Abstract 4928: Clinical utility of circulating tumor DNA (ctDNA) in advanced and metastatic breast cancer
Authors: Austin Laura K. , Jaslow Rebecca , Avery Tiffany , Fortina Paolo , Sebisanovic Dragan , Siew LaiMun , Zapanta Aubrey , Talasaz AmirAli , Cristofanilli Massimo 
Published: August 2015

Abstract
Background
MBC is an incurable disease characterized by genomic abnormalities including somatic mutations, amplifications and gene rearrangements. It is believed that treatment resistance and disease progression is related to genomic instability making “molecular monitoring” and consequent therapeutic management a dynamic and potentially more effective approach. The detection of circulating DNA fragments with tumor-specific sequence alterations (ctDNA) found in the blood of patients is the ideal diagnostic tool for non-invasive molecular monitoring.
Methods
This is a retrospective evaluation of 75 patients with advanced or MBC who both completed primary therapy and were NED (stage 1-3), or failed standard therapies and had baseline plasma analyzed for ctDN before starting new therapy (stage 4). For patients with progression, selection criteria included: progression of disease after standard therapies, need to detect novel molecular abnormalities for possible therapeutic targeting, or confirmation of persistence of genomic abnormalities already demonstrated in tissue or blood analysis. Guardant360™(Guardant Health) involves ctDNA isolation from plasma using a Qiagen circulating nucleic acid kit, then a panel of 54 gene mutations associated with solid tumors as reported in the COSMIC database sequenced using single-molecule digital sequencing technology.
Results
Most of the patients have metastatic disease (95%), but four patients had stage III disease and are now NED after neo-adjuvant therapy and surgery. According to subtype, 41% ER+/HER2-, 17% ER+/HER2+, 11% ER-/HER2+, and 31% TNBC. ctDNA was detected in 84% (63) of all patients; however, only 20% of patients who are now NED had ctDNA detected. Of patients with detected mutations, 52% had an actionable mutation that was incorporated into treatment planning. The most common mutations were TP53 (65%), PIK3CA (38%), ALK (21%) and NOTCH1 (17%). One patient with ER+/HER2- disease had ctDNA drawn at progression demonstrating a PIK3CA mutation, started on clinical trial with Letrozole/Palbociclib with clinical response and no ctDNA detected on two serial draws. Another patient with ER+/HER2- disease with 11 alterations noted in her blood, including PIK3CA and ATM, was started on targeted therapy with Trastuzumab based on HER2+ CTCs with clinical response but upon progression, ctDNA showed a dramatic increase in the resistant ATM clone, increasing from 1.1% to 27.8%.
Conclusions ctDNA can be detected in the majority of patients with MBC irrespective of disease subtype. Actionable mutations can be identified and used for selection of targeted therapies. Longitudinal monitoring can accurately predict treatment response but also detect the onset of new mutations likely related to resistant clones. The real-time molecular monitoring and therapeutic implications hold the promise to significantly change our approach to the management of MBC with survival benefit.
Citation Format: Laura K. Austin, Rebecca Jaslow, Tiffany Avery, Paolo Fortina, Dragan Sebisanovic, LaiMun Siew, Aubrey Zapanta, AmirAli Talasaz, Massimo Cristofanilli. Clinical utility of circulating tumor DNA (ctDNA) in advanced and metastatic breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4928. doi:10.1158/1538-7445.AM2015-4928