Abstract P4-08-08: Genomic progression, detected by circulating tumor DNA (ctDNA) sequencing, as an early predictor of disease progression in metastatic breast cancer (MBC)
Authors: Velimirovic M , Juric D , Niemierko A , Spring LM , Vidula N , Malvarosa G , Yuen M , Moy B , Isakoff SJ , Ellisen LW , Bardia A 
Published: May 2019

Abstract
Background: The availability of multiple therapies has transformed the landscape of MBC, but also brought the challenge of selecting the right therapy for an individual patient. Furthermore, in patients with Hormone Receptor positive (HR+) breast cancer who have bone metastases only it may be difficult to assess effectiveness of therapy via imaging. Peripheral ctDNA detection and analysis by next-generation sequencing (NGS) has gained popularity in cancer diagnosis and therapeutics due to its relative noninvasiveness, ease of use, and high sensitivity. Here, we explore the utility of ctDNA change as a predictor for disease progression in MBC. We hypothesized that genomic progression is a harbinger of subsequent radiologic progression in patients with MBC.
Methods: We analyzed change from pre-treatment (baseline) to on-treatment ctDNA mutant allele fraction (MAF) among patients with MBC. Patients receiving standard-of-care therapies or investigational agents on clinical trials at our institution were included. All patients were followed from the date of baseline test until death or data cutoff (6/20/2018). All peripheral blood specimens were collected and analyzed between 1/7/2016 and 3/1/2018 via NGS (Guardant360®). Peripheral blood specimens were sequenced prior to initiation of a new therapeutic regimen (baseline) and subsequently at least once while on-treatment, on average 4-12 weeks later. All patients had a follow-up CT scan of chest, abdomen and pelvis 2-4 weeks after the on-treatment NGS. A priori, we defined genomic progression as increase in ctDNA total MAF of at least 20% from baseline. We utilized Cox regression analysis to identify whether genomic progression was a predictor of radiologic progression, adjusting for common prognostic variables.
Results: All patients (N= 77) were female, predominantly White (83.1%), and median age was 57 (range 32 to 77). Fifty one out of 77 patients (66.2%) were ER+, 5 HER2+, and 9 had triple negative breast cancer. The median MAF at baseline was 2.2% (range 0% - 61.7%). Common genomic alterations in ctDNA included PIK3CA, TP53, ESR1, AKT1, NF1. 27 out of 77 (35%) patients showed disease progression on the first subsequent CT scan, while 59 out of 77 (76.6%) progressed during the follow up time. We found that an increase in ctDNA MAF of at least 20% was a strong predictor of disease progression (HR =2.46, CI [1.14-5.32], p=0.02), compared to those who had a MAF increase of less than 20% or a decrease in total MAF. In multi-variable analysis, adjusting for age, number of prior therapies, type of therapy, and visceral metastases, increase in ctDNA remained a significant predictor for subsequent disease progression (HR =3.84, CI [1.63-9.07], p=0.002). Subset results in patients with bone metastases only, and relative comparison of ctDNA with standard tumor markers will be presented at the meeting.
Conclusions: Genomic progression, identified by an increase in ctDNA MAF, is potentially an early predictor of subsequent disease progression in patients with MBC. Further research is needed to prospectively evaluate the clinical utility of ctDNA change as a surrogate marker in guiding treatment decision-making for patients with MBC.
Citation Format: Velimirovic M, Juric D, Niemierko A, Spring LM, Vidula N, Malvarosa G, Yuen M, Moy B, Isakoff SJ, Ellisen LW, Bardia A. Genomic progression, detected by circulating tumor DNA (ctDNA) sequencing, as an early predictor of disease progression in metastatic breast cancer (MBC) [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 P4-08-08.