ESR1 and breast cancer: As an example, ESR1 activating mutations are rarely present in primary ER + breast cancer, even in those 15–20% patients that show intrinsic resistance to hormonal therapies22,38,39, whereas they are highly enriched in ER + metastatic tumour samples from patients with acquired endocrine resistance (30–40% of ER + patients) and in particular, are a known mechanism of resistance to aromatase inhibitors (AI)40–42.