Thursday, July 31, 2014
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Comeback Cancers

LONDON, ONTARIO – Progress is being made against many types of cancer, with more patients surviving longer, thanks to research on two fronts: improved methods for earlier detection, and development of therapies that are more effective and less toxic. Indeed, it is estimated that there are now more than 10 million cancer survivors in the United States alone, and this number has been steadily increasing. Similar numbers, in proportion to population sizes, are found in other developed countries.

Cancers that are detected early – when they are small and less likely to have metastasized (spread away from the primary tumor) – are more likely to be treatable with local therapy, whereas successful treatment is ultimately unlikely once metastatic tumors develop. And improved therapies mean that patients can be treated with drugs that work better (and that patients are more likely to receive the full dose needed).

But our dramatic progress in detecting and treating cancer has also led to growing awareness of the problem of tumor dormancy: a patient appears to be cured, only to have the same cancer return years or even decades later. In breast cancer or melanoma, for example, recurrences 25 years after initial treatment have been reported.

With a growing number of cancer survivors, we need to understand better the twin processes of tumor dormancy and metastatic cancer recurrence. While remarkable progress has been made in understanding the biology of cancer – leading in part to the development of new, less toxic drugs – our understanding of the biology of tumor metastasis, and especially the development of metastases after a long period of tumor dormancy, has lagged.

We do know that metastasis is a very inefficient process, with most cancer cells that escape into the blood stream failing to form metastatic tumors in distant organs. Recent studies – from both the laboratory and the clinic – suggest that many cancer cells that leave the primary tumor may lodge themselves in new organs and go into a dormant state.

We also have evidence that says that these dormant cells may resist most current treatments. This means that adjuvant cancer therapy, designed to kill presumed micrometastatic disease, may be missing an important fraction of disseminated cancer cells, some of which may eventually wake up.

Moreover, we are beginning to identify molecular mechanisms that regulate the entry of cancer cells into a dormant state, as well as their re-awakening at later times. Our knowledge of the regulation of tumor dormancy is really in its infancy. But, given the growing numbers of cancer survivors, the need for this knowledge is becoming more pressing.

Indeed, there is evidence suggesting that tumor dormancy is a valid target for therapy. For example, in some types of breast cancer, patients may be treated for more than a decade with anti-hormone therapies, and these long-term treatments are working – they are successful at preventing some of the cancer recurrences that occur with shorter treatment. But, while these long-term therapies are relatively safe, they do have side-effects, and the number of cancer recurrences that they prevent is small.

The challenge today is thus to understand the processes of tumor dormancy and metastasis better, in order to determine more accurately which patients will benefit from long-term therapy. We have much to learn, and at this stage don’t even know all of the questions to ask.

Would intermittent therapy be as useful as long-term treatment? Are there features of the primary cancer, or of individual patients, that can help us predict who will develop late recurrences and metastatic disease? What if late recurrences simply cannot be predicted at diagnosis? Are there modifiable factors – for example, lifestyle, immune-system status, or environmental conditions – that influence whether or not patients develop late recurrences?

The answers to these questions will require research, and research into metastasis and tumor dormancy is difficult. It requires patience, development of models, and willingness to undertake long-term studies. We also need to understand better the prevalence of long-term dormant disease in patients. How common is the phenomenon we are examining? It may be that many cancer patients harbor disseminated tumor cells, and not all of these cells are destined to re-awaken.

In some ways, the success of cancer research is fueling pressure to “cure” cancer quickly, steering clinical and laboratory researchers away from the tricky problems of metastasis and long-term tumor dormancy. This focus ultimately may be shortsighted, as the increasing number of cancer survivors leads to an increase in late recurrences.

Metastases, not the primary tumor, are responsible for most cancer deaths. If we are to continue to improve on cancer survival statistics, we need to learn how to prevent, delay, or thwart the processes that give rise to metastatic disease.

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