Early stage bc "survivors" - and Herceptin

[AlaskaAngel]

Micrometastases often persist in breast cancer patients
Reuters Health
Posting Date: March 8, 2005
Last Updated: 2005-03-08 11:27:01 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Despite undergoing surgery and receiving adjuvant therapy, most patients with early-stage breast cancer have bone marrow micrometastases up to 4 years later, according to a report in the March 10th issue of the International Journal of Cancer.

Dr. Martin J. Slade, from Imperial College London, and colleagues used a quantitative PCR (QPCR) technique they developed to look for transcripts of cytokeratin 19, a cancer marker, in the blood and bone marrow of 131 women with breast cancer, most of whom had node-negative T1 disease. These results were compared with standard immunohistochemistry findings.

All of the patients were treated with surgery and adjuvant therapy and had no evidence of metastatic disease on conventional scans.

About half of the patients had QPCR or immunohistochemistry results that indicated bone marrow micrometastases before surgery, the authors note. Of the 91 subjects who had repeat samples taken, 87% and 65% had evidence of metastatic disease at some point with QPCR and immunohistochemistry, respectively.

Systemic adjuvant therapy seemed to have an effect on residual disease. Among patients with residual disease before treatment or at 3 months, 32 of 44 displayed a drop in the CK19/ABL ratio and 15 of 24 showed a drop in cytokeratin-positive cells during follow-up, the authors point out.

"We have demonstrated that in a substantial proportion of patients, minimal residual disease persists using the techniques that we have developed, and that it is possible to monitor patients, preferably using both QPCR and immunohistochemistry, after breast surgery using bone marrow aspirates," the researchers conclude.

Int J Cancer 2005;114:94-100.

[AlaskaAngel]

The article I just posted is just one study, but I have to continue to ask for more consideration for those who have completed treatment.

As someone with early stage bc I have found it hard to "know" how much risk is involved when choosing how to deal with bc.

I think women who are HER2 should be very, very persistent about understanding what choices they could have, and especially now those with early stage bc.

As someone who completed treatment with Adriamycin in 2002 (without any taxane), the only option I have heard so far that is being offered to women like me is to start Herceptin alone, which MAY provide somewhere around 13% greater protection.

For those with early stage bc who are just now looking at treatment, the Herceptin results indicate that by having Herceptin at the same time as Adriamycin (with taxane), the protection is far better than 13%.

The article I posted indicates that most of us early bc have micromets despite having had chemo. I think it is important for those of us who have completed chemo in the past, and who it seems are only going to be eligible for herceptin alone, push for a complete answer as to whether having more Adriamycin + taxane actually might work to help us avoid or further limit recurrence.

Yes, it might mean losing our hair again, and being sick again.

Yes, there is a lifetime limit on the total amount of Adriamycin we can each have.

Yes, both Adriamycin and Herceptin affect the heart muscle and that has to be considered.

But what I think remains to be determined is whether those of us who have hearts that can be proven to be adequate by way of MUGA scan or echo, and who believe the option should be OURS to consider, could go through perhaps something like dose-dense Adriamycin + taxane + Herceptin rather than just settling for adding Herceptin now -- and get greater benefit similar to that received by those who will be going through treatment now for the first time. Perhaps even having just 2 treatments (to limit the amount of Adriamcin) could make that kind of a difference for us. Who knows?

The population that demonstrated the recent success with Herceptin was a different population, one that had never had chemotherapy at all. So I think we need to have a clinical trial for early bc survivors who have had chemotherapy that was not given concurrent with herceptin and may not have included a taxane -- limited to those whose hearts are capable of withstanding it.

I was told when I chose to do chemotherapy that it does not extend survival, it only puts off recurrence or limits the number of recurrences one would have.

I think a clinical trial needs to be offered in behalf of those of us who went through the torture of chemotherapy that is already proven not to extend survival.

AlaskaAngel

[lori]

I'm confused about what you're proposing. What sort of trial are you suggesting? It sounds like you think you should have more chemo, but perhaps I'm misunderstanding. If micromets exist after treatment, and if chemo and rads only put off recurrance (as you were told), why would you want (for yourself or others) more treatment?

[Lani]

Here is an Abstract from ASCO 2005 which needs clarification---were any of your oncologists in attendance to clarify?

Meeting: 2005 ASCO Annual Meeting <nobr>Printer Fr
<nobr>Bo

Category: Breast Cancer
SubCategory: Adjuvant Therapy



Neoadjuvant chemotherapy does not effect presence of micrometastases in bone marrow of breast cancer patients
Abstract No: 867
Author(s):G. Gebauer, T. Fehm, K. Klich, M. Anna-Maria, P. Baier, H. Maul, M. Eichbaum, N. Fersis, C. Sohn
Abstract:Background: The idea of adjuvant systemic therapy in breast cancer patients is to eliminate occult tumor cells which may already disseminate at a very early stage. The presence of occult tumor cells in bone marrow of breast cancer patients without evidence for clinically relevant metastatic disease is associated with worse overall and disease-free survival. However, it is unclear whether cytostatics may eliminate those occult tumor cells. Methods: Bone marrow aspirates obtained during surgery in breast cancer patients with locally resticed disease without evidence of a metastatic tumor cell spread were immunohistochemically stained with anti-cytokeratin antibodies in order to detect disseminated tumor cells. In a matched pair analysis bone marrow results of patients receiving neoadjuvant chemotherapy were matched with patients undergoing surgery first followed by adjuvant therapy. Results: Thirtyfour patients receiving neoadjuvant CTx were included into the analysis and matched for clinical stage and age with 34 breast cancer patients undergoing primary surgery. Detection rate of micrometastases was 23 out of 34 in the neoadjuvant group compared to 13 out of 34 in patients receiving surgery first followd by adjuvant therapy. Both groups did not significantly differ in clincal stage, age or bone marrow status. Interestingly, in 2 patients receiving trastuzumab in a neoadjuvant setting, no disseminated tumor cells were detected after systemic therapy. Conclusions: Our results suggest, that bone marrow status - which is highly correlated to survival - is not affected by cytostatic therapy. Therefore, adjuvant therapies in patients with micrometastases in bone marrow may include additional strategies in order to specifically target cells of a minimal residual disease.
Associated Presentation(s):

Trranslation--chemo alone did not clear the micrometastasis from the bone marrow, but again neoadjuvant chemo is usually given for a relatively short period of time. What wasn't clear was whether the 2 patients were given Herceptin monotherapy (ie, Herceptin alone) or in combination, or in sequence with chemo.

This may have enormous implications in the recommendations regarding what to do for those who do not feel they received optimal therapy ie, in deciding what makes sense in terms of what to do to "catch up"!

Hope this confusion does not produce more frustration!

Lani

PS They have theorized that, since micromets are found years later in people who function normally with NED that having a few cells around in one's bone marrow is fine as long as there are so few that the immune system keeps them under control. The bottom line is--they just do not know. But just because we can measure something, doesn't mean it is something that can do harm!

[Cheryl]

Thanks Lani. Still a little hard to hear for the first time for me, that micro mets hang around in most of us. Is that what this is saying? And if so, is there evidence that herceptin with Taxol during the first treatment eliminates it?

[*_AlaskaAngel_*]

Thank you, Lani. You covered my question very, VERY well. You explained it much better than I did. Micrometastases are an indicator of worse prognosis, but the importance of maintaining a strong immune system may make a difference in whether one ends up with mets -- we just don't know.

I simply want more investigation as to whether using the combination of Adriamycin, a taxane, and Herceptin simultaneously in early stage HER2 positive bc patients (those who completed treatment before that combination was widely available/known to have such good results in patients newly diagnosed) could effectively deal with the residual micromets in the bone marrow to avoid recurrence.

I would think that this would be worth considering a clinical trial, particularly in those patients who are HER2 positive T1c or those in stage II.

In reading various posts from women with early stage bc and HER2 positive who have already spoken with their oncologists, the only option I've seen discussed is the option of having these women go on Herceptin alone, which has additional benebit but nowhere near as much benefit as the combination therapy had in the women who were newly diagnosed.

Also, there is the question (for the women who have never had Herceptin but who have had standard chemo regimens) as to whether Herceptin is is best reserved for later in the event they do have a recurrence, rather than starting it now.

I keep in mind that there are a number of women who are not going to respond to Herceptin, period. There are also a number of women whose hearts might not be able to handle any added Adriamcyin or Herceptin.

I just don't feel comfortable with the limited explanation from the conference about this, because it seems like lack of more discussion about the possibility will result in many women not understanding or even asking about this option and just going on Herceptin alone.

A.A.

[Percentage points versus percent]

Hi everyone,

I think that you're getting confused by the statistical terms. I have looked at the HERA study closely and for all categories from no node to 4+ nodes, the reduction in risk was around 46%, but this translates into difference percentage POINT gains for different groups, since they start with different chances of recurrence.

I'll try to keep this simple, since I know that stats are confusing (I was one the teaching assistant for a new stats teacher who couldn't teach. Boy did he confuse them).

First you take the chance of recurrence and multiply it by 46% (.46) to get the estimated benefit of one year of herceptin by itself. Then add that number to the existing chance of disease free survival to get the new odds.

So, if there is a person with a 20% chance of recurrence, the gain is 9.2 percentage points (20 * .46). The new chance of disease free survival would be 80% plus 9.2% which is 89.2%.

If someone has a 60% chance of recurrence, the gain is (60*.46) = 27.6 percentage points. The new chance of a disease free survival is 40% + 27.6% which is 67.6%.

Likewise, in the herceptin studies, herceptin reduced the risk of recurrence from somewhere around 30% to 15% or 15 percentage points, but this meant that it reduced the risk of recurrence by 52% (30 * .52). (HERA and the herceptin-based chemo results are not directly comparable, since there was no one standard type of chemo used in HERA).

While I know that the chemo-based herceptin option has had a longer followup time, I am just worried that this misunderstanding may cause people to press for an option that may not benefit them as much as they expect and that has risks.

[*_Christine MH_*]

Sorry everyone. That was me trying to clarify statistics. I confused her2support with the other board I post on, where the line at the top is the postings title! I better watch out or everyone will really believe that academics are completely absent minded.

[*_jeff_*]

Hey Christine,

Would you mind posting the link to your other board so I can try to follow the discussion there?

Best,
Jeff

[*_jeff_*]

Oh, Christine, never mind mine just above--I'm rereading yours and realize you just meant you put a mistaken header. At first I thought you meant that you had meant to post this whole thing on another board.

But I think you're right that lots of us are confused about the numbers and difference between relative risk reduction, absolute risk reduction and so on.
The ASCO presentations were so sketchy that they encouraged this kind of confusion I think. A lot of us (I think) watched those webcasts and came out with the conclusion that the concurrent arm (taxol + herceptin) had a 52% reduction and the consecutive arm (taxol then herceptin) had a 13% reduction. But that's apples and oranges, isn't it? The 52% must be a risk reduction percentage and the 13% must be what you're calling a percentage point gain. Does that sound right?

Jeff

[*_Christine MH_*]

Jeff,

Yes, you've got it! I am glad that I was able to get the point across. I must say that I had to look at some sections of the presentation several times before I figured out what was going on and I am used to reading statistics.

One of the problems with the two studies is that they are not directly comparable. About one-third of the women on the HERA trial had no nodal involvement and any standard chemo was allowed, including rather antiquated ones like CMF!

I think one thing, too, that needs to be kept in mind that HERA was not as far along as the other trials and therefore the results are not quite as certain because it is based on statistics from a smaller number of women. There is something called the p-value, which is the probability that something is purely a coincidence. If there is just a one in a hundred chance that something is pure chance (p=.01), it is definitely considered "statistically significant," although anything below five in a hundred (p=.05) may be considered statistically significant. Right now there is about a two in a hundred chance that the HERA results are pure chance, probably due to a shorter followup time. As I recall, the odds that the combined results of the two other trials were pure chance were below 1 in a billion (I don't know the exact number, partly because I am not used to dealing with such small numbers, but from what Dr. Sledge said in the presentation, neither was he).

Take care,

Christine

[Cheryl]

Thank you for such good insight Christine. Can you tell us then, where can we get any kind of reliable starting point for using this formula? What I mean is, with treatments in the past five years, what are our chances of survival or reoccurrence, really. On the Mayo Clinic website if you follow it to breast cancer, than to adjuvent therapies then to "your own personal chances" there is a calculator that uses age, lymph node status, tumor grade and hormone status, and then shows 10 year survival without reoccurrence at baseline prognosis, then with different treatments. According to them, an early stage bc survivor has say between an 80-93% chance of being alive in 10 years without reoccurrence, depending on the variables. The most aggressive treatment they base their highest success rate on is ACx4 every 2 weeks + Taxol x4 every two weeks + Tamoxifen. I imagine they will at least soon be updating this to replace Tamoxifen with Femara from what we have seen out of ASCO this time. There is no separate consideration given to HER2, but obviously there were HER2 positive people in the overall 10 year tracking of patients of the general population. Also, if these reports about bone marrow micromets are accurate, they certainly must apply to this overall population as well.

[*_jeff_*]

Thanks from me too, Christine. This is (and will continue) to be difficult to understand.

And as you say, there will never be a way to compare the US trials to the HERA trials since the chemo regimens were so varying. Not to mention the hormonal regimens (for er/pr+ women).

But it at least helps to feel like we're interpreting the extant data correctly!

Best,
Jeff

[*_AlaskaAngel_*]

Thank you all for your comments. Even though it is a difficult topic to discuss both emotionally and statistically, from what I've seen in this "conversation", silence by ignorance or fear would be worse.

Human nature being what it is, I think most medical providers are going to be as confused for a while about some of this as we are. I'm holding off from asking my doctors how all of this applies in my situation until more of the dust settles.

I guess the question that still bothers me most is the "my" idea that "the numbers" in regard to the added advantage of herceptin from these clinical trials are based on people who were having chemo for the first time -- not on those who completed it a while back. So, wouldn't it still be important to see what the results were by clinical trial from those who finished chemo some time ago before just putting these people on herceptin alone?

I hope that this forum will continue to provide the opportunity for raising such questions and trying to find the answers to them.