Ongoing unmet needs in treating estrogen receptor-positive/HER2-negative metastatic breast cancer

•Efficacy of later-line endocrine therapy for breast cancer diminishes over time.•Prolonging time to onset of endocrine resistance may delay need for chemotherapy.•Improving both patient survival and health-related quality of life is essential.•There is an unmet need to enhance the efficacy of later-line endocrine treatments.•Combining endocrine and targeted therapies may optimize treatment outcomes. Estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2−) advanced or metastatic breast cancer (MBC) is the most common MBC subtype and currently remains incurable, with a median overall survival of 24.8 months (95% confidence interval, 21.3–30.3). Common sites of metastases are bone, viscera, and brain, causing significant symptoms that negatively affect patient functioning, quality of life (QoL), and work productivity. Guidelines state that endocrine therapy (ET) is preferable to chemotherapy as first-line treatment for patients with ER+ MBC, regardless of limited visceral metastases, unless rapid tumor response is required or ET resistance is suspected. Although response rates up to 40% have been reported for first-line MBC treatment, the majority of initial responders eventually develop ET resistance. Notwithstanding the steep decline in efficacy between first and later lines of ET, some patients may receive chemotherapy earlier than necessary. Although new treatments have been approved for patients with ER+/HER2− advanced or MBC in the past decade, neither survival nor QoL appear to have improved significantly. Thus, there remain significant unmet needs for this patient population, including improved survival, maintaining or improving patient QoL, and emphasizing the importance of treatment selection to assist healthcare practitioners managing patient care. In this review, we identify current challenges and unmet needs in this patient population, review cutting-edge treatments, and provide clinically relevant suggestions for treatment selection that can optimize outcomes and patients’ health-related QoL.