Family History Clinic Research Articles

Roll out and influence of an educational program: Talking about risk, uncertainties of testing in genetics (TRUSTING).

9025 Background: Family history clinics face significant capacity issues making calls for genetic testing of all breast cancer (BC) patients problematic. Mainstreaming of services by health care professionals (HCPs) is needed but many lack confidence and familiarity with genetic counseling. Following successful development and evaluation of the TRUSTING educational program (Fallowfield et al. BJC 2022), facilitators were trained to roll out workshops for BC HCPs. Here we report the workshops’ effect on participants’ knowledge, skills, and self-confidence and influence on mainstreaming. Methods: 1 surgeon, 3 oncologists, 1 nurse specialist facilitated the 8-hr program in pairs. Workshop content included didactic components to enhance knowledge and various exercises to promote self-awareness about individual participants’ tolerance to uncertainty and risk. Groups discussed 6 filmed scenarios showing interactions between surgeons and geneticists with the proband (triple negative BC and BRCA2 pathogenic gene alteration), her sister (BRCA2 +) and their anxious cousin (BRCA2 -). Pre-workshop, participants completed: - 1) an 18-item multiple choice knowledge questionnaire about gene testing in breast cancer 2) a 9-item questionnaire exploring self-confidence when discussing/advising patients about different aspects of BRCA testing, results, and treatments and 3) an Intolerance to Uncertainty Scale. Knowledge and self-confidence together with general feedback questions about overall satisfaction with facilitators and the event were assessed post workshop. Follow-up questionnaires sent 3-12 mths later examined the impact TRUSTING workshops had made on participants’ own practice and implementation of mainstreaming in their clinic. Results: 120 participants (61 surgeons; 41 nurses; 9 oncologists; 9 other) attended 12 UK workshops. There were improvements post workshop in knowledge (mean change = 6.57; 95% CI 5.97 to 7.16; p<0.001) and self-confidence (mean change = 2.64; 95% CI 2.33 to 2.95; p<0.001). Feedback about the facilitators’ approach was uniformly high (mean range 9.65 to 9.90 /10). Most found workshops useful, enjoyable, and informative; 98% would definitively recommend them to colleagues. Follow up data revealed that attendance significantly impacted individuals’ own practice with 59% reporting it had improved their discussions about genetic testing with patients. When asked about mainstreaming more generally 81% reported it as “OK” or “working very well”, others (16%) that it had not yet started or (3%) that it was problematic. Conclusions: Discussing the implications of pathogenic gene alterations on patients’ treatment and risk-reducing interventions is complex when patients are already coming to terms with a BC diagnosis. The TRUSTING educational program is an effective means of helping HCPs now involved in the mainstreaming of genetic testing.

Weight, weight gain and behavioural risk factors in women attending a breast cancer family history, risk and prevention clinic: an observational study

BackgroundWeight and health behaviours impact on breast cancer risk. We describe trends in weight and health behaviours in women at entry to a specialist breast cancer family history clinic in Manchester, UK, and changes after clinic entry.MethodsQuestionnaires were completed at clinic entry (1987–2019, n = 10,920), and updated in 2010–11 (n = 3283). Clinic entry characteristics were compared between joining periods 1989–98, 1999–2008 and 2009–18. Partial Least Squares analysis characterised trends in weight, smoking and alcohol intake by age at entry, year of entry and birth year. Weight changes were compared over time, between joining periods.ResultsObesity at clinic entry increased from 10.6% in 1989–98 to 20.5% in 2009–18. Alcohol intake above recommendations and smoking prevalence decreased from 20.1% to 13.8% and 33.5% to 16.1% respectively. Weight gain was median 9.7 (IQR 1.4–20.6) % between age 20 and clinic entry (mean duration 11.9 ± 5.6 years) and a further 4.5 (0.0–12.5) % between clinic entry and 2010–11 (31.1 ± 10.4 years). Weight gain between age 20 and clinic entry was highest in the most recent joining period.ConclusionsObesity and weight gain are common in women attending a breast cancer family history clinic suggesting a need for weight management advice and support.

Preventative therapy for breast cancer: a clinical experience

BackgroundBreast Cancer incidence in the UK is estimated to rise to 71,000 per year by 2035. Preventative strategies could significantly reduce this. Preventative therapy reduces women’s risk of oestrogen receptor positive breast cancer, but uptake remains low. Having established a preventative therapy clinic as part of a wider breast cancer prevention project, we explored qualitative data to inform future preventative efforts.MethodWomen aged 30 to 60 who had benign diagnoses at a symptomatic breast clinic or were under mammographic surveillance in the moderate risk family history clinic were invited to participate in the study. Those who expressed an interest and completed an initial questionnaire had their breast cancer risk calculated using the IBIS risk calculator. Those at increased risk were invited to a consultation about preventative therapy.Results182 women were identified as increased risk (≥ 17% lifetime or ≥ 3% 10-year risk NICE guidelines: Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer, 20131) of whom 91 women (50%) would not have been identified by family history criteria alone. 96% attended a risk/prevention consultation and all eligible women accepted screening mammography but only 14 (8%) women requested a preventative therapy prescription during the duration of the study. Reluctance to take medication and inconvenient time of life were common reasons for declining preventative therapy. Despite this, the majority were grateful for breast cancer risk and prevention information.ConclusionsWomen at increased risk of breast cancer accept additional screening but are reluctant to take preventative therapy. This suggests that stratified screening methods using risk calculations would have high uptake. Raising awareness of preventative therapy is important and the breast cancer community has yet to find the optimum timing and formula for discussing it and must accept women’s informed preferences above artificial targets.Registration numbersThe PIONEER study was granted Health Research Authority (HRA) ethical approval by the Westminster Ethics Committee. IRAS project ID 265619, ClinicalTrials.gov Identifier: NCT04574063. Recruitment began in September 2020 and was completed in October 2021.

Breast cancer risk prediction models in a moderate risk family history clinic

Breast cancer risk prediction models in a moderate risk family history clinic

Randomised controlled trial of breast cancer and multiple disease prevention weight loss programmes vs written advice amongst women attending a breast cancer family history clinic

BackgroundOverweight and obesity are common amongst women attending breast cancer Family History, Risk and Prevention Clinics (FHRPCs). Overweight increases risk of breast cancer (BC) and conditions including1 cardiovascular disease (CVD) and type-2 diabetes (T2D). Clinics provide written health behaviour advice with is likely to have minimal effects. We assessed efficacy of two remotely delivered weight loss programmes vs. written advice.Method210 women with overweight or obesity attending three UK FHRPCs were randomised to either a BC prevention programme (BCPP) framed to reduce risk of BC (n = 86), a multiple disease prevention programme (MDPP) framed to reduce risk of BC, CVD and T2D (n = 87), or written advice (n = 37). Change in weight and health behaviours were assessed at 12-months.ResultsWeight loss at 12 months was −6.3% (−8.2, −4.5) in BCPP, −6.0% (−7.9, −4.2) in MDPP and −3.3% (−6.2, −0.5) in the written group (p = 0.451 across groups). The percentage losing ≥10% weight in these groups were respectively 34%, 23% and 14% (p = 0.038 across groups).DiscussionBCPP and MDPP programmes resulted in more women achieving ≥10% weight loss, but no evidence of additional benefits of MDPP. A multicentre RCT to test the BCPP across UK FHRPCs is warranted.Clinical Trial Registration ISRCTN16431108.

Evaluating the Acceptance and Usability of an App Promoting Weight Gain Prevention and Healthy Behaviors Among Young Women With a Family History of Breast Cancer: Protocol for an Observational Study.

Breast cancer is the most common form of cancer in women, and around 20% of cases are associated with factors such as adult weight gain, overweight and obesity, and potentially modifiable health behaviors including high alcohol intake, smoking, lack of physical activity, and breastfeeding. Significant weight gain occurs between the ages of 18 and 35 years; hence, this age group could benefit from weight gain prevention interventions. Population studies have reported that women at increased risk of breast cancer account for a disproportionate amount of cases. Thus, there is a particular need to target weight gain prevention and other health behavior interventions for women at increased risk. A literature review identified no evidence-based apps that cover all relevant health behaviors. With patient and participant involvement from the target population, we have developed a new app to promote healthy behaviors among young women at increased risk of breast cancer. Alongside the app, a Facebook group provides peer support, and a virtual welcome event provides an overview of the project and the opportunity to meet the research team and other study participants. The aim of the intervention is to prevent weight gain via changes to eating habits and physical activity levels, and improve other health behaviors associated with breast cancer. The app includes goal setting and self-monitoring of health behaviors and provides education about breast cancer. This study aims to assess the acceptability and usability of the app in young women at increased risk of breast cancer, and the feasibility of the study procedures for a future, larger efficacy study. Young women (n=35, age 18-35 years) at increased risk of breast cancer (>17% lifetime risk) will be recruited via 2 recruitment procedures: mailed invite from the local breast cancer family history, risk and prevention clinic, and advertisements on social media and websites. Participants will have access to the app and the private Facebook group for 2 months. They will complete questionnaires regarding their health behaviors and breast cancer risk belief at the start and end of the study, complete app rating scales in the middle and at the end of the study, and be invited to give feedback on the app during the study period. Approximately 20 participants will have a semistructured interview at the end of the study regarding their views on the app and trial procedures. The trial is ongoing, and the publication of results is anticipated in 2023. The trial will provide evidence regarding the acceptability and usability of the newly developed app for young women at increased risk of breast cancer. Feedback obtained will be used to improve the app. The trial will also assess the feasibility of the study procedures and how these can be refined for a future efficacy study. ClinicalTrials.gov NCT05460650; https://clinicaltrials.gov/ct2/show/NCT05460650. PRR1-10.2196/41246.

“Efficacy of current familial breast cancer screening practices and its impact on national cancer programme”

Introduction: Breast cancer has been the leading cause of cancer in females over the last few decades. Familial inheritance of breast cancer is proven and investigated deeply. The need of the day is to risk stratify it before the actual problem arises and to standardise the process across the UK which is not yet addressed.
 Objective: The objective of this study is to assess the efficacy of current referrals to familial breast cancer clinics from all sources and their impact on the national breast cancer programme.
 Materials and Methods: This is a retrospective study of patients referred to the breast cancer family history clinic at King’s Mill Hospital Breast Surgery Department between Jan-Dec 2017. A case note review of these cases was undertaken and data was collected on a proforma shown below. For analysis data was entered on FaHRAS and according to the risk calculated appropriateness of referrals to secondary care was measured.
 Results: Results of our study showed that 73% of the referrals made in 2017 from primary care were appropriate, while 27% were stratified as in-appropriate referrals. Those missed might be more than expected but there is no way to assess the missed ones.
 Conclusion: In the conclusion, this study identifies the tip of the iceberg regarding the issue but the problem is far bigger. If screening is done in primary care, missed cases and inappropriate referrals could be effectively reduced significantly.

Uptake of bilateral-risk-reducing-mastectomy: Prospective analysis of 7195 women at high-risk of breast cancer

BackgroundBilateral-Risk-Reducing-Mastectomy-(BRRM) is well described in BRCA1/2 pathogenic variant carriers. However, little is known about the relative uptake, time trends or factors influencing uptake in those at increased breast cancer risk not known to be carriers. The aim of this study is to assess these factors in both groups. MethodsBRRM uptake was assessed from entry to the Manchester Family History Clinic or from date of personal BRCA1/2 test. Follow up was censored at BRRM, breast cancer diagnosis, death or January 01, 2020. Cumulative incidence and cause specific and competing risk regression analyses were used to assess the significance of factors associated with BRRM. ResultsOf 7195 women at ≥25% lifetime breast cancer risk followed for up to 32 years, 451 (6.2%) underwent pre-symptomatic BRRM. Of those eligible in different risk groups the 20-year uptake of BRRM was 47.7%-(95%CI = 42.4–53.2%) in 479 BRCA1/2 carriers; 9.0% (95%CI = 7.26–11.24%) in 1261 women at ≥40% lifetime risk (non-BRCA), 4.8%-(95%CI = 3.98–5.73%) in 3561 women at 30–39% risk and 2.9%-(95%CI = 2.09–4.09%) in 1783 women at 25–29% lifetime risk. In cause-specific Cox regression analysis death of a sister with breast cancer<50 (OR = 2.4; 95%CI = 1.7–3.4), mother<60 (OR = 1.9; 95%CI = 1.5–2.3), having children (OR = 1.4; 95%CI = 1.1–1.8), breast biopsy (OR = 1.4; 95%CI = 1.0–1.8) were all independently associated with BRRM uptake, while being older at assessment was less likely to be associated with BRRM (>50; OR = 0.26,95%CI = 0.17–0.41). Uptake continued to rise to 20 years from initial risk assessment. ConclusionWe have identified several additional factors that correlate with BRRM uptake and demonstrate continued increases over time. These factors will help to tailor counselling and support for women.

The Angelina Jolie effect: Contralateral risk-reducing mastectomy trends in patients at increased risk of breast cancer

Contralateral risk-reducing mastectomy (CRRM) rates have tripled over the last 2 decades. Reasons for this are multi-factorial, with those harbouring a pathogenic variant in the BRCA1/2 gene having the greatest survival benefit. On May 14th, 2013, Angelina Jolie shared the news of her bilateral risk-reducing mastectomy (BRRM), on the basis of her BRCA1 pathogenic variant status. We evaluated the impact of this news on rates of CRRM in women with increased risk for developing breast cancer after being diagnosed with unilateral breast cancer. The prospective cohort study included all women with at least a moderate lifetime risk of developing breast cancer who attended our family history clinic (1987–2019) and were subsequently diagnosed with unilateral breast cancer. Rates of CRRM were then compared between patients diagnosed with breast cancer before and after Angelina Jolie’s announcement (pre- vs. post-AJ). Of 386 breast cancer patients, with a mean age at diagnosis of 48 ± 8 years, 268 (69.4%) were diagnosed in the pre-AJ period, and 118 (30.6%) in the post-AJ period. Of these, 123 (31.9%) underwent CRRM, a median 42 (interquartile range: 11–54) days after the index cancer surgery. Rates of CRRM doubled following AJ’s news, from 23.9% pre-AJ to 50.0% post AJ (p < 0.001). Rates of CRRM were found to decrease with increasing age at breast cancer (p < 0.001) and tumour TNM stage (p = 0.040), and to increase with the estimated lifetime risk of breast cancer (p < 0.001) and tumour grade (p = 0.015) on univariable analysis. After adjusting for these factors, the step-change increase in CRRM rates post-AJ remained significant (odds ratio: 9.61, p < 0.001). The AJ effect appears to have been associated with higher rates of CRRM amongst breast cancer patients with increased cancer risk. CRRM rates were highest amongst younger women and those with the highest lifetime risk profile. Clinicians need to be aware of how media news can impact on the delivery of cancer related services. Communicating objective assessment of risk is important when counselling women on the merits of risk-reducing surgery.

Long-Term Evaluation of Women Referred to a Breast Cancer Family History Clinic (Manchester UK 1987–2020)

Simple SummaryThis study reports the management of women at high risk for breast cancer over a 33 years period. The aim was to summarize the numbers seen and to report the results of our studies on gene testing, the outcomes of screening and the success of preventive methods including lifestyle change, chemoprevention and risk-reducing mastectomy. We also discuss how the clinical Family History Service may be improved in the future.Clinics for women concerned about their family history of breast cancer are widely established. A Family History Clinic was set-up in Manchester, UK, in 1987 in a Breast Unit serving a population of 1.8 million. In this review, we report the outcome of risk assessment, screening and prevention strategies in the clinic and propose future approaches. Between 1987–2020, 14,311 women were referred, of whom 6.4% were from known gene families, 38.2% were at high risk (≥30% lifetime risk), 37.7% at moderate risk (17–29%), and 17.7% at an average/population risk who were discharged. A total of 4168 (29.1%) women were eligible for genetic testing and 736 carried pathogenic variants, predominantly in BRCA1 and BRCA2 but also other genes (5.1% of direct referrals). All women at high or moderate risk were offered annual mammographic screening between ages 30 and 40 years old: 646 cancers were detected in women at high and moderate risk (5.5%) with a detection rate of 5 per 1000 screens. Incident breast cancers were largely of good prognosis and resulted in a predicted survival advantage. All high/moderate-risk women were offered lifestyle prevention advice and 14–27% entered various lifestyle studies. From 1992–2003, women were offered entry into IBIS-I (tamoxifen) and IBIS-II (anastrozole) trials (12.5% of invitees joined). The NICE guidelines ratified the use of tamoxifen and raloxifene (2013) and subsequently anastrozole (2017) for prevention; 10.8% women took up the offer of such treatment between 2013–2020. Since 1994, 7164 eligible women at ≥25% lifetime risk of breast cancer were offered a discussion of risk-reducing breast surgery and 451 (6.2%) had surgery. New approaches in all aspects of the service are needed to build on these results.

322 Poster - An audit of chemoprevention provision in a breast cancer family history clinic

322 Poster - An audit of chemoprevention provision in a breast cancer family history clinic

Mammographic density change in a cohort of premenopausal women receiving tamoxifen for breast cancer prevention over 5 years

BackgroundA decrease in breast density due to tamoxifen preventive therapy might indicate greater benefit from the drug. It is not known whether mammographic density continues to decline after 1 year of therapy, or whether measures of breast density change are sufficiently stable for personalised recommendations.MethodsMammographic density was measured annually over up to 5 years in premenopausal women with no previous diagnosis of breast cancer but at increased risk of breast cancer attending a family-history clinic in Manchester, UK (baseline 2010-2013). Tamoxifen (20 mg/day) for prevention was prescribed for up to 5 years in one group; the other group did not receive tamoxifen and were matched by age. Fully automatic methods were used on mammograms over the 5-year follow-up: three area-based measures (NN-VAS, Stratus, Densitas) and one volumetric (Volpara). Additionally, percentage breast density at baseline and first follow-up mammograms was measured visually. The size of density declines at the first follow-up mammogram and thereafter was estimated using a linear mixed model adjusted for age and body mass index. The stability of density change at 1 year was assessed by evaluating mean squared error loss from predictions based on individual or mean density change at 1 year.ResultsAnalysis used mammograms from 126 healthy premenopausal women before and as they received tamoxifen for prevention (median age 42 years) and 172 matched controls (median age 41 years), with median 3 years follow-up. There was a strong correlation between percentage density measures used on the same mammogram in both the tamoxifen and no tamoxifen groups (all correlation coeficients > 0.8). Tamoxifen reduced mean breast density in year 1 by approximately 17–25% of the inter-quartile range of four automated percentage density measures at baseline, and from year 2, it decreased further by approximately 2–7% per year. Predicting change at 2 years using individual change at 1 year was approximately 60–300% worse than using mean change at 1year.ConclusionsAll measures showed a consistent and large average tamoxifen-induced change in density over the first year, and a continued decline thereafter. However, these measures of density change at 1 year were not stable on an individual basis.

What are the benefits and harms of risk stratified screening as part of the NHS breast screening Programme? Study protocol for a multi-site non-randomised comparison of BC-predict versus usual screening (NCT04359420)

BackgroundIn principle, risk-stratification as a routine part of the NHS Breast Screening Programme (NHSBSP) should produce a better balance of benefits and harms. The main benefit is the offer of NICE-approved more frequent screening and/ or chemoprevention for women who are at increased risk, but are unaware of this. We have developed BC-Predict, to be offered to women when invited to NHSBSP which collects information on risk factors (self-reported information on family history and hormone-related factors via questionnaire; mammographic density; and in a sub-sample, Single Nucleotide Polymorphisms). BC-Predict produces risk feedback letters, inviting women at high risk (≥8% 10-year) or moderate risk (≥5 to < 8% 10-year) to have discussion of prevention and early detection options at Family History, Risk and Prevention Clinics. Despite the promise of systems such as BC-Predict, there are still too many uncertainties for a fully-powered definitive trial to be appropriate or ethical. The present research aims to identify these key uncertainties regarding the feasibility of integrating BC-Predict into the NHSBSP. Key objectives of the present research are to quantify important potential benefits and harms, and identify key drivers of the relative cost-effectiveness of embedding BC-Predict into NHSBSP.MethodsA non-randomised fully counterbalanced study design will be used, to include approximately equal numbers of women offered NHSBSP (n = 18,700) and BC-Predict (n = 18,700) from selected screening sites (n = 7). In the initial 8-month time period, women eligible for NHSBSP will be offered BC-Predict in four screening sites. Three screening sites will offer women usual NHSBSP. In the following 8-months the study sites offering usual NHSBSP switch to BC-Predict and vice versa. Key potential benefits including uptake of risk consultations, chemoprevention and additional screening will be obtained for both groups. Key potential harms such as increased anxiety will be obtained via self-report questionnaires, with embedded qualitative process analysis. A decision-analytic model-based cost-effectiveness analysis will identify the key uncertainties underpinning the relative cost-effectiveness of embedding BC-Predict into NHSBSP.DiscussionWe will assess the feasibility of integrating BC-Predict into the NHSBSP, and identify the main uncertainties for a definitive evaluation of the clinical and cost-effectiveness of BC-Predict.Trial registrationRetrospectively registered with clinicaltrials.gov (NCT04359420).

Risk of Contralateral Breast Cancer in Women with and without Pathogenic Variants in BRCA1, BRCA2, and TP53 Genes in Women with Very Early-Onset (&lt;36 Years) Breast Cancer

Early age at diagnosis of breast cancer is a known risk factor for hereditary predisposition and some studies show a high risk of contralateral breast cancer in BRCA1 carriers diagnosed at very young ages. However, little is published on the risk of TP53 carriers. 397 women with breast cancer diagnosed <36 years of age were obtained from three sources: (i) a population-based study of 283 women diagnosed sequentially from 1980–1997 in North-West England, (ii) referrals to the Genomic Medicine Department at St Mary’s Hospital from 1990–2018, and (iii) individuals from (i) and the Family History Clinic at Wythenshawe Hospital South Manchester who tested negative for pathogenic variants (PV) in all three genes. Sequencing of BRCA1, BRCA2, and TP53 genes was carried out alongside tests for copy number for PV on all referred women. Rates of contralateral breast cancer were censored at death, last assessment, or risk-reducing mastectomy. In total, 47 TP53, 218 BRCA1, and 132 BRCA2 PV carriers were identified with breast cancer diagnosed aged 35 years and under, as well as a representative sample of 261 not known to carry a PV in BRCA1, BRCA2, and TP53. Annual rates of contralateral breast cancer (and percentage of synchronous breast cancers) were TP53: 7.03% (4.3%), BRCA1: 3.57% (1.8%), and BRCA2: 2.63% (1.5%). In non-PV carriers, contralateral rates in isolated presumed/tested non-carrier cases with no family history were 0.56%, and for those with a family history, 0.69%. Contralateral breast cancer rates are substantial in TP53, BRCA1, and BRCA2 PV carriers diagnosed with breast cancer aged 35 and under. Women need to be advised to help make informed decisions on contralateral mastectomy, guided by life expectancy from their index tumor.

How acceptable is a weight maintenance programme for healthy weight young women who are at increased risk of breast cancer?

Objective: To determine if a weight gain prevention intervention is acceptable to young women with a normal Body Mass Index and a moderately increased or high risk of breast cancer. Design: Qualitative semi-structured interview study involving 14 women aged 26–35 years who were registered with a Family History Clinic in Manchester, UK, due to family history of breast cancer. Participants’ views were analysed thematically. Results: Four themes were produced: (1) perceptions of a healthy lifestyle: women’s perceptions included health-related behaviours and subjective wellbeing; (2) construing a healthy weight: women rely on appearance, feelings and others opinions to construe weight instead of quantitative indicators; (3) configuring a useful programme: the idea of a programme that is remotely accessible; provides a point of contact; and promotes general wellbeing was appealing. Women believed information explaining the link between lifestyle and breast cancer would facilitate behaviour change; (4) the importance of will(power): women recognised that commitment to a programme is affected by time, money and readiness to change. Conclusion: A weight gain prevention intervention that focuses on wellbeing and behaviour change appears acceptable to many healthy weight women. Future research should examine whether women’s expressed acceptability translates into actual acceptability of such a programme.

Chemoprevention in BRCA1 mutation carriers (CIBRAC): protocol for an open allocation crossover feasibility trial assessing mechanisms of chemoprevention with goserelin and anastrozole versus tamoxifen and acceptability of treatment

IntroductionBRCA1 mutation carriers have a significant lifetime risk of breast cancer, with their primary risk-reduction option being bilateral mastectomy. Preclinical work from our laboratory demonstrated that in BRCA1-deficient breast cells,...

Ten years of a family history clinic: The experience of moderate and high-risk patients in a breast cancer family history clinic

Background: The establishment of a dedicated family history clinic followed NICE guidelines issued originally in 2004. The clinic adapted in line with guidance updates in 2013 and 2017.

A review of the provision of chemoprevention in a breast cancer family history clinic

Background: NICE Familial Breast Cancer guidance issued in 2004 (updated 2006 and 2013) led to the establishment of a family history clinic at Princess Alexandra Hospitals NHS Trust.

Abstract OT3-01-01: Chemoprevention in BRCA1 mutation carriers (CIBRAC): A proof of concept clinical trial

Abstract Introduction Currently, risk management options for BRCA1 mutation carriers include risk-reducing mastectomies (RRM), and selective oestrogen receptor modulators (SERMs). However, the majority of BRCA1-associated tumours are oestrogen receptor negative (ER-ve). SERMs do not reduce the incidence of ER-ve tumours, therefore are unlikely to be effective in this group of women. Oestrogen and its metabolites have been shown to cause DNA damage, resulting in genomic instability in BRCA1 deficient breast cells, an early hallmark of BRCA1-related cancers. Based on this, we hypothesise that oestrogen suppression in BRCA1 carriers may reduce DNA damage in breast tissue, and thereby potentially reducing breast cancer risk. Trial Design The study is an interventional, non-randomised, crossover study without masking. The primary purpose is to assess the impact of these drugs on suppression of DNA damage and therefore their potential for use as chemopreventive agents in this setting. Pre-menopausal BRCA1 mutation carriers will be recruited from the Family History Clinic at Belfast City Hospital. The proportion of women who receive information packs who progress to trial entry will be recorded, with target recruitment of twelve women to the trial. Participants will complete quality of life questionnaires, provide blood and urine samples and undergo baseline ultrasound-guided breast biopsy. Half of these women will receive a SERM (tamoxifen) for 3 months, whilst the other half receives oestrogen suppression therapy (goserelin and anastrazole), and then provide repeat questionnaires and samples (blood, urine and breast biopsy). Treatment groups will cross over for a further 3 months treatment, with a final set of questionnaires and samples taken. Compliance with treatment and adverse events will be monitored throughout the study. Eligibility Criteria Inclusion criteria: · Female · Age ≥18 years · Premenopausal · Known pathogenic BRCA1 mutation · Intact ovaries · No previous breast/ovarian/other carcinoma · No previous use of chemoprevention · Willingness to use non-hormonal methods of contraception Exclusion criteria: · BRCA1 mutation of uncertain significance · Contraindications to study drugs or breast biopsies · Pregnancy or breastfeeding · Inability to give informed consent · Patient awaiting risk reducing surgery Specific Aims The primary objective is to assess the feasibility of treatments by measuring successful recruitment rates and compliance. The secondary objective is to establish tolerability of interventions through quality of life measurements and adverse event occurrence. Exploratory objectives will assess the potential of treatments to reduce DNA damage through analysis of breast biopsies using comet assays and immunohistochemistry for 53BP1 and γH2AX (markers of DNA double-strand breaks). Oestrogen and metabolite levels will be measured in blood and urine samples using UPLC-MS/MS. Statistical Methods Not applicable due to nature and size of pilot study Present accrual: 1 participant Target accrual: 12 participants Contact information for people with specific interest in trial: aideen.campbell@qub.ac.uk or s.mcintosh@qub.ac.uk Citation Format: Campbell AM, Savage KI, McIntosh SA. Chemoprevention in BRCA1 mutation carriers (CIBRAC): A proof of concept clinical trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-01-01.

The provision of Tamoxifen as chemoprevention in a family history clinic

The provision of Tamoxifen as chemoprevention in a family history clinic