Background The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94•7% (95% CI 92•5-96•2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age.Methods MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18-70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0-1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinicalpathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005-002625-31. Recruitment is complete and further long-term follow-up is ongoing.

Summary Background 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov , NCT03471494 . Findings Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding National Institute for Health Research Global Health Research Unit.

506 Background: The 70-gene signature MammaPrint has been shown to identify breast cancer patients for whom adjuvant chemotherapy (CT) could be safely omitted even in the presence of unfavorable standard clinical-pathological criteria. The MINDACT primary endpoint at 5 years median follow-up was met in 2016 (Cardoso et al, NEJM 2016) with a distant metastasis free survival (DMFS) rate at 5 years of 94.7% (95% CI: 92.5-96.2) in clinical high (C-High) / genomic low (G-Low) risk patients who received no CT. Longer follow-up is now available. Methods: 6693 patients were enrolled in the prospective phase III randomized MINDACT study (EORTC 10041/BIG3-04) between 2007-2011. We assessed the DMFS rate at 5 years in the primary test (PT) population of C-High / G-Low patients who were randomized to receive no CT (n = 644). As secondary analysis, we evaluated DMFS and overall survival (OS) in the intention to treat (ITT) population of the C-High / G-Low group randomized to CT vs no CT (n = 749 and 748 respectively). Comparisons between CT and no CT groups are low-powered. We used Kaplan-Meier estimates for time to event endpoints and hazard ratios (HR) with 95% CI from cox-regression models adjusted for stratification factors used for the randomization. Results: The median follow-up is 8.7 years, resulting in an updated 5-year DMFS rate for the PT population of C-High / G-Low patients with no CT of 95.1% (95% CI 93.1-96.6). The updated outcomes of the ITT population of C-High / G-Low patients are shown in the table. Further analyses will update the suggested age-dependent effect of CT omission for luminal breast cancer seen at 5 years in pre- versus post-menopausal women as in Tailor-X (Piccart et al, SABCS 2019). Conclusions: The primary DMFS endpoint at 5 years continues to be met in CT untreated C-High / G-Low risk women, confirming MINDACT as a positive de-escalation study. With longer follow-up and in line with the natural history of luminal breast cancer, more distant relapses do occur but the estimated gain of 2.6% for CT administration in C-High / G-Low patients remains small in light of CT harmful effects. The level IA evidence for the clinical utility of the 70-gene signature for adjuvant CT decision making is maintained. Clinical trial information: NCT00433589 . [Table: see text]

PURPOSE Patients with 70-gene signature ultralow-risk breast cancers have shown excellent survival in historic cohorts, including randomized trials. The ultralow-risk subgroup was characterized to help avoid overtreatment. We evaluated outcomes of ultralow-risk patients in the largest cohort to date. METHODS Of the 6,693 patients enrolled in the EORTC-10041/BIG-3-04 randomized phase III MINDACT trial, profiling revealed an ultralow-risk 70-gene signature in 1,000 patients (15%). Distant metastasis-free interval (DMFI) and breast cancer–specific survival (BCSS) were assessed in patients stratified by 70-gene signature result (high, low, and ultralow) by Kaplan-Meier analysis and hazard ratios with 95% CI from Cox regression. RESULTS Median follow-up was 8.7 years. Of the ultralow-risk patients (n = 1,000), 67% were > 50 years, 81% had tumors ≤ 2 cm, 80% were lymph node–negative, 96% had grade 1 or 2 tumors, and 99% were estrogen receptor (ER)-positive. Systemic therapy was received by 84% of patients (69% endocrine therapy, 14% endocrine therapy plus chemotherapy, 1% other) and 16% received no adjuvant systemic treatment. The 8-year DMFI for ultralow-risk patients was 97.0% (95% CI, 95.8 to 98.1), which was 2.5% higher than for patients with low-risk tumors (n = 3,295, 94.5% [95% CI, 93.6 to 95.3]). The hazard ratio for DMFI was 0.65 (95% CI, 0.45 to 0.94) for ultralow versus low risk, after adjusting for clinical-pathologic and treatment characteristics. The 8-year BCSS for ultralow-risk patients was 99.6% (95% CI, 99.1 to 100). CONCLUSION Patients with an ultralow-risk 70-gene signature have the best prognosis, distinctive from low risk, with 8-year BCSS above 99%, and very few patients developed distant metastases with an 8-year DMFI rate of 97%. These patients could be candidates for further de-escalation of treatment, to avoid overtreatment and the risk of side effects.