Endocrine therapy with or without CDK4/6 inhibitors is the most commonly used frontline treatment option for metastatic hormone receptor-positive breast cancer. Approximately, 25% to 30% of women may have resistance to endocrine therapy, especially in the setting of certain genomic mutations in the tumor. This prompts the need to identify those patients who may benefit from frontline chemotherapy over endocrine therapy. Here, we present a case of a patient who presented with a de novo metastatic hormone receptor-positive breast cancer with visceral involvement (including bone marrow) as well as multiple somatic genomic alterations. The patient was treated with upfront chemotherapy, resulting in clinical and radiographic response, but rapidly progressed when she was transitioned to hormonal therapy. This report focuses on the role of upfront chemotherapy in the setting of visceral crisis including bone marrow involvement, the role of genomic alterations in contributing to endocrine resistance, and the need for biomarker-driven treatment options for hormone receptor-positive breast cancer.