getting bone marrow tests at the time of surgery, after adjuvant treatment MAY ALLOW

[Lani]

second adjuvant therapy of those who do not respond to the first line and improve survival

That was the hypothesis they set out to prove and they got through the first step...showing that persistent cells predict increased risk of relapse. Now the need to give a secondary treatment (hopefully based on the phenotype of the persistent cells detected) and see if this improves survival rates

Wouldn't it be lovely if there was something to do rather than wait for the tumor to come back to determine if the treatment undergone had actually WORKED? A way to quickly determine if the treatment worked (like pCR for those with large tumors who can be treated neoadjuvantly) in order to progress to more effective treatment promptly

This will need determination of the best techniques of harvesting, preserving and preparing the samples for examination, determination of the best techniques to determine and phenotype these cells and wide-spread availability and quality control of these determinations, usually performed by pathology departments.

This article recommends larger studies to determine if using these as indicators for trying a second line of adjuvant treatment will improve survival--about time! Sorry for the editorialization, but I have been trying to find out why bone marrow sampling is not more widespread for quite a long time. I usually hear that patients don't like it--how can they not like what they don't know and haven't been offered? Could a little soreness for a few days possibly be worse than chemo for months?

One oncologist told me it is because they now train oncologists who are not also hematologists (they all used to be both) and they are not used to doing them or good at doing them so they just don't want to and keep hoping the technology of CTCs will improve enough for CTCs to be used as guides.

Articles so far show DTCs (in bone marrow) are much more indicative of failure of treatment/risk of relapse and metastasis) than CTCs and it might be a long time before they sort out all the different systems, antigens to get CTC testing reproducible, as well.

As those who have been through chemotherapy, would you fine ladies volunteer for a trial to see if bone marrow testing could predict failure of the treatment you had just been through....would it be preferable to just waiting for a bone to break,etc (since scans without symptoms have few champions among oncologists as well)?

Clin Cancer Res. 2011 Mar 17. [Epub ahead of print]
Persistence of disseminated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse - a European Pooled Analysis.
Janni WJ, Vogl FD, Wiedswang G, Synnestvedt M, Fehm TN, Jueckstock J, Rack B, Borgen E, Braun S, Solomayer E, Pantel K, Nesland JM, Friese K, Naume B.

Department of Gynecology and Obstetrics, University of Düsseldorf.
Abstract
PURPOSE: The prognostic significance of disseminated tumor cells (DTC) in bone marrow of breast cancer patients at the time of primary diagnosis has been confirmed by a large pooled analysis. In view of the lack of early indicators for secondary adjuvant treatment, we here evaluated whether the persistence of DTC after adjuvant therapy increases the risk of subsequent relapse and death.

EXPERIMENTAL DESIGN: Individual patient data from 676 women with primary diagnosis of early breast cancer stage I-III from three follow-up studies were pooled. During clinical follow-up, patients underwent bone marrow aspiration (BMA) to determine the presence of DTC. Tumor cells were detected using standardized immunoassays. Univariate and multivariable proportional hazards models were estimated to assess the prognostic significance of DTC for disease-free and overall survival.

RESULTS: Patients were followed for a median of 89 months. BMA was performed at median 37 months after diagnosis of breast cancer. At follow-up BMA, 15.5% of patients had DTCs. The presence of DTC was an independent indicator of poor prognosis for disease-free survival, distant disease-free survival, cancer-specific survival and overall survival, during the first five years following cancer diagnosis (log rank test P-values <0.001 for all investigated endpoints).

CONCLUSIONS: Among breast cancer patients, persistent DTC during follow up significantly predicted increased risk for subsequent relapse and death. Analysis of DTC might serve as a clinically useful monitoring tool, and should be tested as an indicator for secondary adjuvant treatment intervention within clinical trials.

PMID: 21415211

[Chelee]

After all I've been through the last 5 yrs, I would gladly volunteer for a trial like this. To be able to determine if your trt worked right away would be so valuable...it's awful to do chemo and not know if it's worked or not? I think this would be another great tool to use & it's way over due.

Lani, you said you have been trying to find out why bone marrow sampling isn't been done more frequently? Onc's can tell you it's the patients...but I feel it's the other way around. My 1st baseline PET showed activity in both femurs and it was highly recommended that metastasis be ruled out. I asked my onc for a bone biopsy at the time and she told me that I did not want to do that because they are so painful! She told me I'd be on crutches for wks after having it done. She scared me out of doing it. It's probably the cost of doing bone biopsies, and bone marrow aspirates that stops them? I can't help but think that plays a big part in it? Even though in the long run it could save lots of money by finding out which chemo's worked for us.

I went to see another onc not long ago due to increased uptake on my ilium & he ordered a bone biopsy. (Something my onc would of never done.) I had a bone marrow biopsy and bone marrow aspiration to my left iliac crest. I was not looking forward to it but it wasn't as bad as I anticipated. I just felt some pushing and pulling...some banging. lol Then they run you in and out of the CT several times to make sure they pinpoint the right spot for the sample. But all in all it wasn't that bad. I have scoliosis..so laying on the table for 45 minutes was the worse part for me. It was well worth it after I read the report that came from those samples. My left femur area was a little sore for about a wk afterwards but it wasn't that bad. So I would definitely do it again knowing the benefits from the biopsy. We need tools like this.

Chelee

[Ellie F]

Interesting, I only got a bone marrow aspirate when I had low platelets. As Chelee said it wasn't pleasant but manageable.
It didn't answer the question about my low platelets (and still hasn't) but at least reassured that there were no cancer cells present!
Ellie

[Debbie L.]

Lani, do you have the full text? I'd like to see the specifics of how reliable this test was. What I've seen before is that it's not very reliable. Yes, a higher number of people with DTCs relapse but it was nowhere close to everyone with DTCs does and no one without them doesn't.

Plus, wouldn't it, at this point, just put us where we are with now with neoadjuvant treatment and no pCR? Wondering what to do? There are only a few "post neoadjuvant" studies looking at this issue and they are pretty much shooting in the dark.

It's one thing to have these tests if we have a treatment to offer. But right now (alas), we've given it our best shot with the first treatment, as tailored to the tumor details as we currently know how to do. Instead of giving more treatment, I would like to see us focus on giving better (more targeted) treatment first time 'round so we didn't have to think about mopping up later.

Right now, I can only see DTCs as useful for learning more. Testing new drugs and/or pinning down treatments that kill stem cells, perhaps. Understanding more about the metastatic process perhaps. But not as a tool for treating any one individual.

Debbie Laxague

[Lani]

Debbie, you sound like an oncologist (in fact your points are those I hear/read again and again in journals and meetings of oncologist, but not in meetings of cancer researchers seeking to understand the disease to better treat it)

There are tests that phenotype single cells, whether ctcs or dtcs, to determine what pathways are driving these cells and they should be much more indicative of what kills individual patients, the mets, rather than the primaries.

What is left over after a PCR (or failure to reach pCR) can be very different from what is in the bone marrow. For one thing the cell usually left the tumor early, long before the tumor was even biopsied and the tumor may have had different characteristics or clones with different characteristics may have developed since. The primary tumor may also be heterogeneous and the area sampled for hr, her2 testing may not indicate all areas of the tumor, let alone the ones which survive the chemo.

Let's say for example that the primary is heterogeneous and has clonal areas which are HR+her2- and HR+her2+ for example. The micromet may be different than that portion of the primary tumor they characterized and so the primary treatment would not work on it. If they are in fact bc cancer stem cells and rarely divide the same chemo which killed the bulk of cells in the primary tumor may not affect them as chemos affect dividing cells.

Knowing what cells are there and what they represent can only IMPROVE treatment. If people keep hiding your head in the sand and saying it won't change treatment how will ever get to a point where treatment CAN BE improved?

I think that the ability to phenotype individual cancer cells eg DTC as the ultimate ability to help an individual cancer patient with their individual cancer--true personalized treatment. Whether society will say personalized treatment is too expensive in the future is another thing altogether.

Until someone tries we will not know and right now few clinical trials even ask for bone marrows, not even the I-Spy trial.

As for the papers, just put K Pantel into PubMed--there are lots of them including those specifically discussing her2+ DTC

Just like her2 testing was not widely performed in an acceptable and reproducible manner at first, bone marrow testing for DTC needs to be improved. But saying not to do it because it is not well tested for and won't change treatment is throwing in the towel without trying. The recent Swiss article posted here was an example of that thinking. How about trying to improve the testing, learn what can be learned and then deciding whether it pans out that we can change the natural history of the disease?

Will get off my soapbox now.

[Trish]

I am hoping there will be a time in the future when personalised medicine will be cheaper as there will not be so many false starts.A lot of money is poured into large scale trials but the problem is that the methodology and statistics assume homogeneity and humans are not homogenous. Yes it will be good to understand metastatic processes but we have to come to grips with the variety of ways in which humans respond. I would have been willing post adjuvant therapy to have have had bone marrow sampling to determine the effectiveness of the treatment if the test had a good chance of being valid and reliable and if it guided future treatment. More to the point I would have been willing to be part of a trial with that end in mind.
Trish

[Debbie L.]

Hi Lani, thanks for the reply. I actually share much of your soapbox with you (if there's room up there, smile), about personalizing and targeting treatment.

I think what I was trying to say was that if we could personalize primary treatment well enough, there would be no need for DTC study. And that would be my first choice.

The other thing is that I'm worried about those who do have circulating DTCs and/or poor neoadjuvant responses. Of course, worried that we don't have something to offer them but also wondering if we should even be doing a test that gives them bad news without offering a course of action based on that news.

I have had it drilled into me (as a nurse, not oncology-related) that you should never do a test unless you know that the results of the test will dictate action. So I guess where that leaves me right now for DTCs is saying that they could be studied in trials, and probably not in trials designed just to look at DTCs -- but as adjuncts to other trials that are looking at more pragmatic and immediately-useful things.

As for better understanding of pathways -- I just don't know. The more we learn about that, and especially about the clever ways cells have to activate other pathways in response to inhibition of the one we think is the driver -- the more complex it all becomes and the less likely it seems to me that we'll be able to stop cancer with this approach. But that's just my uneducated gut-reaction opinion. I hope I'm wrong.

Debbie Laxague

[Lani]

If we never did tests for which we didn't yet know the best course of action to treat the result (disease) or even any action, we would still be bleeding people and placing leeches on them (OH! I guess that is still done! oh well!)

Our knowledge of what causes diseases and how to treat them is tiny in comparison to what we don't know. Only by looking can we hope to find out.

Look at all those women who have volunteered to give tissue, blood and other samples to Dr. Love's program.

I agree that the risk of adverse effects of the test itself must be taken into consideration (including psychological ones) but believe with education and informed consent much is possible.

Not being a nurse, I escaped having my mind drilled into in that way. I guess I just look at things more from the point of view that if you don't look how will you ever discover how things work/don't work?

I also feel trying to graph and make mathematical models of multiple pathways is probably not the way progress will be made. I like to think that scientists observing rare phenomena which shine light on bigger issues make more progress eg the advances in leukemia after the discovery of families bearing the Philadelphia chromosome.

By the way, as I understand it if a "DTC" is "circulating" it is not called a DTC. Those are CTCs and may or may not be the same cells as DTCs, which reside in the bone marrow. So far, it seems DTC are more indicative of poor prognosis or poor response to therapy than CTCs but that may change as the technology to detect and identify CTCs improves.