Cancer Causes and Control, 2, 389 - 394

Risk of breast cancer in relation to use of combined oral contraceptives near the age of menopause

David B. T h o m a s , E l i z a b e t h A. N o o n a n , a n d t h e W H O C o l l a b o r a t i v e S t u d y o f N e o p l a s i a a n d S t e r o i d C o n t r a c e p t i v e s

(Received 3June 1991; accepted in revised form 17July 1991)

Data from a multinational, hospital-based, case-control study were analyzed to determine whether use of combined oral contraceptives (OC) around the time of menopause preferentially increases risk of breast can- cer. Results show that the relative risk (RR) of breast cancer was increased in women of all ages who had used oral contraceptives within the past year, but not to a greater extent in women near the age of menopause than in younger women. RRs did not increase with duration of OC use after age 45 in either pre- or postmeno- pausal women. RRs also were not found to be higher in women who were using OCs near the time of either a natural or artificial menopause than in women who used them at other times. This study thus provides no support for the hypothesis that OCs enhance risk of breast cancer by a greater amount when taken around the time of menopause than when taken at other times.

Key words: Breast cancer, case-control study, international, menopause, oral contraceptive use.

I n t r o d u c t i o n

Risk of breast cancer increases with later age at meno- pause. It has been hypothesized I that this is due to pro- longed stimulation of the mammary epithelial cells by ovarian estrogens and possibly progesterone. Since oral contraceptives (OC) contain both an estrogen and a progestin, use of these products late in a woman's potentially fertile years might be expected also to enhance risk of breast cancer because, similar to a late menopause, such use might extend the period of exposure to ovarian hormones. Data from several epi- demiologic studies have been analyzed to address this question (reviewed by Thomas:). Three studies have

found increased risks in women over age 45 years who had used OCs within the past year, 3 were current users, 4 or had ever used these products after age 45. 5 These findings were not confirmed by Rosenberg et al, 6 who found no increase in risk in women over age 40 who had used OCs within the previous year, or by Stanford et al 7 who found no increase in risk with dur- ation of use after age 40, in either pre- or postmenopau- sal women. Also, although risk in women who used OCs up to two years prior to diagnosis was signifi- cantly elevated in 40- to 44-year-old women in the Nurses' Health Study, 8 it was not elevated similarly in

Dr Thomas and Ms Noonan are with the Fred Hutchinson Cancer Research Center, l 124 Columbia Street, Seattle, WA 98104, USA. The Data Collection Centers and the Principal Investigators, Co-investigators, and Pathologists at each participating center in alphabetical order by country, are given in the Appendix. Address correspondence to Dr Thomas. This research received financial support from the Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, and from Contract No. NO1- HD-52901 from the US National Institute of Child Health and Human Development.

© 1991 Rapid Communications of Oxford Ltd Cancer Causes and Control. Vol 2. 1991 3 8 9

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older women. This is a report of results from a large international case-control study providing additional information on the possible influence of OC use near the time of menopause on risk of breast cancer.

Methods The methods used in this study have been described previously. 9 Briefly, women born either after 1924 or after 1929 (depending on when OCs were first locally available), with cancers of the breast, cervix and corpus uteri, ovary, and hepatobiliary system, were recruited from one or more hospitals in participating centers located in three developed countries (Australia, Ger- many, and Israel) and eight developing countries (Chile, China, Colombia, Kenya, Mexico, Nigeria, Philippines, Thailand). Case accrual began between 1979 and 1982, and ceased between 1982 and 1988, depending on the country. Recruitment was limited to cases who resided within a defined geographic area served by each hospital. Insufficient numbers of women with breast cancer were recruited from Nigeria for inclusion in these analyses.

Controls were selected from among women admit- ted to other than obstetric and gynecologic wards who met the same age and residential criteria for eligibility as the cases, and who were not hospitalized for treat- ment of conditions considered a priori either to be related to OCs or to alter contraceptive practices. Approximately two controls were selected for each case, but controls were not matched to individual cases. Since this was a study of multiple tumors, more than two controls were thus available for each case of breast cancer. The control group consisted of women with a wide variety of conditions; OC use did not vary greatly among women in different diagnostic groups.

A standardized questionnaire was administered to each study participant while hospitalized to obtain information on known and suspected risk factors for the neoplasms under study, and OC use. A calendar and samples of locally available OCs were used to facilitate recall of products taken and times of use.

Slides from all cases were sent to a single pathologist for diagnostic confirmation and uniform histologic classification. Only cases considered to have invasive carcinoma of the breast by the reference pathologist are included in this report.

Of the 2,996 cases and 20,216 controls who were identified as eligible for inclusion in the study, 161 cases and 995 controls were not interviewed, and 39 cases and 321 controls did not give adequate infor- mation on OC use or on one or more variables that appeared to confound the relationship between breast

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cancer and OCs. Thus, 2,796 (93.3 percent) of the eli- gible cases and 18,900 (93.4 percent) of the eligible con- trols are included in the analyses.

Unconditional logistic regression analyses ~° were utilized to estimate relative risks (RR), adjusted simul- taneously for various potentially confounding vari- ables. All variables were entered into regression models as categorical variables. Results are presented with 95 percent confidence intervals (CI). Since RR estimates in women who ever used OCs did not differ signifi- cantly among the 12 participating centers, data from all centers were combined in all analyses. Because cases tended to be older than controls, and both the ratio of controls to cases and the prevalence of OC use varied among centers, all RR estimates were controlled for age and center. Additional variables were considered con- founders if their inclusion in a regression model gave an associated chi-square test for goodness-of-fit that was significant (P < 0.05), and if the resultant estimate of the RR in relation to OC use was altered appreciably. Variables that met these criteria were: number of preg- nancies; an index of socioeconomic status based on the woman's occupation and years of education; use of an intrauterine device; and menopausal status. Use of estrogens for more than one year for treatment of menopausal symptoms was reported by only 17 cases and 72 controls, was not associated with risk of breast cancer, and therefore was not considered further in the analyses.

Women with an artificial menopause were defined as those with: (i) a bilateral oophorectomy prior to natural cessation of menses (89 cases and 525 controls); (ii) a hysterectomy prior to natural menopause, who did not know whether their ovaries were removed (101 cases and 430 controls); or (iii) a history of X-ray treat- ment that resulted in cessation of menses (10 cases and 35 controls). Women were considered to have gone through natural menopause if their last menstrual period had occurred more than 12 months prior to diagnosis (for cases) or hospitalization (for controls), and they were not currently pregnant, lactating, or using injectable hormonal contraceptives.

Results

Data from 76 percent of the cases and 69 percent of the controls included in this paper constituted the data set utilized for an initial report on breast cancer and OCs from this study? That report, based on data accrued by February 1986, revealed an increase in RR of breast cancer (RR = 1.7, CI = 1.3-2.1) in current users of OCs, and a decline in risk with time since last use, regardless of duration of use. After stratifying on time

Breast cancer and oral contraceptives

Table 1. Estimated relative risks a of breast cancer in women of various ages who used oral contraceptives within the past year and more than one year previously

Age at N u m b e r of cases N u m b e r of controls

diagnosis Recent b users Other c users Nonusers Recent b users Other ~users Nonusers

RR CI RR CI

Recent users Other users

< 4 0 118 258 401 1,190 2,583 5,075 1.3 0.99-1.6 1.0 0.84-1.2 40-44 77 176 363 210 1,052 1,807 2.1 1.5 -2.9 1.1 0.86-1.4 45-49 46 196 547 129 892 2,381 1.4 0.94-2.1 1.1 0.87-1.3 > 4 9 5 102 471 29 616 2,673 0.88 0.32-2.4 1.04 0.8 -1.3

TotaF 246 732 1,782 1,558 5,143 11,936

Relative risk (RR) adjusted for age, center, number of pregnancies, socioeconomic status, use of an IUD, and menopausal status; CI = 95 percent confidence interval. b Use within the past year. " Last use more than one year previously. d Excluding 36 cases and 263 controls with unknown time since last use of oral contraceptives.

Table 2. Estimated relative risks a of breast cancer in women age 45 and over in relation to duration of use of oral contraceptives before and after age 45 b

Months Use before age 45 years c Use after age 45 years d Of use

No. of subjects b RR CI No. of subjects RR

Cases Controls Cases Controls

CI

Nonusers 1,018 5,054 1.0 1,018 5,054 1.0

Users < 12 118 646 1.2 0.91-1.4 39 117 1.2 0.82-1.8 12-48 78 462 0.86 0.66-1.1 63 172 1.4 1.04-2.0 49- 96 55 258 0.94 0.68 - 1.3 17 54 1.4 0.76- 2.5 > 96 76 235 1.3 0.94-1.7 1 6 1.4 0.17-12.3

Relative risk (RR) adjusted for age, center, number of pregnancies, socioeconomic status, use of an IUD, menopausal status, and use before/ after age 45 years; CI = 95 percent confidence interval. b Excluding 1,406 cases and 12,076 controls less than age 45 years, and 23 cases and 113 controls with unknown duration of use.

Excluding 22 cases and 56 controls that used oral contraceptives but not before age 45. d Excluding 229 cases and 1,308 controls that only used oral contraceptives before age 45.

since last use, no increase in risk with duration of use was observed. These findings were confirmed in analy- ses of the updated data that were used for this report (not shown). Therefore, for results from this study to be supportive of the hypothesis that OC use around the time of menopause preferentially increases risk of breast cancer, there must be a stronger association be- tween such use and risk of breast cancer than between use under other circumstances and risk of this disease.

Table I shows that the increase in RR is restricted to use of OCs within the previous year, and that the esti- mated values are no greater for older women (whose recent use would be near menopause) than among younger women (whose recent use would not be near the end of their fertile years). The RR estimate for recent users was actually highest for 40- to 44-year-old women. RRs were also found to decline with time since last use in women of all ages (not shown).

Considering only women over age 45, RR estimates were higher for women who used OCs after than be-

fore that age (Table 2), but no trend of increasing risk with duration of use after age 45 was observed. This was true for both pre- and postmenopausal women (not shown).

As shown in Table 3, RR estimates were no greater in women who used OCs within 12 months of their last menstrual cycle than in women whose use terminated earlier, and no trends of decreasing risk with time be- tween last use and menopause are evident. Risks were also not particularly high in women who reported using OCs at the time of their menopause (not shown).

Unexpectedly, the RR estimate in women who ever used OCs was higher in women with an artificial menopause (RR = 1.7, CI = 1.1-2.4) than in women with a natural menopause (RR = 1.04, CI --- 0.77-1.4). This increased risk in users with a subsequent artificial menopause was observed irrespective of the time be- tween last use of OCs and the induced menopause. This also was observed both in women with a known bilateral oophorectomy or pelvic irradiation followed

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D. B. Thomas et al

Table 3. Es t ima ted relative risks ~ of breas t cancer in re la t ion to t ime b e t w e e n last use o f oral con t racep t ive and last mens t rua l pe r i od b

Months between Artificial menopause last use and

No. of subjects RR last menstrual period Cases Controls

Natural menopause

CI No. of subjects RR CI

Cases Controls

Nonusers 133 702 1.0 302 2,386 1.0

Users ~< 12 27 109 1.5 0.89-2.6 16 163 0.74 0.42 - 1.3 13-24 4 16 1.5 0.45-5.1 7 35 1.9 0.74-4.7 25-48 10 36 2.3 1.01-5.1 4 51 0.58 0.20-1.7 49-96 12 54 1.7 0.84-3.6 12 110 1.02 0.53-2.0 > 96 14 73 1.5 0.76-2.9 26 235 1.2 0.78-1.9

Relative risk (RR) adjusted for age, center, number of pregnancies, socioeconomic status, use of IUD, and age at menopause; CI = 95 percent confidence interval. b Excluding 2,215 cases and 14,806 controls who were premenopausal, 12 cases and 68 controls with unknown time of last use or unknown age at menopause, and two cases and 56 controls with unknown menopausal status.

Table 4. Estimated relative risks ~ of breast cancer in users of oral contraceptives with natural and artificial menopause before and after age 45 b

Type of Use of oral menopause contraceptives

< 45 Years at menopause 45 Years at menopause

No. of subjects RR CI No. of subjects RR CI

Cases Controls Cases Controls

Natural No 69 759 1.0 233 1,627 1.0 Yes 13 206 0.93 0.47-1.9 58 425 1.1 0.74-1.5

Artificial No 90 517 1.0 43 185 1.0 Yes 48 249 1.53 0.97-2.4 23 66 2.4 1.60-4.9

Relative risk (RR) adjusted for age, center, number of pregnancies, socioeconomic status, and use of an IUD; CI = 95 percent confidence interval. b Excluding 2,215 cases and 14,806 controls who were premenopausal, two cases and 56 controls of unknown menopausal status, and two cases and four controls with unknown age at menopause.

by cessation of menses, and in women with a hyster- ectomy and unknown ovarian status (not shown). The greater RR estimate for OC users who subsequently had an artificial menopause than for users with a sub- sequent natural menopause was observed irrespective of age at menopause (Table 4).

Women with an artificial menopause were more likely to have used OCs for noncontraceptive reasons (hypermenorrhea, dysmenorrhea, irregular menses) than were women with a natural menopause, but this was true for both cases and controls, and the observed RR estimates associated with OC use before an arti- ficial menopause were not altered appreciably when such users (nine cases and 39 controls) were removed from the analyses.

Compared with premenopausal women who had never used OCs, women of comparable age with an artificial menopause had an estimated RR of 0.65

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(CI -- 0.53-0.8) if they had not used oral contracep- tives, and an RR of 0.9 (CI = 0.67-1.2) if they had used them.

D i s c u s s i o n

Possible sources of bias or confounding that could have resulted in a spurious relationship between use of OCs and breast cancer in this study have been con- sidered previously, 9,1~ and none were identified. An association with duration of use was found to be explained by the inverse relationship between duration and recency of exposure.

The association between breast cancer risk and recent exposure to OCs was confirmed in the analyses on which this report is based. Since this association was observed for women of all ages, it provides no support for the hypothesis that use around the time of meno-

pause preferentially enhances risk of breast cancer. The lack of an increase in observed risk with duration of use after age 45, and the failure to observe an increase in risk in women who used OCs near the time of either a natural or artificial menopause, provide additional evi- dence against this hypothesis.

Any enhancement in risk associated with use after age 45 was no greater for pre- than postmenopausal women in this study. In preliminary results from a study by Brinton et al, 12 there was a trend of increasing risk with duration of use after age 40 in premenopausal women, but no similar trend was observed in sub- sequent analyses of the complete data set from that same investigation. 7 There is consequently no evidence that use of OCs around the time of menopause exerts a greater influence on risk of breast cancer in pre- than postmenopausal women.

This study thus provides no support for the hypoth- esis that risk of breast cancer is increased by use of OCs around the time of menopause. The results from this study were not compatible with the large RRs of 15.5 and 4.0 in users near menopause observed by Jick et aP and Yuan et al, s respectively. They are more consistent with the findings of four other studies 6-8'~3 that also pro- vide little or no evidence that O C use around the time of menopause preferentially increases a woman's risk of breast cancer.

N o clear biological mechanism is available to explain the observed increase in risk associated with use of OCs prior to an artificial menopause. The absence of trends in RR estimates with duration of use before an oophorectomy, or with the passage of time between last exposure and the surgical procedure, also suggest that this observation does not represent a causal relationship. However, it is suggested that other inves- tigators with data from studies of breast cancer and oral contraceptives attempt to replicate our findings.

References 1. Key TJA, Pike MC. The role of estrogens and progesta-

gens in the epidemiology and prevention of breast can- cer. EurJ Cancer Clin Onco11988; 24: 29-43.

2. Thomas DB. Oral contraceptives and breast cancer: review of the epidemiologic literature. Contraception 1991; 43: 547-642.

3. Vessey MP, Doll R, Jones K, McPherson K, Yeates D. An epidemiological study of oral contraceptives and breast cancer. Br Medf 1979; 1: 1755-78.

4. Jick H, Walker AM, Watkins RN, et al. Oral contracep- tives and breast cancer. Am J Epidemiol 1980; 112: 577-85.

5. Yuan JM, Yu MC, Ross RK, Gao YT, Henderson BE. Risk factors for breast cancer in Chinese women in

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Shanghai. Cancer Res 1988; 48: 1949-53. 6. Rosenberg L, Miller DR, Kaufman DW, et al. Breast can-

cer and oral contraceptive use. AmJEpidemiol 1984; 119: 167-76.

7. Stanford JL, Brinton LA, Hoover RN. Oral contracep- tives and breast cancer: results from an expanded case- control study. BrJ Cancer 1989; 60: 375-81.

8. Romieu I, Willett WC, Colditz, et al. Prospective study of oral contraceptive use and risk of breast cancer in women.JNCI 1989; 81: 1313-2I.

9. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and combined oral contra- ceptives: results from a multinational study. BrJ Cancer 1990; 61: 110-19.

10. Breslow NE, Day NE. Statistical Methods in Cancer Research. Volume 1--The Analysis of Case-Control Studies. Lyon, France: International Agency for Research in Cancer, 1980; IARC Sci. Pub. No. 32: 192.

11. Thomas DB, Noonan EA. Letter to editor. (Response to letter from Dr Shelton.) BrJ Cancer 1990; 62: 469-70.

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Appendix The Data Collection Centers and the Principal Investigators (PI), Co-investigators (CI), and Pathologists (P) at each par- ticipating center in alphabetical order by country, are as follows:

University of Sydney, Department of Public Health, Sydney, Australia: Geoffrey Berry (PI), Robert MacLennan (CI), Rodney Shearman (CI), Tatiana Jelihovsky (P), Joan Cooper Booth (P).

University of Chile, Faculty of Medicine, Hospital Jose Joa- quirt Aguirre, Department of Obstetrics and Gynecology, and the Ministry of Health, Hospital Salvador, Depart- ment of Obstetrics and Gynecology, Santiago, Chile: Ramiro Molina (PI), Luis Martinez (CI), Oriana Salas (CI), Alfredo Dabancens (P).

Shanghai Institute of Planned Parenthood Research, Shang- hai, China: Chen Zhiheng (PI), Tao Yun (CI), Hu Yong Wei (P).

Hospital Universitario, WHO Collaborative Center for Research in Human Reproduction, Call, Colombia: Alvaro Cuadros (PI), Nubia Aristizabet (P).

Central lnstitute of Cancer Research, Academy of Sciences of the German Democratic Republic, Berlin, Germany: K. Ebeling (PI), P. Nishan (CI), D. Kunde (P).

Chiam Sheba Medical Center, Department of Clinical Epi- demiology, Tel Hashomer, Israel: Baruch Modan (PI), Elaine Ron (CI), Esther Alfandary (CI).

University of Nairobi, Nairobi Center for Research in Reproduction, Nairobi, Kenya: J. G. Mati (PI), Patrick Kenya (CI), Alfred Kungu (P), D. Gatei (P).

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Hospital General de Mexico, Mexico City: Hector Rodriguez Cuevas (PI), Socorro Benavides Salazar (CI), Antonio Palet (P), Patricia Ontiveros (P).

University of the Philippines, College of Medicine, Manila, Philippines: Ruben A. Apelo (PI), Julietta R. de la Cruz (CI), Jose Baens (CI), Benita Javier (P).

Chiang Mai University, Faculty of Medicine, Chiang Mai, Thailand: Suporn Silpisornkosol (PI), Tieng Pardthaisong (CI), Nimit Martin (CI), Choti Theetranont (P).

Chulalongkorn University, Faculty of Medicine, Depart- ment of Obstetrics and Gynecology, WHO Collaborating Centre for Research in Human Reproduction, Bangkok, Thailand: Banpot Boosiri (PI), Supawat Chutivongse (PI),

Pramuan Virutamasen (CI), Chansuda Wongsrichanalai (CI), Prasarn Jimakorn (P).

Mahidol University, Faculty of Medicine, Siriraj Hospital, Department of Obstetrics and Gynaecology, Family Plan- ning Research Unit, Bangkok, Thailand: Surporn Koetsa- wang (PI), Daungdao Rachawat (CI), Nivat Chantarakul (P).

University of Trorns~, Institute of Medical Biology, Troms~, Norway: Helge Stalsberg (Reference Pathologist).

World Health Organization: Olav Meirik and Timothy M. M. Farley, Special programme of Research, Development and Research Training in Human Reproduction, Geneva, Switzerland.

394 Cancer Causes and Control. Vol 2. 1991