A prospective study of oral contraceptive use and risk of breast cancer (Nurses' Health Study, United States)

Results of previous epidemiologic studies have provided reassurance that there is little, if any, increase in risk of breast cancer with oral contraceptive (OC) use in general. However, in several studies, an increased risk of breast cancer has been observed in two subgroups, young women who used OCs for extended durations and in women who used OCs prior to a first-term pregnancy. We evaluated these relationships using data from the ongoing Nurses' Health Study cohort (United States). We documented 3,383 cases of breast cancer from 1976 to 1992 among 1.6 million person-years of follow-up. We observed no overall relationship between duration of OC use and breast cancer risk, even among women who reported using OCs for 10 or more years (multivariate relative risk [RR]=1.11, 95 percent confidence interval [CI]=0.94-1.32). Among women less than 45 years of age, the multivariate RR for using OCs for 10 or more years was 1.07 (CI=0.70-1.65) compared with never-users. The risk associated with five or more years of OC use prior to a first full-term pregnancy compared with never-use was 0.96 (CI=0.65-1.43). Among women less than 45 years of age, we observed no evidence of an increased risk with OC use before a first full-term pregnancy (use for five or more years: RR=0.57, CI=0.24-1.31). Because of the age distribution of our cohort, we were unable to evaluate these relationships among women less than 40 years of age. Our study provides considerable evidence that long-term past OC use, either overall or prior to a first full-term pregnancy, does not result in any appreciable increase in breast cancer risk in women over 40 years of age.     

Impact of teenage oral contraceptive use in a population-based series of early-onset breast cancer cases who have undergone BRCA mutation testing

Oral contraceptive (OC) use in young women has been associated with an increased risk of breast cancer. This matched case-control study aims to elucidate the combined effects of OC use and genetic factors in a population-based series of BRCA1/2 mutation-tested early-onset breast cancers. A first invasive breast cancer was diagnosed in 259 women aged 40 years between 1990 and 1995 in the South Swedish Health Care Region. A total of 245 women were included in this study. Information on family history of cancer, reproductive factors, smoking and OC use was obtained from questionnaires or patient charts. Three age-matched controls per case were chosen from a prospective South Swedish cohort. Ever OC use and current OC use were not associated with breast cancer. Cases were more likely to have used OCs before age 20 years (adjusted odds ratio (OR) 2.10 (95% CI 1.32-3.33)) and before their first child (adjusted OR 1.63 (95% CI 1.02-2.62)). When stratified by age, the effect of early OC use was limited to women diagnosed prior to age 36 years (OR 1.53 (1.17-1.99) per year of OC use prior to age 20 years). The risks were similar for low-dose and high-dose OCs. The probability of being a BRCA1/2 mutation carrier was three times higher among cases who started OC use prior to age 20 years compared with cases who started at age 20 years or older or who had never used OCs. However, the duration of OC use was similar among cases with and without BRCA1/2 mutations. No association was seen with a first-degree family history of breast cancer. Each year of OC use prior to age 20 years conferred a significantly increased risk for early-onset breast cancer, while there was no risk associated with use after age 20 years.     

Use of oral contraceptives and breast cancer risk: The Norwegian-Swedish Women's Lifestyle and Health Cohort Study.

Current use of oral contraceptives (OCs) has been reported to increase breast cancer risk slightly. In 1991/1992, a prospective cohort study specifically designed to examine the role of hormonal contraceptives in relation to breast cancer was conducted in Norway and Sweden. This study was entitled Women's Lifestyle and Health. Of 196,000 invited women aged 30-49 years, 106,844 women answered a 4-page questionnaire. Altogether, 103,027 women providing information on contraceptive use were included in the analysis presented here, and 1,008 primary invasive breast cancers were diagnosed throughout 1999 (end of follow-up). Proportional hazard regression was used to calculate relative risks (RRs) with adjustment for age and other possible confounders. An increased breast cancer risk was observed among women who were current/recent users of OCs of any type at the start of follow-up [RR, 1.6; 96% confidence interval (CI), 1.2-2.1]. Current/recent use (i.e., use in the year preceding cohort enrolment) of combined OCs (RR, 1.5; 95% CI, 1.0-2.0) and progestin-only pills (RR, 1.6; 95% CI, 1.0-2.4) entailed similar levels of increased risk. An increased risk of borderline significance was found among short-term (i.e., less than 13 months) users before age 20 years (RR, 1.3; 95% CI, 1.0-1.7) and before first full-term pregnancy (RR, 1.4; 95% CI, 1.0-1.8). Long-term users of OCs were at a higher risk of breast cancer than never users (test for trend, P = 0.005). Current/recent use of OCs is associated with an increased breast cancer risk. Use of combined OCs and progestin-only pills seem to increase the risk at the same level.     

Long-term effects of oral contraceptives on ovarian cancer risk

Several epidemiologic studies have reported a protective effect of oral contraceptives (OCs) on ovarian cancer. However, there remain open issues, including better quantification of time-related factors such as time since last use, age at first use and time since first use. We performed a collaborative reanalysis of 6 case-control studies conducted between 1978 and 1999 in the United Kingdom, Greece and Italy, including a total of 2,768 incident, histologically confirmed cases of epithelial ovarian cancer and 6,274 hospital controls under age 70 years. A reduced risk of ovarian cancer was found for ever- compared to never-users [odds ratio (OR) = 0.66, 95% confidence interval (CI) 0.56-0.79], and a stronger reduction was observed for women who had used OCs for > or =5 years (OR = 0.50, 95% CI 0.33-0.76) compared to those who had used them for <5 years. The protective effect of OCs on ovarian cancer was consistent across strata of age, parity, menopausal status and family history of breast or ovarian cancer. After allowance for duration of use, no other time factor was related to ovarian cancer risk: the reduced risk was similar for women who stopped OC use > or =20 years before compared to <10 years; likewise, no significant modification of risk reduction was observed for age at first OC use and time since first OC use. The present analysis indicates that, after taking into account duration of OC use, the OC protection from ovarian cancer persists for a long time after stopping use.     

Oral contraceptives and survival in breast cancer patients aged 20 to 54 years.

Recent oral contraceptive (OC) use is associated with modestly higher breast cancer incidence among younger women, but its impact on survival is unclear. This study examined the relationship between OC use before breast cancer diagnosis and survival. A population-based sample of 1,264 women aged 20 to 54 years with a first primary invasive breast cancer during 1990 to 1992 were followed up for 8 to 10 years. OC and covariate data were obtained by interviews conducted shortly after diagnosis and from medial records. All-cause mortality was ascertained through the National Death Index (n = 292 deaths). Age- and income-adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox regression methods. All-cause mortality was not associated with ever use of OCs or duration of use. Compared with nonusers, mortality estimates were elevated among women who were using OCs at diagnosis or stopped use in the previous year (HR, 1.57; 95% CI, 0.95-2.61). The HR for use of high-dose estrogen pills within 5 years before diagnosis was double that of nonusers (HR, 2.39; 95% CI, 1.29-4.41) or, if the most recent pill included the progestin levonorgestrel, compared with nonusers (HR, 2.01; 95% CI, 1.03-3.91). Because subgroup estimates were based on small numbers of OC users, these results should be cautiously interpreted. Overall, most aspects of OC use did not seem to influence survival, although there is limited evidence that OC use just before diagnosis, particularly use of some pill types, may negatively impact survival in breast cancer patients aged 20 to 54 years.     

Oral contraceptive use and risk of breast cancer in older women (New Zealand)

the effect of oral contraceptive (OC) use at older ages on the risk of breast cancer was examined in a national population-based case-control study conducted in New Zealand. A total of 891 women aged 25 to 54 years with a first diagnosis of breast cancer, and 1,864 control subjects, randomly selected from the electoral rolls, were interviewed. The relative risk (RR) of breast cancer for women aged 45 to 54 years at diagnosis who had ever used OCs was 1.0 (95 percent confidence interval [CI]=0.77–1.3). There was no significant increase in risk of breast cancer among recent users of OCs of any age. Analyses according to age at first and last use among women aged 40 years and older at diagnosis showed no group with an elevated risk of breast cancer. Women who had used OCs for 10 years or longer after age 40 had an apparent increase in risk (RR=2.7, CI=0.97–7.5), but the trend in risk with duration of use was not significant. These findings suggest that OC use in older women does not affect their risk of breast cancer appreciably, but it is not possible to rule out a modest increase in risk with such use.This research was supported by grants from the Medical Research Council of New Zealand and from the Special Programme of Research, Development, and Research Training in Human Reproduction, World Health Organization.     

Oral contraceptives and breast cancer: A cooperative Italian study

The relationship between oral contraceptives (OC) and breast-cancer risk was analysed using data from a case-control study conducted between June 1991 and February 1994 in 6 Italian centres on 1,991 patients below age 65 with histologically confirmed incident breast cancer and 1,899 controls admitted to hospital for a wide range of acute, non-neoplastic, nonhormone-related diseases. “Ever OC use” was reported by 18% of cases versus 14% of controls, corresponding to a multivariate odds ratio (OR) of 1. 1 (95% confidence interval, CI 0.9 to 1.4). The ORs were 1.3 for use lasting < 1 year, 1. 1 for 1 to 4 years, 0.9 for 5 to 8 years, and 1.2 for over 8 years. With reference to age at first use, there was some indication that the OR was elevated in women who had started use before age 30, but not in those starting at a later age. With reference to time since last OC use, the OR was above unity for women who had stopped for less than 10 years (1.6 for 1 to 4 years; 1.7 for 5 to 9 years), but the OR declined to unity for women who had stopped OC use for 10 years or longer. The OR for women who had stopped OC use for less than 10 years was consistently elevated across strata of selected covariates, and was directly related to the duration of use (OR 1.3 for < 5 years, 1.7, for ≥5 years). In contrast, the OR was 0.6, for use lasting ≥ 5 years in women who had stopped for 10 years or more. The elevated OR for women who had recently stopped OC use, together with the absence of association (or the suggestion of some protection) for those who had stopped for 10 years or more is consistent with the pattern of breast-cancer risk observed after a full-term pregnancy, and provides important reassurance on a public health level on the long-term impact of OCs on breast carcinogenesis. © 1995 Wiley-Liss, Inc.     

Reproductive factors, oral contraceptive use, and human papillomavirus infection: pooled analysis of the IARC HPV prevalence surveys.

High parity, early age at first full-term pregnancy (FTP), and long-term oral contraceptive (OC) use increase cervical cancer risk, but it is unclear whether these variables are also associated with increased risk of acquisition and persistence of human papillomavirus (HPV) infection, the main cause of cervical cancer. Information on reproductive and menstrual characteristics and OC use were collected from 14 areas worldwide, among population-based, age-stratified random samples of women aged 15 years or older. HPV testing was done using PCR-based enzyme immunoassay. Unconditional logistic regression was used to estimate the odds ratios (OR) of being HPV-positive according to reproductive and menstrual factors and corresponding 95% confidence intervals (CI). When more than two groups were compared, floating CIs (FCI) were estimated. A total of 15,145 women (mean age, 40.9 years) were analyzed. Women with >or=5 FTPs (OR, 0.90; 95% FCI, 0.76-1.06) showed a similar risk of being HPV-positive compared with women with only one FTP (OR, 1.00; 95% FCI, 0.86-1.16). However, nulliparous women showed an OR of 1.40 (95% CI, 1.16-1.69) compared with parous women. Early age at first FTP was not significantly related to HPV positivity. HPV positivity was similar for women who reported >or=10 years of use of OCs (OR, 1.16; 95% FCI, 0.85-1.58) and never users of OCs (OR, 1.00; 95% FCI, 0.90-1.12). Our study suggests, therefore, that high parity, early age at first FTP, and long-term OC use are not associated with HPV prevalence, but rather these factors might be involved in the transition from HPV infection to neoplastic cervical lesions.     

Early oral contraceptive use and premenopausal breast cancer--a review of studies performed in southern Sweden.

In southern Sweden, extensive oral contraceptive use (OC use) among young women was a reality during the 1960s, thus making our region especially suited for studies investigating the hypothesis that early OC use is associated with the development of premenopausal breast cancer after a possible latency time between the exposure and the disease. The results of this study revealed that the risk of developing premenopausal breast cancer in women, who during the 1960s used the pill as teenagers, is five times greater than nonusers. The risk for early users is further modified by the duration of use at an early age, implying a dose-response relationship. Later use of OCs is not associated with an increased risk for the disease. Women with breast cancer, who at an early age have used the pill, have larger breast tumors, lower estrogen receptor concentrations of their primary tumor, and a worse prognosis compared with later and nonusers with breast cancer. The incidence of breast cancer in Sweden rapidly increased in women 25 to 40 years of age between 1970 and 1984. Conventional risk factors or a change in diagnostic activities of breast cancer cannot explain the increase in incidence which could be due to the OC exposure. Studies on the risk with modern OCs must wait another 20 years because of a too short latency time.     

Oral contraceptive use and mammographic patterns.

High-risk mammographic patterns represent an increased risk of contracting breast cancer and may be used as a surrogate endpoint for the disease. We examined the relationship between oral contraceptive (OC) use and mammographic patterns among 3218 Norwegian women, aged 40-56 years. Information on ever OC use, duration, and age of first OC use and other epidemiological data were obtained through questionnaires. The mammograms were categorized into five groups. Patterns I-III were combined into a low-risk group and patterns IV and V into a high-risk group. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression and adjusted for age, menopausal status, parity, age at first birth, and body mass index. Women who reported ever having used OCs were 20% more likely (OR 1.27, 95% CI 1.0-1.6) to have high-risk mammographic patterns compared with those reporting never having used OCs. There was no dose response between different measures of OC use and high-risk patterns. Among nulliparous women, ever OC users were four times more likely (OR 4.65, 95% CI 2.1-10.3) to have high-risk patterns compared with never users. Our findings suggest that, especially among nulliparous women, ever OC use may exert its effect on breast cancer risk through changes in breast tissue, which can be observed on a mammogram.     

Pooled analysis of 3 European case-control studies of epithelial ovarian cancer: III. Oral contraceptive use

The relationship between use of oral contraceptives (OCs) and other contraceptive methods and the risk of ovarian cancer was examined in a combined analysis of 3 hospital-based case-control studies conducted in Italy, the United Kingdom, and Greece, for a total of 971 ovarian cancer cases and 2,258 controls under age 65. Compared with never-users, the combined multivariate relative risk (RR) for ever-users was 0.6 (95% confidence interval, CI = 0.4-0.8) and the estimates were consistent in the 3 datasets. The protection was also similar across strata of age and parity. Considering various measures of OC use, available in the Italian and British datasets only, the protection conveyed on ovarian cancer risk increased with the duration of use and persisted in the medium-long period: the RR in women reporting their last OC use greater than or equal to 15 years prior to diagnosis was 0.5 (95% CI = 0.2-1.0). The risks in ever-users were appreciably lower in those women who reported their first OC use before 25 years of age (RR = 0.3 for first use before age 25, 0.8 for first use at age 25-34 and 0.7 at 35 years or after). Such findings emerged similarly from Italian and British data. This combined analysis, besides offering further quantitative estimates of the protective effects of OCs on ovarian cancer risk in European populations, provides useful insights into the time pattern of the relationship between OC use and ovarian carcinogenesis, suggesting that the protection persists for 15 years or more after cessation of use and may be larger for use at younger age.     

Early oral contraceptive use and breast cancer: results of another case-control study

We report the results of a case-control study of oral contraceptive use and breast cancer conducted in London, Oxford and Edinburgh between 1980 and 1984. One thousand one hundred and twenty-five women aged 16-64 years with newly diagnosed breast cancer and a like number of matched controls were interviewed and asked about their past due use of oral contraceptives (OCs). Among women aged 45 years or more at diagnosis there was no evidence of an association between OC use and breast cancer. Among the 351 pairs of women aged under 45 years at diagnosis there was a significantly elevated risk associated with increasing duration of use before first full term pregnancy (relative risk for 4+ years use versus never use = 2.6, 95% confidence limits, 1.3-5.4). Since this result is at variance with the findings in some other studies we have investigated the nature of this association with particular emphasis on possible bias, pill type and a latent effect.     

Differential effects of reproductive factors on the risk of pre- and postmenopausal breast cancer. Results from a large cohort of French women

The aim of this study was to obtain a better understanding of the role of hormonal factors in breast cancer risk and to determine whether the effect of reproductive events differs according to age at diagnosis. It analysed the effect of age at menarche, age at first full-term pregnancy, number of full-term pregnancies and number of spontaneous abortions both on the overall risk of breast cancer and on its pre- or postmenopausal onset, using the data on 1718 breast cancer cases, obtained from a large sample of around 100000 French women participating in the E3N cohort study. The results provide further evidence that the overall risk of breast cancer increases with decreasing age at menarche, increasing age at first pregnancy and low parity. No overall effect of spontaneous abortions was observed. The effect of these reproductive factors differed according to menopausal status. Age at menarche had an effect on premenopausal breast cancer risk, with a decrease in risk with increasing age of 7% per year (P<0.05). Compared to those who had their first menstrual periods at 11 or before, women experiencing menarche at 15 or after had an RR of 0.66 (95% CI 0.45-0.97) in the premenopausal group. Age at first full-term pregnancy had an effect on both pre- and postmenopausal breast cancer risk, with significant tests showing increasing risk per year of increasing age (P=0.001 and P<0.05 respectively). A first full-term pregnancy above age 30 conveyed a risk of 1.63 (95% CI 1.12-2.38) and 1.35 (95% CI 1.02-1.78) in the pre- and postmenopausal groups respectively. A protective effect of high parity was observed only for postmenopausal breast cancer risk (P for trend test =0.001), with point estimates of 0.79 (95% CI 0.60-1.04), 0.69 (95% CI 0.54-0.88), 0.66 (95% CI 0.51-0.85) and 0.64 (95% CI 0.48-0.86) associated to a one, two, three and four or more full-term pregnancies. A history of spontaneous abortion had no significant effect on the risk of breast cancer diagnosed before or after menopause. Our results suggest that reproductive events have complex effects on the risk of breast cancer.     

Use of oral contraceptives and risk of breast cancer in young women

Many studies have shown that oral contraceptive (OC) use increases a young woman's risk of breast cancer, although some studies suggest that the risk may be limited to recent use. The objective of this study was to determine what particular aspects of OC use could be important for breast cancer development at an early age in the cohort of women who had the opportunity to use OCs all of their reproductive life. The cases were first diagnosed with breast cancer at age 40 or younger between 1983 and 1988, and identified by the Los Angeles County Cancer Surveillance Program. Control subjects were individually matched to participating cases on birth date (within 36 months), race (white), parity (nulliparous versus parous), and neighborhood of residence. Detailed OC histories were obtained during in-person interviews with subjects. In general the risk estimates were small, and not statistically significant. Compared to no use, having used OCs for 12 years or more was associated with a modest non-significant elevated breast cancer risk with an odds ratio (OR) of 1.4 (95% confidence interval (CI)=0.8–2.4). Long-term (12 years or more) users of high-dose estrogen pills had a non-significant 60% higher breast cancer risk than never users (CI=0.9–3.2). Early use was associated with slightly higher ORs among young women (age 35), and among parous women. Recent use was associated with somewhat higher ORs among parous women and women above age 36. Analyses by stage, body weight, and family history yielded similar results. This study is consistent with a modest effect of early OC use on breast cancer risk in young women.     

Oral contraceptive use and breast cancer risk among African-American women

Recent epidemiologic studies, most of them in predominantly White populations, have suggested that long duration of oral contraceptive (OC) use may increase the risk of breast cancer at young ages. We assessed the relationship of OC use to the risk of breast cancer in African-American women aged 25 to 59 years, using interview data from a multipurpose hospital-based case-control study. Five hundred and twenty-four cases hospitalized for invasive breast cancer were compared with 1,021 controls with nonmalignant conditions unrelated to OC use. Relative risks (RR) and 95 percent confidence intervals (CI) were estimated relative to a reference category of use for less than 12 months; potential confounders were controlled by multiple logistic regression analysis. Among women under age 45, three or more years of OC use was associated with an increased risk of breast cancer: the RR estimate was 2.8 (CI=1.5–5.0) for three to four years of use, and declined to 1.5 (CI=0.8.3.0) for 10 or more years of use. Recency and timing of use did not explain the observed association. Among women aged 45 to 59, OC use was associated with little or no increase in risk: the RR estimate for three or more years of use was 1.3 (CI=0.7–2.4). The findings add to the evidence from studies of White women and a recent study of Black women which have suggested an increased risk of breast cancer at young ages for moderate or long duration use of OCs.This research was supported by the US National Cancer Institute (grants R01 CA55766 and R01 CA45762). Additional support was provided by the US Food and Drug Administration (FD-U-000082); the views expressed do not necessarily represent the views of the Food and Drug Administration. The Slone Epidemiology Unit also receives support from Hoffmann-La Roche, Inc., and Marion Merrell Dow Inc.     

Oral contraceptives and breast cancer in northern Italy. Final report from a case-control study.

To assess the relation between oral contraceptive (OC) use and breast cancer, we analysed data from a case-control study conducted in Northern Italy between 1983 and 1991 on 2,309 cases below age 60 and 1,928 controls admitted to hospital for acute diseases unrelated to OC use and to any of the known or potential risk factors for breast cancer. OC use was reported by 16% of cases and 14% of controls. The multivariate relative risk (RR) for ever vs never use of combination OC was 1.2 (95% confidence interval (CI) 1.0-1.4). However, there was no trend in risk with duration. The RR was elevated for very short use, but declined to 0.8 (95% CI = 0.5-1.0) for five or more years'' use. No noteworthy relationship was found for other major measures of OC use, although RR estimates were above unity for women who had stopped use less than 5 years before (RR = 1.5, 95% CI = 1.1-2.0), started use less than 10 years before (RR = 1.3, 95% CI = 1.0-1.9), started when 25 or more years old (RR = 1.4, 95% CI = 1.1-1.7), or after first birth (RR = 1.2, 95% CI = 1.0-1.5). No interaction was observed between OC use and family history of breast cancer, parity and age at first birth. A separate analysis of 373 cases and 456 control below age 40 showed no association with ever use (RR = 0.9, 95% CI = 0.6-1.2).     

Oral contraceptive and IUD use and endometrial cancer: a population-based case-control study in Shanghai, China

Oral contraceptive (OC) and intrauterine device (IUD) use have been shown to be protective factors for endometrial cancer in several epidemiological studies; however, few studies have been conducted in Chinese populations. We evaluated the association between OC and IUD use and endometrial cancer risk in a population-based case-control study among Chinese women in Shanghai, China. The study included 1,204 newly diagnosed endometrial cancer cases and 1,212 age frequency-matched healthy controls. Logistic regression models were used to estimate adjusted odds ratios (OR) and their 95% confidence intervals (95% CI). In our study population, 18.5% cases and 24.9% controls reported having ever used OCs with an OR of 0.75 (95% CI, 0.60-0.93), after adjusting for known risk or protective factors for endometrial cancer. The risk of endometrial cancer decreased with long-term use of OCs with the OR for more than 72 months of use being 0.50 (95% CI, 0.30-0.85). The effect of OC use remained 25 or more years after cessation of use; the associated OR was 0.57 (95% CI = 0.42-0.78) as compared to nonusers. Similarly, fewer cases than controls had ever used IUD, with the multivariable adjusted OR being 0.53 (95% CI = 0.43-0.65). A reduction in risk was observed regardless the duration of use or age at first and last use. These results suggest that OC and IUD use may confer long-term protection against endometrial cancer.     

Spontaneous and induced abortions and risk of breast cancer.

The relationship between spontaneous or induced abortion and the risk of breast cancer was analyzed in a case-control study conducted in the greater Milan area on 2,394 cases of breast cancer and 2,218 controls in hospital for a spectrum of acute conditions, not gynecological, hormonal or neoplastic. No consistent relationship emerged between spontaneous or induced abortion and breast cancer: compared with women reporting no abortions (spontaneous or induced), the multivariate relative risk (RR) was 1.0 (95% confidence interval, CI, 0.9 to 1.2) in those reporting one abortion and 0.9 (95% CI 0.7 to 1.0) in those reporting two or more. This lack of association was consistent in strata of age and parity, including younger women. We further analyzed the risk of breast cancer associated with an abortion before and after full-term pregnancy. Compared with parous women reporting no induced or spontaneous abortions, those who had an abortion before their first full-term pregnancy had about a 20% higher risk of breast cancer. This finding, however, was not statistically significant (RR 1.2, 95% CI 0.9 to 1.7). No increased risk was observed in women who had had a first abortion after a full-term pregnancy (RR 0.9, 95% CI 0.8 to 1.0). This study does not support the hypothesis that spontaneous or induced abortion appreciably influences subsequent breast-cancer risk.     

Oral contraceptives, menopausal hormone therapy use and risk of B-cell non-Hodgkin lymphoma in the California Teachers Study

We examined oral contraceptive (OC) and menopausal hormonal therapy (MHT) use in relation to risk of B-cell non-Hodgkin lymphoma (NHL). Women under age 85 years participating in the California Teachers Study with no history of hematopoietic cancer were followed from 1995 through 2007. A total of 516 of 114,131 women eligible for OC use analysis and 402 of 54,758 postmenopausal women eligible for MHT use analysis developed B-cell NHL. Multivariable adjusted and age stratified Cox proportional hazards models were fit to estimate relative risks (RRs) and 95% confidence intervals (95% CI). Ever versus never OC use was marginally associated with lower B-cell NHL risk, particularly among women first using OCs before age 25 years (RR=0.72, 95% CI=0.51-0.99); yet, no duration-response effect was observed. No association was observed for ever versus never MHT use among postmenopausal women (RR=1.05, 95% CI=0.83-1.33) overall or by formulation (estrogen alone, ET, or estrogen plus progestin, EPT). Among women with no MHT use, having bilateral oophorectomy plus hysterectomy was associated with greater B-cell NHL risk than having natural menopause (RR=3.15, 95% CI=1.62-6.13). Bilateral oophorectomy plus hysterectomy was not associated with risk among women who used ET or EPT. These results indicate that exogenous hormone use does not strongly influence B-cell NHL risk.     

Her-2/neu and INT2 proto-oncogene amplification in malignant breast tumors in relation to reproductive factors and exposure to exogenous hormones

In previous studies in southern Sweden, early use of oral contraceptives has been found to be accompanied by an increased risk of developing premenopausal breast cancer, and the tumors developing in these patients have shown a more aggressive behavior. In the present study, amplification of the proto-oncogenes Her-2/neu (also known as ERBB2) and INT2 was studied in primary tumor specimens from 72 premenopausal women and was related to starting age of oral contraceptive use and other reproductive risk factors. Amplification of Her-2/neu was more common among early oral contraceptive users (i.e., those starting at less than or equal to 20 years of age) than among nonusers or late users (odds ratio [OR], 5.3; 95% confidence interval [CI], 1.6-16.7), whereas INT2 amplification did not differ significantly among those groups (OR, 0.9; 95% CI, 0.1-5.0). The likelihood of INT2 amplification was greater among users of progestins and those with a history of abortions before the first full-term pregnancy (OR, 9.0; 95% CI, 1.3-51.7; and OR, 18.6; 95% CI, 2.2-165.8, respectively). No significant relationships were found between proto-oncogene amplification and the variables of parity, age at first full-term pregnancy, or late abortion. The increased ORs persisted after adjustment for age at diagnosis and other risk factors. The findings suggest that the higher rate of Her-2/neu amplification among early oral contraceptive users is an effect of the oral contraceptive use per se rather than of the relative youth of the users. Moreover, the relationship between progestin use and early abortion and amplification of the INT2 gene is biologically plausible.