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Current evidence from both randomized trials and real-world studies suggests that older patients with advanced hormone receptor-positive/HER2-negative (HR+/HER2) breast cancer derive clinical benefit from the addition of CDK4/6 inhibitors to endocrine therapy. However, a higher risk for adverse events due to CDK4/6 inhibitors among older patients is evident, leading to a trend of initiating CDK4/6 inhibitors at lower dose in clinical practice, though without evidence. The aim of the IMPORTANT-trial, a pragmatic, multinational, open-label, partly decentralized randomized trial is to investigate whether lower starting dose of CDK4/6 inhibitors combined with endocrine therapy is comparable to full dose in older (≥70 years old) patients with advanced HR+/HER2- breast cancer who are assessed as vulnerable or frail based on comprehensive geriatric assessment. Clinical Trial Registration:NCT06044623 (ClinicalTrials.gov); Registration date: 13 September 2023. Article highlights Breast cancer treatment overview in older patients In patients with advanced hormone receptor- (HR-) positive/HER2-negative breast cancer, the combination of endocrine therapy with CDK4/6 inhibitors is the standard of care as initial treatment approach. Older cancer patients are underrepresented in clinical trials, including pivotal trials on CDK4/6 inhibitors. Real-world evidence studies have showed that older patients are at increased risk for adverse events when treated with implementation of CDK4/6 inhibitors; lower initial dose is common in clinical practice, though without evidence. Comprehensive geriatric assessment (CGA) seems to be a reliable tool for the optimization of treatment strategy in older cancer patients. IMPORTANT trial design IMPORTANT is pragmatic, multi-national, open-label, partly de-centralized randomized trial investigating whether a lower initial dose of CDK4/6 inhibitors combined with endocrine therapy is comparable to a full dose in older (≥70 years old) patients with advanced HR+/HER2- breast cancer that are assessed as vulnerable or frail based on CGA. Eligible patients are older female or male patients (≥70 years old) with advanced HR-positive/HER2-negative breast cancer, not amenable for curative treatment and without prior therapy for advanced disease. The follow-up strategy in terms of treatment efficacy and toxicity resembles the current follow-up strategy in clinical practice without additional blood tests or radiological examinations. The follow-up will include toxicity evaluation before each treatment cycle as well as clinical and radiological evaluation of treatment efficacy every 3 months. Patient-reported outcomes will be captured through self-questionnaires during the study period. A total of 495 patients are to be enrolled with 30-month accrual period with aim to recruit 149 patients for the fit cohort to be treated and followed, and 346 patients for the vulnerable/ frail cohort to be randomized. Categorization & randomization in IMPORTANT trial Patients will be categorized based on self-reported CGA to fit or vulnerable/frail depending on domains of age metrics that are impaired. Patients categorized as vulnerable/frail will be randomized (1:1) to -1 level lower initial dose or full dose of CDK 4/6 inhibitors combined with endocrine therapy. Stratification factors during randomization are the type of CDK4/6 inhibitor used (palbociclib vs ribociclib vs abemaciclib), the type of endocrine therapy (aromatase inhibitors vs fulvestrant) and the level of vulnerability based on CGA (vulnerable vs frail). IMPORTANT trial end points The primary end point is time-to-treatment failure; secondary end points include overall treatment utility, investigator-assessed progression-free survival, overall survival, time to chemotherapy initiation, toxicity, quality-of-life (QoL), time to QoL deterioration and cost-effectiveness. [ABSTRACT FROM AUTHOR]

Background and Purpose: While the prevalence of older breast cancer patients is rapidly increasing, these patients are greatly underrepresented in clinical trials. We discuss barriers to recruitment of older patients to clinical trials and propose solutions on how to mitigate these challenges and design optimal clinical trials through the paradigm of IMPORTANT trial., Patients and Methods: This is a narrative review of the current literature evaluating barriers to including older breast cancer patients in clinical trials and how mitigating strategies can be implemented in a pragmatic clinical trial., Results: The recognized barriers can be roughly divided into trial design-related (e.g. the adoption of strict inclusion criteria, the lack of pre-specified age-specific analysis), patient-related (e.g. lack of knowledge, valuation of the quality-of-life instead of survival, transportation issues), or physician-related (e.g. concern for toxicity). Several strategies to mitigate barriers have been identified and should be considered when designing a clinical trial dedicated to older patients with cancer. The pragmatic, de-centralized IMPORTANT trial focusing on dose optimization of CDK4/6 -inhibitors in older breast cancer patients is a paradigm of a study design where different mitigating strategies have been adopted., Interpretation: Because of the existing barriers, older adults in clinical trials are considerably healthier than the average older patients treated in clinical practice. Thus, the study results cannot be generalized to the older population seen in daily clinical practice. Broader inclusion/exclusion criteria, offering telehealth visits, and inclusion of patient-reported, instead of physician-reported outcomes may increase older patient participation in clinical trials.

Background: Patient reported outcomes (PROs) have an integral role on how to improve patients' overall experience. The optimal PROs delivery in patients with breast disease is an important issue since PROs are steadily integrated in routine care., Methods: An institutional phase 3 randomised controlled, open-label trial. Eligible candidates were adult women with perceived or confirmed breast disease. Computer generated randomization was used to allocate interventions: collection of PROs in electronic or paper form. Our objective was the effectiveness of electronic versus paper form of PROs. The main outcome measures were: response rate, reported experience, administrative resources, and carbon dioxide emissions., Results: Two hundred thirty-eight patients were randomised. After loss-to-follow-up and consent withdrawals, 218 participants (median age, IQR=55, 21; n =110/ n =108) were included in the per-intention-to-treat analysis. Response rate was 61.8% for electronic patient reported outcomes (ePROs) and 63.9% for paper patient reported outcomes (pPROs) (difference=-2.1%, 95% CI: -15.8-11.7%). Only known breast cancer at recruitment was predictive for response in multivariable analysis. ePROs were associated with a 57% reduction in administrative time required, a 95% reduction in incremental costs, and 84% reduction in carbon dioxide emissions, all differences being significant. No difference was detected in perception of PRO significance or ease of completion, but participants experienced that they needed less time to complete ePROs [median, (IQR) 10 (9) respectively 15(10)]. Finally, respondents would prefer ePROs over pPROs (difference 48.1%, 95% CI: 32.8-63.4%)., Conclusion: ePROs do not increase the response rate in patients with perceived or confirmed breast disease. However, they can enhance patient experience, reduce incremental costs, facilitate administrative logistics, and are more sustainable. On the basis of these findings, both modalities should continue to be available., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)