To the Editor: In their article (Clin Cancer Res 2004;10, 8152–62), Meng et al. report on the detection of circulating tumor cells in blood of breast cancer patients even in long-term remission. In a somewhat different approach (1),1
Pachmann et al. submitted for publication.
In Response: We are pleased that experienced investigators like Dr. Pachmann are interested in tumor dormancy, a relatively neglected field. Her provocative hypothesis is that breast cancer dormancy is caused by long-lived breast cancer stem cells. We agree that stem cells may play a major role but neither Pachmann nor ourselves have definitive evidence about this issue. The disagreement is whether circulating tumor cells (CTCs) in dormancy are derived from replicating tumor cells in the tissues or whether CTCs are long lived. Her results indicating maintenance of a high level of epithelial cells in clinically tumor-free patients does not distinguish between our “balance” conclusion and her hypothesis. Our conclusion that replication and cell death are balanced arises from the following evidence: (a) Epithelial cells detached from their underlying stroma and neighboring cells enter an apoptotic program (1). (b) The half-life of CTCs in patients after mastectomy is 1 to 2.4 hours. Hence, CTCs are not exempt from the rapid turnover of normal epithelial cells. (c) CTCs released from breast carcinomas have distorted nuclei, shrink in size if incubated, and, occasionally, display classical apoptotic features. (d) Patients can have CTCs as long as 22 years after mastectomy. This period of time for circulation of long-lived CTCs appears unlikely. (e) In a mouse lymphoma model of dormancy, we proved that there was a balance between replication and cell death of lymphoma cells in the spleen, the major organ site of the tumor (2). However, in human breast cancer dormancy, we lack the formal proof necessary to exclude Pachmann's alternative hypothesis.
However, her studies raise significant questions. The enormous numbers of epithelial cells observed in the blood of breast cancer patients 6 months after surgery (as many as 7 × 104 CTCs/ml blood) is several logs more than any other researcher has reported even in actively growing breast cancer. In our studies of dormancy patients, we used cytomorphology, immunophenotype and aneusomy to unambiguously identify the malignant nature of the epithelial cells. Pachmann presents no proof that the observed epithelial cells are malignant tumor cells (TCs). Therefore, it is possible that almost all of these cells are hematopoietic in origin. Pachmann also refers to a mouse model in which solitary TCs persisting in tissue were shown to be resistant to chemotherapy presumably because they were not dividing (3). Their persistence may not represent the population of TCs that retains the capacity to cause a relapse in patients with cancer dormancy.