- Email: [email protected]
Age at menopause and breast cancer: estimation of floating absolute risks
The Brro\t (1998) 1.27732 Q 199X Harcourt Brace & Co. Ltd
ORIGINAL ARTICLE
Age at menopause and breast cancer: estimation of floating absolute risks C. Braga, E. Negri, C. La Vecchia” and S. Franceschi’ Istituto di Ricerche Farmacologiche ‘Mario Negri’, *Istituto di Statistica Medica e Biometria, Universitir degli Studi di Milano, Milan, ‘Servizio di Epidemiologia, Centro di Rijierimento Oncologico, Aviano PN, Italy S U M MA R Y. Late menopause is consistently related to breast cancer risk, but direct comparison of the modifying effects of type of menopause and of time factors across studies has been made difficult by the heterogeneity in the choice of the reference category, and in the definition of postmenopausal status. These effects were investigated in the absence of an arbitrary baseline category by computing floating absolute risks (FARs). Pooled data from two case-control studies conducted between 1983 and 1994 in major teaching and general hospitals of six Italian centres were used. Participants were 3576 postmenopausal women with incident, histologically confirmed breast cancer, and 3578 postmenopausal controls admitted to hospital for acute, non-neoplastic, non-hormonal, non-gynaecological conditions. When all types of menopause were considered together, FARs were 0.49 for <35 years, 0.81 for 35-39 years, 0.82 for 40-44 years, 0.88 for 45-47 years, 1.02 for 48-50 years, 1.23 for 51-53 years and 1.24 for 54-56 years, with a significant linear trend. The same pattern was seen in women reporting a natural menopause, with FAR of 0.14 for women with menopause when aged ~35 years versus 1.20 for those with menopause at 54-56 years (ratio between extreme FAR estimates = 8.6). No trend emerged in the overall surgical menopause group (including hysterectomy alone or with monolateral oophorectomy, and bilateral oophorectomy). However, when women reporting a bilateral oophorectomy were selected, a significant linear trend was observed. No heterogeneity emerged when risks were evaluated in strata of age at diagnosis/interview. Thus, using a unique large dataset and an innovative method of analysis, this study documented an over &fold ratio of risks between extreme categories of age at menopause, but no evidence of a latency period before the establishment of an effect of age at menopause.
INTRODUCTION
oestrogens may exert their effects on breast cancer risk only after some delay.‘s8 There are also difficulties in understanding and in disentangling the effects of type of menopause. Trends similar to those observed for all menopausal types considered together were detected in women experiencing a surgical menopause,3s6,9although the association was weaker in some studies.4,10This is probably due to the inclusion of cases with hysterectomy alone and monolateral oophorectomy in the definition of age at menopause. When bilateral oophorectomy was considered, a consistent reduction in risk with decreasing age at operation was reported,3~4~‘1 but latency effects following surgery are yet unclear. Analyses considering age at monolateral oophorectomy or at hysterectomy have failed to detect a consistent pattern of risk,4,‘2 suggesting that, if these gynaecological procedures do change ovarian function in a way that modifies breast cancer risk, the strength of the association, if any, is moderate. To provide further information on these issues, we analysed the relationship between age at menopause and breast cancer risk in specific groups of type of menopause, using the combination of data from two large case-control studies
Late menopause is a recognized breast cancer risk factor.‘.* Several questions on the issue remain open, however. These include quantitative assessment and comparison of risk estimates across various studies, which have often used different reference categories, and have shown a variable strength of the association detected. For instance, among women with a natural menopause, the relative risk of breast cancer for women aged under 40 years and those aged 50 years or more differed by about a factor of 4 in a large casecontrol study collecting data from the USA Canada and Israel,3 but only a 20% variation was noted in an American case-control study derived from a nationwide screening programme. The effect of time factors is also unknown, since variable latency periods before the establishment of an effect of age at menopause have been suggested.ti This is consistent with the observation that menopausal exogenous
Address correspondence Farmacologiche ‘Mario
to: Claudia Braga ScD, Istituto di Ricerche Negri,’ Via Eritrea, 62-20157 Milano, Italy.
27
28
The Breast
conducted in Italy. We computed floating absolute risks (FARs)13 to avoid the choice of an arbitrary reference category, to increase comparability across strata and allow for graphic comparison of risks.
SUBJECTS AND METHODS The data were derived from two case-control studies of breast cancer, the first conducted between 1983 and May 1991 in the greater Milan area,14 and the second between June 1991 and February 1994l’ in six Italian areas: in northern Italy, greater Milan, the provinces of Pordenone and Gorizia, the urban area of Genoa and the province of Forli; in central Italy, the province of Latina; in southern Italy, the urban area of Naples. Structured questionnaires were used in both studies. All interviewers were trained centrally, and interviews conducted in hospital were tested for reliability and reproducibility. On average, in both studies, less than 4% of cases and controls approached for interview refused to participate. Cases were women with incident (i.e. diagnosed within the year before interview), histologically confirmed breast cancer, admitted to the major teaching and general hospitals in the areas under surveillance. Women who reported no menses within the year before diagnosis/interview were considered postmenopausal. A total of 3576 cases out of 5984 were postmenopausal, and were therefore included in the present analysis. The age range was 31-74 years, and the median age 61. Controls were women residing in the same areas and admitted for acute conditions to the same network of hospitals where cases had been identified. Women were not included if they had been admitted for gynaecological, hormonal or neoplastic diseases. A total of 3578 postmenopausal women was selected from a sample of 5504 controls. The age range was 34-74 years, and the median age 61. They were admitted to hospital for a wide spectrum of acute diseases unrelated to known or potential risk factors for breast cancer. Of these, 30% had traumatic conditions (mostly fractures and sprains), 28% had non-traumatic orthopaedic disorders (mostly low back pain and disc disorders), 15% were admitted for acute surgical conditions (mostly abdominal, such as acute appendicitis or strangulated hernia), and 27% had miscellaneous other illnesses, such as eye, ear, nose, throat and dental disorders. Information was collected on patients’ personal characteristics, education and other socioeconomic factors, general lifestyle habits, diet and physical activity, gynaecological and obstetric data, and related medical history. Information related to menopausal status included age at menopause, type of menopause (natural/surgical [including hysterectomy alone or with monolateral oophorectomy, and bilateral
oophorectomy]/X-ray/pharmacological) and history of gynaecological surgery. Women included in the present analysis were further classified as to the event causing cessation of menses (natural or surgical: X-ray and pharmacological menopauses were excluded from the stratified analysis, because of the small numbers). Among women who had undergone a surgical menopause, those reporting bilateral oophorectomy were further selected.
Data analysis Odds ratios (ORs) of breast cancer according to age at menopause and in separate strata of type of menopause, and the corresponding 95% confidence intervals (Cls), were derived using unconditional multiple logistic regression.“j All the regression equations included terms for study/centre, age (l-year intervals), education (c 7/7-l l/2 12 years), age at menarche (< 13/2 13 years), parity/age at first birth (nulliparae/< 25/2 25 years), hormone replacement therapy (never/ever), oral contraceptive use (never/ever), history of benign breast disease (no/yes), family history of breast cancer (no/yes), and body mass index (<25/225 kg/m’). From every model, the corresponding FAR estimates were then computed.13 This method supplies estimates simTable 1 Distribution 3578 postmenopausal 1983-1994
of 3576 postmenopausal breast cancer cases and controls according to selected characteristics. Italy, No. of cases (%)
Age (years) <50 50-55 55-59 6&64 65-69 270
181 516 852 866 718 443
Education <7 7-11 212
(years)
Parity/age Nulliparae <25 225
at first
Use of oral Never Ever
contraceptives’
Hormone Never Ever
of benign
Family No Yes
history
239 553 790 800 725 471
(6.7) (15.5) (22.1) (22.4) (20.3) (13.2)
2168 (60.9) 855 (24.0) 539 (15.1)
2459 (69.1) 710 (19.9) 391 (11.0)
665 (18.6) 1157 (32.4) 1754 (49.1)
582 (16.3) 1438 (40.3) 1552 (43.5)
3439 (96.3) 132 (3.7)
3452 (96.6) 122 (3.4)
3231 (90.4) 345 (9.7)
3302 (93.2) 276 (7.7)
3117 (87.2) 459 (12.8)
3280 (9 1.7) 298 (8.3)
3152 (88.1) 424 (11.9)
3400 (95.0) 178 (5.0)
birth”
replacement
History No Yes
(5.1) (14.4) (23.8) (24.2) (20.1) (12.4)
No. of controls
breast
of breast
therapy
disease
cancer
“The totals do not add up because
of missing
values.
(%)
Age at menopause and breast cancer
RESULTS
ilar to the conventional relative risks, in the sense that parameter estimates are identical, but it associates a variance estimate with every single category of the variable examined. The mean risk for the variable can then be defined as the weighted mean of the parameter estimates, with weights proportional to the inverse of these variances, and the odds ratios can be re-expressed as relative to this mean risk. This method provides OR and variance estimates in the absence of a baseline category, is particularly appropriate in situations where a common baseline category valid across strata of a covariate cannot be selected, besides permitting a better graphic comparison of risks.
Table 2 Distribution” of 3576 postmenopausal breast at menopause and type of menopause. Italy, 1983-1994
Table 1 gives the distribution of breast cancer cases and the comparison group according to age and other major identified covariates. Cases were more educated than controls, had a first birth at a later age, and more frequently reported a history of benign breast disease and a family history of breast cancer. Table 2 considers the distribution of cases and controls in three strata of menopausal type according to age at menopause. A natural menopause was reported by 80.5% of cases and 76.9% of controls, surgically induced by 18.3% of cases and 21.7% of controls, while 0.9% of
cancer
cases and 3578 postmenopausal
controls
Age at menopause (years)
Natural menopause Cases Controls No. % No. %
Surgical menopause Cases Controls No. % No. %
Bilateral Cases No. R
<35 35-39 4044 4547 48-50 51-53 54-56
2 45 205 343 948 864 412
48 97 180 128 118 59 21
20 24 66 66 66 31 12
“The totals
do not add up because
0.1 1.6 7.3 12.2 33.6 30.7 14.6 of missing
13 75 274 380 936 683 320
0.5 2.8 10.2 14.2 34.9 25.5 11.9
7.4 14.9 27.6 19.7 18.1 9.1 3.2
88 103 212 166 124 62 22
11.3 13.3 27.3 21.4 16.0 8.0 2.8
according
to age
oophorectomy Controls No. %
7.0 8.4 23.2 23.2 22.2 10.9 4.2
38 39 76 71 66 25 7
11.8 12.1 23.6 22.1 20.5 7.8 2.2
values.
Table 3 Odds ratios” (ORs) with 95% confidence intervals (Cls) 3576 postmenopausal breast cancer cases and 3578 postmenopausal menopause. Italy, 1983-1994
and corresponding floating absolute riskb (FAR) estimates controls according to age at menopause and type of
All types’ OR (95% CI)
FAR
Natural OR (95% CI)
FAR
Surgical OR (95% CI)
FAR
Bilateral oophorectomy OR FAR (95% CI)
<35
0.48 (0.3-0.7)
0.49 (0.34.7)
0.14 (0.0-0.6)
0.14 (0.0-0.6)
0.52 (0.3xl.9)
0.59 (0.44.9)
0.37 (0.24.9)
0.44 (0.2-0.9)
35-39
0.79 (0.61.0)
0.81 (0.6-1.0)
0.63 (0.4-0.9)
0.62 (0.4-0.9)
1.01 (0.7-1.5)
1.15 (0.9-1.6)
0.60 (0.3-1.2)
0.7 1 (0.4-1.3)
40-44
0.80 (0.7-1.0)
0.82 (0.7-0.9)
0.74 (0.60.9)
0.73 (0.60.9)
0.89 (0.6-1.3)
1.02 (0.8-1.3)
0.86 (0.5-l
0.86 (0.7-l
0.88 (0.8-l
0.91 (0.8-l.
0.89 (0.8-l
0.78 (0.5-1.1)
0.89 (0.7-1.1)
0.79 (0.5-l
Age at menopause (years)
45-47 48-50
.O)
.O)
1)
.O)
.5)
1.02 (0.7-I
.5)
.4)
0.94 (0.6-l
.4)
Id -
1.02 (0.9-1.1)
Id -
0.98 (0.9-1.1)
1” -
1.14 (0.9-l
.5)
1” -
1.18 (0.8-1.8)
1.21 (1.1-1.4)
1.23 (1.1-1.4)
1.20 (1.1-1.4)
1.17 (1.1-1.3)
1.03 (0.6-1.6)
1.18 (0.8-I
.7)
1.32 (0.6-2.7)
1.56 (0.9-2.9)
54-56
1.21 (1.0-1.4)
1.24 (1.1-1.4)
1.23 (1.0-1.5)
1.20 (1.0-1.4)
0.94 (0.5-1.9)
1.08 (0.6-2.0)
1.53 (0.54.6)
1.81 (0.6-5.1)
X2we”J
37.60’
51-53
35.07’
29
2.44
“Estimates from multiple logistic regression including terms for study/centre, age, education, birth, oral contraceptive use (never/ever), hormone replacement therapy (never/ever), history family history of breast cancer (no/yes) and body mass index. bFAR estimates relative to the stratum floating reweighted mean. ‘Adjusted also for type of menopause. dReference category. “P < 0.01.
of
8.13’ age at menarche, parity/age at first of benign breast disease (no/yes),
30
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cases and 1.3% of controls reported a menopause of other or unspecified origin. Cases tended systematically to report a later age at menopause, although the differences were small for the overall group of surgical menopause. The multivariate ORs according to age at menopause are reported in Table 3, together with the corresponding FARs. When women of all menopausal types were considered together, FARs for age at menopause were 0.49,0.81,0.82, 0.88,1.02, 1.23 and 1.24 for subsequent age categories, with a significant linear trend in risk (xztrend= 37.60). The same pattern was seen in women reporting a natural menopause, again with a significant linear trend in risk (x*~~,~= 35.07), and FAR of 0.14 for women with menopause when ~35 years old versus 1.20 for those with menopause when 54-56 years old (ratio between FAR estimates = 8.6). No significant trend in risk appeared in the surgical menopause group. However, a linear trend in risk with later menopause was evident when surgical menopause due to bilateral oophorectomy was considered (x’~,,,~ = 8.13), and a significant reduction of risk was observed in women reporting a bilateral oophorectomy at ~35 years. The ratio between FAR estimates in the older versus the younger category of age at menopause was 4.1. The FARs relative to the ORs weighted average for all menopausal types, natural menopause and menopause due to bilateral oophorectomy. are set out in Figures 1-3. A remarkable consistency across menopausal types was observed. No heterogeneity emerged when risks were eval-
uated in strata of age at diagnosis/interview. For example, FARs for women who reported a natural menopause at 51-53 years were 1.17 for women under 54 years, 1.14 for women between 54 and 64 years and 1.19 for those over 64 FAR 2.0j1
1.5
1.0
0.5
2.0
45-47
48-50
51-53
54-56
(years)
of developing breast cancer (from data in Table 3).
by age at
I 1.0
0.5
I
0.0
0.c < 35
4c-44
1.5
‘1
0.5
35-39
Fig. 2 Floating absolute risks menopause: natural menopause
FAF
1.0
1
Age at menopause
2.c
jl
1
<35
FAF
1.:
1
35-39
4c-44
45-47
46-50
51-53
54-56
Age at menopause (years)
Fig. 1 Floating absolute risks of developing breast cancer by age at menopause: all types of menopause (from data in Table 3).
i <35
35-39
4c-M 45-47 46-50 Age at menopause (years)
5153
54-56
Fig. 3 Floating absolute risks of developing breast cancer by age at menopause: bilateral oophorectomy (from data in Table 3).
Age at menopause and breast cancer
d 0.4 :
<35
35-39
4&44
45-47
48-50
51-53
54-56
Ageatme"opa"se(years)
Fig. 4 Floating absolute risks of developing breast cancer by age at menopause across strata of age at diagnosis/interview (all types of menopause). Age group: N <54 years; ,,O.OO.. 544 years; - -WR f3 - 265 years.
years. Figure 4 shows FAR estimates in these three strata of age for all menopausal types together.
DISCUSSION This study provides a more accurate quantification than previously available on the pattern of risks of age at natural menopause and age at surgically induced menopause due to bilateral oophorectomy, with an over S-fold increase in risk between extreme categories. No relation was apparent when all surgically induced menopauses were considered together, underlining that the relationship between breast cancer and hysterectomy with one or both ovaries left remains unclear. No heterogeneity emerged across strata of age at diagnosis/interview for any type of menopause analysed, indicating that age at menopause has a long-term effect on subsequent breast cancer risk, and this is compatible with both an early and a late stage effect of age at menopause on breast carcinogenesis.‘7 The very early risk increase after late menopause in women below the age of 55 may, however, have other explanations. For instance, age at menopause may not only affect breast cancer risk per se, but may also be the indicator of some lifelong characteristic of ovarian function. This is supported by the very strong protection seen in the few women whose ovarian failure
31
occurred naturally below the age of 35. These findings are broadly consistent with overall epidemiological evidence.‘,’ However, direct comparison of results found across studies is made difficult by the heterogeneity in the choice of the baseline category: for this reason we computed FAR estimates as relative to the mean risk in each group analysed. Moreover, if existing or initiated tumours have an increased growth rate around the time of menopause,5 this makes the definition of postmenopausal status all the more crucial, since different definitions may change results substantially.” The definition of natural menopause adopted in this study (i.e. at least 12 months of amenorrhoea not due to other factors such as pregnancy or lactation) is in line with the World Health Organization’s definition.” Definition of age at menopause is clear for women undergoing bilateral oophorectomy, but not for other types of surgical procedures. A possible bias towards unity in estimating ORs for age at natural menopause has been suggested because of errors in patients’ reports.” However, any substantial influence of recall bias due to oral contraceptive use or hormone replacement therapy is unlikely in the population under study, considering the low prevalence of users. Moreover, the comparable age distribution of cases and controls is reassuring with reference to any potential recall bias, and age at diagnosis/interview was allowed for in the analysis in single year categories. A poor recall of operative procedures is also unlikely to have substantially biased the results, since women can be expected to remember abdominal operations that might trigger symptoms of the menopause or necessitate long-term replacement drug use.” The hospital setting for this study should further reduce differential recall bias between cases and controls. Some women who had undergone bilateral oophorectomy may have been misclassified, but major misclassification in the subgroup of women reporting bilateral oophorectomy is unlikely, since hysterectomy is a major condition, and women should report it in a clinical setting. Moreover, clinical records were available and were checked; no systematic discrepancies emerged and there were no errors regarding bilateral versus monolateral oophorectomy. Further, the stronger association observed among women with surgical hysterectomy” also provides an a posteriori evidence of the reliability of the information. The large dataset allowed reasonably precise risk estimates, so the results were not appreciably affected by random variation. Other limitations and strengths of this study are common to most hospital-based case-control studies, and have been widely discussed.16 Hospital controls may differ from the general population in several respects, but we excluded from the control group all patients with diagnoses potentially related to hormonal factors and patients with potential risk factors for breast cancer or factors which might have influenced age at menopause. The same catchment areas, an
32
The Breast
identical interview setting for cases and controls, and an almost complete participation are, moreover, reassuring, particularly regarding selection bias and differences in recall of menopause related variables. In conclusion, using a uniquely large dataset and an innovative method of analysis, we were able to evaluate the relationship between age at menopause and risk of breast cancer in the absence of an arbitrary reference category, documenting an over B-fold ratio of risks across extreme categories of age at menopause.
Acknowledgements This work was conducted within the framework of the CNR (Italian National Research Council) Applied Project ‘Clinical Applications of Oncological Research’ (contracts 95.00562.PF39 and 94.01268.PF39) and ‘Risk Factors for Disease’ (Contract 95.00952.PF41) and with the contributions of the Italian Association for Cancer Research, the Italian League against Tumours, Milan, and Mrs Angela Marchegiano Borgomainerio. The authors thank Mrs Judy Baggott, MS M. Paola Bonifacino and the Cl. A. Pfeiffer Memorial Library staff for editorial assistance.
References 1. Lipworth L. Epidemiology of breast cancer. Eur J Cancer Prev 199.5; 4: 7-30. 2. Kelsey J L, Gammon M D, John E M. Reproductive factors and breast cancer. Epidemiol Rev 1993; 15: 3647. 3. Helmrich S P, Shapiro S, Rosenberg L et al. Risk factors for breast cancer. Am J Epidemiol 1983; 117: 3545. 4. Brinton L A, Schairer C, Hoover R N, Fraumeni J F Jr. Menstrual factors and risk of breast cancer. Cancer Invest 1988; 6: 245-254. 5. Alexander F E, Roberts M M. The menopause and breast cancer. J Epidemiol Community Health 1987; 41: 94-100. 6. Trichopoulos D, MacMahon B, Cole P. Menopause and breast cancer risk. J Nat1 Cancer Inst 1972; 48: 605-613. 7. Brinton L A, Hoover R N, Szklo M. Menopausal estrogen use and risk of breast cancer. Cancer 1981; 47: 2517-2522.
8. Hoover R, Gray L A, Cole P. Menopausal estrogens and breast cancer. N Engl J Med 1976; 295: 401405. 9. Ewertz M, Duffy S W. Risk of breast cancer in relation to reproductive factors in Denmark. Br J Cancer 1988; 58: 99-104. 10. Carter C L, Jones D Y, Schatzkin A, Brinton L A. A prospective study of reproductive, familial, and socioeconomic risk factors for breast cancer using NHANES I data. Public Health Rep 1989; 104: 45-50. 11. Irwin K L, Lee N C, Peterson H B et al. Hysterectomy, tubal sterilization, and the risk of breast cancer. Am J Epidemiol 1988; 127: 1192-1201. 12. Hiatt R A, Fireman B H. Smoking, menopause, and breast cancer. J Nat1 Cancer Inst 1986: 76: 833-838. 13. Easton D F, Peto J, Babiker A G A G. Floating absolute risk an alternative to relative risk in survival and case-control analysis avoiding an arbitrary reference group. Stat Med 1991; 10: 1025-1035. 14. La Vecchia C, Decarli A, Fasoli M et al. Oral contraceptives and cancers of the breast of the female genital tract. Interim results from a case-control study. Br J Cancer 1986; 54: 3 11-317. 15. La Vecchia C, Negri E, Franceschi S et al. Oral contraceptives and breast cancer: a cooperative Italian study. Int J Cancer 1995; 60: 163-167. 16. Breslow N E, Day N E. Statistical methods in cancer research, vol. 1. The analysis of case-control study. IARC Sci Pub1 no. 32, 1980. 17. Day N E. Time as a determinant of risk in cancer epidemiology: the role of multi-stage models. Cancer Surv 1983; 2: 577-593. 18. Morabia A, Flandre P. Misclassification bias related to definition of menopausal status in case-control studies of breast cancer. Int J Epidemiol 1992; 21: 222-228. 19. Sowers M R, La Pietra M T. Menopause: its epidemiology and potential association with chronic diseases. Epidemiol Rev 1995; 17: 287-302. 20. Paganini-Hill A, Krailo M D, Pike M C. Age at natural menopause and breast cancer risk: the effect of errors in recall. Am J Epidemiol 1984; 119: 81-85. 21. Kelly J P, Rosenberg L, Kaufman D W, Shapiro S. Reliability of personal interview data in a hospital-based case-control study. Am J Epidemiol 1990; 13 1: 79-90. 22. Parazzini F, Braga C, La Vecchia C et al. Hysterectomy, oophorectomy in pre menopause and risk of breast cancer. Obstet Gynecol 1997; 90: 453456.
ORIGINAL ARTICLE
Age at menopause and breast cancer: estimation of floating absolute risks C. Braga, E. Negri, C. La Vecchia” and S. Franceschi’ Istituto di Ricerche Farmacologiche ‘Mario Negri’, *Istituto di Statistica Medica e Biometria, Universitir degli Studi di Milano, Milan, ‘Servizio di Epidemiologia, Centro di Rijierimento Oncologico, Aviano PN, Italy S U M MA R Y. Late menopause is consistently related to breast cancer risk, but direct comparison of the modifying effects of type of menopause and of time factors across studies has been made difficult by the heterogeneity in the choice of the reference category, and in the definition of postmenopausal status. These effects were investigated in the absence of an arbitrary baseline category by computing floating absolute risks (FARs). Pooled data from two case-control studies conducted between 1983 and 1994 in major teaching and general hospitals of six Italian centres were used. Participants were 3576 postmenopausal women with incident, histologically confirmed breast cancer, and 3578 postmenopausal controls admitted to hospital for acute, non-neoplastic, non-hormonal, non-gynaecological conditions. When all types of menopause were considered together, FARs were 0.49 for <35 years, 0.81 for 35-39 years, 0.82 for 40-44 years, 0.88 for 45-47 years, 1.02 for 48-50 years, 1.23 for 51-53 years and 1.24 for 54-56 years, with a significant linear trend. The same pattern was seen in women reporting a natural menopause, with FAR of 0.14 for women with menopause when aged ~35 years versus 1.20 for those with menopause at 54-56 years (ratio between extreme FAR estimates = 8.6). No trend emerged in the overall surgical menopause group (including hysterectomy alone or with monolateral oophorectomy, and bilateral oophorectomy). However, when women reporting a bilateral oophorectomy were selected, a significant linear trend was observed. No heterogeneity emerged when risks were evaluated in strata of age at diagnosis/interview. Thus, using a unique large dataset and an innovative method of analysis, this study documented an over &fold ratio of risks between extreme categories of age at menopause, but no evidence of a latency period before the establishment of an effect of age at menopause.
INTRODUCTION
oestrogens may exert their effects on breast cancer risk only after some delay.‘s8 There are also difficulties in understanding and in disentangling the effects of type of menopause. Trends similar to those observed for all menopausal types considered together were detected in women experiencing a surgical menopause,3s6,9although the association was weaker in some studies.4,10This is probably due to the inclusion of cases with hysterectomy alone and monolateral oophorectomy in the definition of age at menopause. When bilateral oophorectomy was considered, a consistent reduction in risk with decreasing age at operation was reported,3~4~‘1 but latency effects following surgery are yet unclear. Analyses considering age at monolateral oophorectomy or at hysterectomy have failed to detect a consistent pattern of risk,4,‘2 suggesting that, if these gynaecological procedures do change ovarian function in a way that modifies breast cancer risk, the strength of the association, if any, is moderate. To provide further information on these issues, we analysed the relationship between age at menopause and breast cancer risk in specific groups of type of menopause, using the combination of data from two large case-control studies
Late menopause is a recognized breast cancer risk factor.‘.* Several questions on the issue remain open, however. These include quantitative assessment and comparison of risk estimates across various studies, which have often used different reference categories, and have shown a variable strength of the association detected. For instance, among women with a natural menopause, the relative risk of breast cancer for women aged under 40 years and those aged 50 years or more differed by about a factor of 4 in a large casecontrol study collecting data from the USA Canada and Israel,3 but only a 20% variation was noted in an American case-control study derived from a nationwide screening programme. The effect of time factors is also unknown, since variable latency periods before the establishment of an effect of age at menopause have been suggested.ti This is consistent with the observation that menopausal exogenous
Address correspondence Farmacologiche ‘Mario
to: Claudia Braga ScD, Istituto di Ricerche Negri,’ Via Eritrea, 62-20157 Milano, Italy.
27
28
The Breast
conducted in Italy. We computed floating absolute risks (FARs)13 to avoid the choice of an arbitrary reference category, to increase comparability across strata and allow for graphic comparison of risks.
SUBJECTS AND METHODS The data were derived from two case-control studies of breast cancer, the first conducted between 1983 and May 1991 in the greater Milan area,14 and the second between June 1991 and February 1994l’ in six Italian areas: in northern Italy, greater Milan, the provinces of Pordenone and Gorizia, the urban area of Genoa and the province of Forli; in central Italy, the province of Latina; in southern Italy, the urban area of Naples. Structured questionnaires were used in both studies. All interviewers were trained centrally, and interviews conducted in hospital were tested for reliability and reproducibility. On average, in both studies, less than 4% of cases and controls approached for interview refused to participate. Cases were women with incident (i.e. diagnosed within the year before interview), histologically confirmed breast cancer, admitted to the major teaching and general hospitals in the areas under surveillance. Women who reported no menses within the year before diagnosis/interview were considered postmenopausal. A total of 3576 cases out of 5984 were postmenopausal, and were therefore included in the present analysis. The age range was 31-74 years, and the median age 61. Controls were women residing in the same areas and admitted for acute conditions to the same network of hospitals where cases had been identified. Women were not included if they had been admitted for gynaecological, hormonal or neoplastic diseases. A total of 3578 postmenopausal women was selected from a sample of 5504 controls. The age range was 34-74 years, and the median age 61. They were admitted to hospital for a wide spectrum of acute diseases unrelated to known or potential risk factors for breast cancer. Of these, 30% had traumatic conditions (mostly fractures and sprains), 28% had non-traumatic orthopaedic disorders (mostly low back pain and disc disorders), 15% were admitted for acute surgical conditions (mostly abdominal, such as acute appendicitis or strangulated hernia), and 27% had miscellaneous other illnesses, such as eye, ear, nose, throat and dental disorders. Information was collected on patients’ personal characteristics, education and other socioeconomic factors, general lifestyle habits, diet and physical activity, gynaecological and obstetric data, and related medical history. Information related to menopausal status included age at menopause, type of menopause (natural/surgical [including hysterectomy alone or with monolateral oophorectomy, and bilateral
oophorectomy]/X-ray/pharmacological) and history of gynaecological surgery. Women included in the present analysis were further classified as to the event causing cessation of menses (natural or surgical: X-ray and pharmacological menopauses were excluded from the stratified analysis, because of the small numbers). Among women who had undergone a surgical menopause, those reporting bilateral oophorectomy were further selected.
Data analysis Odds ratios (ORs) of breast cancer according to age at menopause and in separate strata of type of menopause, and the corresponding 95% confidence intervals (Cls), were derived using unconditional multiple logistic regression.“j All the regression equations included terms for study/centre, age (l-year intervals), education (c 7/7-l l/2 12 years), age at menarche (< 13/2 13 years), parity/age at first birth (nulliparae/< 25/2 25 years), hormone replacement therapy (never/ever), oral contraceptive use (never/ever), history of benign breast disease (no/yes), family history of breast cancer (no/yes), and body mass index (<25/225 kg/m’). From every model, the corresponding FAR estimates were then computed.13 This method supplies estimates simTable 1 Distribution 3578 postmenopausal 1983-1994
of 3576 postmenopausal breast cancer cases and controls according to selected characteristics. Italy, No. of cases (%)
Age (years) <50 50-55 55-59 6&64 65-69 270
181 516 852 866 718 443
Education <7 7-11 212
(years)
Parity/age Nulliparae <25 225
at first
Use of oral Never Ever
contraceptives’
Hormone Never Ever
of benign
Family No Yes
history
239 553 790 800 725 471
(6.7) (15.5) (22.1) (22.4) (20.3) (13.2)
2168 (60.9) 855 (24.0) 539 (15.1)
2459 (69.1) 710 (19.9) 391 (11.0)
665 (18.6) 1157 (32.4) 1754 (49.1)
582 (16.3) 1438 (40.3) 1552 (43.5)
3439 (96.3) 132 (3.7)
3452 (96.6) 122 (3.4)
3231 (90.4) 345 (9.7)
3302 (93.2) 276 (7.7)
3117 (87.2) 459 (12.8)
3280 (9 1.7) 298 (8.3)
3152 (88.1) 424 (11.9)
3400 (95.0) 178 (5.0)
birth”
replacement
History No Yes
(5.1) (14.4) (23.8) (24.2) (20.1) (12.4)
No. of controls
breast
of breast
therapy
disease
cancer
“The totals do not add up because
of missing
values.
(%)
Age at menopause and breast cancer
RESULTS
ilar to the conventional relative risks, in the sense that parameter estimates are identical, but it associates a variance estimate with every single category of the variable examined. The mean risk for the variable can then be defined as the weighted mean of the parameter estimates, with weights proportional to the inverse of these variances, and the odds ratios can be re-expressed as relative to this mean risk. This method provides OR and variance estimates in the absence of a baseline category, is particularly appropriate in situations where a common baseline category valid across strata of a covariate cannot be selected, besides permitting a better graphic comparison of risks.
Table 2 Distribution” of 3576 postmenopausal breast at menopause and type of menopause. Italy, 1983-1994
Table 1 gives the distribution of breast cancer cases and the comparison group according to age and other major identified covariates. Cases were more educated than controls, had a first birth at a later age, and more frequently reported a history of benign breast disease and a family history of breast cancer. Table 2 considers the distribution of cases and controls in three strata of menopausal type according to age at menopause. A natural menopause was reported by 80.5% of cases and 76.9% of controls, surgically induced by 18.3% of cases and 21.7% of controls, while 0.9% of
cancer
cases and 3578 postmenopausal
controls
Age at menopause (years)
Natural menopause Cases Controls No. % No. %
Surgical menopause Cases Controls No. % No. %
Bilateral Cases No. R
<35 35-39 4044 4547 48-50 51-53 54-56
2 45 205 343 948 864 412
48 97 180 128 118 59 21
20 24 66 66 66 31 12
“The totals
do not add up because
0.1 1.6 7.3 12.2 33.6 30.7 14.6 of missing
13 75 274 380 936 683 320
0.5 2.8 10.2 14.2 34.9 25.5 11.9
7.4 14.9 27.6 19.7 18.1 9.1 3.2
88 103 212 166 124 62 22
11.3 13.3 27.3 21.4 16.0 8.0 2.8
according
to age
oophorectomy Controls No. %
7.0 8.4 23.2 23.2 22.2 10.9 4.2
38 39 76 71 66 25 7
11.8 12.1 23.6 22.1 20.5 7.8 2.2
values.
Table 3 Odds ratios” (ORs) with 95% confidence intervals (Cls) 3576 postmenopausal breast cancer cases and 3578 postmenopausal menopause. Italy, 1983-1994
and corresponding floating absolute riskb (FAR) estimates controls according to age at menopause and type of
All types’ OR (95% CI)
FAR
Natural OR (95% CI)
FAR
Surgical OR (95% CI)
FAR
Bilateral oophorectomy OR FAR (95% CI)
<35
0.48 (0.3-0.7)
0.49 (0.34.7)
0.14 (0.0-0.6)
0.14 (0.0-0.6)
0.52 (0.3xl.9)
0.59 (0.44.9)
0.37 (0.24.9)
0.44 (0.2-0.9)
35-39
0.79 (0.61.0)
0.81 (0.6-1.0)
0.63 (0.4-0.9)
0.62 (0.4-0.9)
1.01 (0.7-1.5)
1.15 (0.9-1.6)
0.60 (0.3-1.2)
0.7 1 (0.4-1.3)
40-44
0.80 (0.7-1.0)
0.82 (0.7-0.9)
0.74 (0.60.9)
0.73 (0.60.9)
0.89 (0.6-1.3)
1.02 (0.8-1.3)
0.86 (0.5-l
0.86 (0.7-l
0.88 (0.8-l
0.91 (0.8-l.
0.89 (0.8-l
0.78 (0.5-1.1)
0.89 (0.7-1.1)
0.79 (0.5-l
Age at menopause (years)
45-47 48-50
.O)
.O)
1)
.O)
.5)
1.02 (0.7-I
.5)
.4)
0.94 (0.6-l
.4)
Id -
1.02 (0.9-1.1)
Id -
0.98 (0.9-1.1)
1” -
1.14 (0.9-l
.5)
1” -
1.18 (0.8-1.8)
1.21 (1.1-1.4)
1.23 (1.1-1.4)
1.20 (1.1-1.4)
1.17 (1.1-1.3)
1.03 (0.6-1.6)
1.18 (0.8-I
.7)
1.32 (0.6-2.7)
1.56 (0.9-2.9)
54-56
1.21 (1.0-1.4)
1.24 (1.1-1.4)
1.23 (1.0-1.5)
1.20 (1.0-1.4)
0.94 (0.5-1.9)
1.08 (0.6-2.0)
1.53 (0.54.6)
1.81 (0.6-5.1)
X2we”J
37.60’
51-53
35.07’
29
2.44
“Estimates from multiple logistic regression including terms for study/centre, age, education, birth, oral contraceptive use (never/ever), hormone replacement therapy (never/ever), history family history of breast cancer (no/yes) and body mass index. bFAR estimates relative to the stratum floating reweighted mean. ‘Adjusted also for type of menopause. dReference category. “P < 0.01.
of
8.13’ age at menarche, parity/age at first of benign breast disease (no/yes),
30
The Breast
cases and 1.3% of controls reported a menopause of other or unspecified origin. Cases tended systematically to report a later age at menopause, although the differences were small for the overall group of surgical menopause. The multivariate ORs according to age at menopause are reported in Table 3, together with the corresponding FARs. When women of all menopausal types were considered together, FARs for age at menopause were 0.49,0.81,0.82, 0.88,1.02, 1.23 and 1.24 for subsequent age categories, with a significant linear trend in risk (xztrend= 37.60). The same pattern was seen in women reporting a natural menopause, again with a significant linear trend in risk (x*~~,~= 35.07), and FAR of 0.14 for women with menopause when ~35 years old versus 1.20 for those with menopause when 54-56 years old (ratio between FAR estimates = 8.6). No significant trend in risk appeared in the surgical menopause group. However, a linear trend in risk with later menopause was evident when surgical menopause due to bilateral oophorectomy was considered (x’~,,,~ = 8.13), and a significant reduction of risk was observed in women reporting a bilateral oophorectomy at ~35 years. The ratio between FAR estimates in the older versus the younger category of age at menopause was 4.1. The FARs relative to the ORs weighted average for all menopausal types, natural menopause and menopause due to bilateral oophorectomy. are set out in Figures 1-3. A remarkable consistency across menopausal types was observed. No heterogeneity emerged when risks were eval-
uated in strata of age at diagnosis/interview. For example, FARs for women who reported a natural menopause at 51-53 years were 1.17 for women under 54 years, 1.14 for women between 54 and 64 years and 1.19 for those over 64 FAR 2.0j1
1.5
1.0
0.5
2.0
45-47
48-50
51-53
54-56
(years)
of developing breast cancer (from data in Table 3).
by age at
I 1.0
0.5
I
0.0
0.c < 35
4c-44
1.5
‘1
0.5
35-39
Fig. 2 Floating absolute risks menopause: natural menopause
FAF
1.0
1
Age at menopause
2.c
jl
1
<35
FAF
1.:
1
35-39
4c-44
45-47
46-50
51-53
54-56
Age at menopause (years)
Fig. 1 Floating absolute risks of developing breast cancer by age at menopause: all types of menopause (from data in Table 3).
i <35
35-39
4c-M 45-47 46-50 Age at menopause (years)
5153
54-56
Fig. 3 Floating absolute risks of developing breast cancer by age at menopause: bilateral oophorectomy (from data in Table 3).
Age at menopause and breast cancer
d 0.4 :
<35
35-39
4&44
45-47
48-50
51-53
54-56
Ageatme"opa"se(years)
Fig. 4 Floating absolute risks of developing breast cancer by age at menopause across strata of age at diagnosis/interview (all types of menopause). Age group: N <54 years; ,,O.OO.. 544 years; - -WR f3 - 265 years.
years. Figure 4 shows FAR estimates in these three strata of age for all menopausal types together.
DISCUSSION This study provides a more accurate quantification than previously available on the pattern of risks of age at natural menopause and age at surgically induced menopause due to bilateral oophorectomy, with an over S-fold increase in risk between extreme categories. No relation was apparent when all surgically induced menopauses were considered together, underlining that the relationship between breast cancer and hysterectomy with one or both ovaries left remains unclear. No heterogeneity emerged across strata of age at diagnosis/interview for any type of menopause analysed, indicating that age at menopause has a long-term effect on subsequent breast cancer risk, and this is compatible with both an early and a late stage effect of age at menopause on breast carcinogenesis.‘7 The very early risk increase after late menopause in women below the age of 55 may, however, have other explanations. For instance, age at menopause may not only affect breast cancer risk per se, but may also be the indicator of some lifelong characteristic of ovarian function. This is supported by the very strong protection seen in the few women whose ovarian failure
31
occurred naturally below the age of 35. These findings are broadly consistent with overall epidemiological evidence.‘,’ However, direct comparison of results found across studies is made difficult by the heterogeneity in the choice of the baseline category: for this reason we computed FAR estimates as relative to the mean risk in each group analysed. Moreover, if existing or initiated tumours have an increased growth rate around the time of menopause,5 this makes the definition of postmenopausal status all the more crucial, since different definitions may change results substantially.” The definition of natural menopause adopted in this study (i.e. at least 12 months of amenorrhoea not due to other factors such as pregnancy or lactation) is in line with the World Health Organization’s definition.” Definition of age at menopause is clear for women undergoing bilateral oophorectomy, but not for other types of surgical procedures. A possible bias towards unity in estimating ORs for age at natural menopause has been suggested because of errors in patients’ reports.” However, any substantial influence of recall bias due to oral contraceptive use or hormone replacement therapy is unlikely in the population under study, considering the low prevalence of users. Moreover, the comparable age distribution of cases and controls is reassuring with reference to any potential recall bias, and age at diagnosis/interview was allowed for in the analysis in single year categories. A poor recall of operative procedures is also unlikely to have substantially biased the results, since women can be expected to remember abdominal operations that might trigger symptoms of the menopause or necessitate long-term replacement drug use.” The hospital setting for this study should further reduce differential recall bias between cases and controls. Some women who had undergone bilateral oophorectomy may have been misclassified, but major misclassification in the subgroup of women reporting bilateral oophorectomy is unlikely, since hysterectomy is a major condition, and women should report it in a clinical setting. Moreover, clinical records were available and were checked; no systematic discrepancies emerged and there were no errors regarding bilateral versus monolateral oophorectomy. Further, the stronger association observed among women with surgical hysterectomy” also provides an a posteriori evidence of the reliability of the information. The large dataset allowed reasonably precise risk estimates, so the results were not appreciably affected by random variation. Other limitations and strengths of this study are common to most hospital-based case-control studies, and have been widely discussed.16 Hospital controls may differ from the general population in several respects, but we excluded from the control group all patients with diagnoses potentially related to hormonal factors and patients with potential risk factors for breast cancer or factors which might have influenced age at menopause. The same catchment areas, an
32
The Breast
identical interview setting for cases and controls, and an almost complete participation are, moreover, reassuring, particularly regarding selection bias and differences in recall of menopause related variables. In conclusion, using a uniquely large dataset and an innovative method of analysis, we were able to evaluate the relationship between age at menopause and risk of breast cancer in the absence of an arbitrary reference category, documenting an over B-fold ratio of risks across extreme categories of age at menopause.
Acknowledgements This work was conducted within the framework of the CNR (Italian National Research Council) Applied Project ‘Clinical Applications of Oncological Research’ (contracts 95.00562.PF39 and 94.01268.PF39) and ‘Risk Factors for Disease’ (Contract 95.00952.PF41) and with the contributions of the Italian Association for Cancer Research, the Italian League against Tumours, Milan, and Mrs Angela Marchegiano Borgomainerio. The authors thank Mrs Judy Baggott, MS M. Paola Bonifacino and the Cl. A. Pfeiffer Memorial Library staff for editorial assistance.
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8. Hoover R, Gray L A, Cole P. Menopausal estrogens and breast cancer. N Engl J Med 1976; 295: 401405. 9. Ewertz M, Duffy S W. Risk of breast cancer in relation to reproductive factors in Denmark. Br J Cancer 1988; 58: 99-104. 10. Carter C L, Jones D Y, Schatzkin A, Brinton L A. A prospective study of reproductive, familial, and socioeconomic risk factors for breast cancer using NHANES I data. Public Health Rep 1989; 104: 45-50. 11. Irwin K L, Lee N C, Peterson H B et al. Hysterectomy, tubal sterilization, and the risk of breast cancer. Am J Epidemiol 1988; 127: 1192-1201. 12. Hiatt R A, Fireman B H. Smoking, menopause, and breast cancer. J Nat1 Cancer Inst 1986: 76: 833-838. 13. Easton D F, Peto J, Babiker A G A G. Floating absolute risk an alternative to relative risk in survival and case-control analysis avoiding an arbitrary reference group. Stat Med 1991; 10: 1025-1035. 14. La Vecchia C, Decarli A, Fasoli M et al. Oral contraceptives and cancers of the breast of the female genital tract. Interim results from a case-control study. Br J Cancer 1986; 54: 3 11-317. 15. La Vecchia C, Negri E, Franceschi S et al. Oral contraceptives and breast cancer: a cooperative Italian study. Int J Cancer 1995; 60: 163-167. 16. Breslow N E, Day N E. Statistical methods in cancer research, vol. 1. The analysis of case-control study. IARC Sci Pub1 no. 32, 1980. 17. Day N E. Time as a determinant of risk in cancer epidemiology: the role of multi-stage models. Cancer Surv 1983; 2: 577-593. 18. Morabia A, Flandre P. Misclassification bias related to definition of menopausal status in case-control studies of breast cancer. Int J Epidemiol 1992; 21: 222-228. 19. Sowers M R, La Pietra M T. Menopause: its epidemiology and potential association with chronic diseases. Epidemiol Rev 1995; 17: 287-302. 20. Paganini-Hill A, Krailo M D, Pike M C. Age at natural menopause and breast cancer risk: the effect of errors in recall. Am J Epidemiol 1984; 119: 81-85. 21. Kelly J P, Rosenberg L, Kaufman D W, Shapiro S. Reliability of personal interview data in a hospital-based case-control study. Am J Epidemiol 1990; 13 1: 79-90. 22. Parazzini F, Braga C, La Vecchia C et al. Hysterectomy, oophorectomy in pre menopause and risk of breast cancer. Obstet Gynecol 1997; 90: 453456.