The goal of this prospective study was to determine (a) concentrations of the carbohydrate biomarkers Thomsen Friedenreich (TF) antigen and its precursor, Tn antigen, in nipple discharge (ND) collected from women requiring biopsy because of a suspicious breast lesion; and (b) if concentration levels predicted pathologic diagnosis.Adult women requiring biopsy to exclude breast cancer were enrolled and ND obtained. The samples from 124 women were analyzed using an anti-TF and anti-Tn monoclonal antibodies in direct immunoassay.in situ (DCIS). TF was higher in women with 1) cancer (DCIS or invasive) vs. either no cancer , or benign pathology (p = .018); and 2) abnormal (atypia or cancer) versus benign pathology (p = .016); and was more predictive of atypia or cancer in post- compared to premenopausal women. Tn was not predictive of disease. High TF concentration and age were independent predictors of disease, correctly classifying either cancer or abnormal vs. benign pathology 83% of the time in postmenopausal women.The highest median concentration in ND for TF and Tn was in women with ductal carcinoma TF concentrations in ND were higher in women with precancer and cancer compared to women with benign disease, and TF was an independent predictor of breast atypia and cancer. TF may prove useful in early breast cancer detection. The Thomsen-Friedenreich -N-acetyl-D-galactosamine) antigen and its biosynthetic precursor, Tn , are displayed on cell-surface proteins and lipids in 70% to 90% of adenocarcinomas including those of the breast, prostate, and ovary →3-N-acet,3. ObtaiWe hypothesized that TF and Tn antigen, displaced on proteins and lipids that arise from cancer cells and cancer cell turnover, would be present in ND. To test this hypothesis, an initial blinded screening of 50 banked NAF samples from women with breast cancer and from asymptomatic women without cancer were screened for the presence of TF and Tn antigen. The results of this preliminary study demonstrated significant differences in the expression of TF and Tn between NAF from a breast with cancer compared to asymptomatic women [After receiving Institutional Review Board approval from the three institutions listed below, informed consent was obtained from all subjects prior to enrollment. 166 subjects were prospectively enrolled and samples collected in Grand Forks, ND at the University of North Dakota, in Columbia, MO at the Ellis Fischel Cancer Center and in London, UK at the Royal Marsden Cancer Center. Participants were enrolled from September 2005 to February 2008. The time between sample collection and analysis ranged from 0.7 to 25.9 months, with a median of 7.3 months. A subject was classified as postmenopausal if at least one year had passed without a menstrual period or she had undergone bilateral oophorectomy prior to enrollment. Women who had undergone hysterectomy without bilateral oophorectomy were considered postmenopausal if they were over 50 years old. If follicle stimulating hormone (FSH) levels were available, a level of 34 mIU/mL or greater was used to classify women as postmenopausal. There were four women in this category. All ND samples were collected prior to surgical biopsy. All comparisons of TF and Tn concentrations with disease were based on the histopathologic findings in the clinical report.ND (1-10 μL) samples were obtained from the breast with a lesion prior to surgery. Lesions included women with 1) PND; 2) a suspicious lesion identified on imaging, be it mammogram, ultrasound or breast magnetic resonance imaging; and/or 3) a palpable lesion that was not a simple cyst. Samples were collected as described previously . BrieflyND samples from women with and without breast cancer were analyzed in blinded fashion. All assays were run in triplicate. It was initially thought that an indirect immunoassay would be more sensitive than a direct assay to small changes in TF and Tn concentration, so the 42 initially collected ND samples were analyzed using an indirect sandwich immunoassay. The indirect method entailed capturing TF and Tn antigen molecules in NAF on an antibody coated surface. The surface was interrogated with a biotinylated TF or Tn ligand. Ligand binding was determined by a streptavidin-alkaline phosphate color reaction. TF and Tn concentrations were inversely proportional to the reporter signal. This assay proved unreliable, so a direct assay was developed and proved more reliable. Herein we present results for the 124 ND samples that were analyzed using a direct immunoassay.All reagents were purchased from Sigma  unless specifically noted. The anti-TF antibody A78-G/A7 was purchased from Glycotope  and the BRIC-111 anti-Tn antibody was purchased from Serotec . Both antibodies were raised against desialylated red blood cells of the appropriate blood group. The TF Ab is specific for both anomeric forms of the disaccharide, including related structures on the glycolipids and shows no cross-reactivity with sialylated glycophorin [Each NAF sample was assayed in triplicate on the same ELISA plate for TF or Tn and the mean values were reported to the statistician. Anti-TF and anti-Tn monoclonal antibodies (200 ng/well) in a 0.1 M sodium carbonate pH 9.6 buffer were applied to Nunc-immunomax 96-well plates for 4 h at 37°C. The plates were washed with Tris-buffered saline pH 8.0 containing 0.5% Tween-20 (TTBS) and blocked with 2% bovine serum albumin (BSA) in TTBS for 2 h. One-hundred microliters of diluted ND samples (1:50-1:500) in Tris-buffered saline pH 8.0 (TBS) were added to the wells. Control wells contained various dilutions of asialofetuin (ASF) or asialo-ovine submaxillary mucin (OSM) in TBS (0 ng - 2 ng/well). ASF contains TF antigen while AOSM contains exposed Tn antigen. The ND, ASF and OSM samples were incubated at 25°C for 2 h followed by a TTBS wash. Biotinylated secondary detection proteins, anti-TF antibody (0.625 μg/ml) or Tn binding Vicia villosa lectin (1 μg/mL) in 100 μL TBS, were added to the wells and incubated for 1 hr. The unbound secondary detection proteins were removed by two washes with TTBS, while the bound biotinylated secondary detection proteins were bound with a streptavidin-horse radish peroxidase conjugate (SA-HRP) (100 μL/well of a 1 μg/mL stock) for 1 hour at 25°C. Unbound SA-HRP was removed by two TTBS washes and the wells were developed with 100 μL/well of the chromogenic substrate 2, 2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic) (Sigma) detected at 405 nm. A standard curve was performed on each plate for either TF or Tn. A range of known concentrations of TF or Tn displaying proteins, asialofetuin (TF) or ovine salivary mucin (Tn), were assayed. This allowed us to compare results from plate to plate and account for variation between plates. The data were reported as absorbance (Abs) at 405 nm per microliter of ND. The overall average between batch % coefficients of variation (%CVs) for TF and Tn were 5.5 and 8.9, respectively. The within batch average %CVs were 4.3 and 5.9, respectively. The intraclass correlation coefficient (ICC) for TF is .73 (95% CI .63 - .80) and for Tn it is .68 (95% CI .58 - .77).Biomarker levels for TF and Tn in the ND samples were heavily skewed and not normally distributed. We therefore described and analyzed TF and Tn biomarker levels using medians and log-transformed (Log10) means to achieve normal distributions. Univariate analyses using the Mann-Whitney-Wilcoxon signed ranks test were performed to determine median biomarker levels while t-tests were calculated to determine log10 means of the biomarkers. Logistic regression analyses are based on log10 transformed data. Three logistic regression models were used to examine the effects of TF, Tn, and menopausal status  in predicting (a) cancer vs. no cancer diagnosis; (b) cancer vs. benign diagnosis; and (c) abnormal vs. benign diagnosis. Because menopausal status was a near significant predictor in all three overall logistic models, follow-up logistic models were conducted separately for premenopausal women and for postmenopausal women, controlling for age. ROC curves were calculated based on the logistic regression results for the postmenopausal women's data, and AUC values are presented.Of 137 women, we successfully collected NAF in 111 of 124 (90%) and PND in 13/13 (100%).Among the 124 women evaluated, 72 (58%) were postmenopausal. Ages ranged from 19-86 years, with a median age in pre- and postmenopausal women of 45 and 61, respectively. Thirty-seven postmenopausal women took hormone replacement therapy (HRT) at one point in their lives, with nine taking HRT at the time of NAF collection. HRT use did not significantly influence the ability of TF or Tn to predict either breast abnormal pathology or cancer. Eighty-three (67%) of the participants were found to have breast cancer (11 DCIS and 72 invasive), and 41 (33%) benign disease .ND volume ranged from 0.5-546 microliters, with a mean of 53 and median of 25 microliters. ND volume did not vary by pathologic diagnosis nor by fluid type (NAF vs. PND). We first determined if TF and Tn expression in women requiring diagnostic biopsy due to PND differed from expression in women requiring biopsy who did not have PND. Results of logistic regression analyses conducted with women with PND (n = 13) and NAF (n = 111) were equivalent to results obtained from analyses conducted with only women providing NAF. Therefore, all reported analyses include both PND and NAF samples (N = 124).in situ (DCIS). TF expression trended higher in women with DCIS compared to those with usual hyperplasia (p = .09) and normals (p = .07).Median concentrations of TF and Tn were 7 and 3 fold higher, respectively Figure , in womeUnivariate analysis indicated that TF concentration was higher in women with abnormal (atypia or cancer) than benign pathology  for detecting 1) cancer vs. benign disease, and 2) AH or cancer vs. benign disease. The models performed less well in contrasting cancer with noncancer, in which AH was included in the no cancer category. TF concentrations in ND from women with AH appear to be more similar to women with more advanced disease than in women with benign pathology. Figure 3.0 for dThe study had limitations. First, the ability of TF or Tn to determine if a woman had AH was limited by the small number of women in the study with AH. Second, since only one ND sample collection was feasible in the women who soon after sample collection had surgery on the breast, we do not know the variability in TF or Tn expression independent of disease. A study which collects sequential ND samples from women at increased breast cancer risk, including women with a biopsy demonstrating AH, may help to address these limitations.TF and Tn are unique as biomarkers in that they are carbohydrates, whereas most disease markers both in use and undergoing evaluation are proteins. The expression of TF correlated with the presence of breast atypia and cancer. A multicenter study should be conducted to confirm our findings, and to determine the usefulness of these markers in disease detection.in situ; H: usual hyperplasia; ICC: intraclass correlation coefficient; NAF: nipple aspirate fluid; ND: nipple discharge; OR: odds ratio; P: pathologic; ROC: receiver operating characteristicAbs: absorbance; AH: atypical hyperplasia; CV: coefficient of variation; DCIS: ductal carcinoma ERS is a member of the Scientific Advisory Board of Atossa Genetics, Inc. He does not hold stock nor shares in the company. Atossa Genetics did not assist in the design of the study, did not finance the study, and did not review the manuscript prior to its submission.SLD helped design the study, supervised the TF and Tn analyses, and participated in manuscript review. MD, JN and SK conducted the TF and Tn analyses. GG assisted in participant recruitment, sample collection, and manuscript review. JH, NV-H and JH conducted statistical analyses for the manuscript. JH and NV-H also prepared figures for the manuscript. TQ helped design the study and assisted in manuscript review. ERS helped design the study, recruited participants and collected samples that were analyzed, oversaw the entire project, and wrote the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/10/519/prepub


Sir,We read with interest the article by However, we were surprised by the authors' statement that there have been no previous published data on the patterns of breast cancer in British black women. We recently reported data in this journal on mortality from various cancers including breast cancer by country of birth in the United Kingdom .et al.We reported higher breast cancer mortality, with standardised mortality ratios (SMR) and 95% confidence intervals (CI) among women born in West Africa of 132 (105–163) and in North Africa of 132 (96–176). This was an unexpected finding not reported in previous similar analyses of mortality by country of birth and we were interested to see the potential explanations offered by the findings of Bowen Secondly, we would like to offer an additional explanation for the observed age difference at presentation in the British black women. The national Census indicates that the British black population in the United Kingdom is younger in comparison to the white population . This maFinally, in our study (


We evaluated the risk of angiosarcoma after radiotherapy among all patients with cancers of breast, cervix uteri, corpus uteri, lung, ovary, prostate, or rectum, and lymphoma diagnosed in Finland during 1953–2003, identified from the Finnish Cancer Registry. Only angiosarcomas of the trunk were considered, this being the target of radiotherapy for the first cancer. In the follow-up of 1.8 million person-years at risk, 19 angiosarcomas developed, all after breast and gynaecological cancer. Excess of angiosarcomas over national incidence rates were observed after radiotherapy without chemotherapy (standardised incidence ratio (SIR) 6.0, 95% confidence interval (CI) 2.7–11), after both radiotherapy and chemotherapy , and after other treatments . In the regression analysis however, the adjusted rate ratio for radiotherapy was 1.0 (95% CI 0.23–4.4). Although an increased risk of angiosarcoma among cancer patients is evident, especially with breast and gynaecological cancer, the excess does not appear to be strongly related to radiotherapy. Sarcomas are malignant mesenchymal tumours and angiosarcoma develops from the endothelium of a blood vessel. It is an uncommon cancer type that occurs among men and women, more often among older adults and usually in the skin, soft tissue, breast, or liver .The risk of a second cancer is increased among persons who have had a cancer previously , owing bThe study cohort included patients with first primary cancers diagnosed during 1953–2003 in the Finnish Cancer Registry database, which has almost complete coverage of cancers in Finland since 1953  of the first cancer, sex, and length of follow-up time . Treatment was classified into four groups: treatment without chemotherapy or radiotherapy , chemotherapy without radiotherapy, radiotherapy without chemotherapy, and combined chemotherapy and radiotherapy.The cohort was followed up for subsequent angiosarcomas and lymphangiosarcomas, starting at diagnosis of the first primary cancer and ending at death, emigration, diagnosis of angiosarcoma, or the common closing date (31 December 2003). Information on emigration and vital status was obtained from the Population Register Centre by computerised record linkage.The outcome event was defined as a histologically confirmed angiosarcoma or lymphangiosarcoma on the trunk, those outside the trunk being excluded, as only radiation treatment to the trunk is relevant to the study. The anatomic sites of the first cancer included oesophagus, stomach, small intestine, large intestine, rectum, biliary ducts, gallbladder, liver, pancreas, lung, mediastinum, breast, cervix uteri, corpus uteri, uterus and other female reproductive organs, ovary, prostate, kidney, bladder, urinary tract, skin of the trunk, bone of the trunk, and soft tissue of the trunk.Expected numbers were calculated by multiplying the person-years at risk with the national incidence rates stratified by sex, 5-year calendar period, and 5-year age group. The standardised incidence ratio (SIR) was calculated as the ratio of observed to expected numbers of cases. The 95% confidence intervals (CI) were estimated assuming that the observed number followed Poisson distribution and the expected number being constant . As the The cohort included a total of 332 163 patients with first primary cancers. Among the cohort members, 54% were women and 76% were aged 55 years or more at the time of diagnosis of the first primary cancer. Mean age was 59 years among patients with radiotherapy and 66 years among patients without radiotherapy. The follow-up yielded 1.79 million person-years at risk, with a mean length of follow-up time of 5.4 years. Of the total person-time at risk, 4% was provided by the patients receiving both radiotherapy and chemotherapy, 41% after radiotherapy alone, and 5% after chemotherapy alone.vs 3.8 expected  being among breast cancer patients .In the regression analysis, the crude rate ratio was 0.94 (95% CI 0.34–2.6) for the radiotherapy group, compared to those not so treated, and was not materially affected by adjustment for age, first cancer type, and follow-up time (RR 1.0 95% CI 0.23–4.4). A separate regression analysis for breast cancer patients gave an adjusted RR of 1.0 (95% CI 0.23–4.4) for radiotherapy. The effect of treatment did not differ significantly by age, follow-up time, or site of the first cancer type (Our results indicate that our cancer patients have a five-fold elevated risk of angiosarcoma compared with the rest of the population. All cases were in women and were confined to patients with breast or gynaecological cancers. We did not find a strong relationship with radiotherapy, but our findings are consistent with an increased risk related to combined radiotherapy and chemotherapy. However, despite the large cohort with more than 330 000 patients with first primary cancer, the number of angiosarcomas was small.The results of this study are consistent with the few previous studies of angiosarcoma after radiotherapy. In a SEER data study of second malignancies among 270 000 breast cancer patients, angiosarcomas were found to comprise 56.8% of the sarcomas occurring in the field of prior radiation ; the SIRPost-irradiation sarcomas have mainly followed breast and gynaecologic cancers (In previous studies, the minimal latency for radiation to cause a solid tumour has been estimated as 10 years . In a coPatient or disease characteristics other than treatment may confound the results, if they affect angiosarcoma risk. Several factors influence selection for radiotherapy . FeatureWe were unable to determine whether the angiosarcoma of the trunk occurred within the irradiated volume, or to provide measures of risk related to doses to specific organs, but only estimates of the overall risk of angiosarcoma.By basing our study on comparisons of patients with similar first cancers and different forms of treatment, the effect of aetiologic factors underlying the first cancer were largely eliminated as a possible cause of the angiosarcoma. Another strength of this study was the large, representative study population, covering practically all eligible Finnish cancer patients diagnosed during 1953–2003, while record-linkage with the population registry allowed complete follow-up.These results indicate an increased risk of angiosarcoma among cancer patients, especially those with breast and gynaecological cancers. Similar increased risks were found both among patients treated with radiotherapy and those without radiotherapy. Further analyses focusing more closely on the irradiated tissue and dose–response are needed.


P-value for trend: 0.012), current use of progestagens for longer than 4.5 years being significantly associated with risk . Prolonged use of progestagens after the age of 40 may be associated with an increased risk of breast cancer and the subject needs to be investigated further.We examined the relationship between use of progestagen-only before menopause (except for mini-pills) after the age of 40 and invasive breast cancer risk in 73 664 women from the French E3N cohort study . A total of 2390 cases of invasive breast cancer were diagnosed during follow-up. Risk estimates were calculated using the Cox proportional hazard model. Overall, ever use of progestagen before menopause was not significantly associated with risk (relative risk (RR): 1.01, 95% confidence interval: 0.93–1.11). However, we observed a significant increase in risk associated with the duration of use ( Breast cancer is the most frequent malignancy among women in Western Europe, North America  and hormRandomised trials and observational studies have strongly suggested that some synthetic progestagens, when added to an oestrogen in HRT, increase breast cancer risk more than the use of oestrogen alone  have long been prescribed in France to premenopausal women for menstrual disorders, oral contraception, benign uterine and ovarian diseases and certain benign breast diseases , we haveE3N is a French prospective cohort set up in 1990 to investigate cancer risk factors in women. A total of 98 995 women, aged 40–64 years, belonging to the MGEN, a French health insurance scheme primarily covering teachers, and residing in France agreed to be volunteer by filling in the first questionnaire and a consent form. Since June 1990, participants have been asked at approximately 2-year intervals to complete self-administered questionnaires requesting information on various exposures and medical diagnoses. Information on lifetime use of hormonal treatments, including progestagens, was first recorded in the January 1992 questionnaire. To facilitate accurate recall, a booklet presenting an extensive list and colour photographs of the hormonal treatments marketed in France was mailed to all study participants. Brand name, age at first use and duration of use were recorded for up to 24 periods of treatment. Information on hormonal treatment use was updated in each of the subsequent questionnaires. Information on the dose and the number of treatment days in the cycle was not requested.For the present study, the progestagens on which we focused were oral progestagens prescribed alone before menopause and after the age of 40 years. In France, progestagens are mainly prescribed for gynaecological disorders such as breast pain, uterine or ovarian pathologies and irregular menstruations, for perimenopausal disorders and for contraception. ‘Mini-pills’, because they were only occasionally used in our study population, were classified as OCs and were excluded from the present analysis.Cases were identified from self-reports of participants: all questionnaires asked them whether any cancer had been diagnosed, requesting the address of their physicians and permission to contact them to obtain the pathology reports.For the present study, follow-up started at the date of return of the second questionnaire (sent out in January 1992). It continued until the return of the follow-up questionnaire sent out in June 1993, January 1995, April 1997, June 2000 or July 2002, whichever was answered last. Person-years accrued until that date, or until diagnosis of cancer or death, whichever occurred first.Information on date of menopause, type of menopause, date of last menstruation, date of start of menopausal symptoms and date of hysterectomy were updated on receipt of each new questionnaire. Women for whom age at menopause could not be determined  were considered as menopausal at age 47 if menopause was artificial, and at age 51 otherwise, ages that corresponded in our cohort to the median age at menopause when artificial and natural, respectively.n=11 200) were excluded, as well as women who had never menstruated (n=25), those who never reached the second questionnaire (n=1066) and those who did not report either their date at the start of progestagen treatment or duration (n=5998). To focus the study on intake of progestagen during the perimenopause period, the analysis was restricted to women who had never used a progestagen before the age of 40 and who reached menopause after the age of 40. This left us with 73 664 women for the analysis, accruing 668 033 person-years, with an average age at start of follow-up of 51.78 years (standard deviation (s.d.): 6.8) and a mean follow-up time of 9.07 years (s.d.: 2.4).Women who had a prevalent cancer other than basal-cell carcinoma before inclusion  for breast cancer were estimated using Cox proportional hazards models. Age was used as the timescale. Known risk factors for breast cancer were included in the model, as well as confounding variables if they improved model fit by the P-values for assessing possible heterogeneity in effect estimates were computed from likelihood ratio tests. The P-values for assessing possible trends were computed from likelihood ratio tests on continuous variables. All analyses were performed using SAS® system, version 9.1.Relative risks are given with 95% confidence intervals. The The main characteristics of the 73 664 women included in the analysis according to use of progestagen treatment alone are shown in P=0.77). The relationship between ever-use of progestagens and breast cancer risk did not vary significantly by previous use of OC (P for interaction: 0.57), by personal history of benign breast disease (P for interaction: 0.86), by personal history of benign uterine or ovarian disease (P for interaction: 0.19) or mammographic history (P for interaction: 0.23).During follow-up, 2390 cases of new primary invasive breast cancer were identified among the 73 664 women in the cohort. Pathology reports were obtained for 95.27% of cases. In all, 443 802 person-years were associated with never-use and 224 231 person-years with ever-use, in which 1510 and 880 cases of invasive breast cancer were recorded, respectively. Overall, there was no significant association between ever-use of progestagen and breast cancer risk , but not use shorter than 4.5 years. After discontinuation, and whatever the duration, the risks were close to unity. There was no significant trend towards decreasing risk with increasing time since last use (Results on duration of use were further stratified according to recency of use . We founlast use .Because many women (48.4% of progestagens users) changed or temporarily interrupted their treatment, we verified that this did not modify risk patterns. Analyses conducted separately on women who had never interrupted nor changed their treatment and on women who declared at least one temporary interruption or a change yielded comparable results (data not shown).P for homogeneity: 0.35).Finally, we investigated associations according to whether treatment was possibly antigonadotrophic  or not . Overall, patterns of risk did not show marked differences  and hence could not analyse the risk associated with intermittent or continuous use or with dose. Although the reasons for prescribing progestagens were not recorded, a potential ‘prescription’ bias is unlikely, because we adjusted for the variables ‘personal history of benign breast disease’ and ‘personal history of benign uterine or ovarian disease’, and because the effect of progestagens on breast cancer risk did not vary significantly by personal history of benign breast disease or by personal history of benign uterine or ovarian disease. The effect of progestagens on breast cancer risk did not differ significantly according to OC use. Misclassification of progestagen exposure, which was based on self-reported information, may have affected our results, but given the prospective design, this should be non-differential between cases and non-cases, and would tend to reduce the magnitude of the relationship with risk, and dampen differences in the effects of different progestagens.Finally, there is limited scope for ‘surveillance bias’ owing to progestagen users being more likely to have repeated mammograms, because this was adjusted for, and because the effect of progestagens on risk did not differ significantly according to mammographic history.In conclusion, our study suggests that the use, before menopause, of oral progestagens (without oestrogens) by women over 40 may increase breast cancer risk. Further follow-up study will enable more exhaustive analysis using specific categories of progestagens.


The aim of the study was to compare psychosocial outcomes for 50 new clinic attendees, referred for cancer genetic counselling to five UK centres. The centres represented England, Scotland and Wales, and were randomly selected from groups ranked by different levels of clinical activity in cancer genetics practice. Questionnaires assessed demographic data, risk perception, mental health and use of health services pre-consultation and at 1 and 12 months follow-up. Satisfaction was measured for attendees and referring doctors at follow-up. A total of 256 unaffected adults fulfilled the study criteria. The five centres varied widely with respect to service organisation and activity, but all had a greater proportion of unaffected attendees with a breast cancer risk (61–91%) than either a bowel cancer risk (0–33%) or ovarian cancer risk (3–25%). There were no significant differences in the psychosocial data between centres pre-counselling. No significant change over time occurred for any of the centres for risk perception or general psychological distress. There were significant differences between centres in reduction of cancer worry from baseline to 12 months and with the number of women who were recommended to have mammographic surveillance who had not received this. Overall, one-third of women for whom mammography had been recommended had not been screened within 1 year of follow-up. Subsequent attendance at the GP, but not at a hospital, was associated with risk level, but differences between centres could not be analysed. Satisfaction differed significantly between centres for 4 : 14 aspects of service provision and with 3 : 17 items concerning communication; satisfaction was high overall. Over 90% of referring doctors were moderately/very satisfied with the service, but 23% were dissatisfied with waiting times and 19% with access to preventive treatment. Results differed significantly between centres for doctor's satisfaction with the provision of referral criteria and prescribing information. In conclusion, there were relatively few significant differences in psychosocial outcomes between centres, considering the wide variation in service organisation and activity. These significant differences were not consistent across the centres, therefore, differences could not be linked to specific aspects of service provision. In phase one of this research  have evolved in an et al commented that it was not possible to include other outcomes of risk counselling, such as mammographic screening uptake, because of an insufficiency of studies; findings to date have been inconsistent , and third, to describe regional variations in outcomes that could be attributable to service organisation or activity.During phase 1 of the study, 22 of a possible 24 regional CGSs were recruited to record all of their genetic counselling activity over a pre-specified 4-week period. For the phase 2 studies, 20 centres (with full data available at the time of randomisation) were ranked according to the rate of referrals received per million population, as an indicator of service activity, and formed into five sequential groups. One centre was then randomly selected from each of these groups, and that centre asked to participate. By chance, the five CGSs were located in regions in England, Scotland and Wales.Each CGS was required to recruit 50 individuals newly attending for cancer genetic risk counselling. Individuals were excluded from participation in the study if they had already been diagnosed with cancer at any time or if they were under the age of 18. A nominated member of the CGS staff recruited participants prior to their first genetic counselling consultation. After reading an information sheet and having an opportunity to ask questions about the study, participants gave their written consent. They completed a questionnaire booklet immediately prior to their first consultation and the CGS clinician completed a study report form following the consultation. Participants were sent follow-up questionnaires by post 1 and 12 months after the initial consultation. At approximately 6 months after recruitment, the doctor (GP or clinician) who had referred the individual to the CGS was sent a questionnaire to ascertain satisfaction with the service provided. Response from participating service users and from their referring doctors was encouraged by telephone reminders after 2 weeks and written reminders 2 weeks later. Ethical approval for all aspects of the study was obtained through the Multicentre Research Ethics Committee.Psychosocial outcomes were assessed using patient self-report questionnaires; where available, standardised measures were used. Protocol-specific scales were derived from measures used in other cancer genetics studies .General mental health was assessed using the 28-item General Health Questionnaire (GHQ) , a self-Cancer worry, an indicator of cancer-specific distress, was assessed using the modified Cancer Worry Scale (CWS) , breast self-examination, clinical breast examination, attendance at the GP surgery, well-woman check-ups, private health check-ups and other hospital visits. Subjects were asked to indicate their attendances for health care in the 6 months prior to the genetics consultation (assessed at baseline), in the month following the visit and in the 12 months following the visit.Satisfaction with the service provided was assessed by counsellees using a protocol-specific 14-item scale. Subjects were asked to indicate their satisfaction on a four-point scale .Satisfaction with patient–clinician communication and key aspects of the consultation was measured using a previously tested 17-item scale . RespondReferring GPs and hospital clinicians were asked to indicate their satisfaction with nine aspects of service provision, both in terms of their overall impression of the local service and in respect of the individual study participant they had referred.The GHQ-28 was scored using the preferred binary  system giving an overall score on a scale from zero to 28, with higher scores representing higher distress. A cutoff score of ⩾10 was used to indicate those individuals who were psychologically distressed  also varied widely. Overall, general practitioners made 67% of referrals and specialists (predominantly breast surgeons and gynaecologists) accounted for 34%. GP referrals varied significantly from between 52% (Centre A) to 95% (Centre E), but there was little difference in the reported reason for referral, with 89% or more of doctors specifying risk assessment as the main reason. Both referral routes resulted in a waiting time for appointment of up to 6 months for the majority of referrals.The characteristics of the five participating centres with respect to service activity are shown in A total of 271 individuals consented to participate, of whom 256 fulfilled protocol criteria pre-counsel (range 49–52 by centre). Reasons for exclusion after consent included cancer diagnosis (11) and missing baseline questionnaire (4). Concurrent research studies in two centres interfered with the plan to recruit consecutive attendees and additional time was needed to accrue the study sample in three centres. Thus, the sample can best be described as a sample of convenience. Socio-demographic data  and comprised more individuals who perceived themselves to be at population risk level .Of the eligible sample, 91% provided questionnaire data at 1 month and 79% at 12 months: 75% provided data on all three occasions. Participants who failed to provide follow-up data were significantly younger in age  and at 12 months follow-up . There were no significant variations between centres, as shown in Using broad criteria for risk accuracy (population risk/elevated risk), 63% of attendees perceived their relative risk of cancer in the appropriate category as judged by the geneticist. There were three times as many subjects underestimating (27%) as overestimating (9%). These proportions were nonsignificantly reduced at 1 month . Across centres, reductions in the mean cancer worry scores from baseline to 1 month and from baseline to 12 months were similar for individuals who initially underestimated their risk  and for those who initially overestimated .At baseline, the mean cancer worry score for the overall sample was 11.6 (s.d. 3.0) and the median score was 11.0 . Scores for the five centres are presented in Results are considered for women with a breast cancer risk, who formed the majority of attendees. Of 174 women with a breast cancer family history, 148 (85%) had ever had a breast examination, 40% in the 6 months before attendance at the CGS and 51% at the clinic. In all, 104 (60%) of these women had ever had a mammogram, 20% in the 6 months prior and 24% at the clinic visit. Results for 103 women deemed at increased risk of breast cancer, as judged by the clinicians, were comparable (see P<0.001) and the same range having a clinical breast examination (P=0.003) (data not shown). Two centres with low rates of reported access to mammography provided breast examination for only half of the women at risk, but it is not known whether this was routinely offered. Of note is the finding that 24% women at increased risk, and aged 35–49 years (the commonly recommended age cutoff for starting mammography), did not have a mammogram in the 6 months prior to or 12 months following the genetics consultation . A modest rate (40%) of usage of the frequently recommended monthly breast checking was reported overall, which remained stable over time, irrespective of the type of cancer risk. Women with a breast cancer family history were more likely to be excessive checkers (>once a week) than those with other cancer risks, both at 1-month follow-up (11 vs 0%) and at 12 months (9 vs 3%) (data not shown). Fewer women with a breast cancer history reported never checking compared with those with other cancer family histories (5 vs 21% at 1 month and 10 vs 18% at 12 months).Breast self-examination habits were assessed at 1 and 12 months follow-up. Results showed no significant variation between centres . The likelihood of having a primary care appointment during the month varied by risk level , but the likelihood of a hospital appointment did not. A minority of subjects (30.13%) changed their lifestyles since the consultation. In all, 12 (10 women and two men) adopted a healthier diet (more fruit and vegetables and less fat) and seven reduced weight. One stopped smoking and three reduced their alcohol intake. Numbers were too small for comparison by centre.P<0.001), but was associated with dissatisfaction for only 18% respondents overall, and this did not vary significantly between the centres. There was very little difference in satisfaction ratings at the two follow-up points, except for satisfaction with information given about the centre, which changed from 79 to 91% (data not shown).Across all centres, satisfaction was reported as high at 1 and 12 months follow-up for all 14 aspects of service activity. The areas associated with greatest dissatisfaction are shown in Satisfaction with the genetic consultation focused more specifically on communication and clinician style. Summary scores ranged between 57.0 and 64.2, with little change over the length of follow-up. There were significant differences between centres see , with thn=10); doctor had not made the referral himself (n=4); doctor too busy (n=2).Questionnaires were sent to 198 doctors who had referred 238 participating subjects (range 1–10). Forms were returned by 116 (58.5%) doctors : three doctors were excluded as their role was integral to the genetics service and 79 (40%) doctors failed to reply. Reasons for noncompliance, where known, were: doctor or patient had left the practice (vs 6% GPs).As shown in Centres associated with significant differences in doctors' dissatisfaction were different from those associated with significant differences in attendees' dissatisfaction, so that no particular service model appeared to be disadvantaged.This is the first direct comparison of psychosocial outcomes following genetic risk counselling for individuals with a family history of cancer in a UK-wide study of CGSs. In line with randomised comparisons carried out in Wales and South East Scotland, significant differences in psychosocial outcomes between the centres were small in number, with no discernible pattern in the centres concerned. Therefore, differences are unlikely to reflect a specific type of service configuration. The positive implication for the NHS is that service users will have similar psychosocial benefits despite wide variation in current service provision.At first sight, the lack of differences may seem surprising, given evidence of wide variation in service structure, organisation and clinical workload , and othThis multicentre study confirms earlier published findings  that risThe study also identified variations between centres that warrant attention. First, there were significant differences in the use of mammographic surveillance, which may partly reflect the lack of a national screening policy for high-risk women below the age of 50. Other factors could be a lack of access to mammography provision, poor communication at the interface between tertiary and primary care, or poor uptake/compliance with mammography, which were beyond the scope of this study. However, two initiatives should help to resolve this regional inequity and clarify the role of breast surveillance in this setting: these are the National Institute of Clinical Excellence (NICE) Clinical Guidelines for the classification and care of women at risk of familial breast cancer (The NICE guidance will also address areas of dissatisfaction raised by referring doctors, which warrant improvement. These concerned referral criteria and prescribing advice, while, for both doctors and attendees, there was perceived inadequacy of information about preventive options and access to genetic testing. Evidence is accumulating to support risk management interventions, such as risk-reducing mastectomy (There were high levels of satisfaction across settings, in contrast to findings by Differences between centres were not seen for primary care consultations or use of other health care resources following risk counselling, but the level of cancer risk did impact on resource use. Research initiatives have been undertaken to assist primary care teams in the identification of moderate and high-risk families who warrant further advice , so thatIn contrast to other published work, we planned to evaluate a representative mix of individuals with different cancer risks, but all the five centres were dominated by referrals of women with a family history of breast cancer so that data are limited for smaller risk subgroups. For subjects with a risk of bowel cancer, the next largest subgroup, rates for colonoscopy usage were reported as lower than for screening mammography, but it is not possible to say whether this reflects lack of access or of uptake. Lower than expected rates of recruitment for colonoscopy have been reported elsewhere, and both discomfort and risks associated with the procedure were thought to be contributory factors (Strengths of the study design included the use of standardised assessments and the participation of randomly selected centres representing wide variation in service provision. Compliance with mailed questionnaires was generally good, but responses from referring doctors were lower. Some limitations are also acknowledged. The case mix and small sample quota from each centre, limited for logistical reasons, resulted in some lack of precision with which some outcomes could be assessed. Therefore, the study was designed to be descriptive rather than hypothesis testing. Gender and ethnic differences could not be evaluated and effort will be needed nationally to ensure appropriate representation of men and ethnic minorities in these clinics.In conclusion, in the absence of differences in psychosocial outcomes, centres will need to think carefully about appropriate end points to evaluate the development of their particular service. There is now clear evidence of the information needs and perceived inadequacies of care as well as the level of mental health and satisfaction that can be achieved in this setting, that will form standards for future studies.


Despite the fact that genetic counseling in oncology provides information regarding objective risks, it can be found a contrast between the subjective and objective risk.The aims of this study were to evaluate the accuracy of the perceived risk compared to the objective risk estimated by the BRCApro computer model and to evaluate any associations between medical, demographic and psychological variables and the accuracy of risk perception.130 subjects were given medical-demographic file, Cancer and Genetic Risk Perception, Hospital Anxiety-Depression Scale. It was also computed an objective evaluation of the risk by the BRCApro model.The subjective risk was significantly higher than objective risk. The risk of tumour was overestimated by 56%, and the genetic risk by 67%. The subjects with less cancer affected relatives significantly overestimated their risk of being mutation carriers and made a more innacurate estimation than high risk subjects.The description of this sample shows: general overestimation of the risk, inaccurate perception compared to BRCApro calculation and a more accurate estimation in those subjects with more cancer affected relatives (high risk subjects). No correlation was found between the levels of perception of risk and anxiety and depression. Based on our findings, it is worth pursuing improved communication strategies about the actual cancer and genetic risk, especially for subjects at "intermediate and slightly increased risk" of developing an hereditary breast and/or ovarian cancer or of being mutation carrier. Oncological genetic counseling enables to discover a hereditary component which increases the risk of developing a tumour. The concept of risk is particularly important in this process.The probability that an event occurs can be estimated subjectively through the perception that a single individual has of the risk. Alternatively, it can be measured objectively using well-defined parameters.In oncological genetic counseling, two reasons make it important to measure the objective risk of having a genetic mutation which increases the risk of developing a tumour: it makes it possible to carry out a mutation analysis only on eligible people and also creates suitable prevention programmes for different levels of risk.Subjective risk assessment has also a great importance because it influences decisions on whether to undergo genetic testing or not -3, on whDespite the fact that genetic counseling provides information regarding objective risks, there is frequently a contrast between the perception of the risk of developing a tumour and being a carrier of a genetic mutation and the objective risk ,12. ThesAs regards the relationship between the psychological distress and the risk perception findings are opposing. In fact several studies revealed a correlation between high distress levels and high risk perception, while few researches showed no correlation between these two variables ,18.As far as the family history of tumour is concerned, women with a personal and a family history of cancer usually perceived their risk of developing the disease as higher than that of other women. Nevertheless, comparing the risk perception with an objective estimation of the risk , the women affected by cancer and with a family history of tumour are more accurate in their risk estimation than women with a family history of tumour but healthy ,12. WomeNevertheless, in Italy, the risk perception has been little studied and counselors still miss relevant information like: how the risk perception is spread on Italian population, how the risk is associated to other psycho-social variables and if the risk perception is accurate or not compared to objective methods of risk estimate.The main aim of this research is to study the risk perception among a population enlisted by a department of genetic counseling in the centre of Italy.In particular, this study evaluates the perception levels of the risk to be a mutation carrier and to develop a related-cancer, the association between perceived risk and medical/demographic/psychological variables and the adequacy of the perceived risk compared to the objective risk estimated by BRCA-PRO model ,21.From February 2007 to November 2008, 153 subjects were submitted to genetic counseling at the Unit for Hereditary Breast and/or Ovarian Cancer of the "Regina Elena" National Cancer Institute of Rome. The analysis was carried out on a sample of 130 subjects who had cancer of the breast and/or ovaries and/or a family history of tumours (at least one first-degree affected relative). Twenty-one subjects did not complete the questionnaires and psychological tests, two were illiterate.Subjects who requested counseling to the Unit for Hereditary Breast and/or Ovarian Tumours of "Regina Elena" National Cancer Institute of Rome were referred by their physician or came spontaneously under suggestion from relatives, friends, other oncologic patients or mass media information.The counseling multidisciplinary team included an oncologist/counselor, psychologist, and geneticist. The counseling modalities were designed using a multistep approach as follows:During the first visit the oncologist/counselor, supported by the psychologist, supplied the patient with information about hereditary cancer syndromes, the mutation of BRCA1/BRCA2 genes, and their involvement in the onset of cancer of the breast and/or ovaries. Further information is supplied regarding transmission, the possibility of prevention and treatment.Afterwards, the physician asked the patient to sign in an informed consent to collect the family history in order to assess the genetic and cancer risk estimation.http://www.com.unimo.it/com2000/hbc/alberi/lineeg.htm].Furthermore, risk estimation and eligibility or non eligibility status for genetic test was also performed following the Modena Criteria ,23, http, http23,Applying these criteria, subjects were classified as eligible if they were at "high risk", or non eligible if they resulted at "intermediate, or slightly increased risk", as described in Table During the second visit the oncologist/counselor, supported by the psychologist, asked the patient his/her consent for the blood sample.After six months the subjects knew the genetic test result. During this third visit the physician and the psychologist together communicated the outcome of the test, the possible involvement of the family into genetic counseling and the risk-reducing strategies, they help the subjects to express emotions, doubts, and requests focused on the genetic test outcome and on how to communicate the outcome to the sibling or children ,25.The local Ethic Committee approved the counseling procedures.At the end of each counseling session the psychologist asked to the patients an informed consent to complete questionnaires and psychological tests.During the second counseling step, only eligible subjects were proposed to give the blood sample; while for the others or non eligible subjects were organized an "ad hoc" surveillance programmes. This study refers to the data obtained by the questionnaires completed after the first genetic counseling session by 130 subjects. The sample was made up of eligible and non eligible subjects.The questionnaires and psychological tests evaluate the following variables.Data regarding age, geographic origin, civil status, number of children, education, religion and whether they were religious-practicing or non-practicing, eligibility, pathology, number of relatives affected by cancer of the breast and/or ovaries and the total number of relatives affected by any type of tumour were collected.An item adapted from previous research was used to evaluate the perception of the risk of developing a tumour: "Indicate with a cross, on a scale from 0 to 100, that which you think is your current percentage risk of developing a tumour, or redeveloping a tumour of the breast and/or ovaries" ,17.The answer was given on a visual analogue scale from 0 to 100 (100 corresponds to the highest risk). The scale is a ten centimetres line and each millimetre corresponds to one point percent.An item adapted from previous research was used to evaluate the perception of the risk of being a carrier of the genetic mutation BRCA1/BRCA2 . "IndicaData of the family pedigree were inserted (in a separate moment without the presence of consultant) into the computer programme "Cancer-Gene-Program"  to evaluate the risk of being a carrier of the BRCA1/BRCA2 mutation and the risk to develop breast and/or ovarian tumour,27,28.http://www8.utsouthwestern.edu/utsw/cda/dept47834/files/67943.html.This programme uses Mendelian genetics and the Bayes theory to estimate risk considering the following factors: the number of relatives affected and not affected by a tumour of the breast and/or the ovaries, age at onset, number of generations affected, tumour of the breast in men. The final estimation results are two percent values, one for the risk of being a carrier mutation and one for the risk to develop a tumour. This model has been used on large samples and in many countries. It considers factors which other models omit, and its validity and sensibility (by identifying subjects with probable genetic mutation) has been demonstrated in six centres of genetic consulting ,29,30. TThe percentage risk of developing a tumour and of being a carrier of a genetic mutation evaluated by BRCAPRO were compared to the percentage of perceived risk in order to assess the adequacy of the perceived risk compared to the objective risk .The Hospital Anxiety and Depression Scale (HADS) , ItalianAll instruments used were chosen on the basis of the following characteristics: validation, internal reliability and previous use in literature for populations comparable to the one from which the sample for the present study was drawn.Descriptive statistics were used to summarize pertinent study information.The association between variables was tested by the Pearson Chi-Square test.A paired sample t-test was used to compare the mean values of the subjective perception of risk, with the objective risk, estimated by BRCAPRO.The percentage risk of developing a tumour and of being a carrier of a genetic mutation evaluated by BRCAPRO were compared to the percentage of perceived risk in order to assess the adequacy of the perceived risk compared to the objective risk. To make this comparison, Bluman et al. in 1999  calculatDifferences between groups  with Kruskal-Wallis non parametric test were analyzed for age, number of relatives affected by cancer and for distress levels.Concordance between the subjective perception of risk and the objective risk estimated by BRCAPRO was assessed using Cohen's k coefficient of agreement . Landis Given the small numbers, statistical analyses cannot be performed to assess the differences between male and female in risk perception. The SPSS (11.0) statistical program was used for the analyses.The average characteristics of the sample of 130 subjects (women/men = 119/11) are reported in Table The mean percentage regarding the subjective risk of developing a tumour and of being a carrier of the genetic mutation were 39% and 40%, respectively.The mean percentage regarding the objective risk, calculated using the BRCAPRO model, of developing a tumour and of being a carrier of the genetic mutation were 11% and 19%, respectively.The total mean score was 13, with 24% of the subjects suffering one episode of major depression and 19% experiencing the presence of some disturbance in adaptation.A mean score of 8 was found for the single scales (borderline anxiety) and of 5 . A total of 25% had borderline anxiety levels and the same value was found in subjects suffering from anxiety.Depression was found in 9% of the subjects, while 15% were borderline.Of all the medical-demographical variables, only the condition of eligibility was found to be statistically associated to the perception of risk Table .The subjects who were eligible for genetic testing had a significantly higher perception of risk compared to the non-eligible people .Despite the fact that the pathology was not found to be associated with the perception of risk, the affected subjects were found to have higher percentages than healthy subjects .No correlation was found between the levels of perception of risk and anxiety  and depression .No correlation was discovered between distress levels and family history of tumour (r = 0.050 p = 0.60).No significant differences in distress levels were revealed between affected and non-affected subjects (Distress = 12.42 vs 13.32 p = 0.46) and between eligible and non-eligible subjects (Distress = 18.82 vs 13.37). However, the non-affected and the non-eligible subjects were above the cut-off point of disturbance in adaptation.The subjective risk was found to be correlated to objective risk BRCApro .However, the percentage levels of subjective risk were found to be significantly higher than for objective risk .Compared to the objective risk a significant percentage of individuals overestimated the risk of developing a tumour , while only 11% underestimated the risk. The remaining 32% made an accurate estimation. Concerning the risk of being a carrier of the genetic mutation a significant number of subjects overestimated the risk , while 7% underestimated it and 26% had an accurate perception.Eligible subjects made a significantly more accurate estimate of their risk compared to non-eligible ones, CRP(P = 0.001) and GRP (P = 0.006).The subjects with less cancer affected relatives significantly overestimated their risk of being mutation carrier (p = 0.028). No association was found between other medical-demographic or psychological variables and the accuracy of the risk estimate.The results show that most of the sample overestimated their cancer and genetic risk. This Italian sample, under this aspect, does not differ from samples of subjects with higher risk of breast cancer and/or ovary tumours from other countries, like Spain , United The relevant overestimation of risk leads to the belief that information gathered during counseling sessions does not adequately reach the patient, as elsewhere reported in literature ,38,39.However, in the present study this misunderstanding seems to be associated to eligibility conditions and to the number of cancer affected relatives. Indeed, the subjects with a high family history of tumour  seem to underestimate or make an accurate estimation of their risk, while subjects with at least one affected relative, but not eligible (Intermediate or Slightly increased risk), had a percentage of overestimate of risk significantly higher. Our hypothesis is that the subjects eligible for a genetic test, having a high number of relatives affected by tumours and often stricken themselves, are not only more open to information regarding their risk, but also more aware in comparison to subjects with familiarity or with sporadic events of breast and/or ovarian tumours in their family ,14,40.As far as the association between psychological variables and risk perception is concerned, some studies evidenced that there is a positive correlation between the perception of risk and levels of psychological distress. However, in this study, no such correlation was found, despite the fact that the psychological distress levels reached the cut-off value of disturbance in adaptation. We do not have an Italian regulatory sample of reference for HADs which considers not only subjects with tumours but also healthy subjects. However, in a population of women with breast cancer the percentage of subjects unable to adapt to the situation was of 24% (19% in our sample) and of 9,8% with at least an episode of major depression (24% in our sample) . These tThis could depend on the fact that the HAD's scale, although largely used in genetic counseling for hereditary tumours, reveal a type of "general" psychological distress linked to a pathological event rather than a "cancer-specific" distress.Punctual correlations between distress and perception levels found in literature has been evidenced through the use of cancer-specific instruments (for measuring distress levels due to cancer worries) such as the Cancer Worry Scale of Lerman, or the Impact of Event Scale of Horowitz ,41. The As set forth in the introduction section we suppose that the spirituality has a negative correlation with the risk perception. No difference has arisen between religious and non-religious subjects; however, one have to consider as a limit the measure of religion and religiosity which is not overtly articulated and thorough as far as prayers and the degree of emotional and cognitive involvement in these rites are concerned.Limitations to the current study should be noted. To begin, it is important to take into consideration the self-selection bias. The general overestimation of the risk can be due, from one part to the self-referral way of inclusion in the study and to the other part, to the fact that all the eligible subjects for this study had almost one first degree relative affected by cancer of the breast or ovaries. In actual fact, the subjects of this study asked for a visit because they thought their chances of having a mutation and/or their breast cancer risk was high. Secondly, the BRCAPRO evaluation model can introduce some limitation (that is an underestimation of the risk), not considering in the calculation of the risk relatives with less than first degree of kinship. Moreover, the instrument used to measure the perceived risk, the numerical visual analogue scale, sometimes lead the patients to overestimate their own risk .Thirdly, it could be difficult to know how generalizable these results from a select sample of subjects coming from the centre of Italy are to populations that come from other parts of Italy or to other ethnic groups.In Italy, where health care is mainly a public service concern, and cancer genetic counseling is a relatively new concept and is almost invariably offered within the framework of clinical research units, the variable "perception of risk" has been very little investigated .The present study attempts to describe the perception of risk in subjects who have requested oncological genetic counseling in a sample of Central Italy. The results are similar to other studies carried out in other countries in the following ways: general overestimation of the risk, inaccurate perception compared to systems of objective calculation and an underestimation or more accurate estimation in those subjects with eligibility criteria.From information derived from this study we find that the doctors working in the oncological genetic counseling in Italy, as well in other countries, are face an exacting task to impart information to people who often have high anxiety levels  and an exaggerated perception of personal risk of having a genetic mutation and/or a tumour. In particular we found that the misperception of the risk is higher for the subjects with familiarity or with sporadic events of breast and/or ovarian tumours in their family  in relation to this manuscript.AC main author project of the study and interpretation of the data, CV and BM patient's data collection, data analysis and interpretation of the data, FMS, FC and AS project of the study and study coordinator.


A population-based case-control study of oral contraceptive use and breast cancer was carried out among young women (less than 43 years of age) at Group Health Cooperative of Puget Sound, Seattle, Washington. Use of oral contraceptives before first pregnancy did not materially differ between cases or controls. The rate ratio estimate of breast cancer incidence in women who had used oral contraceptives before first pregnancy compared to those who had not was 0.9 . There were no meaningful patterns of association between breast cancer and duration of use or formulation of oral contraceptive used before first pregnancy.


Epidemiologists have established that women with small families, and particularly nulliparae, are prone to develop breast cancer later in life. We report that physiological mammary hypervascularity may be an intermediate reason against the background that breast-core vascularity is normal in pregnancy but pathological in the vascularisation of cancer. We examined breast ‘core’ vascularity in nulliparae during their potential reproductive life and in parous women after their last birth but before their menopause. Fifty clinically normal pre-menopausal non-pregnant women (100 breasts) were studied daily for one ‘luteal positive’ menstrual cycle. Their parity history varied from zero to five babies. Under controlled domestic conditions each wore a special electronic thermometric bra to automatically record breast ‘core’ temperature changes as a measure of mammary tissue blood flow. In the nulliparae there was a rise of breast vascularity throughout reproductive life. In the parous women, a year or so after each birth, breast vascularity was reset at a lower level than before the pregnancy; thereafter, as in nulliparae, there was progressive increase in mammary vascularity until the menopause.British Journal of Cancer (2002) 87, 1246–1252. doi:10.1038/sj.bjc.6600600www.bjcancer.com© 2002 Cancer Research UK Reproductive factors continue to be highlighted in epidemiological studies of breast cancer. Nuns and other nulliparous women have long been known to have a higher risk of breast cancer than the average. Fairly recently a large Swedish study concluded that each additional birth conferred a 10% risk reduction .post menarche in nulliparae, and at various times post partum in pre-menopausal parous women. The studies were possible because an electronic thermometric bra was available designed to measure breast-core temperatures and to store the readings in real time: the so-called Chronobra  and an inconstant follicular phase. Over 1000 women, of the same order of age as studied here, the standard deviation of the length of the pre-ovulatory phase was 4–5 days, whereas the luteal phase was under 2 days  of a tau=28-day cosine function fitted by least squares to the 28 data. In the averaging procedure, missing data were filled by linear interpolation. In practice, the ‘averaging’ or Mesor methods gave a very similar 28-day result. Underlying this method, as in the counting backwards from the next cycle method, is the observation that the length of the menstrual cycle consists of a fairly constant luteal phase . She also recorded daily oral temperature measurements . Exclusion criteria included anovulatory cycles, fever, certain medications and more than 4 days of missing data. Regarding the oral temperature measurements, occasionally oral temperature was used to assess objectively the situation when subjects reported feeling unwell. In this instance investigators could decide whether to discontinue on the grounds of ‘fever’.The subject also collected a daily 1 ml saliva sample for progesterone analysis to assess the ‘luteal status’ of the particular cycle  of data. One grand average temperature was obtained from these data (e.g. 28 days×2 breasts) for each subject. Overall some 12% of the data are missing for operational and technical reasons.In this way the 50 subjects are represented here by 50×2 breast ‘core’ temperatures, in turn representing 50 menstrual cycles whose timing and luteal status had been attested by daily progesterone estimates. The data come from different women and are therefore serially independent.The averaged breast-core temperatures from the 50 women (100 breasts) are shown in r=0.121; n=50).The 50 menstrual span ‘core’ temperatures are plotted against the ages of the subjects at the time of the study. Inspection of Figure 2Low-value breast-core temperatures appeared to occur particularly in subjects studied in the early post-partum years; to investigate this impression the 50 temperature data were paired with the number of pregnancy-free years immediately prior to the Chronobra study. The regression equation for the 50 pairs is as follows:n=50; t=2.79; P=0.008. Figure 3The mean breast-core temperature of right and left breast=34.7°C+0.0312×years since last pregnancy or menarche A highly significant positive correlation is apparent in The distribution of the parities in To examine further the relationship between breast-core temperature and the reproductive variables of age, parity and pregnancy-free years, a simultaneous fit was made and the results are given in Table 1Of the variables studied, only pregnancy-free years are found to be associated with breast-core temperature.The regression equations for the subsets in which single-tailed ‘P’ values are cited are as follows:Nulliparae: breast-core°C=34.0°C+0.0571×years since menarcheP=0.041 (for the seven subjects)Uniparae: breast-core°C=34.7°C+0.0490×years since pregnantP=0.062 (for seven subjects)Multiparae: breast-core°C=34.7°C+0.0370×years since pregnantP=0.025 (for 36 subjects)In Figure 4From the average ages of the uniparae and multiparae sub-populations and their regression equations we have constructed The highly significant positive correlation between breast-core temperature and pregnancy free years led us to partition the 50 data into those from women  who had had a long interval between the last pregnancy and Chronobra studies and those who had a relatively short span; of the 50 data 27 came from women with less than 11.2 pregnancy-free years and 23 came from women with an interval longer than 11.2 years. The results of this calculation are plotted in Figure 5The data from nulliparae exhibit a significant association between the breast-core temperature and the interval (years) between their menarche and the Chronobra studied menstrual cycle. These particular data also exhibit a significant association between age at study and the menstrual core-temperature.In contrast, however, the 43 parous women exhibit no detectable association of breast-core temperature with either age at menarche or age at study.But when breast temperature is correlated with the pregnancy-free years entering all 50 subjects, parous or not, then a highly significant association is found. We estimate that physiologically, when the breast is not part of the pregnancy/lactation event, there is a rise of 0.03°C per year of breast-core temperature, which we interpret as an increase of vascularity. It is implicit that there is a re-setting of this response after each pregnancy, otherwise there would be a positive correlation with age. The reproduction of the regression lines for the association of breast temperature in nulliparae, uniparae and multiparae is given in At the start of potential reproductive life all women are nulliparous and will be characterised by an average pan-menstrual breast vascularity. In The Natural History of Breast Cancer’; also more specifically and contemporaneously by Folkman (1995).What is the connection between mammary vascularity and breast cancer? In carcinogenesis the blood supply of a cancer is part of the host and not the tumour. To progress beyond a few millimetres, a cancer has to have the genetic potential and phenotypic capability of inducing the host breast tissue to supply a ‘neovascularisation’. Historically this field has been reviewed by The evidence that mammary hypervascularity may herald cancer is from three sources. First, epidemiologists have reported that there is a transient increase in breast cancer in the post partum after the physiological hypervascularity of pregnancy . Third, We interpret the present data along the following lines:In nulliparae, throughout their ‘barren’ reproductive life, there is a progressive rise of mammary vascularity consistent with their particular risk of breast cancer. Indeed, this hypervascularity may contribute to the Wolffe parenchymal risk patterns noted in mammograms of nulliparae (Our model is consistent with the epidemiologists' observations that increasing breast cancer risk occurs in nulliparae up to the age of 32. However, they have also observed that a first birth after this age is associated with a higher risk than nulliparae of the same age. How is this divergence from our model explained? In a previous article, ‘Genesis of breast cancer is in the pre menopause’, we have discussed in a subset the ‘age-specific’ effects of cancer risk factors. We consider that molecular carcinogenesis as opposed to clinical cancer has already occurred and the process is accelerated by pregnancy. The timing of this event will differ in nulliparae. Factors include the age-specific sensitivity of breast epithelium to carcinogenesis by X-rays or chemicals and an elapsed time for processing. See .Our present data are not sufficiently comprehensive to identify the point that many pregnancy-free years and the associated hypervascularity lead to a greater risk from pregnancy.In parous women, there is a putative downward re-setting of the mammary vascularity after each birth to a point below the pre-pregnancy value; then post partum, a progressive rise until the next pregnancy or the end of reproductive life; but this rise is shorter in multiparae, and by the time the menopause is reached, their observed cumulated vascularity is less. This is consistent with the fact that the reported risk of breast cancer in parous women is proportionately less than in nulliparae.During pregnancy-free intervals the progressive hypervascularity is especially marked in the luteal phases of the menstrual cycle see . PhysiolThe thermometric Chronobra offers economic, self-measuring, non-invasive monitoring of the mammary ‘core’ vascularity in health and disease. Whereas numerous Classical Risk Factors are statistically linked to breast cancer, in fact they account for only a small proportion of the total disease. Here we deal with a factor, hypervascularity, which may be on the final common path to cancer . It has


The Breast Cancer Prevention Trial (BCPT-P-1) demonstrated that tamoxifen could reduce the risk of invasive breast cancer in high-risk women by 49%, but that it could also increase the risk of endometrial cancer, vascular events and cataracts. This paper provides an estimate of the net health impacts of tamoxifen administration on high-risk Canadian women with no prior history of breast cancer. The results of the BCPT-P-1 were incorporated into the breast cancer and other modules of Statistics Canada’s microsimulation POpulation HEalth Model (POHEM). While the main intervention scenario conformed as closely as possible to the eligibility criteria for tamoxifen in the BCPT-P-1 protocol, 3 additional scenarios were simulated. Predicted absolute risks of breast cancer at 5 years of 1.66%, 3.32% and 4.15% were calculated for women 35 to 70 years of age. When the BCPT-P-1 results were incorporated into the simulation model, the analysis suggests no increase in life expectancy in this risk group. Tamoxifen appeared to be beneficial for women with a 5-year predicted risk of 3.32% or greater. The results of these simulations are particularly sensitive to the reduction in mortality observed in the BCPT-P-1, as well as being sensitive to other characteristics of the simulation model. Overall, the analysis raises questions about the use of tamoxifen in otherwise healthy women at high risk of breast cancer. © 2001 Cancer Research Campaign


A large-scale trial has been started in the United Kingdom with the aim of evaluating the effectiveness of different methods for the early detection of breast cancer. Two populations, each of 25,000 women aged 45-64 are invited for annual screening by mammography and/or clinical examination. Two further populations, one of 25,000 and one of 40,000 women in the same age range, are invited for education sessions in breast self-examination, and 4 control populations, totalling 120,000 women, are offered no additional services beyond conventional diagnostic facilities. All breast histology, both benign and malignant, in all women in the study is recorded, as are the findings, management and follow-up of all breast cancers. Changes in the populations, and deaths from all causes, are also recorded. This is essentially a non-randomized trial, though in one of the screening centres, where an education programme about breast cancer is provided for the whole population, only women registered with certain randomly selected general practices are invited to be screened. The principal means of evaluation will be the comparison of the mortality rates from breast cancer in each of the study populations. Costs, in terms of use of health resources, unnecessary surgery and radiation hazard, will be assessed. Additional aspects of the trial include studies of women's attitudes to early detection, and of the aetiology of breast cancer.