The antitumor activity of AKT inhibitors is being investigated for the treatment of BC with activation of the PI3K/AKT pathway. Putative predictive biomarkers that are being tested in ongoing trials are PTEN loss/mutation (mut) (around 40% of triple negative BC) and AKT1 mutation (4-5% ER+/HER2- BC). The BEECH trial is evaluating the activity of the pan-AKT1/2/3 inhibitor (AKTi) AZD5363 in combination with the antimicrotubule agent paclitaxel in HER2-negative (HER2-) metastatic BC. We aimed to identify response biomarkers to the single agent AKTi and its degree of synergy in combination with paclitaxel, using HER2- patient-derived tumor xenografts (PDX).
Fifteen PDX have been established from BC patients receiving standard treatment at our Hospital, as well as from those participating in the BEECH trial, when sample was available, by implanting their tumor biopsies at baseline, on-treatment and at progression. The antitumor activity of AZD5363 as single agent and in combination with paclitaxel has been measured in these PDX. Genotyping and protein levels have been analyzed by exome sequencing, capture-based sequencing, Western blot and immunohistochemistry (IHC).
AZD5363 monotherapy results in disease stabilization or tumor regression in 3 out of 15 PDX (2/9 ER-/HER2- and 1/6 ER+/HER2-). We found a positive association between high levels of pAKT S473 by Western blot and antitumor response. Interestingly, the two ER-/HER2- responding PDX harbor a PTEN frameshift mutation or gene loss concomitant with an activating mutation within the PI3K pathway (PIK3CA or PIK3R1). The ER+/HER2- PDX responder harbors an AKT1-p.E17K mutation. AZD5363 plus paclitaxel, at a clinically relevant dose, results in disease stabilization in 2/11 PDX that progress to either single agent (1/7 ER-/HER2- and 1/4 ER+/HER2-); the latter PDX being derived from the baseline tumor biopsy of a BEECH trial patient who benefited from this combination for one year.
Altogether these results suggest that double-altering events in the PI3K pathway, including PTEN loss/mut and a second PI3K-pathway alteration in ER-/HER2- tumors, or AKT1-p.E17K in ER+/HER2- tumors, and consequent high pAkt S473 levels could be associated with intrinsic sensitivity to AKT inhibition. The predictive value of these alterations as determinants of response to AKTi deserves further investigation.
Citation Format: Albert Gris-Oliver, Mafalda Oliveira, Marta Guzman, Olga Rodríguez, Judit Grueso, Maurizio Scaltriti, William J. Howat, J Carl Barrett, Javier Cortés, José Baselga, Gaia Schiavon, Barry R. Davies, Cristina Saura, Violeta Serra. Identification of determinants of sensitivity to AKT inhibition using breast cancer (BC) patient-derived tumor xenografts (PDX) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 150. doi:10.1158/1538-7445.AM2017-150