Cumulative Incidence Of Breast Cancer Research Articles

Effects of Reproductive and Demographic Changes on Breast Cancer Incidence in China: A Modeling Analysis

Breast cancer incidence is currently low in China. However, the distribution of reproductive and lifestyle risk factors for breast cancer among Chinese women is changing rapidly. We quantified the expected effect of changes in breast cancer risk factors on future rates of breast cancer in China. We first validated and calibrated the Rosner-Colditz log-incidence breast cancer model in Chinese women who participated in the Shanghai Women's Health Study cohort (N = 74,942). We then applied the calibrated model to a representative sample of Chinese women who were aged 35-49 years in 2001 using data from the Chinese National Family Planning and Reproductive Health Survey (NFPRHS, N = 17,078) to predict the age-specific and cumulative breast cancer incidence among all Chinese women of this age group. We evaluated the relative impact of changes in modifiable risk factors, including alcohol intake, parity, postmenopausal hormone use, and adult weight gain, on cumulative incidence of breast cancer. Breast cancer incidence in China is expected to increase substantially from current rates, estimated at 10-60 cases per 100,000 women, to more than 100 new cases per 100,000 women aged 55-69 years by 2021. We predicted 2.5 million cases of breast cancer by 2021 among Chinese women who were 35-49 years old in 2001. Modest reductions in hormone and alcohol use, and weight maintenance could prevent 270,000 of these cases. China is on the cusp of a breast cancer epidemic. Although some risk factors associated with economic development are largely unavoidable, the substantial predicted increase in new cases of breast cancer calls for urgent incorporation of this disease in future health care infrastructure planning.

Birth Size and Breast Cancer Risk: Re-analysis of Individual Participant Data from 32 Studies

BackgroundBirth size, perhaps a proxy for prenatal environment, might be a correlate of subsequent breast cancer risk, but findings from epidemiological studies have been inconsistent. We re-analysed individual participant data from published and unpublished studies to obtain more precise estimates of the magnitude and shape of the birth size–breast cancer association.Methods and FindingsStudies were identified through computer-assisted and manual searches, and personal communication with investigators. Individual participant data from 32 studies, comprising 22,058 breast cancer cases, were obtained. Random effect models were used, if appropriate, to combine study-specific estimates of effect. Birth weight was positively associated with breast cancer risk in studies based on birth records (pooled relative risk [RR] per one standard deviation [SD] [= 0.5 kg] increment in birth weight: 1.06; 95% confidence interval [CI] 1.02–1.09) and parental recall when the participants were children (1.02; 95% CI 0.99–1.05), but not in those based on adult self-reports, or maternal recall during the woman's adulthood (0.98; 95% CI 0.95–1.01) (p for heterogeneity between data sources = 0.003). Relative to women who weighed 3.000–3.499 kg, the risk was 0.96 (CI 0.80–1.16) in those who weighed < 2.500 kg, and 1.12 (95% CI 1.00–1.25) in those who weighed ≥ 4.000 kg (p for linear trend = 0.001) in birth record data. Birth length and head circumference from birth records were also positively associated with breast cancer risk (pooled RR per one SD increment: 1.06 [95% CI 1.03–1.10] and 1.09 [95% CI 1.03–1.15], respectively). Simultaneous adjustment for these three birth size variables showed that length was the strongest independent predictor of risk. The birth size effects did not appear to be confounded or mediated by established breast cancer risk factors and were not modified by age or menopausal status. The cumulative incidence of breast cancer per 100 women by age 80 y in the study populations was estimated to be 10.0, 10.0, 10.4, and 11.5 in those who were, respectively, in the bottom, second, third, and top fourths of the birth length distribution.ConclusionsThis pooled analysis of individual participant data is consistent with birth size, and in particular birth length, being an independent correlate of breast cancer risk in adulthood.

Active screening allowing to compare breast cancer staging and its impact at population survival between Brazil and developed countries

Women with a family history of breast cancer are at increased risk of the disease, but no study has been large enough to characterise reliably how, over women's lives, this risk is influenced by particular familial patterns of breast cancer. This report, on the relevance of breast cancer in first-degree relatives, is based on combined data from 52 epidemiological studies.Individual data on breast cancer in first-degree relatives (mothers, sisters, and daughters) of 58 209 women with breast cancer and of 101 986 controls were collected, checked, and analysed centrally. Risk ratios for breast cancer were calculated by conditional logistic regression, stratified by study, age, menopausal status, number of sisters, parity, and age when the first child was born. Breast-cancer incidence and mortality rates for particular family histories were calculated by applying age-specific risk ratios to breast-cancer rates typical for more-developed countries.Altogether 7496 (12·9%) women with breast cancer and 7438 (7·3%) controls reported that one or more first-degree relatives had a history of breast cancer: 12% of women with breast cancer had one affected relative and 1% had two or more. Risk ratios for breast cancer increased with increasing numbers of affected first-degree relatives: compared with women who had no affected relative, the ratios were 1·80 (99% CI 1·69–1·91), 2·93 (2·36–3·64), and 3·90 (2·03–7·49), respectively, for one, two, and three or more affected first-degree relatives (p<0·0001 each). The risk ratios were greatest at young ages, and for women of a given age, were greater the younger the relative was when diagnosed. The results did not differ substantially between women reporting an affected mother (9104) or sister (6386). Other factors, such as childbearing history, did not significantly alter the risk ratios associated with a family history of breast cancer. For women in more-developed countries with zero, one, or two affected first-degree relatives, the estimated cumulative incidence of breast cancer up to age 50 was 1·7%, 3·7%, and 8·0%, respectively; corresponding estimates for incidence up to age 80 were 7·8%, 13·3%, and 21·1%. Corresponding estimates for death from breast cancer up to age 80 were 2·3%, 4·2%, and 7·6%. The age when the relative was diagnosed had only a moderate effect on these estimates.Eight out of nine women who develop breast cancer do not have an affected mother, sister, or daughter. Although women who have first-degree relatives with a history of breast cancer are at increased risk of the disease, most will never develop breast cancer, and most who do will be aged over 50 when their cancer is diagnosed. In countries where breast cancer is common, the lifetime excess incidence of breast cancer is 5·5% for women with one affected first-degree relative and 13·3% for women with two.

Competing Risks Analysis of Correlated Failure Time Data

We develop methods for competing risks analysis when individual event times are correlated within clusters. Clustering arises naturally in clinical genetic studies and other settings. We develop a nonparametric estimator of cumulative incidence, and obtain robust pointwise standard errors that account for within-cluster correlation. We modify the two-sample Gray and Pepe-Mori tests for correlated competing risks data, and propose a simple two-sample test of the difference in cumulative incidence at a landmark time. In simulation studies, our estimators are asymptotically unbiased, and the modified test statistics control the type I error. The power of the respective two-sample tests is differentially sensitive to the degree of correlation; the optimal test depends on the alternative hypothesis of interest and the within-cluster correlation. For purposes of illustration, we apply our methods to a family-based prospective cohort study of hereditary breast/ovarian cancer families. For women with BRCA1 mutations, we estimate the cumulative incidence of breast cancer in the presence of competing mortality from ovarian cancer, accounting for significant within-family correlation.

Stratification of Breast Cancer Risk in Women With Atypia: A Mayo Cohort Study

Atypical hyperplasia is a well-recognized risk factor for breast cancer, conveying an approximately four-fold increased risk. Data regarding long-term absolute risk and factors for risk stratification are needed. Women with atypical hyperplasia in the Mayo Benign Breast Disease Cohort were identified through pathology review. Subsequent breast cancers were identified via medical records and a questionnaire. Relative risks (RRs) were estimated using standardized incidence ratios, comparing the observed number of breast cancers with those expected based on Iowa Surveillance, Epidemiology, and End Results (SEER) data. Age, histologic factors, and family history were evaluated as risk modifiers. Plots of cumulative breast cancer incidence provided estimates of risk over time. With mean follow-up of 13.7 years, 66 breast cancers (19.9%) occurred among 331 women with atypia. RR of breast cancer with atypia was 3.88 (95% CI, 3.00 to 4.94). Marked elevations in risk were seen with multifocal atypia (eg, three or more foci with calcifications [RR, 10.35; 95% CI, 6.13 to 16.4]). RR was higher for younger women (< 45; RR, 6.76; 95% CI, 3.24 to 12.4). Risk was similar for atypical ductal and atypical lobular hyperplasia, and family history added no significant risk. Breast cancer risk remained elevated over 20 years, and the cumulative incidence approached 35% at 30 years. Among women with atypical hyperplasia, multiple foci of atypia and the presence of histologic calcifications may indicate "very high risk" status (> 50% risk at 20 years). A positive family history does not further increase risk in women with atypia.

Breast Cancer in Young Women after Treatment with Irradiation for Hodgkin's Lymphoma.

BACKGROUND: Women who are survivors of Hodgkin's Lymphoma (HL) are at increased risk of developing breast cancer (BCa) as a long-term complication due to the use of extended field (mantle) irradiation (RT) of disease above the diaphragm. Many young women are at significantly increased risk of BCa prior to the age at which routine screening mammography is recommended for the general population. The sensitivity of mammography is lower in these women, in part due to increased breast tissue density characteristic of young pre-menopausal women. Currently, there is a paucity of information on the optimal screening modality and surveillance frequency for these women.METHODS: We reviewed the current BCa screening strategies used for this high risk group at our centre and described the incidence, method of detection, and characteristics of secondary BCas in a cohort of 115 women who received supradiaphragmatic RT for HL before age 30 between 1965 and 2000 at Princess Margaret Hospital (PMH) and who subsequently accepted long-term follow-up in a high-risk screening clinic.RESULTS: Median age at treatment was 22 (range 9–30). Radiation fields were mantle in 106 women, modified mantle in 6, and involved field in 3 (median dose delivered: 35 Gy, range 15–60). RT alone was used for 44 patients while 71 received combined modality therapy, of which 45 (65%) received MOPP. Treatment induced amenorrhea occurred in 15 women (median age 38); hormone replacement therapy was subsequently used by 9. Of the 107 women who participated in annual radiographic BCa screening, 95 were screened with mammogram alone, 1 with breast MRI alone, 8 with mammogram and MRI, and 3 with mammogram and ultrasound. Median age at first mammogram was 36; however, median age decreased with more recent year of HL diagnosis (age 40 for women diagnosed before 1985 compared to age 33 for women diagnosed after 1985, p<0.0001). Women with high breast density received MRI screening more often (p=0.02); however, breast density was not significantly associated with previous breast radiation dose or age at last follow-up. Twelve women were diagnosed with BCa in this cohort, following active breast surveillance for a median of 5 years (representing 584 person-years). The 20-year cumulative incidence of breast cancer was 10.9% (95% CI 5.3–18.8%) in this group of women. This was comparable to the 20-year cumulative incidence of breast cancer of 12% (95% CI 8–17%) in all 448 women with HL treated with supradiaphragmatic radiation before age 30 at PMH during the same time period. BCa occurred after a median of 17 years after treatment for HL (range 13–28). Median age at BCa diagnosis was 40 (range 31–51). Seven cancers were detected by physical exam (6 node-positive invasive BCas, 1 in-situ BCa) and 5 were detected on annual mammograms (1 node-positive invasive BCa, 4 in-situ BCas).CONCLUSIONS: Although women in the more recent treatment cohort are receiving their first mammogram at a younger age, the majority of BCas were still detected clinically, and these BCas had less favorable pathological characteristics. More frequent breast imaging should be considered in women who have had supradiaphragmatic RT for HL. Prospective evaluation of breast MRI as a screening strategy for HL survivors has been initiated at PMH in an effort to detect BCa at an earlier stage.

Incidence and risk factors associated with bilateral breast cancer in area with early age diagnosis but low incidence of primary breast cancer: analysis of 10-year longitudinal cohort in Taiwan

This study aims to examine the incidence and risk factors of bilateral breast cancer in area with low incidence rate. A total of 120 and 1902 women with bilateral and unilateral breast cancers were enrolled; various factors, including those concerning their medical history and life style, were extracted. Using Kaplan-Meier method, we calculate the cumulative incidence of contralateral breast cancer. The results show as follows. The cumulative incidences of contralateral breast cancer at 1, 3, 5 years after diagnosis of first breast cancer were 1.15, 1.94, and 2.97%, respectively. The statistically significant risk factors included menopause (Hazard Ratio (HR) =1.56, (1.00-2.42)), invasive lobular carcinoma (HR=2.98, (1.35-6.56)), receiving chemotherapy (HR=2.21, (1.43-3.42)) and/or radiotherapy (HR=3.32, (2.19-5.05) and a protective factor was tamoxifen therapy (HR=0.5 (0.34-0.74). Size of the second occurred tumour (2.97 cm) tended to be smaller than the first one (3.58 cm) with borderline statistical significance (p=0.0731). Comparing to the existing data on Western countries, we find a higher risk for developing contralateral breast cancer in Taiwan where a low incidence of first breast cancer rate with early age diagnosis is noted. It suggests that first primary breast tumour with early age of onset and lobular carcinoma are found more likely to develop bilateral breast cancers.

Population-Based Study of Changing Breast Cancer Risk in Icelandic BRCA2 Mutation Carriers, 1920–2000

Mutations in the BRCA genes increase the risk of breast cancer. Valid estimates of the magnitude of the lifetime risk of breast cancer in BRCA gene mutation carriers are needed for genetic counseling. Recent results suggest that penetrance has increased in recent birth cohorts. We examined the cumulative breast cancer incidence and mortality before age 70 over a diagnosis period of 80 years in Icelandic women who carried the BRCA2 founder mutation 999del5. Information on all breast cancers diagnosed in Iceland since 1911 was obtained from the Icelandic Cancer Registry. Mutation status was determined by molecular analysis of tissue samples for 847 breast cancer probands who were diagnosed from 1921 through 1985 and selected without knowledge of family history of breast cancer. We estimated the cumulative incidence and mortality from breast cancer before age 70 years in BRCA2 mutation carriers from the observed risks in first-degree relatives who were classified according to mutation status of probands and followed-up through 2002. Poisson modeling of these risks was also carried out. All statistical tests were two-sided. Of the 847 probands, 88 carried the BRCA2 999del5 mutation and 759 did not. According to Poisson modeling, the cumulative incidence of breast cancer before age 70 years in mutation carriers increased from 18.6% (95% CI = 11.0% to 29.5%) in calendar year 1920 to 71.9% (95% CI = 45.9% to 100%) in 2002 (P < .001); in relatives of probands who did not carry the BRCA2 mutation and in the general Icelandic population incidence increased over the same period from 2.6% to 10.7% and from 1.8% to 7.5%, respectively (all increases of approximately fourfold). During the same period, the cumulative risk of death from breast cancer before age 70 years for BRCA2 mutation carriers increased from 12.1% (95% CI = 5.3% to 23.9%) to 26.9% (95% CI = 10.9% to 55.5%) (P = .08). However, because the probands were breast cancer patients and not a random sample from the population, some bias in the estimation of time trends in penetrance cannot be ruled out. The results indicate that the penetrance of the Icelandic BRCA2 founder mutation increased nearly fourfold in 80 years, whereas the risk of death from breast cancer before age 70 years increased only approximately twofold. Changes in penetrance with time should be considered when penetrance is estimated.

Malignant Breast Tumors After Radiotherapy for a First Cancer During Childhood

To assess the specific role of treatment and type of first cancer (FC) in the risk of long-term subsequent breast cancer (BC) among childhood cancer survivors. In a cohort of 1,814 3-year female survivors treated between 1946 and 1986 in eight French and English centers, data on chemotherapy and radiotherapy were collected. Individual estimation of radiation dose to each breast was performed for the 1,258 patients treated by external radiotherapy; mean dose to breast was 5.06 Gy (range, 0.0 to 88.0 Gy) delivered in 20 fractions (mean). Mean follow-up was 16 years; 16 patients developed a clinical BC, 13 after radiotherapy. The cumulative incidence of BC was 2.8% (95% CI, 1.0% to 4.5%) 30 years after the FC and 5.1% (95% CI, 2.1% to 8.2%) at the age of 40 years. The annual excess incidence increased as age increased, whereas the standardized incidence ratio decreased. On average, each Gray unit received by any breast increased the excess relative risk of BC by 0.13 (< 0.0 to 0.75). After stratification on castration and attained age, and adjusting for radiation dose, FC type, and chemotherapy, a higher risk of a subsequent BC was associated with Hodgkin's disease (relative risk, 7.0; 95% CI, 1.4 to 30.9). The reported high risk of BC after childhood Hodgkin's disease treatment seems to be due not only to a higher radiation dose to the breasts, but also to a specific susceptibility.

Is the Risk of Breast Cancer Increased after Hematopoietic Cell Transplantation?.

Survivors of hematopoietic stem cell transplantation (HSCT) are at risk for second malignant neoplasms (SMN). As secondary breast cancer is now reported in excess among survivors of a variety of cancers treated with conventional chemoradiotherapy, we sought to explore the risk among HSCT survivors. Among 4,805 allogeneic transplant recipients treated at the Fred Hutchinson Cancer Research Center between November, 1969 and April, 2003, who survived at least 100 days post transplant, there were 27 females and 1 male with secondary breast cancer, representing the largest single diagnostic group of secondary solid tumors post transplant, following cancers of the skin and mucosa. Confining the analysis to the 2,042 female HSCT recipients, the cumulative incidence of secondary breast cancer at 25 years was 5.4% (95% Confidence Interval [CI]: 3.0%, 8.9%). The risk was twice that of the general population, using US SEER data for expected values (Age and race adjusted standardized incidence ratio = 2.3; 95% CI = 1.5, 3.3). The time to second breast cancer from transplant was 1-24.8 (median 9.3) years. In Cox regression, using time from transplant as the time scale, risk increased with increasing age at time of transplant, with hazard ratios [HR] of 12.6 (95% CI 1.6,97.9) for patients 18–39 years and 54.7 (95% CI 6.6,450.8) for those ≥ 40 years. However, when age was used as the time scale, this age effect was no longer seen (HR: 0.56; 95% CI: 0.06,5,3). We also investigated the role of preparatory regimen and graft versus host disease (GVHD) and found no associations with increased breast cancer risk. Specifically, use of TBI in the conditioning regimen (HR: 1.9; 95% CI: 0.8,4.7), type of alkylating agent used in the conditioning regimen (Busulfan HR: 2.0; 95% CI: 0.1,32.0; Cytoxan HR: 1.3 95%; CI: 0.2,10.5; Busulfan plus Cytoxan HR: 0.8; 95% CI: 0.1,6.7), donor type (related versus unrelated; HR: 1.3; 95% CI 0.5,3.2), nor acute (HR: 1.2; 95% CI: 0.5,2.6) or chronic GVHD (HR: 1.5; 95% CI: 0.7,3.3) increased risk for secondary breast cancer. The only treatment-related risk factor identified was the use of single fraction (versus fractionated) TBI, where the hazard ratio was 4.8 (95% CI: 1.5,16.2). Among 1,015 100+ day survivors of autologous transplants, excluding those transplanted for primary breast cancer, there were 2 female and 1 male breast cancer reported. These data suggest that, in contrast to the risk reported following conventional chemoradiotherapy, transplant preparatory regimens do not significantly increase risk for secondary breast cancer. In addition, GVHD, which is a risk factor for a number of SMNs following HSCT, does not appear to increase the risk for secondary breast cancer. Risk factors other than therapy should therefore be investigated to better understand the increased risk of breast cancer following HSCT and to develop appropriate preventive strategies.

Late Effects after Therapy of Hodgkin's Disease: Update 2003/04 on Overwhelming Post-Splenectomy Infections and Secondary Malignancies

For a long time, a main focus of paediatric therapy studies for Hodgkin's disease (HD) has been on diminishing adverse late effects. Consequently, the long-term follow-up of patients after HD is very important. The HD late effects project of the GPOH, which evolved from 5 consecutive German-Austrian DAL therapy studies, was aimed at establishing a basis for the further improvement of therapy concepts and of long-term surveillance. The original cohort consisted of 1 245 study patients from 92 centres enrolled in the DAL studies HD-78 to HD-90 between 1978 and 1995. Initially, follow-up data were submitted by the participating study centres. When the majority of the patients had reached adult age and were no longer seen by the originally treating paediatric colleagues, we contacted them directly by mail every 2-3 years. At the time of analysis (March 2004) information from the preceding 6 years was available in 78.6 % of the patients alive. The median follow-up period of patients at the date of last information was 11.1 years (max. 25.5 years), the median age was 23.7 years (max. 41.1 years). The present report is focused on three out of a wide range of problems evaluated, namely cause of death in 14 patients expired after 10-21 years' follow-up, overwhelming post-splenectomy infections (18 events, 11 fatal), and 46 secondary malignancies. The OS rate after 24 years is 87 % (SE 3 %) in the total group, 83 % (SE 3 %) in 335 asplenic patients, and 93 % (SE 2 %) in 910 non- or partially splenectomised patients. We have initiated activities to improve the prophylactic measures against overwhelming infections in this risk group of asplenic patients. The cumulative incidences of secondary malignancies (SM) after 22 years is 11 % (SE 2 %) for all SM, 10 % (SE 2 %) for solid tumours, 0.8 % (SE 0.5 %) for NHL, and 0.6 % (SE 0.3 %) for leukaemias. The cumulative incidence of breast cancer in female patients at the age of 35 years is 4.0 % (SE 2 %). The effect of reducing the radiotherapy doses in the studies HD-87/HD-90 will become evident within the next years.

Effects of lactoferrin, soya germ and polyamine on 2‐amino‐1‐methyl‐6‐ phenylimidazo[4,5‐b]‐pyridine(PhIP)‐ induced breast carcinogenesis in rats

The cancer-preventive effects of food-derived bovine lactoferrin(bLF), isoflavone-rich soya germ(SG), and spermidine(SPD) on mammary gland carcinogenesis induced by 2-amino-1- methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP), were investigated in female Sprague-Dawley(SD) rats. Two hundred and six female SD rats were divided into 8 groups. Cumulative breast cancer incidence at 43 weeks was 65.4% in the PhIP group; 80.0% and 76.0% in the 0.2% and 2.0% bLF groups, respectively; 58.3% and 20.0% in the 2% and 10% SG groups, respectively; and 80.0% and 76.9% in the 0.035% and 0.175% SPD groups, respectively. Isoflavone-rich SG significantly suppressed breast cancer, and the tumors showed fibrous or less malignant features upon histological examination.

Cancer incidence in relatives of a population-based set of cases of early-onset breast cancer with a known BRCA1 and BRCA2 mutation status.

Relatives of breast cancer cases have an increased risk of the disease. The risk increases with increasing numbers and decreasing age of onset of affected relatives. In families with a BRCA1 or a BRCA2 mutation, individual carrier status predicts the risk of breast cancer. In relatives of cases where both BRCA1 and BRCA2 mutations are excluded, the risk remains undetermined. Standardized incidence ratios (SIRs) and cumulative cancer incidences were calculated for relatives of a population-based set of early-onset breast cancer index cases (younger than age 41 years) with a defined BRCA mutation status (n = 203). In first-degree relatives (FDRs) of mutation-negative cases, breast cancer incidences (SIR = 2.3), prostate cancer incidences (SIR = 1.7), cervix cancer incidences (SIR = 3.3) and nonmelanoma skin cancer incidences (SIR = 2.8) were increased. The risks of breast cancer, prostate cancer and nonmelanoma skin cancer were further increased in FDRs of breast cancer cases younger than 36 years of age. In high-risk individuals with at least one relative with breast cancer apart from the index case, but no BRCA mutation in the family, breast cancer incidence was increased (SIR = 5.3); again the prostate cancer incidence was elevated (SIR = 2.5). The cumulative incidence of breast cancer at ages 50 and 70 years for FDRs of index cases without a BRCA mutation was 3.6% and 12.8%, respectively. Similarly, the cumulative incidence of breast cancer for high-risk women was 6.3% and 21.1% at ages 50 and 70 years, and that for FDRs of BRCA mutation carriers was 17.2% and 27.7% at the same ages. The incidence of breast cancer is increased for FDRs of women with early-onset breast cancer irrespective of the BRCA status in the family. Risk increases with decreasing age and with increasing number of affected relatives. The incidences of prostate cancer, cervix cancer and nonmelanoma skin cancer are elevated for FDRs of early-onset breast cancer cases without a BRCA mutation, indicating a possible association between these cancers and early-onset breast cancer.

Rationale for a study adding tamoxifen to HRT

Tamoxifen can be classified as a first generation Selective Oestrogen Receptor Modulator (SERM). It is widely used for palliative endocrine treatment of advanced breast cancer and as adjuvant therapy to control micrometastatic relapse and new primaries in women treated surgically for early breast cancer [1]. Tamoxifen has also been investigated in three large cooperative phase III trials for breast cancer prevention in at-risk women. While the preliminary results of two European studies, conducted in Italy (Italian Tamoxifen Prevention Study) and in the United Kingdom (Royal Marsden Tamoxifen Chemoprevention Trial) [2,3], have shown no significant differences so far, the American (National Surgical Adjuvant Breast and Bowel Project, NSABP-P1) trial has shown an approximately 50% reduction of the risk of both invasive and non-invasive breast cancer and a 69% reduction of the occurrence of oestrogen receptor-positive tumours [4]. The Italian Tamoxifen Prevention Study included 5408 healthy hysterectomised women aged 35–70 years who were randomised to receive either 20 mg/day of tamoxifen or placebo for 5 years. After 81.2 months median follow-up, tamoxifen increased the risk of venous vascular events (38 women on tamoxifen versus 18 women on placebo, P=0.0053), mainly consisting of superficial phlebitis. Women entering the Italian trial were allowed to use Hormone Replacement Therapy (HRT) for the treatment of climacteric symptoms (ERT, mostly transdermal). Among women who never used HRT, there was no discernible difference between women allocated to the tamoxifen or placebo arm (P=0.986). 56 of the 79 breast cancers occurred among women who never used HRT at any point during the trial, with equal numbers of cases of breast cancer occurring among women on each arm. Among women who used HRT at some point during the study, either at baseline or during the study, 23 breast cancers occurred: 17 on placebo and 6 on tamoxifen (P=0.022). The difference was also statistically significant when the analysis was restricted to women who were continually using HRT, of whom there were 11 cases in the placebo group and 3 on tamoxifen (P=0.048). After 8 years of follow-up, the cumulative incidence of breast cancer among women who never used HRT was 1.78% on placebo and 1.55% on the tamoxifen arm. In women who used HRT at least some time during the trial, the cumulative incidence of breast cancer was 1.41% among women on the tamoxifen arm and 2.74% on women assigned to placebo. Withdrawal rate (mainly due to menopausal symptoms) differed according to ERT use, compliance being 78 and 75% at 3 and 5 years, respectively, for women who never took ERT and 92 and 88% at 3 and 5 years, respectively, for women not on ERT at baseline, but who took ERT at some time during the trial. Pharmacokinetic and pharmacodynamic (surrogate endpoint biomarkers) studies showed that a lower dose of tamoxifen (such as 5 mg/day) does not affect the drug’s activity on several biomarkers of both cardiovascular and breast cancer risk [5].

Breast cancer and hormone replacement therapy (HRT): collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer

The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed about 90% of the worldwide epidemiological evidence on the relation between risk of breast cancer and use of hormone replacement therapy (HRT). Data on 52,705 women with breast cancer and 108,411 women without breast cancer from 51 studies in 21 countries were collected, checked and analysed centrally. Among current users of HRT or those who ceased use 1–4 years previously, the relative risk of having breast cancer diagnosed increased by a factor of 1.023 (95% confidence interval [CI] 1.011–1.036; 2P = 0.002) for each year of use; the relative risk was 1.35 (95% CI 1.21–1.49; 2P = 0.00001) for women who had used HRT for 5 years or longer (average duration of use in this group 11 years). Five or more years after cessation of HRT use, there was no significant excess of breast cancer overall or in relation to duration of use. There was no marked variation in the results according to hormonal type or dose but little information was available about long durations of use of any specific preparation. Cancers diagnosed in women who had ever used HRT tended to be less advanced clinically than those diagnosed in never-users. In North America and Europe the cumulative incidence of breast cancer between the ages of 50 and 70 in never-users of HRT is about 45 per 1,000 women. The cumulative excess numbers of breast cancers diagnosed between these ages per 1,000 women who began use of HRT at age 50 and used it for 5, 10 and 15 years respectively, are estimated to be 2 (95% CI 1–3), 6 (95% CI 3–9) and 12 (95% CI 5–20). Whether HRT affects mortality from breast cancer is not known.

Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease.

Although childbearing is known to protect against breast cancer, whether or not breastfeeding contributes to this protective effect is unclear. Individual data from 47 epidemiological studies in 30 countries that included information on breastfeeding patterns and other aspects of childbearing were collected, checked, and analysed centrally, for 50302 women with invasive breast cancer and 96973 controls. Estimates of the relative risk for breast cancer associated with breastfeeding in parous women were obtained after stratification by fine divisions of age, parity, and women's ages when their first child was born, as well as by study and menopausal status. Women with breast cancer had, on average, fewer births than did controls (2.2 vs 2.6). Furthermore, fewer parous women with cancer than parous controls had ever breastfed (71% vs 79%), and their average lifetime duration of breastfeeding was shorter (9.8 vs 15.6 months). The relative risk of breast cancer decreased by 4.3% (95% CI 2.9-5.8; p<0.0001) for every 12 months of breastfeeding in addition to a decrease of 7.0% (5.0-9.0; p<0.0001) for each birth. The size of the decline in the relative risk of breast cancer associated with breastfeeding did not differ significantly for women in developed and developing countries, and did not vary significantly by age, menopausal status, ethnic origin, the number of births a woman had, her age when her first child was born, or any of nine other personal characteristics examined. It is estimated that the cumulative incidence of breast cancer in developed countries would be reduced by more than half, from 6.3 to 2.7 per 100 women by age 70, if women had the average number of births and lifetime duration of breastfeeding that had been prevalent in developing countries until recently. Breastfeeding could account for almost two-thirds of this estimated reduction in breast cancer incidence. The longer women breast feed the more they are protected against breast cancer. The lack of or short lifetime duration of breastfeeding typical of women in developed countries makes a major contribution to the high incidence of breast cancer in these countries.

Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58 209 women with breast cancer and 101 986 women without the disease

Women with a family history of breast cancer are at increased risk of the disease, but no study has been large enough to characterise reliably how, over women's lives, this risk is influenced by particular familial patterns of breast cancer. This report, on the relevance of breast cancer in first-degree relatives, is based on combined data from 52 epidemiological studies. Individual data on breast cancer in first-degree relatives (mothers, sisters, and daughters) of 58209 women with breast cancer and of 101986 controls were collected, checked, and analysed centrally. Risk ratios for breast cancer were calculated by conditional logistic regression, stratified by study, age, menopausal status, number of sisters, parity, and age when the first child was born. Breast-cancer incidence and mortality rates for particular family histories were calculated by applying age-specific risk ratios to breast-cancer rates typical for more-developed countries. Altogether 7496 (12.9%) women with breast cancer and 7438 (7.3%) controls reported that one or more first-degree relatives had a history of breast cancer: 12% of women with breast cancer had one affected relative and 1% had two or more. Risk ratios for breast cancer increased with increasing numbers of affected first-degree relatives: compared with women who had no affected relative, the ratios were 1.80 (99% CI 1.69-1.91), 2.93 (2.36-3.64), and 3.90 (2.03-7.49), respectively, for one, two, and three or more affected first-degree relatives (p<0.0001 each). The risk ratios were greatest at young ages, and for women of a given age, were greater the younger the relative was when diagnosed. The results did not differ substantially between women reporting an affected mother (9104) or sister (6386). Other factors, such as childbearing history, did not significantly alter the risk ratios associated with a family history of breast cancer. For women in more-developed countries with zero, one, or two affected first-degree relatives, the estimated cumulative incidence of breast cancer up to age 50 was 1.7%, 3.7%, and 8.0%, respectively; corresponding estimates for incidence up to age 80 were 7.8%, 13.3%, and 21.1%. Corresponding estimates for death from breast cancer up to age 80 were 2.3%, 4.2%, and 7.6%. The age when the relative was diagnosed had only a moderate effect on these estimates. Eight out of nine women who develop breast cancer do not have an affected mother, sister, or daughter. Although women who have first-degree relatives with a history of breast cancer are at increased risk of the disease, most will never develop breast cancer, and most who do will be aged over 50 when their cancer is diagnosed. In countries where breast cancer is common, the lifetime excess incidence of breast cancer is 5.5% for women with one affected first-degree relative and 13.3% for women with two.

Estimation and Inference for Logistic Regression with Covariate Misclassification and Measurement Error in Main Study/Validation Study Designs

In epidemiological studies, continuous covariates often are measured with error and categorical covariates often are misclassified. Using the logistic regression model to represent the relationship between the binary outcome and the perfectly measured and classified covariates, the model for the observed main study data is derived. This derivation relies on the assumption that the error in the continuous covariates is multivariate normally distributed and uses a chain of logistic regression models to describe the misclassification processes. These model assumptions are empirically verified in the validation study, where the misclassified and mismeasured covariates are validated using perfectly measured and classified data. The full data likelihood, including contributions from both the main study and the validation study, is maximized to obtain the maximum likelihood estimates for the parameters of the underlying logistic regression model and of the measurement error model and reclassification models simultaneously. Standard asymptotic theory is applied. An example of this methodology is presented from the Nurses' Health Study investigating the relationship between cumulative incidence of breast cancer and saturated fat, total energy, and alcohol intake. A detailed simulation study was conducted to investigate the small-sample properties of these likelihood-based estimates and inferential quantities. No single estimation/inference option performed satisfactorily when the main study/validation study size was representative of that typically encountered in practice. When the validation size was twice or larger than from the usual one, features of asymptotic optimality were more apparent. By example and through simulation, the procedures appeared to be robust to misspecification of the order of the chain of conditional measurement error/reclassification models.

Breast masses in women treated for childhood cancer: incidence and screening guidelines.

The authors' aims were to define the frequency, characteristics, and methods of detection of breast masses in young women treated for childhood cancer and to develop screening guidelines for the growing population of long term survivors. The authors reviewed medical records of all female patients treated for malignancy at a childhood cancer center over a 34-year period to identify those who developed a breast mass and to determine the cumulative incidence of breast cancer as a second primary cancer. A breast mass was identified in 66 patients who had been diagnosed with a malignancy at a median age of 13.8 years (range, 0.4-24.4 years). Masses were initially detected by breast self-detection in 32 and clinical examination in 28; the method of detection was unknown in 6 cases. Breast lesions were benign in 41 patients and malignant in 26; 1 patient had both a benign and a malignant lesion. Of the 26 malignant masses, 14 represented metastases of the primary malignancy and 12 were primary breast cancers as second primary cancers. The median interval to a primary breast cancer as a second primary cancer was 13.6 years (range, 9.2-24.4 years), and the median age at detection was 27.7 years (range, 12.5-43.1 years). The 25-year cumulative incidence of primary breast cancer as a second primary cancer in this cohort was 1.7% (95% CI, 0.4%-2.9%). This represented a 20-fold increase (95% CI, 10-36) over the expected incidence in age-matched and race-matched controls. Young women treated for childhood cancer have a significantly increased risk of breast cancer compared with age-matched controls. For this group of patients, the authors recommend patient education regarding this risk and the importance of properly conducted self-examination as the foundation of breast cancer screening. In addition, clinical and mammographic screening should be instituted at a younger age and performed more frequently than recommended for the general population of women.

Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer

Background. The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed about 90% of the worldwide epidemiological evidence on the relation between risk of breast cancer and use of hormone replacement therapy (HRT). Methods. Individual data on 52,705 women with breast cancer and 108,411 women without breast cancer from 51 studies in 21 countries were collected, checked, and analysed centrally. The main analyses are based on 53,865 postmenopausal women with a known age at menopause, of whom 17,830 (33%) had used HRT at some time. The median age at first use was 48 years, and 34% of ever-users had used HRT for 5 years or longer. Estimates of the relative risk of breast cancer associated with the use of HRT were obtained after stratification of all analyses by study, age at diagnosis, time since menopause, body-mass index, parity, and the age a woman was when her first child was born. Findings. Among current users of HRT or those who ceased use 1-4 years previously, the relative risk of having breast cancer diagnosed increased by a factor of 1.023 (95% CI 1.011-1.036; 2p = 0.0002) for each year of use; the relative risk was 1.35 (1.21-1.49; 2p = 0.00001) for women who had used HRT for 5 years or longer (average duration of use in this group 11 years). This increase is comparable with the effect on breast cancer of delaying menopause, since among never-users of HRT the relative risk of breast cancer increases by a factor of 1.028 (95% CI 1.021-1.034) for each year older at menopause. 5 or more years after cessation of HRT use, there was no significant excess of breast cancer overall or in relation to duration of use. These main findings did not vary between individual studies. Of the many factors examined that might affect the relation between breast cancer risk and use of HRT, only a woman's weight and body-mass index had a material effect: the increase in the relative risk of breast dancer associated with long durations of use in current and recent users was greater for women of lower than of higher weight or body-mass index. There was no marked variation in the results according to hormonal type or dose but little information was available about long durations of use of any specific preparation. Cancers diagnosed in women who had ever used HRT tended to be less advanced clinically than those diagnosed in never-users. In North America and Europe the cumulative incidence of breast cancer between the ages of 50 and 70 in never-users of HRT is about 45 per 1000 women. The cumulative excess numbers of breast cancers diagnosed between these ages per 1000 women who began use of HRT at age 50 and used it for 5, 10, and 15 years, respectively, are estimated to be 2 (95% CI 1-3), 6 (3-9), and 12 (5-20). Whether HRT affects mortality from breast cancer is not known. Interpretation. The risk of having breast cancer diagnosed is increased in women using HRT and increases with increasing duration of use. This effect is reduced after cessation of use of HRT and has largely, if not wholly, disappeared after about 5 years. These findings should be considered in the context of the benefits and other risks associated with the use of HRT.