We sincerely appreciate the cautious remarks of Pitini et al., who argue conclusively that our results on the prognostic relevance of persisting isolated tumor cells in the bone marrow have to be interpreted with caution. We absolutely agree that the detection of minimal residual disease faces technical challenges by its nature of minimum tumor load and, thus, must not lead to precipitate conclusions. We emphasized these concerns explicitly in our original article.1
The nonproliferative nature of persisting tumor cells, which is mentioned by Pitini et al., is well documented and should be prompted by cell cycle-independent treatment strategies. False-positive results potentially may lead to therapeutic interventions, which may not be necessary, although the incidence of false-positive results in our own patient cohort was significantly lower.2 This argument naturally also holds true for the presence of apoptotic cells, which may not require any treatment.
However, despite the fact that all of these arguments also hold true for the detection of isolated tumor cells at the time of primary diagnosis, the prognostic relevance of the bone marrow status of patients with breast carcinoma has been confirmed by a large, independent pool analysis that included more than 4200 patients.3 The detection of isolated tumor cells always will have to follow an indirect approach based more or less on specific markers and, thus, always will include the risk for false-positive results. However, despite these technical shortcomings, the strong prognostic and independent impact of the bone marrow status has been confirmed by numerous studies. Our own results on the persistence of isolated tumor cells reproduce not only earlier results4 but also the very similar results of Naume et al.,5 and they add to an increasing amount of evidence.
Until now, the benefit of the secondary-adjuvant treatment of persisting tumor cells has not been proven conclusively. The problem of over treatment is well known in the adjuvant setting of breast carcinoma, in which approximately 90% of all patients are treated systemically despite overall recurrence rates of < 50%.6 To identify which patients actually benefit most from extended adjuvant treatment will be one of the major challenges of the coming years. The detection of minimal residual disease during the later course of the disease eventually may add substantially to the solution of this problem.