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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

Addition of granulocyte-colony stimulating factor (G-CSF) may further increase chemosensitive state in premenopausal node-positive breast cancer patients with induced angiogenesis after surgery

PubMe

Hypothesis: Induced angiogenesis after surgery in premenopausal node-positive breast cancer patients is a major underlying reason why adjuvant chemotherapy works particularly well for those patients

BACKGROUND: We suggest that surgical extirpation of primary breast cancer among other effects accelerates relapse for some premenopausal node-positive patients. These accelerated relapses occur within 10 months of surgery for untreated patients. The mechanism proposed is a stimulation of angiogenesis for distant dormant micrometastases. This has been suggested as one of the mechanisms to explain the mammography paradox for women aged 40–49 years. We could imagine that it also plays a role in adjuvant chemotherapy effectiveness since, perhaps not coincidentally, this is most beneficial for premenopausal node-positive patients. HYPOTHESIS: We speculate that there is a burst of angiogenesis of distant dormant micrometastases after surgery in approximately 20% of premenopausal node-positive patients. We also speculate that this synchronizes them into a temporal highly chemosensitive state and is the underlying reason why adjuvant chemotherapy works particularly well for that patient category. Furthermore, this may explain why cancer in younger patients is more often 'aggressive'. TESTING THE HYPOTHESIS: Stimulation of dormant micrometastases by primary tumor removal is known to occur in animal models. However, we need to determine whether it happens in breast cancer. Transient circulating levels of angioactive molecules and serial high-resolution imaging studies of focal angiogenesis might help. IMPLICATIONS: Short-course cytotoxic chemotherapy after surgery has probably reached its zenith, and other strategies, perhaps antiangiogenic methods, are needed to successfully treat more patients. In addition, the hypothesis predicts that early detection, which is designed to find more patients without involved lymph nodes, may not be a synergistic strategy with adjuvant chemotherapy, which works best with positive lymph node patients

Does the act of surgery provoke activation of "latent" metastases in early breast cancer?

This paper is written in support of the challenging article by Retsky and colleagues in this issue of Breast Cancer Research, and develops on the idea that the act of surgery can provoke the outgrowth of dormant micrometastases, which often leads to the failure of screening to deliver its promise. The therapeutic consequence of this idea involves the use of antiangiogenic drugs before surgery

Mathematical modeling of the metastatic process

Mathematical modeling in cancer has been growing in popularity and impact since its inception in 1932. The first theoretical mathematical modeling in cancer research was focused on understanding tumor growth laws and has grown to include the competition between healthy and normal tissue, carcinogenesis, therapy and metastasis. It is the latter topic, metastasis, on which we will focus this short review, specifically discussing various computational and mathematical models of different portions of the metastatic process, including: the emergence of the metastatic phenotype, the timing and size distribution of metastases, the factors that influence the dormancy of micrometastases and patterns of spread from a given primary tumor.Comment: 24 pages, 6 figures, Revie

Molecular biology of breast cancer metastasis: The use of mathematical models to determine relapse and to predict response to chemotherapy in breast cancer

Breast cancer mortality rates have shown only modest improvemen despite the advent of effective chemotherapeutic agents which have been administered to a large percentage of women with breast cancer. In an effort to improve breast cancer treatment strategies, a variety of mathematical models have been developed that describe the natural history of breast cancer and the effects of treatment on the cancer. These models help researchers to develop, quantify, and test various treatment hypotheses quickly and efficiently. The present review discusses several of these models, with a focus on how they have been used to predict the initiation time of metastatic growth, the effect of operative therapy on the growth of metastases, and the optimal administration strategy for chemotherapy

Protocol For A Randomised, Multicentre, Double Blinded Phase III Study Of Perioperative Ketorolac In Women Of African Descent With Operable Breast Cancer

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

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

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