In this thesis, different strategies to optimize therapy for patients with breast cancer are evaluated, either by escalating therapy when necessary or by de-escalating therapy when possible. De-escalating therapy may be possible for patients with a low risk of recurrence and patients with an exceptionally good response to therapy. This reduces morbidity and hence improves quality of life. Therapy should be escalated when necessary to improve efficacy in selected patients with either a high risk of recurrence, insufficient response to therapy or patients with metastatic breast cancer, who are likely to achieve long-term remission, such as patients with oligometastatic breast cancer or patients with HER2-positive metastatic breast cancer. Some of our most valuable observations include: – In small node-negative tumors chemotherapy was associated with better survival but the effect was most evident in patients with tumors >1 cm and might not outweigh harms in patients with smaller tumors. The latter group are therefore candidates to de-escalate therapy. – Oligometastatic breast cancer has a favorable prognosis compared to metastatic breast cancer in general and three or less metastases seems the ideal cut-off to define oligometastatic breast cancer. This allows better selection of patients to escalate therapy. – In patients with HER2-positive metastatic breast cancer, achieving radiological complete remission was the strongest predictor for survival and trastuzumab may be discontinued (de-escalated) in selected patients after achieving radiological complete remission. – Insight into the biology of oligometastatic breast cancer and HER2-positive metastatic breast cancer by a detailed characterization of the tumor immune-microenvironment that can further guide optimization of therapy.