**5. Conclusion**

with exemestane (HR 0.52, p = 0.02). Patients with *ESR1* wild type had similar benefit given either drug. PALOMA3 is a study that compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after prior endocrine therapy. Plasma ctDNA analysis showed *ESR1* mutation rate of 25%, of which 28% where polyclonal. Fulvestrant plus palbociclib gave rise to better PFS compared with fulvestrant alone in both *ESR1* mutant (HR 0.43, p = 0.002) and *ESR1* wild type patients (0.49, p < 0.001) [63]. Analysis of ctDNA from the BOLERO2 study also supported that *ESR1* mutation can be found in around 30% of patients who have failed prior endocrine therapy [50]. Patients with *ESR1* mutation had shorted OS

While fulvestrant is non-inferior to AI in the first line setting, more data on OS is awaited. Yet emerging evidence suggest that testing of *ESR1* mutation could probably guide us in the choice of hormonal therapy in patients who have failed prior endocrine therapy. The approach is limited by the availability of ctDNA analysis, sensitivity of different ctDNA methodology, often difficult-to-obtain tissue biopsy upon the time of progression, and accessibility

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

compared with wild type. This study did not involve the use of fulvestrant.

to *ESR1* test in local laboratory as it is still not a standard practice.

172 Breast Cancer and Surgery

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

Although we are becoming increasingly equipped to overcome resistance to hormonal therapy, these treatment would fail nevertheless. The preliminary OS data for the phase II PALOMA-1 trial was presented in June 2017. It showed that the median OS was 37.5 months in patients who received palbociclib and AI versus 34.5 months in those who received AI (HR 0.897) [67], suggesting the impressive gain in median PFS after adding palbociclib might not translate into long term survival. Interestingly, analysis of OS for BELL2 appears to be trending toward similar observation. The median OS for patients who received buparlisib and fulvestrant versus those who received placebo and fulvestrant was 33.2 and 30.4 months respectively (HR 0.87; 95% CI, 0.74 to 1.02; p = 0.045) [68]. Even in patients who had PI3K pathway activated or PIK3CA mutation, the improvement in median PFS with addition of buparlisib did not translate into better median OS (HR 0.81, p > 0.05). These might be explained by two reasons. Firstly, post-progression survival can be affected by availability and effectiveness of subsequent therapy. Second, progression on CDK4/6 inhibitor might have selected out patients who then became refractory to other treatment especially chemotherapy. More understanding in the mechanism of resistance to hormonal therapy and targeted therapy is needed to overcome these barriers.

HR+ve/HER2−ve MBC is the most common type of breast cancer. The main stay of treatment is hormonal therapy, and the choice of hormonal therapy includes SERM, AI, and SERD. SERD might play a more important role in selected patients, as development of *ESR1* mutation could render patients resistant to AI. Addition of targeted therapy such as CDK4/6 inhibitor or mTOR inhibitor can help prolong the use of hormonal therapy, and should be part of standard treatment for all patients in their treatment journey. Future research would focus on strategies to overcome resistance to these therapies.
