Risk of cervical intra-epithelial neoplasia and invasive cancer of the cervix in DES daughters.

OBJECTIVE: Women exposed to diethylstilbestrol in utero (DES) have an increased risk of clear cell adenocarcinoma (CCA) of the vagina and cervix, while their risk of non-CCA invasive cervical cancer is still unclear. METHODS: We studied the risk of pre-cancerous (CIN) lesions and non-CCA invasive cervical cancer in a prospective cohort of 12,182 women with self-reported DES exposure followed from 2000 till 2008. We took screening behavior carefully into account. Incidence was obtained through linkage with the Netherlands Nationwide Pathology database (PALGA). General population data were also derived from PALGA. RESULTS: The incidence of CIN1 was increased (Standardized Incidence Ratio (SIR)=2.8, 95% Confidence Interval (CI)=2.3 to 3.4), but no increased risk was observed for CIN2+ (CIN2, CIN3 or invasive cancer) compared to the screened general population (SIR=1.1, 95% CI=0.95 to1.4). Women with DES-related malformations had increased risks of both CIN1 and CIN2+ (SIR=4.1, 95%CI=3.0 to 5.3 and SIR=1.5, 95%CI=1.1 to 2.0, respectively). For CIN2+, this risk increase was largely restricted to women with malformations who were more intensively screened. CONCLUSIONS: An increased risk of CIN1 among DES daughters was observed, especially in women with DES-related malformations, probably mainly due to screening. The risk of CIN2+ (including cancer) was not increased. However, among DES daughters with DES-related malformations a true small risk increase for non-CCA cervical cancer cannot be excluded.

An association study of established breast cancer reproductive and lifestyle risk factors with tumour subtype defined by the prognostic 70-gene expression signature (MammaPrint®).

BACKGROUND: Reproductive and lifestyle factors influence both breast cancer risk and prognosis; this might be through breast cancer subtype. Subtypes defined by immunohistochemical hormone receptor markers and gene expression signatures are used to predict prognosis of breast cancer patients based on their tumour biology. We investigated the association between established breast cancer risk factors and the 70-gene prognostication signature in breast cancer patients. PATIENTS AND METHODS: Standardised questionnaires were used to obtain information on established risk factors of breast cancer from the Dutch patients of the MINDACT trial. Clinical-pathological and genomic information were obtained from the trial database. Logistic regression analyses were used to estimate the associations between lifestyle risk factors and tumour prognostic subtypes, measured by the 70-gene MammaPrint® signature (i.e. low-risk or high-risk tumours). RESULTS: Of the 1555 breast cancer patients included, 910 had low-risk and 645 had high-risk tumours. Current body mass index (BMI), age at menarche, age at first birth, age at menopause, hormonal contraceptive use and hormone replacement therapy use were not associated with MammaPrint®. In parous women, higher parity was associated with a lower risk (OR: 0.75, [95% confidence interval {CI}: 0.59-0.95] P = 0.018) and longer breastfeeding duration with a higher risk (OR: 1.03, [95% CI: 1.01-1.05] P = 0.005) of developing high-risk tumours; risk estimates were similar within oestrogen receptor-positive disease. After stratifying by menopausal status, the associations remained present in post-menopausal women. CONCLUSION: Using prognostic gene expression profiles, we have indications that specific reproductive factors may be associated with prognostic tumour subtypes beyond hormone receptor status.

Cancer risks in BRCA2 families: estimates for sites other than breast and ovary.

BACKGROUND: In BRCA2 mutation carriers, increased risks have been reported for several cancer sites besides breast and ovary. As most of the families included in earlier reports were selected on the basis of multiple breast/ovarian cancer cases, it is possible that risk estimates may differ in mutation carriers with a less striking family history. METHODS: In the Netherlands, 139 BRCA2 families with 66 different pathogenic mutations were included in a nationwide study. To avoid testing bias, we chose not to estimate risk in typed carriers, but rather in male and female family members with a 50% prior probability of being a carrier (n = 1811). The relative risk (RR) for each cancer site with the exception of breast and ovarian cancer was determined by comparing observed numbers with those expected, based on Dutch cancer incidence rates. RESULTS: We observed an excess risk for four cancer sites: pancreas (RR 5.9; 95% confidence interval (CI) 3.2 to 10.0), prostate (2.5; 1.6 to 3.8), bone (14.4; 2.9 to 42.1) and pharynx (7.3; 2.0 to 18.6). A small increase was observed for cancer of the digestive tract (1.5; 1.1 to 1.9). Histological verification was available for 46% of the tumours. Nearly all increased risks reached statistical significance for men only. Cancer risks tended to be higher for people before the age of 65 years. Moreover, families with mutations outside the previously defined ovarian cancer cluster region tended to have a higher cancer risk. CONCLUSIONS: We found that BRCA2 carriers are at increased risk for cancers of the prostate and pancreas, and possibly bone and pharynx. Larger databases with extended follow up are needed to provide insight into mutation specific risks of selected carriers in BRCA2 families.

Induced abortion and risk for breast cancer: reporting (recall) bias in a Dutch case-control study.

BACKGROUND: In general, no association has been found between spontaneous abortion (naturally occurring termination of a pregnancy) and the risk for breast cancer. With respect to induced abortion (termination of a pregnancy by artificial means), the results have been more inconclusive. A positive association was found in five studies, no association was found in six studies, and a negative association was found in the only cohort study. It is thought that part of the inconsistency of the reported results may be attributable to reporting (recall) bias, since all but two studies on induced abortion used the case-control design and were based only on information obtained from study subjects. In comparison with breast cancer case patients, healthy control subjects may be more reluctant to report on a controversial, emotionally charged subject such as induced abortion. Thus, differential underreporting may be a cause of spurious associations in case-control studies. PURPOSE: Our goal was threefold: 1) to evaluate the relationship between a history of induced or spontaneous abortion and the risk for breast cancer in a Dutch population-based, case-control study; 2) to examine reporting bias by comparing risks between two geographic areas (i.e., western regions and southeastern regions in The Netherlands that differ in prevalence of and attitudes toward induced abortion); and 3) to compare reporting bias in data on induced abortion with reporting bias in data on oral contraceptive use. METHODS: Data analyzed in this study were obtained from 918 women (20-54 years of age at diagnosis) who were diagnosed with invasive breast cancer during the period from 1986 through 1989 and had been initially enrolled in a population-based, case-control study investigating oral contraceptive use and breast cancer risk. The women resided in one of four geographic areas that were covered by Regional Cancer Registries: two western regions (Amsterdam and West) and two southeastern regions (East and Eindhoven). Each case patient was pair-matched, on the basis of age (within 1 year) and region, with a control subject who was randomly selected from municipal registries that fully covered the Dutch population. Both the case patients and the control subjects were interviewed at home by the same trained interviewer, who used a structured questionnaire. Reporting bias was examined indirectly by comparing risks between the western and the southeastern regions of the country, which differ in the prevalence of and attitude toward induced abortion. Multivariate conditional logistic regression methods for individually matched case-control studies were used to estimate relative risks (RRs). Reported P values are two-sided. RESULTS AND CONCLUSION: Among parous women, a history of induced abortion was associated with a 90% increased risk for breast cancer (adjusted RR = 1.9; 95% confidence interval [CI] = 1.1-3.2). Among nulliparous women, no association between induced abortion and breast cancer was found. Neither among parous women nor among nulliparous women was a history of spontaneous abortion related to the risk for breast cancer. The association between induced abortion and breast cancer was stronger in the southeastern regions of the country, which have a predominantly Roman Catholic population, than in the western regions (adjusted RR = 14.6 [95% CI = 1.8-120.0] versus adjusted RR = 1.3 [95% CI = 0.7-2.6], respectively; test of difference between regions, P = .017), suggesting reporting bias. Support for reporting bias as an explanation for the regional differences was also found in data supplied by both study subjects and their physicians on the use of oral contraceptives. In comparison with physicians, control subjects in the southeastern regions underreported the duration of their oral contraceptive use by 6.3 months more than control subjects in the western regions (P = .007)...

PIP: Data were analyzed from 918 women aged 20-54 years at diagnosis with invasive breast cancer during 1986-89. The women had initially enrolled in a population-based, case-control study investigating oral contraceptive use and the risk of breast cancer. Each case was pair-matched according to age and region of residence, and cases and controls interviewed at home. Among parous women, a history of induced abortion was associated with a 90% increased risk of breast cancer. Among nulliparous women, no association was found between induced abortion and breast cancer. Neither among parous women nor nulliparous women was a history of spontaneous abortion related to the risk of breast cancer. The association between induced abortion and breast cancer was stronger in the southeastern regions of the country, where there is a predominantly Roman Catholic population, suggesting reporting bias. Support for reporting bias as an explanation for regional differences was also found in data supplied by study participants and their physicians on the use of oral contraception. The authors conclude that reporting bias is a real problem in case-control studies of induced abortion and breast cancer risk if study findings are based solely upon information from study subjects.

Physical activity and breast cancer risk in women aged 20-54 years.

BACKGROUND/METHODS: Although several studies have suggested that physical activity is associated with a decreased risk of breast cancer, such a decrease has not been found consistently, perhaps because physical activity was assessed in different ways and for restricted periods. Few studies have assessed the risk of breast cancer in relation to lifetime physical activity. We used data from a population-based, case-control study, including 918 case subjects (aged 20-54 years) and 918 age-matched population control subjects, to examine associations between breast cancer risk and physical activity at ages 10-12 years and 13-15 years, lifetime recreational activity, and title of longest held job. RESULTS: Women who were more active than their peers at ages 10-12 years had a lower risk of breast cancer (odds ratio [OR] = 0.68; 95% confidence interval [CI] = 0.49-0.94). Women who had ever engaged in recreational physical activity had a reduced risk of breast cancer compared with inactive women (OR = 0.70; 95% CI = 0.56-0.88). Neither very early recreational activity (before age 20 years) nor recent activity (last 5 years) was associated with a greater reduction in risk than recreational activity in the intermediate period. Furthermore, women who started recreational activities after age 20 years and women who started earlier and continued their activities throughout adult life experienced a similar reduction in risk. Lean women, i.e., women with a body mass index (weight in kg/[height in m](2)) less than 21. 8 kg/m(2), appeared to have a lower risk associated with recreational physical activity than women with a body mass index greater than 24.5 kg/m(2) (OR = 0.57 [95% CI = 0.40-0.82] and OR = 0. 92 [95% CI = 0.65-1.29], respectively). CONCLUSIONS: Our findings support the hypothesis that recreational physical activity is associated with a decreased risk of breast cancer. Physical activity in early or recent life does not appear to be associated with additional beneficial effects.

Differences in breast cancer risk factors to neu (c-erbB-2) protein overexpression of the breast tumor.

To investigate whether overexpression of the neu protein in breast tumors differentiates risk factor patterns for breast cancer, neu protein overexpression was determined in 296 breast carcinomas of patients participating in an ongoing population-based case-control study. Risk factor information on these patients and 737 controls was obtained during home interviews. Most breast cancer risk factors showed similar associations with neu-positive and neu-negative tumors, but remarkable differences were found for breast-feeding and age at first full-term pregnancy. In contrast to the slightly protective effect of breast-feeding in the neu-negative group, the risk of neu-positive breast cancer was 4.2-fold increased in women who ever breast-fed. Increasing age at first full-term pregnancy was positively associated with both neu-positive and neu-negative breast cancer, but the association was about 2 times stronger for neu-positive tumors. We conclude that neu oncogene overexpression of the breast tumor seems to be associated with a distinct risk factor pattern.

Timing of risk reducing mastectomy in breast cancer patients carrying a BRCA1/2 mutation: retrospective data from the Dutch HEBON study.

It is expected that rapid genetic counseling and testing (RGCT) will lead to increasing numbers of breast cancer (BC) patients knowing their BRCA1/2 carrier status before primary surgery. Considering the potential impact of knowing one's status on uptake and timing of risk-reducing contralateral mastectomy (RRCM), we aimed to evaluate trends over time in RRCM, and differences between carriers identified either before (predictively) or after (diagnostically) diagnosis. We collected data from female BRCA1/2 mutation carriers diagnosed with BC between 1995 and 2009 from four Dutch university hospitals. We compared the timing of genetic testing and RRCM in relation to diagnosis in 1995-2000 versus 2001-2009 for all patients, and predictively and diagnostically tested patients separately. Of 287 patients, 219 (76%) had a diagnostic BRCA1/2 test. In this cohort, the median time from diagnosis to DNA testing decreased from 28 months for those diagnosed between 1995 and 2000 to 14 months for those diagnosed between 2001 and 2009 (p < 0.001). Similarly, over time women in this cohort underwent RRCM sooner after diagnosis (median of 77 vs. 27 months, p = 0.05). Predictively tested women who subsequently developed BC underwent an immediate RRCM significantly more often than women who had a diagnostic test (21/61, 34%, vs. 13/170, 7.6 %, p < 0.001). Knowledge of carrying a BRCA1/2 mutation when diagnosed with BC influenced decisions concerning primary surgery. Additionally, in more recent years, women who had not undergone predictive testing were more likely to undergo diagnostic DNA testing and RRCM sooner after diagnosis. This suggests the need for RGCT to guide treatment decisions.

Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction.

BACKGROUND: Previous studies have reported a breast cancer (BC) risk reduction of approximately 50% after risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers, but may have been subject to several types of bias. The purpose of this nationwide cohort study was to assess potential bias in the estimated BC risk reduction after RRSO. METHODS: We selected BRCA1/2 mutation carriers from an ongoing nationwide cohort study on Hereditary Breast and Ovarian Cancer in the Netherlands (HEBON). First, we replicated the analytical methods as previously applied in four major studies on BC risk after RRSO. Cox proportional hazards models were used to calculate hazard ratios and conditional logistic regression to calculate odds ratios. Secondly, we analyzed the data in a revised design in order to further minimize bias using an extended Cox model with RRSO as a time-dependent variable to calculate the hazard ratio. The most important differences between our approach and those of previous studies were the requirement of no history of cancer at the date of DNA diagnosis and the inclusion of person-time preceding RRSO. RESULTS: Applying the four previously described analytical methods and the data of 551 to 934 BRCA1/2 mutation carriers with a median follow-up of 2.7 to 4.6 years, the odds ratio was 0.61 (95% confidence interval [CI] = 0.35 to 1.08), and the hazard ratios were 0.36 (95% CI = 0.25 to 0.53), 0.62 (95% CI = 0.39 to 0.99), and 0.49 (95% CI = 0.33 to 0.71), being similar to earlier findings. For the revised analysis, we included 822 BRCA1/2 mutation carriers. After a median follow-up period of 3.2 years, we obtained a hazard ratio of 1.09 (95% CI = 0.67 to 1.77). CONCLUSION: In previous studies, BC risk reduction after RRSO in BRCA1/2 mutation carriers may have been overestimated because of bias. Using a design that maximally eliminated bias, we found no evidence for a protective effect.

Agreement between oral contraceptive users and prescribers: implications for case-control studies.

Case-control studies examining the effects of oral contraceptives (OC) are prone to misclassification bias due to errors in assessment of OC use. Concern about inaccurate exposure histories has increased since current studies require women to recall OC use over prolonged periods of time. In preparation for a case-control study of breast cancer and OC use, an investigation was carried out to assess agreement between women's lifetime histories of OC use (covering a period of up to 20 years) and prescribers' records. OC histories were obtained during personal interview with 218 women who had used OC at some point in their lives (127 breast cancer patients, 91 controls). Recall was aided by an album with color photographs of all OC marketed in the Netherlands from 1962 onwards (n = 65), and a calendar that covered the women's life span from date of birth to menopause. The participants were asked for the names of all physicians who prescribed OC for them. The rate of response from the prescribers was high (94%), but only half of the forms provided useful information. Patient-prescriber agreement on brand names (including dosage) was 70%. About half of the women agreed with their prescribers on starting dates to within less than a year's difference. Approximately the same percentage of agreement was found for stopping dates. Multiple linear regression indicated that agreement on brand names and dates of usage was lower for women of low socioeconomic status, for healthy women (as compared to breast cancer patients) and for periods of pill use that had to be recalled from the more distant past. Agreement on total duration of use was high enough to permit testing of a moderately strong duration-response relationship in a case-control study.

PIP: Between January 1983-January 1986, women spoke to 151 breast cancer patients at the National Cancer Institute in Amsterdam, the Netherlands and 93 healthy controls to determine agreement between women's lifetime histories of oral contraceptive (OC) use and prescribers' records. Both cases and controls provided the name of all physicians who ever prescribed an OC to them. Even though 93.6% of prescribers responded to the researchers request for information, only 46.1% of the forms provided information on brand name or date(s) of usage. In fact, only 33.6% had complete information. Median duration of OC use was 8.1 years and 33.1% began taking OCs before July 1965. Patient-prescriber agreement on brand names and dosage stood at 70%. Responses of starting dates of about 50% of the women corresponded within 1 year with that of their prescriber. Breast cancer patients tended to have better agreement than controls, but the difference was not significant. Further 59.1% agreed with their prescriber within 2 years on duration of use. The difference in agreement on duration of OC use between cases and controls was insignificant. The multiple regression analysis showed that women of low socioeconomic status were less likely to agree with their prescribers on brand names and dates of usage than were women of medium and high socioeconomic status. Further healthy women had better agreement than breast cancer patients. Moreover the recall period had a significant effect on agreement on brand names (p=.07) and on stopping dates (p=.0015). Even though women tended to overstate duration of OC use, recall was accurate enough to explore the presence of a moderately strong duration response relationship. This study showed that prescriber data should not be the only data source of a case control study and that they indeed complement women's histories.

[Does breast feeding protect against breast cancer? An epidemiological study]. / Beschermt het geven van borstvoeding tegen borstkanker? Een epidemiologisch onderzoek.

The association between breastfeeding and the risk of breast cancer was studied as part of a Dutch population-based epidemiological study of the aetiology of female breast cancer. A total of 484 breast cancer patients and 484 controls (matched for age; age range: 20-54 years) were compared with regard to their breastfeeding habits. There was no clear association between breastfeeding and breast cancer risk. After adjustment for confounders women who had ever breastfed had no lower risk of breast cancer than women who never had given breastfeeding. Women who had breastfed for prolonged periods (total lifetime nursing of 44 weeks or more) had, after adjustment for confounders, a 29% lower risk of breast cancer compared to women who had never breastfed, but this risk reduction was not statistically significant. These results do not support the hypothesis that (short) periods of breastfeeding reduce the risk of breast cancer in young women. A possible protective effect of longer periods of breastfeeding, which is suggested more strongly in the literature, could not be investigated in this study because the women breastfed their children for relatively short periods.

[Last word on hormone replacement and breast cancer?]. / Het laatste woord over hormoonsuppletie en borstkanker?

A very large meta-analysis of the Collaborative Group on Hormonal Factors in Breast Cancer has revealed an increasing risk of breast cancer with longer durations of use of hormonal replacement therapy (HRT). This risk increase is restricted to current users of HRT or women who ceased use recently. A 35% increase of the relative risk of breast cancer was found after 5 years of HRT use or longer. After cessation of HRT use the excess breast cancer risk disappeared in 5 years, even after long durations of use. The risk increase was greater for women of normal or lean body weight than for more obese women. Tumours found in women who ever used HRT were diagnosed at a lower clinical stage, which suggests that enhanced screening might be involved. However, the increased breast cancer mortality in HRT users, as found in other studies, rather suggests a biologic mechanism Long-term use of HRT is not yet common in the Netherlands, but an increasing trend is present. Thus, the benefits of long-term use of HRT must be carefully weighted against the risks.

The frequency, magnitude and timing of post-diagnosis body weight gain in Dutch breast cancer survivors.

To evaluate the association between systemic treatments and post-diagnosis weight gain in breast cancer patients during longer follow-up periods, we conducted a retrospective cohort study (n=271). Information on adjuvant systemic treatments and repeated body weight measurements was obtained from medical records, and analysed using multi-level regressions. During the first year, a mean weight change of +2.0kg (SD 4.9) was observed. Overall, 29% of all breast cancer patients had gained 5kg or more in body weight during total follow-up (median: 3 years). In multi-level analyses, women who received combined systemic treatment gained significantly more weight as compared with women who received no systemic treatment (4.5kg versus 2.0kg at 5 years post-diagnosis, p<0.05). Significant weight gain occurs in breast cancer patients in the Netherlands during the first year post-diagnosis. After the first year, further weight gain mainly occurs in women who receive chemotherapy in combination with endocrine therapy.

No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study.

BRCA1/2 mutation carriers are offered gynaecological screening with the intention to reduce mortality by detecting ovarian cancer at an early stage. We examined compliance and efficacy of gynaecological screening in BRCA1/2 mutation carriers. In this multicentre, observational, follow-up study we examined medical record data of a consecutive series of 888 BRCA1/2 mutation carriers who started annual screening with transvaginal ultrasonography and serum CA125 between 1993 and 2005. The women were annually screened for 75% of their total period of follow-up. Compliance decreased with longer follow-up. Five of the 10 incident cancers were interval tumours, diagnosed in women with a normal screening result within 3-10 months before diagnosis. No difference in stage distribution between incident screen-detected and interval tumours was found. Eight of the 10 incident cancers were stage III/IV (80%). Cancers diagnosed in unscreened family members had a similar stage distribution (77% in stage III/IV). The observed number of cases detected during screening was not significantly higher than expected (Standardized Incidence Ratio (SIR): 1.5, 95% confidence interval: 0.7-2.8). For the subgroup that was fully compliant to annual screening, a similar SIR was found (1.6, 95% confidence interval: 0.5-3.6). Despite annual gynaecological screening, a high proportion of ovarian cancers in BRCA1/2 carriers are interval cancers and the large majority of all cancers are diagnosed in advanced stages. Therefore, it is unlikely that annual screening will reduce mortality from ovarian cancer in BRCA1/2 mutation carriers.

Risk reduction of contralateral breast cancer and survival after contralateral prophylactic mastectomy in BRCA1 or BRCA2 mutation carriers.

The clinical outcome of contralateral prophylactic mastectomy (CPM) in women with a BRCA1 or BRCA2 mutation and a personal history of invasive breast cancer is unknown. We identified a cohort of 148 female BRCA1 or BRCA2 mutation carriers (115 and 33, respectively) who previously were treated for unilateral invasive breast cancer stages I-IIIa. In all, 79 women underwent a CPM, while the other women remained under intensive surveillance. The mean follow-up was 3.5 years and started at the time of CPM or at the date of mutation testing, whichever came last, that is, on average 5 years after diagnosis of the first breast cancer. One woman developed an invasive contralateral primary breast cancer after CPM, whereas six were observed in the surveillance group (P<0.001). Contralateral prophylactic mastectomy reduced the risk of contralateral breast cancer by 91%, independent of the effect of bilateral prophylactic oophorectomy (BPO). At 5 years follow-up, overall survival was 94% for the CPM group vs 77% for the surveillance group (P=0.03), but this was unexpectedly mostly due to higher mortality related with first breast cancer and ovarian cancer in the surveillance group. After adjustment for BPO in a multivariate Cox analysis, the CPM effect on overall survival was no longer significant. Our data show that CPM markedly reduces the risk of contralateral breast cancer among BRCA1 or BRCA2 mutation carriers with a history of breast cancer. Longer follow-up is needed to study the impact of CPM on contralateral breast cancer-specific survival. The choice for CPM is highly correlated with that for BPO, while only BPO leads to a significant improvement in overall survival so far.

Changes in body mass index in young adults in relation to number of life events experienced.

As part of an extensive longitudinal study, the effect of experiencing few or many life events on the development of the body mass index (BMI = weight/height2) over periods of 1 year and 2 years was examined in 350 men and 395 women, 20-35 years of age. Body weight was measured and a life event questionnaire referring to the preceding 6 months was completed every 6 months from spring 1981 through spring 1984. The change in BMI of subjects who experienced few or many life events was compared with the change in BMI of subjects who experienced an intermediate number of life events (the intermediate group). During the first year of follow-up, several subgroups of men and women who experienced many life events showed a gain in body mass. In several subgroups of men who experienced few life events a comparable effect occurred. After another year of follow-up this gain in body mass had disappeared in almost all subgroups. In the subgroup of men that tried to reduce their body weight by dieting during the follow-up period, the gain in body mass following few or many life events seemed to be permanent. In conclusion, the gain in body mass that may occur following the experience of many life events in women, seems to be effectively counterbalanced by regulatory mechanisms. In men, however, the experience of few or many life events may play a part in the aetiology of overweight.

The role of exogenous hormones in the epidemiology of breast, ovarian and endometrial cancer.

This review focuses on the effects of oral contraceptives (OC) and estrogen replacement therapy (ERT) on the risk of breast, ovarian and endometrial cancer. The relationship between OC and cancer risk is first placed in a historical perspective. Since 1960, when OC were introduced, the hormonal composition of OC as well as the characteristics of the OC user have changed considerably. Studies conducted in the 1970s were generally reassuring, but it was not until the 1980s that studies could evaluate the effect of prolonged OC use after an extended follow-up period. Although the relationship between breast cancer and OC has been investigated in about 40 studies, the issue still remains essentially unresolved. Most studies report no association between ever use of OC and breast cancer risk. Several studies find increased risk for prolonged use and other studies report elevated risks for women who used OC very early in their reproductive years. The inconsistent results of recent studies are attributed to bias or to geographical variation in latency period elapsed, types of OC preparations, or prevalence of other risk factors. In contrast, the use of combined OC has consistently been shown to reduce the risk of ovarian and endometrial cancer. The risk further decreases with increasing duration of use and the protective effect seems to persist in ex-users for at least 5 years. Some evidence indicates that higher parity reduces the protective effect. Though studies relating ERT to breast cancer are far from consistent, overall, there is evidence for a moderately increased risk with high dose and/or long duration. The effect seems to be modified by mode of administration (injections vs. pills) and by type of ERT, but this needs confirmation. The number of adequate studies on the relationship between ERT and ovarian cancer is too small to draw firm conclusions. The positive relationship between ERT and endometrial cancer is now well established. The ERT effect is dose- and duration-dependent and is characterized by a short latency period. The cyclic addition of progesterone (greater than 10 days/cycle) may reduce the risk increase.

Oral contraceptives and risk of breast cancer in women aged 20-54 years. Netherlands Oral Contraceptives and Breast Cancer Study Group.

Although the use of oral contraceptives (OCs) is not generally associated with increased risk of breast cancer, higher risks have been reported for some subgroups of users. We have carried out a population-based case-control study in the Netherlands to assess the effect of timing and duration of OC use on the risk of breast cancer developing at various ages. 918 women with breast cancer (20-54 years at diagnosis) were pair-matched by age with controls randomly selected from municipal registries. Information on OC use obtained from women and their prescribers was combined according to standard decision rules. Overall, long-term use of OCs (> or = 12 years) had an associated relative risk (RR) of 1.3 (95% CI 0.9-1.9; test for trend in risk with months of use p = 0.03). This positive trend was found in both the youngest (< 36 years; p = 0.08) and the oldest (46-54 years, p = 0.004) age groups, but not in women aged 36-45 years. The RR of developing breast cancer before age 36 was 2.1 (1.0-4.5) for 4 or more years of OC use compared with shorter use. In women younger than 36, risk increased for longer OC use before age 20 (1.44 per year, p = 0.04). Recent use (previous 3 years) was associated with increased risk in women of 46-54 (RR 1.9 [0.9-4.1], p = 0.02). We conclude that 4 or more years of OC use, especially if partly before age 20, is associated with an increased risk of breast cancer developing at an early age. There is limited evidence that the excess risk disappears as the cohort of young OC users ages, but this issue needs confirmation.