Abstract P5-11-10: Biomarkers associated with resistance or response to CDK4/6 treatment in patients with metastatic hormone-receptive positive breast cancer
Authors: Mullins JN , Chaudhry A , Ryder J , Valasareddy P , Jain A , Ranganath H , Hare F , Vidal GA 
Published: May 2019

Background:

CDK4/6 inhibitor (CDKi) drugs are the current standard of care for treatment of first and second-line hormone-receptor positive/HER2 negative (HR+/HER2-) metastatic breast cancers. Numerous research efforts have commenced to understand biomarkers of response and resistance. To date, no biomarker of response has been identified. Treatment induced RB1 mutations were noted as mechanism of resistance to palbociclib and fulvestrant in about 5% of patients treated on PALOMA3 trials, whereas PI3K and ESR1 mutations emerged as potential resistance to the anti-hormonal backbone1. Additionally, FGFR1 amplification has been suggested as a resistance pathway to fulvestrant and ribociclib2. A better understanding of the molecular landscape of CDK4/6 treatment is needed. Utilizing next-gen sequencing (NGS), chromogenic in situ hybridization (CISH) and immunohistochemistry (IHC) data from HR+/HER2- patients treated at the University of Tennessee West Cancer Center, we attempted to retrospectively identify a molecular signature of resistance or response as measured by PFS.

Methods:

We analyzed 115 breast cancer patients who received CDKi treatment and 30 matched controls not exposed to CDKi and underwent comprehensive molecular profiling (Caris Life Sciences, Phoenix, AZ). A Cox proportional hazards model was built using genetic test as predictors and progression free survival (PFS) time as response. Only alterations with known pathogenic potential were considered aberrant. The R package glmnet was used to perform regularized lasso regression for feature selection on the entire data set. Important features were then used to construct Kaplan-Meier curves and perform a log-rank test for difference in PFS times.

Results:

Here we report the analysis for 2 known pathogenic biomarkers, ESR1 and TP53 based on PFS for patients who test positive versus negative. The median PFS for all patients was 234 days. Patients who harbored ESR1 mutations had reduced PFS of 180 days compared to 237 days. Patients who had P53 mutations had shorter PFS of 201 days compared to 240 days. When both groups with positive mutations were combined, the median PFS was 191 days compared to 276 days for patients without either ESR1 or P53 mutation with a p-value of 0.011. Further analysis using 4 way Kaplan Meier Curves for controls versus treated, altered versus non-altered genes, or PDL-1 expression is ongoing and will be presented at the conference.

Conclusion:

This data further support, in a real world model, the poor predictive value of ESR1 and P53 mutations on clinical outcome. Because no testing data was used, additional validation will be necessary to confirm the findings from this analysis.

References:

1. Nicholas C. Turner, Ben O'Leary, Ros Cutts, Massimo Cristofanilliet al, Genetic landscape of resistance to CDK4/6 inhibition in circulating tumor DNA (ctDNA) analysis of the PALOMA3 trial of palbociclib and fulvestrant versus placebo and fulvestrant. J Clin Oncol 36, 2018 (suppl; abstr 1001).

2. Luigi Formisano, Yao Lu, Carlos Arteaga et al. Gain of function kinase library identifies FGFR1 amplification as a mechanism of resistance to antiestrogen and CDK4/6 inhibitor in ER+ breast cancer. SABCS 2017 abstract GS6-05.

Citation Format: Mullins JN, Chaudhry A, Ryder J, Valasareddy P, Jain A, Ranganath H, Hare F, Vidal GA. Biomarkers associated with resistance or response to CDK4/6 treatment in patients with metastatic hormone-receptive positive breast cancer [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 P5-11-10.