Abstract Precision medicine requires that a patient's tumor be accurately genotyped to identify a potentially effective targeted therapy. However, genotyping a tumor in patients with oligometastatic disease is complicated by the potential for intratumor and intertumor heterogeneity, and the requirement for sufficient tumor tissue obtained by invasive biopsy for genetic profiling. We sought to determine whether circulating tumor DNA in plasma provides a surrogate for solid tumor biopsy, and captures the genetic heterogeneity of tumors in patients with metastatic breast cancer. We hypothesized that genetic mutations detected in plasma DNA are reflective of the genetic mutations present in all tumors within a patient. Eight patients with advanced/metastatic breast cancer have thus far been enrolled in an ongoing clinical study (NCT01836640). Tumor specimens from two (n=4) or three (n=4) tumor sites and blood were obtained with one month. Blood was separated into plasma and buffy coat fractions. DNA extracted from tissue, buffy coat, and plasma samples was used for massively parallel DNA sequencing using the Ion Proton platform with a custom TargetSeq capture probe set covering all exons of 196 genes (4.1 Mb). All tumor and buffy coat samples, and plasma samples from three patients have thus far been analyzed. Tumor mutations were identified by comparison to buffy coat DNA sequences. We achieved sequencing coverage of ∼100-fold for tumor and buffy coat DNA samples, and ∼1,000-fold for plasma DNA samples. In Patient #1, we obtained 14 tumor nodules from a mastectomy specimen and used 3 nodules for DNA sequencing; Among the 73 point mutations detected in DNA from at least one tumor nodule, 29 mutations (40%) were detected in plasma DNA, and 10 mutations were found in plasma but not in tumors. In Patient #5, we analyzed bilateral breast tumors and a brain metastasis; among 151 mutations detected in at least one tumor, 80 (53%) were found in plasma, and an additional 18 mutations were found in plasma but not tumors; mutations specific to the brain tumor were less likely to be found in plasma; interestingly, the bilateral breast tumors showed genetic and histologic similarity, and so were likely derived from a single clone. Patient #6 had only one lung metastasis evaluable by DNA sequencing; 64/125 (51%) tumor-derived mutations were detected in plasma, and an additional 26 mutations were found in plasma but not the tumor. Preliminary ResultsMutationsTumorPlasma (Plasma only)TotalPlasma concordance with tumorPlasma concordance with totalTumor concordance with totalPatient #17329 (10)8339.7%46.9%87.9%Patient #515180 (18)16952.9%57.9%89.3%Patient #612564 (26)15151.2%59.6%82.8% These data suggest that, although challenging to get multiple biopsies for comparison, plasma is a promising surrogate for solid tumor biopsy to identify potentially targetable mutations. However, the ability of plasma DNA to genetically reflect all tumors in a patient with oligometastatic disease remains to be clarified through further analysis. Citation Format: Chamberlin MD, Shee K, Varn FS, Bean JR, Marotti JD, Gui J, Gemery JM, Barth RJ, Rosenkranz KM, Tsapakos MJ, McNulty NJ, Cheng C, Miller TW. Plasma DNA as a surrogate for tumor biopsy to identify genetic alterations in patients with metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-20.