Early oral contraceptive use and breast cancer among premenopausal women: final report from a study in southern Sweden

In southern Sweden during the 1960s, women began to use oral contraceptives (OCs) extensively at a young age. This case-control study investigates the relationship between the use of OCs and breast cancer development in women in southern Sweden diagnosed in the early 1980s. The risk for breast cancer after OC use among premenopausal women was modeled, after adjustment was made for age, age at menarche, and age at first full-term pregnancy or parity. Both the duration of OC use before 25 years of age and commencement of OC use at a young age were associated with a significant increase in the risk of breast cancer as well as a significant trend. The duration of OC use before the first full-term pregnancy was associated with an increased risk of breast cancer, but it did not show a significant trend. The total duration of OC use was weakly, but not significantly, associated with breast cancer development. The odds ratio for women starting OC use before 20 years of age was 5.8 [95% confidence interval (CI), 2.6-12.8]; for women using OCs for greater than 5 years before age 25, it was 5.3 (95% CI, 2.1-13.2); and for women using OCs for greater than or equal to 8 years before first full-term pregnancy, it was 2.0 (95% CI, 0.8-4.7). In multivariate analyses including the different measurements of OC use, only starting age of OC use was significantly associated with breast cancer. The exposure-response relationship between duration of OC use and risk of breast cancer depended on the age at first use of OCs. Given a fixed duration of OC use, the risk increased with younger starting age of OC use. The findings point to the importance of the early reproductive years as risk determinants for breast cancer after OC use.     

Early oral contraceptive use as a prognostic factor in breast cancer

The survival of 193 premenopausal breast cancer patients was investigated in relation to their history of early use of oral contraceptives. The women were born in 1939 or later and diagnosed in the southern health care region of Sweden. Women, who had started their oral contraceptive use (OC-use) before 20 years of age had a significantly lower survival rate as compared with those who had never used OC and late users (p = 0.02 and = 0.04 respectively, generalized Wilcoxon test). For women who started OC-use between 20 to 25 years of age, a tendency for a shorter survival was seen in comparison with women who had never used OC (p = 0.18). For all patients simultaneously, the relative risk adjusted for age at diagnosis increased for earlier OC-start. When only stages II and III were considered in a stratified multivariate model, a significantly elevated risk was seen for early users of OC irrespective of age or of adjuvant treatment given. The estrogen and progesterone receptor concentrations of the primary tumor were significantly lower among early users (p = 0.001 and p = 0.05 respectively).     

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.     

Oral contraceptive use and risk of melanoma in premenopausal women.

Melanoma has been increasing in white populations. Incidence rates rise steeply in women until about age 50, suggesting oestrogen as a possible risk factor. Oestrogens can increase melanocyte count and melanin content and cause hyperpigmentation of the skin. We examined prospectively the association between oral contraceptive (OC) use and diagnoses of superficial spreading and nodular melanoma among 183,693 premenopausal white women in the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHS II) cohorts. One hundred and forty six cases were confirmed in NHS during follow-up from 1976 to 1994, and 106 cases were confirmed in NHS II from 1989 to 1995. Skin reaction to sun exposure, sunburn history, mole counts, hair colour, family history of melanoma, parity, height and body mass index were also assessed and included in logistic regression models. A significant twofold increase in risk of melanoma (relative risk (RR) = 2.0, 95% confidence interval (CI) 1.2-3.4) was observed among current OC users compared to never users. Risk was further increased among current users with 10 or more years of use (RR = 3.4, 95% CI 1.7-7.0). Risk did not appear elevated among past OC users, even among those with longer durations of use, and risk did not decline linearly with time since last use. In conclusion, risk of premenopausal melanoma may be increased among women who are current OC users, particularly among those with longer durations of use. Further research is needed to determine whether low-dose oestrogen pills in particular are associated with an increase in risk and to describe possible interactions between OC use and sun exposure or other risk factors for melanoma.     

A case-control study of oral contraceptive use and breast cancer

Among 989 cases of breast cancer and 9,890 controls selected from a cohort of married, female registered nurses aged 30-55 years, the relative risk (RR) of breast cancer for women who had ever used oral contraceptives (OC) compared with those who had never used them was 1.0, with 95% confidence limits 0.9-1.2. Among OC users, there was no consistent pattern of excess risk with increasing duration; in fact, the few women who had used OC longest (greater than 10 yr) had a slightly lower risk than never-users. Moreover, there was no association between OC use and breast cancer among women with a positive history of breast cancer in the mother or sister or with OC use before their first pregnancy. The only subgroup of women among whom any adverse effect was apparent was current OC users aged 50-55 years (two onsets expected vs. seven observed). This finding is consistent with earlier reports of an increased risk of breast cancer among older OC users; however, it is also likely to reflect, at least to some extent, the play of chance, since at ages 45-49 and in each younger age group fewer cases than expected were observed among current OC users.     

Paclitaxel: epirubicin in metastatic breast cancer--a review.

Background:Treatment of metastatic breast cancer (MBC) with paclitaxel (T) and doxorubicin has yielded high response rates but the regimen is associated with significant cardiac toxicity. Epirubicin (E) is a less cardiotoxic anthracycline which has also been combined with paclitaxel in the treatment of MBC. Materials and methods:This paper is a review of studies evaluating the pharmacokinetics, toxicity profile, and efficacy of the ET combination in MBC. Results:The ET combination has been studied extensively in Europe. The unique pharmacokinetics of the combination do not lead to the accumulation of cardiotoxic metabolites as in the case of the doxorubicin–paclitaxel combination. In terms of efficacy, the ET combination yields an overall response rate of 50%–70% and complete response rate (CR) 10%–15% in MBC in the same range as the more recent doxorubicin paclitaxel studies. Conclusion:In summary the ET combination is safe and effective in MBC. It is less cardiotoxic than the doxorubicin–paclitaxel combination. Further studies with ET in both the adjuvant setting and in MBC are in progress.     

A cohort study of oral contraceptive use and risk of benign breast disease.

The purpose of the cohort study reported here was to investigate the association between oral contraceptive use and risk of benign breast disease (BBD), overall and by histological subtype, within the 56,537 women in the Canadian National Breast Screening Study (NBSS) who completed self-administered lifestyle and dietary questionnaires. The NBSS is a randomized controlled trial of screening for breast cancer in women aged 40-59 at recruitment. Cases were the 2,116 women in the dietary cohort who were diagnosed with biopsy-confirmed incident BBD. For comparative purposes, a subcohort consisting of a random sample of 5,681 women (including 197 subjects with incident BBD) was selected from the full dietary cohort. After exclusions for various reasons, the analyses were based on 2,116 cases and 5,338 non-cases. There was an inverse association between use of oral contraceptives and risk of all types of BBD combined. The reduction in risk was confined largely to proliferative forms of BBD (BPED), and in particular, to those forms of BPED without histological atypia, in whom there was a progressive reduction in risk with increasing duration of use (the IRR (95% CI) for use of more than 7 years was 0.64 (0.47-0.87)); risk of BPED with atypia was increased somewhat in association with oral contraceptive use (the IRR (95% CI) for use of more than 7 years was 1.43 (0.68-3.01 )), but not in a dose-dependent manner. The results were similar when examined separately in the screened and control arms of the NBSS and for screen-detected and interval-detected BPED.     

A population-based cohort study of HRT use and breast cancer in southern Sweden

The overall tumour incidence and breast cancer incidence related to hormone replacement therapy (HRT) were followed in a population-based cohort of 29 508 women, aged 25-65 when interviewed in 1990-92. By the end of the follow up in December 1999, there were 226 611 person-years of observation. A total of 1145 malignant tumours were recorded (expected 1166.6; SIR = 0.98, 95% CI 0.93-1.04). There was a small excess of breast cancer with 434 observed and 387.69 expected (SIR = 1.12, 95% CI 1.02-1.23). Among about 3 663 ever users of HRT, there was no increase in overall tumour incidence (SIR = 0.98, 95% CI 0.86-1.12) but a significant excess of breast cancer (SIR = 1.35, 95% CI 1.09-1.64) compared with never users (SIR = 1.07, 95% CI 0.96-1.19). Breast cancer increased with increasing duration of use and for 48-120 months use the SIR was 1.92 (95% CI 1.32-2.70). There was no significant interaction with family history of breast cancer although an independent additive effect was suggested between HRT use and family history. In a Cox regression model time to breast cancer in relation to duration of HRT use was analysed adjusting for age at menarche, age at menopause, age at first full term pregnancy, parity and age at diagnosis. A significantly higher risk was seen for longer duration of HRT use compared with never users. No increased risk is seen in women beyond 5 years after stopping HRT. There was no interaction between previous use of oral contraceptives and later HRT use.     

Preoperative chemotherapy treatment of breast cancer--a review

Despite proven benefits of neoadjuvant chemotherapy in patients with locally advanced, invasive breast cancer, no regimen is recommended as the treatment of choice. Neoadjuvant chemotherapy regimens encompass single-agent and combination therapy and sequential treatment. For this report, the author reviewed the literature to determine which regimen, if any, was most beneficial. The results indicated that studies have yielded a wide range of response rates, but no single regimen has emerged as a clear leader. The literature is compounded further by lack of standardized criteria to determine pathologic complete response (which is predictive of survival benefits) and between-study variation in the stringency by which this endpoint is defined. Given the lack of a preferred treatment regimen in the neoadjuvant setting, identifying patients who are likely to respond to specific agents could inform treatment decisions, improve treatment outcomes, and aid in avoiding unnecessary exposure to potential toxicities. The development of novel agents for use alone or in combination with existing agents may improve response rates further in the neoadjuvant setting, especially because a significant proportion of breast tumors can be resistant to many current antineoplastic agents. Particularly noteworthy are the epothilones and their analogs because of their low susceptibility to common tumor-resistance mechanisms. Initial data have indicated that ixabepilone, which is an epothilone analog, has activity in the neoadjuvant setting, and predictive factors for response have been identified. The future of neoadjuvant therapy lies in tailoring treatment to individual patients by identifying response predictors and developing novel agents. This ultimately may lead to improved outcomes for women with breast cancer.     

Recent oral contraceptive use and risk of breast cancer (United States)

We examined the association between recent oral contraceptive (OC) use and the risk of breast cancer in data from a large population-based case-control study in the United States. Cases (n=6,751) were women less than 75 years old who had breast cancer identified from statewide tumor registries in Wisconsin, Massachusetts, Maine, and New Hampshire. Controls (n=9,311) were selected randomly from lists of licensed drivers (if aged under 65 years) and from lists of Medicare beneficiaries (if aged 65 through 74 years). Information on OC use, reproductive experiences, and family and medical history was obtained by telephone interview. After adjustment for parity, age at first delivery, and other risk factors, women who had ever used OCs were at similar risk of breast cancer as never-users (relative risk [RR]=1.1, 95 percent confidence interval [CI]=10–1.2). Total duration of usealso was not related to risk. There was a suggestion that more recent use was associated with an increased risk of breast cancer; use less than two years ago was associated with an RR of 1.3 (CI=0.9–1.9). However, only among women aged 35 to 45 years at diagnosis was the increase in risk among recent users statistically significantly elevated (RR=2.0, CI=1.1–3.9). Use prior to the first pregnancy or among nulliparous women was not associated with increased risk. Among recent users of OCs, the risk associated with use was greatest among non-obese women, e.g., among women with body mass index (kg/m²) less than 20.4, RR=1.7, CI=1.1–2.8. While these results suggest that, in general, breast cancer risk is not increased substantially among women who have used OCs, they also are consistent with a slight increased risk among subgroups of recent users.Authors are with the University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA (Dr Newcomb, Ms Trentham Dietz); NIEHS Epidemiology Branch, Research Triangle Park, NC (Dr Longnecker); Fred Hutchinson Cancer Research Center, Seattle, WA (Dr Surer); Department of Obstetrics and Gynecology, Pritzker School of Medicine, The University of Chicago, Chicago, IL (Dr Mittendorf); Department of Community and Family Medicine, Dartmouth Medical School, Hanover, NH (Dr Baron); Boston University, School of Public Health, Boston, MA (Dr Clapp); Department of Epidemiology and Department of Nutrition, Harvard School of Public Health, and Channing Laboratory, Harvard Medical School and Department of Medicine, Brigham and Women's Hospital, Boston, MA (Dr Willett). Address correspondence to: Dr Polly A. Newcomb, University of Wisconsin-Madison Comprehensive Cancer Center, 1300 University Ave., #4780, Madison, WI 53706, USA. Supported by Public Health Service (National Cancer Institute) grants R01 CA 47147 and R01 CA 47305.     

A pooled analysis of 10 case-control studies of melanoma and oral contraceptive use

Data regarding the effects of oral contraceptive use on women's risk of melanoma have been difficult to resolve. We undertook a pooled analysis of all case-control studies of melanoma in women completed as of July 1994 for which electronic data were available on oral contraceptive use along with other melanoma risk factors such as hair colour, sun sensitivity, family history of melanoma and sun exposure. Using the original data from each investigation (a total of 2391 cases and 3199 controls), we combined the study-specific odds ratios and standard errors to obtain a pooled estimate that incorporates inter-study heterogeneity. Overall, we observed no excess risk associated with oral contraceptive use for 1 year or longer compared to never use or use for less than 1 year (pooled odds ratio (pOR)=0.86; 95% CI=0.74-1.01), and there was no evidence of heterogeneity between studies. We found no relation between melanoma incidence and duration of oral contraceptive use, age began, year of use, years since first use or last use, or specifically current oral contraceptive use. In aggregate, our findings do not suggest a major role of oral contraceptive use on women's risk of melanoma.     

A biological marker, strongly associated with early oral contraceptive use, for the selection of a high risk group for premenopausal breast cancer

In a population-based group of women, consecutively diagnosed, with premenopausal breast cancer there was a significant correlation between tumour size and plasma prolactin (r = 0.30; P less than 0.004). The concentration of estrogen receptor was negatively correlated to tumour size (r = 0.17; P less than 0.09). There were no substantial correlations between tumour size and progesterone receptor, plasma progesterone or estradiol. Adjustments for menstrual cycle day and age did not alter the above findings. The ratio of plasma prolactin and estrogen receptor was significantly greater (P less than 0.037) for the group of the patients that had started using oral contraceptives before the age of 20 as compared with the other patients. Consequently, the tumour size was significantly greater in the group of early users (P less than 0.003). The findings indicate that breast tumours developing in previous early users of oral contraceptives have a low estrogen receptor concentration, while these patients have higher plasma prolactin. The tumour size is greater in early users indicating a poorer prognosis than other women with breast cancer. As early use of oral contraceptives increases breast cancer risk and a high ratio of plasma prolactin and estrogen receptor concentration of the primary tumour characterize early oral contraceptive users the ratio may be a valuable marker for the breast cancer risk.     

Influence of menstrual cycle, parity and oral contraceptive use on steroid hormone receptors in normal breast.

Steroid receptor was assessed immunohistochemically in 158 samples of normal breast for variation through the menstrual cycle. Patterns and intensity of reaction were used in a semi-quantitative scoring system to examine the influence of cycle phase, cycle type, parity and age. The changes in oestrogen receptor for natural cycle and oral contraceptive (OC) cycles indicated down-regulation by progestins. Progesterone receptor did not vary significantly in natural cycles, but increased steadily through OC cycles. This study provides strong evidence that both oestrogen and progesterone influence breast epithelium, but dissimilarities from the endometrium are apparent. The interval since pregnancy had a significant negative effect on frequency and score of oestrogen receptor and score of progesterone receptor. Multivariate analysis established the phase of cycle and OC use as independent significant influences on oestrogen receptor. The interval since pregnancy was an independent significant factor for both oestrogen and progesterone receptor presence.     

The association between oral contraceptive use and lobular and ductal breast cancer in young women

Recent reports indicate that the incidence of lobular breast cancer is increasing at a faster rate than ductal breast cancer, which may be due to the differential effects of exogenous hormones by histology. To address this issue, we examined whether the relationship between oral contraceptive use and incident breast cancer differs between lobular and ductal subtypes in young women. A population-based sample of in situ and invasive breast cancer cases between ages 20 and 44 were recruited from Atlanta, GA; Seattle-Puget Sound, WA and central New Jersey. Controls were sampled from the same areas by random-digit dialing, and were frequency matched to the expected case age distribution. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using polytomous logistic regression. Among the 100 lobular cancers, 1,164 ductal cancers, and 1,501 controls, the odds ratios for oral contraceptive ever use were 1.10 (95% CI = 0.68-1.78) for lobular cancers and 1.21 (95% CI = 1.01-1.45) for ductal cancers, adjusted for study site, age at diagnosis, and pap screening history. Our results suggest that the magnitude of the association between ever use of oral contraceptives and breast cancer in young women does not vary strongly by histologic subtype. These results are similar to previous studies that report little difference in the effect of oral contraceptive use on breast cancer by histology.     

Oral contraceptive use and risk of breast carcinoma in situ.

There is some indication that oral contraceptive use may be associated with a small increase in risk of invasive breast cancer; however, oral contraceptive use in relation to breast carcinoma in situ (BCIS) has rarely been studied. We investigated oral contraceptive use in relation to risk of BCIS in a large population-based case-control study. Female residents of Wisconsin, Massachusetts, and New Hampshire aged 20 to 74 years with a new diagnosis of BCIS (n=1,878) were identified from statewide tumor registries in 1997 to 2001. Age-matched female controls (n=8,041) were randomly selected from population lists. Information on oral contraceptive use and other risk factors was collected during structured telephone interviews. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression. In multivariate models, ever use of oral contraceptives was associated with a small and marginally significant increase in BCIS overall (OR, 1.11; 95% CI, 0.99-1.25) and for ductal carcinoma in situ (OR, 1.15; 95% CI, 1.01-1.31). No strong associations were detected according to age started, duration, time since first or last use, or oral contraceptive use relative to the first full-term pregnancy. The slightly increased risk of BCIS seemed limited to former users (OR, 1.13; 95% CI, 1.00-1.27) and women without a family history of breast cancer (OR, 1.16; 95% CI, 1.01-1.32 for ever versus never use). Consistent with invasive breast cancer, these results suggest that oral contraceptive use is at most a minor contributor to BCIS risk.