Digital interventions to moderate physical inactivity and/or nutrition in young people: a Cancer Prevention Europe overview of systematic reviews.

Background: Strategies to increase physical activity (PA) and improve nutrition would contribute to substantial health benefits in the population, including reducing the risk of several types of cancers. The increasing accessibility of digital technologies mean that these tools could potentially facilitate the improvement of health behaviours among young people. Objective: We conducted a review of systematic reviews to assess the available evidence on digital interventions aimed at increasing physical activity and good nutrition in sub-populations of young people (school-aged children, college/university students, young adults only (over 18 years) and both adolescent and young adults (<25 years)). Methods: Searches for systematic reviews were conducted across relevant databases including KSR Evidence (www.ksrevidence.com), Cochrane Database of Systematic Reviews (CDSR) and Database of Abstracts of Reviews of Effects (DARE; CRD). Records were independently screened by title and abstract by two reviewers and those deemed eligible were obtained for full text screening. Risk of bias (RoB) was assessed with the Risk of Bias Assessment Tool for Systematic Reviews (ROBIS) tool. We employed a narrative analysis and developed evidence gap maps. Results: Twenty-four reviews were included with at least one for each sub-population and employing a range of digital interventions. The quality of evidence was limited with only one of the 24 of reviews overall judged as low RoB. Definitions of "digital intervention" greatly varied across systematic reviews with some reported interventions fitting into more than one category (i.e., an internet intervention could also be a mobile phone or computer intervention), however definitions as reported in the relevant reviews were used. No reviews reported cancer incidence or related outcomes. Available evidence was limited both by sub-population and type of intervention, but evidence was most pronounced in school-aged children. In school-aged children eHealth interventions, defined as school-based programmes delivered by the internet, computers, tablets, mobile technology, or tele-health methods, improved outcomes. Accelerometer-measured (Standardised Mean Difference [SMD] 0.33, 95% Confidence Interval [CI]: 0.05 to 0.61) and self-reported (SMD: 0.14, 95% CI: 0.05 to 0.23) PA increased, as did fruit and vegetable intake (SMD: 0.11, 95% CI: 0.03 to 0.19) (review rated as low RoB, minimal to considerable heterogeneity across results). No difference was reported for consumption of fat post-intervention (SMD: -0.06, 95% CI: -0.15 to 0.03) or sugar sweetened beverages(SSB) and snack consumption combined post-intervention (SMD: -0.02, 95% CI:-0.10 to 0.06),or at the follow up (studies reported 2 weeks to 36 months follow-up) after the intervention (SMD:-0.06, 95% CI: -0.15 to 0.03) (review rated low ROB, minimal to substantial heterogeneity across results). Smartphone based interventions utilising Short Messaging Service (SMS), app or combined approaches also improved PA measured using objective and subjective methods (SMD: 0.44, 95% CI: 0.11 to 0.77) when compared to controls, with increases in total PA [weighted mean difference (WMD) 32.35 min per day, 95% CI: 10.36 to 54.33] and in daily steps (WMD: 1,185, 95% CI: 303 to 2,068) (review rated as high RoB, moderate to substantial heterogeneity across results). For all results, interpretation has limitations in terms of RoB and presence of unexplained heterogeneity. Conclusions: This review of reviews has identified limited evidence that suggests some potential for digital interventions to increase PA and, to lesser extent, improve nutrition in school-aged children. However, effects can be small and based on less robust evidence. The body of evidence is characterised by a considerable level of heterogeneity, unclear/overlapping populations and intervention definitions, and a low methodological quality of systematic reviews. The heterogeneity across studies is further complicated when the age (older vs. more recent), interactivity (feedback/survey vs. no/less feedback/surveys), and accessibility (type of device) of the digital intervention is considered. This underscores the difficulty in synthesising evidence in a field with rapidly evolving technology and the resulting challenges in recommending the use of digital technology in public health. There is an urgent need for further research using contemporary technology and appropriate methods.

Digital interventions to moderate alcohol consumption in young people: a Cancer Prevention Europe overview of systematic reviews.

Background: Strategies to reduce alcohol consumption would contribute to substantial health benefits in the population, including reducing cancer risk. The increasing accessibility and applicability of digital technologies make these powerful tools suitable to facilitate changes in behaviour in young people which could then translate into both immediate and long-term improvements to public health. Objective: We conducted a review of systematic reviews to assess the available evidence on digital interventions aimed at reducing alcohol consumption in sub-populations of young people [school-aged children, college/university students, young adults only (over 18 years) and both adolescent and young adults (<25 years)]. Methods: Searches were conducted across relevant databases including KSR Evidence, Cochrane Database of Systematic Reviews (CDSR) and Database of Abstracts of Reviews of Effects (DARE). Records were independently screened by title and abstract and those that met inclusion criteria were obtained for full text screening by two reviewers. Risk of bias (RoB) was assessed with the ROBIS checklist. We employed a narrative analysis. Results: Twenty-seven systematic reviews were included that addressed relevant interventions in one or more of the sub-populations, but those reviews were mostly assessed as low quality. Definitions of "digital intervention" greatly varied across systematic reviews. Available evidence was limited both by sub-population and type of intervention. No reviews reported cancer incidence or influence on cancer related outcomes. In school-aged children eHealth multiple health behaviour change interventions delivered through a variety of digital methods were not effective in preventing or reducing alcohol consumption with no effect on the prevalence of alcohol use [Odds Ratio (OR) = 1.13, 95% CI: 0.95-1.36, review rated low RoB, minimal heterogeneity]. While in adolescents and/or young adults who were identified as risky drinkers, the use of computer or mobile device-based interventions resulted in reduced alcohol consumption when comparing the digital intervention with no/minimal intervention (-13.4 g/week, 95% CI: -19.3 to -7.6, review rated low RoB, moderate to substantial heterogeneity).In University/College students, a range of E-interventions reduced the number of drinks consumed per week compared to assessment only controls although the overall effect was small [standardised mean difference (SMD): -0.15, 95% CI: -0.21 to -0.09]. Web-based personalised feedback interventions demonstrated a small to medium effect on alcohol consumption (SMD: -0.19, 95% CI: -0.27 to -0.11) (review rated high RoB, minimal heterogeneity). In risky drinkers, stand-alone Computerized interventions reduced short (SMD: -0.17, 95% CI: -0.27 to -0.08) and long term (SMD: -0.17, 95% CI: -0.30 to -0.04) alcohol consumption compared to no intervention, while a small effect (SMD: -0.15, 95% CI: -0.25 to -0.06) in favour of computerised assessment and feedback vs. assessment only was observed. No short-term (SMD: -0.10, 95% CI: -0.30 to 0.11) or long-term effect (SMD: -0.11, 95% CI: -0.53 to 0.32) was demonstrated for computerised brief interventions when compared to counsellor based interventions (review rated low RoB, minimal to considerable heterogeneity). In young adults and adolescents, SMS-based interventions did not significantly reduce the quantity of drinks per occasion from baseline (SMD: 0.28, 95% CI: -0.02 to 0.58) or the average number of standard glasses per week (SMD: -0.05, 95% CI: -0.15 to 0.05) but increased the risk of binge drinking episodes (OR = 2.45, 95% CI: 1.32-4.53, review rated high RoB; minimal to substantial heterogeneity). For all results, interpretation has limitations in terms of risk of bias and heterogeneity. Conclusions: Limited evidence suggests some potential for digital interventions, particularly those with feedback, in reducing alcohol consumption in certain sub-populations of younger people. However, this effect is often small, inconsistent or diminishes when only methodologically robust evidence is considered. There is no systematic review evidence that digital interventions reduce cancer incidence through alcohol moderation in young people. To reduce alcohol consumption, a major cancer risk factor, further methodologically robust research is warranted to explore the full potential of digital interventions and to form the basis of evidence based public health initiatives.

Delivering brief physical activity interventions in primary care: a systematic review.

BACKGROUND: Physical activity (PA) brief interventions (BIs) involving screening and/or advice are recommended in primary care but frequency of delivery is unknown. AIM: To examine the extent to which PA BIs are delivered in primary care, and explore factors associated with delivery, receipt, and patient receptivity. DESIGN AND SETTING: A mixed-methods systematic review of studies conducted worldwide, with a narrative synthesis of results. METHOD: CINAHL, EMBASE, MEDLINE, and APA PsycINFO index databases were searched for qualitative and quantitative studies, dating from January 2012 to June 2020, that reported the level of delivery and/or receipt of PA BIs in primary care, and/or factors affecting delivery, receipt, and patient receptivity. Quality was assessed using the Mixed Methods Appraisal Tool. Attitudes towards and barriers to delivery were coded into the Theoretical Domains Framework and the Capability, Opportunity, and Motivation Behaviour model. RESULTS: After screening a total of 13 066 records, 66 articles were included in the review. The extent of PA screening and advice in primary care varied widely (2.4%-100% and 0.6%-100%, respectively). PA advice was delivered more often to patients with a higher body mass index, lower PA levels, and/or more comorbidities. Barriers - including a lack of time and training/guidelines - remain, despite recommendations from the World Health Organization and National Institute for Health and Care Excellence that PA advice should be provided in primary care. Few studies explored patients' receptivity to advice. CONCLUSION: PA BIs are not delivered frequently or consistently in primary care. Addressing barriers to delivery through system-level changes and training programmes could improve and increase the advice given. Understanding when patients are receptive to PA interventions could enhance health professionals' confidence in their delivery.

STROCSS 2021: Strengthening the reporting of cohort, cross-sectional and case-control studies in surgery.

INTRODUCTION: Strengthening The Reporting Of Cohort Studies in Surgery (STROCSS) guidelines were developed in 2017 in order to improve the reporting quality of observational studies in surgery and updated in 2019. In order to maintain relevance and continue upholding good reporting quality among observational studies in surgery, we aimed to update STROCSS 2019 guidelines. METHODS: A STROCSS 2021 steering group was formed to come up with proposals to update STROCSS 2019 guidelines. An expert panel of researchers assessed these proposals and judged whether they should become part of STROCSS 2021 guidelines or not, through a Delphi consensus exercise. RESULTS: 42 people (89%) completed the DELPHI survey and hence participated in the development of STROCSS 2021 guidelines. All items received a score between 7 and 9 by greater than 70% of the participants, indicating a high level of agreement among the DELPHI group members with the proposed changes to all the items. CONCLUSION: We present updated STROCSS 2021 guidelines to ensure ongoing good reporting quality among observational studies in surgery.

Mammographic density, endocrine therapy and breast cancer risk: a prognostic and predictive biomarker review.

BACKGROUND: Endocrine therapy is effective at preventing or treating breast cancer. Some forms of endocrine therapy have been shown to reduce mammographic density. Reduced mammographic density for women receiving endocrine therapy could be used to estimate the chance of breast cancer returning or developing breast cancer in the first instance (a prognostic biomarker). In addition, changes in mammographic density might be able to predict how well a woman responds to endocrine therapy (a predictive biomarker). The role of breast density as a prognostic or predictive biomarker could help improve the management of breast cancer. OBJECTIVES: To assess the evidence that a reduction in mammographic density following endocrine therapy for breast cancer prevention in women without previous breast cancer, or for treatment in women with early-stage hormone receptor-positive breast cancer, is a prognostic or predictive biomarker. SEARCH METHODS: We searched the Cochrane Breast Cancer Group Specialised Register, CENTRAL, MEDLINE, Embase, and two trials registers on 3 August 2020 along with reference checking, bibliographic searching, and contact with study authors to obtain further data. SELECTION CRITERIA: We included randomised, cohort and case-control studies of adult women with or without breast cancer receiving endocrine therapy. Endocrine therapy agents included were selective oestrogen receptor modulators and aromatase inhibitors. We required breast density before start of endocrine therapy and at follow-up. We included studies published in English. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently extracted data and assessed risk of bias using adapted Quality in Prognostic Studies (QUIPS) and Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tools. We used the GRADE approach to evaluate the certainty of the evidence. We did not perform a quantitative meta-analysis due to substantial heterogeneity across studies. MAIN RESULTS: Eight studies met our inclusion criteria, of which seven provided data on outcomes listed in the protocol (5786 women). There was substantial heterogeneity across studies in design, sample size (349 to 1066 women), participant characteristics, follow-up (5 to 14 years), and endocrine therapy agent. There were five breast density measures and six density change definitions. All studies had at least one domain as at moderate or high risk of bias. Common concerns were whether the study sample reflected the review target population, and likely post hoc definitions of breast density change. Most studies on prognosis for women receiving endocrine therapy reported a reduced risk associated with breast density reduction. Across endpoints, settings, and agents, risk ratio point estimates (most likely value) were between 0.1 and 1.5, but with substantial uncertainty. There was greatest consistency in the direction and magnitude of the effect for tamoxifen (across endpoints and settings, risk ratio point estimates were between 0.3 and 0.7). The findings are summarised as follows. Prognostic biomarker findings: Treatment Breast cancer mortality Two studies of 823 women on tamoxifen (172 breast cancer deaths) reported risk ratio point estimates of ~0.4 and ~0.5 associated with a density reduction. The certainty of the evidence was low. Recurrence Two studies of 1956 women on tamoxifen reported risk ratio point estimates of ~0.4 and ~0.7 associated with a density reduction. There was risk of bias in methodology for design and analysis of the studies and considerable uncertainty over the size of the effect. One study of 175 women receiving an aromatase inhibitor reported a risk ratio point estimate of ~0.1 associated with a density reduction. There was considerable uncertainty about the effect size and a moderate or high risk of bias in all domains. One study of 284 women receiving exemestane or tamoxifen as part of a randomised controlled trial reported risk ratio point estimates of ~1.5 (loco-regional recurrence) and ~1.3 (distance recurrence) associated with a density reduction. There was risk of bias in reporting and study confounding, and uncertainty over the size of the effects. The certainty of the evidence for all recurrence endpoints was very low. Incidence of a secondary primary breast cancer Two studies of 451 women on exemestane, tamoxifen, or unknown endocrine therapy reported risk ratio point estimates of ~0.5 and ~0.6 associated with a density reduction. There was risk of bias in reporting and study confounding, and uncertainty over the effect size. The certainty of the evidence was very low. We were unable to find data regarding the remaining nine outcomes prespecified in the review protocol. Prevention Incidence of invasive breast cancer and ductal carcinoma in situ (DCIS) One study of 507 women without breast cancer who were receiving preventive tamoxifen as part of a randomised controlled trial (51 subsequent breast cancers) reported a risk ratio point estimate of ~0.3 associated with a density reduction. The certainty of the evidence was low. Predictive biomarker findings: One study of a subset of 1065 women from a randomised controlled trial assessed how much the effect of endocrine therapy could be explained by breast density declines in those receiving endocrine therapy. This study evaluated the prevention of invasive breast cancer and DCIS. We found some evidence to support the hypothesis, with a risk ratio interaction point estimate ~0.5. However, the 95% confidence interval included unity, and data were based on 51 women with subsequent breast cancer in the tamoxifen group. The certainty of the evidence was low. AUTHORS' CONCLUSIONS: There is low-/very low-certainty evidence to support the hypothesis that breast density change following endocrine therapy is a prognostic biomarker for treatment or prevention. Studies suggested a potentially large effect size with tamoxifen, but the evidence was limited. There was less evidence that breast density change following tamoxifen preventive therapy is a predictive biomarker than prognostic biomarker. Evidence for breast density change as a prognostic treatment biomarker was stronger for tamoxifen than aromatase inhibitors. There were no studies reporting mammographic density change following endocrine therapy as a predictive biomarker in the treatment setting, nor aromatase inhibitor therapy as a prognostic or predictive biomarker in the preventive setting. Further research is warranted to assess mammographic density as a biomarker for all classes of endocrine therapy and review endpoints.

Prognostic and Predictive Value of HER2 Expression in Ductal Carcinoma In Situ: Results from the UK/ANZ DCIS Randomized Trial.

PURPOSE: HER2 is overexpressed more frequently in ductal carcinoma in situ (DCIS) than in invasive breast cancer but its prognostic significance and predictive role for radiotherapy has not been clearly established. We investigated the prognostic and predictive value of HER2 overexpression in DCIS. EXPERIMENTAL DESIGN: HER2 expression was evaluated by IHC using the HercepTest™ in samples from UK/ANZ DCIS trial participants (n = 755) with IHC 3+ expression categorized as HER2 positive for primary analyses. Sensitivity analyses included HER2 categorization as negative (IHC 0,1+), equivocal (IHC 2+), and positive (IHC 3+) and analyses restricted to a nested case-control component where 181 cases (with recurrence) were matched to 362 controls by treatment arm and age. RESULTS: Two-hundred and forty-five (34.4%) of evaluable 713 samples [181 ipsilateral breast events (IBE)] were HER2 positive. HER2 overexpression was associated with significantly increased risk of IBE [HR = 2.29; 95% confidence interval (95% CI), 1.64-3.14; P < 0.0001] and in situ IBE (DCIS-IBE; HR = 2.90; 95% CI, 1.91-4.40; P < 0.0001), but not of invasive IBE (I-IBE; HR = 1.40; 95% CI, 0.81-2.42; P = 0.23; Pheterogeneity = 0.04). Inclusion of HER2 significantly improved [Δχ2 (1d.f.) 12.25; P = 0.0005] a prognostic model of clinicopathological and treatment variables, HER2 being an independent predictor of IBE (multivariate HR = 1.91; 95% CI, 1.33-2.76; P = 0.0004). Radiotherapy benefit in preventing DCIS-IBE was significantly greater (Pheterogeneity = 0.04) in HER2-positive DCIS (HR = 0.16; 95% CI, 0.07-0.41) compared with HER2-negative DCIS (HR = 0.58; 95% CI, 0.28-1.19). CONCLUSIONS: HER2 overexpression is associated with significantly increased risk of in situ recurrence and is also predictive of radiotherapy benefit, with greater reductions in in situ but not invasive recurrences in HER2-positive DCIS.

Prognostic Value of ER and PgR Expression and the Impact of Multi-clonal Expression for Recurrence in Ductal Carcinoma in situ: Results from the UK/ANZ DCIS Trial.

PURPOSE: The prognostic value of estrogen receptor (ER)/progesterone receptor (PgR) expression in ductal carcinoma in situ (DCIS) is unclear. We observed multi-clonality when evaluating ER/PgR expression in the UK/ANZ DCIS trial, therefore, we investigated the prognostic role of both uni-clonal and multi-clonal ER/PgR expression in DCIS. EXPERIMENTAL DESIGN: Formalin-fixed paraffin embedded tissues were collected from UK/ANZ DCIS trial participants (n = 755), and ER/PgR expression was evaluated by IHC in 181 cases (with recurrence) matched to 362 controls by treatment arm and age. Assays were scored by the Allred method and by a newly devised clonal method-analyses categorizing multi-clonal DCIS as ER/PgR-positive as per current practice (Standard) and as ER/PgR-negative (clonal) were performed. RESULTS: ER expression was multi-clonal in 11% (39/356) of ER-positive (70.6%, 356/504) patients. Ipsilateral breast event (IBE) risk was similarly higher in ER-multi-clonal and ER-negative DCIS as compared with DCIS with uni-clonal ER expression. ER-negative DCIS (clonal) had a higher risk of in situ IBE [OR 4.99; 95% confidence interval (CI), 2.66-9.36; P < 0.0001], but the risk of invasive IBE was not significantly higher (OR 1.72; 95% CI, 0.84-3.53; P = 0.14), P heterogeneity = 0.03. ER was an independent predictor in multivariate analyses (OR 2.66; 95% CI, 1.53-4.61). PgR status did not add to the prognostic information provided by ER. CONCLUSIONS: ER expression is a strong predictor of ipsilateral recurrence risk in DCIS. ER-positive DCIS with distinct ER-negative clones has a recurrence risk similar to ER-negative DCIS. ER should be routinely assessed in DCIS, and ER scoring should take clonality of expression into account.

Breast cancer prevention in high-risk women.

Women at high risk of developing breast cancer are a heterogeneous group of women including those with and without high-risk germline mutation/s. Prevention in these women requires a personalised and multidisciplinary approach. Preventive therapy with selective oestrogen receptor modulators (SERMs) like tamoxifen and aromatase inhibitors (AIs) substantially reduces breast cancer risk well beyond the active treatment period. The importance of benign breast disease as a marker of increased breast cancer risk remains underappreciated, and although the benefit of preventive therapy may be greater in such women, preventive therapy remains underutilised in these and other high-risk women. Bilateral Risk-Reducing Mastectomy (BRRM) reduces the risk of developing breast cancer by 90% in high-risk women such as carriers of BRCA mutations. It also improves breast cancer-specific survival in BRCA1 carriers. Bilateral risk-reducing salpingo-oophorectomy may also reduce risk in premenopausal BRCA2 carriers. Further research to improve risk models, to identify surrogate biomarkers of preventive therapy benefit and to develop newer preventive agents is needed.

Quantitative nuclear histomorphometric features are predictive of Oncotype DX risk categories in ductal carcinoma in situ: preliminary findings.

BACKGROUND: Oncotype DX (ODx) is a 12-gene assay assessing the recurrence risk (high, intermediate, and low) of ductal carcinoma in situ (pre-invasive breast cancer), which guides clinicians regarding prescription of radiotherapy. However, ODx is expensive, time-consuming, and tissue-destructive. In addition, the actual prognostic meaning for the intermediate ODx risk category remains unclear. METHODS: In this work, we evaluated the ability of quantitative nuclear histomorphometric features extracted from hematoxylin and eosin-stained slide images of 62 ductal carcinoma in situ (DCIS) patients to distinguish between the corresponding ODx risk categories. The prognostic value of the identified image signature was further evaluated on an independent validation set of 30 DCIS patients in its ability to distinguish those DCIS patients who progressed to invasive carcinoma versus those who did not. Following nuclear segmentation and feature extraction, feature ranking strategies were employed to identify the most discriminating features between individual ODx risk categories. The selected features were then combined with machine learning classifiers to establish models to predict ODx risk categories. The model performance was evaluated using the average area under the receiver operating characteristic curve (AUC) using cross validation. In addition, an unsupervised clustering approach was also implemented to evaluate the ability of nuclear histomorphometric features to discriminate between the ODx risk categories. RESULTS: Features relating to spatial distribution, orientation disorder, and texture of nuclei were identified as most discriminating between the high ODx and the intermediate, low ODx risk categories. Additionally, the AUC of the most discriminating set of features for the different classification tasks was as follows: (1) high vs low ODx (0.68), (2) high vs. intermediate ODx (0.67), (3) intermediate vs. low ODx (0.57), (4) high and intermediate vs. low ODx (0.63), (5) high vs. low and intermediate ODx (0.66). Additionally, the unsupervised clustering resulted in intermediate ODx risk category patients being co-clustered with low ODx patients compared to high ODx. CONCLUSION: Our results appear to suggest that nuclear histomorphometric features can distinguish high from low and intermediate ODx risk category patients. Additionally, our findings suggest that histomorphometric features for intermediate ODx were more similar to low ODx compared to high ODx risk category.

Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 2: Approaches to Predict and Identify Late Recurrence, Research Directions.

Late disease recurrence (more than 5 years after initial diagnosis) represents a clinical challenge in the treatment and management of estrogen receptor-positive breast cancer (BC). An international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. The underlying biological causes of late recurrence are complex, with the processes governing cancer cell dormancy, including immunosurveillance, cell proliferation, angiogenesis, and cellular stemness, being integral to disease progression. These critical processes are described herein as well as their role in influencing risk of recurrence. Moreover, observational and interventional clinical trials are proposed, with a focus on methods to identify patients at risk of recurrence and possible strategies to combat this in patients with estrogen receptor-positive BC. Because the problem of late BC recurrence of great importance, recent advances in disease detection and patient monitoring should be incorporated into novel clinical trials to evaluate approaches to enhance patient management. Indeed, future research on these issues is planned and will offer new options for effective late recurrence treatment and prevention strategies.

Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 1: Late Recurrence: Current Understanding, Clinical Considerations.

Disease recurrence (locoregional, distant) exerts a significant clinical impact on the survival of estrogen receptor-positive breast cancer patients. Many of these recurrences occur late, more than 5 years after original diagnosis, and represent a major obstacle to the effective treatment of this disease. Indeed, methods to identify patients at risk of late recurrence and therapeutic strategies designed to avert or treat these recurrences are lacking. Therefore, an international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. In this article, the major issues surrounding late recurrence are defined and current approaches that may be applicable to this challenge are discussed. Specifically, diagnostic tests with potential utility in late-recurrence prediction are described as well as a variety of patient-related factors that may influence recurrence risk. Clinical and therapeutic approaches are also reviewed, with a focus on patient surveillance and the implementation of extended endocrine therapy in the context of late-recurrence prevention. Understanding and treating late recurrence in estrogen receptor-positive breast cancer is a major unmet clinical need. A concerted effort of basic and clinical research is required to confront late recurrence and improve disease management and patient survival.

Preventing invasive breast cancer using endocrine therapy.

Developments in breast cancer treatment have resulted in reduction in breast cancer mortality in the developed world. However incidence continues to rise and greater use of preventive interventions including the use of therapeutic agents is needed to control this burden. High quality evidence from 9 major trials involving more than 83000 participants shows that selective oestrogen receptor modulators (SERMs) reduce breast cancer incidence by 38%. Combined results from 2 large trials with 8424 participants show that aromatase inhibitors (AIs) reduce breast cancer incidence by 53%. These benefits are restricted to prevention of ER positive breast cancers. Restricting preventive therapy to high-risk women improves the benefit-harm balance and many guidelines now encourage healthcare professionals to discuss preventive therapy in these women. Further research is needed to improve our risk-prediction models for the identification of high risk women for preventive therapy with greater accuracy and to develop surrogate biomarkers of response. Long-term follow-up of the IBIS-I trial has provided valuable insights into the durability of benefits from preventive therapy, and underscores the need for such follow up to fully evaluate other agents. Full utilisation of preventive therapy also requires greater knowledge and awareness among both doctors and patients about benefits, harms and risk factors. Healthcare professionals should routinely discuss preventive therapy with women at high-risk of breast cancer.

Individualised benefit-harm balance of aspirin as primary prevention measure - a good proof-of-concept, but could have been better .

Guidelines from different organisations regarding the use of aspirin for primary prevention vary despite being based on similar evidence. Translating these in practice presents a further major challenge. The benefit-harm balance tool developed by Puhan et al. (BMC Med 13:250, 2015) for aspirin can overcome some of these difficulties and is therefore an important step towards personalised medicine. Although a good proof-of-concept, this tool has some important limitations that presently preclude its use in practice or for further research. One of the major benefits of aspirin that has become apparent in the last decade or so is its effect in preventing cancer and cancer-related deaths. However, this benefit is clear and consistent in randomised as well as observational evidence only for specific cancers. Additionally, it has long lag-time and carry-over periods. These nuances of aspirin's effects demand a specific and a more sophisticated model such as a time-varying model. Further refinement of this tool with respect to these aspects is merited to make it ready for evaluation in qualitative and quantitative studies with the goal of clinical utility.Please see related article: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-015-0493-2.