Participants completed questionnaires before and immediately after the consultation to assess anxiety, cancer worry, perceived risk, interest in genetic testing and satisfaction. Responses of subgroups of women stratified by clinicians as low, moderate, or high risk were analyzed. There were no significant main effects of study intervention on any outcome variable. Regardless of risk information, there was a statistically significant reduction in state anxiety (P<0.001). Reductions in cancer worry and perceived risk were significant for women at low or moderate risk (P<0.001) but not those at high risk, and satisfaction was significantly lower in the high risk group (P<0.001). In high risk women who received specialist genetic input, there was a marginally significant trend towards increased perceived risk. The effect of risk information on interest in genetic testing was not significant. Breast care specialists other than geneticists might provide assessments of breast cancer risk, reassuring women at reduced risk and targeting those at high risk for specialist genetic counselling and testing services. These findings are discussed in relation to the existing UK Calman-Hine model of service delivery in cancer genetics.The aim was to compare the psychological impact of a multidisciplinary specialist genetics service with surgical provision in women at high risk and those at lower risk of familial breast cancer. Women  86, 233–238. DOI: 10.1038/sj/bjc/6600051www.bjcancer.comThe Cancer Research Campaign© 2002  Breast cancer is the most common cancer in women in the UK. Advances in knowledge of the genetic basis of breast cancer have led to increased public awareness of the importance of a family history in determining susceptibility to the disease. However, the vast majority of breast cancer cases arise sporadically, with no clear familial genetic component. Known inherited gene mutations are implicated in around 5–10% of cases  during an 18-month period from 1996 to 1997. A family history of breast cancer was defined as a first-degree female relative diagnosed with breast cancer before age 50 years, a first-degree female relative with bilateral breast cancer at any age, two or more first-degree relatives with breast cancer, or a first- and second-degree relative with breast cancer. Women were excluded from the trial if they had a personal history of breast cancer, had previously received genetic counselling, or were not resident in Wales. Written informed consent was obtained from each participant. The consent form affirmed patient confidentiality and the right to withdraw from the research study at any time without affecting medical care. Further details of the referral procedure are reported in Figure 1At baseline, participants completed the state scale of the State-Trait Anxiety Inventory , the BreIndividual randomization to the trial clinic or control clinic was based on a computer-generated sequence of random group assignments and took place on receiving the completed baseline questionnaire. In order to minimize response bias, there was no reference to group allocation in the baseline questionnaire or clinic appointment letter.Women randomized to the control clinic were seen by specialist surgical staff who included a breast surgeon and breast care nurse. A standard surgical protocol covered the following components: (i) breast cancer surveillance  and advice on potential risk reducing strategies; (ii) surgical assessment of individual breast cancer risk; (iii) the option of entering the UK Tamoxifen Prevention Trial; and (iv) annual surgical follow-up involving breast cancer surveillance and advice. Referral for genetic counselling or presymptomatic genetic testing was not offered. Surgical assessment of risk was based on non-genetic information collected by the surgeon, including age, reproductive history and minimal family history. This information was presented to women by the breast surgeon in generalized terms and was stratified by the surgeon into one of three categories: low, moderate, or high risk.Women randomized to the trial clinic were seen by a multidisciplinary team that combined clinical input from surgical staff  with specialist genetic risk assessment and counselling provided by a clinical geneticist and genetic nurse specialist. The surgical component of the trial clinic did not include a surgical assessment of risk. The genetic consultation involved genetic assessment of breast cancer risk, education and counselling about familial breast cancer, and the possible offer of presymptomatic testing for the BRCA1/2 gene. Assessment of risk was based on detailed family pedigree data that were collected and analyzed by the geneticist using the statistical model developed by Table 1t-tests or one-way ANOVA. The impact of study group and risk information on satisfaction  and interest in genetic testing  was examined. All results are based on 653 participants who received risk information and completed the questionnaires.A previous report of this trial indicated baseline comparability of study groups =5.92, P<0.001) and moderate risk (t(443)=12.13, P<0.001), but not in those at high risk (t(98)=1.67, P=0.10).There was a significant overall reduction in cancer worry from baseline to follow-up and a significant interaction between risk information and time. Post-hoc analysis indicated that cancer worry declined significantly in women at low risk =17.48, P<0.001) and follow-up =128.56, P<0.001). At both assessments, perceived risk was significantly higher in the high risk group compared to the moderate or low risk groups, and was significantly higher in the moderate risk group compared to the low risk group. The main effect of risk information was modified by a significant risk×time interaction. While perceived risk declined significantly in women at low risk (t(101)=10.78, P<0.001) and moderate risk (t(431)=13.27, P<0.001), there was no significant change in perceived risk in those at high risk (t(96)=0.00, P=1.00). Post hoc analysis of the significant group×risk×time interaction effect indicated that within the trial group, perceived risk decreased significantly in women at low risk (t(49)=6.90, P<0.001) and moderate risk (t(221)=11.83, P<0.001). For high risk women in the trial group, there was a marginally significant trend towards increased perceived risk (t(53)=−1.72, P=0.09). Within the control group there was a significant decrease in perceived risk for women at low risk (t(51)=8.35, P<0.001) and moderate risk (t(209)=7.03, P<0.001), and a marginally significant trend towards reduced perceived risk in the high risk group (t(42)=1.83, P=0.07).There was a significant main effect of risk information. F=13.80, P<0.001). There were no significant main or interaction effects on procedural and affective satisfaction.There was a significant main effect of risk information, but not of study group, on instrumental satisfaction. Post-hoc analysis indicated that women at high risk reported significantly lower instrumental satisfaction than women at low or moderate risk, while those at moderate risk reported significantly lower satisfaction than those at low risk , there was no significant difference between risk groups at baseline (χ2(10)=6.15, P=0.80) or follow-up (χ2(10)=4.93, P=0.90).Although there was a significant overall decline in interest , recommendations were made for a filtered approach to service provision corresponding to the three levels of care described in the Calman-Hine report (1995). These are general practice (primary care), risk assessment at cancer unit level (secondary care), and specialist genetic services involving genetic counselling and, where appropriate, presymptomatic genetic testing at cancer centre level (tertiary care). This filtered approach is a vital first step in developing appropriate service structures and the selective use of specialist genetic resources in breast cancer and, increasingly, other common inherited cancers.It is possible that the current findings reflect the high level of expertise of specialist staff who were involved in the project, which led to enhanced care in the control arm. It remains to be seen whether the findings will generalize to the community setting. Over the next few years, it is likely that initial genetic risk assessment will be conducted in different settings by primary care and, increasingly, nurse specialist staff. Further research must be undertaken to explore their potential role in the appropriate identification and management of at-risk women, the effectiveness of different strategies for assessing and communicating genetic risk information (


The excess risk was striking and statistically significant among women below 50 years of age, but was not evident among older women. Immediate postnatal weight loss  as well as neonatal weight gain rate after the nadir (known to reflect growth hormone levels) was significantly positively associated with premenopausal breast cancer risk.Birth size of a woman has been positively associated with her breast cancer risk, particularly before menopause, but no study has investigated neonatal growth in relation to this risk. We conducted a case–control study nested within a population-based cohort of women, born in Sweden between 1901 and 1961, covering all 405 breast cancer patients and 1081 age- and hospital-matched controls, who were born after newborn charts became available. Compared to neonates who lost <200 g after birth and grew at a rate <25 g day There is much evidence that birth size of women influences their breast cancer risk . No studEvaluating neonatal growth is complicated because weight declines during the first few days after birth, mostly because of water loss, before starting to increase . The ratWe have investigated neonatal growth in relation to breast cancer in adult life by a case–control study nested within a population-based cohort of Swedish women.In Sweden, all residents have equal access to the governmental health-care system, and because there is essentially no private in-patient treatment, hospital services are population-based. Moreover, since 1 January 1947, all residents are assigned an individually unique nine digit national registration number, which contains information on the date of birth and the county in which the individual resided in 1947 or the county of birth for those born in 1947 or later. This number allows linkage with several Swedish registries, including the Swedish National Cancer Registry  neonates with a maximum weight loss of ⩾200 g and growth rate after nadir <25 g day−1; (d) neonates with a maximum weight loss of <200 g and growth rate after nadir ⩾25 g day−1 and (e) neonates with a maximum postnatal weight loss of ⩾200 g and growth rate after nadir ⩾25 g day−1. All neonates in categories b–e remained at the maternity wards for a maximum of 21 days. The weight loss cutoff of 200 g was a round figure derived from the 6.6% reported to be the median percent of birth weight loss for breastfed children . Covariates adjusted in the analysis included maternal age (in years as a continuous variable), maternal socioeconomic status , maternal parity , pregnancy toxaemia (yes/no), neonatal jaundice (yes/no), twin membership , and birth weight .The study was approved by the Institutional Review Boards of the Karolinska Institutet, Sweden, the Harvard School of Public Health, USA, and the US Department of Defense.P<0.0001) and 0.02 (P=0.55), respectively. In these bivariate and possibly confounded patterns, neonatal weight loss appears more pronounced among cases than among controls. There is also some evidence that weight gain after nadir is more pronounced among breast cancer patients below the age of 50 years compared with controls.−1 after nadir .After controlling for confounding through conditional logistic regression, we found no evidence that neonates who did not conform to the usual growth pattern are at different breast cancer risk when compared with the reference category of neonates who lost less than 200 g after birth and grew at a rate less than 25 g dayer nadir . In contIn our case–control study, nested within a well-defined population-based cohort of Swedish women, we have found evidence that immediate postnatal weight loss of the newborn, as well as the neonate's weight gain rate after reaching a nadir of postnatal weight, are significantly positively associated with breast cancer risk among women below the age of 50 years. As indicated in the Introduction, in the light of the literature, we considered the immediate postnatal weight loss as an indicator of water loss, probably reflecting water retention caused by pregnancy hormones, and the postnadir rate of growth as an indicator of higher levels of growth hormones, particularly IGF-1.We interpret our findings as indicating that higher levels of pregnancy hormones and growth hormones during the immediate postnatal period, particularly IGF-1, play an important role in premenopausal breast cancer risk several decades later.No association of postnatal growth pattern with breast cancer risk was evident among women 50 years of age or above, and presumably postmenopausal who, however, were relatively few in this study sample. Besides the numbers, it is also possible that any effect of perinatal factors on risk is gradually diluted as additional adult life breast cancer risk factors are introduced, in line with the conclusion of a major review that birth weight is positively associated with breast cancer risk mostly among premenopausal women . Age at Our study makes use of the unusual opportunities available in Sweden for linking population-based databases and registries. The nested case–control study design retains the advantages of a cohort study in terms of minimisation of information and selection bias. Exclusions were simply on the basis of the availability of linked newborn charts. The sample contained many more women below the age of 50 years  than older women , and so there should be more confidence in the associations found among the former than on their absence among presumably postmenopausal women. In the base of the study, on which we relied, birth size indicators  were very weakly positively related to risk, although mutual adjustment of these indicators tended to increase the positive trends  indicates that the phenomenon is of considerable importance. Confidence limits, however, are wide and the absence of evidence for even additive interaction is of some concern.


Despite its relatively low incidence in Saudi Arabia, breast cancer has been the most common cancer among Saudi females for the past 12 consecutive years. The objective of this study was to report the results of the first national public breast cancer screening program in Saudi Arabia.Women 40 years of age or older underwent breast cancer screening. Mammograms were scored using the Breast Imaging-Reporting and Data System (BI-RADS). Correlations between imaging findings, risk factors and pathological findings were analyzed.2. Sixteen cases of cancer were diagnosed. No cancer was diagnosed in 942 women with R1/R2 scores, and only 1 case of cancer was diagnosed in 228 women with R0/R3 scores. However, among 26 women with R4/R5 scores, 50% had malignant disease and 35% had benign lesions. No correlation was found between known risk factors and imaging score or cancer diagnosis.Between September 2007 and April 2008, 1215 women were enrolled. The median age was 45 years, and median body mass index was 31.6 kg/mPublic acceptance of the breast cancer screening program was encouraging. Longitudinal follow-up will help in better determining the risk factors relevant to our patient population. Breast cancer is the most common cancer worldwide. Incidence and mortality have reached a plateau and appear to be dropping in both United States and parts of western Europe.13Breast cancer is influenced by multiple risk factors, which can be classified into 4 groups: first, family history/genetic background, which accounts for approximately 15% of all breast cancer cases.14Recently, there is emerging evidence that overall caloric intake and obesity with weight gain in particular are related to increased breast cancer risk with different effects for premenopausal and postmenopausal women.15Despite the relatively low incidence of breast cancer in Saudi Arabia compared to other countries, it has been the most common cancer among Saudi females for the past 12 consecutive years . Data on female patients with invasive breast carcinoma reported from different regions in Saudi Arabia show that most patients are in the age group of 40 to 50 years and were predominantly premenopausal. More than 50% were stage II and III, while ductal carcinoma in situ represented <5% of this population.It is now well established that early detection provides survival advantages to women with breast cancer. Mammography, which detects breast cancer at earlier stages, is a major step in reducing the risk of death from this disease. It was estimated to prevent approximately 20% to 40% of all deaths from breast cancer among women undergoing screening mammography.2932On the other hand, many women have no access to mammography due to racial, environmental, financial/ insurance barriers; lack of education; and, most importantly, lack of encouragement by a physician.3539Considering the growth and aging of the population in Saudi Arabia, cancer rates are expected to increase considerably. This will add an enormous burden to the healthcare-utilization costs.The first nationwide breast cancer screening center started accepted participants from all regions, but the majority came from Riyadh since that was the location of the center. The Abdul Lateef Charitable Screening Center was established in Riyadh by a generous donation from a prominent businessman (Shaikh Abdul Lateef Mohamed Abdul Lateef). Screening commenced in September 2007, but the official inauguration of the center took place on October 23, 2007, and was graced by the presence of Mrs. Laura Bush, the former first lady of the United States and a representative from the Susan G. Komen for Cure Organization, who visited the center as part of their tour to the Middle East to promote cancer awareness.In partnership with the Saudi Cancer Society, a well-designed public-awareness program was launched year-round, and women were encouraged to visit the center to be screened for breast cancer. Attendants at the center were directed to a female-exclusive area, wherein a trained female technician, a family physician and a health educator were available. All women who visited the center were self-referred.This was a retrospective study conducted on patients attending the screening center. The study was approved by the Research Committee and Institution Review Board (IRB) of the King Abdullah International Medical Research Center at King Abdulaziz Medical City (KAMC). Data on participants in this study are stored at the screening center, as well as in the KAMC.This was a population-based breast cancer screening registry designed to collect extensive information on known and potential breast cancer risk factors in all women who visit the center.The main objective of this preliminary analysis was to assess the prevalence of breast cancer phenotypes in Saudi women. Additional objectives were to evaluate the association of a diagnosis of breast cancer with the BI-RADS score, potential risk factors and the acceptability of breast cancer screening in this population.The data collected from the screened participants included the following well-known risk factors for breast cancer: age, hormonal status, early menarche, menopausal status, late parity and nulliparity, HRT and breastfeeding status, previous breast pathology and family history.The only inclusion criterion for the current study was being an asymptomatic woman of age ≥40 years; however, since we were providing the first breast cancer screening in our local community, we included some women with symptoms to provide as much population-based data as possible in order not to deprive these women from access to this potentially life-saving test.Conventional 2-view film/screen mammograms were provided and reviewed by two radiologists. Further views were performed when judged to be necessary. Mammograms were scored on a 5-point scale using the American College of Radiology Breast Imaging-Reporting and Data System (BI-RADS). The categories are shown in The main outcome variable was a diagnosis of breast cancer. A breast cancer diagnosis was determined according to the results of fine-needle aspiration and/or biopsy with a written pathological report.Risk factors were patient-reported unless otherwise stated and were defined as follows:A positive family history: the presence of a diagnosis of breast cancer in one or more of the patient’s direct blood relatives Estrogen use : a yes response to “ever used estrogen, currently use estrogen or both”Early menarche: women who started their period before 12 years of ageMenopausal status: women who had menopause at the time of screening, defined as “those who reported an age at which menopause started”Late parity: women who had their first child after the age of 30 years (women with nulliparity were defined as women who did not have any children or who did not report any pregnancies [term or non-term] at the time of the study)Previous breast surgeries included mastectomy, fine-needle aspiration, breast reconstruction (implants) and other surgeriesPatients were symptomatic if they had a history of breast mass, nipple inversion or retraction, pain, nipple discharge or skin changes on clinical examination. Patients were asymptomatic if they lacked all these symptoms. The BI-RADS score was defined as shown in the data collection section. If a patient had a second BI-RADS assessment conducted after the first, the second BIRADS score was utilized in the analysis. Follow-up tests consisted of imaging or procedures performed after the last BI-RADS assessment. Follow-up imaging tests included one or more of the following: mammogram, ultrasound or MRI. Follow-up procedures consisted of fine-needle aspiration, biopsy or both.Demographic and baseline characteristics  were descriptively summarized. The descriptive statistics for continuous variables were mean and standard deviation, median and minimum and maximum. Frequency counts and percentages were tabulated for categorical variables. Categorical data was assessed using the chi-square or the Fisher exact test. Two-sided tests at the 5% significance level were utilized.Logistic regression was used to explore the relationship of a malignant cancer diagnosis as the binary outcome variable with the risk factors  and the BI-RADS score. In the logistic regression, variables were selected using backward selection at the 10% significance level in this preliminary analysis. Data was analyzed using SAS version 9.1.2 .2. Risk factors among participants included a positive family history in 11.7%, early menarche in 11.9%, and menopause in 24.2%; only 9.3% had late parity and 4.4% were nulliparous. Approximately 5.6% of the women had a history of previous breast biopsy or fine-needle aspiration (FNA), reported as a benign lesion. The majority were asymptomatic (n=607), while 475 were symptomatic. Breast pain was the most common symptom reported (n=379)  .For the BI-RADS scores, 54.5% of all the women were R1, 23.2% were R2, 9.2% were R3, 1.3% were R4, 0.8% were R5 and 9.6% were R0. The histological findings for the benign and malignant lesions identified to date in this population are summarized in P<.0001). None of the other risk factors were significantly associated with the outcome (not shown). The percentage of localized breast cancers detected was found to be double that of the Saudi National Cancer Registry data   (ctively) .The current report is the first of a population-based breast cancer screening program of its kind in Saudi Arabia. This study aimed at presenting an overview of the acceptance level of Saudi women for breast cancer screening and evaluating the relationship between common risk factors and breast cancer in Saudi population, in addition to evaluating the association between BI-RADS score and breast cancer diagnosis.Approximately 10 years ago, the WHO predicted that an increase in life expectancy42In a recent publication, Ibrahim et al estimated that the future burden of breast cancer in Saudi Arabia is expected to increase by approximately 350% by 2025.2443What we can learn from this program so far is that with well-conducted breast cancer awareness programs, women themselves will be encouraged to come for screening. Another pilot study was conducted by our group in Riyadh in 2006 as an outreach program. Our main conclusion was the dire need for health education and constant awareness campaigns, in addition to making the test accessible.In addition, our observations during the visit to the country by U.S. former first lady Laura Bush, along with all of the accompanying media coverage, highlight the importance of the role of media in the advertising/ awareness campaigns. After the inauguration of the center till the arrival of Mrs. Bush, a few women per day were being screened at the center; however, after Mrs. Bush’s visit, those numbers increased noticeably. The use of media is especially important in our population due to the high percentage of illiteracy.Finally, the strong correlation between mammographic findings and breast cancer confirmation is an encouraging finding for the center. This means that mammogram is an effective tool in detecting breast cancer in our patient population, which is generally young and may have denser breast tissue compared to elderly women. Long-term follow-up is required to assess the actual benefit; however, results are promising. Out of 16 confirmed malignancies, 8 cases were localized disease and 3 were regional disease. It is noteworthy that the detection rate of localized stages of breast cancer is double the rate revealed on the basis of the National Cancer Registry data. Although the sample size was small, the study is encouraging as it authenticates the goal of screening programs, which is to detect cancer at earlier, potentially more curable stages. There was also one case of ductal carcinoma in situ. Long-term follow-up is definitely needed to assess the impact on outcome. In addition, diagnosis of ductal carcinoma in situ and Stage I disease is an encouraging sign since diagnosis of disease at a lower stage will have a significant effect on outcomes.Our study has a few limitations, including the fact that we had to include women with symptoms, which may contaminate what is supposed to be a “pure screening study.” However, our concerns about the well-being of our patients made us accommodate these patients who may not otherwise have had their cancer detected at an earlier stage for many reasons, including lack of access to care, among other aforementioned barriers.This issue will face any pioneer programs in areas where new tests are being introduced and people find easy access to address their concerns through such programs. The fact that many women with symptoms came to the center raises concerns about the available options for these women outside the center and requires further evaluation. The study did not confirm the value of the well-established and known risk factors of breast cancer. It is too early to accept this as a matter of fact, and analysis of a larger cohort or longer follow-up or a different study design may be needed to address this issue.In conclusion, breast cancer screening is acceptable to our female population, which responded to the media campaign. Using BI-RADS was helpful in identifying malignant lesions with high accuracy. Determining breast cancer risk factors requires further investigations.


We investigated the predictors of the risk of developing a second primary cancer after breast cancer, this occurring in about 12% of affected women. The analysis included 335 191 females, registered in the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database, who had been diagnosed with breast cancer. Observed numbers of subsequent cancers in the SEER database with a first breast cancer diagnosed from 1973 to 2000 were compared with the expected numbers based on age-adjusted incidence rates to calculate standardised incidence ratios. Kaplan–Meier curves were conducted to determine the median time until the second primary cancer diagnosis. Average number of years until diagnosis varied by site and by age as well as median years until second cancer diagnosis. Most cancer risks decreased with age, but there was an increase in aging-related cancers such as lung cancer. The median years of follow-up were well beyond the 5-year mark. Breast cancer survivors should be advised of their increased risk for developing certain cancers in their lifetime. Approximately, 600 000 women in the US are diagnosed with cancer in a given year, and 31% of them will be diagnosed with breast cancer. Breast cancer is the leading cancer for women, and deaths associated with breast cancer are second behind lung cancer and account for 15% of all cancer deaths . SurvivaSecond primary tumours may develop in women previously diagnosed with breast cancer. Yet, little is known about the risk of multiple primary tumours among breast cancer survivors. The purpose of this study was to examine whether women diagnosed with breast cancer have an increased risk of developing a subsequent cancer compared with women of equal age without an initial breast cancer diagnosis. The current study reports the most common second primary tumours following breast cancer, the time to diagnosis for women with a second tumour and how overall survival is affected for these women.in situ or malignant and if the morphology was either ductal, lobular, or medullary neoplasm (ICD-O-2 codes 8500–8540). A total of 2330 women developed a second cancer, but the information was not completely entered into the SEER database. These women were used in the survival analysis, because survival status information was provided, but these 2330 women were excluded from the incidence ratio analyses. Another 3177 women had missing follow-up time. These women were excluded from the survival analysis, but if they developed a second cancer simultaneously, they were then included in the incidence analyses. A total of 332 014 women were used in the survival analysis and were followed up until they were diagnosed with their second tumour, December 2000, or death before December 2000 whichever came first.The study population was derived from the SEER Cancer Registry database, which encompasses approximately 11% of the national cancer burden  estimate and 95% confidence intervals (CI) were calculated assuming a Poisson distribution. Those sites that were statistically significant or showed an association with breast cancer were listed.The cohort includes women diagnosed at earlier ages who survive cancer to the next 10-year age group. For example, women diagnosed before age 30 are included in older age groups if they did not have a second primary tumour diagnosis before age 30. Subsequent data accumulate cohorts similarly.For the women who were diagnosed with a second primary tumour, univariate analysis was performed using Kaplan–Meier curves, to estimate the time function diagnosis. Curves were calculated for all sites combined and for specific sites with at least 100 cases, and women were divided into decades of age at breast cancer diagnosis, 20–29, 30–39, 40–49, 50–59, 60–69, and 70 and older. Several exposure variables were explored in univariate analyses. Variables of interest were grouped and coded accordingly. These include multiple status, grade, AJCC stage or summary staging, and race. All variables were significant in the univariate analysis and included in the multivariate analysis. Multivariate analysis was determined between groups assessed by goodness of fit (GOF) methods .Of those diagnosed with breast cancer during 1973–2000, 40 068 women developed one additional cancer after breast cancer, 3796 women developed two cancers, 351 women developed three cancers, 31 women developed four cancers, and 3 women developed 5 cancers. Of these women, 0.76% were diagnosed by age 29, 6.79% between 30 and 39, 19.72% between 40 and 49, 21.19% between 50 and 59, 22.34% between 60 and 69, and 29.20% at or after age 70. Second cancers were subsequently reported for 11.7% of the patients who were diagnosed with breast cancer before age 50, and 17% of patients diagnosed with breast cancer at or after age 50. Among women with a second tumour diagnosed, the mean time until the second cancer occurred was 6.2 years: 8 years for patients less than 50-years old and 5.7 years for women at or greater than age 50. Among women with a single breast cancer diagnosis, the average time from diagnosis of the breast cancer until death was 6.71 years for women less than 50-years old, and 4.5 years for women at or greater than age 50. 60.28% of the women were still alive at the end of follow-up.The results of the standardised incidence ratio analysis are found in P=0.621) and grade (P=0.511). The figure shows women with multiple primary cancers had poorer survival than women with only a breast cancer diagnosis over time. Women in this young age group who had metastatic breast cancer have a 15-year survival probability of only 23.23%.Survival analysis was then constructed stratifying on the women who only developed breast cancer and those women who were diagnosed with breast cancer and a second primary cancer. Survival curves were adjusted for race and grade. In the 20–29 year old category, grade was categorised as an ordinal variable. In general, overall survival was poorer for women with multiple primary tumours compared with women with no second tumours. In addition to second tumours, grade of the breast cancer, race, and extent of disease played a role in determining the survival for each age group. A woman with a higher-grade breast tumour followed by a second tumour had much poorer survival than a woman with a low-grade breast tumour followed by a second tumour. This is also true for the extent of disease. Time also acted as a contributing factor to poorer survival.Changes in both the breast cancer incidence and the mortality rates have been documented in the past 25 years . This is the largest and most comprehensive study to date of cancer among breast cancer survivors. An international study , leukaemia, lung, ovarian, and thyroid cancer. There are several possible explanations for these correlations, including genetic mutations. Four possible genetic mutations have been identified which can aid in predicting which women with breast cancer will develop multiple primary tumours. All four of these genetic mutations include breast cancer and other cancers. BRCA1 and BRCA2 are considered to be the breast cancer genes, but BRCA1 is also associated with ovarian cancer . BRCA2 iMultiple primary cancers, including acute adult leukaemia, have been associated with a family history of breast cancer . Women wBreast cancer survivors appeared to have protection from developing cervical cancer. Low socioeconomic status is a risk factor for cervical cancer while high socioeconomic status is a risk factor for breast cancer. However, the causal relationship underlying these associations is not well understood.Breast cancer was associated with increased risk of connective tissue cancer for several of the age groups. Two possible explanations are (1) many women with breast cancer undergo radiation, which increases a woman's risk for connective tissue cancer in the surrounding areas and (2) some genetic mutations, including Li–Fraumeni Syndrome are linked with both breast cancer and connective tissue cancer  and pancreas (median years ranging from 15 to about 4). In the past, clinicians used as a general rule that if a woman is cancer free for 5 years after the initial diagnosis, then she is cured of cancer. This analysis shows that a sizeable proportion of women who developed a second tumour were cancer-free 5 years after their initial diagnosis. With the exception of the oldest group, the median time to diagnosis exceeded 5 years for the women who had a second tumour. For women who were diagnosed with breast cancer between the ages of 30 and 39, the median number of years until they were diagnosed with any second tumour was 11.42 years. This long lapse for the 30–39 year old age group is primarily due to the fact that the median number of years until a second breast cancer diagnosis was 18.08 years. It appears that the women in this age group are treated very aggressively and tend to have mastectomies performed on them. The only second cancer where the median number of years was less than 5 was cancer of the cervix uteri, but this estimate is probably unrealistic because of the small number of women who developed cancer of the cervix uteri after breast cancer. On the other hand, connective tissue cancer had a median number of years until diagnosis of over 10 years, except for the 70+ age group.This study has several limitations. Although population-based cancer registries provide the opportunity to study these rare events, the registries lack some important variables such as smoking status, specific doses of treatment, and genetic make-up. Also, quality of data used for classifying multiple primary tumours is not under the control of the registries and may vary across site and over time. Even studies that used data sets known to be accurate found errors that affected the interpretation (In conclusion, it is clear that some women who survive breast cancer are at increased risk of additional cancers. Excess risks attenuate with increasing age at first diagnosis and with increasing years since first diagnosis. Excess risk also varies by cancer type, consistent with existing causal hypotheses regarding genetics mutations and risk of aggressive radiation therapy. More research should focus on isolating the factors that may predispose a breast cancer survivor to the development of subsequent cancers.


An interview study of 1,362 breast cancer cases and 1,250 controls identified through a multi-centre screening project allowed an evaluation of reproductive determinants of breast cancer. Risk increased linearly with age at first livebirth; women with a birth after age 30 showed 4-5-fold excess risks compared to those with a birth prior to 18, while the risk for nulliparous women resembled that for women whose first birth was in their late twenties. The protection conferred by an early first pregnancy prevailed for pregnancies that ended in a livebirth or stillbirth, but not for those that terminated in other outcomes. Among parous women, a first trimester abortion prior to a livebirth was not associated with an elevated risk, except in the event of multiple miscarriages . Although numbers were limited, women who reported an induced abortion in the absence of ever having a livebirth showed some elevation in risk. Age at first livebirth explained most associations, but some residual reduction in risk was noted for multiparous women and those with several births at an early age. There was evidence that delays in birth after marriage increased risk, but this did not explain the high risk associated with late age at first birth.


Subsequent studies showed increased risks of reproductive tract abnormalities, particularly vaginal adenocarcinoma, in exposed daughters. An increased risk of breast cancer in the DES-exposed mothers was also found in some studies. In this report, we present further follow-up and a combined analysis of two cohorts of women who were exposed to DES during pregnancy. The purpose of our study was to evaluate maternal DES exposure in relation to risk of cancer, particularly tumours with a hormonal aetiology. DES exposure status was determined by a review of medical records of the Mothers Study cohort or clinical trial records of the Dieckmann Study. Poisson regression analyses were used to estimate relative risks (RR) and 95% confidence intervals (CI) for the relationship between DES and cancer occurrence. The study results demonstrated a modest association between DES exposure and breast cancer risk, RR = 1.27 (95% CI = 1.07–1.52). The increased risk was not exacerbated by a family history of breast cancer, or by use of oral contraceptives or hormone replacement therapy. We found no evidence that DES was associated with risk of ovarian, endometrial or other cancer. © 2001 Cancer Research Campaign


Multidisciplinary attempts to understand the etiology of breast cancer are expanding to increasingly include new potential markers of disease risk. Those efforts may have maximal scientific and practical influence if new findings are placed in context of the well-understood lifestyle and reproductive risk factors or existing risk prediction models for breast cancer. We therefore evaluated known risk factors for breast cancer in a cancer screening trial that does not have breast cancer as a study endpoint but is large enough to provide numerous analytic opportunities for breast cancer.We evaluated risk factors for breast cancer (N = 2085) among 70,575 women who were randomized in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Using Poisson regression, we calculated adjusted relative risks  for lifestyle and reproductive factors during an average of 5 years of follow-up from date of randomization.2) 35 or more vs. 18.5–24.9: RR = 1.21, 95% CI, 1.02–1.43] was statistically significantly associated with breast cancer.As expected, increasing age, nulliparity, positive family history of breast cancer, and use of menopausal hormone therapy were positively associated with breast cancer. Later age at menarche  or menopause  were less strongly associated with breast cancer than was expected. There were weak positive associations between taller height and heavier weight, and only severe obesity [body mass index (BMI; kg/mThe ongoing PLCO trial offers continued opportunities for new breast cancer investigations, but these analyses suggest that the associations between breast cancer and age at menarche, age at menopause, and obesity might be changing as the underlying demographics of these factors change.http://www.clinicaltrials.gov, NCT00002540. Environment, genes, and lifestyle work together to increase or decrease the probability of developing female breast cancer . Events Most of these conclusions were drawn from individual studies conducted in the 1970s through the late 1990s, or collaborative efforts to quantify risk across many studies -10. Wherhttp://www.clinicaltrials.gov, NCT00002540). Recruitment occurred at ten U.S. screening centers (SCs) between 1993 and 2001. Women were considered eligible if they were between ages 55 and 74 and had no previous diagnosis of lung, colorectal, or ovarian cancer. Women who were receiving cancer treatment or participating in another screening or prevention trial were ineligible. Women who had bilateral oophorectomy or were taking tamoxifen were originally ineligible but later allowed to enroll. All participants provided informed consent. Institutional review boards at the NCI and each screening center approved the study. Although the current analysis does not address the PLCO trial's main objectives, the PLCO trial follows the Consolidated Standards of Reporting Trials guidelines [Prorok et al.  previousidelines .Within-center age- and sex-stratified randomization assigned women to either a control arm, where they were asked to follow their usual medical care, or an intervention arm, where they were offered screening at regular intervals . ParticiParticipants received a mailed annual study update (ASU) around each anniversary of their randomization date. The ASUs ascertained the type and date of any cancer diagnosed in the previous year. Study staff contacted non-responding participants by mail and telephone. To validate the self-reported cancers, staff retrieved medical records , death certificates, data from state cancer registries, and information from next-of-kin for deceased participants.Of 78,231 enrollees , 2085 women were diagnosed with breast cancer (including 388 carcinomas in situ) through May 31, 2003. This included 121 (5.8%) self-reported  and 1964 (94.2%) confirmed breast cancers. Except where noted, self-reported breast cancers from both arms were included as study endpoints for this analysis; incidence did not differ between arms (data not shown).Analysis excluded 659 women (353 from the intervention arm and 306 from the control arm) who never returned an ASU form (and thus for whom breast cancer status was unknown) and women who reported a positive (N = 5119) or unknown (N = 1878) personal history of any cancer before randomization. We considered the 70,575 remaining women at risk for developing breast cancer from the date they completed their baseline questionnaire until the first of the following: breast cancer diagnosis, death, or last ASU.Follow-up is scheduled for at least 13 years . The meaUsing Poisson regression in EPICURE software , we gene2) and approximately one quarter was obese (BMI ≥ 30 kg/m2) or severely obese (BMI ≥ 35 kg/m2).Most participants were white but nearly 7,000 (9.7%) were non-white Table . More thAs expected, age-specific breast cancer incidence rates rose with increasing age Table . CompareOur analysis of postmenopausal breast cancer in the PLCO study revealed interesting differences from the generally established epidemiology of breast cancer. Increasing age, parity, family history of breast cancer, and use of menopausal hormone therapy were all associated with breast cancer as expected. Associations with other key risk factors – age at menarche, age at menopause, and obesity – were slightly different from the previously published literature. These differences have at least two implications for ongoing and future research on breast cancer.First, the magnitude of some risk factor associations may be changing. Published studies have reported consistent, linear risk relationships with older ages at menarche (e.g.: 5% decrease in risk per 1-year delay after age 12) and menopause (e.g.: 3% increase in risk per 1-year delay age at menopause),9,18. In2 BMI increase, 7% per 5-cm height increase, and 6% per 10-kg weight increase [Body size is positively associated with postmenopausal breast cancer . In a poWe observed a higher RR for breast cancer for the combination of low parity and later age at first birth, whereas an earlier meta-analysis reported declining RRs with lower parity in women whose first birth occurred at older ages . Both thThese changes could reflect underlying demographic changes. Mean age of menarche among U.S. females has declined in recent decades, whereas later age at natural menopause is more common than before ,23. The Changing distributions of risk factors will affect the use of risk prediction models that project individual probabilities of breast cancer and influence eligibility for clinical trials. The widely used Gail model  relies oThe known risk factors for breast cancer account for perhaps only 50% of the population burden of breast cancer . A polygWhether known or future genetic markers can improve the performance of existing risk prediction models – or potential new models that incorporate the clinical heterogeneity of breast cancers -is uncerOur large sample size makes it unlikely that the deviations from expectation that we observed were due to chance. Overall exposure and endpoint data were likely good, but residual confounding might exist. The questionnaire lacked information on some risk factors, such as breastfeeding , physicaIn conclusion, this study of over 75,000 post-menopausal women suggests that population-level and demographic changes might influence the magnitude of well-established associations between certain recognized risk factors and breast cancer. These potential changes may become increasingly important as new molecular epidemiologic efforts attempt to expand upon existing methods for understanding relative and absolute risks for breast cancer.The authors declare that they have no competing interests.JVL and PH designed the investigation. JVL analyzed the data. JVL, ARK, SSB, PMM, SCC, MFL, RNH, PCP, CDB and PH interpreted the results. JVL, ARK, SSB, CDB, and PD drafted the manuscript, and JVL, ARK, SSB, PMM, SCC, MFL, RNH, PCP, CDB, and PH edited the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/9/84/prepub


On theoretical grounds, the age of the grandmother and the age of the mother at delivery of her daughter may affect the breast cancer risk of the granddaughter.n=1826). Of these study participants, we were able to retrieve the birth dates of 998 mothers , and for 547 of these we also retrieved the birth dates of the grandmothers . A weighted Cox proportional hazards model was used to estimate the hazard ratios (HRs) for the effect of the age of the grandmother and the age of the mother on the breast cancer risk of the index women, while adjusting for potential confounders.We used the data relating to the Diagnostic Research Mamma-carcinoma cohort (DOM (Diagnostisch Onderzoek Mammacarcinoom) 3), which comprises a population-based sample of 12 178 women aged 41–63 years at enrolment in 1982–85 and followed up until 2000. During follow-up 340 postmenopausal breast cancer cases were identified. To these we applied a case–cohort design together with a random sample from the baseline cohort  had an age-adjusted HR of 0.53 (95% CI 0.24–1.17) and the group with the highest grandmaternal age (⩾40 years) had an age-adjusted HR of 7.29 (95% CI 1.20–44.46), P for trend=0.04. The associations did not change significantly after additional adjustment for various risk factors for breast cancer, neither for maternal age nor for grandmaternal age.Compared with the reference group aged 25–29.9 years, the group with the lowest maternal age (<25 years) had an age-adjusted HR of 0.77 (95% CI 0.19–3.12) and the group with the highest maternal age (⩾40 years) had an age-adjusted HR of 1.58 (95% CI 0.01–267.81), This study does not suggest a major role of maternal age at delivery or grandmaternal age at delivery of the mother for the (grand)daughters' breast cancer risk. Breast cancer is the commonest cancer in women worldwide. Several studies show breast cancer risk to increase with characteristics that can be considered as proxy of early-life events, such as higher paternal and maternal age (Besides hypotheses on the role of post-conception (intrauterine) early-life events, a pre-conception hypothesis on the quality of the oocyte during conception as a risk factor for adult breast cancer has also been put forward .The viability of the oocyte seems to be co-determined by the quality of its mitochondria and their energy/ATP production, which declines with age .Suboptimal energy production by less viable mitochondria may, for example, affect the correct functioning of the cell spindle required for proper chromosome separation during the first five cell divisions. Aberrant spindle function may result either in spontaneous abortion, or, when the fertilised egg survives, in (a higher propensity to) aneuploidy in the fetus and related birth defects which might not be directly noticeable at birth.Mitochondria are passed on from mother to child only; therefore, a high maternal age (resulting in less viable mitochondria) might increase the risk of several cancers in the offspring , 2003. CWe explored whether there is a relation between grandmother's age at birth of the mother and breast cancer risk of the index woman, and whether there is a relation between the mother's age at birth of the index woman, and breast cancer risk of the index woman, using data from the Dutch DOM (Diagnostisch Onderzoek Mammacarcinoom) cohort.n=1826), which was followed up until 1 January 2000, by using regional municipality registries for mortality and movement out of the catchment area of the cancer registry.The DOM cohort consists of 55 519 women, born between 1911 and 1945, who participated voluntarily in a population-based breast cancer screening project (DOM project). The participants were recruited in Utrecht and the surrounding municipalities in the Netherlands between 1974 and 1986. Depending on their year of birth they were included in one of the four distinct cohorts, each of which completed different questionnaires. For the purpose of this study, we used the data of the third cohort consisting of 12 178 women, born in 1932–41 and recruited in 1982–85. For these women data were available on early-life characteristics and on the most important reproductive risk factors for breast cancer. The design and methodology of the DOM project has been described previously  preserves the personal data of deceased persons. These data were primarily collected by the municipal registries: this was by hand on a hardcopy card from 1938–39 onwards until this was computerised in 1994. For each Dutch citizen born before 1994 a personal hardcopy card is stored containing the name, date of birth, nationality, names and birth dates of the parents. In 1994 the personal hardcopy card was replaced by a digital personal record. All persons still living have a digital personal record, which is not yet available at the CBG. We collected these data of the DOM participants using the electronic database of the national municipal administration registration (GBA). In addition, we collected the personal record cards of the mother of the DOM participants, containing the birth dates of the grandparents.Maternal and grandmother's age at delivery were calculated by subtracting the DOM woman's date of birth from the (grand)maternal date of birth. Women with missing data on year of birth or on the year of birth of their (grand)mother were excluded. Through genealogical research we were able to retrieve the birth dates of 998 mothers  and 547 grandmothers . For 547 subjects , we had complete maternal and grandmaternal birth data. The study was approved by the Institutional Review Board of UMC Utrecht.n=436) we imputed the menopausal status at age 52 for smokers and at age 55 for non-smokers  that occurred until 1 January 2000 in the DOM-3 cohort. The DOM project started as a mammographical breast cancer screening project, which was set up to assess its effect on breast cancer occurrence and mortality. For this an active registration team was set up, evolving into the regional cancer registry, which has become complete for the detection of all cancers from 1987 onwards. It is one of the eight comprehensive cancer centres in the Netherlands that together form the national cancer registry that is part of the international databank of the IARC  and the European databank of the ENCR (European Network Cancer Registration) (http://www.ikc.nl). From 1989 onwards, the DOM database is linked to the regional cancer registry on an annual basis to identify all new breast cancer cases within the DOM cohort.We identified all primary invasive breast cancers , birth weight and birth length, adult height, weight at age 18, current weight at baseline, alcohol consumption, physical activity in leisure time, age at menarche, age at menopause, menopausal status at diagnosis, ever oral contraceptive use, ever postmenopausal hormone use, age at first birth, parity, history of benign breast disease and family history of breast cancer among first-degree relatives. In addition, we also considered the number of months of full lactation during the lifetime .http://lib.stat.cmu.edu/general/robphreg) that computes the weighted hazard ratios together with robust s.e.'s, which we used to calculate the 95% confidence intervals. We fitted both age-adjusted and covariate-adjusted Cox proportional hazard models.To establish the possible association between breast cancer risk of the (grand)daughter and (grand)maternal age at the time her daughter was born, we used weighted Cox regression analyses. The methods for these analyses are largely similar to a standard Cox regression and are well described (n=547 women), the final model adjusts for age, age of the grandmother and all breast cancer risk factors (n=547). We analysed the effect of grandmaternal age on breast cancer risk in the granddaughter by fitting again four models as above, now in 547 DOM women. Both maternal and grandmaternal ages were categorised as <25, 25–29.9, 30–34.9, 35–39.9 and ⩾40 years. We chose grandmaternal age 25–29.9 years as the reference group in all models, because this was the largest group in both variables. Trend tests were performed with midpoints of categories.We analysed the effect of maternal age on breast cancer in 998 DOM participants by fitting four models: in the first we adjusted for age only, the second takes account of age and all breast cancer risk factors, the third adjusts for age and age of the grandmother (−2), postmenopausal HRT use (ever/never), a positive history of benign breast disease (dysplasia) (yes/no), a positive family history of breast cancer (yes/no) and age at first delivery , parity  and age at menopause (continuous). Missing data for each covariate were analysed as indicator variables in the model.The covariate-adjusted model included the characteristics of intrauterine exposures, namely birth weight, birth length, prematurity and firstborn. Furthermore, this model was adjusted for the following risk factors: alcohol , BMI , of which 340 cases were postmenopausal. The 1826 participants in the random sample, including all breast cancer cases, contributed 25 906 person-years. The distribution of most personal characteristics of the participants for whom we knew the age of the mother (n=998) did not differ across the categories of maternal age at delivery, but women whose mother was older at delivery were more likely to be prematurely delivered, to have a family history of breast cancer, to be slightly older at first childbirth, to have a slightly lower BMI, and to drink more alcohol, and less likely to be firstborn (n=547) showed the same pattern, except for family history, which was less likely to be present when the grandmother was older at delivery.In 1982–2000, 435 breast cancer cases occurred in the whole DOM3 cohort . When compared with the reference group of maternal age 25–29.9 years, the group with the lowest maternal age (<25 years) had an age-adjusted hazard ratio (HR) of 0.77 (95% CI 0.19–3.12), and the group with the highest maternal age (⩾40 years) showed a HR of 1.58 (95% CI 0.01–267.81) (P for trend=0.76).In age-adjusted analysis, maternal age was not associated with breast cancer risk (–267.81) . The assP for trend=0.05). When compared with the reference group of grandmaternal age 25–29.9 years, the group with the lowest grandmaternal age (<25 years) had an age-adjusted HR of 0.53 (95% CI 0.24–1.17) and the group with the highest grandmaternal age (⩾40 years) had an age-adjusted HR of 7.29 (95% CI 1.20–44.46) (P for trend=0.89); HR for the group with the highest maternal age (⩾40 years) was 1.22 (95% CI 0.25–5.92).Grandmaternal age showed a borderline significant association with the breast cancer risk of the granddaughter after adjustment for age (0–44.46) . After aWhen maternal and grandmaternal age were combined in one model, there was again no evidence for a relation between grandmother's age at birth of the mother and breast cancer risk of the index woman, nor for a relation between the mother's age at birth of the index woman and breast cancer risk of the index woman. Owing to the limited sample size, we were not able to stratify for the birth order, menopausal status, or family history.We did not have detailed nutritional information of the participants, but we did ask for daily milk consumption and for the type of milk that was consumed . Although relations with breast cancer are not consistent maternal age and breast cancer risk in the offspring, our hypothesis may be ‘incorrect’. There is evidence that oocyte quality declines with increasing maternal age at conception, especially after age 30 . It is aAlthough we were able to adjust for most of the known risk factors of breast cancer, we were not able to correct the results for physical activity and oral contraceptive use because these variables had a large number of missing values.Our study has several strengths. We used documented information about birth data instead of recalled information to calculate (grand)mothers’ age at childbirth. In addition, the main purpose of the DOM study was to evaluate the risk factors of breast cancer, thereby allowing the possibility of adjusting for most of these, whereas five of the seven other cohort studies were unable to adjust for several important adult risk factors.In summary, in this prospective follow-up study over an 18-year period, no significant association between (grand)maternal age at delivery and breast cancer risk of their (grand)daughter was found.


Women in the highest quintile of waist-to-hip ratio had 70%  excess risk of pancreatic cancer compared with women in the lowest quintile.A total of 138 503 women in the Women's Health Initiative in the United States were followed (for an average of 7.7 years) through 12 September 2005 to examine obesity, especially central obesity in relation to pancreatic cancer ( Pancreatic cancer ranks as the fourth leading cause of cancer death in the United States . BesidesWe have used the large prospective Women's Health Initiative (WHI) study, with measured anthropometric factors, including hip and waist circumference, to examine the relationship between BMI, central adiposity, and pancreatic cancer risk.The WHI, an ongoing, ethnically and geographically diverse, multi-centre clinical trial (CT) and observational study (OS), was designed to address some of the major causes of morbidity and mortality in postmenopausal women. Briefly, a total of 161 808 women aged 50–79 years were recruited at 40 clinical centres throughout the United States from 1 September 1993 through 1998. The WHI includes three overlapping CT components  and an OS. All participants in WHI gave informed consent and were followed prospectively. Details of the scientific rationale, eligibility requirements and baseline characteristics of the participants in the WHI have been published elsewhere  at baseline, 668 with no follow-up, 7491 with missing values of main exposures and confounders , and 297 (0.18%) with waist-to-hip ratio (WHR) values of beyond 4 s.d. (WHR<0.4 or WHR>1.2), leaving 138 503 women for analysis.All exposures in our analyses were collected at baseline for all participants. During the baseline clinical visit, trained and certified staff performed anthropometric measurements, including height, weight, hip and waist circumferences, and blood pressure. Body mass index was calculated as weight in kilograms divided by the square of height in metres. Waist circumference at the natural waist or narrowest part of the torso and hip circumference at the maximal circumference were measured to the nearest 0.1 cm. WHR was computed as the ratio of these two measurements. Weight changes during the participant's adult lives were obtained by self-report questionnaire, categorized as weight stayed stable (within 10 lb), steady gain in weight, lost weight as an adult and kept it off, and weight has gone up and down again by more than 10 lb.Information on demographic characteristics, medical history, and personal habits (lifestyle) were obtained by interview or by self-report using standardized questionnaires including age at enrolment , smoking status  with information on how many years since quitting for past smokers and how many cigarettes smoked per day for ever smokers, physical activity and history of hypertension and diabetes while not pregnant.Women in the CT were followed through regularly scheduled examinations to ensure timely ascertainment of updated medical histories. All women in the CT were expected to attend annual clinical visits, with intermediate 6-month mail, phone or clinical contacts. The OS participants were contacted annually by mailed self-administered questionnaires. The completion rate of OS annual questionnaires was 93–96%. In this analysis, all participants were followed up until 12 September 2005. Initial reports of cancer were ascertained by self-administered questionnaires, and all self-reports of pancreatic cancer were confirmed by review of medical records, including pathology reports (if a biopsy or resection was done).The hazard ratio (HR) for pancreatic cancer was estimated using the Cox proportional hazards model. Different study cohorts  were treated as strata in the model. In the multivariable models, we adjusted for age, smoking status , and current smoking ). As diabetes could be in the causal pathway between obesity and risk, we performed analyses (both adjusted and unadjusted) for this factor.−2). Tests for trend were performed by creating a continuous variable from the medians of the categories. In addition, to eliminate undiagnosed cases that might have experienced weight loss before completing the baseline questionnaires, we also performed analyses that excluded the first 2 years of follow-up. The proportional assumption was satisfied for all exposure variables of interest and potential confounding variables based on graphs of scaled Schoenfeld residuals  variables in the regression models, except BMI which was categorized  excess risk compared with women in the lowest quintile of WHR. When WHR was analyzed as a continuous variable, risk increased by 27% (95% CI 7–50%) per 0.1 increase. No association was observed between pancreatic cancer risk and other anthropometric variables, including height, BMI, hip circumference, waist circumference, and weight changes during adult life .Finally, we repeated all the above analyses with the exclusion of the first 2 years of follow-up; findings remained broadly similar to those from the full analyses with RR=1.6 (95% CI: 1.0–2.6) comparing women in the highest to the lowest of WHR.In this large prospective study, we observed that central obesity measured by high WHR, rather than general obesity measured by high BMI, was associated with an increased risk of developing pancreatic cancer among postmenopausal women.Our result is consistent with most earlier studies for central adiposity and pancreatic cancer (The link between obesity and pancreatic cancer – similar to the plausible mechanism between diabetes and pancreatic cancer – may arise as a result of elevated fasting and postprandial glucose concentration, hyperinsulinemia, or both (Strengths of our study include the prospective design, the large size of the cohort, the reasonably large number of cases, the high prevalence of obesity, including central adiposity, the detailed information on potential confounders, and the precise measurement of anthropometric factors. Measurement rather than self-reporting is particularly important for waist and hip circumferences, which are likely to be reported less accurately than height and weight. There is a possibility of misclassification among the cases, given the difficulty in diagnosis of this disease. However, this misclassification is likely to be non-differential with respect to anthropometric measurements, which may make our results conservative. A second possibility was weight loss because of undiagnosed disease, but results did not change after excluding the first 2 years of follow-up. It is unlikely that pancreatic cancer advanced enough to cause weight loss would remain undiagnosed for more than 2 years.In conclusion, our large prospective study shows that increased central adiposity was associated with an increased risk of developing pancreatic cancer among postmenopausal women.


Early age at natural menopause or bilateral ovariectomy substantially reduce a woman's lifetime risk of breast cancer. Reversible 'bilateral ovariectomy' can now in effect be achieved by 'high-dose' luteinising hormone releasing hormone (LHRH) agonists (LHRHAs). The harmful effects of such medical reversible bilateral ovariectomy, in particular the increased risks of coronary heart disease and osteoporosis, can in all likelihood be obviated by 'low-dose' oestrogen replacement therapy (ERT), specifically 0.625 mg of conjugated equine oestrogens (CEE) for 21 days in each 28-day treatment cycle, and such ERT use will only negate to a relatively small extent the beneficial effect of such bilateral ovariectomy on breast cancer risk. We calculate that such an LHRHA plus low-dose ERT regimen given to a premenopausal woman for 10 years will, in addition to being a most effective contraceptive, decrease her lifetime risk of breast cancer by more than 50%. We calculate that such a 10-year regimen will also decrease her risk of ovarian cancer by two-thirds. This regimen should leave endometrial cancer risk and bone metabolism unaltered, and may reduce the risk of heart disease. The addition of a 'low-dose' progestogen to the regimen for 12 days in each 28-day treatment cycle would be beneficial to the endometrium, but it will adversely affect risk factors for heart disease and it may significantly reduce the benefit of the regimen as regards breast cancer. A satisfactory compromise may be to add a low-dose progestogen for 12 days at less frequent intervals. Another possibility may be to deliver a progestogen solely to the endometrium with an intra-uterine device; the benefits of such a regimen would be a significant reduction in the incidence of breast, ovarian and endometrial cancer.


The incidence of in situ breast cancer in the USA has increased rapidly in recent years, even among young women. A population-based case-control study of 1616 breast cancer cases aged under 45 in the USA was used to examine risk factors for in situ, local and regional/distant tumours. Almost 60% of in situ tumours were detected by routine mammograms compared with 18% of local tumours and 8% of regional/distant tumours. After adjustment for screening history and established risk factors, family history of breast cancer in a first-degree relative and African-American race were associated with an increased risk of all stages of breast cancer. The associations with nulliparity, a previous breast biopsy and body mass index were significantly stronger for in situ tumours than for local or regional/distant disease. Alcohol consumption was associated with an increasing trend in risk of regional/distant tumours but not of earlier stage tumours, indicating that alcohol may be involved in late-stage events. Analyses by histological type of in situ tumours suggested that both ductal and lobular carcinoma in situ were associated with most established breast cancer risk factors, and the magnitude of association tended to be greater for the ductal form.


The aim of this paper is to compare a service offering genetic testing and presymptomatic surveillance to women at increased risk of developing breast cancer with its predecessor of no service at all in terms of survival and quality-adjusted survival (QALYs) by means of a Markov cohort chain simulation model. Genetic assessment and presymptomatic care provided between 0.07 – 1.61 mean additional life years and 0.05 – 1.67 mean QALYs over no services. Prophylactic surgery and surveillance extended mean life expectancy by 0.41 – 1.61 and 0.32 – 0.99 years, respectively over no services for high-risk women. Model outcomes were sensitive to all the parameters varied in the sensitivity analysis. Providing cancer genetic services increase survival and as long as services do not induce adverse psychological effects they also provide more QALYs. The greatest survival and QALY benefits were found for women with identified mutations. As more cancer genes are identified, the survival and cost-effectiveness of genetic services will improve. Although mastectomy provided most additional life years, when quality of life was accounted for oophorectomy was the optimal strategy. Delayed entry into coordinated genetic services was found to diminish the average survival and QALY gains for a woman utilising these services. Despite the recognition by clinicians for over a century that a hereditary predisposition to cancer exists in certain families, the possibility of utilising this information to help these patients has only become available in the 1990s with the discovery of cancer susceptibility genes  and 10% As a consequence of increased awareness of genetic issues and the technology to test for mutations there has been demand for genetic assessment services , demand In terms of assessing the survival advantages of providing cancer genetic services to women at increased risk of breast cancer the preceding studies have not addressed three important issues. Firstly, despite varying the penetrance estimates (the likelihood of developing cancer), they have confined their analysis to BRCA1/2 mutation carriers only. However, the majority of individuals referred to cancer genetic services due to a family history placing them at increased risk of developing breast cancer do not have BRCA1/2 mutations. Most high-risk and all moderate-risk families have as yet unidentified mutations. Secondly, all women have been assumed to be at high risk of developing both breast and ovarian cancer. However, the Cancer Genetics Service in Wales referral guidelines, which were developed by means of a national multidisciplinary consensus group meeting and GP focus groups, which are subject to ongoing validation, segregate women according to their family history into increased risk of developing breast cancer or breast and ovarian cancer. This has implications both for the type of counselling to be provided and the type of presymptomatic surveillance required. Finally, none of these studies have compared the provision of genetic services with the treatment as usual of no presymptomatic services.This paper stems from the work conducted by the GenQuest research team who conducted a multimethod evaluation of the Cancer Genetics Service in Wales. The aim of this paper is to compare a service offering genetic testing and presymptomatic surveillance to women at high and moderate risk of developing breast cancer with its predecessor of no service at all. This will be done by means of mathematical modelling, using available epidemiological data and reasonable assumptions.A Markov cohort chain simulation model was developed and run on Lotus 123 to estimate survival and quality-adjusted survival for women at increased risk (high and moderate) of developing breast cancer under the care of genetic services compared to women receiving no such service. Three health states were considered: good health, breast cancer and death  diagnosed with breast cancer at 40 years of age or less, two, first-degree relatives diagnosed with cancer at 60 years of age or less, three, first-or second-degree relatives  diagnosed with breast cancer at any age or a first-degree relative with bilateral breast cancer. Women at increased risk are segregated into high and moderate risk using CYRILIC software. Women with a heterozygote risk (chance of having a mutation) of less than 25% are at moderate risk while those with a risk of 25% or more are at high risk. An example of a high-risk family history would be a woman with two first-degree relatives diagnosed with breast cancer at 35 years of age. The genetic testing and presymptomatic surveillance strategies modelled in this study are based upon those used by the Cancer Genetics Service in Wales, a national cancer genetics service  by applying preference ratings. For the health states of bilateral prophylactic mastectomy, prophylactic oophorectomy, having both bilateral prophylactic mastectomy and oophorectomy, cancer, metastatic cancer and death, preference ratings were used from a study of women aged 33 – 50 with a family history of breast and ovarian cancer  were traAs the benefits of cancer genetic services occur in the future these benefits will be discounted. Discounting assumes that future benefits are valued less than current benefits and allows comparison of the benefits of programmes with differing time profiles to be compared . QualityPrevalence of the mutation.Penetrance of the mutation.Percentage deciding to have bilateral mastectomy.The death rate of women receiving genetic services as survival times for screen-detected cancers are artificially inflated by early detection or lead time .The death rate of women not receiving genetic services and presymptomatic surveillance.Mean age of women entering the care pathways of the genetic service.QALY preference ratings.Discount rate.As there is uncertainty about many of the parameters associated with genetic breast cancer . The impact of missed cancers by mammographic surveillance was assumed to be negligible on the outcome measures of the modelling in the base-case analysis. By conducting sensitivity analysis on the death rates of women receiving and not receiving genetic services the lead time and the efficacy of mammography and surgery are accounted for.UK population norms for the self-rated health status scores of the EuroQol EQ-5D , followed by high-risk carriers of unidentified mutations (0.05–1.21 QALYs) and finally moderate-risk mutation carriers (0.05 QALYs). In contrast to the findings for unadjusted survival, when quality of life was accounted for the optimal clinical strategy was oophorectomy with regular surveillance (1.21–1.67 QALYs), followed by surveillance (0.21–0.68 QALYs), bilateral prophylactic mastectomy (0.05–0.61 QALYs) and finally having bilateral prophylactic mastectomy with oophorectomy (−0.55–0.003 QALYs). Unlike the alternative clinical strategies, oophorectomy with regular surveillance recorded more incremental QALYs than unadjusted survival. A result also found by Both life years and QALYs were sensitive to all the parameters varied in this study. Multi-way sensitivity analysis revealed that the gain in mean life years from coordinated genetic services compared to no services were at their maximum of 0.18 when the parameter estimates were set at their most favourable (see 5ates see  and 5.Applying a 0% discount rate to the base-case analysis provided 0.073 QALYs for the average woman attending cancer genetic services. A 6% discount rate however resulted in only an additional 0.036 mean QALYs for these women. Changing the mean age of women in the base-case analysis from 35 to 44 for high-risk women and from 40 to 50 for moderate-risk women resulted in genetic services only extending survival by 0.003 years or 1 day.Varying QALY weightings for the base-case parameters resulted in substantial change in the mean incremental QALY outcomes. Substituting weightings indicative of reducing adverse psychological effects among presymptomatic women see  resultedThe overall gains in survival and QALYs found in this study are low, particularly for high-and moderate-risk carriers of unidentified mutations. However, quality of life was better for women that were under the care of cancer genetic services with the exception of women for who contact with genetic services would induce adverse psychological effects and those women opting to have both prophylactic mastectomy and oophorectomy.In Despite the clear advantage of the three prophylactic surgeries over surveillance alone in terms of extending survival, this was not the case when accounting for quality of life. The preference or QALY weightings used in the current study reflect the fact that although mastectomy and mastectomy with oophorectomy may prevent the physical, social, psychological and economic impact of living with cancer, it may also result in altered body image, a sense of reduced femininity and physical discomfort from surgery (The low incremental survival found for women who postponed entry into the genetic service was a result of two factors. Firstly, older women have less potential gains in life expectancy and less time under the care of genetic service before entering conventional surveillance at 60 years of age. Secondly, due to lack of data it has been necessary to assume equal sensitivity for the 1–1.5 yearly mammography for patients of the genetics service and three yearly mammography provided to women receiving no presymptomatic health services until they enter the national screening programme at 50 years of age.et al ran their models for 50 (In comparison to the findings of s for 50  and 70 (s for 50 , 2002 uss for 50  and lowes for 50 , 2002 weIt should be noted that chemoprevention methods have also been modelled as presymptomatic interventions for women at increased risk of developing breast and ovarian cancer due to BRCA1/2 mutations. Compared to women having surveillance alone raloxifene provided 2.2 incremental life years  and tamoThere are limitations to the current study which must be noted. Firstly, in the absence of age-specific risk or penetrance estimates of developing breast cancer, it was necessary to base annual penetrance estimates upon lifetime risk estimates. Secondly, the data upon mortality as a result of radiation from mammography are based on estimates for women aged 40–49 years . It may In conclusion, the results of the Markov modelling indicate that providing women at increased risk of developing breast cancer with cancer genetic services will give a small increase in their estimated survival. As long as genetic services do not induce adverse psychological effects they also provide greater quality of life. The greatest survival and QALY benefits were found for women with identified mutations such as BRCA1 or BRCA2. As more cancer predisposing genes are identified, the survival benefits and cost-effectiveness of genetic testing and presymptomatic surveillance will improve for women at increased risk of developing breast cancer. Although prophylactic mastectomy and mastectomy with oophorectomy were found to be the most effective in extending survival, when quality of life was accounted for surveillance alone was a better option and oophorectomy accompanied by regular surveillance was found to be the optimal clinical strategy for the average woman. Delayed entry into coordinated genetic services was found to diminish the average survival and QALY gains for a woman utilising these services.


Although the potential carcinogenic risk of radiotherapy is well known, it has become clear that there is a particularly high risk of radiation-induced breast cancer in women treated for Hodgkin's disease at young ages. Thankfully, death from breast cancer in this population is uncommon, but it is important to understand factors contributing to the risk, including treatment parameters, and to develop a logical and efficient method for medical management of those at risk. In this minireview, we examine the evidence which should inform such a management policy. The prognosis of patients with Hodgkin's disease has been improved dramatically over the last 40 years by the development of extended field radiotherapy techniques and then by combination chemotherapy . HoweverThe relative risks of many cancers are higher if patients have been treated for Hodgkin's disease at a younger age .The size of risk of breast cancer found in Hodgkin's disease patients has varied between studies. For patients treated under age 21 years relative risks have generally been around 15–25 . Similaret al , with a relative risk of 4.5 (1.3–16) for ⩾38.5 Gy compared with <4 Gy. This was also shown in the international case–control study (P trend <0.001), which found a RR of 8 in those treated to a dose of more than 40 Gy to the breast, compared with less than 4 Gy. The few other studies that have investigated the relation of risk to dosage have not calculated doses specifically to the part of the breast in which the cancer occurred. Two studies found evidence of a dose–response relation  and risk increased steeply with number of premenopausal years after treatment: relative risks were 0.15, 0.24 and 0.91 for <5, 5–14, and ⩾15 premenopausal years, respectively. P=0.003) with increasing number of alkylating agent cycles and decreased, although the trend was not significant, with younger age at menopause. Thus ovarian hormones may be critical to carcinogenesis after radiation initiation. Such an effect would give a potential explanation of why breast cancer risk decreases with older age at irradiation, as there will be fewer or no years before menopause in patients who are older at radiotherapy. It is notable that after radiotherapy to the ovaries for either HD  in patients with premature menopause, or hormone-based chemopreventative strategies such as Tamoxifen for those at risk, there are insufficient data to give clear advice. In the study by van Leeuwen , not to all, and that a balanced view of all the benefits and potential long-term adverse effects needs to be taken when selecting treatment. There is a trend in current treatment of Hodgkin's disease toward reduced use of radiotherapy. This comes from lack of clear evidence for overall survival benefit in advanced and disseminated disease presentations (For those women who do require supradiaphragmatic radiotherapy at ages less than 30 years, it is important to seek to minimise dose and limit volume of breast tissue in the field and to ensure that they are informed of, and accept, the associated risk of second primary breast cancer.