Abstract P4-06-04: Effect of genomic heterogeneity on breast cancer progression and metastatic spread

Abstract

Abstract Purpose: DNA fingerprinting has revealed discordant patterns of chromosomal alterations in primary breast tumors (PBT) compared to matched metastatic axillary lymph node tumors (MLNT); however, whether these genetic differences reflect the timing of dissemination of cells with metastatic potential from the primary tumor, intratumoral heterogeneity of the primary breast tumor, or independent seeding of lymph nodes with metastatic cells remains unclear. Patients and Methods: From the 30 node-positive patients evaluated in this study, allelic imbalance (AI) data was generated using 52 microsatellite markers from 5-19 areas of each PBT as well as from available MLNT. Data were analyzed using pairwise correlations, ANOVA and PHYLIP. Results: The frequency of genomic changes was significantly higher (P<0.001) in PBT areas (13%) than MLNT (9%). No two PBT areas had identical patterns of AI and the percent concordance (PC) of AI events between tumor regions ranged from 0-65% (average 33%). Of the 196 MLNT from 28 patients, PC between MLNT from the same patient ranged from 0-88% (average = 32%). Neither the overall frequency of AI nor the PC differed significantly between sentinel (SLN) and non-SLNs. Phylogenetic analysis revealed that within patients, many MLNT appeared to be descended from different areas of the PBT, but patterns of descent were complex. Conclusions: Both PBT and MLNT are characterized by extensive molecular heterogeneity, MLNT appear to originate from different areas of the PBT, and SLN metastases are not genomically more advanced than non-SLN metastases. These data suggest that metastatic dissemination may be influenced by both spatial and temporal factors, with cells with metastatic potential colonizing lymph nodes throughout the development of the PBT, and that SLN metastases do not appear to be a source of metastatic cells for non-SLN but rather MLNT arise by independent colonization. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-06-04.