**4. The sequence of endocrine therapy and targeted drugs**

AI has been the standard of care for first line treatment of patients with HR+ve/HER2−ve MBC. The role of fulvestrant has been controversial. Due to the high cost, the need for monthly injection, and similar efficacy in the first line setting, fulvestrant is often an option rather than the preferred choice. Yet much remained to be learnt from this SERD. In the phase 3 FALCON trial, patients given monthly injection of fulvestrant at 500 mg had borderline statistically longer median PFS of 16.6 months (95% CI, 13.83–20.99) compared with those of 13.8 months (95% CI, 11.99–16.59) given oral anastrozole 1 mg daily (HR 0.797, 95% CI, 0.637–0.999; p = 0.0486) [6]. This approach showed that the ceiling PFS ceiling of hormonal therapy could be stretched to 20 months in some patients. More interestingly, subgroup analysis suggested that most of the survival benefit was derived from patients who had bone-only metastatic disease, with a median PFS of 22.3 month in the fulvestrant group versus 13.8 months in the anastrozole group (HR 0.59; 95 CI, 042–0.84). Reanalysis of SOG S0226 according to prior exposure to adjuvant adjuvant tamoxifen, showed that those without prior endocrine exposure had longer median PFS when given fulvestrant compared with anastrozole (16.7 versus 12.7 months; HR 0.73; 95% CI, 0.60–0.89, p = 0.002), which further translated into improved median OS by 1 year (40.3 versus 52.2 months, p = 0.0067) [64]. With the emergence of new treatment option of multiple CDK4/6 inhibitors, and the increasing financial burden associated with them, the practical questions would be how to choose the first line hormonal therapy. There have been international guidelines to lay the general clinical principle that treatment recommendation should be based on if the patient is naïve to endocrine therapy, the type of adjuvant therapy, length of disease free interval and if disease relapsing less than 12 months from the end of adjuvant AI [65, 66]. More updated and detailed guidelines are anticipated in light of new findings.

As to the choice of agent in the second line setting or beyond, the choice would largely depend on prior treatment. Some general principles are becoming apparent. First of all, there is enough data to suggest that CDK4/6 inhibitor should be part of standard treatment in patients with HR+ve/HER2−ve MBC, be it first line (PALOMA-2, MONALEESA-2, MONARCH-3, MONALEESA-7), second line (PALOMA-3, MONARCH-2), or later line in refractory cases (MONARCH-1). Since PI3K/AKT/mTOR plays an important role in hormonal resistance, mTOR inhibitor should also be considered in all patients. The only approved choice currently is everolimus. For the choice of hormonal partner in patients who have progressed on or failed prior AI, testing of *ESR1* mutation status might provide some guidance as to if switching to SERD would be helpful. It is still not clear if patients who progress on first line CDK4/6 inhibitors should be continued this targeted agent with a switch of hormonal partner. Chemotherapy should be reserved for patients who have exhausted the options for hormonal therapy and these targeted therapies, or patients with impending visceral crisis.
