oral contraceptives and risk of breast cancer

In[. J . Cancer: 46, 366-373 (1990) 0 1990 Wiley-Liss, Inc.

Publication of the International Union Against Cancer Publication de I’Union lnternationale Contre 1e Cancer

ORAL CONTRACEPTIVES AND RISK OF BREAST CANCER Charlotte PAUL^, D.C.G. SKEW and G.F.S. SPEARS Department of Preventive and Social Medicine and the Hugh Adam Cancer Epidemiology Unit, University of Otago, Dunedin. New Zealand.

A national population-based case-control study was conducted in New Zealand to assess the effects of hormonal contraception on breast-cancer risk. A total of 891 Women aged 25 to 54 with a first diagnosis of breast cancer, and 1864 control subjects, randomly selected from the electoral rolls, were interviewed. The relative risk of breast cancer for women who had ever used oral contraceptives was 1.0 (95% confidence interval 0.82-1.3). There was no increase in risk with duration of use, even among women who had continued to use oral contraceptives for 14 or more years (relative risk = 1.1, 95% confidence interval 0.78-1.7). The risk of breast cancer was not increased by use of oral contraceptives for long periods before the first pregnancy or by starting use at a young age. Parity, age at menarche, family history of breast cancer, or history of benign breast disease did not modify the effect of oral contraceptives on breast-cancer risk. Rel- ative risk estimates were slightly, although not significantly, increased during the first few years after starting oral contraception and in women under 35 years of age at diagnosis.

The question of whether oral contraceptives increase the risk of breast cancer remains unresolved, despite the publication of at least 7 cohort studies and 25 case-control studies over 2 decades (Schlesselman, 1989; Thomas, 1989; Population In- formation Program, 1988). Although most studies have found no overall association, a disturbing number have shown increased risks in certain sub-groups of women who reported use of oral contraceptives. The sub-groups involved, however, have tended to vary from study to study, and it is difficult to detect any consistent pattern.

One explanation suggested for some of the negative studies was that they involved populations who had not used oral contraceptives frequently enough at young ages, sufficiently long ago, for a latent adverse effect to emerge (McPherson and Drife, 1986). New Zealand is a particularly suitable place for study, because New Zealand women have been exceptionally high users of oral contraceptives since the 1960s. By 1966 it was estimated that 20% of women of reproductive age in New Zealand and Australia were using the pill, as compared with 8% in the USA and 3% in the UK (Guttmacher, 1966). Na- tional population surveys conducted in New Zealand and Great Britain in 1976 showed that a higher proportion of young New Zealanders (aged 15-24) were using oral contraception (Paul ef al., 1990).

In 1983 we started a national case-control study of breast cancer in New Zealand women under 55 years of age. Follow- ing an interim report, based on the first 2 years of data collection (Paul et al., 1986), we now report the findings after com- pletion of this 4-year study.

SUBJECTS AND METHODS

In this population-based study, all New Zealand women aged 25-54 in whom breast cancer had been diagnosed were considered for inclusion as cases; control subjects were selected at random from the electoral rolls. The study population was confined to women whose names were in a current electoral roll and whose telephone number could be found.

Cases The National Cancer Registry (or, in the Auckland region,

the Auckland Breast Cancer Study Group) identified 1452

women aged 25-54 in whom a diagnosis of breast cancer (In- ternational Classification of Diseases, rubric 174) had been confirmed histologically between 1 July 1983 and 30 June 1987. Permission for the release of information was given by all superintendents of public hospitals and by all but 7 of the specialists responsible for private patients.

Patients were excluded from the study if breast cancer had been diagnosed previously, if their names were not in a current electoral roll, or if their telephone number could not be found. After these criteria had been applied, 1126 women remained. We also required that patients be interviewed between 4 and 8 months after diagnosis, extended in the 3rd and 4th years to 12 months after diagnosis; this resulted in the exclusion of a further 104 patients, of whom 17 had died and 87 had been identified too late to be interviewed within 8 or 12 months after diagnosis. Table I shows other reasons why potentially eligible cases were not interviewed. Interviews were completed with 901 (95%) of the 944 suitable women whom we approached.

After the interview, a further 10 women were excluded because they were found to have had breast cancer diagnosed previously or because the final diagnosis was not breast cancer (one case). Thus we finally studied 891 cases.

Controls In New Zealand, electoral registration is compulsory for

adults aged 18 and over. Control subjects were randomly selected from the electoral rolls, and women whose telephone numbers could not be found were excluded. As age is not specified in the electoral rolls, we had to choose more women than were required for the study. We wrote to these women requesting information about their age and seeking their par- ticipation. If they did not reply, we telephoned them. All controls were written to between 1 November 1983 and 31 October 1987. Of 4,725 women to whom we sent letters, all except 65 provided information regarding eligibility. A total of 1,898 women were found to be outside the age range 25 to 55. We randomly excluded half the potential controls under the age of 35 (560 women) to approximate more closely the age distri- bution of the cases. The outcome for the remaining 2,267 potential controls is shown in Table I. Interviews were completed with 1,915 (90%) of 2,134 suitable subjects.

For each control a “reference date” was calculated by sub- tracting six months from the date of interview, to correspond to the mean time between diagnosis and interview among the cases. After the interview, 51 women were excluded because of a history of breast cancer or because they were younger than 25 or older than 54 on the reference date. The final control group thus comprised 1,864 women.

Data collection Information was collected using identical methods for cases

and controls. Women were interviewed by telephone after an

~

‘To whom correspondence and reprint requests should be sent, at De- partment of Preventive and Social Medicine, University of Otago Medical School, Dunedin, New Zealand.

Received: March 3, 1990 and in revised form May 11, 1990.

ORAL CONTRACEPTIVES AND BREAST-CANCER RISK 367

TABLE I - NUMBERS OF CASE AND CONTROL SUBJECTS INTERVIEWED

Potential case and control subjects

Cases Controls

Interviewed: Interviewed and eligible Excluded after interview

because ineligible Reason not interviewed

Died Identifield too late

89 1 1,864 10 51

17 9 87 -

- Previously interviewed as a control 6 Doctor refused 51 Subject refused 43 219 Too ill 8 8 Not traoed 4 71’ Absent overseas 5 23

-

Languag,e difficulties 4 22 Total potentially eligible subjects 1,126 2,261 ’About half of these untraced women would have been outside the age range for the

study.

initial approach by letter. The interview took about 20 min and sought details of medical, social, menstrual, and reproductive histories. Both the letter and interview were designed so that they did not disclose the study hypotheses. All interviews were conducted by 2 nurse-interviewers (94%) or by one of us (CP). Most began with the interviewer being blind as to whether the subject was a case or a control; although case patients generally reported their illness during the interview, this usually occurred after the contraceptive history had been taken. To help recall of past contraceptive use, our initial letter was accompanied by a calendar, 011 which women were asked to mark important dates such as marriages and births of children for reference during the interview. As a check on the interview method, we also wrote to the general practitioners of women who reported recent use of prescribed contraceptives. Replies were received from 363 (95%) out of 382 physicians. There was close agreement between the contraceptive histories received from the general practitioners and from the women themselves. Thus there was agreement as to whether oral contraceptives had been used in the last 5 years for 92% of cases and 91% of controls. Among women who had used oral contraceptives in the last 5 years, there was agreement on the duration of such use (within 2 years) for 100% of cases and 96% of controls.

Definition t$ terms Oral contraceptive use for 1 month or longer was categorized

as ever-use. A full-term pregnancy was a pregnancy lasting 7 months or more. Women were classified as post-menopausal if they had not menstruated in the 12 months before the date of interview. Menopause was further classified as artificial, if menstruation ceased because of surgery or radiation, or else as natural. A ffew women who had not menstruated in the previous 12 months were classified as pre-menopausal because the reason for the cessation of their periods was pregnancy and lac- tation or prolonged progestogen use. A family history of breast cancer was classified as first degree if the subject’s mother, sister, or daughter had breast cancer; as second degree if an aunt or grandmother had breast cancer; as unknown if the history in lirst-degree relatives was not known and no second- degree relatives were known to have breast cancer; otherwise, as no family history.

Statistical analyses For cases, contraceptive use before the date of diagnosis was

considered in the analyses. For controls, the reference date was used. We iused standard statistical methods for the analysis of

case-control studies. Relative risks were estimated by calcu- lating odds ratios, adjusted for age (in 5-year groups) by the method of Mantel and Haenszel (1959). Confidence intervals were estimated by the procedure of Cornfield (1956) as pro- grammed by Thomas (1975). When simultaneously adjusting for several risk factors, we applied the multiple logistic model (Breslow and Day, 1980) using the computer program GLIM (Baker and Nelder, 1978). Age adjustment was again in 5 year groups, except for the analysis reported in Table 111, in which age was adjusted for as a continuous variable within each 10 year age group. For tests of trend, the actual duration of exposure (rather than the category value) was used as the inde- pendent variable.

RESULTS

Characteristics of case and control subjects are summarized in Table 11. The average age was higher among the cases, so the table gives age-adjusted relative risks for all other variables. The relative risk of breast cancer was higher among women with an early menarche, with no full-term pregnancies, with low parity, who did not breast-feed, with a family history of breast cancer, or with a history of benign breast disease. Maori women were also at higher risk of breast cancer. Other potentially confounding variables examined included menopausal status, body-mass index, area of residence, social class, education, cigarette smoking, alcohol consumption, year of interview, and use of depot medroxyprogesterone acetate (DMPA, “Depo-Provera”).

The proportions of cases and controls who had used oral contraceptives at some time were 76.9% (685/891) and 82.5% (1 538/1864) respectively. Three control subjects were unable to recall their duration of oral contraceptive use, or had missing information for other confounding variables, so further analyses were restricted to the remaining 1,861 control women. The relative risk for women who had ever used oral contraceptives, adjusted for potential confounding variables by logistic regres- sion, was 1.0 (95% confidence interval 0.82-1.3). Table 111 shows the risk of breast cancer according to age at diagnosis and duration of oral contraceptive use, relative to women in each age group who had never used oral contraceptives. There was no overall increase in risk with increasing duration of use, even for use for 14 years or longer. Nor did risk increase with duration of use among women aged 35 or over at diagnosis. In young women, aged 25 to 34, oral-contraceptive users had a relative risk of 1.2 (95% confidence interval 0.44-3.4), compared with women who had never used oral contraceptives. Women in this age group who had used oral contraceptives for 10 to 13 years and 14 or more years had relative risks of 2.3 and 1.7 respectively, although the 95% confidence intervals were wide and included 1 .O in each case. There was no statistically significant trend in the relative risk of breast cancer according to duration of use (p = 0.42).

The relative risk associated with duration of oral contraception was examined by age at first use, time since first use, and time since last use of oral contraceptives. Table IV shows the relative risks according to age at first use of oral contraceptives. Use starting very young, at ages 17 to 19 or even before age 17, was not associated with any consistent increase in risk. Similarly, use of oral contraceptives beginning a long time in the past (Table V) was not associated with an increased risk, even after long durations of use. The relative risk of breast cancer in women who had used oral contraceptives for 10 or more years starting 15 or more years earlier was 1.0 (95% confidence interval 0.74-1.3). The risk of breast cancer was slightly, although not significantly, elevated among women who had first used oral contraceptives more recently. The rel-

368 PAUL ET AL.

TABLE I1 - CHARACTERISTICS OF 891 CASES AND 1864 CONTROLS

Number of Number of Re'ative 95 w CP risk of

contra's breast cancer' cases Characteristic

25-29 30-34 35-39 4 w 45-49 50-54

Maori Ethnic group Non-Maori

Age at menarche <12 - 12-14 215 Unknown age

Nulliuarous Age at first full-term pregnancy

<20' 20-24

Parity

Breastfeeding

25-29 230 Unknown age Nulliparous 1 2 3 >4 Never 1-3 mths 4-11 mths 12-23 mths a24 mths Unknown

Post-menopausal (artificial)

Post-menopausal (natural)

None Second-degree

relative only First-degree

relative

Menopausal status Premenopausal

Family history of breast cancer

History of surgery for benign breast disease No

15 49

121 203 258 245 829 62

154 589 146

2

98 105 419 198 71

98 74

260 248 21 1 278 170 234 144 65

605 171

115

658 132

101

774 . . . Yes 117

193 212 404 403 357 295

1174 90

289 1270 303

2

199 260 879 419 106

1 199 168 576 479 442 536 321 484 339 183

1 1436 260

168

1586 192

86

1730 134

1 .o 1.6 1 .o 0.87 0.80

1.0 0.71 0.69 0.65 0.78

1 .o 0.86 0.78 0.72 0.51 1 .o 0.90 0.83 0.74 0.66

1.0 1 .o 0.80

1 .o 1.7

2.5

1 .o 1.7

(1.1-2.3)

(0.69-1.1) (0.59-1.1)

(0.49-1.0) (0.51-0.93) (0.47-0.92) (0.50-1.2)

(0.561.3)

(0.52-0.99) (0.36-0.72)

(0.7G1.2) (0.661.0)

(0.4W.91)

(0.57-1.1)

(0.57-0.96)

(0.8 1-1.3)

(0.57-1.1)

(1.3-2.2)

(1.8-3.5)

( 1.3-2.2) 'Mantel-Haenszel estimate, adjusted for age at diagnosis.-'Confidence interval adjusted for age at diagnosis

ative risk for use for less than 2 years, starting 5 to 9 years before diagnosis, was 1.9 (95% confidence interval 0.92-3.8). But there was no elevation in risk for longer durations of use commencing 5 to 9 years earlier.

Table V1 shows the relative risk of breast cancer according to time since last use of oral contraceptives. Current users (women who used the pill within 1 year of diagnosis) were at no increased risk. Women who used oral contraceptives for less than 2 years and who completed this use 5 to 9 years earlier had a significantly elevated risk (relative risk 2.8, 95% confidence interval 1.5-5.1). Nevertheless, there was no clearly discernible pattern of association between recent use of oral contraceptives and breast-cancer risk.

Oral contraceptive use in relation to pregnancy Breast-cancer risk in women who used oral contraceptives

before their first full-term pregnancy is examined in Table VII. For nulliparous women, all use is included. Risks were calculated relative to never-users for nulliparous women and relative to non-users before the first full-term pregnancy, irrespective of later use, for parous women. There was a pattern of de-

creasing risk with increasing duration of oral contraceptive use. For nulliparous and parous women combined, this trend approached statistical significance (p = 0.07). Table VIII shows a similar analysis restricted to women under age 45 at diagnosis. Again there was a suggestion of decreasing risk with increasing duration of use, but the trend by actual duration of use was not statistically significant.

Oral contraceptive use in relation to other risk factors for breast cancer

In order to examine the suggestion by Stadel et al. (1988) that the effect of oral contraceptive use on the risk of breast cancer might be modified by age at menarche, we attempted to replicate their analyses. Table IX is confined to premenopausal women, adjusting for age, age at menarche, family history of breast cancer, and parity. The group of women with the highest point estimate of relative risk in Stadel's analysis-nulliparous women aged less than 45, with menarche before 13 and with 12 or more years' use of oral contraceptives-were found to have a relative risk of 1.2 (95% confidence interval 0.09-7.7). There was no trend in risk with in-

ORAL CONTRACEPTIVES AND BREAST-CANCER RISK 369

TABLE III - RELATIVE RISK OF BREAST CANCER' (AND 95% CONFIDENCE INTERVAL) ACCORDING TO DURATION OF USE OF ORAL CONTRACEPTIVES AND AGE AT DIAGNOSIS. NUMBERS OF CASES AND CONTROLS ARE SHOWN IN PARENTHESES.

Age at diagnosis 25-34 years 35-44 years 45-54 years All ages

Duration of u:re _ _ _ _ . ~

Never 1.02 1.02

<2 years 1.6 (0.51 to 4.9) 1.3 (0.79 to 2.0)

2-5 years 0.79 (0.26 to 2.4) 1.2 (0.78 to 2.0)

6-9 years 1.3 (0.41 to 4.0) 1.0 (0.62 to 1.8)

10-13 years 2.3 (0.67 to 7.8) 1.0 (0.59 to 1.8)

3 14 years 1.7 (0.13 to 21.5) 1.2 (0.64 to 2.3)

All Users 1.2 (0.44 to 3.4) 1.2 (0.78 to 1.8)

( 5 , 35) (38, 95)

(16, 73) (85, 191)

(16, 156) (97, 242)

(15, 103) (47, 141)

(11, 35) (34, 92)

( 1 , 3) (23, 45)

(59. 370) (286. 71 1)

1.02 (163, 195)

1.2 (0.89 to 1.7) (127, 142)

0.82 (0.57 to 1.2) (79, 126)

0.92 (0.60 to 1.4) (53, 78)

0.87 (0.55 to 1.4) (43, 63)

1.1 (0.70 to 1.9) (38, 46)

1.0 (0.77 to 1.3) (340. 455)

1 .O*

1.2 (0.92 to 1.5)

0.91 (0.70 to 1.2)

0.91 (0.67 to 1.2)

(206, 325)

(228, 406)

(192, 524)

(115, 322) '

0.95 (0.68 to 1.3) (88, 190)

1.1 (0.78 to 1.7) (62, 94)

1.0 (0.82 to 1.3) (685, 1536)

'Adjusted for age and DMPA use (within each 10 year age group), age at fust full-term pregnancy, parity, breastfeeding, family history of breast cancer, and ethnic group.-*Reference category.

creasing duration of oral contraceptive use in this sub-group of women.

Table X shows the relative risk of breast cancer according to duration of oral contraceptive use among women with and without a family history of breast cancer. In women with a mother or sister with breast cancer, the relative risk declined with increasing use of oral contraceptives, although this trend was not statistically significant @ = 0.11). The risk of breast cancer wa!j not affected by oral contraceptive use among women with only a second-degree relative with breast cancer, or with no family member affected, relative to never-users in each group.

We also examined the effect of oral contraceptives in women with a history of benign breast disease. When we restricted attention to women who had undergone surgery for benign breast dise,ase before any oral contraceptive use, for reasons explained by Stadel and Schlesselman (1986), the relative risk in oral contraceptive users (compared with never-users with benign breast disease) was 0.99 (95% confidence interval 0.28-3.5). Since only 8 cases and 7 controls had a history of benign breast disease before they had used oral contraceptives, no firm conclusions could be drawn.

Women were grouped according to menopausal status (Ta- ble XI). There was no relation between the risk of breast cancer and the duration of oral contraceptive use in any category of menopausal status.

DISCUSSION

The results of this large population-based study are consis-

tent with there being no effect of oral contraceptives on breast cancer risk. Even women who had fiist taken oral contraceptives more than 15 years previously and had continued to use them for more than 10 years were at no increased risk. The risk of breast cancer was not increased by use of oral contraceptives for long periods before the first pregnancy, or by starting use at young ages. Relative risk estimates were slightly, although not significantly, increased during the first few years after starting oral contraception and in women under 35 years of age at diagnosis. The number of cases aged under 35 was small and our results are not inconsistent with an adverse effect in this age group, as has been reported recently (Kay and Hannaford, 1988; UK National Case-Control Study Group, 1989).

Three potential sources of bias must be considered in a study of this kind: the selection of cases and controls, the collection of information about past use of contraceptives, and surveillance of contraceptive users (Skegg, 1988). Selection bias should have been minimized by selecting cases and controls from the entire population of New Zealand. Cases and controls were selected using the same criteria-that the woman's name was in a current electoral roll and that her telephone number could be found-and response rates were high in both groups.

Information bias is also unlikely to have affected the results. The cases and controls were not told that the study was concerned with cancer or contraceptive safety. They were interviewed in an identical way and, in most instances, the interviewer was blind as to whether the subject was a case or a control when the contraceptive history was being taken. Inde- pendent contraceptive histories were obtained from the general practitioners of women who reported recent use of prescribed

TABLE IV - RELATIVE RISK OF BREAST CANCER' (AND 95% CONFIDENCE INTERVAL) ACCORDING TO DURATION OF USE OF ORAL CONTRACEPI?VES AND AGE AT FIRST USE (RELATIVE TO ALL NEVER-USERS) NUMBERS OF CASES AND CONTROLS ARE SHOWN IN PARENTHESES ---

Age at first use Duration of use

___-__ <I7 years 17-19 yean 20-24 years 2 2 5 years All ages

<2 yean 0.53 (0.06 to 4.4) 1.6 (0.88 to 2.8) 1.0 (0.68 to 1.5) 1.2 (0.93 to 1.7) 1.2 (0.92 to 1.5)

2-5 yearE, 0.75 (0.24 to 2.3) 0.62 (0.35 to 1.1) 1.0 (0.72 to 1.5) 0.89 (0.64 to 1.3) 0.92 (0.70 to 1.2)

6-9 yearb 0.24 (0.03 to 1.7) 0.82 (0.44 to 1.5) 0.97 (0.63 to 1.5) 0.93 (0.62 to 1.4) 0.91 (0.68 to 1.2)

a 1 0 yeaIs 2.0 (0.70 to 5.5) 0.57 (0.29 to 1.1) 1.1 (0.74 to 1.6) 1.0 (0.71 to 1.5) 1.0 (0.77 to 1.4)

All users 0.83 (0.41 to 1.7) 0.82 (0.55 to 1.2) 1.0 (0.77 to 1.4) 1.1 (0.83 to 1.3) 1.0 (0.82 to 1.3)

'Adjusted for age, age at first full-term pregnancy, parity, breastfeeding, family history of breast cancer, ethnic group, and DMPA use.

(1, 9) (23,551 (59, 152) (145, 190) (228, 406)

(4, 25) (19, 128) (80, 224) (89, 147) (192, 524)

( 1 , 33) (16, 81) (46, 125) ( 5 2 , ~ (115, 322)

(150, 284) (6, 16) (12, 62) (61, 110) (71, 96)

(12, 83) (70, 326) (246, 611) (357, 516) (685, 1536)

370 P A U L ET A L .

TABLE V - RELATIVE RISK OF BREAST CANCER' (AND 95% CONFIDENCE INTERVAL) ACCORDING TO DURATION OF USE OF ORAL CONTRACEF-TIVES AND TIME SINCE FIRST USE (RELATIVE TO ALL NEVER-USERS). NUMBERS OF CASES AND CONTROLS ARE SHOWN IN PARENTHESES.

Time since first use

<S years 5-9 years 10-14 years 3 15 years All times Duration of use

<2 years

2-5 years

6 9 years

2 10 years

All users

1.2 (0.42 to 3.4) 1.9 (0.92 to 3.8) (6, 17) (16, 37)

1.3 (0.20 to 9.1) 1.1 (0.51 to 2.2) (2, 6) (12, 67) - 0.91 (0.32 to 2.6)

(5, 38) - -

1.2 (0.49 to 3.1) 1.3 (0.79 to 2.2) (8. 23) (33. 142)

1.2 (0.88 to 1.5) 1.2 (0.92 to 1.5)

0.92 (0.69 to 1.2) 0.92 (0.70 to 1.2) (167, 261) (228, 406)

(144, 319) (192. 524)

(21, 82) '

(17~47) (133, 237) (150, 284)

(111, 352)

1.2 (0.62 to 2.2) 1.0 (0.74 to 1.3) 1.0 (0.77 to 1.4)

1.1 (0.76 to 1.5) 1.0 (0.80 to 1.31 1.0 (0.82 to 1.31

0.87 (0.63 to 1.2) 0.91 (0.68 to f.2) (89, 202) (115, 322)

(533, 1019)' (685, 1536)' 'Adjusted for age, age at fust full-term pregnancy, parity, breastfeeding, family history of breast cancer, ethnic group, and DMPA use.

TABLE VI - RELATIVE RISK OF BREAST CANCER' (AND 95% CONFIDENCE INTERVAL) ACCORDING TO DURATION OF USE OF ORAL CONTRACEF-TIVES AND TIME SINCE LAST USE (RELATIVE TO ALL NEVER-USERS). NUMBERS OF CASES AND CONTROLS ARE SHOWN IN PARENTHESES.

Time since last use

< I year 1 4 years >9 Years 3 10 vears AIl times Duration of use

<2 years 0.87(0.33to2.3) 1.3(0.54to3.1) 2.8 (1.5t05.1) 1.1 (0.85 to 1.5) 1.2 (0.92 to 1.5)

2-5 years 1.1 (0.48 to 2.6) 1.2 (0.60 to 2.3) 0.85 (0.55 to 1.3) 0.92 (0.69 to 1.2) 0.92 (0.70 to 1.2)

6 9 years 0.74 (0.34 to 1.6) 1.2 (0.68 to 2.2) 0.75 (0.47 to 1.2) 1.0 (0.68 to 1.5) 0.91 (0.68 to 1.2)

310 years 1.2 (0.78 to 1.8) 1.1 (0.70 to 1.7) 0.98 (0.65 to 1.5) 0.48 (0.19 to 1.2) 1 .O (0.77 to 1.4)

All users 1.0 (0.72 to 1.5) 1.1 (0.82 to 1.6) 1.0 (0.75 to 1.3) 1.0 (0.80 to 1.3) 1.0 (0.82 to 1.3)

(6, 24) (9, 22) (27,391 (186, 321) (228, 406)

(8, 51) (14,551 (39, 143) (131, 275) (192, 524)

(9, 73) (20, 63) (30, 95) (56, 91) (115, 322)

(47, 97) (44, 81) (52, 85) (7, 21) (150, 284)

(70, 245) (87, 221) (148, 362) (380, 708) (685, 1536) 'Adjusted for age, age at fust full-term pregnancy, parity, breastfeeding, family history of breast cancer, ethnic group, and DMPA use.

TABLE VU - RELATIVE RISK OF BREAST CANCER' (AND 95% CONFIDENCE INTERVAL) ACCORDING TO DURATION OF USE OF ORAL CONTRACEPTIVES AMONG NULLlPAROUS WOMEN AND DURATION OF USE BEFORE FIRST FULL-TERM PREGNANCY AMONG PAROUS WOMEN. NUMBERS OF CASES AND

CONTROLS ARE SHOWN IN PARENTHESES.

Duration of use Nulliparous w o m e e total use

Parous womew- use before fust meenancv

Nulliparous and parous women- all use before fust Dreenancv

None 1.02 1.02 1 .o* <2 years 0.89 (0.44 to 1.8) 0.83 (0.63 to 1.1) 0.84 (0.64 to 1.1)

2-5 years 0.49 (0.22 to 1.1) 0.80 (0.57 to 1.1) 0.73 (0.53 to 1.0)

3 6 years 0.51 (0.24 to 1.1) 0.62 (0.31 to 1.2) 0.58 (0.35 to 0.98)

All users 0.62 (0.36 to 1.1) 0.82 (0.64 to 1.0) 0.78 (0.62 to 0.99)

(52,521 (603, 1031) (655, 1083)

(21, 34) (105, 305) (126, 339)

(12, 57) (73, 257) (85, 314)

( 1 3 , ~ (12, 69) (25, 125)

(46, 147) (190, 631) (236, 778) 'Adjusted for age, age at first full-term pregnancy, parity, breastfeeding, family history of breast cancer, ethnic group, and DMPA use.-'Reference category.

contraceptives, and these agreed closely with the histories from the women themselves.

If women using oral contraceptives were more likely than other women to examine their breasts frequently, or to have them examined by a physician or nurse, surveillance bias could arise. We assessed this possibility during the second half of the study by asking women about their frequency of breast examinations (if any) prior to 1 year before the interview. The proportions of control subjects reporting one or more breast examinations annually among women who had used oral contraceptives and those who had never used them, respectively, were 66% and 43% in women aged 25-34, 78% and 56% in women aged 35-44, and 75% and 70% in women aged 45-54. Thus the differences were fairly small, although larger at young ages. Detailed information about tumour size and stage was not available for all of the patients with breast cancer, so the possibility of surveillance bias could not be explored further. This

source of bias might be expected to be less likely in New Zealand than in countries such as the United Kingdom, where women taking oral contraceptives have been advised to examine their breasts regularly (Skegg, 1988).

Until recently there was a consensus that the use of oral contraceptives for family spacing-that is, after the first pregnancy-did not affect the risk of breast cancer (McPherson and Drife, 1986). In contrast, several studies suggested that use of oral contraceptives before the first full-term pregnancy increased the risk, especially in women under age 45 at diagnosis (Schlesselman, 1989). Our results do not support this hypoth- esis: relative risk estimates actually decreased with increasing durations of oral contraception before the first pregnancy, irrespective of whether attention was confined to women under 45 (Tables VII and VIII).

McPherson et al. (1986) suggested that an effect of early use of oral contraceptives might be obscured by the existence of a

ORAL CONTRACEPTIVES A N D BREAST-CANCER RISK 371

TABLE VIII -- RELAllVE RISK OF BREAST CANCER’ (AND 95% CONFIDENCE INTERVAL) ACCORDING TO DURATION OF USE OF ORAL CONTRACEPTIVES AMONG NULLIPAROUS WOMEN AND DURATION OF USE BEFORE FIRST FULL-TERM PREGNANCY AMONG PAROUS WOMEN. ANALYSIS RESTRICTED TO

WOMEN LESS THAN 45 YEARS AT DIAGNOSIS. NUMBERS OF CASES AND CONTROLS ARE SHOWN IN PARENTHESES. _- Nulliparous w o m e e Parous warnew- Nulliparous and parous women-

total use use before fust oreanancv all use before fmt pregnancy Duration of use

None 1.02 1.02 1.02

<2 years 0.61 (0.21 to 1.7) 0.82 (0.59 to 1.2) 0.79 (0.58 to 1.1)

2-5 years 0.54 (0.18 to 1.6) 0.77 (0.51 to 1.2) 0.74 (0.50 to 1.1)

2 6 years 0.57 (0.22 to 1.5) 0.59 (0.28 to 1.2) 0.62 (0.35 to 1.1)

All users 0.57 (0.25 to 1.3) 0.80 (0.59 to 1.1) 0.76 (0.57 to 1.0)

(13,261 (192, 472) (205, 498)

(9, 31) (79, 267) (88, 298)

(7, 49) (64, 243) (71, 292)

(12, 54) (12, 69) (24, 123)

(28, 134) (155, 579) (183, 713) ‘Adjusted for age, agc at first full-term pregnancy, parity, breastfeeding, family history of breast cancer, ethnic group, and DMPA use.-2Reference category

TABLE IIC - RELATIVE RISK OF BREAST CANCER’ (AND 95% CONFIDENCE INTERVAL) IN PREMENOPAUSAL WOMEN ACCORDING TO AGE. AGE AT MENARCHE, PARRY AND DURATION OF ORAL CONTRACEPTIVE USE BEFORE FIRST FULL-TERM PREGNANCY. NUMBERS OF CASES AND CONTROLS SHOWN

IN PARENTHESES. ~ - - Parous women Nullipaous women

Duration of use Age at menarche Age at menarche

< 13 years 2 13 years 1 1 3 years a 13 years _______

2 5 4 4 years of age Never 1.02 1.02

( 5 , 12) (6, 12) <4 years 0.81 (0.15 to 4.4) 0.33 (0.07 to 1.6)

( 5 , 21) (5 , 29)

(1, 14) (7, 25)

(2. 121 (2. 15)

4 7 years 0.50 (0.04 to 6.5) 0.64 (0.15 to 2.7)

8-11 years 0.71 (0.09 to 5.5) 0.47 (0.07 to 3.1)

3 12 years 1.2 (0:09 to 7.7) 0.16 (0:Ol to 2.0) (2. 41 (2. 71 . . ,

45-54 years of age Never 1.02 1.02

2.544 years of age 1.02 1.02

(9, 30) (15, 61) 0.91 (0.38 to 2.2) 1.2 (0.63 to 2.5)

(43, 165) (63, 227) 1.1 (0.41 to 3.2) 0.87 (0.35 to 2.1)

(14,441 (12, 74) 1.2 (0.22 to 6.2) 1.3 (0.27 to 6.4)

(3, 10)

(0, 2) (0, 3)

(2, 10) - -

45-54 years of age 1.02 I .O2

‘Adjusted for age, age at menarche, family history of breast cancer and parity.-2Reference category.

TABLE x - RELATIVE RISK OF BREAST CANCER’ (AND 95% CONFIDENCE INTERVAL) ACCORDING TO DURATION OF USE OF ORAL CONTRACEPTIVES AND FAMILY HISTORY OF BREAST CANCER.2 NUMBERS OF CASES AND CONTROLS ARE SHOWN IN PARENTHESES.

All women No family history Family history in Family history in second- of breast cancer fmt-degree relative degree relative only

Duration of use ___-~__

Never 1.03 1.03 1 n3 1 n3

<2 years

2-5 years

6-9 years

210 years

All users

(147, 271) 1.2 (0.86 to 1.6)

(157, 332) ’

0.90 (0.66 to 1.2) (128, 429)

0.93 (0.66 to 1.3) (79, 263)

1.1 (0.81 to 1.5) (105, 220)

1.0 (0.81 to 1.3) (469. 1244)

(23. 121 0.96 (0.38 to 2.4)

(28, 22) 0.89 (0.33 to 2.4)

(20, 18) ’ 0.74 (0.26 to 2.1)

(14, 14) ’

0.51 (0.19 to 1.4) (16, 20)

0.77 (0.35 to 1.7) (78, 74)

(25, 30) 1.1 (0.52 to 2.4)

(26, 39) 1.2 (0.59 to 2.4)

(39. 601

(107, 162) ’

I.”

(195, 313)

(21 1, 393)

(187, 507)

(111, 307)

(145, 273)

(654. 1480)

1.2 (0.89 to 1.5)

0.95 (0.73 to 1.3)

0.95 (0.70 to 1.3)

1.1 (0.81 to 1.4)

1.0 (0.84 to 1.3)

‘Adjusted for age, age at f r s t full-term pregnancy, parity, breastfeeding, ethnic group and DMPA use.-*Excluding women with unknown family history.-’Reference category.

long latent period between exposure to oral contraceptives and the appearance of breast cancer. These authors recommended testing for latency by successive calculation of relative risks, excluding exposure within increasingly long periods before the

date of diagnosis (or the corresponding date for controls). Such analysis of the data collected during the first two years of our study failed to show any latent adverse effect following use of oral contraceptives before the first full-term pregnancy or be-

372 P A U L ET AL.

TABLE XI - RELATIVE RISK OF BREAST CANCER’ (AND 95% CONFIDENCE INTERVAL) ACCORDING TO DURATION OF USE OF ORAL C O N T R A C E ~ V E S AND MENOPAUSAL STATUS. NUMBERS OF CASES AND CONTROLS ARE SHOWN IN PARENTHESES.

Menopausal status

Post-menopausal Post-menopausal - artificial - natural All women

Duration of use Re-menopausal

Never 1.02 1.02 1.02 1.02 (116, 204) (47, 54) (43, 67) (206, 325)

(154, 300) (51, 76) (23,301 (228, 406)

(141, 438) (34. 61) (17, 25) (192, 524)

(79, 268) (22, 35) (14, 19) (115, 322)

(115, 225) ( 1 7 ~ 3 4 ) (18,251 (150, 284)

(489, 1231) (124, 206) (72,991 (685, 1536)

1.2 (0.88 to 1.7) 0.95 (0.55 to 1.6) 1.4 (0.73 to 2.9) 1.2 (0.92 to 1.5)

0.92 (0.70 to 1.2) 0.90 (0.65 to 1.2)

0.91 (0.68 to 1.2) 0.85 (0.59 to 1.2)

1.0 (0.74 to 1.5) 0.70 (0.34 to 1.4) 1.2 (0.58 to 2.5) 1.0 (0.77 to 1.4)

1.0 (0.77 to 1.3) 0.89 (0.56 to 1.4) 1.2 (0.74 to 2.0) 1.0 (0.82 to 1.3)

<2 years

2-5 years

6-9 years

210 years

All users

‘Adjusted for age, age at first full-term pregnancy, parity, breastfeeding, family history of breast cancer, ethnic group, and DMPA use -*Reference category

0.85 (0.47 to 1.5)

0.99 (0.50 to 2.0)

1 . 1 (0.50 to 2.2)

1 . 1 (0.51 to 2.6)

fore age 25 (Paul et al., 1990). We have repeated these analyses with the complete 4-year data set, and obtained similar results (data not shown). There was also no evidence of a latent adverse effect in the large American Cancer and Steroid Hor- mone Study (Schlesselman er al., 1988).

Studies of the effects of using oral contraceptives before the first pregnancy have usually included both women who subse- quently had a full-term pregnancy and those who remained nulliparous. Stadel et al. (1989) re-analyzed data from the Cancer and Steroid Hormone Study and concluded that oral contraceptives might have a specific effect in nulliparous women. They reported an increasing relative risk with duration of use of oral contraceptives among nulliparous, premenopausal women under the age of 45. The numbers of nulliparous women in our study were fairly small but, as shown in Table VIII, relative risk estimates were consistently below unity for nulliparous women who used oral contraceptives. Earlier, Stadel et al. (1988) had suggested that prolonged use of oral contraceptives increased the risk of breast cancer in nulliparous, pre-menopausal women under 45 years of age who experienced menarche before age 13. We attempted to replicate their finding but could provide no support for this hypoth- esis (Table IX).

Apart from nulliparity and early menarche, several other risk factors for breast cancer have been studied to see whether they modify any effect of oral contraceptives. Schlesselman (1989) summarized the conflicting evidence concerning women with a family history of breast cancer or a history of benign breast disease. There were few women in our study with a history of benign breast disease before starting oral contraception, but our results did not show any adverse effect of oral contraceptives in women with a family history of breast cancer (Table X) or with different categories of menopausal status (Table XI).

Two important studies published recently have shifted the focus of attention from the effects of early use of oral contraceptives (before the first pregnancy or before age 25) to effects on the risk of developing breast cancer at an early age (before 35). In a cohort study conducted by the Royal College of General Practitioners, women who used oral contraceptives had an increased risk of breast cancer diagnosed before age 35, although this was of borderline significance (Royal College of General Practitioners, 1981; Kay and Hannaford, 1988). Women who started using oral contraceptives before 25 years of age did not differ materially in breast-cancer risk from those who began at a later age. In a large British case-control study of women diagnosed with breast cancer before age 36, there was a highly significant trend in risk with total duration of oral

contraceptive use (UK National Case-Control Study Group, 1989). The relative risk was estimated to be 1.43 (95% confidence interval 0.97-2.12) for 4-8 years’ use and 1.74 (95% confidence interval 1.15-2.62) for more than 8 years’ use. The relative risks were not higher for use before rather than after the first full-term pregnancy.

In our study, the relative risk of breast cancer diagnosed before age 35 was 1.2 (95% confidence interval 0.44 to 3.4). There was no significant trend in risk with duration of use, but the estimates of relative risk for periods of use over 6 years were all above unity. The study included only 64 cases under 35 years of age, of whom all but 5 had used oral contraceptives at some time. In view of the small number of cases studied, our results are quite consistent with an effect of oral contraceptives in this age group.

Although the 2 reports from the Royal College of General Practitioners both showed an increased risk in women aged 30-34 years, the second one (including cases accrued over another 5 years) provided no evidence that the risk had extended into the next 5-year age group (Kay and Hannaford, 1988). Our own results for women aged 35-44, based on 286 exposed cases and 7 1 1 exposed controls, are also reassuring in this respect. We separately analyzed data for women aged 35-39 and 40-44 years, respectively, and the relative risk estimates were not higher in the younger age group (data not shown).

The inconsistencies in the results of studies of oral contraceptives and breast cancer call for further research, including investigations of the patterns of use of pills with different steroid combinations and dosages in the populations concerned. Viewed in the aggregate, our findings provide considerable reassurance that the extensive use of oral contraceptives by New Zealand women has not increased their risk of breast cancer in middle age.

ACKNOWLEDGEMENTS

This investigation received financial support from the Spe- cial Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, and from the Medical Research Council of New Zealand. We thank Mrs C . Harris and Mrs J . Thomson (the interviewers); Mrs J. Smeijers, Mrs I. Pairman, and Mr P. Herbison; Mr J. Fraser and Miss J . Auld of the National Cancer Registry; Dr. R. Kay, Miss B. Mason, and Mrs L. Neave of the Auckland Breast Cancer Study Group; also the women who participated in the study and the surgeons and general practitioners who supported it.

ORAL CONTRACEPTIVES AND BREAST-CANCER RISK

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373

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