Abstract P6-18-03: Biomarker analysis of CDK 4/6 and endocrine pathways in hormone-receptor positive (HR+) advanced breast cancer (ABC) bone only disease patients: A joint analysis of PALOMA-2 and PALOMA-3 studies
Authors: Finn RS , Turner NC , Liu Y , Rugo HS , Loibl S , Diéras V , Slamon DJ , André F , Gelmon K , DeMichele A , Loi S , Zhang Z , Giorgetti C , Gauthier E , Huang Bartlett C , Cristofanilli M 
Published: May 2019

Abstract
Background: Palbociclib (PAL) in combination with endocrine therapy (ET) is a preferred treatment option for untreated and previously treated patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2 (HER2)–negative ABC. Patients with bone only disease could derive prolong disease control with single agent ET. Further understanding the predictive markers for sensitivity to ET alone and P+ET in both endocrine sensitive and resistant settings could help guide clinical treatment sequencing decision. We performed biomarker (BM) analysis of baseline tumor tissues in both PALOMA-2 (P2) and PALOMA-3 (P3) in bone only (BO) vs non-bone (NBO) only patients.
Methods: Postmenopausal women (N=666) with no prior systemic therapy for ER+/HER2-ABC were randomized 2:1 to receive PAL+LET or matching placebo (PBO)+LET in P2. In P3 women (N=521) who progressed on prior endocrine therapy were randomized 2:1 to receive PAL+ FUL vs matching PBO+FUL. All pts including those with BO disease had to consent to provide tumor tissues to participate the current study. EdgeSeq Oncology Biomarker Panel (HTG Molecular Diagnostics; Tucson, AZ) was used for mRNA profiling. Cox regression analysis was used to evaluate the association of BO disease with treatment effect as well as the association of gene expression with treatment effect in BO vs NBO pts.
Results: Treatment effect in the BM population from each study was consistent with that observed in the respective ITT population. In ITT population, BO disease was reported in 151 (23%) pts of P2 with mPFS 36.2mo PAL+LET arm (n=103) vs 11.2mo LET arm (n=48), HR=0.40 (0.26-0.62) and in 124 (24%) pts of P3 with mPFS 14.3mo PAL+FUL arm (n=86) vs 9.2mo FUL arm (n=38), HR=0.64(0.38-1.06). BO disease was reported in 107 (24%) pts in P2 and 81 (27%) pts in P3 BM population. In P2, longer mPFS was seen with PAL+ LET vs PBO+LET in BO vs NBO disease (30.6 mo vs 11.2 mo; HR=0.42 (0.25-0.69) in BO pts and 22.1 mo vs 13.8 mo HR=0.67 (0.52-0.88) in NBO pts) although the interaction effect was not statistically significant. Similar results were also observed in P3 with longer mPFS in PAL+FUL vs PBO+FUL in BO vs NBO disease (16.6 mo vs 11.2 mo HR=0.79 (0.40-1.56) in BO pts and 11.1mo vs 3.5 mo HR=0.47 (0.34-0.66) in NBO pts) with insignificant interaction effect. In both studies, BO pts had higher incidence of luminal A disease (BO vs NBO: P2=62% vs 47%; P3=54% vs 40%) and lower rate of luminal B disease (P2=19% vs 33%; P3: 26% vs 33%). In both studies, baseline ESR1, Cyclin E and CDK 4 gene expression level were comparable between BO vs NBO pts. Elevated CDK4 gene expression level was associated with resistance to LET in P2 and lower Cyclin E gene expression predicts the effect of PAL in P3.
Conclusion: mPFS was significantly prolonged in BO pts with the addition of PAL to ET. BO disease was more frequently associated with luminal A subtype in ABC setting. CDK4 expression level was similar to NBO disease pts but associated with resistance to single agent LET.
Citation Format: Finn RS, Turner NC, Liu Y, Rugo HS, Loibl S, Diéras V, Slamon DJ, André F, Gelmon K, DeMichele A, Loi S, Zhang Z, Giorgetti C, Gauthier E, Huang Bartlett C, Cristofanilli M. Biomarker analysis of CDK 4/6 and endocrine pathways in hormone-receptor positive (HR+) advanced breast cancer (ABC) bone only disease patients: A joint analysis of PALOMA-2 and PALOMA-3 studies [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-03.