The simultaneous impact of breast cancer therapy on the heart beyond the left ventricle (LV) and its prognostic implications are not understood. Our objective was to determine how breast cancer therapy affects all four cardiac chambers; whether patient clusters based on similarities in changes in multi-chamber measures have different prognosis; and how these patient clusters could be differentiated. In a secondary analysis of a prospectively recruited cohort of women with early-stage human epidermal growth factor receptor 2-positive (HER2+) breast cancer receiving anthracycline and trastuzumab, we performed echocardiography before treatment and every three months (six studies) to assess cardiac chamber size and function (volumes, ejection fraction, longitudinal strain) of all four cardiac chambers (EchoInsight®). Prognostic measures were cardiovascular magnetic resonance (CMR) defined cancer therapy related cardiac dysfunction (CTRCD), and peak oxygen uptake (VO_2peak). Network partition analysis identified patterns in multi-chamber temporal changes and a random forest algorithm evaluated the relative predictive importance of the chamber measures for CTRCD. Amongst 136 women (51.1±9.2 years); three main related patterns of temporal changes in echocardiography measures were identified during treatment: (i) worsening function of all four chambers, (ii) left chambers remodeling, and (iii) right chambers remodeling. Based on similarities in multi-chamber changes, three patient clusters were identified. When further characterized, the three clusters differed in their CTRCD incidence (3%, 7%, and 27%, p=0.004) and post-trastuzumab percentage VO_2peak predicted (92.1% (76.9-100.5), 82.5% (70.2-92.7), and 75.3% (66.4-91.2), respectively, p=0.040). The highest risk group could be identified by early large simultaneous worsening of multi-chamber function. Non-LV parameters had similar or higher relative contribution to CTRCD prediction compared with LV parameters. In this hypothesis generating study, we demonstrate that breast cancer therapy impacts the size and function of all four cardiac chambers. Monitoring multi-chamber function may improve CTRCD risk assessment beyond LV evaluation alone. This approach may be particularly attractive for future artificial intelligence-based echocardiographic algorithms.