Jack Cuzick

BackgroundThe US Food and Drug Administration supports innovations to facilitate new indications for high-risk human papillomavirus testing. This report describes the retrospective testing of stored specimens and analysis of existing data to efficiently and cost-effectively support a new indication for the Onclarity human papillomavirus assay (Becton, Dickinson and Company, BD Life Sciences - Integrated Diagnostic Solutions, Sparks, MD). The performance of this index test was compared with that of a predicate test, the cobas human papillomavirus assay (Roche Diagnostics, Indianapolis, IN). Both human papillomavirus assays are based on real-time polymerase chain reaction platforms that detect the presence of 14 high-risk human papillomavirus genotypes. The predicate assay reports human papillomavirus types 16 and 18 as individual results and the other 12 human papillomavirus genotypes as 1 pooled …

Professor Hall will have reviewed his studies on the impact of lower doses of tamoxifen on changes in breast density, an important risk factor. Here I will review the work of Professor Decensi’s team on the ability of 5mg/d of tamoxifen (baby-Tam) on the progression rate of DCIS (69%) and other intraepithelial lesions (11% LCIS, 20% atypical ductal hyperplasia). This trial involved 500 pre- and postmenopausal women randomized equally between baby-Tam and placebo with a 9.7 year median follow up. All breast cancer progression (invasive (77%) and DCIS (23%)) was reduced by 42% (25 vs 41 events, P = 0.03) and contralateral tumours by 64% (6 vs 16 events, P = 0.025). No significant increase was seen in any side effect (Table). I will also briefly discuss their new award for a project to compare baby Tam to baby exemestane in a randomized trial in a similar population as above, initially for side effects, but …

BackgroundAn increased risk of breast cancer is associated with high serum concentrations of oestradiol and testosterone in postmenopausal women, but little is known about how these hormones affect response to endocrine therapy for breast cancer prevention or treatment. We aimed to assess the effects of serum oestradiol and testosterone concentrations on the efficacy of the aromatase inhibitor anastrozole for the prevention of breast cancer in postmenopausal women at high risk.MethodsIn this case-control study we used data from the IBIS-II prevention trial, a randomised, controlled, double-blind trial in postmenopausal women aged 40–70 years at high risk of breast cancer, conducted in 153 breast cancer treatment centres across 18 countries. In the trial, women were randomly assigned (1:1) to receive anastrozole (1 mg/day, orally) or placebo daily for 5 years. In this pre-planned case-control study, the …

Background Previous studies have demonstrated that incorporating a polygenic risk score (PRS) to existing risk prediction models for breast cancer improves model fit, but to determine its clinical utility the impact on risk categorization needs to be established. We add a PRS to two well-established models and quantify the difference in classification using the net reclassification improvement (NRI). Methods We analyzed data from 126,490 post-menopausal women of “White British” ancestry, aged 40 to 69 years at baseline from the UK Biobank prospective cohort. The breast cancer outcome was derived from linked registry data and hospital records. We combined a PRS for breast cancer with 10-year risk scores from the Tyrer–Cuzick and Gail models, and compared these to the risk scores from the models using phenotypic variables alone. We report metrics of discrimination and …

Background: Since 2006 three studies, involving 289,089 adolescents, demonstrated a significant association (1.67(0.79-3.55),1.7(1.03-2.70),2.37(1.19-4.73)) between pubertal acne and poor outcome prostate cancer(PC) 30+ years later. This suggested Cutibacterium acnes, amicroaerophylic bacterium, might be contributing to PC bacterial dysbiosis analogous to the role of H. pylori in stomach cancer and explain why circumcision reduces PC risk. Six years ago, using MALDI-TOF, we demonstrated that the presence of seven obligate anaerobe species in addition to C. acnes were increased in PC and linked to increased PSA. This presentation studies stored samples from the PROVENT chemoprevention randomised PC active surveillance phase 2 trial analysed using 16S rDNA sequencing, and comparing obligate anaerobe frequency with those detected by culture and MALDI-TOF identification and their …

Methylation markers have shown potential for triaging high‐risk HPV‐positive (hrHPV+) women to identify those at increased risk of invasive cervical cancer (ICC). Our aim was to assess the performance of the S5 DNA methylation classifier for predicting incident high‐grade cervical intraepithelial neoplasia (CIN) and ICC among hrHPV+ women in the ARTISTIC screening trial cohort. The S5 classifier, comprising target regions of tumour suppressor gene EPB41L3 and L1 and L2 regions of HPV16, HPV18, HPV31, and HPV33, was assayed by pyrosequencing in archived hrHPV+ liquid‐based samples from 343 women with high‐grade disease (139 CIN2, 186 CIN3, and 18 ICC) compared to 800 hrHPV+ controls. S5 DNA methylation correlated directly with increasing severity of disease and inversely with lead time to diagnosis. S5 could discriminate between hrHPV+ women who developed CIN3 or ICC and …

BackgroundUptake to anastrozole for breast cancer prevention is low, partly due to women’s concerns about side effects including gains in weight and specifically gains in body fat. Previous evidence does not link anastrozole with gains in weight, but there is a lack of data on any effects on body composition i.e. changes in fat and fat free mass. Here we assess association of anastrozole with body composition changes in a prospective sub-study from the second international breast intervention trial (IBIS-II).MethodsParticipants had DXA scans at baseline and for five years of anastrozole/placebo and beyond (between March 2004 and September 2017. Primary outcomes were changes in body weight, body fat and fat free mass at 9–18 months. A linear model was used to estimate the size of a differential effect in these outcomes by randomised treatment allocation adjusted for baseline value and time since last scan …

It is well known that serum levels of oestradiol and testosterone, esp free hormone levels, influence the risk of developing breast cancer in postmenopausal women (Thomas et al 1997, Hankinson et al 1998, Kaaks et al 2005, Tin Tin et al 2021). However very little is known about how these hormone levels influence the effectiveness of aromatase inhibitors. In the IBIS-II Prevention Trial we compared anastrozole to placebo in 3864 women at high risk of breast cancer (Cuzick et al 2020). Of these women 3644 (94.3%) had a baseline blood sample. In those with a valid blood sample, 72 in the anastrozole arm and 142 in the placebo arm developed breast cancer (including DCIS) after 12.9 years of follow up (OR = 0.49, 95% CI 0.37–0.66 P< 0.0001). For each case two controls were selected, matched on age, treatment arm and follow up longer than the matching case. In these women oestradiol (E2), testosterone …

P240 Computerized Quantification of Tumor Infiltrating Lymphocyte (TIL) as a prognostic and predictive factor in ductal carcinoma in situ: Results from the UK/ANZ DCIS randomized trial Toggle navigation Login Toggle navigation P240 Computerized Quantification of Tumor Infiltrating Lymphocyte (TIL) as a prognostic and predictive factor in ductal carcinoma in situ: Results from the UK/ANZ DCIS randomized trial QMRO Home Wolfson Institute of Preventive Medicine Centre for Cancer Prevention P240 Computerized Quantification of Tumor Infiltrating Lymphocyte (TIL) as a prognostic and predictive factor in ductal carcinoma in situ: Results from the UK/ANZ DCIS randomized trial QMRO Home Wolfson Institute of Preventive Medicine Centre for Cancer Prevention P240 Computerized Quantification of Tumor Infiltrating Lymphocyte (TIL) as a prognostic and predictive factor in ductal carcinoma in situ: Results from the …

PurposeObesity is a risk factor for postmenopausal breast cancer and evidence supports the pivotal role of adiponectin in the association between obesity and breast cancer. We aimed to investigate whether the effect of baseline body mass index (BMI) on postmenopausal breast cancer risk was mediated by adiponectin or other circulating biomarkers.MethodsWe measured adiponectin, leptin, IGF-I, IGFBP-1, high-sensitivity C-reactive protein, glycemia, insulin, HOMA-IR index, and SHBG in baseline and 12-month serum samples from 123 cases and 302 matched controls in the placebo arm of the IBIS-II Prevention trial. We conducted the main mediation analysis considering BMI at baseline as an exposure and the increase in adiponectin at 12 months as a mediator after adjustment for the Tyrer-Cuzick score and the use of lipid-lowering medications and supplements.ResultsThe 12-month increase in adiponectin levels was significantly associated with a 40% decrease in the risk of breast cancer [hazard ratio (HR), 0.60; 95% confidence interval (95% CI), 0.36-1.00]. The estimate of the association of BMI was low, indicating only a 5% increase in breast cancer risk (HR, 1.05; 95% CI, 1.00-1.09). The increase in adiponectin levels at 12 months did not mediate the effect of BMI on breast cancer risk (HR, 1.00; 95% CI, 0.98–1.02).ConclusionMediation analysis indicated an independent role of adiponectin in postmenopausal breast cancer risk. Raising adiponectin levels might be an attractive target for postmenopausal breast cancer prevention.

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 …

Human papillomavirus (HPV) testing for cervical screening increases diagnosis of precancer and reduces the incidence of cervical cancer more than cytology alone. However, real‐world evidence from diverse practice settings is lacking for the United States (U.S.) to support clinician adoption of primary HPV screening. Using a population‐based registry, which captures all cervical cytology (with or without HPV testing) and all cervical biopsies, we conducted a real‐world evidence study of screening in women aged 30 to 64 years across the entire state of New Mexico. Negative cytology was used to distinguish cotests from reflex HPV tests. A total of 264 198 cervical screening tests (with exclusions based on clinical history) were recorded as the first screening test between 2014 and 2017. Diagnoses of cervical intraepithelial neoplasia grades 2 or 3 or greater (CIN2+, CIN3+) from 2014 to 2019 were the main …

It is uncommon for risk groups defined by statistical or artificial intelligence (AI) models to be chosen by jointly considering model performance and potential interventions available. We develop a framework to rapidly guide choice of risk groups in this manner, and apply it to guide breast cancer screening intervals using an AI model. Linear programming is used to define risk groups that minimize expected advanced cancer incidence subject to resource constraints. In the application risk stratification performance is estimated from a case–control study (2044 cases, 1:1 matching), and other parameters are taken from screening trials and the screening programme in England. Under the model, re-screening in 1 year for the highest 4% AI model risk, in 3 years for the middle 64%, and in 4 years for 32% of the population at lowest risk, was expected to reduce the number of advanced cancers diagnosed by approximately …

As good health is a lifetime issue, long-term follow up is an important part of evaluating any medical condition or treatment. This is well appreciated in epidemiologic studies where exposure to a harmful substance is often long-term, and its impact on health can appear many years after first occurrence. Examples include the classic study of Doll and Peto [1] on 34,439 male British doctors, which began in 1951 and last reported in 2004 after 50 years of follow up, in which lifelong cigarette smoking was shown to reduce life expectancy by an average of 10 years, but cessation at age 60, 50, 40 or 30 years reduced this by about 3, 6, 9, or almost the full 10 years, respectively. Other classic long-term epidemiologic studies have focussed on diet and alcohol consumption [2, 3], hormone replacement therapy [4], or have been more general and studied a wider set of risk factors, often among healthcare professionals; for …

BackgroundRadiotherapy has become much better targeted since the 1980s, improving both safety and efficacy. In breast cancer, radiotherapy to regional lymph nodes aims to reduce risks of recurrence and death. Its effects have been studied in randomised trials, some before the 1980s and some after. We aimed to assess the effects of regional node radiotherapy in these two eras.MethodsIn this meta-analysis of individual patient data, we sought data from all randomised trials of regional lymph node radiotherapy versus no regional lymph node radiotherapy in women with early breast cancer (including one study that irradiated lymph nodes only if the cancer was right-sided). Trials were identified through the EBCTCG's regular systematic searches of databases including MEDLINE, Embase, the Cochrane Library, and meeting abstracts. Trials were eligible if they began before Jan 1, 2009. The only systematic …

BackgroundRisk 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).MethodsRisk 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–<8% 10-year) to have appointments to discuss prevention and additional screening.ResultsOverall 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 …

BackgroundObesity in early adulthood is associated with lower breast cancer rates in later life. This could be interpreted as a positive reinforcement of excess weight amongst younger women however, the wider implications of higher weights are less well known. This study examined the association between both obesity in early adulthood and body mass index (BMI) change through adulthood, and all-cause mortality.MethodsThe Predicting Risk of Cancer At Screening (PROCAS) study recruited 57,902 women aged 46–73 years (median age 57.2, IQR 51.8–63.7 years) from the Greater Manchester National Health Service breast screening programme in North West England between 2009 and 2015. It was used to assess associations between BMI at 20 years and cohort entry with all-cause mortality ascertained via deaths recorded on the National Breast Screening System to June 2020. Hazard ratios were …

Background Accurate breast cancer risk assessment after a negative screening result could enable better strategies for early detection. Purpose To evaluate a deep learning algorithm for risk assessment based on digital mammograms. Materials and Methods A retrospective observational matched case-control study was designed using the OPTIMAM Mammography Image Database from the National Health Service Breast Screening Programme in the United Kingdom from February 2010 to September 2019. Patients with breast cancer (cases) were diagnosed following a mammographic screening or between two triannual screening rounds. Controls were matched …

BackgroundWomen with dense breasts have an increased risk of breast cancer. However, breast density is measured with variability, which may reduce the reliability and accuracy of its association with breast cancer risk. This is particularly relevant when visually assessing breast density due to variation in inter- and intra-reader assessments. To address this issue, we developed a longitudinal breast density measure which uses an individual woman’s entire history of mammographic density, and we evaluated its association with breast cancer risk as well as its predictive ability.MethodsIn total, 132,439 women, aged 40–73 yr, who were enrolled in Kaiser Permanente Washington and had multiple screening mammograms taken between 1996 and 2013 were followed up for invasive breast cancer through 2014. Breast Imaging Reporting and Data System (BI-RADS) density was assessed at each screen. Continuous …

Computerized Quantification of Tumor Infiltrating Lymphocyte (TIL) as a prognostic and predictive factor in ductal carcinoma in situ: Results from the UK/ANZ DCIS randomized trial Toggle navigation Login Toggle navigation Computerized Quantification of Tumor Infiltrating Lymphocyte (TIL) as a prognostic and predictive factor in ductal carcinoma in situ: Results from the UK/ANZ DCIS randomized trial QMRO Home Institute of Population Health Sciences Institute Director's Office Computerized Quantification of Tumor Infiltrating Lymphocyte (TIL) as a prognostic and predictive factor in ductal carcinoma in situ: Results from the UK/ANZ DCIS randomized trial QMRO Home Institute of Population Health Sciences Institute Director's Office Computerized Quantification of Tumor Infiltrating Lymphocyte (TIL) as a prognostic and predictive factor in ductal carcinoma in situ: Results from the UK/ANZ DCIS randomized trial All of …