Breast cancer risk feedback to women in the UK NHS breast screening population.

INTRODUCTION: There are widespread moves to develop risk-stratified approaches to population-based breast screening. The public needs to favour receiving breast cancer risk information, which ideally should produce no detrimental effects. This study investigates risk perception, the proportion wishing to know their 10-year risk and whether subsequent screening attendance is affected. METHODS: Fifty thousand women attending the NHS Breast Screening Programme completed a risk assessment questionnaire. Ten-year breast cancer risks were estimated using a validated algorithm (Tyrer-Cuzick) adjusted for visually assessed mammographic density. Women at high risk (⩾8%) and low risk (<1%) were invited for face-to-face or telephone risk feedback and counselling. RESULTS: Of those invited to receive risk feedback, more high-risk women, 500 out of 673 (74.3%), opted to receive a consultation than low-risk women, 106 out of 193 (54.9%) (P<0.001). Women at high risk were significantly more likely to perceive their risk as high (P<0.001) and to attend their subsequent mammogram (94.4%) compared with low-risk women (84.2%; P=0.04) and all attendees (84.3%; ⩽0.0001). CONCLUSIONS: Population-based assessment of breast cancer risk is feasible. The majority of women wished to receive risk information. Perception of general population breast cancer risk is poor. There were no apparent adverse effects on screening attendance for high-risk women whose subsequent screening attendance was increased.

Can multiple SNP testing in BRCA2 and BRCA1 female carriers be used to improve risk prediction models in conjunction with clinical assessment?

BACKGROUND: Several single nucleotide polymorphisms (SNPs) at different loci have been associated with breast cancer susceptibility, accounting for around 10% of the familial component. Recent studies have found direct associations between specific SNPs and breast cancer in BRCA1/2 mutation carriers. Our aim was to determine whether validated susceptibility SNP scores improve the predictive ability of risk models in comparison/conjunction to other clinical/demographic information. METHODS: Female BRCA1/2 carriers were identified from the Manchester genetic database, and included in the study regardless of breast cancer status or age. DNA was extracted from blood samples provided by these women and used for gene and SNP profiling. Estimates of survival were examined with Kaplan-Meier curves. Multivariable Cox proportional hazards models were fit in the separate BRCA datasets and in menopausal stages screening different combinations of clinical/demographic/genetic variables. Nonlinear random survival forests were also fit to identify relevant interactions. Models were compared using Harrell's concordance index (1 - c-index). RESULTS: 548 female BRCA1 mutation carriers and 523 BRCA2 carriers were identified from the database. Median Kaplan-Meier estimate of survival was 46.0 years (44.9-48.1) for BRCA1 carriers and 48.9 (47.3-50.4) for BRCA2. By fitting Cox models and random survival forests, including both a genetic SNP score and clinical/demographic variables, average 1 - c-index values were 0.221 (st.dev. 0.019) for BRCA1 carriers and 0.215 (st.dev. 0.018) for BRCA2 carriers. CONCLUSIONS: Random survival forests did not yield higher performance compared to Cox proportional hazards. We found improvement in prediction performance when coupling the genetic SNP score with clinical/demographic markers, which warrants further investigation.

MRI breast screening in high-risk women: cancer detection and survival analysis.

Women with a genetic predisposition to breast cancer tend to develop the disease at a younger age with denser breasts making mammography screening less effective. The introduction of magnetic resonance imaging (MRI) for familial breast cancer screening programs in recent years was intended to improve outcomes in these women. We aimed to assess whether introduction of MRI surveillance improves 5- and 10-year survival of high-risk women and determine the accuracy of MRI breast cancer detection compared with mammography-only or no enhanced surveillance and compare size and pathology of cancers detected in women screened with MRI + mammography and mammography only. We used data from two prospective studies where asymptomatic women with a very high breast cancer risk were screened by either mammography alone or with MRI also compared with BRCA1/2 carriers with no intensive surveillance. 63 cancers were detected in women receiving MRI + mammography and 76 in women receiving mammography only. Sensitivity of MRI + mammography was 93 % with 63 % specificity. Fewer cancers detected on MRI were lymph node positive compared to mammography/no additional screening. There were no differences in 10-year survival between the MRI + mammography and mammography-only groups, but survival was significantly higher in the MRI-screened group (95.3 %) compared to no intensive screening (73.7 %; p = 0.002). There were no deaths among the 21 BRCA2 carriers receiving MRI. There appears to be benefit from screening with MRI, particularly in BRCA2 carriers. Extended follow-up of larger numbers of high-risk women is required to assess long-term survival.

Breast cancer risk assessment in 8,824 women attending a family history evaluation and screening programme.

Accurate individualized breast cancer risk assessment is essential to provide risk-benefit analysis prior to initiating interventions designed to lower breast cancer risk and start surveillance. We have previously shown that a manual adaptation of Claus tables was as accurate as the Tyrer-Cuzick model and more accurate at predicting breast cancer than the Gail, Claus model and Ford models. Here we reassess the manual model with longer follow up and higher numbers of cancers. Calibration of the manual model was assessed using data from 8,824 women attending the family history evaluation and screening programme in Manchester UK, with a mean follow up of 9.71 years. After exclusion of 40 prevalent cancers, 406 incident breast cancers occurred, and 385.1 were predicted (O/E = 1.05, 95 % CI 0.95-1.16) using the manual model. Predictions were close to that of observed cancers in all risk categories and in all age groups, including women in their forties (O/E = 0.99, 95 % CI 0.83-1.16). Manual risk prediction with use of adjusted Claus tables and curves with modest adjustment for hormonal and reproductive factors was a well-calibrated approach to breast cancer risk estimation in a UK family history clinic.

Increased rate of phenocopies in all age groups in BRCA1/BRCA2 mutation kindred, but increased prospective breast cancer risk is confined to BRCA2 mutation carriers.

BACKGROUND: To establish, if among unaffected noncarrier relatives in a family with an established BRCA1/2 mutation, there is an increased risk of breast cancer. METHODS: We identified 49 women with breast cancer who were first-degree relatives of a pathogenic mutation carrier among 807 BRCA1/2 families but who tested negative for the specific mutation. A prospective analysis of breast cancer from date of family ascertainment was performed for first-degree relatives of proven BRCA1/2 mutation carriers and compared with population-expected incidence rates. RESULTS: Women who prospectively test negative for BRCA1/2 mutations showed excess risk of breast cancer to be confined to BRCA2 noncarriers with an observed:expected (O/E) ratio of 4.57 [95% confidence interval (CI) 2.50-7.67; P < 0.0001; O/E in BRCA1 noncarriers, 1.77]; this dropped to 2.01 for BRCA2 [relative risk (RR), 1.99; 95% CI, 0.54-5.10] from date of predictive test. Genotyping of 18 breast cancer susceptibility single-nucleotide polymorphisms (SNP) defined an RR of 1.31 for BRCA2 breast cancer phenocopies with a breast cancer diagnosis at age less than 60 years. CONCLUSION: Noncarriers remain at risk in the prospective follow-up of women who tested negative for BRCA1/2. Women testing negative in BRCA2 families may have increased risk of breast cancer compared with population levels, particularly with strong breast cancer history in close relatives. Any increased risk in BRCA1 families is likely to be insufficient to recommend additional interventions. IMPACT: Our work can help with counseling women from BRCA1/2 families who have tested negative, and could impact on how individual breast cancer risk is related back to these women.

Risk-reducing surgery increases survival in BRCA1/2 mutation carriers unaffected at time of family referral.

The aim of this study was to establish if risk-reducing surgery (RRS) increases survival among BRCA1/2 carriers without breast/ovarian cancer at the time of family referral. Female BRCA1/2 carriers were identified from the Manchester Genetic Medicine Database. Those patients alive and unaffected at the date of first family ascertainment were included in this study. Female first-degree relatives (FDRs) without predictive genetic testing who otherwise met eligibility criteria were also included. The effect of breast and ovarian RRS on survival was analysed. The survival experiences of RRS and non-RRS patients, stratified by BRCA status, were examined with Kaplan-Meier curves and contrasted using log-rank tests and Cox models. 691 female BRCA1/2 mutation carriers without breast or ovarian cancer at time of family ascertainment were identified; 346 BRCA1 and 345 BRCA2. 105 BRCA1 carriers and 122 BRCA2 carriers developed breast cancer during follow-up. The hazard of death was statistically significantly lower (P < 0.001) following RRS versus no RRS. 10-year survival for women having RRS was 98.9 % (92.4-99.8 %) among BRCA1 and 98.0 % (92.2-99.5 %) among BRCA2 carriers. This survival benefit with RRS remained significant after FDRs were added. Women who had any form of RRS had increased survival compared to those who did not have RRS; a further increase in survival was seen among women who had both types of surgery. However, formal evidence for a survival advantage from bilateral mastectomy alone requires further research.

Reduced life expectancy seen in hereditary diseases which predispose to early-onset tumors.

There are several hereditary diseases that are a predisposition to early-onset tumors. These include syndromic conditions like neurofibromatosis 1 and 2, von Hippel-Lindau syndrome, Gorlin syndrome, multiple endocrine neoplasia, and familial adenomatous polyposis; and conditions which are usually not possible to diagnose clinically in a single individual, such as Lynch syndrome and BRCA1/2. Understanding of the mortality in hereditary cancer predisposing diseases is important for developing effective disease treatment programs. A number of studies have been undertaken to investigate the genetic predictors, prevalence and incidence, and treatment outcomes of these diseases; however, the majority examine only the most common of these diseases (eg, neurofibromatosis or BRCA), or look into postoperative survival. The mortality of individuals who are diagnosed with one of these hereditary diseases remains an area for investigation. This review is the first to attempt identification of studies investigating life expectancy in hereditary diseases which predispose to early-onset tumors.

Contralateral mastectomy improves survival in women with BRCA1/2-associated breast cancer.

BRCA1/2 mutation carriers with breast cancer are at high risk of contralateral disease. Such women often elect to have contralateral risk-reducing mastectomy (CRRM) to reduce the likelihood of recurrence. This study considers whether CRRM improves overall survival. 105 female BRCA1/2 mutation carriers with unilateral breast cancer who underwent CRRM were compared to controls (593 mutation carriers and 105 specifically matched) not undergoing CRRM and diagnosed between 1985 and 2010. Survival was assessed by proportional hazards models, and extended to a matched analysis using stratification by risk-reducing bilateral salpingo-oophorectomy (RRBSO), gene, grade and stage. Median time to CRRM was 1.1 years after the primary diagnosis (range 0.0-13.3). Median follow-up was 9.7 years in the CRRM group and 8.6 in the non-CRRM group. The 10-year overall survival was 89 % in women electing for CRRM (n = 105) compared to 71 % in the non-CRRM group (n = 593); p < 0.001. The survival advantage remained after matching for oophorectomy, gene, grade and stage: HR 0.37 (0.17-0.80, p = 0.008)-CRRM appeared to act independently of RRBSO. CRRM appears to confer a survival advantage. If this finding is confirmed in a larger series it should form part of the counselling procedure at diagnosis of the primary tumour. The indication for CRRM in women who have had RRBSO also requires further research.

Contralateral breast cancer risk in BRCA1/2-positive families needs to be adjusted for phenocopy rates particularly in second-degree untested relatives.

In the previous issue of Breast Cancer Research, Rhiem and colleagues report contralateral breast cancer risks in relatives of BRCA1/2 mutation carriers as well as those testing negative. The authors quote 25-year risks of 44.1% for BRCA1 and 33.5% for BRCA2. The risks quoted are somewhat lower than might be inferred from previous estimates in BRCA1/2 carriers, which have been as high as 40% at 10 years . This discrepancy may be explained in part by the decision to exclude index cases in which there may have been testing bias to bilateral disease. However, the authors dismiss a second bias of including many non-carriers in their analysis as 'putative' carriers.

Ovarian cancer among 8,005 women from a breast cancer family history clinic: no increased risk of invasive ovarian cancer in families testing negative for BRCA1 and BRCA2.

BACKGROUND: Mutations in BRCA1/2 genes confer ovarian, alongside breast, cancer risk. We examined the risk of developing ovarian cancer in BRCA1/2-positive families and if this risk is extended to BRCA negative families. PATIENTS AND METHODS: A prospective study involving women seen at a single family history clinic in Manchester, UK. Patients were excluded if they had ovarian cancer or oophorectomy prior to clinic. Follow-up was censored at the latest date of: 31/12/2010; ovarian cancer diagnosis; oophorectomy; or death. We used person-years at risk to assess ovarian cancer rates in the study population, subdivided by genetic status (BRCA1, BRCA2, BRCA negative, BRCA untested) compared with the general population. RESULTS: We studied 8005 women from 895 families. Women from BRCA2 mutation families showed a 17-fold increased risk of invasive ovarian cancer (relative risk (RR) 16.67; 95% CI 5.41 to 38.89). This risk increased to 50-fold in women from families with BRCA1 mutations (RR 50.00; 95% CI 26.62 to 85.50). No association was found for women in families tested negative for BRCA1/2, where there was 1 observed invasive ovarian cancer in 1613 women when 2.74 were expected (RR 0.37; 95% CI 0.01 to 2.03). There was no association with ovarian cancer in families untested for BRCA1/2 (RR 0.99; 95% CI 0.45 to 1.88). DISCUSSION: This study showed no increased risk of ovarian cancer in families that tested negative for BRCA1/2 or were untested. These data help counselling women from BRCA1/2 negative families with breast cancer that their risk of invasive ovarian cancer is not higher than the general population.

Assessing individual breast cancer risk within the U.K. National Health Service Breast Screening Program: a new paradigm for cancer prevention.

The aim of this study is to determine breast cancer risk at mammographic screening episodes and integrate standard risk factors with mammographic density and genetic data to assess changing the screening interval based on risk and offer women at high risk preventive strategies. We report our experience of assessing breast cancer risk within the U.K. National Health Service Breast Screening Program using results from the first 10,000 women entered into the "Predicting Risk Of breast Cancer At Screening" study. Of the first 28,849 women attending for screening at fifteen sites in Manchester 10,000 (35%) consented to study entry and completed the questionnaire. The median 10-year Tyrer-Cuzick breast cancer risk was 2.65% (interquartile range, 2.10-3.45). A total of 107 women (1.07%) had 10-year risks 8% or higher (high breast cancer risk), with a further 8.20% having moderately increased risk (5%-8%). Mammographic density (percent dense area) was 60% or more in 8.3% of women. We collected saliva samples from 478 women for genetic analysis and will extend this to 18% of participants. At time of consent to the study, 95.0% of women indicated they wished to know their risk. Women with a 10-year risk of 8% or more or 5% to 8% and mammographic density of 60% or higher were invited to attend or be telephoned to receive risk counseling; 81.9% of those wishing to know their risk have received risk counseling and 85.7% of these were found to be eligible for a risk-reducing intervention. These results confirm the feasibility of determining breast cancer risk and acting on the information in the context of population-based mammographic screening.

Life expectancy in hereditary cancer predisposing diseases: an observational study.

BACKGROUND: Neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), familial adenomatous polyposis (FAP), von Hippel-Lindau syndrome (VHL), and Gorlin syndrome (GS) are single gene diseases that predispose to early onset tumours. Few studies have assessed the effect of these diseases on life expectancy. This study's aim was to assess this effect, and to test the hypothesis that genetic registers increase survival. METHOD: NF1, NF2, VHL, FAP, and GS patients were identified through the North West Regional Genetic Register Service and the North West Cancer Intelligence Service. Information on benign and malignant tumours, and deaths were obtained. Kaplan-Meier curves were used to show actuarial survival rates for each disease, compared to the local population, and in patients diagnosed pre/post the regional genetic register. Log rank (Mantel-Cox) tests were used to compare survival between groups. RESULTS: Life expectancies were significantly reduced for all diseases investigated compared with the local population (80.0 years) (p=0.05). GS had the longest life expectancy at 73.4 years, followed by NF1 at 71.5 years, NF2 at 69.0 years, FAP at 63.6 years, and VHL at 52.5 years. Patients diagnosed after establishment of the genetic register had an increase in survival compared to those diagnosed pre-1990: NF2 (14.7 years), FAP (13.9 years), VHL (16.3 years), and GS (11.2 years). CONCLUSION: Life expectancy for all five diseases was less than normal, although in recent years this reached the level of the local population in GS. Although there have been improvements in all conditions which may in part be attributable to better targeted care through the genetic register service, more needs to be done to address the very poor life expectancy in VHL.

Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989.

Neurofibromatosis 1 (NF1) is a comparatively common autosomal dominant disorder. However, relatively few studies have assessed lifetime risk; and information about the effect of NF1 on mortality remains uncertain. NF1 patients were identified using The North West regional family Genetic Register, which covers the 4.1 million people living in North West England, including the regions of Greater Manchester, Cheshire and Cumbria. Data relating to tumours and malignancies were obtained from The North West Cancer Intelligence Service. Death data for the general North West population were obtained from the Office of National Statistics. We identified 1186 individuals with NF1, of whom 1023 lived within the strict regional boundaries (constituting a region of North West England bound by The Pennines to the east and Irish Sea to the west, but excluding the conurbation of Liverpool (Merseyside) and the Wirral peninsula) and 131 had died. MPNST and glioma were found to be the two most common causes of reduced life expectancy among NF1 patients. In Kaplan-Meier analyses the median survival for NF1 patients was shown to be 71.5 years, with women living ∼7.4 years longer than men. On average both men and women lived ∼8 years less than their counterparts in the general population. Reduction in life expectancy for NF1 patients was found to be much lower (8 years) than the previously estimated 15-year decrease. Limitations relating to the underreporting of NF1 on death certificates were once again highlighted and should be considered in future investigations.

Malignant peripheral nerve sheath tumours in NF1: improved survival in women and in recent years.

BACKGROUND: Malignant peripheral nerve sheath tumours (MPNST) are the main soft tissue malignancy associated with neurofibromatosis 1. These uncommon tumours are known to occur at high frequency and lead to poor survival. Our aim was to determine risk of MPNST in NF1 patients, and survival rates. METHODS: The incidence of MPNST in NF1 was identified through the NF1 genetic register and The North West Cancer Intelligence Service (NWCIS). Data were used to generate incidence and survival curves. Strict regional boundaries were adhered to avoid ascertainment bias. Kaplan-Meier curves were used to determine five and ten-year survival. RESULTS: Of the 1059 NF1 patients 52 developed MPNST (30 cases in females and 22 in males), 43 cases were resident within the strict regional boundary. The risk of MPNST was 10.2% in males and 12.7% in females by age 70 years (p=0.9), with a statistically better survival in females than males (5 and 10 year survival 46% and 41.5% versus 22% and 8.2%; p=0.05). Survival was also significantly improved for patients diagnosed in the last 14 years compared to the previous 13-year period (p=0.03). CONCLUSION: With fifteen strict regional MPNSTs in the fourteen years since our previous population study an annual incidence of above 1 per 1000 NF1 patients has now been maintained over a 27-year period. No significant increase in risk of MPNST in females compared to males was found, though the difference in survival is intriguing. Male survival is particularly poor with <10% alive at 10 years.

Nottingham knee osteoarthritis risk prediction models.

OBJECTIVES: (1) To develop risk prediction models for knee osteoarthritis (OA) and (2) to estimate the risk reduction that results from modification of potential risk factors. METHOD: This was a 12-year retrospective cohort study undertaken in the general population in Nottingham, UK. Baseline risk factors were collected by questionnaire. Incident radiographic knee OA was defined by Kellgren and Lawrence (KL) score ≥2. Incident symptomatic knee OA was defined by KL ≥2 plus knee pain. Progression of knee OA was defined by KL ≥1 grade increase from baseline. A logistic regression model was used for prediction. Calibration and discrimination of the models were tested in the Osteoarthritis Initiative (OAI) population and Genetics of Osteoarthritis and Lifestyle (GOAL) population. ORs of the models were compared with those obtained from meta-analysis of existing literature. RESULTS: From a community sample of 424 people aged over 40, 3 risk prediction models were developed. These included incidence of radiographic knee OA, incidence of symptomatic knee OA and progression of knee OA. All models had good calibration and moderate discrimination power in OAI and GOAL. The ORs lied within the 95% CIs of the published studies. The risk reduction due to modifying obesity at the individual and the population levels were demonstrated. CONCLUSIONS: Risk prediction of knee OA based on the well established, common modifiable risk factors has been established. The models may be used to predict the risk of knee OA, and risk reduction due to preventing a specific risk factor.

Development and validation of self-reported line drawings for assessment of knee malalignment and foot rotation: a cross-sectional comparative study.

BACKGROUND: For large scale epidemiological studies clinical assessments and radiographs can be impractical and expensive to apply to more than just a sample of the population examined. The study objectives were to develop and validate two novel instruments for self-reported knee malalignment and foot rotation suitable for use in questionnaire studies of knee pain and osteoarthritis. METHODS: Two sets of line drawings were developed using similar methodology. Each instrument consisted of an explanatory question followed by a set of drawings showing straight alignment, then two each at 7.5 degrees angulation and 15 degrees angulation in the varus/valgus (knee) and inward/outward (foot) directions. Forty one participants undertaking a community study completed the instruments on two occasions. Participants were assessed once by a blinded expert clinical observer with demonstrated excellent reproducibility. Validity was assessed by sensitivity, specificity and likelihood ratio (LR) using the observer as the reference standard. Reliability was assessed using weighted kappa (kappa). Knee malalignment was measured on 400 knee radiographs. General linear model was used to assess for the presence of a linear increase in knee alignment angle (measured medially) from self-reported severe varus to mild varus, straight, mild valgus and severe valgus deformity. RESULTS: Observer reproducibility (kappa) was 0.89 and 0.81 for the knee malalignment and foot rotation instruments respectively. Self-reported participant reproducibility was also good for the knee (kappa 0.73) and foot (kappa 0.87) instruments. Validity was excellent for the knee malalignment instrument, with a sensitivity of 0.74 (95%CI 0.54, 0.93) and specificity of 0.97 (95%CI 0.94, 1.00). Similarly the foot rotation instrument was also found to have high sensitivity (0.92, 95%CI 0.83, 1.01) and specificity (0.96, 95%CI 0.93, 1.00). The knee alignment angle increased progressively from self reported severe varus to mild varus, straight, mild valgus and severe valgus knee malalignment (ptrend <0.001). CONCLUSIONS: The two novel instruments appear to provide a valid and reliable assessment of self-reported knee malalignment and foot rotation, and may have a practical use in epidemiological studies.