Histologic Discordance Between Primary Tumor and Nodal Metastasis in Breast Cancer: Solving a Clinical Conundrum in the Era of Genomics

Next-generation sequencing (NGS) technologies have become increasingly used for managing breast cancer. In addition to the conventional use of NGS for predicting recurrence risk and identifying potential actionable mutations, NGS can also serve as a powerful tool to understand clonal origin and evolution of tumor pairs and play a unique role in clarifying complex clinical presentations. We report an unusual case of early-stage breast cancer in which the primary tumor and draining axillary node were histologically discordant. The primary tumor was invasive lobular carcinoma, whereas the nodal metastasis was invasive ductal carcinoma. This discordance led us to question whether the tumors had the same origin. NGS performed on both specimens identified no overlapping variants, leading us to conclude that the patient had two separate primary breast cancers, with the nodal tumor representing metastasis from an occult breast cancer. DNA sequencing of the primary tumor and the nodal metastasis allowed us to predict the patient's recurrence risk, and we initiated adjuvant chemotherapy and hormonal therapy based on these results. This case illustrates the utility of NGS for successfully managing a rare and challenging case. Key Points A degree of molecular concordance is expected for tumors originating from a common stem or progenitor cell. The histological discordance and absence of any genomic overlap should raise suspicion for two separate primary tumors. Paired DNA sequencing of the primary tumor and nodal metastasis can inform clinical decisions when primary breast tumor and axillary metastasis are histologically discordant. Molecular/Precision Oncology Tumor Board is the best setting to facilitate such decisions in these challenging cases. Paired DNA sequencing under these rare circumstances may suggest an occult breast tumor.