Risk factors and novel biomarkers in breast cancer

Efforts continue to identify and validate novel risk factors / biomarkers for breast cancer and improve current risk prediction models in the general population due to ongoing issues with sensitivity and specificity. The overall goal of this PhD study is to add to this effort. Specific aims are to (1) examine which is the best source of getting notified for breast cancer diagnosis in the general population since accurate data is crucial for risk assessment studies (2) investigate the association of sex steroids, gonadotrophins and novel assays of sex steroid hormone receptor serum bioactivity (SB) in breast cancer (3) examine whether they can be combined to improve breast cancer risk assessment and (4) identify new DNA methylation markers that might add to such a strategy in the future. To achieve this, a nested case-control study was undertaken within UK Collaborative Trial of Ovarian Cancer Screening. 2629 trial participants were identified via cancer registry (CR) or self-reporting to have breast cancer. Diagnosis was confirmed by the treating clinician. The largest study was undertaken in England and Wales to examine completeness of breast cancer diagnosis within UKCTOCS. Analysis of complete data obtained in 1083 of these women showed CR to be more accurate than self-reporting but associated with time-delays. Serum samples from 200 eligible breast cancer cases identified through the process and 400 matched-controls were analysed for oestradiol, free-oestradiol, oestrone, androstenedione, testosterone, free-testosterone, progesterone, dehydroepiandrosterone sulphate (DHEAS), sex steroid hormone binding globulin (SHBG), luteinising hormone (LH), follicle stimulating hormone (FSH) and oestrogen receptor-α and -β and androgen receptor SB. Results showed that sex steroid receptor SB assays could add to breast cancer risk prediction. Additionally, the best oestrogen for breast cancer risk prediction is oestrone and the best androgen is testosterone. High testosterone and FSH levels up to 5 years prior to diagnosis predict breast cancer with high power and may have a synergistic effect. In a separate case control study of 189 paraffin-embedded breast tissue samples, 55 genes were investigated using MethyLight. DNA methylation alterations were found to be homogeneous in breast cancer with 13 genes being predictive of the disease, suggesting that such changes could be useful as future biomarkers. Further studies (already underway) involve using high-throughput technology to analyse serum DNA methylation changes and correlate these with the observed serum hormonal changes and build better breast cancer risk prediction models

Socioeconomic indicators of health inequalities and female mortality: a nested cohort study within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Evidence is mounting that area-level socioeconomic indicators are important tools for predicting health outcomes. However, few studies have examined these alongside individual-level education. This nested cohort study within the control arm of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) assesses the association of mutually adjusted individual (education) and area-level (Index of Multiple Deprivation-IMD 2007) socioeconomic status indicators and all-cause female mortality

Breast cancer risk reduction:is it feasible to initiate a randomised controlled trial of a lifestyle intervention programme (ActWell) within a national breast screening programme?

BackgroundBreast cancer is the most commonly diagnosed cancer and the second cause of cancer deaths amongst women in the UK. The incidence of the disease is increasing and is highest in women from least deprived areas. It is estimated that around 42% of the disease in post-menopausal women could be prevented by increased physical activity and reductions in alcohol intake and body fatness. Breast cancer control endeavours focus on national screening programmes but these do not include communications or interventions for risk reductionThis study aimed to assess the feasibility of delivery, indicative effects and acceptability of a lifestyle intervention programme initiated within the NHS Scottish Breast Screening Programme (NHSSBSP).MethodsA 1:1 randomised controlled trial (RCT) of the 3 month ActWell programme (focussing on body weight, physical activity and alcohol) versus usual care conducted in two NHSSBSP sites between June 2013 and January 2014. Feasibility assessments included recruitment, retention, and fidelity to protocol. Indicative outcomes were measured at baseline and 3 month follow-up (body weight, waist circumference, eating and alcohol habits and physical activity. At study end, a questionnaire assessed participant satisfaction and qualitative interviews elicited women¿s, coaches and radiographers¿ experiences. Statistical analysis used Chi squared tests for comparisons in proportions and paired t tests for comparisons of means. Linear regression analyses were performed, adjusted for baseline values, with group allocation as a fixed effectResultsA pre-set recruitment target of 80 women was achieved within 12 weeks and 65 (81%) participants (29 intervention, 36 control) completed 3 month assessments. Mean age was 58¿±¿5.6 years, mean BMI was 29.2¿±¿7.0 kg/m2 and many (44%) reported a family history of breast cancer.The primary analysis (baseline body weight adjusted) showed a significant between group difference favouring the intervention group of 2.04 kg (95%CI ¿3.24 kg to ¿0.85 kg). Significant, favourable between group differences were also detected for BMI, waist circumference, physical activity and sitting time. Women rated the programme highly and 70% said they would recommend it to others.ConclusionsRecruitment, retention, indicative results and participant acceptability support the development of a definitive RCT to measure long term effects.Trial registrationThe trial was registered with Current Controlled Trials (ISRCTN56223933)

Colorectal cancer ascertainment through cancer registries, hospital episode statistics, and self-reporting compared to confirmation by clinician: A cohort study nested within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

BACKGROUND: Electronic health records are frequently used for cancer epidemiology. We report on their quality for ascertaining colorectal cancer (CRC) in UK women. METHODS: Population-based, retrospective cohort study nested within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Postmenopausal women aged 50-74 who were diagnosed with CRC during 2001-11 following randomisation to the UKCTOCS were identified and their diagnosis confirmed with their treating clinician. The sensitivity and positive predictive value (PPV) of cancer and death registries, hospital episode statistics, and self-reporting were calculated by pairwise comparisons to the treating clinician's confirmation, while specificity and negative predictive value were estimated relative to expected cases. RESULTS: Notification of CRC events were received for 1,085 women as of 24 May 2011. Responses were received from 61% (660/1,085) of clinicians contacted. Nineteen women were excluded (18 no diagnosis date, one diagnosed after cut-off). Of the 641 eligible, 514 had CRC, 24 had a benign polyp, and 103 had neither diagnosis. The sensitivity of cancer registrations at one- and six-years post-diagnosis was 92 (95% CI 90-94) and 99% (97-100), respectively, with a PPV of 95% (95% CI 92/93-97). The sensitivity & PPV of cancer registrations (at one-year post-diagnosis) & hospital episode statistics combined were 98 (96-99) and 92% (89-94), respectively. CONCLUSIONS: Cancer and death registrations in the UK are a reliable resource for CRC ascertainment in women. Hospital episode statistics can supplement delays in cancer registration. Self-reporting seems less reliable

Evaluation in pre-diagnosis samples discounts ICAM-1 and TIMP-1 as biomarkers for earlier diagnosis of pancreatic cancer.

Circulating intercellular adhesion molecule-1 (ICAM-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) have been widely proposed as potential diagnostic biomarkers for pancreatic ductal adenocarcinoma (PDAC). We report on serum protein levels prior to clinical presentation of pancreatic cancer. Serum ICAM-1 and TIMP-1 were measured by ELISA in two case–control sets: 1) samples from patients diagnosed with pancreatic cancer (n = 40), chronic pancreatitis (n = 20), benign jaundice due to gall stones (n = 20) and healthy subjects (n = 20); 2) a preclinical set from the UK Collaborative Trial of Ovarian Cancer Screening biobank of samples collected from 27 post-menopausal women 0–12 months prior to diagnosis of pancreatic cancer and controls matched for date of donation and centre. Levels of ICAM-1 and TIMP-1 were significantly elevated in set 1 in PDAC patients with jaundice compared to PDAC patients without jaundice and both proteins were elevated in patients with jaundice due to gall stones. Neither protein was elevated in samples taken 0–12 months prior to PDAC diagnosis compared to non-cancer control samples. In conclusion, evaluation in pre-diagnosis samples discounts ICAM-1 and TIMP-1 as biomarkers for earlier diagnosis of pancreatic cancer. Failure to account for obstructive jaundice may have contributed to the previous promise of these candidate biomarkers

Evaluation of serum CEA, CYFRA21-1 and CA125 for the early detection of colorectal cancer using longitudinal preclinical samples

Blood-borne biomarkers for early detection of colorectal cancer (CRC) could markedly increase screening uptake. The aim of this study was to evaluate serum carcinoembryonic antigen (CEA), CYFRA21-1 and CA125 for the early detection of CRC in an asymptomatic cohort

Histological confirmation of breast cancer registration and self-reporting in England and Wales: a cohort study within the UK Collaborative Trial of Ovarian Cancer Screening

In research studies, accurate information of cancer diagnosis is crucial. In women with breast cancer (BC), we compare cancer registration (CR) in England/Wales and self-reporting with independent confirmation

Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: Reanalysis of eighteen prospective studies

Epidemiological studies have examined breast cancer risk in relation to sex hormone concentrations measured by different methods: "extraction" immunoassays (with prior purification by organic solvent extraction, with or without column chromatography), "direct" immunoassays (no prior extraction or column chromatography), and more recently with mass spectrometry-based assays. We describe the associations of estradiol, estrone and testosterone with both body mass index and breast cancer risk in postmenopausal women according to assay method, using data from a collaborative pooled analysis of 18 prospective studies. In general, hormone concentrations were highest in studies that used direct assays and lowest in studies that used mass spectrometry-based assays. Estradiol and estrone were strongly positively associated with body mass index, regardless of the assay method; testosterone was positively associated with body mass index for direct assays, but less clearly for extraction assays, and there were few data for mass spectrometry assays. The correlations of estradiol with body mass index, estrone and testosterone were lower for direct assays than for extraction and mass spectrometry assays, suggesting that the estimates from the direct assays were less precise. For breast cancer risk, all three hormones were strongly positively associated with risk regardless of assay method (except for testosterone by mass spectrometry where there were few data), with no statistically significant differences in the trends, but differences may emerge as new data accumulate. Future epidemiological and clinical research studies should continue to use the most accurate assays that are feasible within the design characteristics of each study

Alcohol intake and endogenous sex hormones in women: Meta‐analysis of cohort studies and Mendelian randomization

Background: The mechanisms underlying alcohol‐induced breast carcinogenesis are not fully understood but may involve hormonal changes. Methods: Cross‐sectional associations were investigated between self‐reported alcohol intake and serum or plasma concentrations of estradiol, estrone, progesterone (in premenopausal women only), testosterone, androstenedione, dehydroepiandrosterone sulfate, and sex hormone binding globulin (SHBG) in 45 431 premenopausal and 173 476 postmenopausal women. Multivariable linear regression was performed separately for UK Biobank, European Prospective Investigation into Cancer and Nutrition, and Endogenous Hormones and Breast Cancer Collaborative Group, and meta‐analyzed the results. For testosterone and SHBG, we also conducted Mendelian randomization and colocalization using the ADH1B (alcohol dehydrogenase 1B) variant (rs1229984). Results: Alcohol intake was positively, though weakly, associated with all hormones (except progesterone in premenopausal women), with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal estradiol to 6.6% for postmenopausal dehydroepiandrosterone sulfate. There was an inverse association of alcohol with SHBG in postmenopausal women but a small positive association in premenopausal women. Two‐sample randomization identified positive associations of alcohol intake with total testosterone (difference per 10 g/day increment: 4.1%; 95% CI, 0.6–7.6) and free testosterone (7.8%; 4.1–11.5), and an inverse association with SHBG (–8.1%; –11.3% to –4.9%). Colocalization suggested a shared causal locus at ADH1B between alcohol intake and higher free testosterone and lower SHBG (posterior probability for H4, 0.81 and 0.97, respectively). Conclusions: Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk