Person:

Retsky, Michael

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.

Much has occurred since our 2010 report in Cancers. In the past few years we published several extensive reviews of our research so a brief review is all that will be provided here. We proposed in the earlier reports that most relapses in breast cancer occur within 5 years of surgery and seem to be associated with some unspecified manner of surgery-induced metastatic initiation. These events can be identified in relapse data and are correlated with clinical data. In the last few years an unexpected mechanism has become apparent. Retrospective analysis of relapse events by a Brussels anesthesiology group reported that a perioperative NSAID analgesic seems to reduce early relapses five-fold. We then proposed that primary surgery produces a transient period of systemic inflammation. This has now been identified by inflammatory markers in serum post mastectomy. That could explain the early relapses. It is possible that an inexpensive and non-toxic NSAID can reduce breast cancer relapses significantly. We want to take this opportunity to discuss database quality issues and our relapse hazard data in some detail. We also present a demonstration that the computer simulation can be calibrated with Adjuvant-on-line, an often used clinical tool for prognosis in breast cancer.

The combination of mathematics – queen of sciences – and the general utility of computers has been used to make important inroads into insight-providing breast cancer research and clinical aids. These developments are in two broad areas. First, they provide useful prognostic guidelines for individual patients based on historic evidence. Second, by suggesting numeric tumor growth laws that are correlated to clinical parameters, they permit development of biologically relevant theories and comparison with patient data to help us understand complex biologic processes. These latter studies have produced many new ideas that are testable in clinical trials. In this review we discuss these developments from a clinical perspective, and ask whether and how they translate into useful tools for patient treatment.

Introduction: Information on the metastasis process in breast cancer patients undergoing primary tumour removal may be extracted from an analysis of the timing of clinical recurrence. Methods: The hazard rate for local-regional and/or distant recurrence as the first event during the first 4 years after surgery was studied in 1173 patients undergoing mastectomy alone as primary treatment for operable breast cancer. Subset analyses were performed according to tumour size, axillary nodal status and menopausal status. Results: A sharp two-peaked hazard function was observed for node-positive pre-menopausal patients, whereas results from node-positive post-menopausal women always displayed a single broad peak. The first narrow peak among pre-menopausal women showed a very steep rise to a maximum about 8–10 months after mastectomy. The second peak was considerably broader, reaching its maximum at 28–30 months. Post-menopausal patients displayed a wide, nearly symmetrical peak with maximum risk at about 18–20 months. Peaks displayed increasing height with increasing axillary lymph node involvement. No multi-peaked pattern was evident for either pre-menopausal or post-menopausal node-negative patients; however, this finding should be considered cautiously because of the limited number of events. Tumour size influenced recurrence risk but not its timing. Findings resulting from the different subsets of patients were remarkably coherent and each observed peak maintained the same position on the time axis in all analysed subsets. Conclusions: The risk of early recurrence for node positive patients is dependent on menopausal status. The amount of axillary nodal involvement and the tumour size modulate the risk value at any given time. For pre-menopausal node-positive patients, the abrupt increase of the first narrow peak of the recurrence risk suggests a triggering event that synchronises early risk. We suggest that this event is the surgical removal of the primary tumour. The later, broader, more symmetrical risk peaks indicate that some features of the corresponding metastatic development may present stochastic traits. A metastasis development model incorporating tumour dormancy in specific micro-metastatic phases, stochastic transitions between them and sudden acceleration of the metastatic process by surgery can explain these risk dynamics.

Cancer remains one of the leading causes of morbidity and mortality worldwide. Breast cancer is the most common form of malignancy occurring in women around the world. The aim of this present protocol is to outline the procedure for a randomised, multicentre, double blinded phase III study of perioperative Ketorolac in Women of African Descent with Operable Breast Cancer. The typical type of breast cancer in sub Saharan Africa is triple negative breast cancer (TNBC) and is usually considered the worst early breast cancer diagnosis since there are no known targeted therapies and patients often relapse and die early. sub-Saharan Africa seems the perfect place to conduct a randomized controlled double blinded clinical trial of perioperative NSAID Romano Demicheli 1, Erhabor Osaro 2, Michael Retsky 3 Forget Patrice 4.Vaidya Jayant S 5. Scientific Directorate Fondazione IRCCS Istituto Nazionale Tumori di Milano Italy 1, Usmanu Danfodiyo University, Sokoto, Nigeria 2, Harvard TH Chan School of Public Health Boston MA USA 3, Department of Anesthesiology, Universite catholique de Louvain, St-Luc Hospital, Av. Hippocrate 10-1821, 1200 Brussels, Belgium 4, University College Hospital, London, UK 5.etorolac to potentially reduce early relapses in breast cancer. The primary and secondary objectives of this trial are to evaluate and compare the Disease Free Survival (DFS) and Overall Survival (OS) of operable breast cancer patients randomised to standard treatment versus standard treatment plus perioperative Ketorolac and to compare the safety and tolerability of the treatment as well as to identify pre- and post-operative factors with prognostic relevance and establish correlations with clinical outcomes. It is anticipated that trial will be successful and would turn TNBC from the worst prognosis to the best and potentially help improve the quality of life of African women suffering from breast cancer.