What Can Be Learnt about Disease Progression in Breast Cancer Dormancy from Relapse Data?

Abstract

Breast cancer patients have an anomalously high rate of relapse many years–up to 25 years–after apparently curative surgery removed the primary tumour. Disease progression during the intervening years between resection and relapse is poorly understood. There is evidence that the disease persists as dangerous, tiny metastases that remain at a growth restricted, clinically undetectable size until a transforming event restarts growth. This is the starting point for our study, where patients who have metastases that are all tiny and growth-restricted are said to have cancer dormancy. Can long-term follow-up relapse data from breast cancer patients be used to extract knowledge about the progression of the undetected disease? Here, we evaluate whether this is the case by introducing and analysing four simple mathematical models of cancer dormancy. These models extend the common assumption that a random transforming event, such as a mutation, can restart growth of a tiny, growth-restricted metastasis; thereafter, cancer dormancy progresses to detectable metastasis. We find that physiopathological details, such as the number of random transforming events that metastases must undergo to escape from growth restriction, cannot be extracted from relapse data. This result is unsurprising. However, the same analysis suggested a natural question that does have a surprising answer: why are interesting trends in long-term relapse data not more commonly observed? Further, our models indicate that (a) therapies which induce growth restriction among metastases but do not prevent increases in metastases' tumourigenicity may introduce a time post-surgery when more patients are prone to relapse; and (b), if a number of facts about disease progression are first established, how relapse data might be used to estimate clinically relevant variables, such as the likely numbers of undetected growth-restricted metastases. This work is a necessary, early step in building a quantitative mechanistic understanding of cancer dormancy.

Association of Time From Primary Diagnosis to First Distant Relapse of Metastatic Melanoma With Progression of Disease and Survival

“…Different models of cancer evolution demonstrated that the physiopathological mechanisms underlying metastatic progression could not be extracted from relapse data in many cancers, including melanoma. 7,8 Moreover, biology of the switch from dormant cells to an active metastatic process is largely unknown and the factors underlying this switch are only beginning to be discovered. 9,10 Permissive metastatic niches seem to play an important role in this switch, but it is unclear to what extent A, Overall survival according to treatment.…”

Mechanisms of Cancer Cell Dormancy—Another Hallmark of Cancer?

“…Mathematical modeling of late recurrence suggests that the most likely explanation is the presence of a prolonged period of dormancy as opposed to slow but uninterrupted growth (21), which can potentially be explained by 1) individual disseminated cells entering a state of prolonged dormancy at a distant site, or 2) the presence of micrometastatic lesions in a growth equilibrium defined by a balance between cellular proliferation and death. As a variety of models can account equally well for different trends in long-term follow-up relapse data (22), however, further insight into this phenomenon can only be gained through understanding the driving biological pathways.…”

Risk of recurrence and death in patients with breast cancer after delayed deep inferior epigastric perforator flap reconstruction

“…This might be a direct consequence of the imbalance between increased levels of angiogenic agonists such as vascular endothelial growth factor, as measured in surgical wound fluid collected within few hours of surgery, along with reduced levels of angiogenesis inhibitors such as thrombospondin 1. Major surgery may also induce immunomodulation, leading to deterioration of cellular immune defences by a shift from a Th1‐ to a Th2‐dominant cytokine profile, and the production of growth factors and immunomodulatory substances. Allawi and colleagues studied whether accidental trauma or surgery might activate dormant micrometastases leading to increased rates of breast cancer relapse, but did not find any association.…”

“…Reactivation may be initiated through an inflammatory response with subsequent production of cytokines and growth factors caused by surgical trauma. Other mechanisms could be new mutations, scattering of secondary micrometastases, lack of vasculature surveillance or inefficient immunosurveillance.…”