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Published OnlineFirst July 21, 2014; DOI: / CAPR

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Research Article Cancer Prevention Research Breast Cancer Risk in Young Women in the National Breast Screening Programme: Implications for Applying NICE Guidelines for Additional Screening and Chemoprevention
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Research Article Cancer Prevention Research Breast Cancer Risk in Young Women in the National Breast Screening Programme: Implications for Applying NICE Guidelines for Additional Screening and Chemoprevention D. Gareth Evans 1,2,3, Adam R. Brentnall 4, Michelle Harvie 1, Sarah Dawe 1, Jamie C. Sergeant 1,5,6, Paula Stavrinos 1, Susan Astley 1,5, Mary Wilson 1, John Ainsworth 7, Jack Cuzick 4, Iain Buchan 7, Louise S. Donnelly 1, and Anthony Howell 1,3 Abstract In the United Kingdom, women at moderate and high risk of breast cancer between the ages of 40 and 49 years are eligible for annual mammographic screening and preventive therapy with tamoxifen. Here, we estimate the numbers of women in a population eligible for this service and the proportion of breast cancers detected in this group compared with the whole population. Women 50 attending for mammographic screening in the National Health Service Breast Screening Programme (NHSBSP) completed a risk questionnaire. The proportion at moderate and high risk according to National Institute of Health Care Excellence (NICE) guidelines was estimated. An estimate was also made using a different model of risk estimation (Tyrer Cuzick). The numbers of cancers detected in the moderate/high risk groups were compared with numbers detected in the whole population. Completed questionnaires were available for 4,360 women between ages 46 and 49 years. Thirty women [0.7%; 95% confidence interval (CI), %] were at high risk and 130 (3.0%, %) were at moderate risk according to NICE guidelines. Thirtyseven cancers were detected by mammography in the whole group. Five of these were found in the moderate-/high-risk group giving a 3.2-fold increase in detection compared with the standard risk group. More women were assigned to the moderate- or high-risk group using the Tyrer Cuzick model (N ¼ 384), but the numbers of cancers in this group were not appreciably increased (N ¼ 8). Systematic assessment of family history in primary care or through population-based screening will identify appreciable numbers of women in their forties, eligible for additional surveillance and chemoprevention Cancer Prev Res; 7(10); Ó2014 AACR. Introduction Breast cancer is a major burden to society and individuals with 49,936 women developing the disease in the United 1 Genesis Breast Cancer Prevention Centre, University Hospital of South Manchester NHS Trust, Wythenshawe, Manchester, United Kingdom. 2 Genetic Medicine, Manchester Academic Health Science Centre, Central Manchester Foundation Trust, St. Mary's Hospital, Manchester, United Kingdom. 3 Manchester Breast Centre, Manchester Cancer Research Centre, University of Manchester, Christie Hospital, Withington, Manchester, United Kingdom. 4 Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London. 5 Centre for Imaging Sciences, Institute of Population Health, University of Manchester, Manchester, United Kingdom. 6 NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, United Kingdom. 7 Institute of Population Health, University of Manchester, Oxford Road, Manchester, United Kingdom. Note: Supplementary data for this article are available at Cancer Prevention Research Online ( Corresponding Author: D.G.R. Evans, Consultant Clinical Geneticist, Genomic Medicine, MAHSC, St. Mary's Hospital, Oxford Road, Manchester, M13 9WL, UK. Phone: ; Fax: ; doi: / CAPR Ó2014 American Association for Cancer Kingdom (population 60 million) in 2011, and 11,684 dying (1). Although deaths from breast cancer have been decreasing in many Western countries, the incidence of the disease continues to increase. In particular, in countries with historically low incidence breast cancer rates are rising rapidly, making it now the most prevalent cancer in the world. The increase in incidence may well be related to changes in weight and reproductive patterns associated with Western lifestyles. Indeed, there is evidence from genetic studies in the United States, Iceland, and the United Kingdom (2 4) of a 3-fold increase in incidence not only in the general population but also in those at the highest level of risk with BRCA1 and BRCA2 mutations in the last 80 years (4). Breast cancer rates are also rising in women who have not generally been screened, such as those in their forties (1). Although cure rates continue to improve, the cost of treating breast cancer is considerable for both the women concerned and the health service. Therefore, there is a need not only to predict which women will develop the disease but also to apply drug and lifestyle measures to prevent the disease. Currently, women ages 47 to 73 years are invited for breast screening with 3-yearly mammography in the United 993 Evans et al. Kingdom. A recent review of the National Health Service Breast Screening Programme (NHSBSP) estimated that it saved around 1,300 lives annually (5). Although, the vast majority of women in the United Kingdom receive only 3- yearly screening invitations, more frequent screening has been recommended by the National Institute of Health Care Excellence (NICE; ref. 6) since 2004 for those at increased familial risk. This includes annual mammography ages 40 to 49 years for women at moderate risk and annual screening ages 40 to 60 years in those at high risk (annual MRI is recommended ages 30 to 50 years in mutation carriers and those with at least a 30% chance of a mutation in BRCA1/2 or TP53). This guidance has just been updated and the highrisk recommendations are already being implemented in the NHSBSP as highlighted recently (7). Recent evidence suggests that stratification of risk and screening frequency is likely to be more cost effective (8 10). A substantial amount of breast cancer is preventable but chemoprevention has, thus, far not been applied to moderate-/high-risk UK women outside randomized trials. Chemoprevention involves 5 years of the selective estrogen receptor modulators (SERM) tamoxifen or raloxifene, which reduce risk by 35% to 40% (11 13). NICE have reviewed chemoprevention for women at moderate/high familial breast cancer risk (17% lifetime). Final guidance states: offering/considering tamoxifen/raloxifene for women at high/moderate risk (13, 14). It is difficult to apply the NICE guidelines for additional surveillance or offer of chemoprevention within the NHS because there is currently no systematic mechanism for identifying moderate-/high-risk women. Many/most moderate-/high-risk women remain unaware of their breast cancer risk and only those women who present with concerns about family history get referred to Family History Clinics (FHC) where they receive additional screening (every months) and could now be offered chemoprevention. We are undertaking an NIHR funded study (PROCAS, Predicting Risk Of Cancer At Screening) in Greater Manchester, which is investigating the feasibility of assessing and communicating breast cancer risk to women in the NHSBSP (15). More than 53,000 women have been recruited to date from those invited for mammography (39% uptake). Interestingly, 95% of recruited women indicated that they wished to know their risk of breast cancer. Because risk is not estimated in the general population, it has not been possible to assess the proportion of women in the National Screening Programme who are at moderate or high risk by NICE criteria, or by models of risk, which include additional factors to family history. An important age group in respect of the NICE guidance are those ages 40 to 49 years. Of these women, those identified as moderate/high risk would gain access to annual mammography screening as well as being considered for chemoprevention with tamoxifen. The greatest population impact of tamoxifen would be in this age group, with long-term risk reduction and fewer risks of serious complications such as endometrial cancer and thromboembolism (11 13). In PROCAS, we have assessed family history by questionnaire in 4,360 women attending the NHSBSP ages 46 to 49 years, and identified those that meet either the NICE algorithm for moderate or high risk, or who meet the 10-year risk thresholds at age 40 years of 3% for moderate risk and 8% for high risk, assessed using the Tyrer Cuzick model. We also assessed whether women were diagnosed with breast cancer in the first 3 years of PROCAS and whether women had previously had risk assessment in the genetic and family history services. Materials and Methods We devised a two-page questionnaire to collect family history, hormonal, and lifestyle risk factors for breast cancer (15). Women invited for routine mammographic screening across 15 screening areas in Greater Manchester were mailed the questionnaire, study information, and a consent form. Consent was obtained at the time of screening. Information on each questionnaire was imported into the study database (and checked for inconsistencies) and the risk estimated automatically using the Tyrer Cuzick model (16). The study was approved by the Central Manchester Research Ethics Committee (ref: 09/H1008/81). Only women 50 years of age were included for the main analysis for reasons given above. The NICE algorithms (Appendix; ref. 6) were used to assess whether first-degree relative (FDR) or combined FDR and second-degree relative (SDR) family history met either the high- or moderate-risk criteria. NICE guidance advises to use a woman s 10-year risk at their current age in their mid to late forties adjusted to the 10-year risk at age 40 years (6). Four examples in Table 1 compare risk from NICE guidelines and Tyrer Cuzick. The high-risk examples show that the Tyrer Cuzick relative risk decreases as a woman gets older. The moderate-risk examples show that the relative risk is more constant as a woman gets older. Partly on this Table 1. Examples to compare examples of family histories that meet moderate and high risk in NICE algorithm with the equivalent risk in Tyrer Cuzick from an example pedigree Mother Sister 10-year risk 10-year risk Relative risk Relative risk NICE age age age 40 age 49 age 40 age 49 High % 7.8% High % 6.3% Moderate % 5.8% Moderate % 4.8% Cancer Prev Res; 7(10) October 2014 Cancer Prevention Research Population Prevalence of High and Moderate Breast Cancer Risk basis the following strategy was used to convert a risk age 46 to 49 years to a high or moderate category, based on the NICE guidance for a woman ages 40 years. First, an absolute risk of 8% was taken for high risk, as although the baseline incidence increases due to age, relative risk from family history decreases as a woman gets older as she is less likely to have inherited a genetic predisposition. Second, the boundary for moderate risk was taken to be the same relative risk for each year at ages 46 to 49 as 40 years. For example, the population 10-year risk at age 46 years is 2.25% and, therefore, the 10-year moderate-risk threshold with a 1.9- fold risk would be 4.3% (Table 2). The population risk in the Tyrer Cuzick model age 40 years was approximately 1.6%, so moderate risk is taken to be a relative risk more than 1.9 (3.0/1.6) but an absolute risk less than 8.0%. The absolute risk cutoffs used are shown in Table 2, for other ages the same strategy of multiplying the population 10- year risk by 1.9 could be used to determine moderate risk. A sensitivity analysis of the high-risk group was undertaken by plotting the percentage of women and breast cancers diagnosed for different 10-year cutoffs. Breast cancers in all women [ICD10 codes C50 and D05; invasive and ductal carcinoma in situ (DCIS)] were actively sought through the NHSBSP reporting system. Breast cancer rates, sensitivity, and specificity were assessed in each risk category and by closeness of affected relatives. In addition, we interrogated our FHC attendance against the local population estimates from the National Census to assess the number of women who have already identified themselves with at least moderate risk. Profile likelihood confidence intervals were used for ORs and binomial parameters. Results Sixty-one percent of the general population of Greater Manchester ages 46 to 49 years and unaffected by breast cancer who were invited for breast cancer screening attended, and 46.1% of these (n ¼ 4360) enrolled in PROCAS (Fig. 1). Although there have been some potentially expected issues with women s responses to some questions, overall the questionnaires were filled in to completeness by the vast majority of women and 10-year risks were readily identifiable. As in our initial article, women entering PROCAS were more likely to come from less deprived areas (15). Baseline characteristics of the sample are in Table 3. Some 30.4% (1,327) indicated on their questionnaire that they had a relative with breast cancer: 9.4% (410) with one FDR or more, 14.9% (649) not having an FDR but at least one SDR and 6.1% (268) with a third or more distant relative with breast cancer. To date, 37 breast cancers have been detected in this population; 24 of which occurred at the prevalent screen; 4 were interval cancers, and 9 were detected at the second mammography screen. Table 4 shows the main results by NICE and Tyrer Cuzick categories. Thirty women [0.7%; 95% confidence interval (CI), 0.5% 1.0%] met the NICE algorithm for high risk and 130 (3.0%; 95% CI, 2.5% 3.5%) were moderate risk. Using the Tyrer Cuzick algorithm the 10-year high risk threshold of 8% was met by 37 women (0.8%; 95% CI, 0.6% 1.2%) and 347 (8.0%; 95% CI, 7.2% 8.8%) met the moderate-risk category. Thus, around 3.7% (95% CI, 3.1% 4.3%) of women ages 46 to 49 years would meet NICE moderate-/ high-risk criteria following the NICE algorithm; 8.8% (95% CI, 8.0% 9.7%) when using Tyrer Cuzick. The largest difference was that 240 women were identified by the Tyrer Cuzick groupings to be at moderate risk that were not identified by the NICE algorithm. However, the proportion of breast cancer events was similar in both the NICE and Tyrer Cuzick categories. The OR in the NICE moderate or above category versus other was 4.2 (95% CI, ); for the Tyrer Cuzick model it was 2.9 (95% CI, ). Furthermore, with the NICE algorithm the 160 (3.7%) in the moderate- or high-risk groups identified 5 of 37 (13.5%; 95% CI, 5.1% 26.8%) of the breast cancers occurring after enrollment. The Tyrer Cuzick group of 384 (8.8%) moderate or high risk identified 8 of 37 (21.6%, 95% CI, 10.5% 36.5%) of the breast cancers occurring after enrollment. These compared with 20 of 37 (54.1%; 95% CI, ) of cancers that occurred in 1,327 (30.4%) of women with any blood relative, including 5 with only third or more distant relatives affected. The distribution of reproductive risk factors in all women identified by one or both risk assessments as being at least moderate risk are shown in Table 5. This table also shows correlations between risk categorization between NICE algorithm and Tyrer Cuzick 10-year risks. The NICE categorization does not use parity, age at menarche, or menopause. It can be seen that these factors explain some of the difference in categorizations with Tyrer Cuzick. For example, women who were found to be moderate risk by Tyrer Cuzick but not by the NICE algorithm were more likely to be nulliparous (OR, 1.5; 95% CI, ). The Tyrer Cuzick model provides a continuous range of absolute risks, and so it is possible to explore the effect of different cutoffs in absolute risk for any age. If a 3% 10-years risk is used as the threshold at all ages (rather than the 3% 10-year risk at age 40 years) then 17 of 37 (45.9%, 95% CI 30.6% 61.9%) of the cancers are identified by assessing 1,269 women (29.1%; 95% CI, 27.8% 30.5%). Conversely, no breast cancers occurred to date in 583 women (13.4%; 95% CI, 12.4% 14.4%) with a Tyrer Cuzick 10-year risk of Table 2. Ten-year risk at age in forties in Tyrer Cuzick with equivalent risks ages 46 to 49 years Age 40 Age 46 Age 47 Age 48 Age 49 Moderate risk High risk 8.0% 8.0% 8.0% 8.0% 8.0% Cancer Prev Res; 7(10) October Evans et al. 9,457 (61%) attended for screening 5,097 (53.9%) attended for baseline mammogram 15,504 women ages years Invite to 4,360 (46.1%) consented to NHSBSP and PROCAS filled in questionnaire PROCAS and had baseline mammogram 6,047 (39%) did not attend for screening 4 found with interval breast cancers 24 (0.55%) detected with breast cancer (prevalence) 1,550 women have had a second mammogram 9 (0.58%) detected with breast cancer (incidence) Figure 1. Consort diagram of the PROCAS study. 1.8% at initial assessment. Using the 2.5% 10-year risk cutoff suggested by Cambridge (17), 23 of 37 (62.2%; 95% CI, 46.1% 76.6%) of the cancers are identified by assessing 2,243 women (51.4%; 95% CI, 50.0% 52.9%). A sensitivity analysis of the Tyrer Cuzick high-risk group is available in the Supplementary Figure. In our FHC that covers Central and South Manchester and Trafford, we compared the number of women we currently see who have been identified with at least moderate risk by NICE criteria ages 40 to 49 years against the Census record of women in that age group. In Trafford, there are currently 203 women at moderate risk representing 1.2% of the population. In Central and South Manchester, there are 213 women representing 0.8% of the population. Of the 160 women meeting NICE guideline criteria only 28 (17.5%; 95% CI, 12.2% 23.9%) had been seen in the FHC or clinical genetics service previously, indicating that only one sixth of those at moderate or high risk of breast cancer had come forward for assessment. This dropped to only 2 of 31 (6.5%; 95% CI, 1.1% 18.6%; P ¼ 0.02) of those whose family history risk was predominantly paternally related. Of those at high-risk, 10 of 30 (33.3%; 95% CI, 18.3% 51.1%) had been previously assessed compared with 19 of 130 (14.6%; 95% CI, 9.3% 21.4%) of those at moderate risk, so those at high-risk had a 2.9 (95% CI, )-fold likelihood of being FHC assessed. To assess whether women identified at increased risk may have gone for breast cancer risk assessment elsewhere, we checked for this in the 257 women at 8% 10- year risk in the whole PROCAS cohort who had been interviewed by study clinicians (D.G. Evans and A. Howell). Although only 46 of 257 (18%) had been assessed previously in our FHC, none of the remaining women were aware of their high-risk status or had undergone a risk assessment elsewhere. A small proportion of women interviewed at both high and low risk had minor adjustments made to their 10-year risks based on a few inaccurate details on their questionnaire. However, 95% remained in the same risk category. Women at high-risk received a detailed letter outlining their risks and potential options to deal with these. Copies of these letters were sent to the primary care physicians. We finally assessed the potential impact in North America of using the 1.65% 5-year threshold approved by the FDA in North America for chemoprevention with tamoxifen. Of note, 961 of 4,360 (22%) of women reached the equivalent 3.3% 10-year risk threshold in Tyrer Cuzick. This would have identified 13 of 37 (35%) of the breast cancers. In the whole dataset of enrollees ages 46 to 73 years 14,281 (29%) of 49,288 women without breast cancer at entry met the 3.3% threshold. Of women 65 years of age, 3,526 of 11,146 (32%) met tamoxifen criteria. Again in the expanded full population 637 (1.3%) met the high-risk 8% 10-year NICE threshold. Discussion Only one study to our knowledge has identified the proportion of the female population who are at moderate or high risk of breast cancer and, hence, eligible for increased surveillance and the offer of chemoprevention as per NICE guidance (18). We have shown that among women entering the PROCAS population-based screening cohort study in Greater Manchester, 0.7% met high- and 3.0% moderate-risk criteria. Only 5 of 37 (13.5%) of the 996
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