The influence of candidates' race on examiners' ratings in standardised assessments of clinical practice.

PURPOSE: Delivering fair and reliable summative assessments in medical education assumes examiner decision making is devoid of bias. We investigated whether candidate racial appearances influenced examiner ratings in undergraduate clinical exams. METHODS: We used an internet-based design. Examiners watched a randomised set of six videos of three different white candidates and three different non-white (Asian, black and Chinese) candidates taking a clinical history at either fail, borderline or pass grades. We compared the median and interquartile range (IQR) of the paired difference between scores for the white and non-white candidates at each performance grade and tested for statistical significance. RESULTS: 160 Examiners participated. At the fail grade, the black and Chinese candidates scored lower than the white candidate, with median paired differences of -2.5 and -1 respectively (both p < 0.001). At the borderline grade, the black and Chinese candidates scored higher than the white candidate, with median paired differences of +2 and +3, respectively (both p < 0.001). At the passing grade, the Asian candidate scored lower than the white candidate (median paired difference -1, p < 0.001). CONCLUSION: The racial appearance of candidates appeared to influence the scores awarded by examiners, but not in a uniform manner.

Intervention to reduce age bias in medical students' decision making for the treatment of older women with breast cancer: A novel approach to bias training.

Objectives: Despite NICE guidelines to 'treat people with invasive breast cancer, irrespective of age, with surgery and appropriate systemic therapy, rather than endocrine therapy alone', older patients receive differential treatment and experience worse outcomes. Research has evidenced the prevalence of ageism and identified the role of implicit bias in reflecting and potentially perpetuating disparities across society, including in healthcare. Yet age bias has rarely been considered as an explanatory factor in poorer outcomes for older breast cancer patients nor, consequentially, has removing age bias been considered as an approach to improving outcomes. Many organizations carry out bias training with the aim of reducing negative impacts from biased decision making, yet the few evaluations of these interventions have mostly seen small or negative effects. This study explores whether a novel intervention to address age bias leads to better quality decision making for the treatment of older women with breast cancer.Methods: An online study compared medical students' treatment recommendations for older breast cancer patients and the reasoning for their decision making before and after a novel bias training intervention. Thirty-one medical students participated in the study.Results: The results show that the bias training intervention led medical students to make better quality decisions for older breast cancer patients. The quality of decision making was measured by decreases in age-based decision making and increased efforts to include patients in decision making. These results suggest there is value in exploring whether if anti-bias training interventions could usefully be applied in other areas of practice where older patients experience poorer outcomes.Conclusions: This study evidences that bias training improves the quality of decision making by medical students in respect of older breast cancer patients. The study findings show promise that this novel approach to bias training might usefully be applied to all medical practitioners making treatment recommendations for older patients.

Bridging The Age Gap: observational cohort study of effects of chemotherapy and trastuzumab on recurrence, survival and quality of life in older women with early breast cancer.

BACKGROUND: Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy. METHODS: A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage. RESULTS: Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19-0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20-0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08-0.49];BCSS: HR 0.12 [95% CI 0.03-0.44]).Transient negative quality-of-life impacts were observed. CONCLUSIONS: Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient. TRIAL REGISTRATION: ISRCTN 46099296.

Cost-Effectiveness Modeling of Surgery Plus Adjuvant Endocrine Therapy Versus Primary Endocrine Therapy Alone in UK Women Aged 70 and Over With Early Breast Cancer.

OBJECTIVES: Approximately 20% of UK women aged 70+ with early breast cancer receive primary endocrine therapy (PET) instead of surgery. PET reduces surgical morbidity but with some survival decrement. To complement and utilize a treatment dependent prognostic model, we investigated the cost-effectiveness of surgery plus adjuvant therapies versus PET for women with varying health and fitness, identifying subgroups for which each treatment is cost-effective. METHODS: Survival outcomes from a statistical model, and published data on recurrence, were combined with data from a large, multicenter, prospective cohort study of over 3400 UK women aged 70+ with early breast cancer and median 52-month follow-up, to populate a probabilistic economic model. This model evaluated the cost-effectiveness of surgery plus adjuvant therapies relative to PET for 24 illustrative subgroups: Age {70, 80, 90} × Nodal status {FALSE (F), TRUE (T)} × Comorbidity score {0, 1, 2, 3+}. RESULTS: For a 70-year-old with no lymph node involvement and no comorbidities (70, F, 0), surgery plus adjuvant therapies was cheaper and more effective than PET. For other subgroups, surgery plus adjuvant therapies was more effective but more expensive. Surgery plus adjuvant therapies was not cost-effective for 4 of the 24 subgroups: (90, F, 2), (90, F, 3), (90, T, 2), (90, T, 3). CONCLUSION: From a UK perspective, surgery plus adjuvant therapies is clinically effective and cost-effective for most women aged 70+ with early breast cancer. Cost-effectiveness reduces with age and comorbidities, and for women over 90 with multiple comorbidities, there is little cost benefit and a negative impact on quality of life.

National inter-rater agreement of standardised simulated-patient-based assessments.

PURPOSE: The forthcoming UK Medical Licensing Assessment will require all medical schools in the UK to ensure that their students pass an appropriately designed Clinical and Professional Skills Assessment (CPSA) prior to graduation and registration with a licence to practice medicine. The requirements for the CPSA will be set by the General Medical Council, but individual medical schools will be responsible for implementing their own assessments. It is therefore important that assessors from different medical schools across the UK agree on what standard of performance constitutes a fail, pass or good grade. METHODS: We used an experimental video-based, single-blinded, randomised, internet-based design. We created videos of simulated student performances of a clinical examination at four scripted standards: clear fail (CF), borderline (BD), clear pass (CPX) and good (GD). Assessors from ten regions across the UK were randomly assigned to watch five videos in 12 different combinations and asked to give competence domain scores and an overall global grade for each simulated candidate. The inter-rater agreement as measured by the intraclass correlation coefficient (ICC) based on a two-way random-effects model for absolute agreement was calculated for the total domain scores. RESULTS: 120 assessors enrolled in the study, with 98 eligible for analysis. The ICC was 0.93 (95% CI 0.81-0.99). The mean percentage agreement with the scripted global grade was 74.4% (range 40.8-96.9%). CONCLUSIONS: The inter-rater agreement amongst assessors across the UK when rating simulated candidates performing at scripted levels is excellent. The level of agreement for the overall global performance level for simulated candidates is also high. These findings suggest that assessors from across the UK viewing the same simulated performances show high levels of agreement of the standards expected of students at a 'clear fail,' 'borderline,' 'clear pass' and 'good' level.

Opportunities and priorities for breast surgical research.

The 2013 Breast Cancer Campaign gap analysis established breast cancer research priorities without a specific focus on surgical research or the role of surgeons on breast cancer research. This Review aims to identify opportunities and priorities for research in breast surgery to complement the 2013 gap analysis. To identify these goals, research-active breast surgeons met and identified areas for breast surgery research that mapped to the patient pathway. Areas included diagnosis, neoadjuvant treatment, surgery, adjuvant therapy, and attention to special groups (eg, those receiving risk-reducing surgery). Section leads were identified based on research interests, with invited input from experts in specific areas, supported by consultation with members of the Association of Breast Surgery and Independent Cancer Patients' Voice groups. The document was iteratively modified until participants were satisfied that key priorities for surgical research were clear. Key research gaps included issues surrounding overdiagnosis and treatment; optimising treatment options and their selection for neoadjuvant therapies and subsequent surgery; reducing rates of re-operations for breast-conserving surgery; generating evidence for clinical effectiveness and cost-effectiveness of breast reconstruction, and mechanisms for assessing novel interventions; establishing optimal axillary management, especially post-neoadjuvant treatment; and defining and standardising indications for risk-reducing surgery. We propose strategies for resolving these knowledge gaps. Surgeons are ideally placed for a central role in breast cancer research and should foster a culture of engagement and participation in research to benefit patients and health-care systems. Development of infrastructure and surgical research capacity, together with appropriate allocation of research funding, is needed to successfully address the key clinical and translational research gaps that are highlighted in this Review within the next two decades.

Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.

Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.

Establishment and molecular characterisation of seven novel soft-tissue sarcoma cell lines.

BACKGROUND: Soft-tissue sarcomas (STS) are a diverse group of malignancies that remain a diagnostic and therapeutic challenge. Relatively few reliable cell lines currently exist. Rapidly developing technology for genomic profiling with emerging insights into candidate functional (driver) aberrations raises the need for more models for in vitro functional validation of molecular targets. METHODS: Primary cell culture was performed on STS tumours utilising a differential attachment approach. Cell lines were characterised by morphology, immunocytochemistry, proliferation assays, short tandem repeat (STR) and microarray-based genomic copy number profiling. RESULTS: Of 47 STS cases of various subtypes, half formed adherent monolayers. Seven formed self-immortalised cell lines, including three undifferentiated pleomorphic sarcomas, two dedifferentiated liposarcomas (one of which had received radiotherapy), a leiomyosarcoma and a myxofibrosarcoma. Two morphologically distinct yet genetically identical variants were established in separate cultures for the latter two tumours. All cell lines demonstrated genomic and phenotypic features that not only confirm their malignant characteristics but also confirm retention of DNA copy number aberrations present in their parent tumours that likely include drivers. CONCLUSIONS: These primary cell lines are much-needed additions to the number of reliable cell lines of STS with complex genomics available for initial functional validation of candidate molecular targets.

Modeling the Cost-Effectiveness of Alternative Upper Age Limits for Breast Cancer Screening in England and Wales.

BACKGROUND: Currently in the United Kingdom, the National Health Service (NHS) Breast Screening Programme invites all women for triennial mammography between the ages of 47 and 73 years (the extension to 47-50 and 70-73 years is currently examined as part of a randomized controlled trial). The benefits and harms of screening in women 70 years and older, however, are less well documented. OBJECTIVES: The aim of this study was to examine whether extending screening to women older than 70 years would represent a cost-effective use of NHS resources and to identify the upper age limit at which screening mammography should be extended in England and Wales. METHODS: A mathematical model that allows the impact of screening policies on cancer diagnosis and subsequent management to be assessed was built. The model has two parts: a natural history model of the progression of breast cancer up to discovery and a postdiagnosis model of treatment, recurrence, and survival. The natural history model was calibrated to available data and compared against published literature. The management of breast cancer at diagnosis was taken from registry data and valued using official UK tariffs. RESULTS: The model estimated that screening would lead to overdiagnosis in 6.2% of screen-detected women at the age of 72 years, increasing up to 37.9% at the age of 90 years. Under commonly quoted willingness-to-pay thresholds in the United Kingdom, our study suggests that an extension to screening up to the age of 78 years represents a cost-effective strategy. CONCLUSIONS: This study provides encouraging findings to support the extension of the screening program to older ages and suggests that further extension of the UK NHS Breast Screening Programme up to age 78 years beyond the current upper age limit of 73 years could be potentially cost-effective according to current NHS willingness-to-pay thresholds.

A common coding variant in CASP8 is associated with breast cancer risk.

The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 -202 C --> A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3' UTR A --> G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9-15 studies, comprising 11,391-18,290 cases and 14,753-22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85-0.94) and 0.74 (95% c.i.: 0.62-0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; P(trend) = 1.1 x 10(-7)) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02-1.13) and 1.16 (95% c.i.: 1.08-1.25), respectively; P(trend) = 2.8 x 10(-5)). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies.

The relationship between semaphorin 3C and microvessel density in the progression of breast and oral neoplasia.

This study aimed to identify the expression of semaphorin 3C (SEMA3C) in the normal-metastatic spectrum of breast and oral cancers, and correlate expression with microvessel density (MVD, CD31), a surrogate marker of angiogenesis. Histological analysis revealed that SEMA3C expression was reduced in the development of oral cancer from normal oral tissue (P<0.0001) and expression was inversely correlated with MVD (r=-0.394, P=0.05). In contrast, SEMA3C expression increased in the transition from normal to invasive breast disease in epithelial/tumour cells (P=0.001) and endothelial cells (P=0.006), with both correlating weakly with MVD (r=0.35, p=0.03 and r=0.243, p=0.041 respectively). Furthermore, histological analysis of a breast cancer tissue microarray revealed a weak positive correlation with tumour grade (r=0.305, P=<0.001) and biological phenotype (r=0.237, p=0.004) with tumour cell expression of SEMA3C highest in triple negative and ER-, PR-, HER2+ subtypes. These data suggest that SEMA3C expression is differentially regulated in the development and progression of breast versus oral neoplasia, and that increased expression of SEMA3C may be modulating breast cancer progression and angiogenesis, and could represent a biomarker of metastatic disease.

Neuropilin-1 and neuropilin-2 expression in the adenoma-carcinoma sequence of colorectal cancer.

AIMS: Neuropilin-1 (NRP1) and neuropilin-2 (NRP2) are transmembrane glycoproteins which interact with vascular endothelial growth factor (VEGF) to prevent tumour cell apoptosis and regulate angiogenesis. However, the precise role of NRP1 and NRP2 in the adenoma-carcinoma sequence (ACS) of colorectal cancer remains unclear, and we aimed to determine this in surgical specimens comprising the ACS. METHODS AND RESULTS: Histological analysis demonstrated that epithelial NRP1 expression increased significantly across the ACS (P = 0.0007), and correlated with microvessel density (MVD; r = 0.505, P = 0.0003) and weakly with VEGF (r = 0.251, P = 0.001). In contrast, although NRP2 epithelial expression was increased significantly in all carcinomas (P < 0.002), there was no correlation with MVD, VEGF or NRP1. Furthermore, patients showing coexpression of NRP1 and NRP2 had a potentially worse prognosis than those expressing a single neuropilin or neither one. Although vascular expression of NRP1 increased significantly across the ACS (P = 0.0004) and correlated with MVD (r = 0.361, P = 0.0006), NRP2 vascular expression decreased significantly (P = 0.0001) and showed an inverse correlation with MVD (r=-0.506, P = 0.0001), suggesting differential roles for neuropilins in the angiogenic process during colorectal cancer development. CONCLUSIONS: These data suggest that an increase in NRP1 and NRP2 epithelial/tumour expression, as well as in NRP1 vascular expression, may be associated with disease progression in colorectal cancer.

Anti-angiogenic therapy: concept to clinic.

It has been 40 years since Folkman hypothesized the use of anti-angiogenic therapy as a strategy in the treatment of cancer. Since then, vascular endothelial growth factor (VEGF) has been identified as the most potent cytokine to induce angiogenesis and drugs targeting VEGF, principally the humanized monoclonal antibody bevacizumab and the tyrosine kinase inhibitors sunitinib and sorafenib, have proven therapeutic benefit. The initial high expectations of tumor vascular targeting agents, however, have yet to be fulfilled. In unselected patient populations, the benefits of these agents is often marginal, they cause harmful side effects, and drug resistance is quickly established. Biomarkers to identify patients suitable for anti-angiogenic therapy will be key to the future development of these drugs.

Evaluation of fluorescent plasma markers for in vivo microscopy of the microcirculation.

This study evaluated four fluorescent-protein conjugates to monitor microcirculatory variables using the murine cremaster muscle and determined acute and long-term responses to repeated administration of FITC-BSA [conjugated at the University of Sheffield (UoS)] within a dorsal microcirculatory chamber (DMC) in rats. For analysis of the cremaster muscle, male C3H/HeN mice were anaesthetized, the cremaster muscle was exteriorized, then TRITC-BSA, TRITC-dextran, FITC-BSA, FITC-BSA (UoS) or FITC-dextran (0.25 ml/100 g) were administered systemically. The microcirculation was viewed with epi-illumination every 10 min for 120 min. For analysis of the DMC, male Wistar rats were implanted with the chamber. Three weeks later, FITC-BSA (UoS) was administered systemically, and the microcirculation response was monitored using three different protocols. In addition, in vitro stability of fluorescent conjugates was measured over 8 h. With regard to the cremaster muscle, initially no differences in interstitial fluorescence or vessel diameter were observed between the four fluorescent conjugates. By the end of the study, interstitial fluorescence from TRITC-dextran, FITC-dextran and FITC-BSA (Sigma) was significantly (p < 0.05) increased compared to FITC-BSA (UoS). With regard to the DMC, there was no interstitial fluorescence leakage after 180 min or 5 weeks despite repeated administration, but a significant (p < 0.05) leak was detected between 4 and 24 h. FITC-BSA (UoS) was the most stable fluorescent conjugate both in vitro and in vivo and was comparable with other conjugates for evaluating skeletal muscle microcirculation using fluorescent in vivo microscopy.

A role for XRCC2 gene polymorphisms in breast cancer risk and survival.

BACKGROUND: The XRCC2 gene is a key mediator in the homologous recombination repair of DNA double strand breaks. It is hypothesised that inherited variants in the XRCC2 gene might also affect susceptibility to, and survival from, breast cancer. METHODS: The study genotyped 12 XRCC2 tagging single nucleotide polymorphisms (SNPs) in 1131 breast cancer cases and 1148 controls from the Sheffield Breast Cancer Study (SBCS), and examined their associations with breast cancer risk and survival by estimating ORs and HRs, and their corresponding 95% CIs. Positive findings were further investigated in 860 cases and 869 controls from the Utah Breast Cancer Study (UBCS) and jointly analysed together with available published data for breast cancer risk. The survival findings were further confirmed in studies (8074 cases) from the Breast Cancer Association Consortium (BCAC). RESULTS: The most significant association with breast cancer risk in the SBCS dataset was the XRCC2 rs3218408 SNP (recessive model p=2.3×10(-4), minor allele frequency (MAF)=0.23). This SNP yielded an OR(rec) of 1.64 (95% CI 1.25 to 2.16) in a two-site analysis of SBCS and UBCS, and a meta-OR(rec) of 1.33 (95% CI 1.12 to 1.57) when all published data were included. This SNP may mark a rare risk haplotype carried by two in 1000 of the control population. Furthermore, the XRCC2 coding R188H SNP (rs3218536, MAF=0.08) was significantly associated with poor survival, with an increased per-allele HR of 1.58 (95% CI 1.01 to 2.49) in a multivariate analysis. This effect was still evident in a pooled meta-analysis of 8781 breast cancer patients from the BCAC (HR 1.19, 95% CI 1.05 to 1.36; p=0.01). CONCLUSIONS: These findings suggest that XRCC2 SNPs may influence breast cancer risk and survival.

Occult breast carcinoma in breast reduction specimens in European women.

Breast reduction is a common surgical procedure performed by plastic and oncoplastic breast surgeons. The authors report on the incidence and management of cancer and atypical hyperplasia in breast reduction specimens from one institution over a 10-year period. All patients who underwent breast reduction surgery at Northern General Hospital, Sheffield were identified from an electronic prospective database. The histopathology reports were analyzed. Case records of all patients with significant abnormalities were retrieved and examined to identify their management and follow-up. Between October 1999 and April 2010, 1,588 patients underwent breast reduction. Nine specimens showed atypical hyperplasia (0.57%). Five cancers were detected (0.31%). Four of the five patients had normal screening mammograms 1-3 years before the reduction operation. Of these cancers, four were invasive (three lobular, one ductal) (0.25%) and one was DCIS (0.06%). A lump was felt macroscopically by the pathologist in two of the four patients with invasive cancer. The patients with DCIS did not undergo further surgery, whereas those with invasive disease underwent mastectomy (three patients) and axillary nodal staging (four patients). None of the patients with normal post-reduction breast imaging had residual cancer on histology. The incidence of occult carcinoma in breast reduction specimens is low. Patients should be counseled with regards to the possible consequences preoperatively.

Process evaluation of the Bridging the Age Gap in Breast Cancer decision support intervention cluster randomised trial.

BACKGROUND: The Bridging the Age Gap in Breast Cancer research programme sought to improve treatment decision-making for older women with breast cancer by developing and testing, in a cluster randomised trial (n = 1339 patients), two decision support interventions (DESIs). Both DESIs were used in the intervention arm and each comprised an online risk prediction model, brief decision aid and information booklet. One DESI supported the decision to have either primary endocrine therapy (PET) or surgery with adjuvant therapies and the second supported the decision to have adjuvant chemotherapy after surgery or not. METHODS: Sixteen sites were randomly selected to take part in the process evaluation. Multiple methods of data collection were used. Medical Research Council (MRC) guidelines for the evaluation of complex interventions were used. RESULTS: Eighty-two patients, mean age 75.5 (range 70-93), provided data for the process evaluation. Seventy-three interviews were completed with patients. Ten clinicians from six intervention sites took part in telephone interviews. Dose: Ninety-one members of staff in the intervention arm received intervention training. Reach: The online tool was accessed on 324 occasions by 27 clinicians. Reasons for non-use of the online tool were commonly that the patient had already made a decision or that there was no online access in the clinic. Of the 32 women for whom there were data available, fifteen from the intervention arm and six from the usual care arm were offered a choice of treatment. Fidelity: Clinicians used the online tool in different ways, with some using it during the consultation and others checking the online survival estimates before the consultation. Adaptation: There was evidence of adaptation when using the DESIs. A lack of infrastructure, e.g. internet access, was a barrier to the use of the online tool. The brief decision aid was rarely used. Mediators: Shared decision-making: Most patients felt able to contribute to decision-making and expressed high levels of satisfaction with the process. Participants' responses to intervention: Six patients reported the DESIs to be very useful, one somewhat useful and two moderately useful. CONCLUSIONS: Clinicians who participated were mainly supportive of the interventions and had attempted some adaptations to make the interventions applicable, but there were practical and engagement barriers that led to sub-optimal adoption in routine practice. TRIAL REGISTRATION: ISRCTN46099296 . Registered on 11 August 2016-retrospectively registered.

Age specific recruitment and retention to a large multicentre observational breast cancer trial in older women: The Age Gap Trial.

INTRODUCTION: Recruitment and retention are two of the most important factors in successfully running clinical trials. Many trials encounter problems with both, causing delays or preventing study progress. These issues are greater in older adults and patients with cancer. MATERIALS AND METHODS: We assessed recruitment and retention in a large, multicentre, observational breast cancer study in older female patients (>70 years, N = 3440). Data collected by the Age Gap study were used to assess rates of, and reasons for, patients not being recruited or retained. Statistical analysis assessed the impact of age as a predictor of recruitment and retention. RESULTS: Between February 2013 and June 2018, 6876 patients were screened and 3456 were consented across 56 United Kingdom (UK) breast units. Reasons for non-recruitment included ineligibility, clinician issues, staffing resource issues, patients' lack of interest or time and trial burden. In comparison with the age demographics of patients with breast cancer in the UK, women aged 70-75 years were over-represented compared to older age groups. Logistic regression demonstrated that older age significantly reduced the odds of consent (OR = 0.96, CI: 0.938-0.982; p < 0.001). Multivariate analysis showed that age (p < 0.001), markers of poor functional ability (Eastern Cooperative Oncology Group Performance Status (p = 0.011)) and instrumental activities of daily living (p = 0.026) were significant predictors of withdrawal. DISCUSSION: This study has demonstrated that selection and attrition bias for age are apparent despite a range of 'age friendly' study design measures. Exploration of the underlying reasons for this and development of measures to address this should be the focus of further research.

Bridging the age gap in breast cancer. Impacts of omission of breast cancer surgery in older women with oestrogen receptor positive early breast cancer. A risk stratified analysis of survival outcomes and quality of life.

BACKGROUND: Age-related breast cancer treatment variance is widespread with many older women having primary endocrine therapy (PET), which may contribute to inferior survival and local control. This propensity-matched study determined if a subgroup of older women may safely be offered PET. METHODS: Multicentre, prospective, UK, observational cohort study with propensity-matched analysis to determine optimal allocation of surgery plus ET (S+ET) or PET in women aged ≥70 with breast cancer. Data on fitness, frailty, cancer stage, grade, biotype, treatment and quality of life were collected. Propensity-matching (based on age, health status and cancer stage) adjusted for allocation bias when comparing S+ET with PET. FINDINGS: A total of 3416 women (median age 77, range 69-102) were recruited from 56 breast units-2854 (88%) had ER+ breast cancer: 2354 had S+ET and 500 PET. Median follow-up was 52 months. Patients treated with PET were older and frailer than patients treated with S+ET. Unmatched overall survival was inferior in the PET group (hazard ratio, (HR) 0.27, 95% confidence interval (CI) 0.23-0.33, P < 0.001). Unmatched breast cancer-specific survival (BCSS) was also inferior in patients treated with PET (HR: 0.41, CI: 0.29-0.58, P < 0.001 for BCSS). In the matched analysis, PET was still associated with an inferior overall survival (HR = 0.72, 95% CI: 0.53-0.98, P = 0.04) but not BCSS (HR = 0.74, 95% CI: 0.40-1.37, P = 0.34) although at 4-5 years subtle divergence of the curves commenced in favor of surgery. Global health status diverged at certain time points between groups but over 24 months was similar when adjusted for baseline variance. INTERPRETATION: For the majority of older women with early ER+ breast cancer, surgery is oncologically superior to PET. In less fit, older women, with characteristics similar to the matched cohort of this study (median age 81 with higher comorbidity and functional impairment burdens, the BCSS survival differential disappears at least out to 4-5 year follow-up, suggesting that for those with less than 5-year predicted life-expectancy (>90 years or >85 with comorbidities or frailty) individualised decision making regarding PET versus S+ET may be appropriate and safe to offer. The Age Gap online decision tool may support this decision-making process (https://agegap.shef.ac.uk/). TRIAL REGISTRATION NUMBER: ISRCTN: 46099296.

Observational cohort study in older women with early breast cancer: Use of radiation therapy and impact on health-related quality of life and mortality.

BACKGROUND: Radiotherapy reduces in-breast recurrence risk in early breast cancer (EBC) in older women. This benefit may be small and should be balanced against treatment effect and holistic patient assessment. This study described treatment patterns according to fitness and impact on health-related quality-of-life (HRQoL). METHODS: A multicentre, observational study of EBC patients aged ≥ 70 years, undergoing breast-conserving surgery (BCS) or mastectomy, was undertaken. Associations between radiotherapy use, surgery, clinico-pathological parameters, fitness based on geriatric parameters and treatment centre were determined. HRQoL was measured using the European Organisation for the Research and Treatment of Cancer (EORTC) questionnaires. RESULTS: In 2013-2018 2811 women in 56 UK study centres underwent surgery with a median follow-up of 52 months. On multivariable analysis, age and tumour risk predicted radiotherapy use. Among healthier patients (based on geriatric assessments) with high-risk tumours, 534/613 (87.1%) having BCS and 185/341 (54.2%) having mastectomy received radiotherapy. In less fit individuals with low-risk tumours undergoing BCS, 149/207 (72.0%) received radiotherapy. Radiotherapy effects on HRQoL domains, including breast symptoms and fatigue were seen, resolving by 18 months. CONCLUSION: Radiotherapy use in EBC patients ≥ 70 years is affected by age and recurrence risk, whereas geriatric parameters have limited impact regardless of type of surgery. There was geographical variation in treatment, with some fit older women with high-risk tumours not receiving radiotherapy, and some older, low-risk, EBC patients receiving radiotherapy after BCS despite evidence of limited benefit. The impact on HRQoL is transient.