Risk Factors for Breast Cancer in Chinese
Transcripción
Risk Factors for Breast Cancer in Chinese
[CANCER RESEARCH 48, 1949-1953, April 1, 1988] Risk Factors for Breast Cancer in Chinese Women in Shanghai •1 Jian-Min Yuan, Mimi C. Vu,2 Ronald K. Ross, Yu-Tang Gao, and Brian E. Henderson Shanghai Cancer Institute, Shanghai, People's Republic of China [J-M. Y., Y-T. G.]; and the Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles, California fM. C. Y., R. K. R., B. E. H.] ABSTRACT Five hundred thirty-four histologically confirmed incident cases of breast cancer in Chinese women of Shanghai and an equal number of age and sex-matched population controls were interviewed as part of an epidemiológica! study of breast cancer risk factors. Early age at menarche was positively associated with breast cancer risk whereas early age at first full term pregnancy, high parity, and long duration of nursing were each negatively associated. We found high average body weight to be a risk factor, especially among women over age 60. Use of oral contracep tives after age 45 also was a risk factor, but use in general was not. Personal history of benign breast disease and history of breast cancer in first degree female relatives both increased risk. Multivariate analysis showed that each of these risk (or protective) factors was independently related to breast cancer. In addition to confirming most of the breast cancer risk factors of Western populations in a low risk developing Asian country, this study demonstrates a clear beneficial effect on breast cancer risk of lactation in a population characterized by a long cumulative duration of nursing in the majority of women. Finally, this study supports several other recent reports of a residual and beneficial effect of parity on breast cancer risk after controlling for age at first full term pregnancy. INTRODUCTION The incidence of female breast cancer in Shanghai is among the lowest in the world, based on data reported in the recent volume of Cancer Incidence in Five Continents (1). During the period 1973-1977, the average annual age-standardized inci dence rate of breast cancer in Chinese women of Shanghai was 19/100,000, about one-fifth the comparable rate in U. S. white women. However, breast cancer rates in young women of Shanghai (those under age 55) have been steadily increasing in recent years (Table 1). In an attempt to explain such increases as well as to better define the risk factors for breast cancer in Chinese women, we initiated a case-control study of breast cancer among female residents of the Shanghai urban area in 1984. In this paper, we describe nondietary risk factors. Dietary factors will be reported in a separate paper. METHODS Cases were histologically confirmed incident cases of breast cancer diagnosed between June 1, 1984 and May 31, 1985 among female residents of Shanghai aged 20-69 years. Cases were identified through the Shanghai Cancer Registry, a population-based registry covering the entire Shanghai urban area. The registry records all cases of cancer that are microscopically verified or mentioned on a death certificate. Five hundred sixty-eight cases were identified by the registry as eligible for inclusion in the study. We were unable to locate 30 patients, one patient had a mental disorder, and three others refused to be interviewed. Thus, 94% (534/568) of all eligible patients were interviewed. Controls were chosen from the general populations of the Shanghai urban area according to the following scheme: Shanghai is administra tively divided into 1450 neighborhood committees, each of which was assigned a unique number. We generated a list of 600 random numbers within the range of 1 to 1450, which determined the neighborhood committees from which the controls were selected, as cases entered chronologically into the study. The matched control for the ith case was selected from the neighborhood committee with an assigned num ber identical to the ith entry of the random number listing. We next randomly chose a household group from the approximately 20-30 household groups within each neighborhood committee. We identified all women belonging to the selected household group who were in the same 5-year age group (20-24, 25-29, .. . 65-69) as the index case. We randomly chose and ranked two of these as potential controls. The second control was asked to participate if the first control refused. In all but seven instances, we interviewed the first control chosen. All interviews were conducted in person by four trained interviewers employing a structured questionnaire. The interview took approxi mately an hour and requested information on certain demographic and anthropométriecharacteristics, family history of cancer, lifetime occu pational history including exposures to specific substances, smoking and drinking habits, medical and medication history including use of oral contraceptives and other hormones, exposure to x-rays, menstrual and reproductive history, and the usual adult consumption of 64 food groups. All interviews were conducted in the period 1984-1985. The mean time interval between diagnosis and interview of cases was 1.83 months, and 88% of cases were interviewed within 3 months of diagnosis. The mean time interval between interview of the index case and her matched control was 3.05 months. Five-hundred and one (94%) of the 534 casecontrol pairs were interviewed within 6 months of each other. We used standard matched pair methods (2) to analyze the interview data of the 534 completed pairs. Study variables were examined indi vidually and then simultaneously for confounding and interaction ef fects. For each study variable, odds ratios (RR3 estimates) and their corresponding P values and 95% CL were calculated. We used the exact binomial test on individual dichotomous variables. The multivariate conditional logistic regression method was used on single variables with more than two possible outcomes, as well as for multivariate analysis. All P values quoted are two-sided. RESULTS The majority (59%) of the cases were age 50 or older at the time of diagnosis; the mean age was 50.76 years. The mean age of the controls at the time of interview was 50.57 years. A similar number of cases (49%) and controls (51%) were born in Shanghai. However, cases (60%) were more likely than controls (53%) to have lived primarily in a city environment before age 15 (RR = 1.53, 95% CL = 1.13, 2.07 relative to a rural environment). Also, cases were more educated with 11% having attended university compared to 3% of controls (RR = 5.26, 95% CL = 2.82, 9.81 relative to no formal education), even though cases and controls reported similar levels of family income at three requested time points during the previous 20 years (1965, 1975, and 1982). Table 2 presents data on menstrual and reproductive char acteristics in cases versus controls. Age at menarche was in versely related to risk of breast cancer (P value for linear trend Received 9/10/87; revised 12/18/87; accepted 1/6/88. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1The work was supported by a grant from the Chinese Ministry of Public Health, Public Health Service Grant K04 CA00884 from the U.S. National Cancer Institute, and Grant SIG-2A from the American Cancer Society. Presented at the Fifth Symposium on Epidemiology and Cancer Registries in the Pacific Basin, November 16-21, 1986, Kauai, HI. 2 To whom requests for reprints should be addressed, at the Department of 3The abbreviations used are: RR, relative risk; CL, confidence limits; FTP, Preventive Medicine, University of Southern California School of Medicine, Los full term pregnancy; OC, oral contraceptive. Angeles, CA 90033. 1949 RISK FACTORS FOR BREAST CANCER IN CHINESE WOMEN IN SHANGHAI Table 1 Average annual age-specific incidence rates of female breast cancer in Shanghai risk of breast cancer. The inverse association remained signifi cant after adjustment had been made for age at first FTP and Rate/100,000 duration of nursing (Table 3). Women with five or more FTPs group0-1415-2425-3435-4445-5455-6465-7475+Age-standardized Age experienced a risk of breast cancer only 39% that in primiparous women (95% CL = 0.19, 0.80). Increasing duration of nursing was also significantly associated with decreasing risk of breast cancer. The association remained significant after we controlled for age at first FTP and number of FTPs (Table 3). Relative to women whose total nursing time was under 3 years, long-term nursing mothers (more than 9 years) exhibited a 63% reduction (worldpopulation) in risk of breast cancer (95% CL of RR = 0.14, 0.98). The rate1973-19760.00.35.727.740.957.664.652.817.61977-19800.00.36.130.047.155.053.961.218.01981-19840.00.26.243.448.759.768.459.720.9 protective effect of long term nursing was independent of age at diagnosis; there was no significant interaction between age and the effect of total years of nursing (P = 0.53). Table 2 Menstrual and reproductive history of breast cancer cases and controls Risk of breast cancer was positively associated with high CL0.71, absolute body weight (Table 4). The RR for breast cancer in Age (yr)18+17161514131 at menarche women weighing 60 kg or more relative to those weighing 45 kg or less was 2.41 (95% CL = 1.38, 4.22). There was no 2.370.88, 2.661.06,3.210.96, increase in risk of breast cancer among women weighing 4660 kg relative to those weighing 45 kg or less. There was a 3.011.11,3.321.16,4.151.08,3.190.93, significant interaction between age and the effect of excess earlierUsual 2 or weight (P = 0.01). The elevation in risk for breast cancer among women weighing over 60 kg showed a steady increase with age, (day)24 cycle length and was especially pronounced in women over age 60. Among under25-3132 and this group of older women, the RR for breast cancer in those overNever and 1.760.54, weighing 61 kg or more relative to those weighing 50 kg or less 2.070.74, regularAge was 4.34 (95% CL = 1.41, 13.37). In contrast to average (yr)19 at first FTP absolute weight, high average relative weight (as measured by under20-2425-2930 and overNulliparousPostmenopausalNoYesAge and 1.571.09,2.481.55,4.591.28,3.450.62, Table 3 Distribution by number of FTP and duration of nursing among parous cases and controls Pairs in which either the case or the control was nulliparous were excluded from the analysis. There were 429 pairs of parous women. RR CL)7710074611173522011040241.000.61 (95% CL)1.00°0.72 (95% 1.750.62, Number FTP12345+Duration of (yr)"44 at menopause under45-4950 and 1.670.77, (0.39,0.47 (0.45,0.67 (0.28,0.33(0.19,0.19(0.11,1.11 (0.38,0.59 1.56 and overCases2751891158610957373661131868182152646823430042135134Controls45659610584944521397981892230135334423330143140128RR.00.29.53.84.70.922.19.86.00.28. (0.30,0.39(0.19,1.05(0.64,1.00*0.81 " Include only case-control pairs of age 50 and over. nursing(mo)Never1-3637-7273-108109+Cases1161137855674726596138RRControls of test = 0.004). Women who began menstruation at age 12 or younger had a RR of 2.19 (95% CL = 1.16, 4.15) relative to those who began menstruation after age 17. Short menstrual cycles were associated with an increased risk of breast cancer. Women reporting usual cycle lengths of shorter than 25 days had a 1.86 (95% CL = 1.08, 3.19)-fold increased risk of breast cancer compared to those with cycle lengths of 25 to 31 days. A similar number of cases and controls were postmenopausal (a subject was classified as postmenopausal if there had been no menstrual periods for at least 6 months prior to the time of diagnosis/interview), and most of the subjects achieved meno pause naturally (91% of cases and 93% of controls). Among postmenopausal women, age at menopause was not signifi cantly associated with breast cancer risk (P value for linear trend test = 0.20). Excluding women who used oral contracep tives after age 45 did not affect the results relating to age at menopause. Delayed age at first FTP and nulliparity were associated with a significantly elevated risk of breast cancer. Compared to parous women whose first FTP occurred before the age of 20, those who had their first FTP after age 29 showed a RR of 2.67 (95% CL = 1.55, 4.59). The comparable RR for nulliparous women was 2.10 (95% CL = 1.28, 3.45). Increasing parity was significantly associated with decreasing 1950 (0.68,1.000.58 (0.40,0.20(0.10,0.19(0.08,0.96)0.79)0.60)0.34)1.79)0.84)0 (0.53,0.35(0.16,0.37(0.14,1.16)1.21)1 1RR adjusted for age at first FTP and duration of nursing. ' RR adjusted for age at first FTP and number of FTP. Table 4 Average weight of breast cancer cases and controls (kg)45 Weight CL0.61, below46-5051-5556-6061 and 1.260.78, 1.610.56, 1.271.38,4.220.74, aboveUnder and 5050 age below51-6061 and aboveAge and 1.580.82, 5.250.88,2.111.14,5.150.52, 50-5950 below51-606 and aboveAge 1 and over50 60 and below51-6061 and 1.441.41, and aboveCases88143164825710510314698724575619Controls90169149103231131027888 13.37 RISK FACTORS FOR BREAST CANCER IN CHINESE WOMEN IN SHANGHAI the Quetelet's Index = weight/height2) was only weakly asso ciated with breast cancer risk. Nonetheless, similar to the trend observed with absolute weight, the association with high Quetelet's Index was strongest among women age 60 or older. A history of any OC use and the total duration of use were similar between cases and controls (Table 5). However, there was a significant excess of cases who used OCs during their perimenopausal years. Thirteen cases and only four controls used OCs after age 45 (RR = 4.00, 95% CL = 1.15, 16.59). Furthermore, the mean duration of use after age 45 was longer among case users relative to control users (3.5 versus 1.8 years). Seven cases but no controls reported four or more years of OC use after age 45. A similar number of cases and controls (48% cases, 51 % controls) reported an abortion, and the total number of abor tions was comparable between the two groups (Table 5). Slightly more cases than controls reported having had an abortion prior to first FTP (nulliparous women who had had abortions were included). The excess was confined to women under age 40. Twelve cases versus five controls indicated such an experience (RR = 2.40, 95% CL = 0.84, 7.08). Significantly more cases than controls reported a history of benign breast disease (RR = 4.56, 95% CL = 2.24, 9.58) (Table 6). Sixty-one % of such cases were diagnosed with the benign condition more than 10 years prior to the diagnosis of breast cancer; the mean interval was 12.8 years. Excluding those with a recent history (10 years or less) had little effect on the strength of the association (RR = 4.60). Table 5 Use of oral contraceptives and abortion experience among cases and controls CL0.74, Ever OCNoYesDuration used 1.510.69, (yr)4 less5-910 or 1.530.49, 1.890.62, 3.171.15, moreUsed or Eight cases (and five controls) reported a personal history of other cancers and similar numbers of cases and controls re ported a history of cancer among first degree relatives (RR = 1.12) (Table 6). However, 17 cases compared to only six con trols reported a history of breast cancer among female first degree relatives (RR = 2.83, 95% CL = 1.09, 7.32). Eleven cases (and three controls) indicated their mother as the affected family member; the remaining six cases indicated a sister as the affected family member. Of the remaining two controls with a positive family history, one had a daughter with breast cancer, and one had a mother and a sister with breast cancer. There was no association, positive or negative, between risk of breast cancer and occupational exposure to chemicals, ciga rette smoking, and alcohol consumption. Forty-two cases and 53 controls had ever smoked cigarettes (RR = 0.76, 95% CL = 0.49, 1.19). Only 12 cases and 14 controls had ever drunk alcoholic beverages regularly (at least once a week). The conditional logistic regression method was employed to examine the simultaneous effect of all significant risk factors identified by the univariate analysis. When the individual risk factors were introduced into the regression model in the order shown in Table 7, the additional effect of each of the risk factors was statistically significant. Similar results were obtained when we included childhood residence (rural, town, city) and highest level of formal education in the regression model prior to the stepwise procedure. Unadjusted and adjusted regression coef ficients for each of the risk (or protective) factors are presented in Table 7. Adjusted and unadjusted regression coefficients were similar for all factors except the three highly correlated reproductive factors: age at first FTP, number of FTPs, and duration of nursing. As expected, inclusion of these three cor related variables in a regression model weakened somewhat the association of each of these variables with the disease. None of the associations reported above showed any appreciable change when dietary findings were taken into consideration. DISCUSSION 45NoYesEver OC after age This represents the first large population-based case-control study of breast cancer to be conducted in the People's Republic of China. The study demonstrates a high degree of reproduciabortionNoYesTotal1234 had bility of most established menstrual and reproductive breast 1.150.64, cancer risk factors of Western populations in a low risk devel oping country. Henderson et al. (3) have interpreted these risk 1.140.68, 1.370.46, factors under a unifying hypothesis that endogenous levels of 1.720.38, biologically available estrogen, and perhaps prolactin, play a or moreCases435996320165211327625814983188Controls43995622112530426227216482197RR1.001.061.030.971.401.004.001.000.890.850.960.891.0795% 3.00 critical role in the genesis of breast cancer. Had abortion prior to first FTP 42 37 1.14 0.72,1.84 Onset of menstruation is shown to relate to risk over a wide 16.590.70, Age at diagnosis (yr) Under 40 40 or over 12 30 5 32 2.40 0.93 0.84,7.08 0.54,1.58 Table 6 Personal and family history of benign breast disease and cancer Cases Controls RR 95% CL Personal history of benign breast disease No Yes 493 41 525 9 1.00 4.56 2.24,9.58 First degree relative had cancer No Yes 420 114 429 105 1.00 1.12 0.82,1.54 Female first degree relative had breast cancer No Yes 517 17 528 6 1.00 2.83 1.09,7.32 Table 7 Unadjusted and adjusted regression coefficients for various risk (or protective) factors of breast cancer 0"-0.0780.6200.012-0.168-0.0811.8421.0681.429 P*)(0.052)(0.043)(0.194)(0.004) .;-0.1050.5660.072-0.229-0.1901.3860.9341.5161.041Adjusted FactorAge (yr)Usual at menarche 25daysAge cycle length under (yr)Number at first FTP FTPDuration of (yr)Used of nursing 4561+OC after age weightHad kg average diseaseFemale benign breast relativehad first degree breast cancerUnadjusted " Parameters estimated from conditional logistic regression model which in cluded childhood residence, highest level of formal education, and all factors in the table. * Two-sided P value associated with adjusted /3/SE(adjusted ß),where SK(adjusted >¡) = standard error of adjusted 0. 1951 RISK FACTORS FOR BREAST CANCER IN CHINESE WOMEN IN SHANGHAI age range; risk increases almost monotonically with single decrements in age at menarche. Nulliparous women are at high risk and early age at first FTP is a protective factor for breast cancer in this population. The frequent observation (4, 5) that risk in women with a very late first pregnancy actually exceeds that in nulliparous women also is confirmed in this study. A late menopause had no apparent effect on breast cancer risk in Shanghainese women. As observed by others studying Western populations (6, 7), there is an age-dependent relation ship between unadjusted body weight and breast cancer risk in Chinese women. The effect of high body weight is most appar ent in the older age groups. This increase in breast cancer risk with increased body weight, especially among postmenopausal women, might be explicable by the associated increased levels of endogenous estrogens derived from peripheral conversion of adrenal androgens (3). Our study also confirms the importance of a personal history of benign breast disease and a family history of breast cancer in a first degree relative as breast cancer risk factors in a low risk Asian population. The relative increase in risk associated with each of these conditions is at least as high as that seen in high risk countries (8, 9). Two recent articles have reported a beneficial effect of lacta tion on risk of breast cancer in premenopausal Western women (10, 11). Our study confirms this negative association in Chinese women, independent of age or menopausa! status. The large cumulative number of nursing months by a high propor tion of mothers in our population allows for more precise estimates of the effects of lactation on breast cancer risk than those obtained from most previous epidemiológica! studies. Henderson et al. (12) recently reviewed the epidemiológica! and experimental evidence which suggests that the cumulative num ber of ovulatory cycles is directly related to breast cancer risk. Based on this hypothesis, a beneficial effect of long duration of nursing, as observed in the current study, comes as no surprise, as nursing results in a substantial delay in reestablishment of ovulation following a completed pregnancy. It is useful to compare the observed risk estimates associated with lactation to those expected using the published statistical model of breast cancer incidence of Pike et al. (5). This model has the form I(t) = a[d(t)]4S where I(t) is the probability of being diagnosed with breast cancer at age t (the incidence rate at age t) and d(t) is the "relevant age" of the breast tissue. d(t) incorporates the effects of age at menarche, age at first FTP and age at menopause: the model assumes that "breast tissue aging" starts at menarche, moves regularly at rate/) = 1 to first FTP when there is a one-time increase in d(t). After first FTP, d(t) slows to rate f¡=0.7 until age 40 when it experiences a linear decrease to 0.1 at menopause, after which the rate stays constant at 0.1. Using a model developed by Risch et al. (13), we can calculate that 1 year of lactation results, on the average, in 8.1 months of anovulation. We can estimate that in a typical anovulatory monthly cycle induced by lactation, breast tissue aging is comparable to that of a postmenopausal woman. The median age (reported age +0.5) at menarche, at first FTP, and at menopause of our population controls are 14.6, 22.7, and 48.3 years, respectively. Substituting these values in the Pike et al. model, we obtained a predicted RR of 0.70 for a Shan ghainese woman of age 52 (median age of our case series), who has nursed for 5 years, relative to her counterpart who has never nursed. The RR actually observed in our study was 0.67. Most previous epidemiológica! studies have demonstrated a protective effect on breast cancer risk of an early first FTP (8). This observation is confirmed in the current study. Recently, several studies in other populations have observed a residual protective effect of an increasing number of births (14-17). In Shanghainese women, each subsequent full term pregnancy after the first was associated with an approximately 15% further reduction in breast cancer risk after controlling for age at FTP and other menstrual and reproductive factors. Several other factors evaluated in this study are of interest in comparison to findings from previous epidemiológica! studies in higher risk populations. Whereas OC use during the middle reproductive years has no apparent effect on breast cancer risk, five studies have reported on use during the perimenopausal period and all find some increase in risk relative to nonusers (18-22). Henderson et al. (12) have argued that this effect is explicable on the basis of greater hormonal exposure to breast tissue when on OCs than would have "normally" occurred during this period of frequent anovulatory cycles. We observe a substantial influence of OC use during the perimenopausal period on breast cancer risk in Shanghai, consistent with this hypothesis. Epidemiológica! studies have been inconsistent in their find ings relating abortion to breast cancer risk. However, two studies concentrating on breast cancer risk following a first trimester abortion before a full term pregnancy in young women all found an increase in risk (23-24). Self-reported abortion appears to be unrelated to risk overall in this low risk popula tion, but our results are consistent with an elevation in risk in young women following an abortion prior to a full term preg nancy. Significant associations between alcohol consumption and breast cancer have recently been reported, with relative risk estimates of approximately 1.5-2.0 (25-30). No biological mechanism has been proposed to explain this association. We do not observe an association between alcohol consumption and breast cancer risk in the present study; however, only a few cases and controls had ever drunk alcoholic beverages at least once a week. 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