Predictive markers of everolimus efficacy in hormone receptor positive (HR+) metastatic breast cancer (MBC): Final results of the TAMRAD trial translational study.

Abstract

510 Background: Hormone resistance is linked in part to cross-talk between ER signalling and PI3K/Akt/mTOR pathway. Following results of the BOLERO-2 trial, everolimus (E), a potent mTOR inhibitor, has recently been approved in combination with exemestane in women with HR+ MBC refractory to aromatase inhibitor (AI). However, E is frequently associated with specific toxicities, and predictive markers of efficacy are needed. We report here the final results of translational studies within the TAMRAD randomized Phase II trial, comparing tamoxifen (TAM) to TAM+E in AI pre-treated MBC. Methods: Tumor samples from 51 patients among the 111 treated in the TAMRAD trial were retrieved. Hot spot mutations of PI3K (exon 9-20), and KRAS (exon 2) were described. TMA analysis evaluated IHC expression of PTEN, pAkt, PI3K, LKB1, S6K, pS6K, 4EBP1, p4EBP1, and eIF4E. Exploratory analysis of E efficacy in each biomarker subgroup (high vs low expression defined by median percentage of marked cells) was done. Results: Patients characteristics and treatment efficacy among this sub-population were similar to the results from the whole population: Time to progression was 10 months for the TAM+E treated patients vs. 5.5 months for the TAM treated patients, HR: 0.59 (95% CI 0.33-1.07). PI3K-Akt pathway: All patients derived benefit from E regardless of PI3K mutational status, PTEN or pAkt expression. Surprisingly, E efficacy was greater in patients with low PI3K expression (n=12, HR=0.11, 95%CI 0.01-0.96) than in patients with high PI3K expression (n= 28, HR=0.9; 95%CI 0.49-2.41) PI3K independent pathway: Patients with low expression of the anti-oncogene LKB1 derived greater benefit from E (n=22, HR=0.33; 95%CI 0.13-0.89) than patients with high LKB1 expression (n=25, HR=0.75; 95%CI 0.32-1.74) mTOR downstream effectors: Patients with high p4EBP1 (n=27, HR=0.37; 95%CI 0.15-0.90) or low 4EBP1 (n=21, HR=0.39; 95%CI 0.14-1.08) were the subgroups most likely to benefit from E. Conclusions: Those results are in favor of a better efficacy of E for patients with PI3K independent activation of mTOR. If confirmed, they could have important implications for future patient selection. Clinical trial information: NCT01298713.