Aims Anthracyclines increase heart failure (HF) risk, but the long‐term prevalence of myocardial dysfunction in young breast cancer (BC) survivors is unknown. Early measures of left ventricular myocardial dysfunction are needed to identify BC patients at risk of symptomatic HF. Methods and results Within an established cohort, we studied markers for myocardial dysfunction among 569 women, who were 5–7 years (n = 277) or 10–12 years (n = 292) after BC treatment at ages 40–50 years. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were assessed by echocardiography. N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) was measured in serum. Associations between patient‐related and treatment‐related risk factors and myocardial dysfunction were evaluated using linear and logistic regression. Median ages at BC diagnosis and cardiac assessment were 46.7 and 55.5 years, respectively. Anthracycline‐treated patients (n = 313), compared to the no‐anthracycline group (n = 256), more often had decreased LVEF (10% vs. 4%), impaired GLS (34% vs. 27%) and elevated NT‐proBNP (23% vs. 8%). GLS and LVEF declined in a linear fashion with increasing cumulative anthracycline dose (GLS: +0.23 and LVEF: −0.40 per cycle of 60 mg/m2; P < 0.001) and GLS was worse for patients with left breast irradiation. The risk of NT‐proBNP >125 ng/L was highest for patients who received 241–300 mg/m2 anthracycline dose compared to the no‐anthracycline group (odds ratio: 3.30, 95% confidence interval: 1.83–5.96). Conclusion Impaired GLS and increased NT‐proBNP levels are present in a substantial proportion of young BC survivors treated with anthracyclines. Whether this will lead to future cardiac disease needs to be evaluated by longitudinal assessment.

Treatment for cancer has improved in the last decades, resulting in a significantly reduced morbidity and mortality. 1-3 Unfortunately, many systemic treatment options are associated with an increased risk of adverse cardiac effects. 4 These adverse cardiac effects have given rise to the field of cardiooncology. This review summarizes recent findings related to the pathophysiology and treatment of drug-induced cardiac dysfunction in cancer treatment and looks ahead at new developments in the field.

IMPORTANCE Trials of adjuvant high-dose chemotherapy (HDCT) have failed to show a survival benefit in unselected patients with breast cancer, but long-term follow-up is lacking. OBJECTIVE To determine 20-year efficacy and safety outcomes of a large trial of adjuvant HDCT vs conventional-dose chemotherapy (CDCT) for patients with stage III breast cancer. DESIGN, SETTING, AND PARTICIPANTS This secondary analysis used data from a randomized phase 3 multicenter clinical trial of 885 women younger than 56 years with breast cancer and 4 or more involved axillary lymph nodes conducted from August 1, 1993, to July 31, 1999. Additional follow-up data were collected between June 1, 2016, and December 31, 2017, from medical records, general practitioners, the Dutch national statistical office, and nationwide cancer registries. Analysis was performed on an intention-to-treat basis. Statistical analysis was performed from February 1, 2018, to October 14, 2019. INTERVENTIONS Participants were randomized 1:1 to receive 5 cycles of CDCT consisting of fluorouracil, 500 mg/m 2 , epirubicin, 90 mg/m 2 , and cyclophosphamide, 500 mg/m 2 , or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m 2 , thiotepa, 480 mg/m 2 , and carboplatin, 1600 mg/m 2 , followed by hematopoietic stem cell transplant. MAIN OUTCOMES AND MEASURES Main end points were overall survival and safety and cumulative incidence risk of a second malignant neoplasm or cardiovascular events. RESULTS Of the 885 women in the study (mean [SD] age, 44.5 [6.6] years), 442 were randomized to receive HDCT, and 443 were randomized to receive CDCT. With 20.4 years median follow-up (interquartile range, 19.2-22.0 years), the 20-year overall survival was 45.3% with HDCT and 41.5% with CDCT (hazard ratio, 0.89; 95% CI, 0.75-1.06). The absolute improvement in 20-year overall survival was 14.6% (hazard ratio, 0.72; 95% CI, 0.54-0.95) for patients with 10 or more invoved axillary lymph nodes and 15.4% (hazard ratio, 0.67; 95% CI, 0.42-1.05) for patients with triple-negative breast cancer. The cumulative incidence risk of a second malignant neoplasm at 20 years or major cardiovascular events was similar in both treatment groups (20-year cumulative incidence risk for second malignant neoplasm was 12.1% in the HDCT group vs 16.2% in the CDCT group, P = .10), although patients in the HDCT group more often had hypertension (21.7% vs 14.3%, P = .02), hypercholesterolemia (15.7% vs 10.6%, P = .04), and dysrhythmias (8.6% vs 4.6%, P = .005). CONCLUSIONS AND RELEVANCE High-dose chemotherapy provided no long-term survival benefit in unselected patients with stage III breast cancer but did provide improved overall survival in very high-risk patients (ie, with Ն10 involved axillary lymph nodes). High-dose chemotherapy did not affect long-term risk of a second malignant neoplasm or major cardiovascular events. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03087409

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