Breast cancer is the second most commonly diagnosed form of cancer among U.S. women, according to the National Cancer Institute (NCI), and the second leading cause of cancer deaths in this group. For the year 2003 alone, the NCI estimated more than 212,000 new diagnoses and more than 40,000 deaths from breast cancer. A woman’s risk increases with her age: breast cancer is the most common cause of cancer death after age 65, and nearly half of all breast cancers are found in this age group—a figure that is likely to increase significantly as baby boomers age into the next decade. Plus, black women have the highest death rates from breast cancer. To address these concerns, the NIEHS-sponsored Sister Study plans to explore on a nationwide basis, beginning in October 2004, how genetic and environmental influences may work together to cause breast cancer.The study has been in development since 2001 and under way in pilot form for the past year. A total of 50,000 female volunteers aged 35–74 whose sisters have been diagnosed with breast cancer will be recruited and receive health evaluations over a period of 10 or more years. First-degree relatives, including sisters, have about twice the risk as the average woman of developing breast cancer.Past studies have focused on pesticides, solvents, and electromagnetic fields as possible contributors to breast cancer, but have failed to find consistent links to the disease. Study authors Dale Sandler, chief of the NIEHS Epidemiology Branch, and Clarice Weinberg, chief of the Biostatistics Branch, believe this study—unlike past studies—will be able to effectively characterize levels of a participant’s environmental exposure prior to onset of cancer, a feat that can’t be accurately accomplished retrospectively.Recruiting began in fall 2002 for a pilot phase in four cities—Phoenix, St. Louis, Tampa, and Providence—involving a total of 2,000 participants. “We wanted to go slowly at first,” explains Sandler. The pilot phase gave the researchers time to fine-tune recruiting strategies and data collection methods, arrange for field staff training, and streamline the lengthy questionnaire. The original four cities were chosen for their economic, ethnic, and geographic diversity, Sandler says, and by early 2004 the study spread beyond city limits to encompass the entire states of Arizona, Missouri, Florida, and Rhode Island. In August the study also began recruiting in Illinois, Ohio, Virginia, and North Carolina.Getting adequate participant diversity is important, Sandler says. She believes the study results will be useful to all U.S. women only if a diverse cross-section of women participate. “With a diverse population, we will have a wider range of [health and environmental] exposures, increasing our ability to detect associations,” she says.The original eight states were chosen in part because they had community- and church-based breast cancer awareness programs, heavy minority interest, and what Sandler pragmatically terms “good connections” in both public and private sectors. “Our contacts in the breast cancer advocacy community help with grassroots recruitment,” she says.Participants receive a welcome kit by mail with instructions on how to prepare for the study. A staff member calls first to walk the participant through the kit and later to conduct the survey, which takes about two hours. Next, independent phlebotomists working under contract to the NIEHS make home visits to draw blood samples, collect household dust samples and toenail clippings, and take blood pressure, weight, height, and body measurements.“Even though it’s an enormous national study, we’re doing everything we can to make it as personal as possible,” Sandler says. “We want to make sure that the women get something back, thus we have a duty to let them know what we learn from the study. We plan to contact them regularly over the years with news from the study.”Sandler and Weinberg will closely evaluate the expected 1,500 women who will develop breast cancer within five years of the study’s start, analyzing environmental, genetic, and health data captured from the very beginning. “We’ve learned what works [in terms of study design and implementation], and what doesn’t,” Sandler says. “We’re ready.”


The purpose of this report was to classify mammograms according to four methods and to examine their agreement and their relationship to selected risk factors for breast cancer.Mammograms and epidemiological data were collected from 987 women, aged 55 to 71 years, attending the Norwegian Breast Cancer Screening Program. Two readers each classified the mammograms according to a quantitative method (Cumulus or Madena software) and one reader according to two qualitative methods (Wolfe and Tabár patterns). Mammograms classified in the reader-specific upper quartile of percentage density, Wolfe's P2 and DY patterns, or Tabár's IV and V patterns, were categorized as high-risk density patterns and the remaining mammograms as low-risk density patterns. We calculated intra-reader and inter-reader agreement and estimated prevalence odds ratios of having high-risk mammographic density patterns according to selected risk factors for breast cancer.P < 0.05). After adjustment for percentage density, the Wolfe classification was not associated with any of the risk factors for breast cancer, whereas the association with number of children and BMI remained statistically significant for the Tabár classification. Adjustment for Wolfe or Tabár patterns did not alter the associations between these risk factors and percentage mammographic density.The Pearson correlation coefficient was 0.86 for the two quantitative density measurements. There was moderate agreement between the Wolfe and Tabár classifications . Age at screening, number of children and body mass index (BMI) showed a statistically significant inverse relationship with high-risk density patterns for all four methods (all The four assessments methods seem to capture the same overall associations with risk factors for breast cancer. Our results indicate that the quantitative methods convey additional information over the qualitative methods. Different measures of mammographic images or density patterns -5 have bThe first qualitative classification of mammographic density patterns was described by Wolfe in 1976 . Wolfe aThe percentage density methods and the Wolfe patterns have consistently been shown to be strongly related to breast cancer risk in different populations ,15,25-29The Mammography and Breast Cancer Study is a research project using mammographic density patterns as surrogate endpoints for breast cancer among postmenopausal women attending the Norwegian Breast Cancer Screening Program in Tromsø. The purpose of this study was to classify mammograms according to four methods and to examine their agreement and their relationship to selected risk factors for breast cancer.The study was conducted during 15 and 17 consecutive weeks in spring 2001 and 2002, respectively. In brief, women residing in the municipality of Tromsø, aged 55 to 71 years, attending the Norwegian Breast Cancer Screening Program at the University Hospital of North Norway were eligible. After giving informed consent, the study subjects were interviewed by a trained nurse about their current and previous postmenopausal hormone therapy use, reproductive and menstrual factors, previous history of cancer, and smoking status. The participants had their height measured to the nearest centimeter and weight to the nearest half kilogram. Waist and hip circumferences were measured in a standardized way to the nearest centimeter. In 2001, the women were asked to complete a four-page questionnaire at home. The questionnaire elicited information on demographic, menstrual and reproductive factors, as well as lifestyle and dietary factors. In 2002, another four pages with questions about diet were added. The National Data Inspection Board and the Regional Committee for Medical Research Ethics approved the study. Appropriate measures were taken to ensure confidentiality of the data. Altogether, 1,041 women entered the study. This accounted for 70.1% of the women attending the breast cancer screening program.We excluded 22 women with a new or previous breast cancer diagnosis, 1 currently using chemotherapy, and 31 lacking classification from one of the three readers, leaving 987 women for analysis. Women were classified as postmenopausal if they were 56 years or older or reported having had no period during the last 12 months, or if the serum follicle-stimulating hormone level was above 20 IU/L. By these criteria three women were equivocal for menopausal status. Excluding these women did not alter the results, and they were included as postmenopausal. The readers were blinded to all characteristics of the study subjects. A total of 21 mammograms were marked as difficult to read by at least one of the readers. We reran all analyses without these mammograms, but the results were essentially the same. The 987 mammograms that were read four times were used in the analyses presented in this paper.For the computer-assisted density assessments, we digitized the left cranio-caudal using both a Kodak LS-85 X-ray digitizer (reader GM) with a pixel size of 260 μm  and an older version of the Cobrascan scanner (Cobrascan CX 312-T) from Radiographic Digital Imaging  at a resolution of 150 pixels per inch (reader GU). Reader GM used the Cumulus software from Canada , and reaThe experienced radiologist (NB) , classifThirty-seven randomly selected mammograms were mixed and read blindly a second time by the three readers; the readings were 3 months apart for readers GM and NB and 18 months apart for reader GU. Subsequently, reader GU reread the dense area on a subset of 189 mammograms that had been scanned for reader GM. We calculated the percentage density from both the new and old dense area readings by reader GU.We calculated the Pearson's correlation coefficient and the crude and weighted Kappa statistics to test the intra-reader and inter-reader reliabilities for the mammographic readings. The Kappa coefficient does not require any assumption about 'correct' categorization and includes a correction for the amount of agreement that would be expected by chance alone. A Kappa of 0% indicates that the agreement between two measurements is no greater than would be expected by chance. Kappa values of 50% or more indicate moderate agreement, 60 to 80% good agreement, those over 80% very good agreement, and those over 90% excellent agreement .We calculated the median percentage density for the four Wolfe and five Tabár pattern categories for each of the two readers. Similarly, we categorized the mammograms according to reader-specific quartiles with the corresponding proportion of high-risk versus low-risk Wolfe and Tabár patterns for the different quartiles. We also estimated prevalence odds ratios of having high-risk mammographic density patterns with 95% confidence intervals (CI) to express the degree of association between selected risk factors for breast cancer and the mammographic density patterns. Each of the following factors was evaluated as a potential confounder of the relation between the factor of interest and mammographic patterns: age , age at menarche , age at menopause , number of children , age at first birth  and body mass index (BMI (defined as weight in kilograms divided by the square of the height in meters) less than 25.0, 25.0 to 29.9, 30.0 or more).P value was 0.05 or less. We performed data management and statistical analyses with the SAS statistical software package, version 8.2  [We performed multivariate analyses with models that included all the above listed variables as independent variables and the high-risk density patterns according to each of the four readings as the dependent variable. Subsequently, we reran the models with the Wolfe and Tabár patterns as outcome variables adjusting for percentage density from each of the two readers as a continuous variable. Similarly, we adjusted the models with percentage density as outcome variable for the two categories of Wolfe and Tabár patterns. Statistical trend tests were obtained by creating an ordinal exposure variable with equally spaced scores and including it in the logistic regression model. Results were considered as statistically significant if the two-sided NC, USA) .Table The Pearson correlation coefficient was 0.93 and 0.86 for the repeated quantitative readings conducted 3 months (GM) and 18 months (GU) apart, respectively. The intra-rater agreement for the upper reader-specific quartile versus the three lower quartiles was moderate for reader GM  and reader GU . For reader NB the intra-reader agreement was good for the Wolfe classification  and very good for the Tabár classification . The Pearson correlation coefficient was 0.86 for the two original percentage density readings and 0.93 for the subset of 189 mammograms. Both the agreements between the reader-specific upper quartiles  and between all four quartiles  were good. The agreement between high-risk and low-risk Wolfe and Tabár patterns was moderate .Table P = 0.07) and the Wolfe classification (P = 0.05)).Table None of the associations displayed in the table between risk factors and the two quantitative readings changed when adjusted for the Wolfe or Tabár classification.P = 0.14), number of children (P = 0.54) and BMI (P = 0.57) were no longer associated with the Wolfe classification. The association between age (P = 1.0) and the Tabár classification disappeared, whereas the inverse association with number of children (P < 0.05) and BMI (P < 0.03) remained statistically significant after adjustment for percentage density.After adjustment for percentage density as assessed by either reader, age at entry . The mammograms in this study were rather dark, and differences in the appearance of the mammographic images due to the properties of the scanners did lead to variations in defining both areas. The two readers have both trained with Dr NF Boyd in Canada and have also worked together on previous studies ,36. NeveThe Kappa values for inter-rater agreement in our study are of the same magnitude as or better than those found in several other studies examining different kinds of mammographic reading. Venta and colleagues found a Kappa value of 0.46 for density measurements on X-ray and digital mammograms recorded by two radiologists . In a prOur results are in agreement with a recent study describing that the Wolfe pattern classification was redundant when percentage density was available as a measure for breast cancer risk . In contThe present results are in agreement with studies finding no associations between ages at menarche  and menoOur study has several strengths. It was a part of a population-based screening project with a high attendance rate. The three readers were experienced and blinded to the risk factors. A study from the Finnish screening program using the Wolfe classification showed that at younger ages there was a greater probability of misclassification from low-risk to high-risk and at older ages there was a greater probability of misclassification from high-risk to low-risk . BecauseThe high-risk classification of mammograms varied to some extent according to the four assessment methods commonly used previously. Our results indicate that the quantitative methods convey additional information over the qualitative methods. Quantitative measures should therefore be preferred when high-risk density patterns are used as surrogate endpoints in etiologic research, clinical or preventive trials. The difference between Tabár and Wolfe categories in relation to breast cancer risk and quantitative density assessment needs to be investigated further. Once breast cancer screening programs start to use digital mammograms, a quantitative method may become usable also in large-scale screening programs.BMI = body mass index; CI = confidence interval; OR = odds ratio.The authors declare that they have no competing interests.ITG conceived the study, had full access to all of the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analyses. Classification of mammograms was performed by NB, GM and GU. Analysis and interpretation of data were performed by ITG, YB, GU, GM and EL. ITG and YB drafted the manuscript. ITG, YB, NB, GU, GM and EL revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.


A consecutive series of 644 women who presented with breast nodularity between 1976 and 1982 have been followed up to determine their rate of subsequent breast cancer. Fifteen women have developed breast cancer, 14 of these were among 352 women with an aspirated cyst (relative risk 4.4). Women with multiple cysts had the highest risk and women with breast nodularity had no excess risk. Review of histology specimens from those women who had undergone biopsy showed an excess of florid epithelial hyperplasia in women who subsequently developed breast cancer and women with multiple aspirated cysts were more likely to have florid epithelial hyperplasia. Multiple cysts are clinical markers of histological breast proliferation and women who have had multiple breast cysts aspirated have an increased risk of breast cancer and should be advised to practice regular self examination.


Mechanic LE, Millikan RC, Player J, de Cotret AR, Winkel S, Worley K, et al. 2006. Polymorphisms in nucleotide excision repair genes, smoking and breast cancer in African Americans and whites: a population-based case–control study. Carcinogenesis 27:1377–1385.Previous research has established cigarette smoking as a risk factor for a number of cancers, including those of the lung, pancreas, and head and neck. A link between cigarette smoking and breast cancer is not as clear; however, scientists do know that breast cancer occurs at different rates in different racial groups. In this paper, NIEHS grantee Robert C. Millikan of the University of North Carolina at Chapel Hill and his colleagues document findings suggesting that specific combinations of polymorphisms on certain nucleotide excision repair (NER) genes may modify the risk of breast cancer in black women who smoke.NER is the primary means by which smoking-induced DNA damage is repaired. There are several known polymorphisms on genes involved in NER. These investigators conducted a genetic epidemiologic study aimed at determining whether such polymorphisms alter the association between smoking and breast cancer.The investigators analyzed exposure histories and DNA samples extracted from peripheral blood lymphocytes of 3,863 women  aged 21 to 74. The women were participating in the Carolina Breast Cancer Study, a large population-based case–control study of breast cancer in North Carolina. Next the investigators calculated odds ratios for breast cancer and smoking and for breast cancer and nine polymorphisms on six NER genes. Then they examined how odds ratios for smoking were modified by single and combined NER genotypes.In general, they found, smoking was more strongly associated with breast cancer in black women than in white women. The association increased even more for black women with particular patterns of polymorphisms when combined with different smoking characteristics including amount of smoking, duration, time since smoking cessation, age at smoking initiation, and being a former smoker. No interactions were seen in white women.The investigators believe this is the first study to examine multiple NER polymorphisms together as susceptibility factors for breast cancer in combination with smoking. Further studies with larger numbers of participants are needed to confirm these results.


A seasonal variation in the month of initial detection of breast cancer has been previously observed in pre-menopausal women, and it has been proposed that this may be due to cyclic changes in tumour growth mediated by the effects of melatonin on ovarian function. To investigate this possibility serum melatonin concentrations have been measured every 2 h for 24 h at the summer and winter solstice in 20 pre-menopausal women with previous breast cancer and nine controls. Twelve women had detected their tumour in winter and eight in summer. Overall melatonin secretion assessed by either amplitude of the nocturnal melatonin pulse or the area under the 24 h melatonin curve (AUC) was not different between breast cancer women or controls. However, the amplitude and AUC fell in winter in breast cancer patients , whereas the winter minus summer values were significantly positive in controls compared with cancer patients. The abnormal fall in winter values in the women with previous breast cancer was confined to the group of women who had been winter detectors  whereas there was no significant seasonal alteration in these measurements in summer detectors. The acrophase of the nocturnal pulse of serum melatonin was significantly advanced in both groups of women with previous breast cancer  with a similar although nonsignificant trend in control women. The abnormal reduction of serum melatonin seen in wintertime in winter detectors of breast cancer could promote tumour growth at this season and so contribute to the decreased survival previously observed in this group compared with summer detectors. The relatively normal seasonal profile of melatonin observed in summer detectors could allow increased ovarian steroidogenesis in spring/summer with a resulting increase in tumour growth and consequent rise in tumour detection rate at this time.


BRCA1 or BRCA2.Several anthropometric measures have been found to be associated with the risk of breast cancer. Current weight, body mass index, and adult weight gain appear to be predictors of postmenopausal breast cancer. These factors have been associated with a reduced risk of premenopausal breast cancer. We asked whether there is an association between changes in body weight and the risk of breast cancer in women who carry a mutation in either breast cancer susceptibility gene, BRCA1 (n = 797 pairs) or BRCA2 (n = 276 pairs). Women diagnosed with breast cancer were matched to control subjects by year of birth, mutation, country of residence, and history of ovarian cancer. Information about weight was derived from a questionnaire routinely administered to women who were carriers of a mutation in either gene. Conditional logistic regression was used to estimate the association between weight gain or loss and the risk of breast cancer, stratified by age at diagnosis or menopausal status.A matched case–control study was conducted in 1,073 pairs of women carrying a deleterious mutation in either BRCA1 mutation carriers who had at least two children, weight gain of more than 10 pounds between age 18 and 30 was associated with an increased risk of breast cancer diagnosed between age 30 and 40 . Change in body weight later in life (at age 30 to 40) did not influence the risk of either premenopausal or postmenopausal breast cancer.A loss of at least 10 pounds in the period from age 18 to 30 years was associated with a decreased risk of breast cancer between age 30 and 49 (odds ratio (OR) = 0.47; 95% confidence interval (CI) 0.28–0.79); weight gain during the same interval did not influence the overall risk. Among the subgroup of BRCA-associated breast cancers. Weight gain should also be avoided, particularly among BRCA1 mutation carriers who elect to have at least two pregnancies.The results from this study suggest that weight loss in early adult life (age 18 to 30) protects against early-onset  BRCA1 or BRCA2, has been associated with a lifetime risk of breast cancer of 45% to 87% [BRCA1 and BRCA2 mutation carriers, and many implicate estrogen-induced stimulation as a probable contributor . Genetiiewed in , as welliewed in -13. Non-iewed in ). Reprodiewed in ).BRCA-carcinogenesis and the current chemopreventive options available for BRCA carriers are based on the interruption of the estrogen-signalling pathway .BRCA carriers. We performed a matched case–control study to investigate whether or not there is an association between changes in body weight and the risk of breast cancer in women with a deleterious BRCA1 or BRCA2 mutation. The identification of non-genetic modifiers of risk may be useful for preventing hereditary breast cancer.Studies are needed to determine if the known anthropometric risk factors for sporadic breast cancer may also influence the penetrance of breast cancer in BRCA1 or BRCA2 gene. These women were identified from 41 participating centers in five countries and were participants in previous and ongoing clinical research protocols at the host institutions. All study subjects received counselling and gave their written informed consent for genetic testing.Eligible study subjects included women who were alive and known to be carriers of deleterious mutations of the BRCA1 or BRCA2 mutation was identified in a proband or her relative, genetic testing was offered to other at-risk women in the family. Mutation detection was performed using a range of techniques, but all nucleotide sequences were confirmed by direct sequencing of DNA. A woman was eligible for the current study when the molecular analysis established that she was a carrier of a pathogenic mutation. Most (>95%) of the mutations identified in the study subjects were nonsense mutations, deletions, insertions, or small frameshifts.The study was approved by the institutional review boards of the host institutions. In most cases, testing was initially offered to women who had been affected with breast or ovarian cancer. When a BRCA1 or BRCA2 mutations and who provided information on weight at ages 18, 30, and 40. Potential case subjects were selected from among the study subjects with a diagnosis of invasive breast cancer. Case subjects were excluded if they had been diagnosed with ovarian cancer (29 women) or any other form of cancer (28 women) before being diagnosed with breast cancer, or if information about their menopausal status was missing (31 women). Control subjects were women who had never had breast cancer and who were carriers of a mutation in the BRCA1 or BRCA2 gene. A subject was not eligible to be a control for a given case subject if she had had a protective bilateral mastectomy before the date of diagnosis in the case (88 women). After exclusions, there was a total of 3,115 eligible women, including 1,471 women with breast cancer  and 1,644 women without breast cancer .There was information on cancer history and mutation carrier status for a total of 3,291 women who carried BRCA1 or BRCA2), year of birth (within 1 year), and the country of residence. A diagnosis of ovarian or other form of cancer in the control had to be after the year of diagnosis of breast cancer of the matched case subject for her to be eligible. In addition, the date of interview of the control was after the date of breast cancer diagnosis of the matched case. A total of 1,073 matched case–control pairs was generated for the analysis, including 797 pairs with BRCA1 mutations and 276 pairs with BRCA2 mutations. The 2,146 study subjects included in the analysis were identified from 1,534 distinct families (1.4 subjects per family). In the instance of 1,179 subjects, the subject was the only member of the family to be included. These were prevalent cases and had breast cancer before they knew their mutation status. On average, 8.8 years had passed between the subject's age at diagnosis (mean 39.8 years) and age at interview (mean 48.6 years).A single control subject was selected for each case subject, matched according to mutation in the same gene  and weight (in pounds). The participants were requested to think back to when they were 18 years old (about the time they graduated from high school) and to recall their weight then and subsequently at ages 30 and 40. Women were asked to report their weight at birth, their current weight, and their height, as well as the most they had ever weighed (excluding pregnancy). Only case and control data before the time of the diagnosis of breast cancer in the matched case were considered.2)) at ages 18, 30, and 40 years, and weight change between age 18 and 30 and between 30 and 40 .We converted the reported weights from pounds to kilograms and the heights from inches to meters for BMI calculations. Variables that were created in this study included BMI (weight (kg)/height, 95% confidence intervals (CIs), and tests for linear trend were estimated by use of conditional logistic regression. A multivariate analysis was also carried out to control for the potential confounding effects of oral contraceptive use, smoking, oophorectomy, and parity. Smoking use was coded as 'ever' or 'never' smoker; oral contraceptive use was coded as 'ever' or 'never' user; oophorectomy was coded as yes or no; and parity was coded as zero, one, or two or more births. Weight change was categorized into quartiles according to the distribution of the variables among the controls.A matched case – control analysis was performed to examine the association between weight and changes in body weight, and the risk of breast cancer. Because menopausal status has been shown to modify the association between anthropometric factors and the risk of breast cancer, our analyses were stratified according to menopausal status at the time the subject received a diagnosis of breast cancer diagnosis. Birthweight, height, weight, weight gain, and BMI were compared between the case subjects and control subjects within each stratum, using a paired P value of <0.05 was taken to be significant. All analyses were performed using the SAS statistical package, version 8.1 .The reference group were those women whose weight remained stable (weight gain or loss of not more than 10 pounds from baseline). The weight-loss group included women who lost at least 10 pounds. We examined the effect of weight change between ages 18 and 30 and between ages 30 and 40 among subgroups defined according to the subject's age at diagnosis of the case. This effect was further evaluated according to mutation and menopausal status. There were 26 menopausal case subjects who reported having had a hysterectomy before their breast cancer had been diagnosed but who still had intact ovaries. These 26 pairs were excluded from the subanalyses stratified by menopausal status. Odds ratios were generated for these subgroups with the matched-pair subsets. All statistical tests were two-sided. A P = 0.04), and parity was also slightly higher in the case than control subjects (P = 0.06).Case and control subjects were similar with regard to year of birth, year of interview, current age, mutation status, smoking history, and country of residence Table . Oral coTable P = 0.0001, 0.02, and 0.02, respectively).The extent of weight gain experienced by our study subjects varied according to their year of birth Fig. . Those bTo further examine the relationship between adult weight change and the risk of breast cancer, we performed univariate conditional logistic regression. The adjusted ORs were similar to the unadjusted values; therefore, only univariate results are reported here. As Table BRCA mutation status showed that among women with a BRCA1 mutation, weight loss of at least 10 pounds was associated with a 65% reduction in cancer risk compared with women in the reference group (OR = 0.35) .Subgroup analyses according to 5) Table . A modesBRCA1 mutation carriers who lost more than 10 pounds was 142.5 pounds (range 115 to 230 pounds). These women experienced a mean weight loss of 18.6 pounds (range 10 to 86 pounds) between age 18 and 30. Forty percent of these women had a mean baseline weight greater than 150 pounds and 35% had a BMI greater than 25.The mean baseline weight (weight at age 18) of the per se was associated with weight gain, we compared mean weight gain among the carriers, according to parity. The mean weight gain across the groups was similar (data not shown). Therefore, the increased risk of breast cancer associated with parity and any weight gain is not attributable to greater weight gain among those who had higher parity. A modifying effect of parity and weight gain was not seen among women with a BRCA2 mutation . A large proportion of the group who experienced weight loss had a baseline BMI of greater than 25, the BMI cut-point for the classification of overweight individuals [We conducted our study to examine whether change in body weight modifies the risk of breast cancer among women who carry a deleterious ividuals . This suBRCA-associated breast cancers is young age at diagnosis [The role of early adult weight gain and subsequent risk of breast cancer is not well defined. The majority of studies report either no association or a decrease in risk with weight gain for premenopausal women, and inconsistent results for postmenopausal women ,21. It hiagnosis .BRCA carriers, changes in body weight throughout early adult life may have a more important influence on the risk of early-onset breast cancer than current weight or BMI [BRCA2 mutation. These findings suggest that the timing of weight loss may play a more important role in BRCA1-associated than in BRCA2-associated carcinogenesis, though the lack of a significant finding for the latter group might also be attributable to a smaller sample size. The effect may be of greater importance for women belonging to more recent birth cohorts, since there appears to be a greater increase in average weight at ages 30 and 40 with each decade  may be attributed to host metabolic factors that may also influence breast cancer risk . In addiBRCA1 and/or BRCA2 carriers [BRCA1 and BRCA2 carriers; however, such an effect could be attributable to either weight gain increasing the risk of early-onset breast cancer or to weight gain protecting against late-onset breast cancer [BRCA1 carriers found no significant effect of current BMI on the age at disease onset; however, the sample size was small [Only two studies have evaluated the association between anthropometric risk factors or physical activity and the risk of breast cancer in carriers ,38. Kingt cancer . An earlBRCA carriers, weight gain did not affect the risk of breast cancer.The role of sex hormones in the etiology of breast cancer has been well established . It is gOther metabolic consequences of obesity, more specifically central adiposity, that have been suggested to be factors in the development of breast cancer include hyperinsulinemia and insulin resistance, as well as elevated levels of glucose and triglycerides -50. ObesHigh concentrations of circulating insulin-like growth factor1 (IGF-1) appears to be a risk factor for premenopausal breast cancer in the general population, yet no such relation has been observed for postmenopausal breast cancer . StudiesBRCA mutation carriers. Current height was not associated with the risk of breast cancer, and this observation is in agreement with a pooled analysis of 52 epidemiological studies whereas height did not modify risk in women who had one or more affected first-degree relatives in comparison with women who had no affected relatives [Both birthweight ,62 and helatives .BRCA1 and BRCA2 carriers argues against recall bias.A potential drawback of our study was the use of self-reported risk factor data, which may have introduced measurement error and led to a spurious result or attenuation of results. However, validation studies have shown that current and recalled self-reported weight and height measurements are highly correlated with measured data -72. SelfBRCA mutation carriers. This study involved 1,073 matched pairs selected from a total of approximately 3,291 documented mutation carriers and is by far the largest study addressing the role of anthropometric measures on the risk of hereditary breast cancer. Our matching strategy and exclusion criteria resulted in case and control groups that were similar in most respects. We believe that our study participants are representative of women who have had BRCA mutations identified during the course of genetic counselling. Our study was based on known mutation carriers and included patients from numerous participating centers and of different ethnic backgrounds.Despite the primary limitation of recall bias and other inherent limitations associated with the use of case–control studies, the primary strength of our study is the large sample of known per se) decreases the risk of BRCA-associated breast cancer diagnosed at an early age. More specifically, the period between age 18 and 30 years appears to be a critical one when weight gain should be avoided in mutation carriers. The effect may be greatest in BRCA1 carriers experiencing at least two full-term pregnancies, but further study is necessary to confirm this subgroup analysis. The maintenance of a healthy weight during early adult life represents a potentially modifiable risk factor in hereditary breast cancer syndromes.Our findings suggest that weight loss in early adult life (and not weight BRCA1 = breast cancer susceptibility gene 1; BRCA2 = breast cancer susceptibility gene 2; CI = confidence interval; IGF-1 = insulin-like growth factor 1; OR = odds ratio.The authors declare that they have no competing interests.SAN conceived and designed the study. JK drafted the manuscript and helped with the analysis. PS performed the statistical analysis. OIO, PG, JL, HTL, CI, BW, CK-S, PA, WDF, and AI coordinated study activities for their centers and helped with the preparation of the manuscript. All authors read and approved the final version of the manuscript.


It has been suggested that hormonal risk factors act predominantly on estrogen receptor and progesterone receptor (ER/PR)-positive breast cancers. However, the data have been inconsistent, especially in younger women.+PR+ with ER-PR- case patients.We evaluated the impact of age at menarche, pregnancy history, duration of breastfeeding, body mass index, combined oral contraceptive use, and alcohol consumption on breast cancer risk by ER/PR status in 1,725 population-based case patients and 440 control subjects aged 20 to 49 years identified within neighborhoods of case patients. We used multivariable unconditional logistic regression methods to conduct case–control comparisons overall as well as by ER/PR status of the cases, and to compare ER+PR+ breast cancer (ptrend = 0.005), whereas recent average alcohol consumption was associated with an increased risk of ER+PR+ breast cancer (ptrend = 0.03). Neither of these two factors was associated with the risk of ER- PR- breast cancer. Late age at menarche and a longer duration of breastfeeding were both associated with decreased breast cancer risk, irrespective of receptor status .The number of full-term pregnancies was inversely associated with the risk of EROur results suggest that the number of full-term pregnancies and recent alcohol consumption affect breast cancer risk in younger women predominantly through estrogen and progesterone mediated by their respective receptors. Late age at menarche and breastfeeding may act through different hormonal mechanisms. Results from studies of young women under the age of 50 years [+PR+ and ER- PR-) in a large study of women aged 20 to 49 years, using both case–control and case–case comparisons.It has been well documented that estrogen and progesterone are important in breast tumorigenesis -3, and t50 years -21 or pr50 years ,22 are en = 428), no longer living in Los Angeles County (n = 37), inability to be located (n = 88), death (n = 38), serious illness or disability (n = 18), physician refusal (n = 50), or inability to schedule the interview within 18 months of diagnosis (n = 429). We successfully interviewed 1,794 (62%) eligible case patients .Case patients were identified through the Los Angeles County Cancer Surveillance Program (CSP), the population-based cancer registry that is part of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) cancer registry program. Eligible case patients were US-born English-speaking, white (including Hispanic) or African-American, female residents of Los Angeles County aged 20 to 49 years when diagnosed with histologically confirmed first primary invasive breast cancer. We identified 2,882 eligible case patients . White patients were diagnosed between February 1998 and May 2003 and African-American patients were diagnosed between January 2000 and May 2003. We were unable to interview 1,088 of the 2,882 eligible case patients (38%) because of patient refusal , no longer living in Los Angeles County (n = 18), death (n = 1), serious illness (n = 2), or inability to schedule the interview within 18 months from the date of initial household contact (n = 61). We successfully interviewed 444 (74%) of eligible control subjects . On average, 20 houses were canvassed to find an eligible control subject who agreed to be interviewed.Because this study was originally designed as a case–case study to examine genetic risk factors for breast cancer, we did not collect control subjects for all case patients. The control subjects who were recruited were matched by race and age (within 5 years and aged 20 to 49 years) to a subset of case patients who were diagnosed between July 2000 and March 2003. Control subjects were US-born English-speaking white or African-American women who had never been diagnosed with invasive or  studies ,24. FielAll participants were interviewed in person with the use of a structured questionnaire, which was a modified version of the questionnaire used for the Women's Contraceptive and Reproductive Experiences (CARE) Study . Our que+PR+, 92 (6%) were ER+PR-, 41 (3%) were ER- PR+, and 405 (29%) were ER- PR- .Information on ER and PR status for interviewed case patients was obtained from the CSP. Among the 1,794 case patients, 1,510 (84%) had information on both ER and PR status; 91 of these were reported as weakly or borderline positive (84 cases) or undecided (7 cases) for either ER or PR. Among the other 1,419 case patients, 881 (62%) were ERF tests for differences in means and Pearson χ2 tests for differences in frequency distributions. When the two-sided p value comparing all three groups was less than 0.05, we also performed pairwise comparisons by using Bonferroni t tests or Pearson χ2 tests, imposing a Bonferroni correction to the p value, restricting the overall type I error to 5% by setting as statistically significant only two-sided p values less than 0.017 for each pairwise comparison [We compared demographic and hormone-related risk factors among case patients with known ER and PR information, borderline positive or undecided results, and patients without ER or PR information, with the use of mparison .2) one year before the participant's reference date, duration of combined oral contraceptive (COC) use, alcohol drinking status during reference age , and the average number of alcoholic drinks per week in the 5-year period that ended 2 years before the reference age. One alcoholic drink was defined as 12 ounces (355 ml) of beer, 4 ounces (118 ml) of wine, or 1.5 ounces (44 ml) of liquor.Analyses were conducted to assess the association between breast cancer and the following factors: age at menarche, number of full-term (greater than 26-week gestation) pregnancies, age at first full-term pregnancy (defined for each woman as the age at which that pregnancy ended), duration of breastfeeding, body mass index  and 95% confidence intervals (CIs). Tests for trend were conducted by fitting ordinal values corresponding to categories of exposure in our models and testing whether the coefficient (slope of the dose response) differed from zero.We conducted case–control comparisons for overall, ERgression  to compaapproach  for the 2), COC use , the average number of alcoholic drinks per week in the recent 5 years , and a three-category variable combining menopausal status and hormone therapy use . When estimating the effects of parity or restricting analyses to parous women, we did not include gravidity in our models. A single model was fitted to assess the joint effects of age at first full-term pregnancy  and breastfeeding duration  among parous women. All variables were included as categorical variables in the models. In reporting the results of trend tests, we considered a two-sided p value of less than 0.05 as statistically significant. All analyses were performed with the SAS statistical package .Adjustment was made for race , age , and education  in all our models. Additionally, multivariable models included variables selected a priori as potential confounders: first-degree family history of breast cancer , age at menarche , gravidity , number of full-term pregnancies , BMI 1 year before reference date .To maintain a constant sample size for all analyses, we excluded 69 case patients and 4 control subjects for the following reasons: missing information on educational attainment (15 cases and 1 control), age at menarche (3 cases), parity (4 cases and 1 control), duration of breastfeeding (6 cases), BMI (4 cases), duration of COC use (17 cases and 1 control), recent alcohol consumption (14 cases); missing information on two or more of these factors (6 cases and 1 control). This resulted in 1,725 case patients and 440 control subjects available for the overall case–control analyses. Among the 1,725 case patients, 1,449 (84%) had information on both ER and PR status; 83 of these were reported as weakly, borderline positive or undecided for either ER or PR and were excluded from the analyses by receptor subtypes. Among the other 1,366 case patients, 63% were ERgistries ,28. In aAs described above, our control subjects were identified through matching to a subset of the cases. An alternative to conditional logistic regression in matched studies with disproportionate numbers of cases and controls is to break the match and conduct unconditional logistic regression with detailed adjustment for the matching factors . We condpF test = 0.0001), education level ( = 0.01), age at first full-term pregnancy (pF test = 0.002), and percentage of case patients who ever breastfed ( = 0.01) differed across the three case groups. Pairwise analyses revealed that the differences were between case patients with known ER/PR status and those without ER/PR information. In comparison with case patients without ER/PR information, case patients with known ER/PR status were on average 1.5 years younger at diagnosis (pt test <0.0001), better educated ( = 0.001), on average 1.8 years older at first full-term pregnancy (pt test = 0.001), and had a higher percentage of case patients who had breastfed ( = 0.004).Table ptrend≤ 0.008; Table +PR+ case patients, ER- PR- case patients, and all case patients combined. The associations with age at menarche did not differ between ER+PR+ and ER- PR- case patients (ptrend = 0.85).Age at menarche was negatively associated with breast cancer risk regardless of ER/PR status . Parous women who had four or more full-term pregnancies had an approximately 50% reduction in the risk of ER+PR+ breast cancer compared with women who never had a full-term pregnancy. ER+PR+ case patients were less likely to have had many full-term pregnancies than ER- PR- case patients (ptrend = 0.09).A protective effect of parity was confined to women with ERer Table . The OR +PR+ breast cancer and a reduced risk for ER- PR- breast cancer was observed with increasing age at first full-term pregnancy, but none of the confidence limits for the risk estimates excluded 1.0 and no linear trend in risk was observed for either cancer type .A slight increase in risk for ERptrend≤ 0.03; Table ptrend = 0.63).Duration of breastfeeding was negatively associated with breast cancer risk regardless of ER/PR status  but was not associated with ER- PR- breast cancer (Table +PR+ breast cancer (ptrend = 0.08) but not ER-PR- breast cancer (ptrend = 0.54). In comparison with premenopausal women who had a low BMI (less than 25 kg/m2), the OR among premenopausal women in the highest BMI category (at least 35 kg/m2) was 0.58 (95% CI 0.34 to 1.00) for ER+PR+ breast cancer and 1.07 (95% CI 0.58 to 1.97) for ER- PR- breast cancer. ER+PR+ case patients were less likely to have had a higher BMI than ER- PR- case patients (ptrend = 0.005).Increasing BMI was associated with a non-statistically significant decreasing risk of ER+PR+ or ER-PR- breast cancer  but a lower OR of ER+PR+ breast cancer  compared with never users. ER+PR+ case patients were less likely to have had longer duration of COC use than ER- PR- case patients (ptrend = 0.008).COC use was not associated with risk of either ERer Table . Women w+PR+ breast cancer (ptrend = 0.03), weakly associated with all types of cancer together (ptrend = 0.12), and not associated with ER- PR- breast cancer (ptrend = 0.42). Overall, ER+PR+ case patients seemed more likely to have drunk larger quantities of alcohol than ER- PR- case patients, but the difference was not statistically significant (ptrend = 0.23).Alcohol drinking status during reference age was not associated with breast cancer risk Table . HoweverOverall in this study of women under age 50 years, we found associations that differed by ER/PR status for the number of full-term pregnancies, recent alcohol consumption, and possibly age at first full-term pregnancy and BMI. Risk reductions associated with late age at menarche and long duration of breastfeeding did not differ by ER/PR status. COC use was not associated with breast cancer risk in this study.+PR+ breast cancer in our study is similar to that observed in a previous study of young women [+PR+ cancer for women having three or more live births compared with nulliparous women) [The magnitude of the protective effect from multiple full-term pregnancies for ERng women , smallers women) , and gres women) ,20. A grs women) , therebys women) .Our results on age at first full-term pregnancy are consistent with the bulk of the evidence that early age at first full-term pregnancy is not a strong protective factor in young women. This may be due to a transient increase in breast cancer risk after pregnancy . However+PR+ breast cancer but not ER- PR- breast cancer [+PR+ breast cancer, which did not quite reach statistical significance. A possible mechanism that would explain a protective effect of BMI on receptor-positive tumors is that high BMI results in anovulatory menstrual cycles with reduced exposure to ovarian hormones [Five previous studies have examined the effect of BMI according to ER/PR status among young ,20 or prt cancer ,22. The t cancer ,20,33. Ohormones ,35.+PR+ cancer, which was not statistically significant, for women at the highest category of alcohol consumption versus women who had never drunk alcohol [+PR- subtype [+PR+ and ER- PR- receptor subtypes [Among five previous epidemiological studies that examined the effect of alcohol consumption according to ER/PR status among young women ,36 or pr alcohol ,37; one subtypes . Our effsubtypes  and crossubtypes  data hav+PR+ and ER- PR- breast cancer is consistent with two [+PR+ or ER-PR- breast cancer among young [- PR- cancer among women who had ever used oral contraceptives [Our finding that late age at menarche is associated with a reduced risk of both ERwith two ,20 of fowith two ,20 or prwith two ,22. The with two ,20. The with two ,21 or prwith two  parous wwith two ,19. The with two ,20,22 ofng young ,22; the +PR+ cancer, whereas increasing recent average weekly alcohol consumption is associated with greater risk, and that ER- PR- cancers are not affected by these risk factors, support the hypothesis that these factors act predominantly through this type of hormonal mechanism.It has been argued ,12 that - stem cell population gives rise to ER+ progenitor cells [- cells to proliferate. Thus, late age at menarche and breastfeeding may still act through hormonal mechanisms that involve ER and PR, but our results suggest that the exact mechanism differs from that involved in the effect of parity and alcohol consumption.In contrast, it could be hypothesized that hormonal factors should affect receptor-positive and receptor-negative breast cancer similarly. It has been hypothesized that an ERor cells , which wOne strength of our study is the large number of case patients included. Our analysis included more young breast cancer patients than six of the eight previously published studies with results for ER/PR status among women under the age of 50 years -21,36 or+PR+ cancer as the Women's CARE Study [+PR+ and the ER- PR- case patients, whereas we did not detect any statistically significant associations when comparing each of the subtypes with the control subjects.Several limitations of this study must also be considered. The number of control subjects in this study was relatively small. This could explain why we detected a similar magnitude of effect for late first full-term pregnancy on ERRE Study , but in +PR+ cancer was statistically significant in the Women's CARE Study but not in ours. In comparison with the prospective data from the Nurses' Health Study [Because of our decision not to retain the case–control match during data analyses, we used an unconditional instead of a conditional logistic regression approach, which could have biased our relative risk estimates toward the null value, as described by Rothman and Greenland . Howeverth Study  for bothWe have no data on the methods and cutoff points for receptor status used by each laboratory because we obtained this information from the CSP, which bases its classifications on information in pathology reports from a variety of laboratories. Although we assume that most laboratories used immunohistochemistry assays and consistent cutoff points, it is possible that some laboratories used different methods or different cutoff points. However, we believe that any such inconsistencies would be unlikely to cause the observed associations and, if anything, that they would bias our relative risk estimates toward the null value.+PR+ and ER- PR- cancer. Furthermore, this would not have influenced our case–control analysis using all case patients combined. Because our results from the case–case and the case–control analysis by receptor subtypes or using all case patients combined were generally consistent, we think it unlikely that these issues caused important bias in this study.Another limitation is that in our analyses by receptor subtypes, we excluded 21% of our case patients, because 16% of patients had no ER or PR status information and 5% were borderline positives or undecided for either ER or PR. The percentage of case patients without information from the cancer registry in this study (16%) is similar to that reported by previous studies conducted within the SEER registries . It is uOur results suggest that the number of full-term pregnancies and recent alcohol consumption affect breast cancer risk in young women predominantly through estrogen and progesterone mediated by their respective receptors. Late age at menarche and breastfeeding may protect against breast cancer through a different hormonal mechanism.BMI = body mass index; CARE = Contraceptive and Reproductive Experiences; CI = confidence interval; COC = combination oral contraceptive; CSP = Cancer Surveillance Program; ER = estrogen receptor; OR = odds ratio; PR = progesterone receptor; SEER = Surveillance, Epidemiology, and End Results.The authors declare that they have no competing interests.HM cleaned the data, performed the data analysis, and drafted the manuscript. LB and RKR participated in the design of the study and revised the manuscript. GU designed the study, supervised the data collection and data analysis, and revised the manuscript. All authors read and approved the final manuscript.


Between 1946 and 1976 over 9,000 women with breast cancer were seen within one year of diagnosis at the A. Maxwell Evans Clinic (AMEC) in Vancouver, British Columbia. By 1978, 275 had a subsequent diagnosis of a second primary in the contralateral breast: 100 were diagnosed within 1 year, and 175 after 1 year of the first primary. Two separate comparison groups of AMEC patients with unilateral breast cancer were selected to identify risk factors for bilateral breast cancer and to determine the incidence. The average annual incidence rates for a second primary in the contralateral breast were 5.0, 4.1 and 3.0 per 1,000 women for women less than 45 years, 45-54 years, and over 55 years of age at diagnosis of first primary breast cancer, respectively. These rates remained stable for at least 15 years after the diagnosis of the first primary. Two risk factors were found for bilateral cancer within 1 year of the first primary, histologic diagnosis of lobular carcinoma and absence of pathologic involvement of axillary nodes; one risk factor was found for bilateral breast cancer after 1 year of the first primary, family history of breast cancer.


It has been suggested that the percentage of non-protein-bound or free oestradiol (E2) is abnormally high in patients with breast cancer. In this study, the serum oestradiol profiles of a large group of women were analysed to determine whether a significant correlation could be found between serum oestradiol and various breast diseases. In addition oestradiol levels were measured in relation to sex hormone binding globulin (SHBG), albumin levels, oestrogen receptor status and family history of breast cancer. Serum samples were taken from a total of 300 women who had either no breast disease, benign breast disease or breast cancer. The percentage of free oestradiol was found to be highest in women with breast cancer, lowest in the control group and intermediate for the women with benign breast disease. These differences were most marked in post-menopausal women. The absolute values for total and free oestradiol were not statistically different in the three groups studied. There did not appear to be a correlation between oestrogen receptor (ER) concentration in breast cancer tissue and free E2 percentage levels. Women who had a family history of breast cancer did not appear to have higher percentage levels of free E2 than those with no such history. The presence of elevated proportions of free oestradiol in the serum of women with breast cancer may be significant in regard to understanding the aetiology of breast neoplasia. There also may be important implications for the use of this measurement in the earlier diagnosis and detection of breast cancer.


CYP17) 5'-untranslated region MspA1 genetic polymorphism and breast cancer risk have yielded inconsistent results. Higher levels of estrogen have been reported among young nulliparous women with the A2 allele. Therefore we assessed the impact of CYP17 genotypes on the risk of premenopausal breast cancer, with emphasis on parity.Studies on the association between the cytochrome P450c17α gene  assay.We used data from a population-based case–control study of women aged below 51 years conducted from 1992 to 1995 in Germany. Analyses were restricted to clearly premenopausal women with complete information on CYP17 A1/A2 and A2/A2 genotypes compared with the A1/A1 genotype were not associated with breast cancer, with adjusted odds ratios (ORs) of 1.04 and 1.23, respectively. Among nulliparous women, however, breast cancer risk was elevated for the A1/A2  0.74 to 2.32) and the A2/A2 genotype  compared with the A1/A1 genotype, with a trend towards increasing risk associated with number of A2 alleles (P = 0.04). Otherwise, the CYP17 polymorphism was found neither to be an effect modifier of breast cancer risks nor to be associated with stage of disease.The frequencies of the variant allele among the cases and controls were 43% and 41%, respectively. Overall, CYP17 MspA1 polymorphism on the risk of premenopausal breast cancer, but suggest that it may have an impact on breast cancer risk among nulliparous women. The finding, however, needs to be confirmed in further studies.Our results do not indicate a major influence of  BRCA1 and BRCA2 are associated with some cases of familial breast cancer, though this association accounts for only about 5% of all breast cancer cases [CYP17, which codes for the enzyme cytochrome P450c17α, responsible for catalyzing steroid 17α-hydroxylase and 17,20-lyase activities at key branch points in the estrogen biosynthesis pathway [CYP17 gene is a thymidine substitution for cytosine (T to C) giving rise to an MspA1 restriction site at nucleotide 27 in the 5'-untranslated region (5'-UTR) promoter [MspA1 polymorphism has three genotypes: a homozygous wild type (A1/A1), a heterozygous variant (A1/A2), and the homozygous variant (A2/A2) [The risk of breast cancer is related to genetic, environmental, and lifestyle factors that influence the level of exposure to estrogens and other sex hormones . Regardier cases . These l pathway . One of  (A2/A2) . The T-t (A2/A2) ,9, but t (A2/A2) -12.CYP17 MspA1 polymorphism and breast cancer risk, with inconsistent findings [CYP17 and breast cancer risk by Dunning and colleagues concluded that risk was not significantly altered by CYP17 genetic polymorphisms [CYP17 MspA1 polymorphism may be a weak modifier of breast cancer risk but is not a significant independent risk factor [CYP17 acts as an effect modifier of breast cancer risk, especially with factors that influence endogenous estrogen levels. Similar to findings of other studies, they reported a protective effect of late age at menarche [The A2 allele has been associated with higher levels of estrogen than the wild-type allele ,14. In pfindings -19. A syorphisms . In addik factor . Howeverk factor . Ambrosok factor  also foumenarche ,13,22, aCYP17 in relation to parity [CYP17 genotype according to parity (nulliparous versus parous) and other risk factors for breast cancer among premenopausal women.It has been shown that premenopausal nulliparous women with the A2/A2 genotype have higher mean levels of serum estradiol than those with the A1/A1 genotype ,23, implo parity ,24. Thisin-situ or invasive breast cancer within the study period were identified through frequent monitoring of hospital admissions, surgery schedules, and pathology records from about 40 hospitals serving the study regions. There were also periodic checks of pathology institutions serving these hospitals, in order to identify any overlooked cases. There were 1,020 eligible case subjects, of whom 1,005 (98.5%) were alive when identified. Of these living subjects, 706 (70.2%) completed the study questionnaire and constituted the original population of case subjects, 152 (15.1%) refused to participate, 85 (8.5%) failed to respond, 51 (5.1%) were not contacted because of the physician's refusal to allow contact, and 11 (1.1%) were unable to participate because of health problems.We used data from a population-based case–control study conducted from 1992 to 1995 in two regions of southern Germany  . The ethControls were randomly selected from population registers of the study regions. An attempt was made to recruit two population controls per case, matched by age and study region. Subjects were not eligible as controls if they could not speak German, had moved out of the study region, had a previous history of primary breast cancer, were mentally handicapped, or had died. Of 2,257 eligible population controls, 1,381 (61.2%) participated , 658 (29.1%) refused to participate, and 218 (9.7%) did not respond.All subjects were asked to complete a self-administered questionnaire on demographic factors, anthropometric measures, menstrual, reproductive, and breast feeding histories, use of contraceptives and exogenous hormones, medical and screening histories, first- and second-degree family history of breast cancer, occupational exposures, smoking history, and alcohol consumption. Information on exposure for cases and controls was truncated at a reference date, which was the date of diagnosis for cases and the date of completion of the questionnaire for controls. All subjects were asked to provide a blood sample, which was used for genotyping. The median time between diagnosis and interview for cases was 2 months.The study population was homogeneous, with 95.1% being of German origin and 88.6% of the non-Germans being of European descent. A total of 99.5% of the sudy subjects (Germans and non-Germans) were of European descent. The mean age was 41.6 years (± 5.8 standard deviations) for the cases and 41.7 years (± 5.7 standard deviations) for the controls.CYP17 5'-UTR MspAI polymorphism was analyzed using the previously described PCR-RFLP assay [MspAI, subjected to electrophoresis through a 3% agarose gel, and visualized by staining the gel with ethidium bromide. Different genotypes could then be distinguished based on the size of the digested fragments.Genomic DNA was extracted from the blood samples drawn into ethylenediaminetetraacetic acid tubes using Blood and Cell Culture DNA kits as described by the manufacturer . The CYP17 genotype, and therefore these 527 cases and 904 controls were included in the analysis.We restricted our analysis to women clearly defined as premenopausal, since risk factors for breast cancer vary depending on menopausal status. Only women who still had menstrual cycles or reported natural amenorrhea for less than 6 months or more before the reference date (date of diagnosis for case subjects and date of completion of questionnaire for controls) were considered premenopausal. Women who reported natural amenorrhea 6 months before the reference date or bilateral oophorectomy were considered postmenopausal and hence not included in the analysis. Menopausal status for those who reported hysterectomy alone was classified as unknown and these subjects were also excluded, leaving 558 (79.0%) cases and 1,116 (80.8%) controls. Of these premenopausal subjects, 527 case subjects (94.4%) and 904 controls (81.0%) had complete information on 2 test. The distributions of potential risk factors for breast cancer by CYP17 genotype in cases and controls were compared. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed using multivariate conditional logistic regression analysis. Maximum-likelihood estimates were produced using the PHREG procedure in the SAS statistical software package . One-year age stratification was used to optimize age adjustment. Assessment of the association between CYP17 genotype and breast cancer was adjusted for potential confounders, including age at menarche, having ever used an oral contraceptive, total months of breastfeeding, family history of breast cancer in first-degree relatives, parity (defined as the number of full-term pregnancies resulting in either a live or a stillbirth), age at first full-term pregnancy (for parous women only), current body mass index, alcohol consumption, and level of education. Other variables such as study region, marital status, and smoking did not materially affect the risk estimates and were therefore not included in the model.The distribution of demographic characteristics and potential risk factors of breast cancer in this study population was compared with that of the original study population. Allele and genotype frequencies among cases and controls were calculated and deviation from Hardy–Weinberg equilibrium was examined using the χCYP17 genotype by parity (nulliparous and parous) and by other risk factors was examined to identify differential effects. We tested for trends in the logistic analyses by categorizing the exposure variables and treating the scored variables as continuous. All P values computed in the analyses were two-tailed. We tested for multiplicative interaction by computing the cross product of the variables and including it in the model alongside its separate components. We also assessed the distribution of the CYP17 genotype with respect to stage of the disease  and investigated trends with the Cochran–Armitage test.The effect of P = 0.217) and controls (P = 0.380).There were no major differences in the distribution of demographic characteristics and potential risk factors of breast cancer between the original study population and this study population Table . SubjectCYP17 genotype. χ2 tests for distribution revealed no significant differences among cases and controls in any of the genotype groups  with respect to age at menarche, age at first full-term pregnancy, parity, total months of breastfeeding, current body mass index, and educational level. Case subjects with the A1/A2 genotype were more likely than controls with this genotype to have used oral contraceptives. Compared with controls, case subjects with the A1/A1 genotype had significantly more family history of breast cancer and consumed more alcohol.Table CYP17 genetic polymorphism and breast cancer risk (Table P = 0.04) but nonsignificant among parous women (P for interaction = 0.87) .Overall, there was no significant association between the sk Table . The odd7) Table . Table 4CYP17 genotype, both overall and with further stratification by parity. Because of limited power for subgroup analyses, we combined A1/A2 and A2/A2 genotypes, as both groups are considered putative high-risk groups. Late age at menarche was not associated with breast cancer risk, irrespective of genotype and parity. The odds ratio for nulliparous women with the A1/A1 genotype who had ever used oral contraceptives was elevated compared with those who had never used oral contraceptives (OR = 2.60). The effect of breastfeeding among parous women (those who had ever breastfed versus those who had never breastfed) did not differ by genotype. However, among the parous women who had ever breastfed, breastfeeding for more than 12 months was associated with a risk reduction (OR = 0.56) when compared with 1 to 12 months of breastfeeding (Table CYP17 genotype (P for interaction = 0.48). Age at first full-term pregnancy was not associated with breast cancer risk in this study and the result was not altered when genotype status was taken into consideration.In Table n OR = 0.6 when coCYP17 genotype and stage of breast cancer, with 65.5% of those with local disease and 68.1% of those with the advanced disease, respectively, being carriers of the A2 allele.We did not find any evidence of an association between CYP17 genetic polymorphism on the risk of breast cancer gained a lot of interest after Feigelson and colleagues first reported an increase in risk of advanced breast cancer for carriers of the A2 allele [The impact of 2 allele . With a 2 allele ,26, most2 allele ,24,27-312 allele ,14, alth2 allele . Hong an2 allele . Despite2 allele ,33.We did not observe an overall increase in risk associated with the A2/A2 genotype compared with the A1/A1 genotype. However, we found an increased risk associated with the A2/A2 compared with the A1/A1 genotype among nulliparous women. This observation supports findings from a previous study indicating that nulliparous women with the A2/A2 genotype have higher mean levels of serum estradiol than those with the A1/A1 genotype . JernstrCYP17 genotype.We found no evidence of the previously reported effect modification for later age at menarche by the A1/A1 genotype ,13,21,22CYP17 on stage of breast cancer, and, as in other studies [We also assessed the impact of  studies ,30,31, w studies ,26. The P = 0.21). This contradicts the findings of Spurdle and colleagues [2 = 0.25; P = 0.62). Jernström and colleagues in their study on nulliparous young women also reported that carriers of the A2/A2 genotype had less family history of breast cancer in first- or second-degree relatives than carriers of the A1/A2 and A1/A1 genotypes combined [We found fewer A2/A2 carriers in cases with a positive family history of breast cancer in first-degree relatives than in all controls, irrespective of family history of breast cancer  declare that they have no competing interests.VTE performed the statistical analysis and drafted the manuscript. WGS carried out the molecular genetic studies and participated in the preparation of the manuscript. CCJ conceived the study, participated in its design and coordination, and contributed to the statistical analysis and the preparation of the manuscript. All authors read and approved the final manuscript.


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


Most studies have found no increased risk of colon cancer associated with hormone replacement therapy (HRT), or even a decreased risk. But information about the effects of different HRT preparations is lacking.A case-control study was performed within Germany in collaboration with regional cancer registries and tumor centers. Up to 5 controls were matched to each case of colon cancer. Conditional logistic regression analysis was applied to estimate crude and adjusted odds ratios (OR) and 95% confidence intervals (95% CI). Stratified analyses were performed to get an impression of the risk associated with different estrogens and progestins.A total of 354 cases of colon cancer were compared with 1422 matched controls. The adjusted overall risk estimate for colon cancer (ColC) associated with ever-use of HRT was 0.97 (0.71 – 1.32). No clinically relevant trends for ColC risk were observed with increasing duration of HRT use, or increasing time since first or last HRT use in aggregate.Whereas the overall risk estimates were stable, the numbers in many of the sub-analyses of HRT preparation groups (estrogens and progestins) were too small for conclusions. Nevertheless, if the ColC risk estimates are taken at face value, most seemed to be reduced compared with never-use of HRT, but did not vary much across HRT formulation subgroups. In particular, no substantial difference in ColC risk was observed between HRT-containing conjugated equine estrogens (CEE) or medroxyprogesterone acetate (MPA) and other formulations more common in Europe.Ever-use of HRT was not associated with an increased risk of colon cancer. In contrary, most risk estimates pointed non-significantly toward a lower ColC risk in HRT ever user. They did not vary markedly among different HRT formulations . However, the small numbers and the overlapping nature of the subgroups suggest cautious interpretation. Complex discussions surrounding the role of steroid hormone formulations, particularly concerning Hormone Replacement Therapy (HRT), experienced a revival after the publication of the Women's Health Initiative (WHI) Study in 2002 .Many earlier studies reported no significant increase in colon cancer for ever-use of HRT, and more often a decreased risk ,3. The tThe primary aim of this publication is to present data on colon cancer risk associated with use of different HRT formulations and administrations.The study method has been recently described in greater detail elsewhere . In brieThe lifetime history of exposure to sex steroid hormones was recorded by month and year of exposure . This information was compiled primarily on the basis of a questionnaire. Relevant approvals of the study were obtained .Eligible cases were histologically confirmed malignant neoplasms of the colon  diagnosA potential total of 354 cases was included in the analysis. Up to five controls were matched for each ColC case, using the same age (year of birth +/- two years) and residency (Bundesland) as matching criteria. A pool of potential controls from a large cohort study was used – as described in a previous publication 6. We found 1422 matched controls for 354 ColC cases.Time-related information on lifetime history of hormone use as well as data on reproductive life, lifestyle pattern, conditions/diseases, and some other factors were obtained via a self-administered postal questionnaire.HRT preparations ever used were classified according to the route of administration , type of combination , estrogen type ), and progestin type (Noretisterone acetate (NETA), Levonorgestrel (LNG), Medroxyprogesterone acetate (MPA), Medrogestone, and Tibolone); the numbers for other progestins were too small for calculating risk estimates).notmutually exclusive. Therefore, comparison of risk estimates across exposure groups can be used only as a first impression as to whether there are substantial differences or not. We also refrained from defining categories of HRTs in terms of "longest used during lifetime", because of the arbitrary character of the decision as well as the assumed incompatibility for what "longest" might mean across different compounds.Each participant who had ever used HRT in more than one of the above HRT categories was counted more than once across the analyses (depending on switching pattern), i.e. the categories are We excluded stepwise information on exposure close to the date of diagnosis, because we cannot exclude the possibility that prior to the final diagnosis of colon cancer, the women and/or their physicians might have been aware of "warning signs"  that may have led to a decision to start HRT or not previously. A series of index dates was introduced, such as 0.5, 2, 4, and 6 years, i.e. all exposure-related information between these dates and the date of diagnosis was ignored in the respective analyses. We intended to estimate the possible magnitude of such a bias if it exists. In this report, we focus on a lag-time of 0.5 year prior to diagnosis in order to avoid the effects of decisions related to a perceived ColC risk in the time immediately preceding the cancer diagnosis.Conditional logistic regression was used as primary analysis. Crude and adjusted odds ratios (OR) were reported with 95% confidence intervals (95% CI). Adjustment variables were BMI, family history of colon cancer, child-bearing history, age at first live birth, duration of breast-feeding, age at menarche, OC use, and education, whereby missing values were imputed  to allow the analysis. For sub-group analyses of HRT categories, we additionally adjusted for age and residency because the matching effect was lost in the individual subgroups. We were not able to use age at menopause as a co-variable because it could not be reliably determined for a high proportion of participants. Moreover, we refrained from complex adjustment in these subgroup analyses to prevent unstable risk estimates. For the same reason, we did not calculate risk estimates if any cell of the "two-by-two" table contained fewer than 5 women.We analyzed the impact of duration of HRT as well as time since first and last HRT use for each of four categories. The statistical packages SAS 9.1 and STATA 8.0 were used.Table However, increasing age was significantly associated with increased risk of colon cancer, i.e. both as a continuous (OR = 1.64 per year) and a dichotomized categorical variable (OR = 4.38), as was first-degree family history of colon cancer (OR = 3.40). Significantly reduced ColC risk was observed for higher education (OR = 0.64).Higher number of children (OR = 0.75 per child), ever breast-feeding (OR = 0.31), and ever-use of oral contraceptives (OR = 0.64) were apparently associated with lower ColC risk. However, the association with HRT use was marginal only, i.e. the effect as confounder negligible.The result for BMI showed a slight decrease with increasing BMI . All other factors listed in Table All the above variables were significant effect modifiers of the association between HRT exposure and ColC risk (data not shown) and therefore included in the analyses to control for confounding, but had a marginal effect only (compare crude and adjusted ORs in the following tables).Table Table Table Ever-use of HRTs via oral and transdermal routes of administration showed no significant association with colon cancer in aggregate, but there was a significantly increasing trend with longer duration of use. The latter was not observed for the other routes of administration but the numbers were tiny.Both sequential and continuous combined formulations showed virtually identical, non-significantly reduced ColC risk estimates in aggregate. An increasing trend of risk with increasing duration of use was found for sequential formulations but not for continuous-combined, although the confidence intervals were largely overlapping and the numbers in the strata for duration small in continuous-combined HRTs. This was similar for the respective subgroups of duration of use, taking the overlapping confidence intervals into account. This was also true for all estrogen + progestin combinations together.The seemingly increasing risk estimates with longer duration of use in the subgroup of sequential formulations, for example, showed largely overlapping confidence intervals, as can also be seen for other trends with increasing duration of use.No obvious or meaningful difference in risk for ColC was found between ever-use of CEE and ever-use of MPA; however, the numbers were too small for the fixed combination of CEE plus MPA.No meaningful difference in ColC risk was observed between ever-use of estrogen and ever-use of progestin-only formulations, although the numbers for progestin only were too small for meaningful analysis.A risk of ColC was not significantly associated with either of the two analyzable estrogens, i.e. it was similar and at least not increased .Of the progestins, only NETA, LNG, MPA, Medrogestone, and to some extend also Tibolone showed mainly non-significantly decreased ColC risk estimates if taken at face value. Many of the subgroups for duration of use were too small to permit meaningful calculations.Colorectal cancers altogether are the fourth most common cancer worldwide and commonly thought to be associated with food and nutrition – except for genetic risk and polyposis – as recently expressed by an expert committee from the American Institute for Cancer .We observed other potential risk markers for colon cancer beyond food and nutrition in our case-control study . Like OC ever-use, information on reproductive history was obtained in a search for differences between cases and controls that possibly could explain different risk of HRT user . Although OC ever-use is closer to the research question of an effect of HRT on colon cancer risk, the study was not designed to analyse the impact of OCs on ColC. Fortunately – taken at face-value – the point estimates of OC use and HRT use (irrespective of formulation) point in a similar direction, i.e. toward lower risk of colon cancer, but mainly non-significant.The above-mentioned expert panel from the American Institute for Cancer did not assign external sex-steroid hormones a convincing role among important risk factors . On the Most but not all of the previously published epidemiological studies on colon cancer in women found a reduced risk associated with external use of sex-steroid hormones . A revieThe distribution of ColC risk estimates for different HRT formulation categories is compatible with the notion that no obvious differences were observed. All point estimates were non-significantly around or below unity (1.0). Taken at face value, some point estimates for HRT use would be compatible with a decreased risk of colon cancer. The largely overlapping confidence intervals across various HRT formulation groups argue strongly against convincing differences. The interpretation of the statistically significant trend of increasing risk estimates with increasing duration of use in some but not all HRT subgroups – in contrast to no significant risk trend of duration of HRT use in aggregate – is not clear. This might be a biased or random observation or real, important or clinically meaningless. At least we cannot explain this finding and would hesitate to draw any clinical conclusions from it unless it is confirmed in other studies, i.e. particularly in absence of evidence for an increased ColC risk.It is a shortcoming of our study that we had small numbers of cases in many of the interesting sub-analyses, and thereby were not able to detect significant differences in colon cancer risk according to different hormone preparations or ways of administration.Analysis of the effect of external hormones on colon cancer must take into account the lag time in cancer development, although it is difficult for observational studies to account sufficiently for time-dependence. Lag time is likely to be long and may vary depending on complex unknown causal mechanisms, and is therefore an issue involving complex, time-dependent risk factors. Moreover, even observational studies with "state-of-the-art" performance face an important methodological problem if the observed risk estimates are small. Given the great potential for residual confounding and different forms of bias, even a statistically significant small positive or inverse association cannot be ruled out and the results might be inconclusive. Such small associations could well be situated below reliable resolution levels of the "epidemiological microscope", i.e. it is not possible to differentiate between causation and bias/confounding ,13.We assume that the results of our study have not been substantially affected by differential surveillance or prevention bias, self-selection or recall bias, although we cannot exclude these possibilities. Another potential source of bias is diagnostic suspicion bias. Nobody can be sure that tumor cases are equally identified (diagnosed) among HRT users and non-users. This, however, would not explain the low point estimates of ColC risk observed, i.e. this would be a conservative estimate.Despite some advantages of our study over many others in considering time-dependent exposure during the lifetime, or in introducing different lag times to perform stratified analyses, we do not know the impact of the above-mentioned biases on the observed risk estimates. Therefore, our interpretation of the ColC risk estimates observed in the case-control study should be taken with care.Our study together with the available literature supports the notion that use of HRT is not associated with an increased risk or even the possibility of an inverse association between colon cancer and HRT use. Obviously, the observed risk did not vary markedly among different HRT formulations . However, the small numbers and the overlapping nature of some of the subgroups suggest cautious interpretation. In addition, there might be differences that were not detectable in our study due to the "limited resolution of the epidemiological microscope". And finally, residual confounding and bias cannot be ruled out.This study was funded by the authors' institution. No conflict of interest is declared.JCD: contributed to the design the study and revision of the manuscript, and was involved in the data analysis; LAJH: responsible for the design of the study and prepared the data analysis plan, responsible for writing the manuscript; SM: responsible for collaboration with the tumor centers as well as quality checks and management of the initial database, contributed to the manuscript; DMT: responsible for final data management and data analysis; contributed to the manuscript; AA: responsible for development of all questionnaires (together with SM), contributed to organizing field work and quality checks, contributed to the manuscript.The pre-publication history for this paper can be accessed here: