GYNECOLOGIC ONCOLOGY 32, 41-45 (1989)

The contributions of estrogen replacement therapy, smoking, regimen, or time since discontinuation of use on the risk

and other risk factors to the development of advanced-stage (2- of advanced-stage endometrial cancer is not yet clear.

4) endometrial cancer were evaluated in a case-control study of In reviewing the evidence on smoking and estrogen- women 40-69 years old from upstate New York. Eighty-four cases related disease, Baron [15] inferred that smoking may and 168 matched community controls were interviewed in person have an “anti-estrogenic” effect which could modify the about estrogen exposure and other risk factors. Despite a statistically risk of estrogen-related disease, including endometrial significant increase in risk with longer use of estrogen pills (P < cancer. Some data suggest that women who smoke are O.OS), estrogen exposure actually contributed little to the overall at lower risk of developing endometrial cancer than women risk of advanced-stage endometrial cancer. Other physical conditions (increased weight, lower parity, diabetes) and socioeconomic factors

who are nonsmokers 116-181, and we [ 191 found that

(education, access to medical services) largely accounted for ad- smoking modifies the risk associated with weight for early-

vanced-stage disease. The evidence in this study does not support stage endometrial cancer.

the hypothesis that women who smoke have a lower risk than In the present study, we have examined the risk of

nonsmokers of developing advanced-stage endometrial cancer. advanced-stage endometrial cancer associated with es-

0 1989 Academic Press, Inc. trogen use and several other established risk factors, as well as the relative contributions of the significant risk

INTRODUCTION factors. We have also examined the hypothesis that smoking reduces the risk of advanced-stage endometrial

The association between estrogen use and endometrial cancer. cancer has been well established [l-13]. While most case- control studies have focused on early-stage disease, several METHODS studies have found a significant association of estrogen use with advanced-stage tumors, [6,8,9,14]. However, Cases. The diagnostic files of a stratified sample of the association tends to be weaker for advanced-stage hospitals in upstate New York were searched to identify than for early-stage tumors, suggesting that estrogen use women between the ages of 40 and 69 who had been contributes less to the development of advanced-stage initially diagnosed as having advanced-stage (stages 2- endometrial cancer. The influence of estrogen dosage, 4) endometrial cancer in 1979-1981. We then reviewed

the medical records, using the International Federation

Advanced-Stage Endometrial Cancer: Contributions of Estrogen Use, Smoking, and Other Risk Factors’

CHARLES LAWRENCE, PH.D., *,* IRENE TESSARO, M.A., M.S.N. ,t SALLY DURGERIAN, B.S. ,§ THOMAS CAPUTO, M.D. ,)I RALPH M. RICHART, M.D. ,ll AND PETER GREENWALD, M.D., DR.P.H.$

*Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, New York 12201; fStokes County Health Department, Danbury, North Carolina; #National Cancer Institute, Division of Cancer Prevention and Control, Bethesda, Maryland;

JHoward Hughes Medical Institute School of Medicine M-013, VC San Diego, La Jolla, California; JINew York Hospital-Cornell Medical Center, Department of Obstetrics and Gynecology, New York, New York; and lcolumbia University College of Physicians

& Surgeons, New York, New York

Received April 20, 1987

Address inquiries and reprints to: Dr. Charles E. Lawrence, Wadsworth of Gynecology and Obstetrics (FIGO) staging system,

Center for Laboratories and Research, New York State Department and 120 living patients who were confirmed to have had

of Health, Albany, NY 12201 advanced-stage cancer were selected for the study. In ’ This investigation was supported by Grant 1ROl CA 24367 awarded 20 cases, physicians refused us permission to interview

by the National Cancer Institute, National Institutes of Health. the patients, and 16 of the 100 contacted declined to ’ To whom correspondence and reprint requests should be addressed. participate in the study.

41 0090~8258189 $1.50

Copyright 0 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.

42 LAWRENCE ET AL.

Controls. Controls were selected from the files of licensed drivers maintained by the New York State De- partment of Motor Vehicles. Drivers were matched to cases by county of residence and year of birth, Two controls with intact uterus at the reference date were selected at random from this pool for each patient, and 69% agreed to participate in the study.

Data collection. Trained interviewers conducted a structured interview in the home of each participant to collect information on medical history (menstrual, re- productive, menopausal, and general health), character- istics of menopausal estrogen use, smoking history, health care behavior, sociodemographic characteristics, and ill- ness behavior related to symptoms and diagnosis. Only events occurring up to the reference date were included. The interviews averaged 45 min.

Recall of estrogen use was aided by color pictures of common estrogen preparations. For study purposes es- trogen use was defined as any use of estrogens for any length of time for relief of menopausal symptoms. In- dividuals who had used estrogen were asked the brand name, dosage, dates and pattern of use, and mode of administration.

Current and former smokers were asked how much they smoked at the reference date and earlier, the years they first/last smoked, and the total number of years they smoked up to the reference date.

Analysis. Matched logistic regression [20,21] was used to test hypotheses and analyze multivariate effects. Given the published evidence of an elevated risk for estrogen use, a single-sided test of significance was employed for testing the estrogen hypothesis. Maximum likelihood pa- rameter estimates and likelihood ratio test statistics were employed throughout the analysis. The odds ratio ap- proximation to the relative risk was used as a measure of strength of association.

To measure the relative contribution of each variable, we included an entropy measure of association R [221. This measure is a generalization of R2 in least-squares regression. As such it measures the percentage contri- bution of each additional variable. However, since perfect separation of cases and controls is required for a 100% score, the value of R for case control studies tends to be smaller than values of R* for least-squares regres- sion [23].

RESULTS

Estrogen use. Several variables of estrogen exposure were examined simultaneously in a stepwise forward regression analysis: any use of estrogen replacement therapy; conjugated estrogen use; use (and duration of use) of pills, injections, and creams; and combinations

TABLE 1 Duration of Use of Estrogen Pills by Advanced-Stage

Endometrial Cancer Cases and Controls

Patients Controls Duration (years) (n = 84) (n = 168)

None 57 126 <1 8 21 1-5 10 15 >5 5 5 Unknown 4 I

” Trend statistically significant (P < 0.05).

Odds ratio”

1.00 0.84 1 Al 2.21 -

and interactions of these variables. The risk of advanced- stage endometrial cancer increased significantly (P < 0.05) only with the duration of use of estrogen pills (Table 1).

No significant association was found for any other variables or for interaction between longer estrogen use and dosage >0.625 mg, continuous mode of administration, or recency interval (the time interval from the last use of estrogen to diagnosis).

To determine whether the association with estrogen use may be influenced by other established risk factors, another multivariate analysis was undertaken. Medical risk factors considered were a history of diabetes, hy- pertension, gallbladder disease, arthritis, or ovarian cysts. Additional parameters were weight, parity, various char- acteristics of menstruation and menopause, socioeconomic characteristics, and health care indicators.

Increased weight, lower parity, a history of diabetes, less education, and a greater time interval since a last medical visit were all significantly associated with risk of advanced-stage endometrial cancer (Table 2). As in- dicated in Table 2, the association between risk and du- ration of estrogen use remained significant (P < O.OS), while controlling for these other significant factors. This table also indicates that only a small portion of the overall risk of advanced-stage disease is associated with estrogen use, R = 2.63%. By comparison, body weight explains a much larger proportion of the risk, R = 14.11%.

Smoking. No index of smoking, including amount and duration, was significantly associated with risk for ad- vanced-stage disease. For example, there was no sig- nificant change in risk with the amount smoked (P > 0.3) for either current or former smokers (Table 3). Logistic regression analysis of the smoking variables and the po- tentially confounding risk factors listed in Table 2 yielded the same results.

In a study of early-stage endometrial cancer [193, we found a strong interaction between smoking and body weight as risk factors. In the present study this interaction was not significantly associated with risk (P > 0.3).

ESTROGEN, SMOKING, AND ENDOMETRIAL CANCER 43

TABLE 2 Logistic Regression of Significant Factors in Advanced-Stage Endometrial Cancer”

Likelihood 95% confidence Measure ratio test interval of statistic Odds association

Factor Unit Zb (P <I ratio’ Lower Upper (R”)

Weight Pounds 3.760 0.0003 1.02 1.01 1.03 14.11 Time since last

medical visit Years 2.615 0.009 1.21 I .05 1.39 5.21 Parity Live births -2.587 0.009 0.80 0.68 0.95 4.23 Education Years - 2.444 0.01 0.84 0.73 0.96 3.45 Diabetes Yes/no 2.352 0.01 4.14 1.27 13.49 3.37 Estrogen pill use Months 2.103 0.03 1.01 1.00 1.03 2.63

” Log likelihood, 61.8094. ’ Logistic regression coefficient standardized value. ’ e*, where b = logistic regression coefficient. Each odds ratio is adjusted for all other variables in the table and represents the proportional

change (increase or decrease) in relative odds per unit of the independent variable (e.g., the odds ratio for weight increases by a factor of 1.02 or <2% for each pound of body weight).

d Entropy-based measure of association [22]. This measure is a generalization of the R2 measure used in least-squares regression. It gives the percentage of variation in the risk of disease explained by each variable. Total R = 33%.

DISCUSSION

Despite a statistically significant correlation between duration of estrogen use and advanced-stage endometrial cancer, estrogen use actually contributed little to the risk of advanced-stage disease. Other physical conditions (in- creased weight, diabetes, lower parity) and behavioral factors (little education, less access to health care) largely accounted for the risk of advanced-stage disease in this study. Unlike other studies [16-191, we found no evidence to support a lower risk of endometrial cancer for smokers.

The response rate for this study was somewhat low (69%), as in other studies of this disease which employed personal interviews [12]. Some physicians denied us per- mission to interview their patients. Although these denials could have resulted in sampling bias [24], we have no reason to believe that the physicians based their denials on any of the factors found significant in the study. Fur-

TABLE 3 Smoking by Advanced-Stage Endometrial Cancer Patients

and Controls

Patients Controls Smoking status (n = 84) (n = 168)

Never smoked 41 78

Current smokers 6 1 pack/day 13 39 > 1 pack/day 6 12

Former smokers s 1 pack/day 28 64 > 1 pack/day 14 26

a Trend not statistically significant (P > 0.3).

Odds ratio”

1.00

.63

.9.5

.83 I .02

thermore, confounding was controlled for in the analysis, and our findings agreed with previously reported findings for many of the risk factors.

Since only living patients were included in the study, a selective survival bias may have influenced the results. However, the average time from diagnosis to interview was 6 months; thus the mortality loss was small.

Our finding that a longer duration of estrogen use was associated with endometrial cancer is consistent with past reports [4-6, g-121. Unlike other studies, however, we did not find an increased risk with dose greater than 0.625 mg [3-5,8,10-121 or with continuous as opposed to cyclic administration [3,4]. We also found no decrease in risk after cessation of use, in agreement with the recent findings by Shapiro et al. [14] but not with earlier studies [3, 1 l-121.

Obesity is the most important and most consistently found single risk factor for endometrial cancer [6,9,10,12,13,27-291. Our findings support this observation with regard to advanced-stage disease. Our data also support the findings of an increased risk for women with diabetes [5,6,10,28] and lower parity [3,10,12,13,27-291. However, our analysis differs from previous studies. In previous studies, the data were analyzed as if the estrogen factors all operated independently. This is clearly not the case for several of these variables. For example, time since first use and duration of use are not independent. The multivariate analysis shown here takes into account such nonindependent effects.

Our finding of less education among women diagnosed with advanced-stage endometrial cancer has not been shown previously. Some studies have suggested that the positive association observed between higher socioeco-

44 LAWRENCE ET AL.

nomic status and endometrial cancer[27] can be partially M., and Garcia, R. Endometrial cancer and estrogen use: Report explained by the tendency of better-educated women to of a large case-control study, N. Engl. J. Med. 300, 9-13 (1979).

use estrogen replacement therapy [12,30,311. Those stud- 9. Hulka, B. A., Fowler, W. C., Kaufman, D. G., Grimson, R. C.,

ies, however, focused primarily on early-stage cases, Greenberg, B. G., Hogue, C. .I., Berger, G. S., and Pulliam, C.

which are more strongly associated with estrogen use. C. Estrogen and endometrial cancer: Cases and two control groups

In our present study both a longer duration of estrogen from North Carolina, Amer. J. Obsret. Gynecol. 137, 92-101 (1980).

use and lower education were significantly related to the 10. Spengler, R. F., Clarke, A. E., Woolever, C. A., Newman, A.

M., and Osform, R. W. Exogenous estrogens and endometrial risk of advanced-stage endometrial cancer, suggesting cancer: A case-control study and assessment of potential biases, that the contribution of estrogen use is independent of Amer. J. Epidemiol. 114, 497-506 (1981).

that of socioeconomic level. We also found that the risk 11. Stavraky, K. M., Collius, J. A., Donner, A., and Wells, G. A. A

of this disease increased between the time of the last visit to a health care provider and the diagnosis. Thus a high proportion of the risk of advanced-stage endometrial 12 cancer was explained by socioeconomic factors and health care behavior. These factors may be associated with delays in disease diagnosis rather than with disease etiology. 13.

Unlike studies which have found a lower risk of en-

comparison of estrogen use by women with endometrial cancer, gynecologic disorders and other illnesses, Amer. J. Epidemiol. 141, 547-555 (1981).

dometrial cancer for smokers [16-191, we found no evi- dence of such a trend in advanced-stage disease. This l4 difference may reflect a physiologic difference of advanced- stage tumors. It may also arise from a difference in health behavior of women whose tumors become advanced in stage. The fact that these patients visited doctors less 15. often suggests that they may have been disposed toward other untoward health behaviors, including smoking. If 16. so, any reduction in risk associated with smoking could be masked by their overall health behavior. 17.

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