Background: Dose dense adjuvant chemotherapy is the preferred treatment option in high-risk early breast cancer patients. We report the updated results of the MIG-1 study comparing the efficacy of fluorouracil, epirubicin and cyclophosphamide (FEC) regimen administered every 3 (FEC21) or every 2 (FEC14) weeks in early breast cancer patients. Methods: In this Italian, open-label, multicentre phase III randomized trial, node positive and high-risk node negative breast cancer patients were randomised to receive 6 cycles of FEC21 or FEC14 (including support with a granulocyte colony-stimulating factor). The study primary end-point was overall survival (OS) and secondary endpoint was event-free survival (EFS). Results: From November 1992 to June 1997, 1214 patients were randomly assigned to receive FEC14 (n ¼ 604) or FEC21 (n ¼ 610). Median follow-up was 15.8 years. 15-year OS was 68% (95% CI 64-72) in FEC21 group and 71% (95% CI 67-75) in FEC14 group (HR ¼ 1.13; 95% CI 0.92-1.40; p ¼ 0.25). 15-year EFS was 43% (95% CI 37-48) in FEC21 group and 47% (95% CI 41-52) in FEC14 group (HR ¼ 1.13; 95%CI 0.94-1.35; p ¼ 0.19).In a pre-planned subgroup analysis, among patients with hormone receptor-negative tumors, 15-year OS was 65% (95% CI 58-72) in FEC21 group and 70% (95% CI 63-77) in FEC14 group (HR ¼ 1.34; 95% CI 0.94-1.92; p ¼ 0.11; p interaction ¼0.25); 15-year EFS was 43% (95% CI 33-52) in FEC21 group and 58% (95% CI 48-67) in FEC14 group (HR ¼ 1.47; 95% CI 1.08-2.01; p ¼ 0.016; p interaction ¼0.02). No differences between the two regimes was observed in patients with hormone receptor-positive tumors. Conclusions: Updated results from the MIG1 study did not show a significant benefit with the use of dose-dense FEC chemotherapy in early breast cancer patients; EFS was prolonged with the use of dose-dense chemotherapy in patients with hormone receptor-negative disease.

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Introduction Previous studies have shown that available tools such as ‘Adjuvant Online!” are not able to accurately predict the prognosis of patients aged 65 years or older with breast cancer. Furthermore, all available tools predict prognosis in terms of recurrence-free survival or overall survival, whilst the risk of other-cause mortality is often high in the older patient with breast cancer. This is highly relevant as it may influence treatment decisions. Patient characteristics such as comorbidity and various geriatric variables have shown to be predictive for these outcomes and could enhance the precision of prognostic tools for this target population. The objective of this study was to develop a prediction tool for recurrence, survival and other-cause mortality for older patients with breast cancer who received locoregional treatment, with incorporation of patient-, tumor- and geriatric variables. The tool additionally predicts expected benefits of systemic treatment. Methods Data from the large population-based FOCUS cohort was used, consisting of consecutive breast cancer patients in the South-Western part of the Netherlands, diagnosed between 1997 and 2004, aged 65 years and older. It contains detailed information on tumor characteristics, treatment, comorbidity and geriatric parameters. We developed a risk prediction model using a Cox proportional hazards regression model for overall survival and cause-specific Cox proportional hazards models for recurrence and other-cause mortality (defined as mortality without recurrence). The included predictors were derived from the PREDICT tool (consisting of age and various tumor variables), since this tool was previously shown to have the best performance in older adults so far. Predictors were complemented with comorbidity and geriatric variables. Discrimination accuracy was evaluated using time-dependent area under the curve (AUC). The potential annual benefit of chemotherapy was calculated assuming a relative risk of chemotherapy on recurrence of 0.7, derived from data from the most recent updates of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Additional benefit of endocrine treatment will be included in further development of the tool. Results A total of 2,744 patients were included for the initial development. For all patients, 5-year follow-up was complete with a high event-rate including 343 recurrences and 831 total deaths of which 586 without recurrence. The strongest predictors for overall survival and non-recurrence mortality were age (HR = 2.14, 95% CI: 1.89 - 2.43 and HR = 2.87, 95% CI: 2.46 - 3.35, respectively) and dementia (HR = 1.52, 95% CI: 1.16 - 1.99 and HR = 1.9, 95% CI: 1.49 - 2.65, respectively), and for recurrence, nodal status (HR = 1.80, 95% CI: 1.45 - 2.24) and tumor grade (HR = 2.96, 95% CI: 1.88 - 4.66). The time-dependent AUC at 5 years for recurrence-specific and other-cause mortality were 0.78 (95% CI: 0.76 - 0.81), and 0.75 (95% CI: 0.72 - 0.78), respectively. The AUC for overall survival was 0.75 (95% CI: 0.72 - 0.78). External validation is currently being performed in a large dataset retrieved from the national cancer registry (N= 13,631). These results will be presented during the symposium. Conclusion We have developed a model for predicting 5-year recurrence, other-cause mortality and overall survival, including expected benefits of adjuvant treatment, for older patients with breast cancer, with a good discrimination performance within a large-population based cohort. To our knowledge, this is the first model specifically designed for the older population, including competing risk as a predicted outcome and with incorporation of geriatric variables. Citation Format: Willeke van der Plas-Krijgsman, Daniele Giardiello, Hein Putter, Ewout W Steyerberg, Esther Bastiaannet, Anne M Stiggelbout, Simon P Mooijaart, Johanneke EA Portielje, Gerrit J Liefers, Nienke A de Glas. The PORTRET-tool: A prediction tool for older patients with breast cancer that predicts recurrence, survival and other-cause mortality [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-08.

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