Abstract PS18-28: Genomic heterogeneity and associated clinical outcomes of breast cancers treated with CDK4/6 inhibitors: Insights from real-world clinical genomic data
Authors: Yu Junhua , Ton Christopher , Marino Enrique , Kumar Naveen , Kucharlapati Rajesh , Chavali Rajesh , Nayak Gautam , Hanna David , Hardin Aaron , Raymond Victoria M , Lang Kathryn 
Published: February 2021

Abstract
Background: The CDK4/6 inhibitors (palbociclib, abemaciclib, and ribociclib) have heralded a paradigm shift in the management of people with metastatic ER+/ HER2- breast cancer. Traditionally assessment of genomic status has relied on tumor testing from a solid tumor biopsy, however, circulating tumor DNA (ctDNA) has demonstrated strong concordance proving the viability of ctDNA as a diagnostic alternative to tissue testing. Using a real-world clinical-genomic dataset, we aimed to describe the clinical outcomes of patients who underwent ctDNA testing and were treated with an FDA approved CDK4/6 inhibitor and report on the genomic diversity observed following disease progression.
Methods: The GuardantINFORM™ clinical-genomic database was interrogated for women aged 18 or over with a confirmed diagnosis of breast cancer, at least one instance of a claim for one of palbociclib, abemaciclib, or ribociclib monotherapy, and at least one resulted comprehensive ctDNA genomic profile (Guardant360®, Guardant Health). Time to next treatment, defined as discontinuation of CDK4/6 inhibitor therapy or treatment with an additional therapy, and time to death was calculated for first- and second- line treatment through a proprietary algorithmic approach. A subset of patients with a Guardant360 test completed both pre and post CDK4/6 inhibitor monotherapy was analyzed to determine changes in genomic profile following treatment.
Results: In total 1,616 patients who matched inclusion and exclusion criteria were identified in the GuardantINFORM database, of these 79% were not known to have died as of the most recent data cut. All three major CDK 4/6 inhibitors were represented in the dataset.
150 patients had a Guardant360 test completed pre and post CDK4/6 inhibitor monotherapy. Somatic alterations more commonly observed in post-treatment tests included those in TP53 (16% pre-treatment vs. 24% post-treatment), ESR1 (8% vs. 15%), CCND1 (7% vs. 11%), ERBB2 (5% vs. 11%), AR (4% vs. 6%), BRCA2 (3% vs. 7%), TERT (2% 5%), and MYC (4% vs. 9%). Alterations in ARID1A were more commonly observed pre-treatment (8% vs 6%). There was no difference in the occurrence of alterations in FGFR1.
Conclusions: The results presented here demonstrate clinical outcomes similar to those previously reported for CDK4/6 inhibitor monotherapy demonstrating the ability to use this real-world database to generate clinically meaningful treatment data. Incorporation of genomic data pre and post treatment identified changes in the genomic profile of several genes indicating the impact of therapy on the cancer molecular pathogenesis. The ability to simultaneously query the somatic genomic profile and the therapeutic regimen provides novel clinical information to aid in understanding of treatment optimization, disease mechanism, and future drug development for metastatic breast cancer.
Table 1. Comparison of First and Second Line CDK4/6i MonotherapyFirst Line CDK4/6i monotherapySecond Line CDK4/6i monotherapyNot Known to be Deceased81%74%Record of a subsequent therapy following CDK4/6 treatment62%85%Median Time to Next Treatment (months)11.95.2Median Time to Death (months)26.626.6
Citation Format: Junhua Yu, Christopher Ton, Enrique Marino, Naveen Kumar, Rajesh Kucharlapati, Rajesh Chavali, Gautam Nayak, David Hanna, Aaron Hardin, Victoria M Raymond, Kathryn Lang. Genomic heterogeneity and associated clinical outcomes of breast cancers treated with CDK4/6 inhibitors: Insights from real-world clinical genomic data [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-28.