Oncogenetic counselling is seldom followed through, even when individuals are eligible according to the test criteria. The basic variables which influence the decision to undergo the genetic counselling process are: risk perception, expected benefit or limitations of genetic testing, general psychological distress or cancer-specific distress, lack of trust in one's emotional reactions when faced with negative events, expected level of family support and communications within the family. The aim of this study was to describe the psychosocial variables of an Italian sample that forgoes genetic counselling.From May 2002 to December 2006 a psychological questionnaire was sent out to one hundred and six subjects, who freely requested a first genetic informative consultation, and never asked to have a second visit and the family tree drawn up in order to inquire about their eligibility for genetic testing. Statistical analysis was performed by Pearson chi-square test, t-test and Spearman RHO coefficient.The survey presents a lack of emotional cohesion and structured roles and rules within the family system and a positive correlation between the number of children, anxiety and risk perception. The main reasons for giving up on counselling were a sense that testing was a waste of time and the inability to emotionally handle the negative consequences of the test outcome. The subjects who maintained that test and an early diagnosis were a "waste of time" experienced more anxiety.The study revealed the importance to ac knowledging the whole persona and their family system as well as provide information highlighting usefulness of early diagnosis. The possibility of taking advantage of genetic counselling for familial/hereditary breast/ovarian cancer enables a woman, with a family history of cancer, to understand their risk of developing the disease during their life time and undertake adequate provision to manage the risk through a programme of clinical observation or eventual precautionary surgery. Furthermore, the possibility of being made aware of one's risk, also enables the counselees to protect their family and in particular their children, involving them in the process of genetic counselling and prevention programs.A number of studies have reported that counselees claim a great interest in undergoing the genetic test-3; but iThe present study aims at describing some psychosocial variables in an Italian group of patients who interrupted the process of genetic counselling for hereditary/familial breast/ovarian cancer, following an initial informative session. Furthermore, it aims at evaluating motivations, reported by the subjects themselves, which have led to their decision to discontinue the process of counselling and probable association between motivation and psychosocial variables.From May 2002 to December 2006, 380 subjects requested a first appointment for genetic counselling at the Department for Hereditary Tumours of the Breast and/or Ovaries of "Regina Elena" National Cancer Institute of Rome. An informative pre-counselling session by the primary care physician is not envisaged, the subjects freely telephone the out-patient office to learn one's risk of developing a breast and/or ovarian tumour. During the initial informative genetic session the oncologist, supported by a psychologist, supplies the patient information concerning BRCA1 and BRCA2 mutation genes which predisposes one to breast/ovarian tumours, concerning the method of transmission, the possibility of prevention and treatment of hereditary pathologies.The physician offers the counselee to initiate the next appointment in which a family history will be obtained and eligibility for genetic testing will be determined.Of these 380 subjects who received the first counselling informative session, 106 never asked for a second counselling session to have the family tree drawn up in order to inquire about their eligibility for genetic testing, 28% of the sample.These 106 subjects were contacted by telephone by a psychologist, in order to request participation in the study. Once permission from patients was obtained, some questionnaires were sent out to be filled in by the counselee and returned in the enclosed stamped envelope provided. This was to be done within 20 days following the first contact, failing which, a second telephone call was made, requesting the return of the questionnaire. The subject was dropped from the study if their questionnaire was not received in forty days. All the procedure was discussed and approved by local Ethic Committee.From December 2006 to March 2007, 106 subjects, 3 men and 103 women, were contacted. Six subjects refused to take part in the study, 35 did not return the questionnaire, and 9 sent them back incomplete. The study was then carried out on a sample of 56 subjects, 2 men and 54 women, affected by breast and/or ovarian cancer, or healthy but with a family history of cancer (at least one affected relative). 53% took part in the study.The test variables were; age, gender, place of birth, civil status, number of children, education, employment, religion or whether they are practicing, cancer, number of relatives affected by cancer.One item taken from prior research ,15, was Another item taken from prior research, was to The Hospital Anxiety and Depression Scale (HADS) , ItalianFamily Adaptability and Cohesion Evaluation Scale (FACES III) of D.H. Olson , ItalianThis Circumplex model classifies the family into 16 specific types, or more generally, according to a three-way division defined as " balanced", "mid-range" and "extreme". Moreover, this measure is used to obtain information about the true or ideal functioning of families The discrepancy between the true and ideal family indicates the measure of family dissatisfaction The test is made up of 40 multiple-choice items .A questionnaire was composed of 22 true/false items to indicate the reasons behind the decision to choose not to pursue genetic counselling. The questionnaire was adapted from prior research to indicate limitations and benefits derived from the test  as well Descriptive statistics were used to summarize the pertinent information. Association between dichotomous or categorical variables was tested by the Pearson Chi-Square test (for the trend when necessary). Rank-order correlation was measured by the Spearman RHO coefficient. The SPSS (11.0) statistical program was used for analysis.The description of the sample is reported in table The sample was made up of 56 subjects, 2 men and 54 women. Eighteen were affected by breast or ovarian cancer . Thirty-eight were healthy but with a family history of cancer. The average age was 48.6 years and the average number of family members affected by cancer was 3.9.Most of the sample were Roman Catholic (92%), but only 50% claimed to be practicing, 46% had finished high school, 19% had a university degree and more than a third of the sample had a middle or elementary school level. Seventy percent were married and 73% had at least one child. An equal number of subjects were either unemployed or employed (52%v 48%). There are no significant differences between cancer affected women and healthy women regarding socio-demographic characteristics, risk perception and anxiety levels.The mean percentage of risk perception of developing cancer is 49.8%. The score was correlated positively with the number of children (p = 0.01 r = 0.371) and with the level of anxiety (p = 0.07 r = 0.274). 25% of the subjects could give no indication of their risk perception of developing breast/ovarian cancer.The mean percentage of risk perception of being a carrier of BRCA1 and BRCA2 mutation shown is 46.7%. this score was positively correlated with the number of children (p > 0.04 r = 0.338) and level of anxiety (p = 0.04 r = 0.332), and 26,7% of subjects could give no indication of their perception of risk of being a carrier of genetic mutation predisposing one to breast/ovarian cancer.The mean total score obtained from the HAD scale is within the cut off for adaptation disorders (13.9). In 46.4% of subjects there were no signs of anxiety or depression, the rest of the sample showed an equal distribution between a major depressive episode (26.8%) and adaptation disorders (26.8%). In each scale there was an average score of 8.3 (borderline anxiety) and 5.6 .The borderline anxiety level was 30.4%, anxiety disorders 25%, depressive disorders 12.5% and the same percentage of subjects had a borderline level of depression. The score for the single scale of anxiety correlated with the number of children (p = 0.001 r = 0.421).The average score of true and ideal cohesion were 39.7 (separated families) and 42.1 (connected families), respectively. The mean index of family dissatisfaction for cohesion was -2.35 . The average of true and ideal adaptability was 30.1 and 34.5  The average index of family dissatisfaction with adaptability was -4.50 (negative score indicates the desire for change towards greater structuring of rules/roles between family members). A third of the families were considered to be extreme 30%, mid-range 59%, and balanced only 11%.One of the reasons given for discontinuing counselling as reported by 48% of the subjects is the fear of the consequences for their family brought about by the results of the genetic test. In particular, 32% believed it was not right to involve their family. The same percentage of subjects, did not feel they could pass on negative information to their family, and 9% of subjects felt guilty towards their family members. Amongst the counselees who claimed their partner to be against genetic testing, 5.4% harboured a level of genetic risk perception, significantly lower (p = 0.002) compared to the rest of the sample. Forty-three percent of counselees showed fear arising from the stress of hospital visits as their reason for discontinuing the counselling, a further 43% the fear of knowing that they had a high risk of developing cancer and 18% felt they would not be able to confront the idea of frequent preventative clinical surveillance if they were found to be mutation carriers. This latter data was reported principally by subjects affected by cancer and answered 'true' to this item, significantly more than healthy subjects(p = 0.047). Thirty four percent of subjects stated that they did not have the time to attend the visits required for counselling, this reason was given by significantly more single, divorced or widowed women compared to married women (p = 0.048). Thirty seven percent claimed that the distance between the hospital and their home was the reason for discontinuing counselling, and 39% held that it was impossible to obtain an appointment for the visits because the phone lines were always busy.Twelve percent maintained they did not have a good reception from the medical staff, 27% of the subjects had no desire to know whether or not they were predisposed to genetic mutation for breast or ovarian cancer. Amongst these individuals there was an average number of family members affected by cancer, significantly less than those who have a desire to know their likelihood of genetic risk (p = 0.004). Believing the test was a waste of time because it would not halt the disease, was given as the excuse for discontinuing counselling by 41%. This group encountered significantly higher levels of anxiety and depression  than the subjects who felt that genetic testing was useful. Among the subjects whose motivation for discontinuing counselling was the idea that genetic investigation does not improve ones quality of life (25%), higher levels of depression were seen compared to the subjects who, on the contrary, believed genetic analysis could improve the quality of life (p = 0.06). Eighteen percent were not sure of the aim of the genetic test, 7% felt that early diagnosis was a "waste of time" and moreover, this group had significantly higher levels of anxiety and depression compared to those who believed early diagnosis to be useful. Ten percent of the subjects, felt that genetic testing was of no value as they were already symptomatic.According to available literature, certain similarities and even novelties in the psychosocial variables emerged in this Italian sample compared to subjects in other countries who take advantage of oncological-genetic counselling. For the risk perception variable, in agreement with previous works, ,16,22,23The latter data, frequently reported in literature, would confirm that the "anticipated emotional response" seen as unmanageable and insupportable, is one of the most frequent variables hindering the decision to undergo genetic testing. ,32. A laThis study showed the importance to take into consideration, during the process of genetic counselling, not only the single variables but also the whole picture gathered from the cognitive and emotional aspects from both the individual and family spheres, in order to assure adequate care of the patient. Moreover, given the evidence in this sample of a lack of knowledge regarding preventive measures for consultants or their family, it appears necessary to provide information highlighting usefulness of early diagnosis, and information regarding how the process of genetic counselling can be helpful for this purpose.With the aim of verifying the effective importance of each variable in the decision to discontinue genetic counselling, a comparison between subjects who decline or those who wish to continue genetic counselling will be carried out in a further study.The authors' declare there no financial competing interests  with the study.  AC main author project of the study and interpretation of the data, CV patient's data collection, data analysis and interpretation of the data, GM patient's data collection, FS patient's data collection, FC study coordinator, AS project of the study and study coordinator.


The incidence of a second primary breast cancer in the contralateral breast among 56,237 women with a first primary breast cancer diagnosed between the years 1943-80 in Denmark was established. The relative risk (RR) for a breast cancer patient to get yet another breast cancer was studied, taking account of age, stage and treatment of the first primary breast cancer. Based on 345,573 women years at risk and 1,840 non simultaneous contralateral breast cancer cases the overall relative risk (RR) of invasive cancer in the contralateral breast following a first primary breast cancer, was found to be 2.8 ; 2.7-3.0). Among women who survived 10 or more years the risk was higher among those irradiated for the primary breast cancer (RR = 2.6) than among non-irradiated (RR = 2.0). In the large group of patients with localized disease the association with radiation was obvious for all ages combined , but not obvious among premenopausal (age less than 45 years) and perimenopausal (age 45-54 years) women at primary breast cancer until followed for 20 years. The RR was higher among irradiated than non-irradiated post-menopausal (age greater than 55 years) women from the time of diagnosis of the first cancer, but was not significant after 14 years of follow-up. The probability for a woman diagnosed with breast cancer at 45 years of age or younger, of developing a contralateral breast cancer if surviving to the age of 75 years, is 25%. Close surveillance of the remaining breast of breast cancer patients is advised, especially if young or following an irradiated localized primary breast cancer.


Lobular carcinoma in situ (LCIS) is an unusual histological pattern of non-invasive neoplastic disease of the breast occurring predominantly in women aged between 40 and 50 years. LCIS is frequently multicentric and bilateral, and there is evidence that it is associated with an elevated familial risk of breast cancer. Although women with LCIS suffer an increased risk of invasive breast disease, this risk is moderate suggesting that LCIS may result from mutation of a gene or genes conferring a high risk of LCIS, but a lower risk of invasive breast cancer. The high frequency of somatic mutations in E-cadherin in LCIS, coupled with recent reports that germline mutations in this gene can predispose to diffuse gastric cancer, raised the possibility that constitutional E-cadherin mutations may confer susceptibility to LCIS. In order to explore this possibility we have examined a series of 65 LCIS patients for germline E-cadherin mutations. Four polymorphisms were detected but no pathogenic mutations were identified. The results indicate that E-cadherin is unlikely to act as a susceptibility gene for LCIS. © 2000 Cancer Research Campaign


In this review, we propose that age-related changes in mammographic density and breast tissue involution are closely related phenomena, and consider their potential relevance to the aetiology of breast cancer. We propose that the reduction in mammographic density that occurs with increasing age, parity and menopause reflects the involution of breast tissue. We further propose that age-related changes in both mammographic density and breast tissue composition are observable and measurable phenomena that resemble Pike's theoretical construct of ‘breast tissue ageing’. Extensive mammographic density and delayed breast involution are both associated with an increased risk of breast cancer and are consistent with the hypothesis of the Pike model that cumulative exposure of breast tissue to hormones and growth factors that stimulate cell division, as well as the accumulation of genetic damage in breast cells, are major determinants of breast cancer incidence. Since then, there have been advances in our understanding of the relationship between both breast histology and mammographic density to the risk of breast cancer, and of the factors that influence these features. In this review, we discuss some of the literature related to mammographic density, breast tissue involution, and breast cancer risk. We propose that age-related changes in mammographic density and breast involution are closely related phenomena, and consider their potential relevance to the aetiology of breast cancer in the light of the Pike model of mammary carcinogenesis.The radiographic appearance of the breast varies among women of the same age because of variations in breast tissue composition (see further in ‘Age and breast tissue composition’ section below) and the X-ray attenuation properties of the different types of tissue . Fat attAs reviewed recently by Extensive breast density is therefore one of the strongest known risk factors for developing breast cancer, second only to age and carrying a BRCA1 or BRCA2 mutation. Although less than 5% of unselected breast cancer patients have a BRCA1 or BRCA2 mutation, extensive mammographic density is common among women with breast cancer, and estimates of attributable risk show that densities in more than 50% of the breast may account for about a third of all breast cancers (in situ breast cancer increased 9.7-fold (95% CI: 1.75–53.97) in women with density in more than 75% of the mammogram , and that of atypical hyperplasia and Percent mammographic density is less extensive in parous than in nulliparous women and in postmenopausal than premenopausal women, and it is inversely associated with body weight Complete lobular involution was present in 5.8% of women aged 40–49 years and in 21.6% of women aged 50–59 years, and the degree of involution was greater in nulliparous than in parous women.  of breast cancer was 1.88 (95% CI 1.59–2.21) for those with no involution, 1.47 (95% CI 1.30–1.51) for those with partial involution, and 0.91 (95% CI 0.75–1.10) for those with complete involution.Lobular involution was associated with risk of breast cancer independently of other histological, reproductive, and demographic risk factors for the disease, but mammographic density was not among the risk factors considered. The extent of lobular involution modified risk in all of the subsets examined, most notably for women with cellular atypia on biopsy, where the RRs were 7.79 (95% CI 3.56–14.81) for those with no involution and 1.49 (95% CI 0.41–3.81) for those with complete involution.Mammographic density shares many of the features of ‘breast tissue age’ in the Pike model. Density is greatest at early ages, declines with increasing age, and is reduced by successive pregnancies and menopause  and genetic damage to proliferating cells by mutagens (mutagenesis) may underlie the increased risk of breast cancer associated with extensive mammographic density. There is clearly a need for an improved understanding of the specific factors that are involved in these processes and of the role played by the several breast tissue components that contribute to density. In particular, the identification of the genes and their biological functions, which are responsible for most of the variance in percent density, is likely to provide insights into the biology of the breast and may identify potential targets for preventive strategies for breast cancer. In the light of the other similarities with mammographic density described above, similar genetic factors may be responsible for the variations in breast tissue involution that are also associated with differences in the risk of breast cancer.In this paper, we have proposed that the changes in mammographic density that occur with increasing age, parity, and menopause, as well as lobular involution in the breast, are closely related phenomena that both resemble Pike's theoretical concept of ‘breast tissue ageing’. Extensive mammographic density for a given age and delayed breast involution are both associated with an increased risk of breast cancer and are consistent with the hypotheses of the Pike model that the cumulative exposure of breast tissue to hormones and growth factors that stimulate cell division, as well as the accumulation of genetic damage in breast cells, are major determinants of breast cancer incidence.There are, however, several gaps in our knowledge of these risk factors. Breast involution has to date been defined only in terms of breast lobules. The effects of extending the definition of involution beyond breast lobules to include stroma have not yet been examined. Both the epithelium and stroma are influenced by age, parity, and menopause, and stroma is known to have a function in the development and maintenance of the epithelium through paracrine growth stimuli and is thought to have a function in mammary carcinogenesis .The relationship between mammographic density and histological definitions of involution in individuals, although suggested by the histological studies referred to above, has not yet been explicitly examined, and it is not known whether histological definitions of involution predict breast cancer risk independently of mammographic density.It is quite likely that within the next few years the principal genetic variants that are associated with differences in mammographic density will be identified (


Pesticides are widely used in households to control insects and weeds. Several studies, over the past decades, have examined the possible relationship of serum concentration of organochlorine pesticides and the development of breast cancer. However, little data exists regarding an association between self-reported, residential exposure to pesticides and breast cancer risk. We, therefore, present a case-control study examining self-reported exposure to household pesticides with regard to associated risk of breast cancer.This study was conducted in the area in and around New York City, NY and included 1205 patients (447 cases and 758 controls). Cases were defined as women with newly diagnosed breast cancer or carcinoma in-situ, while controls included women with benign breast diseases or those undergoing non-breast related surgery. All patients were asked a series of questions to determine their pesticide exposure, including the type of pesticide, location of exposure (inside vs. outside the home), who applied the pesticide  and duration of pesticide use. Logistic regression models were used to estimate unadjusted and adjusted odds ratios (OR) and corresponding 95% confidence intervals (CI).The most common pests encountered in participants' homes were ants, carpenter ants, and cockroaches. The calculated adjusted odds ratios for both self and professionally applied pesticides, specifically against the above mentioned insects, with regard to breast cancer risk were 1.25 (95% CI: 0.79-1.98) and 1.06 (95% CI: 0.65-1.73), respectively. Similarly, odds ratios and confidence intervals were calculated for other types of pesticides.Overall, the results of our study did not show an association between self-reported exposure to pesticides and breast cancer risk. Future studies, utilizing a larger sample size and more specific detail on time frame of pesticide exposure, are needed to further explore this question. Self-reported exposure to pesticides and risk of cancer has been an area of much debate in epidemiological research. Recently a paper by Teitelbaum et al.  has agaiTeitelbaum et al.  revisiteA case-control study was conducted at Long Island Jewish Medical Center and at North Shore University Hospital from October 1994 through October 1996. The results of this study have been described in detail previously [Trained interviewers used a structured questionnaire to collect data which included known risk factors for breast cancer such as age at diagnosis, family history of cancer in first-degree relatives, body mass index, menstrual history and oral contraceptive use. Though family history of all types of cancer was taken, only family history of breast cancer was included in the final statistical analysis.All patients who reported pesticide use were then asked a series of questions on pesticide exposure, which included the types of pesticides to which the patient was exposed, whether it was applied by a professional insect exterminator or the patient herself, delivery method, and location of dispersal. Types of pesticides, including both insecticides and herbicides, were classified into seven categories. These included agents used for:1. Ants, carpenter ants, cockroaches2. Bees or wasps3. Flies or mosquitoes in the home or yard4. Fleas or ticks in the home5. Weeds6. Lawn insects7. Insects or diseases of outdoor plantsIf the patient reported the use of any of the above pesticides in the past, then specific questions were asked regarding the period of exposure. These included, how many months of the year pesticides were used and how often they were used during those months, with possible responses ranging from daily or continuous use to less than once-per-week. It was uncertain whether the risk of breast cancer would be greater with a professional application since higher concentrations of pesticides are often used, or with off-the-shelf agents since the patient would be performing the pesticide application herself. Likewise, data was collected regarding various product types since particle density and pesticide dose could not be assumed to be uniform across different application modalities. It should be noted that our analysis was limited by the data collection tool not specifically addressing the start and stop years of pesticide use. Thus, it was not possible to know the timing of first exposure and to estimate the lifetime exposure.For each of the seven pest categories, we calculated the risk of breast cancer according to who applied the pesticide, the method of application, and the location of application (inside or outside the home). The frequency of exposure was estimated by asking the subject how many months of the year pesticides were used and during those months how often the product was used. The answers to both these questions were used to generate an estimate of cumulative exposure. This calculated exposure density was arranged in progressive tertiles, and then analyzed for association to breast cancer risk.Furthermore, some patients may have been exposed to multiple products. Thus, exposure categories could not be mutually exclusive. The most common mode of application was by sprayer. The use of foggers and powders was infrequent; therefore data from these two groups was combined into a single categorical variable. Similarly, few subjects reported applying pesticides both inside and outside the home. So, these subjects were combined with participants who reported using pesticides only inside the house. Data as to who actually applied the pesticide was divided into application of pesticides by the study participant and application by other individuals, who may have been pest-control professionals or household members other than the study participant. In pesticide-specific analysis, persons who reported not being exposed to the specific pesticide under analysis were classified as the non-exposed referent group.Logistic regression models were used to estimate adjusted and unadjusted odds ratios (OR) and corresponding 95% confidence intervals (CI), regarding associations between pesticide use and development of breast cancer. Specifically, unconditional logistic regression models were selected to determine the risk according to 1) who applied the product, 2) what type of product was applied, or 3) where the product was applied. The models were adjusted for the following confounding variables: subject's age at the time of disease diagnosis, race, religion, level of education, family history of breast cancer, body mass index, age at menopause, and age at menarche. A separate model was created to test the effect of cumulative exposure in comparison to those who were never exposed. For each of the seven categories of pests, cumulative exposure to pesticide was calculated and then categorized into upper, middle and lower tertiles.Finally, a third model was developed based on multiple exposures (yes/no) to all pesticides. For this analysis, subjects were assigned to one of the following categories: never exposed to pesticides, exposed to one type of pesticide, exposed to two types of pesticides, exposed to three types of pesticides, exposed to four types of pesticides, or exposed to five or more types of pesticides. The never-exposed category only included subjects who reported not being exposed to any pesticide. A test for trend was conducted across these categories using the Cochran-Armitage test. All data analyses were conducted using SAS statistical software version 9.1 .A total of 1205 patients were included in this study. Regarding the age of study subject 30% of the cases and 48% of the controls were younger than 50 years of age, respectively and 20% of cases and 12% of controls were older than age of 70, respectively. As regard to menopause, 42% of cases and 51% of controls had menopause by 49 years of age, respectively. Level of education was used as a substitute for the socioeconomic status. There were no significant differences between cases and controls with regard to religious status, race, oral contraceptive use, or age at menarche  and 229 controls (30%), respectively. When the relationship between breast cancer and the type of pesticides used was analyzed with regard to who applied the product, both the unadjusted and adjusted odds ratios were not found to be significant. For example, the most commonly used pesticides were for ant, carpenter ant, and cockroach infestations. The adjusted odds ratio for self-application of pesticide and application by other individuals were 1.25 (95% CI: 0.79-1.98) and 1.06 (95% CI: 0.65-1.73), respectively  (Table Organochlorine pesticides have received more attention in the past because of their persistence in the environment, continued detection in the food supply and breast milk and their ability to be stored in the adipose tissue of both animals and humans . FurtherComparison between our study and the LIBSCP study  shows coOne possible explanation for the difference in findings between our study and the LIBCSP study is that LIBSCP used randomly selected population controls. In our study, women with a suspicious breast mass did not know their tissue diagnosis at the time of questionnaire completion. Thus, the design of our study may have minimized recall bias. Furthermore, positive findings in the LIBCSP study could have been due to chance as the authors note that they did not observe a dose-response relationship.The major strength of our study is that the data was collected in-person, by an interviewer before the disease diagnosis was established and assignment to either the case or control group occurred after the review of tissue pathology reports. This potentially would have minimized any possibility of a reporting bias, despite the high profile of breast cancer risk studies from Long Island, NY. The use of two control groups serves to validate these findings, where subjects with benign breast disease likely had very similar referral patterns as breast cancer cases, and the use of general surgical controls reduced possible methodological bias if an association between pesticide use and benign breast disease existed.The main limitation of our study is that the questionnaire did not specify the time frame of exposure. This might be important since we know that there is potential of a long lag time between exposure to pesticides and development of breast cancer, as reported by Hoyer et al. . This laIn conclusion, our case-control study did not show an association between self-reported residential exposure to pesticides and breast cancer risk. The real strength of this study is that the interviews were conducted before tissue-based diagnosis of disease. However, our study was limited by the lack of detail on the time of initial exposure, a smaller sample size, and an absence of information regarding the chemical constituents of different categories of pesticides. Therefore, we recommend that a follow-up study with more precise information about the time frame of exposure, a larger sample size, and a detailed account of chemical constituents of the pesticides should be conducted to further explore this question.LIBCSP: Long Island Breast Cancer Study Project.The authors declare that they have no competing interests.UF participated in study design, prepared the datasets, oversaw the analysis and drafted the manuscript. MJ participated in study design, and helped drafting the manuscript. VN participated in study design, and helped drafting the manuscript. PC participated in the study design, prepared the datasets, oversaw the analysis and, helped drafting the manuscript. DF reviewed the manuscript and revised it critically for important intellectual content. NJG helped prepare the datasets and performed the statistical analysis. SDS was principal investigator, reviewed the manuscript and revised it critically for important intellectual content. JM participated in the study design, oversaw the analysis, reviewed the study results, and revised the manuscript critically for important intellectual content.All authors read and approved the final manuscript.


Previous prospective studies have found an association between prolactin (PRL) levels and increased risk of breast cancer. Using data from a population-based breast cancer case–control study conducted in two cities in Poland (2000–2003), we examined the association of PRL levels with breast cancer risk factors among controls and with tumour characteristics among the cases.We analysed PRL serum levels among 773 controls without breast cancer matched on age and residence to 776 invasive breast cancer cases with available pretreatment serum. Tumours were centrally reviewed and prepared as tissue microarrays for immunohistochemical analysis. Breast cancer risk factors, assessed by interview, were related to serum PRL levels among controls using analysis of variance. Mean serum PRL levels by tumour characteristics are reported. These associations also were evaluated using polytomous logistic regression.P=0.05) but not in postmenopausal women. Associations in postmenopausal women included an inverse association with increasing body mass index (P=0.0008) and direct association with use of recent/current hormone therapy (P=0.0006). In case-only analyses, higher PRL levels were more strongly associated with lobular compared with ductal carcinoma among postmenopausal women (P=0.02). Levels were not different by tumour size, grade, node involvement or oestrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 status.Prolactin levels were associated with nulliparity in premenopausal (Our analysis demonstrates that PRL levels are higher among premenopausal nulliparous as compared with parous women. Among postmenopausal women, levels were higher among hormone users and lower among obese women. These results may have value in understanding the mechanisms underlying several breast cancer risk factor associations. Phet=0.95) (Prolactin (PRL) is a peptide hormone implicated in growth and differentiation of breast epithelial cells . Serum samples were available from 1155 of these women. We excluded women treated before collection of blood (n=353) or tumour tissue (n=23), resulting in 779 cases for PRL serum analyses. Controls were matched to cases on menopausal status, age (in 5-year increments), time of day of blood draw (within 2 h), study site, and, for premenopausal women, day in menstrual cycle (±2 days).Of 2386 eligible cases with questionnaire data, we selected the subset with invasive cancer tissue prepared as tissue microarrays (TMAs)  using an immunoassay and concentrations calculated by the ADVIA Centaur instrument , which was calibrated with known PRL concentrations. Approximately 3% of samples that included low, medium and high levels of PRL were retested in masked fashion to assess intra- and interbatch variation. The overall coefficient of variation for the PRL serum assay was <5% and the intraclass correlation coefficient was >99%.Histopathologic features including histology, grade, tumour size, and axillary lymph node metastases were assessed using surgical pathology reports. Tumour features were independently evaluated by the study pathologist (MES). Results for immunohistochemical stains for oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) from the invasive cancers, prepared as TMAs with duplicate representation as 0.6-mm diameter cores , were determined as reported previously .T-test (continuous) and χ2 analyses . Analyses were based on natural log transformation of serum PRL levels. The association of PRL concentrations with known risk factors was evaluated among controls using analysis of variance. Details of the entire Poland breast cancer case–control study population with questionnaire data have been reported previously (Associations between subjects’ demographic and breast cancer risk factors and serum PRL levels were assessed using –2), age in 5-year categories, and study site. For premenopausal women, the additional matching variable of menstrual status was also adjusted for in models. For postmenopausal women, models were also adjusted for oral hormone replacement therapy (HRT) use . Never users of oral HRT were those individuals who used oral HRT for 1 month or less and, among users, current/recent users were those for whom it had been 2 years or less since last use and past users were those for whom the last use was >2 years ago. P-values to test for heterogeneity of ORs between tumour characteristics were calculated using logistic regression analyses restricted to cases with the relevant tumour characteristic as the outcome and PRL serum hormone levels as the explanatory variable. Mean serum PRL levels across important tumour characteristics are reported to illustrate the relationship between serum PRL levels and breast cancer histology.To determine if serum PRL levels varied by important tumour characteristics, we initially performed polytomous logistic regression to estimate odds ratios (OR) and 95% CI for PRL serum levels with the relevant tumour characteristics as the outcome variables. The final models adjusted for the following variables: time of blood collection in 2-h categories, years of education, age at menarche , age at menopause , number of full-term births , age at first full-term birth , family history of breast cancer among first-degree relatives, previous breast disease (history of a benign breast biopsy 1 year before date of diagnosis for cases and date of interview for controls), body mass index (BMI) , which excluded 4% (n=19) of the premenopausal population and 3% (n=35) of the postmenopausal from the analysis. PRL levels were significantly different between premenopausal and postmenopausal controls. Therefore, separate quartiles were established for pre- and postmenopausal women using the distributions from the control population. For premenopausal women the quartiles were ⩽7.70, 7.71–10.20, 10.21–15.00, and >15.00 ng ml–1. For postmenopausal women the quartiles were ⩽5.30, 5.31–6.70, 6.71–8.40, and >8.40 ng ml–1. To estimate the association between PRL serum levels and breast cancer risk, we used conditional logistic regression models separately for pre- and postmenopausal women, as described above for the analysis with tumour characteristics, to compute OR and 95% CIs. Statistical significance was defined as two-sided P<0.05 and all analyses were completed with SAS  or STATA  software.In The study population consisted of 230 premenopausal and 543 postmenopausal breast cancer cases and an equal number of matched controls. The mean age was approximately 45 (±5.3) years old for premenopausal women and 61 (±7.7) years old for postmenopausal women. With respect to breast cancer risk factors and tumour characteristics, the distributions for the population selected for the analyses presented herein (data not shown) did not significantly differ from the entire Poland breast cancer case–control parent population  (P=0.0008). In separate analyses of height and current weight, height was positively associated (P=0.04) and current weight was inversely associated (P=0.01) with serum PRL levels in postmenopausal women (data not shown), suggesting that the association with current weight is the dominant factor in the inverse association of PRL levels with BMI.The association of PRL levels with established breast cancer risk factors was examined among controls. Geometric mean PRL levels were 10.9 ng mlcontrols . Among p P=0.05) . Other cP=0.0006). After mutually adjusting for BMI and HRT, the associations of serum PRL levels with BMI and HRT were still significant .With regard to oral contraceptive use, this population included only 10 current and 28 former premenopausal oral contraceptive users, precluding a meaningful analysis of the relationship of use to PRL levels. Among postmenopausal controls, women currently using HRT had significantly higher PRL levels than never or former users (P=0.003) when comparing the highest with the lowest PRL quartile and, among premenopausal women, PRL levels were not associated with increased breast cancer risk.In P=0.02, P=0.03). This difference in PRL levels translated into a stronger risk association for lobular  than ductal  tumours. No other significant differences in PRL levels were noted across the tumour characteristics of tumour grade, size, node involvement, and ER, PR, or HER2 expression.We further evaluated the association of PRL levels with clinically important tumour characteristics among cases . In postOur analysis of serum PRL levels among population-based controls in the Polish study demonstrated significant relationships with three established breast cancer risk factors: nulliparity, among premenopausal women, and HRT and BMI among postmenopausal women. Consistent with previous reports, we found that PRL levels among parous premenopausal women were lower than those among nulliparous women (in vitro oestrogen upregulates expression of PRL (In this study, PRL levels were inversely associated with BMI among postmenopausal women, whereas other analyses have shown null (Although there have been reports demonstrating a positive association of oral contraceptive use with PRL levels . In our Previous data have suggested that a positive family history of breast cancer may be related to higher PRL levels, especially among premenopausal women (In addition, we examined the association of serum PRL levels with tumour characteristics. We did not find significant difference in geometric mean PRL levels by either tumour size or the presence of lymph node metastases, suggesting that PRL levels may not be related to time of clinical diagnosis. In this population, we did identify a stronger relationship between high PRL levels and postmenopausal invasive lobular carcinoma. This finding is interesting and in contrast to previous reports in which no heterogeneity between invasive ductal and lobular cancers was detected (Prolactin levels were not related to ER, PR, or HER2 status. These data did not replicate the finding from NHS I and II where the association with PRL was stronger among ER+/PR+ tumours (The analyses presented herein have some limitations. Notably, our case–control results must be interpreted with caution as PRL is a stress hormone and we cannot exclude that the relationship with breast cancer was influenced by a stress responses . If PRL In this study, PRL also was measured by an immunoassay that does not discriminate between PRL isoforms, some of which are reported to have varying biological activity , 2007a. The strengths of this study include its population-based design, and extensive collection of risk factor, pathologic and immunohistochemical data. Our analyses were based on incident cases from whom serum was collected at the time of diagnosis of breast cancer. In addition, PRL measurements have been shown to be reliable and most likely a reflection of cumulative exposure over time , we foun


In Canada, cancers of the endometrium, ovaries, vulva, vagina, placenta and adnexa account for 11% of all malignant neoplasms in women and 81% of all genital cancers. Although the incidence and mortality from vulvar and vaginal cancers are very low, endometrium and ovarian cancer are important public health problems.In Canada, there has been no appreciable improvement in survival for women with advanced endometrial (EC) or ovarian cancer (OC) over the past 30 years. The prognosis of EC is good for most patients because diagnosis is made at early stages. However, survival of OC is poor; more than 70% of cases are diagnosed at late stages. Up to 10% of OCs is linked to familial aggregation. Cancers of the vulva and of the vagina are very rare. The survival experience for women with the latter is worse than for those with the former. Both share many risk factors with cervical cancer and the recent developments in the study of HPV infection should be applicable to these diseases as well. Of particular interest will be the advent of vaccines for the primary prevention of HPV infection.At present, the best available means to diagnose gynecologic malignancies is a detailed clinical examination, considering the totality of information on potential and proven risk factors, such as age, reproductive health, sexual practices, use unopposed estrogens or of oral contraceptives or tubal ligation, obesity, diet, smoking, and the familial clustering of some of these cancers. In 2000, there were more than 4.7 million cases of cancer in women worldwide, 54% of which occurred in less developed countries.  GynecoloAlthough the incidence and mortality from endometrial and ovarian cancer are important public health problems, other female genital cancers are very rare. Primary tumours of the vagina, vulva, placenta and adnexa total 0.6% of all female cancers. Neoplasia developing elsewhere in the female genital tract is even less common. Because neoplastic disease in these sites is rare, there is very little information on it; most of the data available are from case series or hospital- and clinic-based studies.Data on incidence rates and rates of mortality from gynecologic cancers in Canada were obtained from Statistics Canada and in the United States from the Surveillance, Epidemiology, and End Results (SEER) Program. Other epidemiologic and risk factor information was found in published surveillance and research reports.Most neoplasias of the corpus of the uterus develop in the endometrium and are endometrioid type adenocarcinomas. Endometrial cancer (EC) is the seventh most common malignancy affecting women worldwide, with almost 190,000 cases annually. It is thThere is great variation in the incidence rates of EC internationally. The highest risk areas are Central and North America and Polynesia, whereas rates that are 10 times lower occur in western Africa. Figure An estimated 3,500 new cases were diagnosed in Canada in 2001, which is more than twice the number of cervical cancer cases. [Figure The prognosis of EC is generally favourable because in 75% to 90% of cases the disease is confined to the uterus at diagnosis, a condition that is highly curable by surgical removal of the uterus.  Stage atEC risk is influenced by reproductive and hormonal factors. The greatest impact on the risk of endometrial cancer comes from the exposure to estrogens without concomitant intake of progesterone. Several case-control studies have demonstrated the effects of estrogen replacement therapy on the risk of EC.  In premeNulliparity, ,13 high Obesity has consistently been shown to be associated with increased risk (two to five times as great) of EC, possibly through a combination of mechanisms. Obese women may be more prone to an increased endogenous production of estradiol. Increased risk may also result from continued anovulation, causing progesterone deficiency. Several studies have examined the relation between EC and physical activity because exercise lowers serum estrone levels. Most studies report a weak to moderate protective effect, but this question is still unsettled, since the effect does not vary with the duration and intensity level of activity and it is difficult to determine whether obesity, a strong risk factor, is a cause or a consequence of inactivity. Diets rich in whole grains, fresh fruit and vegetables as well as consumption of fatty fish exert a protective effect against EC, whereas high animal fat intake seems to increase EC risk. ,20,21 A Women receiving unopposed estrogens should undergo endometrial sampling biennially (risk increases only after two years of estrogen use), particularly if endometrial hyperstimulation has previously been documented and has not been treated by short-term administration of progestins. At present, there are no guidelines for the surveillance of women using tamoxifen, and in particular those taking tamoxifen who have used estrogen replacement therapy in the past. Because these women may be at increased risk of endometrial cancer, information on abnormal bleeding should be obtained on a routine basis; decisions on additional tests should be taken by their gynecologists. Use of newer estrogen antagonists, such as raloxifene, which seem to provide similar preventive effects for breast cancer and none of the risk effects for endometrial cancer, are likely to change this perception. Women at high risk who request an endometrial evaluation may undergo an office-based investigative procedure to rule out pathology.  An endomHigh-risk women should be evaluated by any of the following detection tests: (i) cervico-vaginal cytology, (ii) endometrial cytology, (iii) endometrial biopsy, (iv) dilatation and curettage, (v) transvaginal ultrasonography, (vi) magnetic resonance imaging or computerized tomography, or (vii) hysteroscopy.The only group of women for whom there are explicit guidelines for screening are those with a positive test or positive family history of hereditary non-polyposis colon cancer. The American Cancer Society recommends annual screening beginning at age 35. Routine screening of asymptomatic women using any of the techniques noted has not been proven to be of benefit.  No screeOne could argue that although EC is common, its attendant morbidity is relatively low as compared with that of other female neoplasms, such as breast and cervical cancers. The high cost and discomfort to the patient of most procedures make them unattractive as large-scale, cost-effective screening tools.Preventing EC through public and professional education seems to be a sensible approach. Physician education should include increasing awareness that EC is the most common gynecologic malignancy and that risk can be reduced by early intervention with endometrial biopsy and treatment in the setting of abnormal uterine bleeding, by administration of progestational therapy for post-menopausal patients on estrogen-only regimens, and by referral for endometrial biopsy of those patients who have endometrial or atypical glandular cells on Pap smear. Public education concerning the risks of endometrial cancer should include awareness of (i) the need to maintain a proper weight, (ii) the risks associated with unopposed estrogen therapy, (iii) the value of OC use in reducing risk, and (iv) the most common signs and symptoms of the disease. Accounting for 3% of all cancers in women and figureing more than 165,000 new cases estimated in2001, ovarian cancer is the sixth most frequent female cancer and the sixth leading cause of death in women worldwide. [There is substantial variation in incidence rates of ovarian cancer internationally, from 3/100,000 in central Africa to 13/100,000 in northern Europe. Developing nations have incidence rates that are approximately half those of the most resource-rich countries. Canada and the United States are among the countries with the highest rates of ovarian cancer worldwide, with rates of 12 and 11 per 100,000 respectively [The incidence of ovarian cancer rises sharply after the age of 40 and peaks in the eighth decade of life ,4 Figur. In CanaFigure Most ovarian cancers are epithelial in origin, but there are many different histological presentations of the tumour. Nonetheless, there seems to be evidence for the existence of precancerous lesions,  althoughOvarian cancer tends to be a fatal disease because it is usually not detected before extensive intraperitoneal spread. The most important factor in predicting survival from ovarian cancer is stage at diagnosis.  Since 70Of all ovarian cancers, 5% to 10% are hereditary, and most of these (65% to 75%) belong to the hereditary breast-ovarian cancer syndrome group that is linked to mutations in BRCA1 or BRCA2 tumour suppressor genes. ,35 The mSome reproductive factors result in significant protection against ovarian cancer: OC use reduces the risk by 30% to 40% and so does a term pregnancy (40%). ,37,38 TuSeveral other risk factors  that have been studied have not shown consistent effects.Several factors render screening for ovarian cancer impractical: there is no defined precursor lesion as the target, there are many possible etiologic pathways, access to the ovaries is difficult, and most ovarian pathologies that produce an abdominal mass are not malignant.® program has evaluated the CA 125 test, transvaginal ultrasound, and pelvic examination and has concluded that there is insufficient evidence to recommend any of these methods. Similar conclusions were reached by the U.S. Preventive Services Task Force and by the Canadian Task Force on Preventive Health Care. [Tumour markers, of which the CA 125 test is the most promising, have been the focus of considerable attention. The U.S. NCI-PDQth Care.  Large rath Care. OC use, tubal ligation and prophylactic oophorectomy have been suggested as possible manoeuvres to prevent ovarian cancer in women who have a strong family history or have been found to be positive for a BRCA mutation. However, none of these approaches has been shown to reduce the mortality from ovarian cancer or the incidence of advanced disease.Although tumours in the vulva occur two to three times as frequently as those in the vagina, they are still a rare finding. The cancer registry reporting the most elevated incidence rate of vulvar cancer is that of Prince Edward Island in Canada . Rates above 2/100,000 are found elsewhere, in Peru and Brazil .  All provThe overall survival rate of vulvar cancer is 46%.  The mainThere seem to be two distinct risk factor profiles for vulvar cancer that are age-dependent. Cancers developing in younger women (< 65 years) tend to have the same risk profile as other anogenital cancers, i.e. association with low socio-economic status, high-risk sexual behaviours, and the presence of human papillomavirus (HPV) infection and smoking. -48 In adWomen with late-onset vulvar cancers (55 to 85 years) are typically without a previous history of sexually transmitted infections and tend not to be smokers. HPV DNA is found in only 15% of these cancers. It is not yet well understood whether the trend of increasing rates of vulvar neoplasia is due to greater public and physician awareness about the risk of HPV-associated diseases or whether it is a cohort effect associated with changes in sexual practices that began in the late 1960s, such as increased sexual activity and increased prevalence of smoking among women of reproductive age.Because there is evidence of diagnostic delays, that is, women seek medical care in advanced stages of the disease, some authors recommend that women perform self-examination monthly and also that physicians be made aware of the features of this disease.  Given thNeoplasms of the vagina are extremely rare. The reported annual age-standardized incidence rate (ASIR) is fewer than 1/100,000 women in all countries with the exception of Argentina  and Colombia .  Nova ScoThe survival of patients with vaginal cancers is generally poor: stage I disease has a five-year survival rate of 64% to 90%, stage II of 29% to 66%, and stages III and IV of 0% to 40%. Most vaginal cancers are squamous. Clear cell adenocarcinomas used to occur in young women as a consequence of maternal exposure to diethylstilbestrol (DES) before the 12th week of gestation.  Other riA recent population-based study found that HPV infection, lifetime number of sexual partners, early age at first intercourse, and smoking were associated with an increased risk of in situ and invasive vaginalneoplasia. In additBecause cancer in the vagina may appear in association with other anogenital cancers, the follow-up of women with a diagnosis of these other cancers should include routine cytological screening and colposcopic examination of the vagina. The health care provider should keep in mind that this procedure should be performed even if the patient has had a hysterectomy.Smoking cessation should be advised, since smoking is a risk factor for cancer of the vagina as well as for neoplasms of other anogenital sites. In addition, the risk of a second cancer for women with cancer of the vagina and of the vulva is greater than that expected according to the incidence rate of these cancers. A study using data from the U.S. SEER program found that most of the excess second cancers were related to smoking  or to HPV infection . Although there is a relative wealth of information on the factors that may cause women to be at higher risk of any of these gynecologic cancers, data on the efficacy of various screening strategies are still incompleteModifiable risk factors such as exposure to unopposed estrogens, obesity and diet play an important role in increasing the risk of endometrial cancer. Therefore, public and professional education to prevent this disease should be encouraged and improved. Concerning risk factors, there is good evidence for a protective role of oral contraceptives, which should be taken into consideration by practitioners when judging risks of familial ovarian cancer.Although several screening methods have been studied, including several tumour markers, none has been found yet to be particularly useful in reducing the incidence of advanced disease or mortality from ovarian cancer; thus further research is needed to develop diagnostic methods capable of diagnosing disease at an early stage. At present, the best available means of diagnosing gynecologic malignancies is through a detailed clinical examination as part of routine health care, provided that the physician considers the totality of information on potential and proven risk factors, such as age, reproductive health, sexual practices, smoking and the familial clustering of some of these cancers.


Early menarche increases breast cancer risk but, aside from weight, information on its determinants is limited.Age at menarche data were collected retrospectively by questionnaire from 81 606 women aged 16–98, resident in the UK and participating in the Breakthrough Generations Study.Ptrend<0.001), were singletons (P<0.001), had prenatal exposure to pre-eclampsia (P<0.001) or maternal smoking (P=0.01), were not breastfed (Ptrend=0.03), were non-white (P<0.001), were heavy (Ptrend<0.001) or tall (Ptrend<0.001) compared with their peers at age 7 and exercised little as a child (Ptrend<0.001). Menarcheal age increased with number of siblings (P<0.001) independently of birth order, and had an inverse association with birth order after adjustment for sibship size (P<0.001). In a multivariate model, birthweight, ethnicity, weight, height, exercise, sibship size and birth order remained significant, and maternal age at birth became significant .Menarche occurred earlier in women who had a low birthweight (Age at menarche was influenced by both pre- and post-natal factors, and these factors may affect breast cancer risk through this route. Early menarche increases risk of breast cancer, probably as a consequence of earlier onset of ovulation and cyclic exposure to female sex hormones, and hence potentially an increased cumulative exposure to these hormones over the course of life . Taller It is unclear which other factors are important. In particular, the effects of prenatal and early life factors on age at menarche remain uncertain, in the main due to a lack of adequately powered studies. For example, there is weak evidence that menarche is delayed in girls who were heavier at birth , to improve understanding of the causation of menarche both as a significant biological event and as a breast cancer risk factor.The BGS is a cohort study of breast cancer aetiology, for which all women aged 16 or older who live in the UK are eligible. The South Thames Multicentre Research Ethics Committee approved the study. Recruitment began in 2003 and 111 595 women have joined. The initial participants were supporters of the Breakthrough Breast Cancer charity, and women who referred themselves. Participants nominated other women and the majority of participants were recruited in this way. Therefore, there are a large number of BGS participants who have other family members in the study.N=100 594). We excluded 6409 women with a history of breast cancer or ductal carcinoma in situ at study entry (who were greatly over-represented), 16 women whose menarche occurred later than age 20 years, because often their menses were initiated by exogenous hormone treatment and 2 women who reported intermittent menses at ages 3 or 4 years followed by a later menarche. If two or more first-degree relatives were eligible for the analysis, then only the youngest relative was included (Nexcluded=12 561). These analyses therefore included 81 606 women.Participants were eligible for the analyses if they reported their age at menarche on the baseline questionnaire (N=9278). Furthermore, data on maternal smoking were only available if the subject was the first-born child (N=6340).Most variables were reported on a detailed baseline questionnaire that was completed by all participants. The exceptions were the breastfeeding and maternal smoking variables, which were obtained by record linkage to the mother's questionnaire, and so these analyses were restricted to women whose mothers were also study members . Analyses were repeated excluding participants who were aged 30 years or older at study entry, because recall of age at menarche and its determinants might be less accurate in the older women , whose mother had pre-eclampsia or eclampsia (P<0.001), or who smoked (P=0.01) during the pregnancy with the subject, who were not breastfed (Ptrend=0.03), were not white (P<0.001), were heavier (Ptrend<0.001) or taller (Ptrend<0.001) than their peers at age 7 years, did not exercise (Ptrend<0.001), had no siblings (Ptrend<0.001) and were the first-born child (Ptrend<0.001). Twins had a later menarche than singletons  but, when analysed by type of twin, the difference was significant for participants who were part of an opposite-sex dizygotic or a monozygotic twin pair but not those who were part of a same-sex dizygotic twin pair (Ptrend=0.15) or being a vegetarian before age 8 years (P=0.18). These results were all similar after adjustment for socio-economic status and birth year (data not shown).Baseline characteristics of the 81 606 women included in these analyses are shown in win pair . There wPtrend<0.001), ethnicity (P<0.001), weight (Ptrend<0.001), height (Ptrend<0.001), exercise (Ptrend<0.01) and number of siblings (Ptrend<0.001) remained significant. A higher birth order (Ptrend<0.001) and a younger maternal age at birth (Ptrend<0.001) were now associated with an earlier menarche. Twinning and exposure to pre-eclampsia or eclampsia had a significant effect in univariate analyses, but not in the multivariate model.In the multivariate model , the assThe multivariate model suggests that the variables can combine to give large differences. For example, a non-white girl who was much heavier and taller than her peers at age 7 could reach menarche nearly 2 years earlier on average than a white girl of average weight and height, assuming that all other factors were the same .Ptrend<0.001; Ptrend<0.001, N=28 033; second: effect=0.3, Ptrend=0.02, N=16 875), but not in women of a higher birth order . In each height category, weight had a significant inverse association with menarcheal age .In subgroup analyses, birthweight had a positive association with menarcheal age within each childhood weight category (P=0.08) and the association with exercise was stronger than in the unrestricted analyses (effect=2.8 months).In the univariate analyses restricted to participants who were younger than age 30 years at recruitment, pre-eclampsia exposure did not have a significant effect , as did the effect of twin status after adjustment for birthweight . When analysed separately, age at menarche increased by 1.1 (Ptrend<0.001) and 0.8 (Ptrend<0.001) months per sister and brother respectively. There was a significant negative association with birth order after adjustment for sibship size only (Ptrend<0.001).In additional analyses (data not shown), the effect of birthweight remained significant after adjustment for gestation length (In this study of more than 80 000 women, age at menarche was influenced by both pre- and post-natal factors, and some of these factors appear to interact with each other.Menarche was delayed in girls who were heavier at birth, which agrees with weak evidence from some previous studies .Previous findings for twins are inconsistent (Our study adds to the growing evidence that women with prenatal exposure to cigarette smoke have an earlier menarche. Of the three previous studies that have investigated this factor, two also found this result (in utero oestrogen levels, whereas exposure to pre-eclampsia or eclampsia probably reduces breast cancer risk as they are associated with lower in utero oestrogen levels (It has been hypothesised, and there is evidence supporting this, that higher birthweight, maternal age and twinning probably increase breast cancer risk as they are associated with higher Other factors, however, were both associated with an earlier menarche in our results and are factors that lead to reduced risk of breast cancer. First, we found that girls who exercised more had a later menarche, which is consistent with previous findings  and has White women had a later menarche than non-white women in accord with fairly strong evidence from many (We found that height was inversely associated with age at menarche, in accord with previous findings (We observed a significant positive association between number of siblings and age at menarche, which strengthened after adjustment for birth order. In previous, small studies, the relation with sibship size was unclear . Our resAfter adjustment for sibship size, birth order had a significant inverse association with age at menarche. Previous studies found that birth order has a positive association with age at menarche . Birth oAlthough association is far from indicating causality, causal relationships are plausible between age at menarche and several of these factors; for instance, weight loss can induce secondary amenorrhoea . This maThere are limitations to our study. The participants were volunteer recruits, and not a population-based random sample, which could potentially bias the associations. This might have affected the analyses for ethnicity because non-white participants were a more-selected, and perhaps differently selected, sample of all non-white women than the white participants. However, it is unlikely that there was material bias for other variables because, after adjusting for socio-economic status, women who had been breastfed, for example, were unlikely to have been selected on age at menarche in any different way from women not breastfed. As in many other large studies of this type, our data were retrospectively reported. In conclusion, our results suggest that pre- and post-natal growth, body size and endogenous hormones affect age at menarche, and several of the causes of early menarche are themselves associated with increased breast cancer risk; thus, they may affect breast cancer risk through this route.


P=0.02). Parity was negatively associated with risk (P-trend=0.02) but age at first live birth was not significant (P=0.16). Importantly, breast cancer risk decreased by 7% for every 12 months of breastfeeding (P-trend=0.005). It is worth noting that the distribution of reproductive risk factors changed significantly from early to late birth cohorts in the direction of increasing breast cancer incidence. Our findings also highlight the heterogeneity of breast cancer aetiology across populations, and indicate the need for further studies among indigenous sub-Saharan women.As the relation between reproductive factors and breast cancer risk has not been systematically studied in indigenous women of sub-Saharan Africa, we examined this in a case–control study in Nigeria. In-person interviews were conducted using structured questionnaires to collect detailed reproductive history in 819 breast cancer cases and 569 community controls between 1998 and 2006. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI). Compared with women with menarcheal age <17 years, the adjusted OR for women with menarcheal age ⩾17 years was 0.72 (95% CI: 0.54–0.95,  Nigeria is the most populous nation in Africa with about 140 million people, and one in five Black persons all over the world has Nigerian ancestry. Historically, Nigeria has a lower incidence rate of breast cancer compared with the United States and other developed countries , ethnicity , education , family history of breast cancer , benign breast disease , hormonal contraceptive use , alcohol drinking , height, body mass index (BMI), and menopausal status . Alcohol drinking was defined as consumption of alcoholic beverages at least once a week for 6 months or longer.t-tests or Wilcoxon rank-sum tests for continuous variables and χ2 tests for categorical data. Logistic regression models were used to examine the relationship of breast cancer risk with reproductive factors. Odds ratio (OR) and 95% confidence intervals (CI) were computed as measures of association from the logistic models. Multiple logistic regression models were used to adjust for age and other potential confounders listed above. We also tested whether the effects of reproductive factors varied according to menopausal status by adding an interaction term in the logistic models. All five reproductive factors were included as both continuous and categorical variables in the models. Parity was further modelled using a linear spline function with a knot at one live birth to assess the effect of first live birth and trend after the first live birth, simultaneously . In the age-adjusted analysis, women with menarche at or after age 17 years showed about 40% lower risk than those with menarche at less than 17 years. Cases were more likely than controls to be nulliparous, and there was an inverse trend between parity and risk (P=0.02). In the spline regression, the age-adjusted OR was 0.69 (95% CI: 0.43–1.09) for the first live birth and 0.97 (95% CI: 0.91–1.03) for each later additional birth. No significant difference was found between cases and controls with regard to age at first live birth. All but four parous women (0.3%) had breastfed their babies. The lifetime duration of breastfeeding was quite long, averaging 66 months (range: 1–294 months) with overall, only 1.4% for less than 6 months. There was a dose–response relationship between lifetime duration and risk (P=0.005). Mean duration of breastfeeding per child was also negatively associated with risk (P=0.007). Women who had breastfed at least 12 months per child had their risk decreased by one-third.P<0.001). Women with missing data were included in the multivariate analysis to avoid unnecessary loss of power and potential bias. Twenty data sets were generated by multiple imputation such that the efficiency of estimating OR was greater than 99.5% for the fraction of missing information up to 0.08.Overall, there were 220 (1.1%) missing values of 14 variables in P=0.02) for menarche at or after age 17 years, compared with age less than 17 years. In the multivariate analysis, there was still an inversed association between parity and risk (P=0.02). In the spline regression, the multivariate-adjusted OR was 0.81 (95% CI: 0.49–1.34) for the first live birth and 0.95 (95% CI: 0.88–1.02) for each additional birth. Since there was a strong correlation between lifetime duration of breastfeeding and parity , the association between multiparity (in parous women) and risk was further examined after adjusting for duration of breastfeeding: the small beneficial effect disappeared with OR=1.04  for each additional birth beyond the first. Conversely, the association between breast cancer and lifetime duration of breastfeeding persisted after adjustment for parity, age at first live birth, and other potential confounders . Similarly, mean duration of breastfeeding per child was negatively associated with risk: women who had breastfed at least 12 months per child had one-quarter decreased risk (P=0.06). Age at first live birth remained nonsignificant in the multivariate analyses. We also tested whether the effect of these reproductive factors varied by menopausal status and found no significant interaction between these factors and menopausal status (data not shown).To examine how the prevalence of reproductive factors changed for women born in earlier and later decades, we grouped healthy controls into five birth cohorts as shown in This study demonstrates that reproductive factors play an important role in breast cancer aetiology among indigenous African women. We found that ages at menarche, parity, and breastfeeding were significant predictors, although their distributions in our population were quite different from those in industrialised countries. We did not find that early age at first live birth was associated with decreased risk of breast cancer after extensive statistical adjustment.Later age at menarche has been consistently associated with decreased risk of breast cancer in both premenopausal and postmenopausal women . In the Parous women have a lower risk than nulliparous women, but the relationship between parity and breast cancer is complex  found that only about 25% of tumours were ER+, though a recent study in Nigeria found that 65% were ER+ (We did not find significant association between age at first live birth and risk, which seems inconsistent with all the evidence from studies mainly in Caucasian and Asian populations . Risk faThe current study documented that 30% of Nigerian women started menarche after age 16, the majority had multiple live births, they almost always breastfed their babies, more than half for 12 months or longer per child. These factors probably contribute to the low incidence of breast cancer in Nigerian women. However, these protective effects may be diminishing as women adopt a more western lifestyle. In community controls, their patterns should show similar changes to those in the general population. We found that all reproductive factors changed in the direction towards increased breast cancer risk. We estimated that risk increased by about 37% in women born in 1960s compared to those born in 1930s, due to change in menarcheal age, parity, and duration of breastfeeding. Therefore, incidence in Nigerian population might have increased in the past three decades, and we speculate that it will continue as women born after 1960s become older. A systematic study of the secular trend of incidence in Nigeria is of public health importance.Several limitations are relevant. First, reproductive history was self-reported and may be subject to recall bias. Women can reliably report the number of children they have had, so differential reporting of parity is probably not a serious problem. Duration of breastfeeding, age at menarche, and age at first live birth are less accurate, but presumably not differentially recalled by cases and controls. Second, although the multiple imputation method was employed reasonably to address the missing age at menarche, additional ‘measurement error’ is unavoidable. Third, the estimated trend of breast cancer incidence in Nigeria may have limited accuracy because it is based on the reproductive histories of women from a single community, relative risks from this single study, and the assumption that the population structure is constant over time.Our study population provides an important opportunity to elucidate the effect of reproductive risk factors on risk in prevalence ranges that are not seen in the developed world. A live birth, extended breastfeeding, and later onset of menstruation are protective in Nigerian women, but we found no independent effect of age at first live birth. The study also documents the changing pattern in reproductive factors, which could explain the generally low incidence of breast cancer in Nigerian women and suggests that this may increase over time.


The UK National Case-Control Study Group has examined the relationship between smoking (both own smoking and passive), alcohol consumption and caffeine consumption and the risk of breast cancer. A total of 755 women with breast cancer diagnosed before the age of 36, each with an age-matched general population control, were interviewed, and detailed information on reproductive, contraceptive and medical history, personal attributes and habits were obtained. Additional data on passive smoking were obtained from a subgroup of women. There was no evidence of a statistically significant difference in breast cancer risk between subjects who had ever smoked as much as one cigarette per day and those who had not . Most relative risks for passive smoking exceeded unity, but there was little evidence of significant trends with increasing exposure. The lack of effect of own smoking, and the fact that such smokers are also themselves exposed to the effects of passive smoking, makes any relationship between exposure to others' smoking and breast cancer risk implausible. Alcohol consumption during the year prior to diagnosis and at ages 18 and 25 was examined. Consumers of 0.1-4.9 and 5.0-14.9 g per day generally had non-significantly increased risks compared with never drinkers, but consumers of more than 15 g per day had reduced risks.


Counselees are more aware of genetics and seek information, reassurance, screening and genetic testing. Risk counseling is a key component of genetic counseling process helping patients to achieve a realistic view for their own personal risk and therefore adapt to the medical, psychological and familial implications of disease and to encourage the patient to make informed choices ,2.The aim of this study was to conceptualize risk perception and anxiety about cancer in individuals attending to genetic counseling.The questionnaire study measured risk perception and anxiety about cancer at three time points: before and one week after initial genetic counseling and one year after completed genetic investigations. Eligibility criteria were designed to include only index patients without a previous genetic consultation in the family. A total of 215 individuals were included. Data was collected during three years period.Before genetic counseling all of the unaffected participants subjectively estimated their risk as higher than their objective risk. Participants with a similar risk as the population overestimated their risk most. All risk groups estimated the risk for children's/siblings to be lower than their own. The benefits of preventive surveillance program were well understood among unaffected participants.The difference in subjective risk perception before and directly after genetic counseling was statistically significantly lower in all risk groups. Difference in risk perception for children as well as for population was also statistically significant. Experienced anxiety about developing cancer in the unaffected subjects was lower after genetic counseling compared to baseline in all groups. Anxiety about cancer had clear correlation to perceived risk of cancer before and one year after genetic investigations.The affected participants overestimated their children's risk as well as risk for anyone in population. Difference in risk perception for children/siblings as for the general population was significant between the first and second measurement time points. Anxiety about developing cancer again among affected participants continued to be high throughout this investigation.The participant's accuracy in risk perception was poor, especially in low risk individuals before genetic counseling. There was a general trend towards more accurate estimation in all risk groups after genetic counseling. The importance of preventive programs was well understood. Cancer anxiety was prevalent and associated with risk perception, but decreased after genetic counseling. (accessed November 25th 2007) National Julian-R There is increasing public demand for oncogenetic counseling. Today counselees are more aware of genetics and seek more information, reassurance, screening and genetic testing. For the oncogenetic clinics, it is challenging to provide individualized counseling in the way that it contains all relevant information and fulfill the specific needs and requests of every patient. Risk information is a key component of this process. It is intended to help patients gain realistic views of their personal risk and adapt that risk to the medical, psychological and familial implications of cancer. Information about cancer risk facilitates confidence in making choices about the need of surveillance interventions and in choosing between different control programs and prophylactic procedures. Risk information can be experienced as severe or harmful, and therefore needs to be adapted to the patient's ability and willingness to cope ,2.Risk counseling integrates assessments of the: (1) probability that a genetic susceptibility to cancer exists within the family, 2) probability that the patient has inherited predisposing gene(s) and 3) risk that the patient develops a genetically inherited cancer. These questions concern not only the patient but also close family members and offspring . A total of 47 (25%) female participants were affected, the corresponding figure for men was 8 (35%).Affected participants were statistically significantly older  participants were referred to oncogenetic counseling by their own initiative, 110 (51%) by general practitioners, 14 (7%) by a relative and 9 (4%) by "somebody else". The participants could choose more than one response alternative to this item and 12 patients answered that they participated in counseling both on their own initiative and on the request of a relative.n = 104), ovarian- (n = 5), colorectal- (n = 43) endometrial (n = 1) or gastric- (n = 3) cancer. Information about cancer type and objective risk was missing in four unaffected participants because they returned the first questionnaire partly completed and never attended genetic counseling. However, responses from these four participants were used in some of the analysis.A total of 156 patients (60%) had no previous history of cancer and were categorized as "unaffected" The unaffected participants were referred to genetic counseling due to a family history of breast- (n = 22) ovarian- (n = 9), colon- (n = 15) and endometrial cancer (n = 1). For 8 patients the information about cancer type is missing because these participants only returned the first questionnaire partly filled and never attended genetic counseling. These 8 responses were used in some of the analyses.The affected participants were referred to oncogenetic counseling based on a family history of breast- (n = 61) or on general practitioners (n = 62) did not appear to influence their own risk perception  nor risk perception for children/siblings  or risk estimates for general population .Whether the patients were referred to oncogenetic counselling on their own initiative (n = 93) and in colon cancer families 56.1% (n = 34), (p = 0.132). After genetic counseling the mean risk perception in colon cancer families was 45.1% (n = 29) and 48.0% in breast cancer families (n = 69), (p = 0.593). There were no statistically significant differences in risk perception for children either between individuals with breast cancer  or colon cancer , (p = 0.379) in the family.The type of cancer history in the family did not appear to influence the risk perception. The difference in risk perception between the two most prominent cancer types was not statistically significant before genetic counseling; mean risk perception in breast cancer families was 62.5%  of unaffected participants altered their risk perception after genetic counseling Figure . Of themThe difference in subjective risk perception before and directly after genetic counseling was statistically significant . Difference in risk perception for children was also statistically significant , as well as difference in risk perception for the population . The perception of one's own cancer risk was more accurate directly after genetic counseling in the groups with the same risk as the general population and low risk  or preventive surgery. The hypothetical risk perception was lower if the participants would take part into preventive programs than without such interventions (37% versus 56%) . The moderate and high-risk individuals reported the largest difference in risk estimation depending on whether or not they considered attending preventive programs . After genetic counseling the risk estimation were 34.9% versus 41.0% (p = 0.534). Subsequently, results from the total sample have been analyzed together.Perceived risk for siblings/children was significantly lower than personal risk estimation  when measured on the first occasion and also after genetic counseling . One year after genetic investigations the correlation between risk perception for themselves and for the general population was also statistically significant when asking hypothetically the patients if they would participate in a preventive program  or if they would not participate .Experienced anxiety about developing cancer according to the risk group and point of time for assessment is displayed in Figure n = 140, r = 0.412, p < 0.001], after genetic counseling  and one year after genetic investigations among unaffected patients. One year after genetic investigations, the question was presented depending on what the patients thought the risk would be if they would participate in preventive programs  and if they would not participate in preventive programs .The correlation between perceived risk and anxiety about developing cancer was statistically significant before genetic counseling . Risk perception remained about the same one year after genetic investigations .Differences in risk perception for the general population were also statistically significant before (mean 37.2%) versus after genetic counseling (mean 29.5%) . There was no difference in risk perception between the second and third assessment for the general population.Anxiety about developing cancer again among affected participants continued to be high throughout this investigation Figure . AnxietyThe current study reveals the personal risk perception related to the objective cancer risk and associates the personal risk perception to the risk for children and the general population. The results indicate that before genetic counseling subjective risk was overestimated by the majority of participants, especially among those with low objective risk. Risk perception, however, were more accurate after genetic counseling among the low risk subjects that had been most worried. The perceived risk for siblings, children and the general population was overestimated by both affected and unaffected patients, but was also more accurately assessed after genetic counseling. Participating in preventive programs was considered to result in decreased risk. Cancer anxiety in unaffected patients decreased after genetic counseling, but was still associated with perceived risk throughout the year following genetic investigation. Cancer anxiety in affected patients did not appear to be influenced by genetic counseling.An accurate perception of one's own risk and level of anxiety are important. In the literature, data indicate that increasing perception or personal vulnerability, such as greater anxiety, is associated with a higher use of health care actions . PatientParticipants perceived their own risk as being higher than the risk for anyone in the general population, results which are in concordance with a previous Swedish study . Even thIn 1993 a pilot study of risk perception indicated that only 11% of women in a family affected with breast cancer were able to identify the accurate risk for women in the general population. Less than half were able to identify their own lifetime risk within 50% range of the counselor's estimation . A folloet al. reported that the risk estimations varied widely, but suggested that the most important task in genetic counseling is to ensure that those with increased risk attend surveillance programs and do not suffer from anxiety or depression.In the present study, a radical overestimation of the risk was shown in unaffected individuals with low or similar risk as the general population. This finding is in concordance with a German study showing that moderate and low risk individuals made the most marked overestimation . This phThe finding in this study of more accurate risk estimation after genetic counseling is supported by a number of studies ,27. HoweIn the present study the unaffected subjects considered their risk to be lower if they considered participation in a preventive program as compared to not participating in such a program. The largest difference in risk perception considering participation in preventive programs was found among moderate and high risk individuals. These participants reported the risk as being 40% lower with a surveillance program. The importance of preventive programs is thus understood and the results demonstrate the importance of giving recommendations and supporting patients to participate in check-up procedures. The most of the participants were not included in preventive programs during the time of the current study. A study about predictive testing for HNPCC post-test delineated that none of the non-carriers and all of the mutation carriers adhered to the recommendations . Many otet al [et al describes that after genetic counseling, women with over- or underestimated risk perception had significantly higher general health distress levels than women with accurate risk-knowledge. As their main concern, the women reported not only risk of breast cancer but even themes of loss, unresolved grief and problems within relationships [Experienced anxiety about cancer in the unaffected patients reduced significantly in all risk groups after genetic counseling in accordance with previous studies ,32. The et al ; anxietyionships . Thus a Affected patients had a tendency to overestimate the general population risk for cancer. The same was found in a study of breast cancer concerns in women attending a genetic counseling clinic at a comprehensive cancer center. Affected and unaffected individuals perceived that the women who had already developed cancer are less likely in risk to develop cancer again. When asking the affected patients to recall what they thought their risk was before cancer onset, they estimated the risk of developing breast cancer from 0 to 100% with a mean of 31%. The unaffected women estimated their risk to be approximately 15% with a range 5-100%. The lowest risks were reported by the youngest and by women who have undergone bilateral mastectomy. Many women thought that their risk was confined to the next 10 years, being 33% (mean) for affected with 0-75% range and for unaffected 56% (mean) varying between 0 and 100% .Women with a family history of cancer and overestimation of risk have been shown to report significantly higher breast cancer specific distress . In the The present study has some limitations. The questionnaires were developed by the researchers and not formally validated or reliably tested. Cancer anxiety was assessed by one question which could be considered imprecise. However, it showed changes over time, giving at least an indication that anxiety decreased after genetic counseling. In addition, associations between personal risk estimation and cancer anxiety were revealed. Perceived risk (subjective risk) was assessed by a VAS scale where risk was stated as a point estimate. Objective risk was based on the family pedigree (cancer history) and stated in four categories. This difference might have impacted the findings as small changes in perceived risk were recorded and compared to the wide categories of objective risk.According to a review on approaches to communicating health risks, numerical information regarding the probability that a health problem occurs is difficult to understand. The patients found risk information through numerical probabilities such as absolute numbers, relative risks, ratio and frequency of events or proportions as too scientific. This problem has been underestimated by clinicians in health care. An alternative way to inform patients about the risks is to give verbal descriptions like "an unlikely event" or "risk higher than average" . This waThe participant's accuracy in risk perception was poor, especially in low risk individuals before genetic counseling. There was a general trend towards more accurate estimation in all risk groups after genetic counseling. The importance of preventive programs was well understood. Cancer anxiety was prevalent and associated with risk perception, but decreased after genetic counseling.The authors declare that they have no competing interests.The questionnaires were jointly designed by AL, YB, UP and GL. UP collected the questionnaires and participated in study design and coordination. The statistical analyses were performed by JR and BN. JR drafted the manuscript. All authors read and approved the final manuscript.