Relationship of Mammographic Parenchymal Patterns with Breast Cancer Risk Factors and Risk of Breast Cancer in a Prospective Study

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1 Intenational Jounal of Epidemiology Intenational Epidemiological Association 1990 Vol. 19, No. 2 Pinted in Geat Bitain Relationship of Mammogaphic Paenchymal Pattens with Beast Cance Risk Factos and Risk of Beast Cance in a Pospective Study B L DE STAVOLA #, I H GRAVELLE", D Y WANG *,DS ALLEN*, R D BULBROOK*. I S FENTlMANt J L HAYWARDt AND M C CHAUDARYt De Stavola B L (Impeial Cance Reseach Fund, PO Box 12, Lincoln's Inn Fields, London WC2A PX, UK) Gavelle IH, Wang D Y, Allen DS, Bulbook RD, Fentiman IS, Haywad JL and Chauday MC. Relationship of mammogaphic paenchymal pattens with beast cance isk factos and isk of beast cance in a pospective study. Intenationa/Jounal of Epidemiology 1990, 19: A pospective study has been conducted on 4954 female voluntees fom the Island of Guensey between 1977 and 1985 to examine isk factos fo beast cance and thei elationship to mammogaphic paenchymal pattens as assessed by Wolfe's method of gading. Up to Septembe 1988,69 women had developed beast cance, 11 of whom wee pevalent cases being diagnosed within six months of mammogaphy. The emaining incident cases wee diagnosed six to 126 months (median 65 months) afte enty to the study. Univaiate analysis showed that the distibution of Wolfe gades in the population was significantly associated with menopausal status, age, paity, adiposity, age at menache, age at fist childbith and use of oal contaception, but not with a family histoy of beast cance. Multivaiate analysis of the data fo these vaiables fom eithe pe- and/o postmenopausal women indicated that age, paity and adiposity wee significantly elated to Wolfe gade patten. Age had an opposite effect in pe- compaed with postmenopausal women thus the pobability of eithe a o patten inceased with inceasing age in pemenopausal but deceased in postmenopausal women so that incidence peaked aound the menopause. Othe vaiables did not achieve significance in the multivaiate analysis. Odds atios (ORs) wee calculated fo women with o pattens using those with N1 o P1 gades as the efeence goup. The ORs wee detemined at two censoing times; one at five yeas and the othe to include the most ecent of this cohot. The ORs wee adjusted fo yeas of, age and adiposity and in postmenopausal women adjustment was also made fo age at menache. At the ealie censoing time thee was an appoximate twofold inceased isk of beast cance in both pe- and postmenopausal women. At the late censoing time postmenopausal women still had an OR of about 2.0 although in pemenopausal women the OR fell to unity. Inclusion of pevalent cases had a mino effect on the ORs. It is concluded that mammogaphic paenchymal pattens do indicate an inceased isk of beast cance but the degee of discimination is not as maked as fist suggested by Wolfe. It is also unlikely that such pattens could be used in a pactical way to identify a high isk goup of women fo eithe intensive sceening o pevention studies. It has been claimed by Wolfe that mammogaphic paenchymal pattens can be used to identify women at an inceased isk of beast cance. 1 " 2 Howeve, esults fom pospective studies ae not all in ageement with this claim using eithe alone o plus categoies of mammogaphic pattens. 4 This may stem 'Depatments of Mathematics, Statistics and Epidemiology & Ginkal Endocinology, Impeial Cance Reseach Fund, PO Box 12, Lincoln's Inn Fields, London WC2A PX, UK. "Depatment of Radiology, Univesity Hospital of Wales, Cadiff, UK. tclinicaj Oncology Unit, Guy's Hospital, London SE1 9RT, UK. Coespondence to: B L De Stavola. fom diffeences in the populations examined and because few of these studies have contolled fo the possible confounding effects of age, weight, paity and length of. Othe easons fo this disageement have been dealt with in depth. ' 4 We have had the oppotunity to (median time seven yeas) a cohot of 5000 nomal women living on the Island of Guensey fo whom mammogaphic pattens and anamnestic vaiables ae known. Duing this time 69 women have developed beast cance. Ou ealie epot on the elationship between mammogaphic pattens and beast cance isk, published befoe final accual to the study, did not contol 247

2 248 INTERNATIONAL JOURNAL OF EDEMIOLOGY fo possible confounding factos and made no distinction between pevalent and incident cases. 5 Since then, 8 moe cases of beast cance have been diagnosed so that a new analysis, based on the incident cases only and contolled fo confounding factos, would seem timely. METHODS Subjects The cohot studied wee 5104 ostensibly nomal women living on the Island of Guensey who had volunteeed to ente a pospective tial between 1977 and On enty to the study the voluntees undewent mammogaphy and wee given a clinical examination. Mammogams wee obtained on 4954 women. Details of this study have aleady been descibed. 5 " 7 Mammogaphy The mammogaphic techniques wee as set out peviously and Wolfe classifications wee as follows: Nomal: low density of paenchyma with lage popotion of fat. Ductal pominence involving less than a quate of the beast. Ductal pominence involving moe than a quate of the beast and often with a nodula component. Inceased density of the paenchyma with o without aeas of nodulaity. Mammogams wee ead by two adiologists and in a compaison of ove 000 thee was a epoducibility of classification in excess of 90%. 5 The esults of only one of the adiologists wee used because of the geate numbe (n = 4954) classified by that individual. 5 Diagnosis Beast cance was diagnosed and histologically confimed at biopsy in 69 women. Of these, 11 wee discoveed within six months of sceening and 58 wee cances diagnosed six to 126 months (median 65 months) afte enteing the tial. Statistical Methods Two main questions wee addessed in the analysis. The fist concened the elationship between Wolfe gtade categoies and the known isk factos fo beast cance of age, paity, adiposity, age at menache, age at fist childbith, and family histoy of beast cance. Oal contaceptive use has also been included. Univaiate coss-classifications and multivaiate analyses wee pefomed with Wolfe gade as the dependent vaiable. In the univaiate analysis the null hypothesis of no association between each isk facto and Wolfe gade was tested by chi-squaed tests. In the multivaiate analyses Wolfe gade was dicothomized into low- <N1 + ) and high isk gade ( + ) and modelled as a binomial vaiable with the isk factos enteed as covaiates. The eason fo this dichotomy was to examine the claim that women with o mammogaphic pattens have an inceased isk of beast cance compaed with those having o pattens. 1 ' 2 The most impotant covaiates wee identified and odds atios (ORs) computed. The second question concened the link between mammogaphic paenchymal patten and occuence of beast cance. This was assessed by computing the ORs fo beast cance associated with high isk Wolfe gade elative to the low isk categoy. 8 Because of inteactions and confoundings, adjustments wee made fo the effect of time, age, paity, adiposity and, in the case of postmenopausal women, age at menache. RESULTS The popotions of Wolfe gades,, and in the population of women studied ae shown in Table 1. Because of the clea diffeence in Wolfe gade pattens between pe- and postmenopausal women (x 2 = 2.7; p<0.001) the following analyses have been pefomed sepaately on these two goups. Univaiate Analysis Age Thee was a significant association between age and Wolfe gade categoies fo both pe- and postmenopausal women (Table 2) but younge pemenopausal women had lage popotions of and pattens, whilst younge postmenopausal women had lage popotions of and. Paity In both pe- and postmenopausal women thee was a significantly negative association between paity and and Wolfe gade (Table ). Nullipaous women had highe fequencies of and pattens than all paous women. The chi-squaed tests fo paous women only wee also highly significant (X 2 = 25.0; df = 9 and * 2 = 79.0; df=9, espectively). Adiposity The Quetelet's Index, which is defined as weight (kg) divided by height (metes) squaed, has TABLE 1 Row pecentage distibution of Wolfe gades in the cohot AJJ PostmenopausaJ *The 11 pevalent cance cases have been excluded. No.*

3 TABLE 2 Age «5 6^ >45 Row pecentage distibution of Wolfe gade categoies by age 27% 7% ^=126.6; df=9;p<0.001 « >65 5^= 102.0; 4 47% 20% 54% 50% Postnicnopausal 2% 1% 42% 4% 4 51% 4 4% df=12;p<0.001 MAMMOGRAPHY AND BREAST CANCER No menopausa i women nau ai some nnne taken oal cononly 2 of the postmenopausal subjects taceptives wee in this categoy. In both goups a significant association between oal contaceptive use and Wolfe TABLE Paity *4 X ;df=l Row pecentage distibution of Wolfe gade and paity 4% 6% Pi *4 2 47% 52% 50% 4 42% j>5.4; df=12; p< % 2% 4 54% 47% 47% 46% 0% No been used as a measue of body build. Thee was a significant negative association between QI values of peand postmenopausal women and and Wolfe gade categoies (Table 4). Age at menache. Thee was a significant tendency fo late age of menache to be associated with dense Wolfe gade. This was the case fo both pe- and postmenopausal women (Table 5). Age atfistchildbith. In both pe- and postmenopausal women thee was a significant positive association between age at fist childbith and dense Wolfe gade pattens (Table 6). Women who had theifistbabies at an ealie age had highe fequencies of low isk gades (opl). Oal contaception. Whilst the majoity (70%) of pegades was found (Table 7) although its diection was diffeent fo pe- and postaenopausal women, possibly because of the confounding effect of age. Family histoy The distibution of Wolfe gade pattens of pe- o postmenopausal women with a fist o second degee family histoy of beast cance was not significantly diffeent fom that of the goup of subjects without a family histoy of beast cance (Table 8). Multivaiate Analysis Univaiate analysis had shown that all the vaiables consideed, except a family histoy of beast cance, wee significantly associated with mammogaphic patten. These wee all examined in the multivaiate models fo the pobability of a high isk classification ( and ) in pe- and postmenopausal women. Stepwise fowad selection pocedues led to simila models fo the two goups which included age, paity and Quetelet's Index. In addition, the model fo postmenopausal women included age at menache. Age at fist childbith and histoy of oal contaceptive use wee not significantly elated to Wolfe gade classification once the effect of paity and age, espectively, wee taken into account and theefoe wee not included in the final model. Family histoy of beast cance was also examined in the multivaiate famewok but again found to be non-significant. Finally, the pobability of a woman having eithe a o D Y compaed with o Wolfe gade has been expessed as an odds atio (Table 9). TABLE 4 QI" (Quintiles) 1st 2nd d 4th 5th Row pecentage distibution of Wolfe gades and Quetelet's Index 14% 22% y?= 182.9; df= 12; p< st 2nd d 4th 5th X 2 =240.4; df= 6% 6% 1 >12;p< % 47% 1 52% 20% 54% 27% 46% 21% 4 0% 47% 2% 52% 46% 42% 7% Quintiles have been calculated using the total cohont of pe- and postmenopausal women. The 1st to 5th quintilest efe to Quetelet's Index of "S21.8, , , and >27.7, espectively. "Thee was one pemenopausal woman fo whom Quetelet's Index was unknown 1% 2% 2 7% 2% No."

4 250 INTERNATIONAL JOURNAL OF EDEMIOLOGY TABLE 5 Age < *15 ^=45 2; df= < »15 X"=9 6; df= Row pecentage distibution of Wolfe gade categoies and age at menache ;p< ;jX0 001 Pemcnopausal % 4 50% 42% 6% 42% 47% 4% % 21% No.* Thee wee 1 pemenopausal and seven postmenopausal women fo whom this infomation was not available The esults of the multivaiate analysis ae simila to those found fo the univaiate analysis in that age had an opposite effect on pe- and postmenopausal women. women age 40 o moe had twice the isk of women unde 6 whilst postmenopausal women ove 55 had about half the isk of postmenopausal women unde 51 of having a o Wolfe gade patten (Table 9). The changes in mammogaphic density associated with menopause may be the eason, since we could not find any majo confounding facto fo this vaiable. In pe- and postmenopausal women thee was a TABLE 6 Age < *0 X 2 =27.2;df= < S0 je-1.;df- Row pecentage distibution of Wolfe gade and age at fist childbith 20% 12; p< % 12; p< % 20% 50% 47% 51% 4 6% 41% 4 4% 42% 44% 2% 50% 14% 20% 14% No.* *In addition to nullipaous women thee was one pe- aad one postmenopausal woman, fo whom no infomation was available, who have been excluded. highly significant tendency fo the isk of having a o patten to decease with inceasing Quetelet's Index. The effect of inceasing paity also was vey simila in pe- and postmenopausal women and in both the coefficients had significant linea tends (x 2 = 26.8, p<0.001 and x 2 = 55.9, p<0.001, espectively). Namely, having one child instead of none appeas to decease the ORs of a o Wolfe gade by about and 0%, espectively, and thee childen instead of none by about 50% and 4. Finally, the effect of age at menache was found to diffe between pe- and postmenopausal women, being significant fo the latte goup only whee isk inceased with age (x 2 fo tend = 17.5; p<0.001). Wolfe Gade and Risk of Beast Cance In the pevious analysis of this cohot pevalent and incident cases wee combined when computing the odds atios fo beast cance associated with high and low isk Wolfe gades. 5 Theefoe, fo compaative puposes the pesent data have been analysed using all beast cances as well as only incident cases. Again fo compaison with ous and othe studies the analysis of isk has been taken at two times, the fist at five-yeas and the second at the latest data update (15 Septembe 1988). The latte goup included the latest beast cance case whose disease was diagnosed 126 months afte enty into the study. The analysis of the total cohot censoed atfiveyeas o at total, iespective of menopausal status, showed that and pattens wee associated with an inceased isk of beast cance compaed with those having o gades (Table 10). Howeve, only when combined pevalent and incident cases wee consideed did the inceased isk appoach being fomally significant. In all the analyses it can be seen that the isk at total was less than the coe- TABLE 7 Row pecentage distibution of Wolfe gade and oal contaceptive use OCuse Neve Eve ^=4.9; 20% df-; p<0.001 Neve Eve X 2 =.6; df=; p< % 47% Postmenopausa) 7% 44% 26% 50% 21% No.* Thee was one pemenopausal and fou postmenopausal women fo whom no oal contaceptive infomation was available.

5 TABLE 8 Row pecentage distibution of Wolfe gade and familial histoy of beast cance Familial histoy None 1st degee 2nd degee 20% Both 21% X 2 =15.8; df=9;p=0.07 None 1st degee 2nd degee Both X 2 =6.5; df=9; p= % 46% 4 4% 46% 4% 4 2% 4% 1% 4 MAMMOGRAPHY AND BREAST CANCER % 20% 21% 7% No In pemenopausal women thee was an appoximately doubled isk in women with o gades when data wee censoed atfiveyeas of ; this being highe when pevalent cases wee included. Howeve, none of these odds atios eached fomal significance. At the latest update the odds atios wee diminished and appoximated to unity (Table 11). High isk o categoies in postmenopausal women wee associated with about a twofold inceased isk of beast cance compaed with o pattens (Table 12). In contast to pemenopausal women, the inceased isk seen at thefiveyeas censoing time was maintained ove the longe peiod to include the latest cances. Inclusion of pevalent cases did not sensibly alte the value of the odds atio. Nevetheless, all odds atios wee not significantly diffeent fom one. sponding isk atfiveyeas and that cude and adjusted DISCUSSION values wee vey simila. Of the seven pospective studies (which exclude ou Vaiable Age 6^tO 41^5 * S>66 X 2 (tend) Quetelet's Indext 2nd d 4th 5th X 2 (tend) Paity 1 2 *4 X 2 (tend) TABLE 9 Multivaiale analysis of high-isk Wolfe gades (+) OR* *" 7.'" 26.8*" 9 CI Age al menache » X 2 (tend) 17.5* OR# " 77.*" 55.9*" 9 CI O **p< tquetelet's index quintiles have been calculated using the total cohot of pe- and postmenopausal women. The 1st to 5th quintiles efe to indexes of <21.8, , , and >27.7, espectively. $ Relative to age <5, 1st Quetelet's Index quintile and zeo paity. Thee was one peson omitted because of missing infomation egading Quetelet Index. #Relative to age «50, 1st Quetelet's Index quintile, zeo paity and age at menache *12 yeas. Thee wee seven women who wee omitted because age at menache was unknown.

6 252 INTERNATIONAL JOURNAL OF EDEMIOLOGY TABLE 10 Odds atios and 9 confidence limits- pe- and poslmcnopausal women Incident cases Incident and pevalent cases Censoing time Wolfe gade Contols Cude Adjusted* * Contols Cude Adjusted* * Fives yeas of + Pl + + Pl I 1.85 (0.74-^.78) 1.7 ( ) 1.72 (0 72^t.88) 1.1 ( ) ( ) 1 51 ( ) 2.08 ( ) 1.51 ( ) Refeence goup. ' Adjusted fo yeas of, paity, age, Ouetelefs Index and age at menache. TABLE 11 ealie one) eviewed by Saftlas and Szklo 4 the median pecentage of and gades is 4 with a ange of 4%-to 84%. This compaes with a value of fo the pesent study. Apat fom vaiations due to the definition of mammogaphic pattens and obseve vaiability, some of these diffeences might eside within the populations studied since it is clea that age, weight and epoductive factos influence mammogaphic paenchymal pattens and thei distibutions may vay accoding to county and time. It is theefoe not supising that thee is such a wide vaiation in Wolfe gade classification. In this study we have attempted to examine the elationship between some of the moe impotant isk factos fo beast cance and Wolfe gade. Age showed a majo effect in accod with numeous othe studies.*" 16 This effect had opposite signs in pe- and postmenopausal women suggesting that ovaian function is a poweful deteminant of mammogaphic patten. Bisson et a/ 17 also found a significant diffeence in Wolfe gades of pe- and postmenopausal women of the same age. Age at fist childbith and paity have been epoted to be significantly associated with Wolfe gade pattens. l0 ' In this study the multivaiate analysis showed that age at fist childbith was not significant when due consideation was made of paity which confims the findings of De Waad et a/. 19 Thee was a significant univaiate elationship between age at menache and beast stuctue but the stong influence of adiposity 16 ' 719 was found to explain fully the effect of age of menache in pemenopausal women. This was because of the highly significant association between age at menache and adiposity in the Guensey population. 20 In postmenopausal women, howeve, age at menache still emained statistically significant. In confimation of ou pevious analysis 6 and that of Leinsteand Whitehouse, 21 the eve-taking of oal contaceptives in pemenopausal women was found to be associated with an incease in o pattens. Howeve, this association was explicable by the confounding influence of age. In common with othes 1015 " we wee not able to detect an association between Wolfe gade patten and family histoy of beast cance. Thee wee of women with a fist o second degee family histoy of beast cance. Since a much smalle pecentage than Odds atios and 9 confidence luntts: pemenopausal women Incident cases Incident and pevalent cases Censoing time Wolfe gade Contols Cude Adjusted" Contols Cude Adjusted** Fives yeas of +Pl ( ) > * 1.51 ( ) ( ) 1.99 ( ) +Pl ( ) 0.81 ( ) ( ) 0.94 ( ) * Refeence goup. "Adjusted fo yeas of, paity, age and Ouetelet's Index.

7 MAMMOGRAPHY AND BREAST CANCER 25 TABLE 12 Odds atios and 9 confidence limits: postmenopausal women Incident cases Incident and pevalent cases Censoing time Fives yeas of Wolfe gade +Pl + +Pl Contols Cude 1.94 ( ) 1.88 ( ) Adjusted* * 2.0 ( ) 1.71 ( ) Contols Cude 2.08 ( ) 1.95 ( ) Adjusted" 2.46 ( ) 1.99 ( ) Refeence goup. **Adjusted fo yeas of, paity, age, Quetelet's Index and age at menache. this of beast cance cases ae genetically linked 22 the influence of this vaiable could be 'diluted' by the emaining non-genetically linked women and the lack of significant association between Wolfe gade and family histoy of beast cance does not necessaily imply that beast paenchymal stuctue is not genetically influenced. Once confounding effects wee taken into account, o Wolfe gades wee geneally found to be associated with an inceased isk of beast cance but none of the odds atios wee significantly diffeent fom unity whethe cude o adjusted and whethe pevalent cases wee included o not. Thus, these esults confim the geneal consensus that Wolfe gading does identify a high isk goup but that the magnitude of the isk is much lowe than that oiginally epoted by Wolfe. - 4 Indeed, all things being equal, it would have equied a population thee to fou times lage fo the odds atios to have become statistically significant. Analysis of isk at total time, which anged fom.5 to 11 yeas, showed that the odds atio of and high isk pemenopausal women had fallen to unity but that the postmenopausal countepat maintained a two fold incease in isk. This diffeence between the menopausal goups might be explained by the changes in beast stuctue associated with the menopause since some of the pemenopausal women had become postmenopausal when diagnosed as having beast cance. Such changes might obscue the elationship between Wolfe gade and beast cance isk. These esults ae at vaiance with those of the only compaable study of Bisson et a/ 17 who showed that the inceased isk was maintained afte nine yeas in women aged 5-49 yeas with mammogaphically glandula o dense, o intemediate paenchyma compaed with those with fatty paenchyma. In that study women aged had deceased isks with inceasing time. A poblem that has been identified with assigning an inceased isk of beast cance in women with dense paenchymal pattens is that of 'masking' since tumous, especially small ones, ae moe likely to be missed in such beasts than in fatty lucent beasts 2 because the latte ae moe pevalent in postmenopausal women. This would esult in a lead time bias which would be less of a poblem in postmenopausal women than pemenopausal women. Howeve, it would be expected that this bias should be substantially eoded at the censo time of five yeas. The esults of this study confim that o D Y Wolfe gades ae associated with an appoximately twofold incease in beast canceiskcompaed with a o gade. This level of inceased isk is simila to that found fo most 'classical' isk factos. Howeve, it is unlikely that Wolfe gade pattens could be used in a pactical way to identify women at an inceased isk fo sceening o pevention puposes since in the pesent study 62% of the population had o pattens and yielded 6 of the beast cance cases. Combinations of isk factos can incease isk thus Saftlas et at* ecently showed that women with o D Y patten and a fist-degee family histoy had an odds atio of 5.5. Howeve, ove 90% of the beast cances would have been missed using these citeia. We would thus concu with Whitehead et ap who calculated a multivaiate disciminant and concluded that such a disciminant 'does not have the powe to allow eliable pediction of the disease in an individual woman'. ACKNOWLEDGEMENTS The authos ae indebted to the women of Guensey fo the suppot they have shown in volunteeing fo this study. They would also like to thank Ms Maueen Cobbing fo he help in pepaing the manuscipt. REFERENCES ' Wolfe J N. Risk of beast cance development detemined by mammogaphic paenchymal patten. Cono 1976; 7:

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