Friday, January 14, 2005

Breast cancer "dormancy"

Breast cancer is unusual among cancers. For most cancers, if a patient makes it out to five years, they are pretty much home free, as far as recurrence goes. That is one reason why long term cancer survival rates are usually quoted as five year survivals. In the public's mind (and even in some doctors' minds), "five year survival rate" equates with "cure rate." Breast cancer is different in that it has a much higher rate of late recurrences than most tumors. Breast cancer can recur 10, 15, 20, or even 30 years after seemingly successful treatment, usually as metastatic disease elsewhere in the body. (Melanoma behaves like that too, perhaps even more so. My partner has treated one patient who recurred 50 years after successful surgery.) In fact, after seven years, the recurrence rate for breast cancer is approximately 1% per year for 20 years. That means a woman who is tumor-free at seven years would still have a roughly 13% chance of developing a recurrence by the time she is 20 years out. Why is this?

This study by Jonathan W. Uhr and colleagues at the University of Texas Southwestern addresses the question of why breast cancer can recur so late after apparently successful treatment and reports a provocative observation. Such observations (and others) have led to the concept of tumor "dormancy," in which a patient lives apparently tumor-free but harbors viable tumor that is undetectable by present clinical tests. Certainly tumor dormancy has been shown conclusively in animal models. For instance, Judah Folkman has shown that aangiogenesis inhibitors can induce tumor dormancy in mice. Other researchers are working to develop strategies to induce tumor dormancy as a therapeutic strategy for cancer, in effect turning cancer into a chronic, manageable disease like diabetes or hypertension.

Here's what they did. They looked at women who had had mastectomies for breast cancer and had no clinical evidence of recurrent disease for seven or more years. Their hypothesis was that breast cancer patients could still have tumor cells circulating in the blood that long out (which is why they chose mastectomy patients, to avoid the confounding possibility that there were still tumor cells in the breast after lumpectomy) and that such patients still had "dormant" tumors that served as a source for these CTCs. They compared these women to age-matched controls. Blood samples were taken and special flow cytometry assays done for CTCs. Amazingly, they found that 13 of 36 of these patients had CTCs in their blood with the morphology of breast cancer cells. One patient positive for CTCs was 22 years out from her mastectomy. They next measured the half life of these cells by studying women undergoing mastectomy. CTC levels in the blood were measured before surgery started and then at various time points after the tumor was removed. The half-life of the CTCs was found to be between 1 and 2.5 hours, and in all cases the level fell to background levels within 24 hours. Recurrent tumor as a source of CTCs was excluded using clinical examination and imaging studies. The patients were followed for 1-2 years, and none were reported to have had a recurrence during that time.

Uhr concluded from these observations that a significant number (1/3) still had CTCs in their blood up to 22 years after definitive treatment, but had not developed developed recurrent disease. Moreover, because the half-life of these cells was short, that suggests that there must be active, replicating tumor cells within the body serving as a source of these CTCs. (One could postulate that the half life of dormant tumor cells in the blood is considerably longer than that of active tumors being surgically resected, but it is unlikely that the half life would be many years, which is what would be required to support an explanation in which no dormant tumor is present in the body but CTCs are still detectable many years later.) That supports the concept of "dormant" tumors, in which there is a balance between replication and tumor death, such that microscopic deposits of tumor do not increase in size or spread.

Unfortunately, this study produces more questions than answers. For example, we have no way yet to know whether the presence of these cells is an indicator that the patient's tumor will recur, although certainly that is certainly the next hypothesis that will need to be tested. Because recurrence occurs only at a 1% per year rate to begin with, it would take a large study with many patients followed over several years to work this out. If CTC levels are bad prognostic factors for late recurrence, then perhaps they could be used clinically as a test, much like Her-2/neu (whose presence on breast cancer cells indicates a more aggressive tumor). Next, we have no idea whether treating patients who are found to have CTCs in their blood would prevent or lower the rate of recurrence. That would take even a study with even more patients. Even more interesting would be to be able to gather enough of these cells to isolate RNA to do whole genome gene expression profiling on (the "Gene Chip"), to see how their gene expression patterns differ from that of the original tumor. Obviously something is different, if the tumor hasn't recurred. The results could suggest strategies for inducing tumor dormancy.

In any case, because my main research interest is tumor angiogenesis. Given that blockers of tumor angiogenesis can cause tumor dormancy in experimental tumor models, my interest in this is more than passing. I have to give a tip of the hat to one of my partners for pointing this paper out to me. (The issue of Clinical Cancer Research containing the paper arrived while I was on vacation over Christmas, and I never got around to looking through it.) We will be hearing more about tumor dormancy in the next few years.

10 example(s) of insolence returned:


At 1/14/2005 5:49 AM, Blogger AnthroPax said...

Not related to the above topic, but how do you put links at the side of your blog? I'm not great with computer things, so any help would be great. Thanks

 

At 1/14/2005 9:59 AM, Blogger Orac said...

It’s a little hard to explain. I’m no expert in HTML, but I stumbled upon this through trial and error. Basically, I took the bookmarks file from my web browser, opened it in Microsoft Word, edited it down to the list of websites I wanted to post (along with headers), and then saved the file. I then opened it in a text editor, took the raw HTML, and pasted it into the sidebar. I played around with it until I liked the way it looked, and then republished it.

I'm sure someone here could tell me a better, faster way to do it.

 

At 1/14/2005 11:03 AM, Anonymous Anonymous said...

You say "breast cancer is unusual among cancers." Rightly so. That's why I'm amazed at Dr. Lorraine Day and others who extrapolate their experience with breast cancer to the whole gamut, from mesothelioma to brain tumors to pancreatic cancer.

 

At 1/14/2005 12:48 PM, Blogger AnthroPax said...

Thanks. I'll try to get a more HTML able chum to give me a hand. Thanks anyway

 

At 1/15/2005 12:25 PM, Blogger Epador said...

Circulating CTC is not a newly described phenomena, nor the question of thier clinical relevance in patients clinically in remission. Angiogenisis is but one facet of the microenvironment that can influence malignancy, but its relevance to single cells or clusters of cells seems low.

Renal cell carcinoma and malignant melanoma are two relatively common tumors besides breast cancers (I believe lumping breast cancers into a single entity is no more appropriate than lumping all lung cancers together) that demonstrate what could be described as "dormancy."

I'd recommend looking at the CTC in the blood, not in vitro, to determine its true half life - there are likely factors in vivo that may be affecting their half lives. A poor metaphor would be stating that all fish live only a minute or two because once you grab one out of the water they die quickly. These cells may be exhibiting longer half-lives in vivo while being simultaneously inhibited from dividing or settling down (which mirrors most malignant cell behavior - not increased mitiotic activity, but decreased apoptic loss).

 

At 1/15/2005 12:51 PM, Blogger Orac said...

I'm aware that CTCs are not a newly described phenomenon, and perhaps I should have pointed that out. (In fact, if I submit this post to the Tangled Bank in a couple of weeks, I will probably correct that oversight.) What is new, however, is the detection of CTCs in patients so many years after definitive treatment of their cancer and after so many years of apparently cancer-free survival. That, to me, is what made this study interesting and worth commenting on.

Also, I must point out here again that the investigators did look at the half-life of CTCs in the blood. As I explained, they measured the number of CTCs in breast cancer patients before surgery and then drew blood at various times after removal of the cancer. From the CTC counts measured at various time points, they used one- and two-compartment models to estimate the half-life of the CTCs in the blood.

Finally, I apologize if I was unclear, but I do not see how I was lumping breast cancers into a single entity when I said that breast cancer is unusual among cancers in its propensity to recur very late. True, I did leave out renal cell cancer as a cancer that can recur very late, but renal cell cancers are not really all that common compared to breast cancer.

 

At 4/12/2005 12:05 AM, Anonymous Angela said...

What about the notion of cancer stem cells as an explanation for tumor dormancy? Notably, Al Hajj while a post-doc at Michigan, authored a fascinating paper in PNAS in 2003 demonstrating that breast cancer stem cells do exist and can be isolated/identified by flow cytometry. Extrapolating to other cancers therefore is not unrealistic since most tissues have stem cells, and although rare, have the same probability of mutation as differentiated cells.

 

At 6/20/2005 8:11 AM, Anonymous Anonymous said...

What does CTC stand for? (Please excuse my ignorance . . .)

 

At 7/22/2005 7:31 PM, Blogger hollywoodjaded said...

Circulating tumor cells (CTCs)

 

At 7/29/2005 12:12 PM, Blogger utenzi said...

In addition to Angela's suggestion of cancer stem cells is micrometastatic clusters. These small clusters of cells seem to remain dormant, by that I mean that there's no angigenesis thus restricting size, for years sometimes decades. What activates them is unknown as far as I know but DNA microarrays are being used in a shotgun attempt at ferreting out this information.

 

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