Project: Aalytic Strategy Nutriets Mai effect Foods Because ovaria cacer is a less commo cacer, may prospective cohort studies have ot bee able to look at this associatio o their ow. So we decided to look at this withi the Poolig Project of Prospective Studies o Diet ad Cacer. Because I work o this study, I decided to describe it i a little more detail. This is a iteratioal cosortium of cohort studies, with the goal to evaluate diet ad cacer associatios usig stadardized aalytical criteria across all studies. So it s a example of a meta-aalysis of the idividual data as opposed to a meta-aalysis of the published literature where you ca oly extract the risk estimates from the published literature. Data collectio Food groups No-dietary risk factors Study-specific aalyses Iput from Co-Ivestigators Tumor subtypes Effect modificatio Poolig Curretly, there are 28 studies i the Poolig Project, with a overall cohort size of about 2.2 millio. Milk, Hormoes & Huma Health October,

3 Poolig Project: Statistical Aalysis Study-specific relative risks (RRs) calculated usig the Cox proportioal hazards model Multivariate RRs adjusted for Age HRT use Age at mearche Physical activity Oral cotraceptive use Body mass idex Parity Smokig status Meopausal status Eergy itake Study-specific RRs pooled usig a radom effects model Weighted by iverse of variace For the ovaria cacer aalyses, we adjusted for these risk factors. The age-adjusted results were very similar to the multivariate results, so I m oly presetig the multivariate results. I the pooled aalysis, we weight the idividual studies by the iverse of the variace of their estimates. I wat to preface the followig slides by sayig that Jeaie Gekiger, a post-doctoral fellow who is workig o the Poolig Project, is the oe that coducted these aalyses ad she is sittig i the back. # of Cases 53 AHS 142 CPS II 223 IWHS 278 NHSII 208 BCDDP 208 NHSb 77 WHS 65 NHSa 120 NYU 315 CNBSS 52 NLCS 287 SMC 104 NYSC 8 oz = 245g Mea Milk Itake by Study Milk Itake (g/d) Aother advatage of the pooled aalysis is that we have wide variatio i itake. Lookig at mea milk cosumptio across the 12 studies icluded i the Poolig Project, there is about a twofold differece betwee those with the lowest ad highest itakes. Also show for referece are the umber of cases withi each study, the smallest studies havig about 50 cases, ad the largest study, which is the Nurses' Health Study, havig about 300 cases as with the Caadia Natioal Breast Screeig Study. Pooled RRs for Milk ad Ovaria Cacer # cases: oz = 245 g = 12 studies; 2,132 cases Milk (g/d) We categorized milk cosumptio ito categories, usig idetical categories across the studies. We compared 500 or more grams of milk cosumed per day, which is more tha two cups of milk a day, to o cosumptio, ad we really foud o evidece of a associatio for milk cosumptio. Pooled RRs for Whole ad Low-fat Milk ad Ovaria Cacer oz = 245g = studies; 2,055 cases Milk (g/d) Low-fat Whole We were iterested i whether this differed by the fat cotet of the milk, ad, agai, whe we looked at low fat milk ad whole milk separately, the associatios still were ull. Food Item Milk Cheese Pooled RRs of Dairy Products ad Ovaria Cacer 12 RR (5% CI) 1. ( ) 1.30 ( ) Exposure (ref=0 g/d) 500 (16 oz) g/d 4 (_ cup) g/d Cottage Cheese 0.88 ( ) 50 (~2 oz) g/d Yogurt 1.04 ( ) 53 (_ cup) g/d Ice Cream 0.1 ( ) 66 (_ cup) g/d p for tred > 0.3 Dairy Products, Calcium, Vitami D, Lactose ad Ovaria Cacer: Results from a Pooled Aalysis of Cohort Studies Stephaie Smith-Warer 3

4 We also looked at a variety of other dairy products, ad i the iterest of time, I show oly the relative risk for the highest category i compariso to the referece. Ad i all cases, the referece was o cosumptio of that product. The results for milk were a o-sigificat, 10 or percet elevatio i risk. Noe of the results for these dairy products was statistically sigificat. Ad the oly oe where there was a suggestio of a positive associatio was cheese. For cheese, that positive associatio was really limited to the highest category, which was approximately 2 ouces of hard cheese a day compared to oe. Mea Calcium Itake by Study SMC CPS II NLCS BCDD AHS NYSC NYU NHSII IWHS WHS NHSa NHSb CNBSS Calcium Itake (mg/d) Dietary Total Show here is the variatio i calcium itake by study. Calcium itake from food is referred to as dietary, ad from both foods ad supplemets, as total calcium itake. Pooled RRs for Calcium ad Ovaria Cacer Itake (mg/d) < < < < < p for tred = 12 studies; 2,132 cases Dietary ( ) 0.38 Total ( ) 0.4 We categorized the calcium itake, ad, agai, for both dietary ad total calcium itake, we see really o evidece of a associatio. Pooled RRs for Vitami D ad Ovaria Cacer Itake (IU/d) Dietary Total < < < < < p for tred = 12 studies; 2,132 cases * 1.37 ( ) 0.04 *p< ( ) 0.60 Whe we also looked at Vitami D, both dietary ad dietary plus supplemetal itake we saw this peculiar fidig of a elevatio i risk for the high categories of Vitami D from food sources oly, which was really ot observed whe we looked at total Vitami D itake. We also looked at other dietary sources of Vitami D, such as from fish ad cereals, ad we saw o evidece of a positive associatio for those sources. So we thik it is ulikely that this associatio is causal. Pooled RRs for Lactose ad Ovaria Cacer # cases: oz. milk cotais ~10g of lactose = 12 studies; 2132 cases < Lactose (g/d) Fially, we looked at the associatio betwee lactose ad ovaria cacer risk. For these aalyses Jeaie calculated the lactose itake for each of the studies because we had the dairy product itake data. We foud a 20 percet elevatio i the risk of ovaria cacer that was margially sigificat for idividuals who cosumed 30 grams of lactose a day, about the amout of lactose i 3 cups of milk, compared to idividuals who cosumed less tha 10 grams of lactose a day, about the amout of lactose i 1 cup. Milk, Hormoes & Huma Health October,

5 Study-Specific RRs for Lactose ad Ovaria Cacer (>30 vs <10g/day) New York State Cohort Caadia Natioal Breast Screeig Study New York Uiversity Wome's Health Study Advetist Health Study Nurses' Health Study II Netherlads Cohort Study Wome's Health Study Nurses' Health Study (part a) Breast Cacer Detectio Demostratio Project Iowa Wome's Health Study Swedish Mammography Cohort Nurses' Health Study (part b) Cacer Prevetio Study II = 2,132 Combied p for heterogeeity = oz. milk cotais ~10g of lactose I also wat to show you the study specific results for lactose. Sice ovaria cacer is less commo, oe of the studies have that may cases, ad oe of these associatios was statistically sigificat. The squares are the risk estimates for the idividual studies. The square size is the weight that the study was give i the pooled aalysis, ad is proportioal to the iverse of the variace. Studies that had about 200 cases are at the bottom of the graph ad studies that had fewer tha 100 cases are at the top of the graph. May of the idividual estimates were o the right side of oe, suggestig a positive associatio, but we did have some that were o the iverse side, but, agai, those were ot statistically sigificat. It's oly whe we pool them that we see this margially sigificat 20 percet elevatio i risk. I wat to poit out that the Iowa Wome's Health Study, The Swedish Mammography cohort ad the Nurses' Health Study, which are the oes ear the bottom of the graph, are more heavily weighted i the aalysis. Each published previously o the associatio betwee lactose ad ovaria cacer, probably because they had more cases tha these other idividual studies ear the top of the graph. I additio, they had lactose data available i their databases. Pooled RRs for Lactose ad Ovaria Cacer by Histologic Type All Cacers Serous Edometrioid Mucious P for commo effect by type = 0.63 Icremet = 10 g/d RR (5% CI) 1.04 ( ) 1.06 ( ) 1.07 ( ) 0.7 ( ) We also looked at whether the associatio varied by ovaria cacer subtype, because previous prospective studies suggested that maybe the associatio was limited to serous ovaria cacer, which is the most commo type of ovaria cacer. We did ot see evidece that the associatio differed by histological subtype, although we did have small umbers of edometrioid ad mucious ovaria cacers i this pooled aalysis. Additioal Results Results similar for serous, edometrioid, ad mucious cacers Results similar whe the first 2 years of follow-up were excluded No effect modificatio by Age at diagosis HRT use Parity Meopausal status OC use Fat itake We also looked at the other diary products to see whether the associatio varied by histological subtype, ad for oe of those did we fid a statistically sigificat differece betwee the subtypes. We also evaluated whether the results were similar whe the first two years of follow-up were excluded, just i case idividuals who had udiagosed ovaria cacer maybe had chaged their diets so that their baselie diet was ot reflective of their true adult diet, ad we foud the results were similar. We foud o effect modificatio by a variety of ovaria cacer risk factors Dairy Product ad Ovaria Cacer Associatios from a Pooled Aalysis ad a Meta-aalysis Dairy Product Milk Low-fat Whole Cheese Yogurt 12 highest vs. lowest category *p for heterogeeity 0.03 Pooled Aalysis of Cohort Studies RR (5% CI) 1. ( ) 1.07 ( ) 0.5 ( ) 1.30 ( ) 1.04 ( ) Meta-aalysis of Case- Cotrol Studies RR (5% CI) 0.87 ( )* 0.80 ( )* 1.27 ( )* 0.3 ( ) 1.1 ( ), Larsso et al 2006 I wat to put these results i perspective as to what is available i the published literature. Show here are the results that I just preseted from the pooled aalysis juxtaposed to Alicja Wolk s group that at about the same time published a meta-aalysis of case cotrol ad cohort studies. I mostly iclude their case cotrol results because there were oly three published cohort studies o dairy products ad ovaria cacer ad all of them are icluded i the pooled aalysis. I've actually icluded oe cohort study ad 7 case cotrol studies i the milk results because the results from the 7 case cotrol studies were ot reported separately. Oe of the differeces betwee a meta-aalysis ad a pooled aalysis is that i the former you are limited to the comparisos that are i the published literature. There was statistically sigificat heterogeeity amog the associatios for milk ad by type of milk i the case cotrol studies that was ot observed i our pooled aalysis where we were able to defie the cotrast idetically across the studies ad cotrol for the same risk factors. Dairy Products, Calcium, Vitami D, Lactose ad Ovaria Cacer: Results from a Pooled Aalysis of Cohort Studies Stephaie Smith-Warer 5

6 But i all cases, the associatio with ay of the dairy products was ot sigificat i the pooled aalysis or amog the case cotrol studies, except for cheese, where it is margially sigificat i the pooled aalysis but ot suggestive i the case cotrol studies. Study Pooled Aalysis Meta-aalysis Desig RR (5% CI)* RR (5% CI)* Cohort ( ) (-1.22) Lactose ad Ovaria Cacer: Results from a Pooled Aalysis ad a Metaaalysis Case- Cotrol ( ) Both 1.02 ( ) compared idividuals who were cosumig three or more servigs of milk compared to oe servig. So we thik that there should be more evaluatio of whether this is really true because the curret recommedatios are to cosume at least three servigs of dairy products per day. Ackowledgemets Jeaie Gekiger Aita Koushik Leo Schoute Sherry Yau Christie Rivera Ruifeg Li David Huter Doa Spiegelma Walter Willett * Icremet = 10 g/d p for heterogeeity = 0.04, Larsso et al 2006 Vicki Chi Alicja s group also reported results for lactose i their metaaalysis. These results are also show juxtaposed to our pooled results. The results from the three published cohort studies were stroger tha what we observed for the 12 studies i the pooled aalysis. I oe of these three cohort studies the case umber is almost idetical, but i the pooled aalysis there is at least five more years of follow-up tha i the other two cohort studies. I the process of there beig more follow-up, the associatio has actually become weaker. So eve if we limit our aalysis to these three published studies, the associatio is weaker tha what was reported previously. There was o evidece of a associatio i the case cotrol studies. I wat to also ote that there was statistically sigificat heterogeeity i the meta-aalysis betwee the case cotrol ad cohort studies, which is idicated at the bottom of the slide, so that you really should't be poolig the two study types together to come up with a combied estimate. Coclusios Overall No strog or sigificat associatios with dairy products or calcium No-sigificat higher risk with vitami D Modest positive associatio with lactose I wat to agai ackowledge Jeaie, who is the oe who coducted these aalyses as well as the other Poolig Project members at Harvard. Ackowledgemets, cot d Advetist Health Study Breast Cacer Detectio Demostratio Project Caadia Natioal Breast Screeig Study Cacer Prevetio Study II Nutritio Cohort Iowa Wome s Health Study Netherlads Cohort Study New York State Cohort New York Uiversity Wome s Health Study Nurses Health Study Nurses Health Study II Swedish Mammography Cohort Wome s Health Study Wheever I give a talk o the pooled results, I must also ackowledge the ivestigators for each of the idividual studies because without their collaboratio this project would ot be possible. Associatios did ot vary by histological type Results were ot modified by several ovaria cacer risk factors I coclusio, we foud that there were o strog or sigificat associatios with dairy products. This result was also observed i the meta-aalysis of the case cotrol studies. We also foud o associatio with calcium itake either from foods oly or from food ad supplemetal sources. We foud a o-sigificat higher risk with Vitami D that was stroger i the aalyses from foods oly compared to those that icluded supplemetal itake, so we do ot believe that this is a causal associatio. Ad the we foud this modest positive associatio with lactose whe we Milk, Hormoes & Huma Health October,