Estimating the Complier Average Causal Effect for Exponential Survival in the Presence of Mid-Trial Switching

The intention-to-treat (ITT) rate ratio estimator is conservatively biased for the treatment effect among compliers (who stick with their assigned arm) when individuals switch treatment in two-arm randomised trials. In this article we propose simple ways to estimate the complier average causal effect (CACE) with mid-trial switching. The estimators use aggregate data of events and times rather than individualised data. The motivating model considers survival times as exponentially distributed conditional on whether the individual would comply with randomisation. To estimate the CACE the ante-switch treatment effect and the post-switch treatment effect amongst the compliers are combined. Furthermore, we discuss ways of estimating the counterfactual intent-to-treat (ITT) effect, which is defined as the rate ratio if switching was not permitted. This approach might be a useful alternative to CACE estimation, and so a time and event adjustment of the non-compliers data is developed. Finally, simulated switching scenarios are used to illustrate the importance of correcting for informative switching

International study into the use of intermittent hormone therapy in the treatment of carcinoma of the prostate : A meta-analysis of 1446 patients

OBJECTIVE: To review pooled phase II data to identify features of different regimens of intermittent hormone therapy (IHT), developed to reduce the morbidity of treating metastatic prostate cancer, and which carries a theoretical advantage of delaying the onset of androgen-independent prostate cancer, (AIPC) that are associated with success, highlighting features which require exploration with prospective trials to establish the best strategies for using this treatment. METHODS: Individual data were collated on 1446 patients with adequate information, from 10 phase II studies with >50 cases, identified through Pubmed. RESULTS: Univariate and multivariate Cox proportional hazard models were developed to predict treatment success with a high degree of statistical success. The prostate-specific antigen (PSA) nadir, the PSA threshold to restart treatment, and medication type and duration, were important predictors of outcome. CONCLUSIONS: The duration of biochemical remission after a period of HT is a durable early indicator of how rapidly AIPC and death will occur, and will make a useful endpoint in future trials to investigate the best ways to use IHT based on the important treatment cycling variables described above. Patients spent a mean of 39% of the time off treatment. The initial PSA level and PSA nadir allow the identification of patients with prostate cancer in whom it might be possible to avoid radical therapy.Peer reviewe

Breast density predicts endocrine treatment outcome in the adjuvant setting

PMCID: PMC3680935See related research article by Kim et al., http://breast-cancer-research.com/content/14/4/R10

Bone versus breast density

The common link with oestrogen levels suggests that bone mineral density and mammographic density might also be linked. One study found weak support for this, but another study failed to provide confirmation. Overall, the relationship is very weak, if it exists at all. Other factors such as weight-bearing exercise, which have opposing impacts on these variables, may have a more dominant effect

Increased cardiovascular mortality more than fifteen years after radiotherapy for breast cancer: a population-based study.

BACKGROUND: Breast radiotherapy as practised in the 1970s and 1980s resulted in significant myocardial exposure, and this was higher when the left breast was treated. It has been proposed that this difference might result in greater cardiovascular mortality following irradiation of the left breast when compared with the right. METHODS: All cases of female breast cancer diagnosed between 1971 and 1988 and recorded on the Thames Cancer Registry database were followed up to the end of 2003 to identify cases who had died from ischaemic heart disease (IHD) or any cardiovascular disease (CVD). A proportional hazards regression analysis was performed, stratified by time since diagnosis, using as the baseline group those women with right-sided disease who did not receive radiotherapy, and adjusting for age at diagnosis. RESULTS: A total of 20,871 women with breast cancer were included in the analysis, of which 51% had left-sided disease. Mortality at 15+ years after diagnosis was increased in recipients of left-breast radiotherapy compared to non-irradiated women with right-sided breast cancer, both for IHD (hazard ratio 1.59; 95% confidence interval 1.21-2.08; p = 0.001) and all CVD (hazard ratio 1.27; 95% confidence interval 1.07-1.51; p = 0.006). When irradiated women with left-sided breast cancer were compared with irradiated women with right-sided breast cancer, cardiovascular mortality at 15+ years after diagnosis was raised by around 25% (IHD: hazard ratio 1.23; 95% confidence interval 0.95-1.60; p = 0.114; CVD: hazard ratio 1.25; 95% confidence interval 1.05-1.49; p = 0.014). CONCLUSION: We have found an elevation in cardiovascular mortality more than 15 years after breast radiotherapy in women diagnosed with breast cancer between 1971 and 1988. The risk was greater following irradiation of the left breast compared with the right. This confirms that radiotherapy as practised in the 1970s and 1980s has resulted in significant long-term cardiac toxicity. In absolute terms, the increase in cardiovascular mortality induced by radiotherapy may be substantial, as these mortality events are relatively common.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Uptake of breast cancer preventive therapy in the UK: results from a multicentre prospective survey and qualitative interviews

Purpose: Uptake of preventive therapy for women at increased breast cancer risk in England is unknown following the introduction of UK clinical guidelines in 2013. Preventive therapy could create socioeconomic inequalities in cancer incidence if it is more readily accepted by particular socio-demographic groups. In this multicentre study, we investigated uptake of tamoxifen and evaluated socio-demographic and clinical factors associated with initiation. We explored women’s experiences of treatment decision-making using qualitative interview data. Methods: Between September 2015 and December 2016, women (n=732) attending an appointment at one of 20 centres in England to discuss breast cancer risk were approached to complete a survey containing socio-demographic details and nulliparity. Of the baseline survey respondents (n=408/732, 55.7% response rate), self-reported uptake of tamoxifen at 3-month follow-up was reported in 258 (63.2%). Sixteen women participated in semi-structured interviews. Results: One in seven (38/258=14.7%) women initiated tamoxifen. Women who had children were more likely to report use of tamoxifen than those without children (OR=5.26; 95%CI: 1.13–24.49, p=0.035). Interview data suggested that women weigh up risks and benefits of tamoxifen within the context of familial commitments, with exposure to significant other’s beliefs and experiences of cancer and medication a basis for their decision. Conclusions: Uptake of tamoxifen is low in clinical practice. There were no socio-demographic differences in uptake, suggesting that the introduction of breast cancer preventive therapy is unlikely to create socioeconomic inequalities in cancer incidence. Women’s decision-making was influenced by familial priorities, particularly having children

External validation of a mammographic texture marker for breast cancer risk in a case–control study

Purpose: The pattern of dense tissue on a mammogram appears to provide additional information than overall density for risk assessment, but there has been little consistency in measures of texture identified. The purpose of this study is thus to validate a mammographic texture feature developed from a previous study in a new setting. Approach: A case–control study (316 invasive cases and 1339 controls) of women in Virginia, USA was used to validate a mammographic texture feature (MMTEXT) derived in a independent previous study. Analysis of predictive ability was adjusted for age, demographic factors, questionnaire risk factors (combined through the Tyrer-Cuzick model), and optionally BI-RADS breast density. Odds ratios per interquartile range (IQ-OR) in controls were estimated. Subgroup analysis assessed heterogeneity by mode of cancer detection (94 not detected by mammography). Results: MMTEXT was not a significant risk factor at 0.05 level after adjusting for classical risk factors (IQ-OR  =  1.16, 95%CI 0.92 to 1.46), nor after further adjustment for BI-RADS density (IQ-OR  =  0.92, 95%CI 0.76 to 1.10). There was weak evidence that MMTEXT was more predictive for cancers that were not detected by mammography (unadjusted for density: IQ-OR  =  1.46, 95%CI 0.99 to 2.15 versus 1.03, 95%CI 0.79 to 1.35, Phet 0.10; adjusted for density: IQ-OR  =  1.11, 95%CI 0.70 to 1.77 versus 0.76, 95%CI 0.55 to 1.05, Phet 0.21). Conclusions: MMTEXT is unlikely to be a useful imaging marker for invasive breast cancer risk assessment in women attending mammography screening. Future studies may benefit from a larger sample size to confirm this as well as developing and validating other measures of risk. This negative finding demonstrates the importance of external validation

Factors Predicting Late Recurrence for Estrogen Receptor-Positive Breast Cancer

This is a pre-copy-editing, author-produced PDF of an article accepted for publication in JNCI: Journal of the National Cancer Institute following peer review. The definitive publisher-authenticated version of 'Sestak, Ivana, et al. "Factors Predicting late recurrence for estrogen receptor–Positive Breast cancer." Journal of the National Cancer Institute (2013): djt244' is available online at: http://dx.doi.org/10.1093/jnci/djt24

Future possibilities in the prevention of breast cancer: Breast cancer prevention trials

The available results from breast cancer chemoprevention trials are reviewed. Four trials using tamoxifen have been performed, of which three have reported efficacy results. A fifth trial using raloxifene has also been reported. The largest tamoxifen trial showed approximately 50% reduction in breast cancer incidence in the short term, but the two smaller trials did not find any reduction. Greater agreement exists for side effects; incidences of thromboembolic disease and endometrial cancers are raised approximately threefold when tamoxifen is used for 5 years. The possible reasons for the discrepancy in breast cancer reduction are explored. A review of trial parameters does not clearly explain this difference, and a meta-analysis indicates that all results are compatible with a 40% reduction in short-term incidence. Several important questions remain regarding the clinical implications of this result, including the effect on mortality, the appropriate risk groups for chemoprevention and the long-term effects on incidence. Continued follow up of these trials is crucial for resolving these issues