Presence of bone marrow micrometastasis (BMM) in breast cancer patients predicts a poor-prognosis pattern of first distant metastasis: Results from the pooled analysis

567 Background: As a putative surrogate marker of ubiquitous distant metastasis, which is assessable both at initial diagnosis of breast cancer and during adjuvant therapy, BMM would be a valuable end-point marker for adjuvant clinical trials. Methods: Based on individual pt data of 4,686 breast cancer pts with a 10-year follow-up (median, 62 months), we analyzed distant disease-free survival (DDFS) of BMM+/BMM− pts, and looked specifically into sites of first metastatic relapse, expressed as bone metastasis-free (BFS), visceral metastasis-free (VFS), and multiple metastasis-free survival (MFS; i.e., simultaneous diagnosis of bone and visceral metastases). We performed Kaplan-Meier analysis and computed incidence rates (IR)/ incidence rate ratios (IRR) for the occurrence of metastasis at different sites. Results: BMM were detected in 1,432 (30.6%) of pts overall and significantly more often in pts with subsequent diagnosis of distant metastasis as compared to those who survived without metastases (48.5% vs. 26.0%, P<0.001). BMM+ pts had a significantly shorter DDFS than BMM- pts (IRR 2.36; 95%CI, 2.07–2.69; P<0.001). This was also true when we analyzed either bone (IRR 2.73; 95%CI, 2.27–3.29; P<0.001) or visceral metastases only (IRR, 2.48; 95%CI, 2.11–2.91; P<0.001). Among 952 pts with occurrence of distant metastasis, IR of such an event was 1.28-fold (95%CI, 1.12–1.46; P<0.001) higher in BMM+ pts than in BMM- pts. Among 462 BMM+ pts (but not among those 490 BMM- pts), IRs for MFS were significantly increased as compared to both VFS (IRR 1.72; 95%CI, 1.36–2.18; P<0.001) and BFS (IRR 1.85; 95%CI 1.21–2.06; P=0.001). IR for BFS of BMM+ patients (1.08; 95%CI 0.87–1.34) was not significantly increased over VFS. Conclusion: Our data provide conclusive evidence that presence of BMM predicts an early onset and a poor prognosis pattern of overt distant metastasis. With the similar likelihood of the occurrence of subsequent metastasis in bone and at visceral sites, BMM appears to be a marker of generalized tumor cell spread. No significant financial relationships to disclose.