The role of reproductive factors and use of oral contraceptives in the aetiology of breast cancer in women aged 50 to 74 years

It is unclear whether age at menarche is causally involved in breast‐cancer aetiology, or serves a correlate of other early‐life exposures. Other aspects of reproductive life, including cycle length and regularity, climacteric symptoms, reproductive history and oral contraceptive use, are also incompletely investigated. We examined these issues in a population‐based case‐control study, including 3,016 women aged 50 to 74 years with invasive breast cancer, and 3,263 controls of similar age. Mailed questionnaires and telephone interviews were used to collect information on menstrual and reproductive characteristics as well as use of oral contraceptives. We found a statistically significant negative association between increasing age at menarche and breast‐cancer risk in women born before 1925 but not after. Length of the menstrual cycle at age 30 seemed to be adversely related to breast‐cancer risk, with OR for women with cycle lengths <24 days and >30 days being 0.76 and 1.18, as compared with women with a cycle length of 28 days. There was a strong trend of decreasing breast‐cancer risk with increasing parity (OR per borne child 0.85, 95% CI 0.80–0.90). Lactation, menopausal symptoms or past use of oral contraceptives did not appear associated with breast‐cancer risk. Our findings provide some evidence of a role of environmental correlates of early menarche in breast‐cancer aetiology, and underline the importance of childbirth, especially early in life, in the prevention of breast cancer. Our data are not readily compatible with an important influence of former oral contraceptive use on post‐menopausal breast‐cancer risk. Int. J. Cancer 80:231–236, 1999. © 1999 Wiley‐Liss, Inc.     

A case-control study of breast cancer in Tianjin, China.

In a population-based case-control study of breast cancer in Tianjin, China, involving 300 cases and 300 population controls interviewed during 1985-1986, a number of strong risk factors were identified. Although average age at menarche was late by Western standards in this developing country (14.4 years), it was clearly related to risk. Women with their first menstrual period at age 12 years or earlier had 80% greater risk than women who started at age 17 years or later. Age at first full-term pregnancy was also strongly related to risk, with women whose first birth after age 30 years having 3.2 times the risk of women whose first birth was under age 20 years. Other established breast cancer risk factors in Western populations (family history of breast cancer, a history of benign breast disease, and use of oral contraceptives late in reproductive life) were also risk factors in this population. Parity and duration of lactation were both strongly protective against breast cancer development in univariate analyses. These two variables were highly correlated with each other and with age at first full-term pregnancy. Although the effects of each variable dissipated somewhat in multivariate analysis, our data strongly suggest that both parity and lactation independently contribute to breast cancer risk.     

Risk factors for breast cancer in Chinese women in Shanghai

Five hundred thirty-four histologically confirmed incident cases of breast cancer in Chinese women of Shanghai and an equal number of age and sex-matched population controls were interviewed as part of an epidemiological study of breast cancer risk factors. Early age at menarche was positively associated with breast cancer risk whereas early age at first full term pregnancy, high parity, and long duration of nursing were each negatively associated. We found high average body weight to be a risk factor, especially among women over age 60. Use of oral contraceptives after age 45 also was a risk factor, but use in general was not. Personal history of benign breast disease and history of breast cancer in first degree female relatives both increased risk. Multivariate analysis showed that each of these risk (or protective) factors was independently related to breast cancer. In addition to confirming most of the breast cancer risk factors of Western populations in a low risk developing Asian country, this study demonstrates a clear beneficial effect on breast cancer risk of lactation in a population characterized by a long cumulative duration of nursing in the majority of women. Finally, this study supports several other recent reports of a residual and beneficial effect of parity on breast cancer risk after controlling for age at first full term pregnancy.     

Breast Cancer in Denmark Incidence, risk factors, and characteristics of survival

In Denmark, incidence of female breast cancer remained constant from 1943 to around 1960, whereafter a steady increase has occurred, the level today being about 50% higher than in 1960. No equivalent rise has been observed for breast cancer mortality. Influence of hormonal and dietary factors on breast cancer risk and survival was evaluated in a combined population-based case-control and follow-up study, including 2 445 women, aged less than 70 years, diagnosed with breast cancer in Denmark between 1 March 1983 and 31 August 1984, identified from the files of the nation-wide clinical trial of the Danish Breast Cancer Co-operative Group (DBCG) and the Danish Cancer Registry. the control group was an age-stratified random sample of the general female population, selected from the Central Population Register. Data on risk factors were collected by self-administered questionnaires. Clinical and pathological tumour characteristics derived from DBCG. the case-control analysis confirmed an overall increased risk of breast cancer associated with urban residence, high social status, nulliparity, early age at menarche, late age at natural menopause, hormonal replacement therapy, high dietary fat intake, and high alcohol consumption in a subgroup. It failed to detect an association with age at first childbirth, oral contraceptives, smoking, intake of vegetables, tea, coffee, and sweeteners. Survival was determined by tumour size, skin invasion, number of positive lymph nodes, and grade. There was no relation between survival and reproductive or hormonal factors, dietary variables, alcohol consumption, or smoking. However, a complex relationship may exist between survival and body mass index.     

Oral contraceptives as related to cancer and benign lesions of the breast.

We conducted a case-control study to search for any relationship between use of oral contraceptives and development of breast cancer or benign breast disease. Women less than 50 years old with these diseases were matched with 2 controls by age, race, religion, and hospital. Home interviews elicited information on oral contraceptive use and other host and environmental factors. The study population comprised 1,770 women, including 452 with breast cancer and 446 with benign breast disease. The relative risk of developing cancer or benign disease was measured by matched set and summary chi-square analyses. Although the relative risk of developing breast cancer among "ever-users" of oral contraceptives was 1.1, the risk among women using oral contraceptives for 2-4 years was 1.9 (significantly increased). This risk estimate reached 2.5 for the 2- to 4-year users if they were still taking oral contraceptives when entered into study. Moreover, prior biopsy for benign breast disease increased the cancer risk among long-term users by as much as 11-fold. The relative risk of breast cancer did not vary by age, interval since first use, earliest year of use, or interval since last use. These results could be interpreted to indicate that oral contraceptives did not induce breast cancer but may have accelerated the growth rate of preexisting breast cancer. The relative risk of developing benign breast disease among ever-users of oral contraceptives was 0.8 (significantly reduced); it decreased with longer duration of use until it reached 0.2 for women who took these hormones 8 years or more. The relative risk of benign breast was not affected by earliest year of use or interval since last use. We concluded that oral contraceptives reduced the incidence of benign breast disease, but that use of steroid hormones is ill-advised for women with already established benign breast disease.     

Some further consideration on the role of oral contraceptives in breast carcinogenesis

Available evidence concerning oral contraceptives and their potential interaction with reproductive history on breast cancer risk is reviewed. The relative risks in 15 out of 15 studies were above unity among younger women (i.e., below age 35 and perhaps up to 45) for long-term oral contraceptive use, although apparent heterogeneities emerged in the risk estimates. The overall evidence is reassuring in subsequent age groups, whereas the modifying effects or interactions between oral contraceptives, reproductive factors and breast cancer risk are still largely undefined. Thus we suggest that, besides chance and bias, the apparent discrepancies between various studies should be considered within the framework of the complex time- and age-effects of hormone-related risk factors on breast carcinogenesis.     

Active and passive smoking and the risk of breast cancer in women aged 36-45 years: a population based case-control study in the UK

Active smoking has little or no effect on breast cancer risk but some investigators have suggested that passive smoking and its interaction with active smoking may be associated with an increased risk. In a population based case-control study of breast cancer in women aged 36-45 years at diagnosis, information on active smoking, passive smoking in the home, and other factors, was collected at interview from 639 cases and 640 controls. Women were categorised jointly by their active and passive smoking exposure. Among never smoking controls, women who also reported no passive smoking exposure were significantly more likely to be nulliparous and to be recent users of oral contraceptives. Among those never exposed to passive smoking, there was no significant association between active smoking and breast cancer, relative risk (RR) of 1.12 (95% confidence interval (CI) 0.72-1.73) for past smokers and RR of 1.19 (95% CI 0.72-1.95) for current smokers, nor was there an association with age started, duration or intensity of active smoking. Compared with women who were never active nor passive smokers, there was no significant association between passive smoking in the home and breast cancer risk in never smokers, RR of 0.89 (95% CI 0.64-1.25), in past smokers, RR of 1.09 (95% CI 0.75-1.56), or in current smokers, RR of 0.93 (95% CI 0.67-1.30). There was no trend with increasing duration of passive smoking and there was no heterogeneity among any of the subgroups examined. In this study, there was no evidence of an association between either active smoking or passive smoking in the home and risk of breast cancer.     

Oral contraceptives and risk of breast cancer

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. 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 pill and breast cancer: is there a connection?

Experts remain unsure if using oral contraceptives increases the chances that a woman will contract breast cancer. Although early studies generally indicated that there was no connection between pill usage and breast cancer, 3 recent longterm reports suggest otherwise. The Fertility and Maternal Health Drugs Advisory Committee of the Food and Drug Administration concluded that the new studies were inconclusive and recommended no changes to labeling of the pill. Known risk factors for breast cancer are a woman's age, menstrual history, reproductive experience, diet, benign breast disease, and family or personal history of breast cancer. In a reexamination of 1 of the studies, the risk of breast cancer was found to increase fourfold before age 54 for a subgroup of women--those who began menstruating before age 13, had no children, and had used the pill for more than 8 years. The 2nd study found that breast cancer risk by age 45 doubled for women using the pill for less than 10 years and quadrupled when used for at least 10 years. However, the overall risk did not increase according to length of pill usage. The 3rd study found a 200% increase in breast cancer among women aged 30-34 years who had previously used the pill, but no correlation in the overall results. Additional research following pill users over as long a period of time as possible should be undertaken. The National Cancer Institute will begin a 3-year study involving 2,000 American women in mid-1989 to examine roles of oral contraceptives, alcohol, and diet in breast cancer risk. It also will look at possible reasons for discrepancies found in the previous studies.     

Reproductive factors and the risk of renal cell cancer among women

In etiologic studies of renal cell carcinoma the role of reproductive variables and the use of exogenous hormones have not been well examined. In a population-based case-control study including 165 female cases and 227 controls, we assessed the risk of renal cell cancer associated with reproductive factors and use of oral contraceptives and menopausal hormones. Odds ratios were computed using logistic regression analyses. Risk was positively associated with number of births and inversely associated with age at first birth, with the largest increases in risk (more than 2-fold) among women with 5 or more births after age 25. After adjustment for age, smoking status, body mass index and age at first birth, women with 5 or more births had a 2-fold risk (OR = 2.2, 95% CI = 1.2-4.0) relative to those with 1 or 2 births. Age at first birth, however, was no longer a risk factor when the number of births was adjusted for. The association with parity was considerably stronger among women with a history of hypertension or above-median body mass index than among those without these conditions. In addition, risk was reduced among long-term oral contraceptive users but elevated among women who had had a hysterectomy or used menopausal hormones. Our findings suggest that reproductive factors, particularly the number of births, may play an etiologic role in renal cell cancer among women and deserve further study. © 1995 Wiley-Liss, Inc.     

Oral contraceptives and breast cancer: results from an expanded case-control study

The relationship between oral contraceptives and breast cancer was evaluated among 2,022 cases and 2,183 controls participating in a multicentre breast cancer screening programme. Ever use of oral contraceptives was not related to breast cancer risk (RR = 1.0, 95% CI 0.9-1.2), and no overall patterns of increasing or decreasing risks were observed according to the duration of use, or time since first or most recent use. Although we had no women with extended periods of oral contraceptive use early in life, no evidence of adverse effects attributable to short-term use before age 25, before first live birth or during the perimenopausal period were observed. Further, oral contraceptives did not interact with other breast cancer risk factors, except among those with a history of two or more breast biopsies (RR = 2.0). Analyses by stage of disease revealed that risk was related to the duration of oral contraceptive use: greater than or equal to 5 years use was associated with reduced risk for in situ cancer (RR = 0.59) and increased risks for invasive cancers (RR = 1.5 and 1.4 respectively for small and large lesions). These data suggest that oral contraceptive effects may vary by stage of disease, but provide no overall evidence of an association between oral contraceptives and breast cancer.     

Role and impact of menstrual and reproductive factors on breast cancer risk in Japan.

The aim of this study was to clarify the role and impact of menstrual and reproductive factors in relation to breast cancer and its hormone receptor-defined subtype, overall and separately among premenopausal and postmenopausal women in a low-risk population, using data from the Japan Public Health Center-based Prospective study. A total of 55 537 women aged 40-69 years completed a self-administered questionnaire, which included items about menstrual and reproductive history. During 1990-2002, 441 newly diagnosed cases of breast cancer were identified. Early age at menarche for premenopausal women, late age at natural menopause, nulliparity and low parity for both premenopausal and postmenopausal women, and late age at first birth for postmenopausal women were significantly associated with an increased risk of breast cancer. No overall significant associations were seen between the use of exogenous female hormones or breast feeding and breast cancer risk. Age at menarche and age at natural menopause were somewhat more closely associated with the risk of progesterone receptor-negative than positive breast cancer although no difference was observed for estrogen receptor status. Risks associated with parity, number of births and age at first birth did not significantly differ by hormone receptor-defined breast cancer. Our findings suggest that menstrual and reproductive factors may play an important role in the development of breast cancer among low-risk populations, similarly as they do in Western populations, and that risk factors might differ by hormone receptor status.     

Reproductive factors,exogenous female hormone use and breast cancer risk in Japanese: the Miyagi Cohort Study

The incidence of breast cancer among Japanese women is substantially increasing. This population-based prospective cohort study in Japan evaluated the associations of reproductive factors and exogenous female hormone use with breast cancer risk, both overall and separately among premenopausal and postmenopausal women. A total of 24,064 women aged 40–64 were followed from 1990 to 2003. During 309,424 person-years of follow-up, 285 breast cancer cases were documented. In overall evaluation, nulliparity was significantly associated with an increased risk of breast cancer. There was a significant decrease in risk with increasing parity number among parous women (trend P = 0.008). No association was observed between age at menarche or age at first birth and breast cancer risk. Neither oral contraceptive (OC) use nor the use of exogenous female hormones other than OC was associated with breast cancer risk. The evaluation according to menopausal status revealed that nulliparity and parity number were significantly related to breast cancer risk only among postmenopausal women. Later age at natural menopause was associated with an increased risk of breast cancer among postmenopausal women (trend P = 0.02). Our findings suggest that parity number and age at menopause have great effects on breast cancer risk among Japanese women.     

Lower prevalence of breast cancer and cancers of the reproductive system among former college athletes compared to non-athletes

The prevalence (lifetime occurrence) rate of cancers of the reproductive system (uterus, ovary, cervix and vagina) and breast cancer was determined for 5,398 living alumnae, 2,622 of whom were former college athletes and 2,776 non-athletes, from data on medical and reproductive history, athletic training and diet. The former athletes had a significantly lower risk of cancer of the breast and reproductive system than did the non-athletes. The relative risk (RR), non-athletes/athletes, for cancers of the reproductive system was 2.53. 95% confidence limits (CL) (1.17, 5.47). The RR for breast cancer was 1.86, 95% CL (1.00, 3.47). The analysis controlled for potential confounding factors including age, family history of cancer, age of menarche, number of pregnancies, use of oral contraceptives, use of oestrogen in the menopausal period, smoking, and leanness. Of the college athletes, 82.4% had been on pre-college teams compared to 24.9% of the college non-athletes. We conclude that long term athletic training may lower the risk of breast cancer and cancers of the reproductive system.     

Risk factors for breast cancer among young women in southern Iran

Age standardized incidence rates of breast cancer in developed countries is nearly threefold higher than in developing countries. Iran has had one of the lowest incidence rates for breast cancer in the world, but during the last four decades increasing incidence rates of breast cancer made it the most prevalent cancer in Iranian women. After adjustment for age, Iranian young women are at relatively higher risk of breast cancer than their counterparts in developed countries. The purpose of this study was to investigate some established risk factors of breast cancer in Iranian young women. A hospital-based case control study comprising 521 women with histologically confirmed, incident breast cancer and 521 controls frequency-matched by age and province of residence was conducted. Logistic regression performed to investigate associations of reproductive and anthropometric factors with breast cancer risk. In multivariate analysis, family history [odds ratio (OR): 1.61; 95% confidence interval (CI): 1.07-2.42], oral contraceptives (OC) usage (OR: 1.52; 95% CI: 1.11-2.08), low parity (OR parity ≥ 3 vs. 1-2: 0.33; 95% CI: 0.23-0.49), employment (OR: 1.83; 95% CI: 1.05-3.23) and shorter period of breast feeding (OR ≥ 37 months vs. < 37: 0.61; 95% CI: 0.44-0.84) were related to a higher risk of breast cancer in young women. This was the first study focusing on risk factors of breast cancer in Iranian young women. The trend of decreasing parity and shortened duration of breast feeding along with OC usage might partly explain the rapid rising of breast cancer incidence in Iranian young women.     

Hormonal factors and pancreatic cancer risk in women: The Malmö Diet and Cancer Study

The incidence of pancreatic cancer is leveling between sexes. Smoking, high age and heredity are established risk factors, but evidence regarding the influence of hormonal factors is unclear. In this study, we investigated the associations of reproductive factors, use of oral contraceptives (OC) and hormone replacement therapy (HRT) with pancreatic cancer risk in the Malmö Diet and Cancer Study, a prospective, population‐based cohort encompassing 17,035 women. Up until 31 December 2015, 110 women were identified with incident pancreatic cancer through the Swedish Cancer Registry. Higher age at menarche was significantly associated with pancreatic cancer risk (age‐adjusted [hazard ratio] HR = 1.17; 95% confidence interval [CI] 1.04–1.32, and fully adjusted HR = 1.17; 95% CI 1.04–1.32). Ever use of OC was not significantly associated with pancreatic cancer risk but ever use of HRT was significantly associated with a decreased risk of pancreatic cancer (age‐adjusted HR = 0.47, 95% CI 0.23–0.97, and fully adjusted HR = 0.48, 95% CI 0.23–1.00), in particular use of estrogen‐only regimen (age‐adjusted HR = 0.21; 95% CI 0.05–0.87 and fully adjusted HR = 0.22; 95% CI 0.05–0.90). Age at menopause or first childbirth, parity and breastfeeding history were not significantly associated with pancreatic cancer risk. Collectively, these findings suggest a protective role of female hormones against pancreatic cancer. Further studies are needed, and potential modifying genetic factors and indirect hazardous effects of smoking should also be considered.     

Reproductive factors in hereditary breast cancer

Background: An early age at menarche, a short menstrual cycle length, and a high age at first full term pregnancy or nulliparity are known risk factors for breast cancer. These risk factors have previously been reported to differ between breast cancer patients with and without a family history of breast cancer and also between breast cancer patients and controls. Methods: Self-administered questionnaires were filled out by 95 women belonging to 24 families with known BRCA1 mutations, 16 women belonging to nine families with known BRCA2 mutations, and 95 women belonging to 65 families with hereditary breast cancer where no BRCA1 or BRCA2 mutations could be detected. Thirty-nine women were BRCA1 mutation carriers and 56 women were BRCA1 negative, 11 women were BRCA2 carriers and five BRCA2 negative. All women were born between 1905 and 1979. Results: Age at menarche, physiological menstrual cycle length at age 30 or at current age in younger women (when not using oral contraceptives), age at first full term pregnancy, and nulliparity did not significantly differ between BRCA1 mutation carriers and BRCA1 negative women. Too few women were BRCA2 negative to serve as a control group. BRCA2 mutation carriers were therefore compared with BRCA1 negative and BRCA2 negative women. None of the above reproductive factors did significantly differ between BRCA2 mutation carriers and from BRCA1 and BRCA2 families. Women from non-BRCA1/BRCA2 hereditary breast cancer families had a higher age at menarche, but this was no longer significant after adjustment for other factors in a multivariate model. Conclusion: Our results suggest that reproductive risk factors of breast cancer are not related to BRCA1 or BRCA2 carrier status. There was also no indication that these factors differ in carriers of unknown susceptibility genes compared with non-carriers from BRCA1 and BRCA2 families.     

Influence of selected lifestyle factors on breast and ovarian cancer risk in BRCA1 mutation carriers from Poland

Summary It has been estimated that the lifetime risk of breast cancer among women who inherit a BRCA1 or BRCA2 mutation is as high as 80%, and the risk estimates for ovarian cancer range from 15 to 40%. Several environmental and lifestyle factors are believed to contribute to the development of breast cancer in the general population and it is of interest to establish if these factors operate among mutation carriers as well. To evaluate the effects of age of menarche, parity, breast-feeding, oophorectomy and oral contraceptive use, as well as smoking and coffee consumption, on the risks of breast and ovarian cancer, we conducted a matched case–control study of Polish women with BRCA1 mutations. There were 348 breast cancer patients, 150 ovarian cancer patients and similar numbers of age-matched controls. BRCA1 carriers with late age of menarche, lower parity and long-term breast-feeding were less likely to develop breast cancer. Oral contraceptives protected against ovarian cancer.     

Oral contraceptives and primary liver cancer

The relative risk for developing primary liver cancer in northern Italian users of oral contraceptives, compared to matched controls was calculated based on reported cases in hospitals in the greater Milan area from 1984-1987. The incidence of and mortality from primary liver cancer, as well as the prevalence of oral contraceptive usage, have both been rising to Italy since the late 1950s. 21 cases of liver cancer, in women aged 32-59 (median 50), occurred in the Milan area during the study period. These women, and 145 controls matched for age but admitted to hospitals for a variety of non-neoplastic diseases, were interviewed with a structured questionnaire covering socio-demographics, life style, diet, medical history, and history of use of oral contraceptives and other drugs. 19.0% of the cases had used oral contraceptives compared to 7.6% of controls, a relative risk of 1.8 for up to 5 years' use, and 8.3 for 5 years. History of hepatitis was associated with 14% of cases and 7% of controls. Italians have a higher incidence of liver neoplasms that northern Europeans and Americans, probably because of higher incidence of risk factors, such as hepatitis and alcohol use. The attributable risk for oral contraception, however, is lower in this population.     

Oral contraceptives,menopausal estrogens,and the risk of breast cancer: A case-control study in greece

In a hospital-based case-control study in Athens, we examined the association between the use of oral contraceptives and menopausal estrogens and the risk of breast cancer. Eight hundred and twenty patients with confirmed breast cancer were compared with 795 orthopedic patient controls and 753 healthy visitor controls, matched to the cases by age and interviewer. The data were modeled through logistic regression, controlling for demographic and reproductive variables. Odds ratio patterns were similar for the 2 control series, which were therefore combined to increase precision of the estimates. The risk for breast cancer was not elevated among ever-users of oral contraceptives, regardless of age at diagnosis of breast cancer, duration of oral contraceptive use or timing of use in relation to first full-term pregnancy. Among peri- and post-menopausal women who ever used menopausal estrogens, with never-users as the baseline, a statistically significant elevated odds ratio was found after adjusting for age at menopause. © 1995 Wiley-Liss, Inc.