Background: We sought to understand the genomic alterations in tumors of MBC pts who had extreme durations of response to capecitabine (C). Methods: Following IRB-approved informed consent, targeted next generation sequencing (NGS) was performed on pts’ FFPE primary breast cancer (n=4) or MBC (n=2) specimens at a CLIA-certified laboratory to characterize genomic alterations across 287 cancer-related genes. Reverse phase protein microarray (RPMA) was also performed. Results: Six postmenopausal pts with ER+/HER2- MBC and ERs with C were studied. Metastases comprised bone/lymph node (n=1) or liver (n=5; liver only, liver/bone, liver/bone/chest wall). Four pts had received ≥2 prior chemotherapy regimens for metastatic disease. Four pts received C + paclitaxel (mean 17 mos; range 4–57); three of these then continued C alone (mean 86 mos; range 59–118). Two pts received C monotherapy (54 and 91+ mos). C was discontinued after a mean of 66 mos in four pts (range 54–86); two pts remain on C (91+ and 122+ mos). On NGS, 50% (3/6) of pts’ tumors had likely functional alterations in DNA repair and chromatin remodeling genes (Table) – a higher than expected prevalence in ER+ MBC. Three pts had variants of unknown significance (VUS) in these pathways. PIK3CA substitutions or amplifications of AKT2, FGFR1, ZNF703, as well as phosphorylation of HER family receptors and their downstream proteins on RPMA did not appear to preclude ERs to C. Conclusions: Three MBC pts with ERs to C (54–122+ mos) had genomic alterations in DNA repair pathways (double strand break response and homologous recombination) and in histone acetyl- and methyltransferase genes. We are exploring the potential function of the VUS in the other three pts. Preclinical data show that sensitivity to 5-FU is enhanced by deficiencies in chromatin remodeling and homologous recombination genes (Matuo, et al. Genet Mol Res, 2013), suggesting a strategy for pt selection for C.