Tailored guidance to apply the Estimand framework to Trials within Cohorts (TwiCs) studies.

Objective: The estimand framework offers a structured approach to define the treatment effect to be estimated in a clinical study. Defining the estimand upfront helps formulating the research question and informs study design, data collection and statistical analysis methods. Since the Trials within Cohorts (TwiCs) design has unique characteristics, the objective of this study is to describe considerations and provide guidance for formulating estimands for TwiCs studies. Methods: The key attributes of an estimand are the target population, treatments that are compared, the endpoint, intercurrent events and their handling, and the population-level summary measure. The estimand framework was applied retrospectively to two TwiCs studies: the SPONGE and UMBRELLA Fit trial. The aim is to demonstrate how the estimand framework can be implemented in TwiCs studies, thereby focusing on considerations relevant for defining the estimand. Three estimands were defined for both studies. For the SPONGE trial, estimators were derived. Results: Intercurrent events considered to occur exclusively or more frequently in TwiCs studies compared to conventional randomized trials included intervention refusal after randomization, misalignment of timing of routine cohort measurements and the intervention period, and participants in the control arm initiating treatments similar to the studied intervention. Considerations for handling refusal after randomization related to decisions on whether the target population should include all eligible participants or the subpopulation that would accept (or undergo) the intervention when offered. Considerations for handling treatment initiation in the control arm and misalignments of timing related to decisions on whether such events should be considered part of treatment policy or whether interest is in a hypothetical scenario where such events do not occur. Conclusion: The TwiCs study design has unique features that pose specific considerations when formulating an estimand. The examples in this study can provide guidance in the definition of estimands in future TwiCs studies.

Cyclophosphamide exposure assessed with the biomarker phosphoramide mustard-hemoglobin in breast cancer patients: The TailorDose I study.

Cyclophosphamide (CPA) dosing by body surface area (BSA, m2) has been questioned as a predictor for individual drug exposure. This study investigated phosphoramide mustard-hemoglobin (PAM-Hb, pmol g-1 Hb) as a biomarker of CPA exposure in 135 female breast cancer patients receiving CPA during three courses based on BSA: 500 mg/m2 (C500 group, n = 67) or 600 mg/m2 (C600 group, n = 68). The inter-individual difference was calculated for both groups by dividing the highest through the lowest PAM-Hb value of each course. The inter-occasion difference was calculated in percentage for each individual by dividing their PAM-Hb value through the group mean per course, and subsequently dividing this ratio of the latter through the previous course. A multivariable linear regression (MLR) was performed to identify factors that explained the variation of PAM-Hb. During the three courses, the inter-individual difference changed from 3.5 to 2.1 and the inter-occasion difference ranged between 13.3% and 11.9% in the C500 group. In the C600 group, the inter-individual difference changed from 2.7 to 2.9 and the inter-occasion difference ranged between 14.1% and 11.7%. The MLR including BSA, age, GFR, and albumin explained 17.1% of the variation of PAM-Hb and was significantly better then the model including only BSA. These factors should be considered when calculating the first dose of CPA for breast cancer patients.

Risk of death from cardiovascular disease following breast cancer: a systematic review.

PURPOSE: Breast cancer incidence and survival is high, which results in high prevalence of breast cancer survivors. The risk of (death from) cardiovascular disease (CVD) is higher in patients exposed to cardiotoxic treatments, in particular if they have pre-existing CVD risk factors. This study systematically summarized the risk of death from CVD following breast cancer. METHODS: Databases of Medline, Embase, and the Cochrane Library were systematically searched using the following terms and synonyms: breast cancer, cardiovascular disease, and cause of death. Articles reporting on both risk and risk factors of CVD mortality following breast cancer were eligible for inclusion. The methodological quality of each article was assessed using the Newcastle Ottawa quality assessment scale for cohort studies. RESULTS: Fourteen articles were included assessing the risk of CVD mortality among 1,217,910 women with breast cancer. The methodological quality was high for the majority of the studies. Studies were heterogeneous in design, study population, length of follow-up, CVD outcomes, and risk factors. 1.6-10.4% of all women with breast cancer died of CVD. Women with breast cancer had a higher risk of CVD mortality than women from the general population. The risk of CVD mortality was higher among women with breast cancer with older age at diagnosis, left-sided tumor, diagnosis in an earlier calendar period, and black ethnic origin. CONCLUSIONS: CVD is an important cause of death following breast cancer. Identification of patients at high risk of CVD is important to optimize CVD prevention and tailor breast cancer treatment.

Risk of death from cardiovascular disease following breast cancer in Southeast Asia: a prospective cohort study.

Breast cancer incidence and survival is high in Southeast Asia. As such, many women diagnosed with breast cancer are at risk of dying of other causes. Given the increased risk of cardiotoxicity induced by breast cancer treatments, it is important to identify patients at high risk of cardiovascular disease (CVD) mortality. The aim of this study was to investigate if this risk varies by age and ethnicity. Patient details were obtained from 5,868 Chinese, Malay, and Indian women diagnosed with in situ or non-metastasized invasive breast cancer at the National University Hospital of Singapore and KK Women's and Children's Hospital in Singapore. Death causes were obtained from the National Registry of Births and Deaths. Flexible parametric survival models estimated CVD mortality rates and hazard ratios. During a median follow-up of six years, 1,010 deaths occurred of which 6.8% were due to CVD. CVD mortality rates of older women peaked within the first year following diagnosis and increased over time since diagnosis. Indian had more than double the risk of CVD mortality than Chinese, independent of age at diagnosis and stage. Taking ethnicity and age into account may promote CVD risk stratification and management in (Southeast Asian) women with breast cancer.