Abstract P2-04-03: Circulating tumor DNA (ctDNA) provides molecular monitoring for inflammatory breast cancer (IBC)
Authors: Laura Austin, Paolo Fortina, Dragan Sebisanovic, LaiMun Siew, Aubrey Zapanta, Benjamin J Schiller, Gangwu Mei, Helmy Eltoukhy, AmirAli Talasaz, Massimo Cristofanilli
Journal: Cancer Research (2015)

Abstract Background Inflammatory Breast Cancer (IBC) is a clinicopathologic diagnosis characterized by rapid progression, resistance to treatment and poor prognosis. It is often an incurable disease with complex molecular features including somatic mutations that evolve in relation to genomic instability and selective treatment pressure. Monitoring disease by performing multiple biopsies may not be feasible and puts the patient at risk with each invasive procedure. Circulating DNA fragments carrying tumor-specific sequence alterations (ctDNA) are found in blood and offer the possibility of longitudinal non-invasive molecular monitoring of the disease by detecting actionable mutations. Methods This is an observational analysis of 35 IBC patients who failed standard therapies and had plasma analyzed for ctDNA detection. Selection criteria included progression of disease after standard therapies, need to detect novel molecular abnormalities for possible therapeutic targeting, or confirmation of genomic abnormalities already demonstrated in tissue analysis. Guardant Health performed the plasma analysis (Guardant360™); first ctDNA was isolated from plasma, then a panel of 54 gene mutations associated with solid tumors as reported in the COSMIC database were sequenced to concurrently analyze somatic mutations and gene amplification using single-molecule digital sequencing technology. Results All patients had IBC and 80% had metastatic disease; 37% of patients were ER+/HER2-, 14% ER+/HER2+, 23% ER-/HER2+, and 26% ER-/HER2-. 94% of patients with stage III or IV tumors had ctDNA alterations detected. The most common mutations were TP53 (49%), PIK3CA (20%), ERBB2 (17%), NOTCH1 (17%), and ALK (11%). Twelve patients also had next generation sequencing (NGS) analysis of tissue biopsy and 75% of these patients demonstrated at least one concordant mutation. The genomic information obtained from ctDNA, NGS or both was used to select treatments in 11 cases (31%). HER2 targeted therapy was continued in four patients with HER2+ disease after ctDNA confirmed ERBB2 alteration or amplification. A patient with ER+/HER2+ disease who progressed on HER2 targeted therapies, demonstrated ERBB2 and PIK3CA mutations on ctDNA; she was changed to exemestane/everolimus with objective response for several months. Repeat ctDNA at time of progression showed ERBB2 mutation only; she was changed to Trastuzumab/everolimus/vinorelbine. Moreover, a combination of lapatinib and capecitabine was initiated on a patient with a triple negative, chemo-refractory tumor that on ctDNA revealed EGFR and ERBB2 mutations; a repeated ctDNA after 5 months of therapy EGFR and ERBB2 mutations were not detected and she remains without evidence of progression. Conclusions Evaluation and longitudinal monitoring of IBC patients using ctDNA allows for identification of genomic abnormalities in all patients with advanced disease and to perform real-time molecular monitoring. The discovery of actionable genomic abnormalities is driving the management of this aggressive and treatment refractory form of breast cancer with potential future impact on outcome. Citation Format: Laura Austin, Paolo Fortina, Dragan Sebisanovic, LaiMun Siew, Aubrey Zapanta, Benjamin J Schiller, Gangwu Mei, Helmy Eltoukhy, AmirAli Talasaz, Massimo Cristofanilli. Circulating tumor DNA (ctDNA) provides molecular monitoring for inflammatory breast cancer (IBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-04-03.