Genomic heritage of sentinel lymph node metastases: Implications for clinical management of breast cancer patients

571 Background: Sentinel lymph node (SLN) biopsy status is a key prognostic factor for breast cancer patients. Sentinel nodes are believed to receive early disseminating cells from the primary tumor, but little is known about the origin of metastases colonizing the sentinel nodes. We used allelic imbalance (AI) to examine genomic relationships among metastases in the sentinel and non-sentinel axillary lymph nodes from complete axillary dissections in 15 patients with lymph node positive breast cancer. Methods: Sentinel nodes were localized by standard scintigraphic and gamma probe techniques using 1.0 mCi technetium-99m sulfur colloid. Pathologically positive nodes were identified by H&E histology and immunohistochemistry. Primary breast tumors and metastases in sentinel and axillary nodes were isolated by laser microdissection. AI was assessed at 26 chromosomal regions and used to examine the timing and molecular mechanisms of metastatic spread to the sentinel and axillary nodes. Results: Overall AI frequencies were significantly higher (p<0.05) in primary breast tumors compared to lymph node metastases. A high level of discordance was observed in patterns and frequencies of AI events between metastases in the sentinel and non-sentinel axillary nodes. Phylogenetic analyses showed that 1) multiple genetically-divergent lineages of metastatic cells independently colonize the lymph nodes; 2) some lymph node metastases appeared to acquire metastatic potential early in tumorigenesis, while other metastases evolved later; and 3) importantly, lineages colonizing the sentinel nodes appeared to originate at different times and to progress by different molecular mechanisms. Conclusions: Genomic diversity and timing of metastatic nodal spread may be important factors in determining outcomes of breast cancer patients. Metastases colonizing the sentinel nodes appear to arise at different times during disease progression and may not be descendants of progenitor cells that colonize the lymph nodes early in tumorigenesis. Metastatic growth in the sentinel nodes thus may be a consequence of stimulating factors from the primary tumor that affect proliferation of previously disseminated cells rather than the timing of metastatic spread. No significant financial relationships to disclose.