Abstract 618: Comparison of mutational spectra in metastatic tumors and cell-free DNA in breast cancer patients
Authors: Maxwell Kara N. , Soucier-Ernst Danielle J. , Carpenter Erica L. , Troxel Andrea B. , Colameco Christopher , Clark Candace , Feldman Michael D. , Kakrecha Bijal , Langer Melissa , Lee Joy , Lewis David A. , Lieberman David , Morrissette Jennifer , Pan Tien-chi , Yee Stephanie S. , Shih Natalie , Chodosh Lewis A. , DeMichele Angela M. 
Published: August 2015

Abstract
While massively parallel sequencing technology has greatly expanded the number of molecular genetic tests available in oncology, little is known about the spectrum and clinical utility of findings obtained from testing tumors and circulating tumor material in specific patient populations. Here we report findings from the METAMORPH study, in which stage IV breast cancer patients had metastatic tumor biopsies (metDNA) and concurrently collected cell-free circulating tumor DNA (cfDNA). Illumina TruSeq Cancer Panel (for metDNA) and Guardant360 (for cfDNA) were performed. 28 patients had both tests; results are shown in the Table. 68% of patients had at least one alteration in metDNA and 86% in cfDNA. PIK3CA mutations were most common, occurring in 43% and 36% of patients’ metDNA and cfDNA, respectively. Overall, 16 of 28 (57%) of patients had the same alterations identified in both metDNA and cfDNA. Excluding ERBB2 amplifications in HER2+ patients, 43% of patients’ metDNA and 57% of patients’ cfDNA contained pathogenic mutations or variants of uncertain significance (VUS) for which there are approved targeted therapies or clinical trials. Overall, 80 alterations were identified, 23 of which were detected by both assays. Multiple reasons for discordance in calls between metDNA and cfDNA assays were identified. While biological phenomena (e.g. tumor heterogeneity) may contribute to discordance, technical issues played an important role. Additional studies using whole exome sequencing and other platforms to further assess biological evolution of metastatic disease and clinical utility of molecular profiling of metastatic tumors and cell-free DNA are needed.
Table 1
Tumor DNA (metDNA)Cell-free DNA (cfDNA)# pts with alteration (%)19/28 (68%)24/28 (86%)ER+/Her2- (n = 17)10/1715/17Her2+ (n = 4)4/42/4TNBC (n = 7)5/77/7Total # alterations in # genes31 in 7 genes72 in 19 genesGenes w/alterations (total); Bold: genes for which exists a possible targeted therapeuticPIK3CA (13), TP53 (10), ERBB2 (4), EGFR, RB1, SMAD4, STK11PIK3CA (14), TP53 (14), EGFR (9), ERBB2 (6), BRAF (6), MET (6), JAK2 (3), NOTCH1 (2), FBXW7 (2), ARAD, FGFR2, JAK3, KRAS, MYC, NPM1, PROC, RET, SMAD4, SMARCB1Variants only covered by one assay033Variants detected in both but only reported by one assay3 (2 indels, 1 VUS)1 (1 synonymous)Variants detected by only one assay1 amplification at 7-fold; 4 SNVs (AF range 19-75%)2 amplifications at &lt;3-fold; 13 SNVs (AF range 0.1-0.8%)
Citation Format: Kara N. Maxwell, Danielle J. Soucier-Ernst, Erica L. Carpenter, Andrea B. Troxel, Christopher Colameco, Candace Clark, Michael D. Feldman, Bijal Kakrecha, Melissa Langer, Joy Lee, David A. Lewis, David Lieberman, Jennifer Morrissette, Tien-chi Pan, Stephanie S. Yee, Natalie Shih, Lewis A. Chodosh, Angela M. DeMichele. Comparison of mutational spectra in metastatic tumors and cell-free DNA in breast cancer patients. [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 618. doi:10.1158/1538-7445.AM2015-618