A few clinical investigations suggest that while primary breast cancer surgical removal favorably modifies the natural history for some patients, it may also hasten the metastatic development for others. The concepts underlying this disease paradigm, i.e. tumor homeostasis, tumor dormancy and surgery-driven enhancement of metastasis development, have a long history that is reviewed. The review reveals the context in which these concepts were conceived and structured to explain experimental data and shows that they are not so new and far fetched. The idea that surgical cancer resection has both beneficial and adverse effects upon cancer spread and growth that result from the modulation of tumor dormancy by the resection should be considered a potentially fruitful working hypothesis.

We review our work over the past 14 years that began when we were first confronted with bimodal relapse patterns in two breast cancer databases from different countries. These data were unexplainable with the accepted continuous tumor growth paradigm. To explain these data, we proposed that metastatic breast cancer growth commonly includes periods of temporary dormancy at both the single cell phase and the avascular micrometastasis phase. We also suggested that surgery to remove the primary tumor often terminates dormancy resulting in accelerated relapses. These iatrogenic events are apparently very common in that over half of all metastatic relapses progress in that manner. Assuming this is true, there should be ample and clear evidence in clinical data. We review here the breast cancer paradigm from a variety of historical, clinical, and scientific perspectives and consider how dormancy and surgery-driven escape from dormancy would be observed and what this would mean. Dormancy can be identified in these diverse data but most conspicuous is the sudden synchronized escape from dormancy following primary surgery. On the basis of our findings, we suggest a new paradigm for early stage breast cancer. We also suggest a new treatment that is meant to stabilize and preserve dormancy rather than attempt to kill all cancer cells as is the present strategy.

To explain a bimodal pattern of hazard of relapse among early stage breast cancer patients identified in multiple databases, we proposed that late relapses result from steady stochastic progressions from single dormant malignant cells to avascular micrometastases and then on to growing deposits. However in order to explain early relapses, we had to postulate that something happens at about the time of surgery to provoke sudden exits from dormant phases to active growth and then to detection. Most relapses in breast cancer are in the early category. Recent data from Forget et al. suggest an unexpected mechanism. They retrospectively studied results from 327 consecutive breast cancer patients comparing various perioperative analgesics and anesthetics in one Belgian hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant therapy. Relapse hazard updated Sept 2011 are presented. A common Non-Steroidal Anti-Inflammatory Drug (NSAID) analgesic used in surgery produced far superior disease-free survival in the first 5 years after surgery. The expected prominent early relapse events in months 9-18 are reduced 5-fold. If this observation holds up to further scrutiny, it could mean that the simple use of this safe, inexpensive and effective anti-inflammatory agent at surgery might eliminate early relapses. Transient systemic inflammation accompanying surgery could facilitate angiogenesis of dormant micrometastases, proliferation of dormant single cells, and seeding of circulating cancer stem cells (perhaps in part released from bone marrow) resulting in early relapse and could have been effectively blocked by the perioperative anti-inflammatory agent.

Retsky MW, Demicheli R, Hrushesky WJM, Baum M, Gukas ID. Dormancy and surgery-driven escape from dormancy help explain some clinical features of breast cancer. APMIS 2008;116:730-41.To explain bimodal relapse patterns observed in breast cancer data, we have proposed that metastatic breast cancer growth commonly includes periods of temporary dormancy at both the single cell phase and the avascular micrometastasis phase. The half-lives of these states are 1 and 2 years respectively. We also suggested that surgery to remove the primary tumor often terminates dormancy resulting in accelerated relapses. These iatrogenic events are very common in that over half of all metastatic relapses progress in that manner. Assuming this is true, there should be ample and clear evidence in clinical data. We review here the breast cancer paradigm from early detection, through treatment and follow-up, and consider how dormancy and surgery-driven escape from dormancy would be observed. We examine mammography data, effectiveness of adjuvant chemotherapy, heterogeneity and aggressiveness, timing of surgery within the menstrual cycle and racial differences in outcome. Dormancy can be identified in these diverse data but most conspicuous is the sudden escape from dormancy following primary surgery. These quantitative findings provide linkage between experimental studies of tumor dormancy and clinical efforts to improve patient outcome.

No abstract