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Abstract Background Risk stratification as a routine part of the NHS Breast Screening Programme (NHSBSP) could provide a better balance of benefits and harms. We developed BC-Predict, to offer women when invited to the NHSBSP, which collects standard risk factor information; mammographic density; and in a sub-sample, a Polygenic Risk Score (PRS). Methods Risk prediction was estimated primarily from self-reported questionnaires and mammographic density using the Tyrer–Cuzick risk model. Women eligible for NHSBSP were recruited. BC-Predict produced risk feedback letters, inviting women at high risk (≥8% 10-year) or moderate risk (≥5– Results Overall uptake of BC-Predict in screening attendees was 16.9% with 2472 consenting to the study; 76.8% of those received risk feedback within the 8-week timeframe. Recruitment was 63.2% with an onsite recruiter and paper questionnaire compared to P Discussion We have shown that a real-time offer of breast cancer risk information (including both mammographic density and PRS) is feasible and can be delivered in reasonable time, although uptake requires personal contact. Preventive medication uptake in women newly identified at high risk is high and could improve the cost-effectiveness of risk stratification. Trial registration Retrospectively registered with clinicaltrials.gov (NCT04359420).

There is great promise in breast cancer risk stratification to target screening and prevention. It is unclear whether adding gene panels to other risk tools improves breast cancer risk stratification and adds discriminatory benefit on a population basis.In total, 10,025 of 57,902 women aged 46 to 73 years in the Predicting Risk of Cancer at Screening study provided DNA samples. A case-control study was used to evaluate breast cancer risk assessment using polygenic risk scores (PRSs), cancer gene panel (n = 33), mammographic density (density residual [DR]), and risk factors collected using a self-completed 2-page questionnaire (Tyrer-Cuzick [TC] model version 8). In total, 525 cases and 1410 controls underwent gene panel testing and PRS calculation (18, 143, and/or 313 single-nucleotide polymorphisms [SNPs]).Actionable pathogenic variants (PGVs) in BRCA1/2 were found in 1.7% of cases and 0.55% of controls, and overall PGVs were found in 6.1% of cases and 1.3% of controls. A combined assessment of TC8-DR-SNP313 and gene panel provided the best risk stratification with 26.1% of controls and 9.7% of cases identified at1.4% 10-year risk and 9.01% of controls and 23.3% of cases at ≥8% 10-year risk. Because actionable PGVs were uncommon, discrimination was identical with/without gene panel (with/without: area under the curve = 0.67, 95% CI = 0.64-0.70). Only 7 of 17 PGVs in cases resulted in actionable risk category change. Extended case (n = 644)-control (n = 1779) series with TC8-DR-SNP143 identified 18.9% of controls and only 6.4% of stage 2+ cases at1.4% 10-year risk and 20.7% of controls and 47.9% of stage 2+ cases at ≥5% 10-year risk.Further studies and economic analysis will determine whether adding panels to PRS is a cost-effective strategy for risk stratification.

BACKGROUND: Capivasertib, an AKT inhibitor, added to fulvestrant, was previously reported to improve progression-free survival in women with aromatase inhibitor-resistant oestrogen receptor (ER)-positive, HER2-negative advanced breast cancer. The benefit appeared to be independent of the phosphoinositide 3-kinase (PI3K)/AKT/phosphatase and tensin homologue (PTEN) pathway alteration status of tumours, as ascertained using assays available at the time. Here, we report updated progression-free survival and overall survival results, and a prespecified examination of the effect of PI3K/AKT/PTEN pathway alterations identified by an expanded genetic testing panel on treatment outcomes.METHODS: This randomised, multicentre, double-blind, placebo-controlled, phase 2 trial recruited postmenopausal adult women aged at least 18 years with ER-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2, who had relapsed or progressed on an aromatase inhibitor, from across 19 hospitals in the UK. Participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a 500 mg loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off, starting on cycle 1 day 15. Treatment continued until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment was allocated by an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival in the intention-to-treat population. Secondary endpoints shown in this Article were overall survival and safety in the intention-to-treat population, and the effect of tumour PI3K/AKT/PTEN pathway status identified by an expanded testing panel that included next-generation sequencing assays. Recruitment is complete. The trial is registered with ClinicalTrials.gov, number NCT01992952.FINDINGS: Between March 16, 2015, and March 6, 2018, 183 participants were screened for eligibility and 140 (77%) were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up at the data cut-off of Nov 25, 2021, was 58·5 months (IQR 45·9-64·1) for participants treated with fulvestrant plus capivasertib and 62·3 months (IQR 62·1-70·3) for fulvestrant plus placebo. Updated median progression-free survival was 10·3 months (95% CI 5·0-13·4) in the group receiving fulvestrant plus capivasertib compared with 4·8 months (3·1-7·9) for fulvestrant plus placebo (adjusted hazard ratio [HR] 0·56 [95% CI 0·38-0·81]; two-sided p=0·0023). Median overall survival in the capivasertib versus placebo groups was 29·3 months (95% CI 23·7-39·0) versus 23·4 months (18·7-32·7; adjusted HR 0·66 [95% CI 0·45-0·97]; two-sided p=0·035). The expanded biomarker panel identified an expanded pathway-altered subgroup that contained 76 participants (54% of the intention-to-treat population). Median progression-free survival in the expanded pathway-altered subgroup for participants receiving capivasertib (n=39) was 12·8 months (95% CI 6·6-18·8) compared with 4·6 months (2·8-7·9) in the placebo group (n=37; adjusted HR 0·44 [95% CI 0·26-0·72]; two-sided p=0·0014). Median overall survival for the expanded pathway-altered subgroup receiving capivasertib was 38·9 months (95% CI 23·3-50·7) compared with 20·0 months (14·8-31·4) for those receiving placebo (adjusted HR 0·46 [95% CI 0·27-0·79]; two-sided p=0·0047). By contrast, there were no statistically significant differences in progression-free or overall survival in the expanded pathway non-altered subgroup treated with capivasertib (n=30) versus placebo (n=34). One additional serious adverse event (pneumonia) in the capivasertib group had occurred subsequent to the primary analysis. One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment.INTERPRETATION: Updated FAKTION data showed that capivasertib addition to fulvestrant extends the survival of participants with aromatase inhibitor-resistant ER-positive, HER2-negative advanced breast cancer. The expanded biomarker testing suggested that capivasertib predominantly benefits patients with PI3K/AKT/PTEN pathway-altered tumours. Phase 3 data are needed to substantiate the results, including in patients with previous CDK4/6 inhibitor exposure who were not included in the FAKTION trial.FUNDING: AstraZeneca and Cancer Research UK.

SummaryStudies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular rhythms in non-cancerous and cancerous human breast tissues are largely unknown. We reconstructed rhythms informatically, integrating locally collected, time-stamped biopsies with public datasets. For non-cancerous tissue, the inferred order of core-circadian genes matches established physiology. Inflammatory, epithelial-mesenchymal transition (EMT), and estrogen responsiveness pathways show circadian modulation. Among tumors, clock correlation analysis demonstrates subtype-specific changes in circadian organization. Luminal A organoids and informatic ordering of Luminal A samples exhibit continued, albeit disrupted rhythms. However, CYCLOPS magnitude, a measure of global rhythm strength, varied widely among Luminal A samples. Cycling of EMT pathway genes was markedly increased in high-magnitude Luminal A tumors. Patients with high-magnitude tumors had reduced 5-year survival. Correspondingly, 3D Luminal A cultures show reduced invasion following molecular clock disruption. This study links subtype-specific circadian disruption in breast cancer to EMT, metastatic potential, and prognosis.

PurposeTo investigate the frequency of germline pathogenic variants (PVs) in women with bilateral breast cancer.MethodsWe undertookBRCA1/2andCHEK2c.1100delC molecular analysis in 764 samples and a multigene panel in 156. Detection rates were assessed by age at first primary, Manchester Score, and breast pathology. Oestrogen receptor (ER) status of the contralateral versus first breast cancer was compared on 1081 patients with breast cancer withBRCA1/BRCA2PVs.Results764 women with bilateral breast cancer have undergone testing ofBRCA1/2andCHEK2; 407 were also tested forPALB2and 177 forATM. Detection rates wereBRCA111.6%,BRCA214.0%,CHEK22.4%,PALB21.0%,ATM1.1% and, for a subset of mainly very early onset tumours,TP534.6% (9 of 195). The highest PV detection rates were for triple negative cancers forBRCA1(26.4%), grade 3 ER+HER2 forBRCA2(27.9%) and HER2+ forCHEK2(8.9%). ER status of the first primary inBRCA1andBRCA2PV heterozygotes was strongly predictive of the ER status of the second contralateral tumour since ~90% of second tumours were ER− inBRCA1heterozygotes, and 50% were ER− inBRCA2heterozygotes if the first was ER−.ConclusionWe have shown a high rate of detection ofBRCA1andBRCA2PVs in triple negative and grade 3 ER+HER2− first primary diagnoses, respectively. High rates of HER2+ were associated withCHEK2PVs, and women ≤30 years were associated withTP53PVs. First primary ER status inBRCA1/2strongly predicts the second tumour will be the same ER status even if unusual for PVs in that gene.

Purpose: Breast cancer stem-like cells (CSC) are an important therapeutic target as they are predicted to be responsible for tumor initiation, maintenance, and metastases. Interleukin (IL)-8 is upregulated in breast cancer and is associated with poor prognosis. Breast cancer cell line studies indicate that IL-8 via its cognate receptors, CXCR1 and CXCR2, is important in regulating breast CSC activity. We investigated the role of IL-8 in the regulation of CSC activity using patient-derived breast cancers and determined the potential benefit of combining CXCR1/2 inhibition with HER2-targeted therapy.Experimental Design: CSC activity of metastatic and invasive human breast cancers (n = 19) was assessed ex vivo using the mammosphere colony-forming assay.Results: Metastatic fluid IL-8 level correlated directly with mammosphere formation (r = 0.652; P < 0.05; n = 10). Recombinant IL-8 directly increased mammosphere formation/self-renewal in metastatic and invasive breast cancers (n = 17). IL-8 induced activation of EGFR/HER2 and downstream signaling pathways and effects were abrogated by inhibition of SRC, EGFR/HER2, phosphoinositide 3-kinase (PI3K), or MEK. Furthermore, lapatinib, which targets EGFR/HER2, inhibited the mammosphere-promoting effect of IL-8 in both HER2-positive and negative patient-derived cancers. CXCR1/2 inhibition also blocked the effect of IL-8 on mammosphere formation and added to the efficacy of lapatinib in HER2-positive cancers.Conclusions: These studies establish a role for IL-8 in the regulation of patient-derived breast CSC activity and show that IL-8/CXCR1/2 signaling is partly mediated via a novel SRC and EGFR/HER2-dependent pathway. Combining CXCR1/2 inhibitors with current HER2-targeted therapies has potential as an effective therapeutic strategy to reduce CSC activity in breast cancer and improve the survival of HER2-positive patients. Clin Cancer Res; 19(3); 643–56. ©2012 AACR.

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PDF file - 106K, Supplementary Figure 1. CXCR1/2 and EGFR/HER2 regulate mammosphere formation/self-renewal and the proportion of aldefluor positive cell in HER2 positive breast cancer cell lines.

PDF file - 94K, Supplementary Figure 2. IL-8 induced mammosphere formation in SKBR3 cells is dependent on activation of EGFR and AKT signalling pathways.

Supplementary Figure Legend from Regulation of Breast Cancer Stem Cell Activity by Signaling through the Notch4 Receptor

Supplementary Table 1 from Regulation of Breast Cancer Stem Cell Activity by Signaling through the Notch4 Receptor

Supplementary Figure 1 from Regulation of Breast Cancer Stem Cell Activity by Signaling through the Notch4 Receptor

Supplementary Table 3 from Regulation of Breast Cancer Stem Cell Activity by Signaling through the Notch4 Receptor

Background: CDK7 inhibition is a promising therapeutic strategy in cancer. CDK7 is a key kinase, regulating cell division, transcription and nuclear receptor function [1]. Although recent advances have been made in the treatment of TNBC this disease is still one of significant unmet need. Materials and Methods: Tolerability and efficacy of Samuraciclib were assessed in a TNBC expansion cohort of the first in human study of Samuraciclib. These patients had metastatic or locally advanced TNBC and had received prior taxane and anthracycline therapy including at least one line of chemotherapy for metastatic or locally advanced disease. Results: From 29th January 2019 to 12th April 2021, 23 women with advanced TNBC were recruited and dosed with Samuraciclib 360mg OD. Treatment has generally been well tolerated with all patients remaining on treatment until disease progression. The most common adverse drug reactions (AE) were: G1-2 Nausea (96%), Vomiting (52%) and Diarrhea (91%). There were 4 dose reductions to manage upper GI adverse events of nausea and/or vomiting. G3 events were as follows: 2 Grade 3 Diarrhea, 1 Grade 3 Vomiting, 1 Grade 3 Fatigue, 1 Grade 3 Stomatitis, 1 Grade 3 Anaemia and 1 Grade 4 Thrombocytopenia21 patients have had follow-up evaluations for assessment of efficacy. Stable disease was achieved in 14 patients, 1 with partial response (being on treatment for 72 weeks) and 7 patients with progressive disease; two additional patients remain on compassionate use treatment, following disease progression by RECIST. 5 patients have been on treatment for at least 24 weeks of whom 3 have exceeded 1 year. Conclusions: Samuraciclib demonstrated an acceptable safety and tolerability profile with evidence of antitumour activity in advanced TNBC. References1.Patel et al. ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment. Mol Cancer Ther. 2018. doi: 10.1158/1535-7163.MCT-16-0847. PMID:29545334. Citation Format: Sacha J Howell, Laura M Kenny, Simon Lord, Matthew G Krebs, Tobias Arkenau, Richard Baird, Iain R MacPherson, Ash Bahl, Glen Clack, Edward Ainscow, Anthony GM Barrett, Paul A Dickinson, Matthew J Fuchter, Manfred Lehnert, Simak Ali, Stuart McIntosh, Charles Coombes. A clinical study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-10.

Background Bilateral-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. Methods BRRM 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. Results Of 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 cancer50; OR = 0.26,95%CI = 0.17–0.41). Uptake continued to rise to 20 years from initial risk assessment. Conclusion We 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., Highlights • BRRM continues even 20 years post original breast cancer risk assessment. • Potential triggers include death of mother/sister, children and a breast biopsy. • Uptake is clearly informed by lifetime risk of BC and higher in younger the women.

Polygenic risk scores (PRS) for disease risk stratification show great promise for application in general populations, but most are based on data from individuals of white European origin. We assessed two well validated PRS (SNP18, SNP143) in the Predicting-Risk-of-Cancer-At-Screening (PROCAS) study in North-West England for breast cancer prediction based on ethnicity. Overall, 9475 women without breast cancer at study entry, including 645 who subsequently developed invasive breast cancer or ductal carcinoma in situ provided DNA. All were genotyped for SNP18 and a subset of 1868 controls were genotyped for SNP143. For white Europeans both PRS discriminated well between individuals with and without cancer. For n=395 Black (n=112), Asian (n=119), mixed (n=44) or Jewish (n=120) women without cancer both PRS overestimated breast cancer risk, being most marked for women of Black and Jewish origin (p

PurposeTo investigate frequency of germline pathogenic variants (PVs) in women with ductal carcinoma in situ (DCIS) and grade 1 invasive breast cancer (G1BC).MethodsWe undertookBRCA1/2analysis in 311 women with DCIS and 392 with G1BC and extended panel testing (non-BRCA1/2) in 176/311 with DCIS and 156/392 with G1BC. We investigated PV detection by age at diagnosis, Manchester Score (MS), DCIS grade and receptor status.Results30/311 (9.6%) with DCIS and 16/392 with G1BC (4.1%) had aBRCA1/2PV (p=0.003), and 24/176-(13.6%) and 7/156-(4.5%), respectively, a non-BRCA1/2PV (p=0.004). Increasing MS was associated with increased likelihood ofBRCA1/2PV in both DCIS and G1BC, although the 10% threshold was not predictive for G1GB. 13/32 (40.6%) DCIS and 0/17 with G1BC BRCA1/2) and 9/90 (non-BRCA1/2), and 8/47 (BRCA1/2) and 8/45 (non-BRCA1/2), respectively. 6/9BRCA1and 3/26BRCA2-associated DCIS were oestrogen receptor negative-(p=0.003). G1BC population testing showed no increased PV rate (OR=1.16, 95% CI 0.28 to 4.80).ConclusionDCIS is more likely to be associated with bothBRCA1/2and non-BRCA1/2PVs than G1BC. Extended panel testing ought to be offered in young-onset DCIS where PV detection rates are highest.

Background: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).Method: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.Results: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0. 902 for patients with ER-positive tumours (p = 2.3 x 10(-6)) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.Conclusion: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predic-tions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration. (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

PURPOSE To investigate the contribution of PALB2 pathogenic gene variants (PGVs, PALB2_PGV) and the CHEK2 c.1100delC (CHEK2_1100delC) PGV to familial breast and ovarian cancer, and PALB2_PGV associated breast cancer pathology. METHODS Outcomes of germline PALB2_PGV and CHEK2_1100delC testing were recorded in 3,127 women with histologically confirmed diagnoses of invasive breast cancer, carcinoma in situ, or epithelial nonmucinous ovarian cancer, and 1,567 female controls. Breast cancer pathology was recorded in PALB2_PGV cases from extended families. RESULTS Thirty-five PALB2 and 44 CHEK2_1100delC PGVs were detected in patients (odds ratio [OR] PALB2 breast-ovarian = 5.90 [95% CI: 1.92-18.36], CHEK2 breast-ovarian = 4.46 [95% CI: 1.86-10.46], PALB2 breast = 6.16 [95% CI: 1.98-19.21], CHEK2 breast = 4.89 [95% CI: 2.01-11.34]). Grade 3 ER-positive HER2-negative, grade 3 and triple negative (TN) tumors were enriched in cases with PALB2 PGVs compared with all breast cancers known to our service (respectively: 15/43, 254/1,843, P = 0.0005; 28/37, 562/1,381, P = 0.0001; 12/43, 204/1,639, P

BACKGROUND Breast cancer is the most common female cancer and around 20% of cases are associated with factors such as adult weight gain, overweight and obesity, and potentially modifiable health behaviours 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 behaviour interventions to women at increased risk. With Patient and Participant Involvement from the target population we have developed an app to promote healthy behaviours amongst young women at increased risk of breast cancer. The app includes goal setting and self-monitoring of health behaviours, and provides education about breast cancer. Social/peer support and contact with the research team is provided via a separate, private, Facebook group. OBJECTIVE To assess the acceptability and usability of the app in young women at increased risk of breast cancer, and feasibility of the study procedures for a future efficacy study. METHODS Young women (n=35, age 18-35 years) at increased risk of breast cancer (>17% lifetime risk) will be recruited via two 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 two months. They will complete questionnaires regarding their health behaviours 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 be interviewed at the end of study regarding their views on the app and trial procedures. RESULTS The trial is ongoing. Publication of results is anticipated in 2023. CONCLUSIONS The trial will provide evidence regarding the acceptability and usability of the newly-developed app to 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 planned for a future efficacy study and use the results to refine the trial procedures. CLINICALTRIAL ClinicalTrials.gov NCT05460650

Background: Breast cancer screening recommendations vary around the world, but most are based on age or inherited genetic risk factors. For instance, the American Cancer Society recommends annual mammography plus breast MRI starting at age 30yr for women at high risk of breast cancer based mainly on family history or high-risk genes. Women at average risk (no strong family history or high-risk genes) are recommended to have the option of annual mammography starting at age 40yr. Risk-based screening, which aims to personalise screening to an individual woman’s risk of breast cancer based on a more comprehensive risk assessment than just age, family history, or high-risk genes, might improve current screening strategies. Methods: We developed a deterministic model to estimate the incidence of advanced (node-positive) breast cancer (plus number of screens) for different risk-based screening strategies in a UK setting. The proportion of screen-detected and interval cancers was estimated for various screening intervals using a model developed by Launoy et al. and parameters for sensitivity (0.92) and annual transition rate from asymptomatic to symptomatic disease (0.25) from The Swedish Two-County Trial. The proportion of node-positive cancers was estimated for screen-detected (22%) and interval (53%) cancers, using data from the NHS Breast Screening Programme (England, 2015-18, women aged 47yr+). Choice of mammography screening regimen was based on Tyrer-Cuzick 10yr risk (v8 including age, family history, reproductive factors, benign breast disease, SNPs and breast density). The proportion of women in each risk group was estimated from a UK cohort study investigating breast cancer risk at screening (PROCAS). In a hypothetical cohort of 3.45M women, 1M women would be identified as either high-risk (>8% 10yr risk; n=241,379) or low-risk (< 1.4% 10yr risk; n=758,621). In these 1M high/low-risk women, we evaluated two risk-based screening scenarios, comparing their effects with usual triennial screening starting at age 50yr (which was proposed for the 2.45M women at intermediate-risk (1.4-8% 10yr risk)). Scenario (1): Changing screening interval based on risk (high-risk every 1yr; low-risk every 5yr) for screening between 50-70yr. Scenario (2): Changing the starting age of screening based on risk (high-risk start annual screening at 45yr followed by triennial screening from 50yr; low-risk start triennial screening at 55yr); follow-up 45-55yr. We assessed the trade-off between the decreased/increased number of node-positive breast cancers and increased/decreased number of screens with the high/low-risk regimens, respectively. A sensitivity analysis considered risk stratification without breast density. Results: Scenario (1): Changing screening interval based on risk reduced the number of node-positive cancers in high-risk women by 2,194 (with 3.14M additional mammograms) and increased the number of node-positive cancers in low-risk women by 910 (with 2.28M fewer mammograms) when compared with usual screening; a difference of 1,284 fewer node-positive cancers and 862,069 additional screens. Scenario (2): Additional annual mammograms for high-risk women at 45-49yr reduced the number of node-positive cancers by 1,392 (with 1.21M additional mammograms); starting triennial screening at 55yr rather than 50yr for low-risk women increased the number of node-positive cancers by 841 (with 1.52M fewer mammograms); a difference of 551 fewer node-positive cancers and 310,345 fewer screens. Excluding breast density from risk assessment reduced the number identified as high or low-risk, and thus the number of advanced cancers prevented and screens required, but the overall findings were unchanged. Conclusion: Changing the starting age of screening based on risk of breast cancer is likely to be more effective per screen required at reducing the rate of advanced breast cancer than changing the screening interval based on risk. Table 1: Results for Scenario (1) Risk-based screening (changing screening interval based on risk: high-risk every 1 year; low-risk every 5 years) versus usual screening (every 3 years) between age 50-70 years (plus an additional 3 years of follow-up to adjust for the effect of screening on risk of breast cancer). N: Number; %: percentage; node+: Node-positive breast cancer; Δ: Difference; yr: Year; N/A: not applicable. Table 2: Results for Scenario (2) Risk-based screening (changing the starting age of screening based on risk: high-risk start annual screening at age 45-49 years followed by triennial screening from age 50 years; low-risk start triennial screening at age 55 years) versus usual screening (triennial screening starting at age 50 years), with follow-up from age 45-55 years. n: Number; 1M: 1 million; node+: Node-positive breast cancer; Δ: Difference; yr: Year. Table 3: Results for sensitivity analysis - Scenarios (1) and (2) with risk assessment including/excluding breast density Scenario (1): Risk-based screening (changing screening interval based on risk: high-risk every 1 year; low-risk every 5 years) versus usual screening (every 3 years) between age 50-70 years (plus an additional 3 years of follow-up to adjust for the effect of screening on risk of breast cancer). Scenario (2): Risk-based screening (changing the starting age of screening based on risk: high-risk start annual screening at age 45-49 years followed by triennial screening from age 50 years; low-risk start triennial screening at age 55 years) versus usual screening (triennial screening starting at age 50 years), with follow-up from age 45-55 years. n: Number; node+: Node-positive breast cancer; Δ: Difference; yr: Year. Citation Format: Emma C. Atakpa, Jack Cuzick, Stephen W. Duffy, D. Gareth Evans, Sacha J. Howell, Adam R. Brentnall. PD14-01 A model to assess the utility of risk-based screening algorithms [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD14-01.

Background: MEN1611 (MEN) is an oral PI3K inhibitor active on the p110α mutant and wild type, β and γ isoforms, while sparing the δ. B-PRECISE-01 is an open-label, 2-arm, phase 1b study investigating MEN1611 in combination with trastuzumab ± fulvestrant in patients with HER2 positive/PIK3CA mutated metastatic breast cancer (MBC). No dose-limiting toxicities were observed during the dose-escalation step and MEN1611 48 mg BID was selected as the recommended phase 2 dose (RP2D) for cohort expansion (CE). Methods: Eligible patients had HER2+/PIK3CA-mutated MBC and were treated with at least 2 prior lines of anti-HER2-based therapy in the advanced/metastatic setting including trastuzumab. Patients received MEN1611 + trastuzumab (MEN+T); hormone receptor positive (HR+) postmenopausal women received M+ T + fulvestrant (MEN+T+F). Recruitment was closed in December 2021. Pooled safety and efficacy data from the two subpopulations of CE are presented herein. Results: As of June 2022, 62 female patients were treated: 56 of them with MEN1611 48 mg BID (25 MEN+T and 31 MEN+T+F). Median age 55.5 years (range 34-78), 21% premenopausal, ECOG PS 0-1: 95.2%. Median metastatic regimens 4; 71.0% had prior pertuzumab and 91.9% had prior T-DM1. Common treatment-emergent adverse events (TEAEs, ≥20%) were diarrhea 66.1%, nausea 45.2%, hyperglycemia 43.6%, anemia 35.5%, asthenia 29.0%, decreased appetite 27.4%, rash 25.8%, aspartate aminotransferase increased 22.6%, vomiting 22.6%, and pyrexia 22.6%. Common TEAEs with CTCAE grade ≥3 (≥10%) were hyperglycemia (22.6%) and diarrhea (11.3%). Most treatment-related AEs (TRAEs) were reversible and manageable by supportive care. TEAEs leading to permanent treatment discontinuation occurred in 9 patients (14.5%), the only TEAE occurring in more than one patient was lipase increased (3.2%). TEAEs caused temporary treatment interruptions in 32 patients (51.6%), the most common being hyperglycemia (21.0%) and diarrhea (9.7%). TEAEs leading to dose reduction occurred in 14 patients (22.6%), the most common being diarrhea (6.5%), hyperglycemia (3.2%) and stomatitis (3.2%). Serious TRAEs were experienced by 12 patients (19.4%): hyperglycemia 6 patients, diarrhea 3 patients, anemia, general physical health deterioration, generalized edema, lipase increased, ketoacidosis and pneumonitis (1 patient each). In the efficacy-evaluable population at the RP2D (n=41) 14 patients (34.1%) showed partial response (MEN+T 5/15, MEN+T+F 9/26), 1 patient (2.4%) had a complete response (MEN+T 1/15) and 23 patients (56.1%) had stable disease (MEN+T 6/15, MEN+T+F 17/26) as best response. At the RP2D, the median (95% CI) overall survival (OS) was 21.9 (11.9, NE) months and the median (95% CI) progression free survival (PFS) 5.6 (3.7, 7.2) months. In the MEN+T group, the median OS was 11.9 (5.7, NE) months and median PFS 3.9 (2.3, 6.7) months. In the MEN+T+F group the median OS was 21.9 (16.9, NE) months and median PFS 5.7 (3.7, 11.5) months. Five patients continue on treatment. Conclusions: Updated results from B-PRECISE-01 demonstrated that MEN1611 combined with trastuzumab ± fulvestrant continued to show a manageable safety profile with encouraging anti-tumor activity and duration of response in heavily pre-treated patients with HER2+/PIK3CA-mutated advanced or metastatic breast cancer. Citation Format: Martine Piccart, Audrey Hennequin, Manuel Ruiz Borrego, Santiago Escrivá-de-Romani, Anja Williams, Begoña Jiménez Rodríguez, Gianluca Del Conte, Sacha J. Howell, Michela Palleschi, Matteo Simonelli, Francois P. Duhoux, Diego Tosi, Bernard Doger de Speville Uribe, Yolanda Jerez Gilarranz, Pierfrancesco Tassone, Giuseppe Curigliano, Simon Waters, Philippe Aftimos, Hans Wildiers, Simona Scartoni, Bartomeu Piza Vallespir, Ram Charan Shankaraiah, Krzysztof Grzegorzewski, Nassir Habboubi. MEN1611, a PI3K inhibitor, combined with trastuzumab ± fulvestrant for HER2+/PIK3CA mutant advanced or metastatic breast cancer: updated safety and efficacy results from the ongoing phase 1b study (B-PRECISE-01) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-05.

BackgroundWomen testing positive for BRCA1/2 pathogenic variants have high lifetime risks of breast cancer (BC) and ovarian cancer. The effectiveness of risk reducing surgery (RRS) has been demonstrated in numerous previous studies. We evaluated long-term uptake, timing and effectiveness of risk reducing mastectomy (RRM) and bilateral salpingo-oophorectomy (RRSO) in healthy BRCA1/2 carriers.MethodsWomen were prospectively followed up from positive genetic test (GT) result to censor date. χ² testing compared categorical variables; Cox regression model estimated HRs and 95% CI for BC/ovarian cancer cases associated with RRS, and impact on all-cause mortality; Kaplan-Meier curves estimated cumulative RRS uptake. The annual cancer incidence was estimated by women-years at risk.ResultsIn total, 887 women were included in this analysis. Mean follow-up was 6.26 years (range=0.01–24.3; total=4685.4 women-years). RRS was performed in 512 women, 73 before GT. Overall RRM uptake was 57.9% and RRSO uptake was 78.6%. The median time from GT to RRM was 18.4 months, and from GT to RRSO–10.0 months. Annual BC incidence in the study population was 1.28%. Relative BC risk reduction (RRM versus non-RRM) was 94%. Risk reduction of ovarian cancer (RRSO versus non-RRSO) was 100%.ConclusionOver a 24-year period, we observed an increasing number of women opting for RRS. We showed that the timing of RRS remains suboptimal, especially in women undergoing RRSO. Both RRM and RRSO showed a significant effect on relevant cancer risk reduction. However, there was no statistically significant RRSO protective effect on BC.

Background: Identifying women aged 30–39 years at increased risk of developing breast cancer could allow them to consider screening and preventive strategies. Research is underway to determine the feasibility of offering breast cancer risk assessment to this age group. However, it is unclear how best to deliver and communicate risk estimates to these women, in order to avoid potential harms such as undue anxiety and increase benefits such as informed decision-making. Objectives: This study aimed to investigate women’s views on, and requirements for, this proposed novel approach to risk assessment. Design: A cross-sectional qualitative design was used. Methods: Thirty-seven women aged 30–39 years with no family history or personal history of breast cancer participated in seven focus groups (n = 29) and eight individual interviews. Data were analysed thematically using a framework approach. Results: Four themes were developed. Acceptability of risk assessment service concerns the positive views women have towards the prospect of participating in breast cancer risk assessment. Promoting engagement with the service describes the difficulties women in this age group experience in relation to healthcare access, including mental load and a lack of cultural awareness, and the implications of this for service design and delivery. Impact of receiving risk results focuses on the anticipated impacts of receiving different risk outcomes, namely, complacency towards breast awareness behaviours following low-risk results, an absence of reassurance following average-risk results and anxiety for high-risk results. Women’s information requirements highlights women’s desire to be fully informed at invite including understanding why the service is needed. In addition, women wanted risk feedback to focus on plans for management. Conclusion: The idea of breast cancer risk assessment was received favourably among this age group, providing that a risk management plan and support from healthcare professionals is available. Determinants of acceptability of a new service included minimising effort required to engage with service, co-development of invitation and risk feedback materials and the importance of educational campaigning about the potential benefits of participation in risk assessment.

Purpose The aim of this study was to identify factors associated with progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer (MBC) treated with eribulin in a real-world setting, to improve information provision in those considering treatment. Methods Patients treated with eribulin for MBC at The Christie NHS Foundation Trust, Manchester, UK, between August 2011 and December 2018 were included (n = 439). Data were collected by retrospective review of medical records and electronic prescribing systems. Factors such as biological subtype, distant recurrence-free interval, previous lines of chemotherapy and the ‘average duration of previous treatment lines’ (ADPT) (calculated as: (date of initiation of eribulin–date of MBC) / the number of previous treatment lines in the metastatic setting) were evaluated for prognostic impact using Cox proportional hazards regression. Results In the full cohort, the median PFS and OS were 4.1 months (95% CI 3.7–4.4) and 8.6 months (95% CI 7.4–9.8), respectively. Outcomes were significantly inferior for those with triple-negative breast cancer (TNBC) (n = 92); PFSTNBC: 2.4 months (95% CI 2.1–3.0), p = TNBC: 5.4 months (95% CI 4.6–6.6), p = 8.7 months) had a median OS of 12.1 months (p = 0.004). Conclusion Our results indicate that the ADPT lines is an important factor when predicting the outcome with eribulin chemotherapy in a palliative setting and that quantitative guidance on the likely PFS and OS with treatment can be provided using ADPT. Validation in additional cohorts is warranted.

Whilst panel testing of an extended group of genes including BRCA1/2 is commonplace, these studies have not been subdivided by histiotype or by a priori BRCA1/2 probability. Patients with a breast cancer diagnosis undergoing extended panel testing were assessed for frequency of actionable variants in breast cancer genes other than BRCA1/2 by histiotype and Manchester score (MS) to reflect a priori BRCA1/2 likelihood. Rates were adjusted by prior testing for BRCA1/2 in an extended series. 95/1398 (6.3%) who underwent panel testing were found to be positive for actionable non-BRCA1/2 breast/ovarian cancer genes (ATM, BARD1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, TP53). As expected, PALB2, CHEK2 and ATM were predominant with 80-(5.3%). The highest rate occurred in Grade-3 ER+/HER2− breast cancers-(9.6%). Rates of non-BRCA actionable genes was fairly constant over all likelihoods of BRCA1/2 but adjusted rates were three times higher with MS &lt, 9 (BRCA1/2 = 1.5%, other = 4.7%), but was only 1.6% compared to 79.3% with MS ≥ 40. Although rates of detection of non-BRCA actionable genes are relatively constant across BRCA1/2 likelihoods this disguises an overall adjusted low frequency in high-likelihood families which have been heavily pre-tested for BRCA1/2. Any loss of detection sensitivity for BRCA1/2 actionable variants in breast cancer panels should lead to bespoke BRCA1/2 testing being conducted first.

Background Palbociclib is approved in 1st line for hormone receptor (HR)-positive HER2-negative advanced breast cancer (ABC). A Compassionate Access Program (CAP) previously allowed patients to receive it in 4th line. However, Palbociclib has not been specifically tested in this population. We aimed to determine the safety and efficacy profile of Palbociclib within the CAP across ten institutions in the United Kingdom. Methods We retrospectively identified HR-positive HER2-negative ABC patients on the Palbociclib CAP between December 2015 and September 2017. Demographics, disease characteristics, prior treatments, blood tests, toxicities, treatment delays and responses were recorded. Simple statistics, Fisher's exact test, chi-squared method and Cox regression were used as appropriate. Results 118 patients identified had median age of 59 (32-82). 97 (82.20%) were postmenopausal and 109 (92.37%) had ECOG Performance Status 0-1. 96 (81.36%) had visceral involvement, 19 (16.10%) bony only and 15 (12.71%) visceral only disease. Patients received a median 5 (range 3-11) prior lines of treatment and 3 (range 0-8) prior chemotherapy lines. 105 patients (89.74%) developed neutropenia (grade ≥3 in 59 [56.19%]). 6 experienced febrile neutropenia (5.13%). 57 (48.72%) had a dose reduction, down to 100mg in 48 (41.03%) and 75mg in 9 (7.69%) due to hematologic toxicity in 46 (80.70%). Dose delays were in median 7 days long (range: 0-56). Palbociclib was discontinued due to disease progression in 97 (82.91%) and to toxicity in 5 (4.27%). Grade 3 neutropenia occurred in 45 patients (67.16%) who received ≥3 and in 22 (32.84%) who received Palbociclib produced clinical benefit rate (CBR) of 47.52% and overall response rate of 15.84% in 101 patients assessed. CBR was 45.45% with previous endocrine treatment (ET) progression-free survival (PFS) Overall, median PFS was 4.5 months (95% CI 3.7-5.9). The PFS seen in different subgroups showed no impact in relation to the number of lines of prior chemotherapy ( Median OS was 15.8 months (95% CI 13.3-18.7) for the whole cohort and it was greater in patients who derived longer PFS from prior ET (≥6 months: 18.1 months [95% CI 13.0-NR]; Conclusions To date, this is the most extensive analysis of Palbociclib outcomes in ≥4th-line setting. In this heavily pretreated population clinical benefit was confirmed particularly for endocrine-sensitive disease and predominantly involving the bones and in earlier lines of treatment. Grade ≥3 neutropenia rates were similar to PALOMA trials, but the higher incidence of febrile neutropenia need to be carefully considered. Citation Format: Battisti NML, Kingston B, King J, Denton A, Waters S, Sita-Lumsden A, Rehman F, Stavraka C, Kristeleit H, Sawyer E, Houghton D, Davidson N, Howell S, Choy J, Harper P, Roylance R, Fharat R, Mohammed K, Ring A, Johnston S. Palbociclib and endocrine therapy in fourth line and beyond for hormone receptor-positive HER2-negative advanced breast cancer: The UK compassionate access program experience [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-23.

This abstract was withdrawn by the authors. Citation Format: Howell SJ, Waters S, Twelves C, Joffe J, Moon S, Bale C, Venkitaraman R, Bezecny P, Casbard A, Wilhelm-Benartzi C, Carucci M, Butler R, Alchami F, Jones R. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-07.

Palbociclib is approved in 1st line for hormone receptor (HR)-positive HER2-negative advanced breast cancer (ABC). A Compassionate Access Programme previously allowed patients to receive it in 4th line. However, Palbociclib has not been specifically tested in this population. We aimed to determine the safety and efficacy profile of Palbociclib within the Programme across ten institutions in the United Kingdom. We retrospectively identified HR-positive HER2-negative ABC patients on the Programme between December 2015 and September 2017. Demographics, disease characteristics, prior treatments, blood tests, toxicities, treatment delays and responses were recorded. Simple statistics, Fisher’s exact test, χ2 method and Cox regression were used. 118 patients identified had a median age of 59. 82.2% were postmenopausal and 92.4% performance status 0–1. 81.4% had visceral involvement and 6.8% bone-only disease after a median of 5 prior treatments and 3 prior chemotherapies. Clinical benefit rate was 47.5%, overall response rate 15.8%, median PFS 4.5 months and median OS 15.8 months. Longer progression-free survival on prior endocrine therapy was a predictor of longer PFS and OS. 89.7% developed neutropenia (grade ≥ 3 in 56.8%). 5.1% experienced febrile neutropenia. 48.3% had dose reductions and 3.4% discontinued Palbociclib following toxicity. No statistically significant difference in grade ≥ 3 neutropenia was observed according to metastatic sites nor previous treatments. This is the most extensive analysis of palbociclib in ≥ 4th-line setting. Clinical benefit was confirmed particularly for endocrine-sensitive, predominantly bony disease and in earlier lines of treatment. Safety was similar to PALOMA trials with higher febrile neutropenia rate.

IntroductionObesity and overweight are strong potentially modifiable risk factors for postmenopausal breast and endometrial cancer. Bariatric surgery can achieve considerable weight loss and risk reduction of weight-related cancer but is unlikely to be a feasible cancer prevention strategy. Total diet replacement (TDR) can also lead to significant weight reduction. This study aims to examine the cellular and molecular changes in breast and endometrial tissue in high-risk women following TDR-induced weight loss, as well as longer-term adherence to a 12-month TDR weight loss intervention.Methods and analysisPROBE-TDR (PRevention Of Breast and Endometrial cancer using Total Diet Replacement) is a prospective, non-blinded, randomised controlled trial of 47 women at increased risk of breast and/or endometrial cancer. Randomisation is 2:1 to either an immediate 12-month TDR weight loss programme (n=31) or delayed dietary intervention (control) (n=16). The TDR programme includes an initial 12-week period of TDR (850 kcal/day) followed by a 40-week food-based diet, based on the nutritional principles of a Mediterranean diet, as either continued weight loss (~1500 kcal/day) or weight loss maintenance (~2000 kcal/day). Menstrual phase-matched biopsies of the breast and endometrium will be assessed at baseline and at the end of the 12-week TDR in the immediate diet group, compared with women randomised to the control group following their usual diet. The trial will also assess longer-term adherence and weight loss success across the 12-month programme in both the immediate and control groups.Ethics and disseminationApproval for this study has been obtained from the Health Research Authority and Health and Care Research Wales (approval 20/NW/0095). Results will be published in peer-reviewed journals, presented at conferences and shared with trial participants.Trial registration numberInternational Standard Randomised Controlled Trial Number Registry (ISRCTN15358157).