It May Be Possible to Prevent both Early and Late Relapses in Breast Cancer; Perhaps This Is an Opportunity for Sensors or Biosensors to Help.

Data presented in 1993 showed an unexpected bimodal relapse pattern in surgically treated breast cancer [...].

Interpreting Breast Cancer Survival Data by the Hazard Function: Remarkable Findings from Event Dynamics.

The report addresses the role of the hazard function in the analysis of disease-free survival data in breast cancer. An investigation on local recurrences after mastectomy provided evidence that uninterrupted growth is inconsistent with clinical findings and that tumor dormancy could be assumed as working hypothesis to understand the clinical course of the disease. Additionally, it was deemed that the lag-time between primary tumor removal and tumor recurrence is dynamically dependent on the subclinical metastasis development within the host-tumor system and, therefore, may be informative about the biology of the disease. Accordingly, the hazard function, which estimates the event risk pattern through the time, was adopted to analyze survival data. The multipeak pattern of the hazard function suggested that the process metastasis development has discontinuous features. A new paradigm of breast cancer metastatic development was proposed, involving the notions of tumor homeostasis, tumor quiescence in specific metastatic microscopic phases and surgery-related acceleration of the metastatic process. All analyses by prognostic factors (e.g., by menopausal status) or treatment modalities (e.g., by adjuvant chemotherapy) or other parameters (e.g., site of metastasis), provided coherent data in agreement with the model. The hazard rate function allowed addressing several clinical questions including meaning of ipsilateral breast tumor recurrence (IBTR), oncologic effect of delayed breast reconstruction, surgery related metastasis acceleration, possible role of anti-inflammatory drugs and body mass index (BMI) to modulate the recurrence risk. We conclude that the hazard function is a powerful tool to investigate the post-surgical course of early breast cancer and other operable tumors and to make inferences on their biology.

Breast cancer and the black swan.

Most current research in cancer is attempting to find ways of preventing patients from dying after metastatic relapse. Driven by data and analysis, this project is an approach to solve the problem upstream, i.e., to prevent relapse. This project started with the unexpected observation of bimodal relapse patterns in breast and a number of other cancers. This was not explainable with the current cancer paradigm that has guided cancer therapy and early detection for many years. After much analysis using computer simulation and input from a number of medical specialties, we eventually came to the conclusion that the surgery to remove the primary tumour produced systemic inflammation for a week after surgery. This systemic inflammation apparently caused exits of cancer cells and micrometastases from dormant states and resulted in relapses in the first 3 years post-surgery. It was determined in a retrospective study that the common inexpensive perioperative non-steroidal anti-inflammatory drug (NSAID) ketorolac could curtail the early relapse events after breast cancer surgery. A second retrospective study strongly confirmed this but an apparently underpowered prospective study showed no advantage. We are analysing these data and are now proposing to test the perioperative NSAID at Beth Israel Deaconess Medical Centre with triple-negative breast cancer (TNBC) patients, the category that could respond best to the perioperative NSAID. If this works as well as we expect, we would then transfer this technology to low- and/or middle-incomes countries (LMICs), starting with Nigeria where early onset type of TNBC is common. There is an unmet need in LMICs, especially in countries like Nigeria (190 million population), for a means to prevent surgery induced relapse that we are attempting to resolve. This work aims, thus, to describe eventual mechanisms, and ways to test a solution addressing an unmet need. But first, we consider the context, including within an historical perspective, important to explain how and why a Kuhnian paradigm shift may be considered.

How Anesthetic, Analgesic and Other Non-Surgical Techniques During Cancer Surgery Might Affect Postoperative Oncologic Outcomes: A Summary of Current State of Evidence.

The question of whether anesthetic, analgesic or other perioperative intervention during cancer resection surgery might influence long-term oncologic outcomes has generated much attention over the past 13 years. A wealth of experimental and observational clinical data have been published, but the results of prospective, randomized clinical trials are awaited. The European Union supports a pan-European network of researchers, clinicians and industry partners engaged in this question (COST Action 15204: Euro-Periscope). In this narrative review, members of the Euro-Periscope network briefly summarize the current state of evidence pertaining to the potential effects of the most commonly deployed anesthetic and analgesic techniques and other non-surgical interventions during cancer resection surgery on tumor recurrence or metastasis.

Breast Cancer Relapse, Post-Surgical Confusion, and Dementia in the Elderly: An Unexpected Connection but with the Same Proposed Solution.

A simple solution may exist for both the problem of sudden dementia and confusion after surgery in the elderly and the bimodal relapse pattern among breast cancer patients who were treated with a mastectomy. Systemic inflammation by a variety of mechanisms can induce tumor outgrowth from dormant states, such as single dormant cells and avascular micrometastases. This may also explain sudden confusion and dementia for the elderly after surgery. We propose that surgery-induced inflammation may be addressed by "protective anesthesia". We suggest ketorolac for 4 days starting at the time of surgery to prevent early relapse in breast and probably other cancers; perhaps that or something similar could be used before surgery in elderly patients to prevent post-operative cognitive dysfunction.

Multimodal hazard rate for relapse in breast cancer: quality of data and calibration of computer simulation.

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.

Reduction of breast cancer relapses with perioperative non-steroidal anti-inflammatory drugs: new findings and a review.

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.

NSAID analgesic ketorolac used perioperatively may suppress early breast cancer relapse: particular relevance to triple negative subgroup.

To explain a bimodal relapse hazard among early stage breast cancer patients treated by mastectomy we postulated that relapses within 4 years of surgery resulted from something that happened at about the time of surgery to provoke sudden exits from dormant phases to active growth. Relapses at 10 months appeared to be surgery-induced angiogenesis of dormant avascular micrometastases. Another relapse mode with peak about 30 months corresponded to sudden growth from a single cell. Late relapses were not synchronized to surgery. This hypothesis could explain a wide variety of breast cancer observations. We have been looking for new data that might provide more insight concerning the various relapse modes. Retrospective data reported in June 2010 study of 327 consecutive patients compared various perioperative analgesics and anesthetics in one Belgian hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant therapy. Follow-up was average 27.3 months with range 13-44 months. Updated hazard as of September 2011 for this series is now presented. NSAID ketorolac, a common analgesic used in surgery, is associated with far superior disease-free survival in the first few years after surgery. The expected prominent early relapse events are all but absent. In the 9-18 month period, there is fivefold reduction in relapses. If this observation holds up to further scrutiny, it could mean that the simple use of this safe and effective anti-inflammatory agent at surgery might eliminate most early relapses. Transient systemic inflammation accompanying surgery could be part of the metastatic tumor seeding process and could have been effectively blocked by perioperative anti-inflammatory agents. In addition, antiangiogenic properties of NSAIDs could also play a role. Triple negative breast cancer may be the ideal group with which to test perioperative ketorolac to prevent early relapses.

Promising development from translational or perhaps anti-translational research in breast cancer.

BACKGROUND: A great deal of the public's money has been spent on cancer research but demonstrable benefits to patients have not been proportionate. We are a group of scientists and physicians who several decades ago were confronted with bimodal relapse patterns among early stage breast cancer patients who were treated by mastectomy. Since the bimodal pattern was not explainable with the then well-accepted continuous growth model, we proposed that metastatic disease was mostly inactive before surgery but was driven into growth somehow by surgery. Most relapses in breast cancer would fall into the surgery-induced growth category thus it was highly important to understand the ramifications of this process and how it may be curtailed. With this hypothesis, we have been able to explain a wide variety of clinical observations including why mammography is less effective for women age 40-49 than it is for women age 50-59, why adjuvant chemotherapy is most effective for premenopausal women with positive lymph nodes, and why there is a racial disparity in outcome. METHODS: We have been diligently looking for new clinical or laboratory information that could provide a connection or correlation between the bimodal relapse pattern and some clinical factor or interventional action and perhaps lead us towards methods to prevent surgery-initiated tumor activity. RESULTS: A recent development occurred when a retrospective study appeared in an anesthesiology journal that suggested the perioperative NSAID analgesic ketorolac seems to reduce early relapses following mastectomy. Collaborating with these anesthesiologists to understand this effect, we independently re-examined and updated their data and, in search of a mechanism, focused in on the transient systemic inflammation that follows surgery to remove a primary tumor. We have arrived at several possible explanations ranging from mechanical to biological that suggest the relapses avoided in the early years do not show up later. CONCLUSIONS: We present the possibility that a nontoxic and low cost intervention could prevent early relapses. It may be that preventing systemic inflammation post surgery will prevent early relapses. This could be controlled by the surgical anesthesiologist's choice of analgesic drugs. This development needs to be confirmed in a randomized controlled clinical trial and we have identified triple negative breast cancer as the ideal subset with which to test this. If successful, this would be relatively easy to implement in developing as well as developed countries and would be an important translational result.

Surgery triggers outgrowth of latent distant disease in breast cancer: an inconvenient truth?

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.

New concepts in breast cancer emerge from analyzing clinical data using numerical algorithms.

A small international group has recently challenged fundamental concepts in breast cancer. As a guiding principle in therapy, it has long been assumed that breast cancer growth is continuous. However, this group suggests tumor growth commonly includes extended periods of quasi-stable dormancy. Furthermore, surgery to remove the primary tumor often awakens distant dormant micrometastases. Accordingly, over half of all relapses in breast cancer are accelerated in this manner. This paper describes how a numerical algorithm was used to come to these conclusions. Based on these findings, a dormancy preservation therapy is proposed.

Comments on John D. Keen and James E. Keen, What is the point: will screening mammography save my life? BMC Medical Informatics and Decision Making, 2009.

This paper by John D. Keen and James E. Keen addresses a thorny subject. The numerical findings and commentaries in their paper will be disturbing to some readers and seem to defy logic and well established viewpoints. It may well generate angry letters to the editor. However such numerical analysis and reporting including civil discussion should be welcomed and are the basis for informed decision making - something that is highly needed in this field.

Hypothesis: primary antiangiogenic method proposed to treat early stage breast cancer.

BACKGROUND: Women with Down syndrome very rarely develop breast cancer even though they now live to an age when it normally occurs. This may be related to the fact that Down syndrome persons have an additional copy of chromosome 21 where the gene that codes for the antiangiogenic protein Endostatin is located. Can this information lead to a primary antiangiogenic therapy for early stage breast cancer that indefinitely prolongs remission? A key question that arises is when is the initial angiogenic switch thrown in micrometastases? We have conjectured that avascular micrometastases are dormant and relatively stable if undisturbed but that for some patients angiogenesis is precipitated by surgery. We also proposed that angiogenesis of micrometastases very rarely occurs before surgical removal of the primary tumor. If that is so, it seems possible that we could suggest a primary antiangiogenic therapy but the problem then arises that starting a therapy before surgery would interfere with wound healing. RESULTS: The therapy must be initiated at least one day prior to surgical removal of the primary tumor and kept at a Down syndrome level perhaps indefinitely. That means the drug must have virtually no toxicity and not interfere meaningfully with wound healing. This specifically excludes drugs that significantly inhibit the VEGF pathway since that is important for wound healing and because these agents have some toxicity. Endostatin is apparently non-toxic and does not significantly interfere with wound healing since Down syndrome patients have no abnormal wound healing problems. CONCLUSION: We propose a therapy for early stage breast cancer consisting of Endostatin at or above Down syndrome levels starting at least one day before surgery and continuing at that level. This should prevent micrometastatic angiogenesis resulting from surgery or at any time later. Adjuvant chemotherapy or hormone therapy should not be necessary. This can be continued indefinitely since there is no acquired resistance that develops, as happens in most cancer therapies.

Recurrence dynamics does not depend on the recurrence site.

INTRODUCTION: The dynamics of breast cancer recurrence and death, indicating a bimodal hazard rate pattern, has been confirmed in various databases. A few explanations have been suggested to help interpret this finding, assuming that each peak is generated by clustering of similar recurrences and different peaks result from distinct categories of recurrence. METHODS: The recurrence dynamics was analysed in a series of 1526 patients undergoing conservative surgery at the National Cancer Institute of Milan, Italy, for whom the site of first recurrence was recorded. The study was focused on the first clinically relevant event occurring during the follow up (ie, local recurrence, distant metastasis, contralateral breast cancer, second primary tumour), the dynamics of which was studied by estimating the specific hazard rate. RESULTS: The hazard rate for any recurrence (including both local and distant disease relapses) displayed a bimodal pattern with a first surge peaking at about 24 months and a second peak at almost 60 months. The same pattern was observed when the whole recurrence risk was split into the risk of local recurrence and the risk of distant metastasis. However, the hazard rate curves for both contralateral breast tumours and second primary tumours revealed a uniform course at an almost constant level. When patients with distant metastases were grouped by site of recurrence (soft tissue, bone, lung or liver or central nervous system), the corresponding hazard rate curves displayed the typical bimodal pattern with a first peak at about 24 months and a later peak at about 60 months. CONCLUSIONS: The bimodal dynamics for early stage breast cancer recurrence is again confirmed, providing support to the proposed tumour-dormancy-based model. The recurrence dynamics does not depend on the site of metastasis indicating that the timing of recurrences is generated by factors influencing the metastatic development regardless of the seeded organ. This finding supports the view that the disease course after surgical removal of the primary tumour follows a common pathway with well-defined steps and that the recurrence risk pattern results from inherent features of the metastasis development process, which are apparently attributable to tumour cells.

Tumor dormancy and surgery-driven interruption of dormancy in breast cancer: learning from failures.

Primary tumor removal, usually considered intrinsically beneficial, can perturb metastatic homeostasis, and for some patients results in the acceleration of metastatic cancer. The continuous-growth model is required to yield to an interrupted-growth model, the implications of which are episodes of tumor dormancy. This Review analyzes the recent evolution of two paradigms related to the development of breast cancer metastases. The evolution of the paradigms described herein is supported by a growing body of findings from experimental models, and is required to explain breast cancer recurrence dynamics for patients undergoing surgery with or without adjuvant chemotherapy.

Enhanced surgery-induced angiogenesis among premenopausal women might partially explain excess breast cancer mortality of blacks compared to whites: an hypothesis.

There is excess breast cancer mortality for African-Americans (AA) compared to European-Americans (EA) of 1.5-2.2 fold that first appeared in 1970s and has been worsening since. This disparity may not be explained solely by reduced access to medical care. We proposed that surgery to remove a primary tumor induces angiogenesis of distant dormant micrometastases in 20% of premenopausal node-positive patients. This hypothesis helps explain the reduced benefit of mammography for women aged 40-49. Interestingly, for AA the average age at diagnosis is 46 while for EA it is 57. The resultant increased proportion of AA premenopausal breast cancer suggests a possible explanation for the AA/EA excess mortality. Early detection, which began in the 1970s, is more effective in postmenopausal women than in premenopausal women. Since AA breast cancer is mostly premenopausal and EA breast cancer is mostly postmenopausal, it might be anticipated that starting in the 1970s because of surgery-induced early mortality, outcome would be superior for EA compared to AA.

Racial disparities in breast cancer outcome: insights into host-tumor interactions.

Since the 1970s, overall age-adjusted breast cancer mortality rates in the U.S. have been higher among African American (AA) women than among Caucasian American (CA) women. The racial disparity is not fully explainable based on socioeconomic factors. Suspected biologic factors underlying this trend may be interpreted by both epidemiologic and clinical perspectives. Descriptive epidemiologic studies suggest that breast cancer may be a mixture of at least 2 main diseases and/or causal pathways. The first breast cancer is early-onset, with peak incidence near age 50 years and generally more aggressive outcome. The second breast cancer is late-onset, with peak incidence near age 70 years and more indolent course. The early-onset type of breast cancer is overrepresented among AA women compared with CA women. Clinical studies suggest that the course of breast cancer may be characterized by a common pathway through sequential dormant and active states eventually resulting in clustered appearance of clinical metastases. A balance between tumor and host traits influences the pace of the common pathway. Therefore, the recurrence risk profile of a single patient is seemingly determined by a specific mix of hierarchical prognostic factors, resulting from the unique genetic, environmental, or behavioral traits of that individual, which may be affected by race-related factors. We suggest that the components of the AA versus CA disparity not attributable to socioeconomic factors are a particular case of the more general issue of host-tumor interaction and that epidemiologic and clinical views are complementary; each is observing biologic parameters, which are not completely captured by the other. A 'unifying hypothesis' incorporating findings from genetics, epidemiology, and clinical studies should be aggressively pursued.