Molecular screening using next generation sequencing (NGS) with the aim of guiding therapy for patients with refractory cancer, is becoming increasingly more common in clinical practice. Given that tumors with alterations in PI3K/ATK/mTOR (PI3K) pathway exhibit sensitivity to mTOC1 inhibitor everolimus, everolimus is often off-label used to target PI3K pathway. However, efficacy of off-label-use of everolimus in refractory breast cancer is unknown. We conducted this retrospective study to assess the efficacy of molecular matched off-label use of everolimus for refractory breast cancer patients with mutations in PI3K pathway, compared with conventional therapy.
Patients with refractory metastatic breast cancer who received NGS with the aim of guiding therapy between 2015 and 2017, were screened for eligibility at two sites in China. Patients with mutations in PI3K pathway and treated with everolimus-based or conventional therapy were included. Everolimus was used outside its indications. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall response rate (ORR), disease control rate (DCR) and safety profile.
33 patients with mutations in PI3K pathway were included in this analysis. 18 (54.5%) patients were hormone receptor positive and 14 (42.4%) patients were HER2 positive. 20 patients received everolimus-based therapy and 13 patients received conventional therapy. The PFS was shorter in everolimus group than conventional group (median, 2.05 vs 6.1 months; HR, 4.45; 95% CI, 1.64-12.10; P = 0.0016). ORR was 14.3% (2/14) in everolimus group and 23.1% (3/13) in conventional group (P = 0.648). DCR was 35.7% (5/14) in everolimus group and 100% (13/13) in conventional group (P = 0.001). The incidence of grade 3 or worse treatment-related adverse event was similar between groups (5 [38.5%] of 13 in everolimus group, 5 [25.0%] of 20 in conventional group, P = 0.393).
The off-label use of everolimus to target the PI3K/AKT/mTOR pathway is associated with poorer outcome in patients with refractory breast cancer. These data suggests that off-label use of everolimus to target PI3K/AKT/mTOR should not be encouraged.
Clinical trial identification
Legal entity responsible for the study
Yongmei Yin, Xiaojia Wang.
National Natural Science Foundation of China.
All authors have declared no conflicts of interest.