Abstract 3596: Biomarkers of response to CDK4/6 inhibitor (CDK4/6i) in hormone receptor (HR) positive and HER2-positive breast cancer (BC) patient-derived xenografts (PDX)

Abstract

Abstract The cell cycle G1-restriction point is frequently deregulated in HR+ BC by alterations of cyclin D1 (CCND1), p16 (CDKN2A) or pRb (RB1). CDK4/6i (ribociclib, abemaciclib and palbociclib) have shown clinical activity in metastatic HR+ BC, both as single agents and in combination with endocrine therapy. Currently, no biomarkers of response to CDK4/6i have been identified beyond HR expression and little is known about mechanisms of acquired resistance. Twenty-one PDXs were established from HR+, HER2+ or HR+/HER2+ BC patient biopsies and their response to ribociclib was evaluated in vivo and ex vivo in matrigel cultures. Acquired-resistance was generated in vivo by isolating tumors that escaped therapy overtime. In order to identify response biomarkers, genetic and proteomic analysis of PDXs were performed and correlated with ribociclib antitumor activity. Candidates were validated in a cohort of 8 tumor samples from patients treated with abemaciclib monotherapy and in vitro. Combination with the PI3K-alpha inhibitor (PI3Ki) BYL719 was explored in vivo. In vivo, ribociclib exhibited antitumor activity in five out of 21 PDXs (24%), two of which acquired resistance after continuous dosage (75mg/kg, 6IW). Ex vivo matrigel cultures recapitulated the in vivo response with 75% sensitivity and 92% specificity (p=0.01), providing a novel approach for high throughput screening. Baseline levels of ER, PR and Ki67 protein or PIK3CA/ESR1 mutations did not discriminate between ribociclib-resistant/sensitive PDXs, whereas CCND1/D2-amplification/overexpression were only found in ribociclib-resistant models. Importantly, sensitive PDXs exhibited significant Ki67 reduction upon ribociclib treatment, higher baseline pRb- and lower p16-staining compared to ribociclib-resistant PDXs (p=0.004, 0.02 and 0.03, respectively). Three out of 8 acquired-resistant tumors (37.5%) exhibited pRb loss. In vitro, RB1 knockdown and cyclin D1/D2-overexpression resulted in higher BrdU incorporation and higher IC50 than control cells upon ribociclib treatment. p16 expression was significantly lower in samples of patients exhibiting clinical benefit with abemaciclib monotherapy (p=0.04). Remarkably, combination of ribociclib with a PI3Ki resulted in appreciable antitumor activity in 18 out of 20 PDXs (90%), including two models resistant to fulvestrant given in combination with ribociclib. In conclusion, HR+, HER2+ and HR+/HER2+ BC PDXs expressing both high Rb- and low p16-protein levels are sensitive to CDK4/6i whereas deregulation of the G1-restriction point due to low pRb or high cyclin D1/D2 protein levels is associated with resistance to ribociclib monotherapy. Addition of a PI3Ki markedly improves the antitumor response of ribociclib in most of PDXs, suggesting that the PI3K pathway may play a pivotal role in limiting the efficacy of CDK4/6 inhibition. Citation Format: Marta Palafox, María Teresa Herrera-Abreu, Meritxell Bellet, Mafalda Oliveira, Alejandra Bruna, Olga Rodriguez, Marta Guzmán, Judit Grueso, Cristina Vilaplana, Joaquín Arribas, Emmanuelle di Tomaso, Faye Su, Carlos Caldas, Nicholas C. Turner, Rodrigo Dienstmann, José Baselga, Maurizio Scaltriti, Javier Cortés, Cristina Saura, Violeta Serra. Biomarkers of response to CDK4/6 inhibitor (CDK4/6i) in hormone receptor (HR) positive and HER2-positive breast cancer (BC) patient-derived xenografts (PDX) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3596.