Endocrine sensitive metastatic breast cancer and bone only disease: are the new treatments always better?

The standard first-line for endocrine sensitive metastatic breast cancer (BC) is represented by endocrine therapy. Several phase III clinical trials searched for more effective strategies. The SWOG, FACT and FALCON trials analyzed the role of Fulvestrant (Fv), producing contradictory results. The Monaleesa2, Monaleesa7, Monarch3 and Paloma2 trials showed that the addition of a CDK4/6 inhibitor to an aromatase inhibitor (AI) increases the PFS. The use of the combination for the first-line treatment of bone-only disease (BoD) is widely discussed. Our meta-analysis aims to explore the role of the new endocrine strategies in BoD. The Prisma statement was used. A systematic review of electronic databases identified the phase III clinical trials comparing the standard AI to a novel experimental strategy. The hazard ratios (HR) for PFS for the subgroup of BoD were pooled in a meta-analysis. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. 7 studies were included in the analyses. 4 trials explored the role of CDK4/6 inhibitors (Monaleesa2 and 7, Monarch3 and Paloma2), 2 trials analyzed Fv + AI (SWOG and FACT), while one trial studied Fv monotherapy (FALCON). 5 trials reported data regarding the BoD, while 2 trials included the BoD in the non-visceral disease. Overall, the meta-analyses showed a PFS advantage for the experimental arms [HR 0.67 p 0.01], with a significant moderate/high heterogeneity [I2 69.88% p 0.003]. Only the FALCON and Paloma2 showed a significant improvement in PFS, respectively for Fv and Palbociclib + Letrozole. Considering only trials reporting data for BoD, the experimental arms significantly improved the PFS [HR 0.60 p 0.001], with a low/ moderate non-significant heterogeneity [I2 37.73% p 0.17]. The meta-analyses of trials reporting data for BoD, showed that the novel strategies are able to improve the PFS. Nonetheless, only Palbociclib + Letrozole provided statistically significant data of advantage in this setting. In clinical trials, BoD is often included in the non-visceral disease subgroup. Future clinical trials should take into account the differences in natural history and better prognosis of BoD, in order to define the best approach to these patients.