putting risk of brain mets as first evidence of recurrence in perspective

[Lani]

These researchers could not identify a group of early breast cancer patients in whom THEY FELT prophylactic MRIs of the brain were justified --now for Stage IV patients that may be a different story...(and, of course, they were not the patients themselves)

Will try to look at original article and see if their her2+ group was defined by IHC (AND HOW POSITIVE WITHIN THIS GROUP) OR FISH--

ABSTRACT: Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG) [Annals of Oncology; Subscribe; Sample]
Background: We sought to determine whether a high-risk group could be defined among patients with operable breast cancer in whom a search of occult central nervous system (CNS) metastases was justified.

Patients and methods: We evaluated data from 9524 women with early breast cancer (42% node-negative) who were randomized in International Breast Cancer Study Group clinical trials between 1978 and 1999, and treated without anthracyclines, taxanes, or trastuzumab. We identified patients whose site of first event was CNS and those who had a CNS event at any time.

Results: Median follow-up was 13 years. The 10-year incidence (10-yr) of CNS relapse was 5.2% (1.3% as first recurrence). Factors predictive of CNS as first recurrence included: node-positive disease (10-yr = 2.2% for > 3 N+), estrogen receptor-negative (2.3%), tumor size > 2 cm (1.7%), tumor grade 3 (2.0%), < 35 years old (2.2%), HER2-positive (2.7%), and estrogen receptor-negative and node-positive (2.6%). The risk of subsequent CNS recurrence was elevated in patients experiencing lung metastases (10-yr = 16.4%).

Conclusion: Based on this large cohort we were able to define risk factors for CNS metastases, but could not define a group at sufficient risk to justify routine screening for occult CNS metastases.

[athena453]

Well, I certainly think I would fit into the "nonexistent" group for whom screening would be recommended, since I am Her2+, under 35, had a grade 3 tumor and was hormone negative...

Had a clear brain MRI 5/6/06.

[R.B.]

"and treated without anthracyclines, taxanes, or trastuzumab"

This is how the evaluation group above is defined if I read it correctly.

The risk are below or round 5% at ten years except for the group with lung mets.

I have not searched the subject but my recollections of the rate of brain tumours for those treated with chemo and herceptin was a lot higher.

Does anybody have the figures for brain tumours fro those treated with chemo and herceptin.

IF it is indeed higher is this a reflection on chemo or herceptin / AND what is chemo hercepin doing to cause any higher incidence.

Any idea when this trial was done or its aim.

IF it is indicating what it seems to suggest fascinating indeed.

RB

[Lani]

I haven't had a lot of time in the last few days, but I did get the original article and found it used IHC but not with the DAKO test. No FISH was done. As with many studies out of Europe UNTIL RECENTLY, they did not treat anyone with very small tumors at all(systemically, anyway) and ER+ node negative tumors only got tamoxifen(or more recently an AI). I did see from a quick look at the table that tumors were both ER+ and ER-. I did not look to see if they counted microinvasion as "tumor" Will try to get around to studying it further, but I did not feel this article was the DEFINITIVE one or I would not have added " they FELT" to my post.

Also patients in the clinical trials are a distinct population--they disqualify people in the wrong age group (too old), with other diseases, they test her2 centrally (or at least in labs with better accuracy), and they try to make sure certain characteristics are fulfilled (US studies node positive generally, HERA both + and -). And the type of patients who participate in clinical studies are more compliant (only 50% OF PATIENTS DO ACTUALLY TAKE THEIR ANTIHORMONALS IT HAS BEEN ESTIMATED) THESE ARE BUT A FEW OF THE DIFFERENCES OF THE PATIENT POPULATION SO COMPARISONS ACROSS STUDIES IS FRAUGHT WITH DANGER. THERE WAS A LOT OF CRITICISM EVEN THAT THE TWO US ADJUVANT HERCEPTIN STUDIES WERE COMBINED!

HOPE THIS HELPS!

[Becky]

I will let you know my theory on why folks treated with chemo and herceptin may experience more CNS mets that those who do not. Again - my thoughts only (based on cell biology mechanisms that are known).


1. when there is a primary tumor present, that primary tumor does send out anti-VEGF factors into the body. These factors prevent any micro mets that may be present not to be able to grow at the rate of the the primary tumor. This is a smart self preservation technique. The primary tumor says "I want all the nutrients etc. I am king here!!!" This is one reason why the oncs want you to start chemo asap after surgery and not wait too long (usually they want you to start within 3-4 wks of surgery) because, if micro mets are out there, they do not want them to take hold and be able to grow blood vessels (since the "king" is now gone). That said....

2. Let's say you did have a rash of cancer cells leave your tumor and lodge in various (and lets say common) places in your body - lungs, liver, bones and brain. You get your tumor removed and have chemo and herceptin. Neither crosses the blood brain barrier. Therefore, lets say this tx is successful and kills all the micromets.... except for the one(s) in your brain since the drugs could not reach it.

I think this might be the reason that if you do have systemic mets, CNS mets happen much much later in the process. Your "liver" mets curtail the growth of the brain mets (at least until a chemo/herceptin regime starts to knock out the liver mets and thus, the anti VEGF substances produced by the mets (which are secondary to the primary breast tumor but since that was knocked out (with surgery) the mets become the "new king".). (I sure hope I am making myself clear here).

So... why less CNS mets if only a hormonal is employed? It is well know that tamoxifen crosses the blood brain barrier so that is easily one answer.

Secondly, although it is not absolutely, entirely clear if aromatase inhibitors (AIs) cross the blood brain barrier, it is not important that they do in order for them to protect the brain. The reason for this is that they work to reduce and/or eliminate the production of estrogen. No estrogen, no binding to the estrogen receptor, no stimulation for a ER+ bc cell to grow and divide. So, all ER+ cells would be starving for estrogen and die (no matter where they are located and lodging).

Basically - chemo and herceptin protect the body but AIs and tamoxifen protect the brain (something we all hope Tykerb will do for those with Her2 and Her1 disease - especially if you are also NOT hormone positive as well).

I hope this is understandable because I do have a tendency to get ahead of myself.

Kindest regards

Becky

[R.B.]

Interesting idea.

My developing strictly amateur think in the wind is:

The more I read the more evident how complex it all is. So on the balance of probabilties the result of intervention is likely to be equally complex if all the ramifications were fully understood. It is unlikely to be just one mechanism.

As to grabbing resources it sounds like the way a baby behaves at a very basic level. Maybe that is what a cancer is - an evolutionary survival strategy brought about in an emegergency situation where the body has lost the ability to cope, so in some ways reproducing reproductive mechanisms.

But what caused the conditions for the stromal bed to develop, and then the tumour to develop in the first place.

If it is as least in part fats linked

- does chemo tamoxifen herceptin etc at least in part intervene in the fat pathways.
- I have seen trials that suggest herceptin and tamoxifen do,
- and odd hints that I have not followed up that chemo might.

So you have interupted the omega six eicosanoid pathways, at some level or other, Archnidonic acid production, Cox 1 and 2, or at the lower PG LOX levels, (which lower levels are reported also as having strong links to reproductive pathways - taking things apart re building new blood supplies fundmantal level access to gene instructions).

The growth signals are interupted and cancers are inhibited to varying extents - except the body being very robust and endlessly resourceful trys to find ways round these road blocks and often suceeds.

BUT chemical or biological Interruption of fat pathways could/would also mean long chain omega three shortages - so? the body does what it does in pregnancy and robs the brain of DHA to supply other needs. This increases the omega three six imbalance in the brain and pushes the stromal condtions towards those that are conducive to cancer. (it is reported brain tumours have been observed to show low n3 and high n6)

The situation is exacerbated by the lack of omega three in most diets. The body is denied the body the raw materials. It start emergency procedures using second and third preference fats in membranes etc. If the brain is not blocked from fatty acid synthesis because chemo herceptin etc do not reach into the brain it is going into fat production overdrive to try and make up DHA depletion. High six continues to fuel the PGs etc. Breakdown!!! Emergency evolution procedure - We call it cancer.

Further once the omega three six balance is pushed beyond certain limits the preferential pathways of long chain omega three production are reported as breaking down so the ability to produce may well be limited by lack of omega three sources, excess of omega six, and chemical / biologicial inhibition, contributed to by poor digestions, liver function etc.

Add to that the suggestion I have seen reported that trans fats are incorporated instead of omega three - new fats unknown to the body - Chaos?

IF the omega three six imbalance is a factor the draining of the brain of DHA to fufill other body needs would put the brain at a high level of risk.

End result? - a higher level of brain tumours in those receiving treatments that intervene in the fat pathways combined with poor diet, digestive imbalance, lowering of the immune system leading DHA depletion in the brain by a number of mechanisms, but leaving the brain free to go down eicosanoid pathway in an attempt to catch up.... no raw materials..... emergenecy.... more panic.... use any fat to hand...... eventual breakdown - emergency evolutionary evacuation procedures - outcome unknown - cancer except for the few who find another path.

RB

[karenann]

Becky,

Your theory makes sense!

Thanks,

Karen

[Bev]

Thanks RB and Becky. I keep trying so hard to understand all this and I think it will eventually sink in after a year or 2. So Becky is saying ER+ that do hormonals shouldn't have cns mets, and RB is saying if diet isn't balanced, therapy itself may cause mets? Looking forward to the day when we have the answer. BB

[R.B.]

Bev: Succinct Summary!


We need statistics (assuming RT and excision as standard)

1. % Brain mets with treatment chemo and herceptin

2. % Brain mets with treatment chemo herceptin and hormonals.

3. % Brain mets with treatment hormonals

The figures above as observed seem to relate to the third group.

It was be interesting to see if hormonals have the same impact with or without chemo and Herceptin. It would provide additional in sight into the impact and workings of chemo and herceptin.

Can any body help with a link on stats for the other two. I know I have seen some material on chemo and herceptin but do not recall where. I think there was an expression of concern in the HERA trail.

RB

[R.B.]

Some more data on brain tumour figures.

Not the most cheerful of reading.

From Lani's post early BC follow up median 13 years no chemo no herceptin - Risk less than 2-5%.

From below metastic BC - treatment status unknown - follow up period unknown 10-15%

HER 2 - threatment status unknown - follow up unknown 25-35%.

I will try and see what else I can find.

Can anybody add to this?

RB

http://www.azcentral.com/health/wome...survivors.html

ABSTRACT

.................About 150,000 Americans a year are diagnosed with "metastatic" brain tumors, meaning the cancer has spread from another location, usually their lungs or breasts. The chances that a woman with metastatic breast cancer will develop brain tumors is 10 to 15 percent. But these odds appear to be worse for a woman such as Soscia, whose breast cancer has a genetic mutation known as HER2-positive that makes it very aggressive. Twenty-five to 35 percent of women with metastatic HER2-positive cancer end up with brain cancer, Winer said...............

[Becky]

RB


The 25% - 35% statistic for Her 2 is correct for women who have metastatic disease to begin with (ie: they are being treated for bc in their liver or lungs etc). I do know that for Her2 bc that metastasizes, in 10% of the cases the brain is the first metastatic site (the #1 site for a first met is the bones and I think 45% is the statistic there).

Now, that 10% is of the percentage of Her2s that do have a recurrence. This depends on stage etc so you can use published statistics there for all bc then add 10% (this is what my onc told me).

For example, if you are Stage 2A, statistics are that you will be disease free for 5 years at 76% but he told me that Her2s would be 66% (before Herceptin as an adjuvant). So, lets use 66% anyway. It means that 34% will have a recurrence. 72% of recurrences are local (this is a general statistic and not a Her2 statistic but we will use it for this exercise anyway) so that means that 28% are distant. 10% of that is 2.8% get a brain met (as the first distant met) (and most Stage 2s get chemo - let's face that as the tumor has to be over 2cm with no nodes or any size up to 5 cm with 1-3 nodes).

All brain met statistics with herceptin have to be coming from those with metastatic disease first (at this point) since using Herceptin as an adjuvant is so new (even for the women who were the first ones in the trial).

I will look for some stats in my files (but later on today as we are going out shortly).

Kind regards

Becky

[R.B.]

An earlier "small" trial suggestion no difference between herceptin group and control group in rate of spread to brain in metastatic patients.

But much better prospects as to spread to bone if I reas the trial correctly.

RB


http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum

ABSTRACT

1: Clin Breast Cancer. 2003 Jun;4(2):114-9. Related Articles, Links
Click here to read
Increased rate of brain metastasis with trastuzumab therapy not associated with impaired survival.

Lower EE, Drosick DR, Blau R, Brennan L, Danneman W, Hawley DK.

University of Cincinnati Medical Center, Department of Internal Medicine, OH, USA. lowere@uc.edu

Trastuzumab is important for treatment of metastatic breast cancer patients with tumors that overexpress HER2/neu, but its penetration to the brain is poor. The aims of this study are to determine the prevalence of bone and brain metastasis during therapy, to compare the survival of breast cancer patients with brain metastasis who received trastuzumab to those patients not receiving trastuzumab, and to assess the impact of brain metastasis on the overall survival of trastuzumab patients. Of 103 patients treated with trastuzumab, 16 had brain metastasis and 43 had bone metastasis at the beginning of trastuzumab. The control group consisted of 196 patients with metastatic breast cancer who had never received trastuzumab. Six had brain metastasis and 75 had bone metastasis at the beginning of therapy. During therapy, only 9 of 60 trastuzumab patients (15%) developed bone metastasis, while 170 of 186 control patients (91%; c2 = 129.8, P < 0.0001) developed bone metastasis. In addition, 22 of 87 trastuzumab patients (25%) and 58 of 190 control patients (31%) subsequently developed brain metastasis. Control patients without brain metastasis experienced significantly better survival (median survival = 928 days) than those with brain metastasis (median survival = 639 days, c2 = 8.34, P < 0.005). There was no difference in survival for trastuzumab-treated patients if they acquired brain metastasis (median survival = 1400 days) or no brain metastasis (median survival > 2000 days, c2 = 0.12, P > 0.05). Patients receiving trastuzumab were unlikely to develop new bone metastasis but were as likely as control patients to develop brain metastasis. However, patients who developed brain metastasis experienced better survival compared with those patients with brain metastasis who never received trastuzumab.

PMID: 12864939 [PubMed - indexed for MEDLINE]

[R.B.]

Here is another summary which leave the conclusion open, but suggests increase in due to survival rather than effect of Herceptin.

RB.

RB
http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract

1: Br J Cancer. 2004 Aug 16;91(4):639-43. Related Articles, Links
Click here to read
Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer.

Clayton AJ, Danson S, Jolly S, Ryder WD, Burt PA, Stewart AL, Wilkinson PM, Welch RS, Magee B, Wilson G, Howell A, Wardley AM.

Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester M20 4BX, UK.

Trastuzumab is an effective treatment for patients with metastatic breast cancer (MBC) that overexpresses HER-2. A high incidence of brain metastases (BM) has been noted in patients receiving trastuzumab. A retrospective chart review was conducted of 100 patients commencing trastuzumab for metastatic breast cancer from July 1999 to December 2002, at the Christie Hospital. Seven patients were excluded; five patients developed central nervous system metastases prior to starting trastuzumab, and inadequate data were available for two. Out of the remaining 93 patients, 23 (25%) have developed BM to date. In all, 46 patients have died, and of these 18 (39%) have been diagnosed with BM prior to death. Of the 23 patients developing BM, 18 (78%) were hormone receptor negative and 18 (78%) had visceral disease. Univariate analysis showed a significant association between the development of cerebral disease and both hormone receptor status and the presence of visceral disease. In conclusion, a high proportion of patients with MBC treated with trastuzumab develop symptomatic cerebral metastases. HER-2-positive breast cancer may have a predilection for the brain, or trastuzumab therapy may change the disease pattern by prolonging survival. New strategies to address this problem require investigation in this group of patients.

PMID: 15266327 [PubMed - indexed for MEDLINE]

[Alice]

I asked my onc about brain mets hearing so much about them. What she told me was put very simply.She said that we are getting so much better results at curing systemic disease that we are now seeing more brain mets only because many of the people who get them would have in the past died from the systemic disease before brain mets were discovered. Also chemo and herceptin don't cross the blood brain barrier. The new drug latunib (bad spelling)however does cross.

Alice

[R.B.]

Complex as usual.

And an interesting thread.

And as Lani points out its dangerous to jump to conclusions. I try not to but had wondered if a non chemo herceptin group might expose differences of any sort with a chemo herceptin group.

My mind direction was, is there a greater incidence of brain mets consequent on treatment by Chemo or Herceptin or both. Most of the discussion I had seen in passing was those already in treatment with herceptin and chemo, and hence my belief that the figures were higher. I do vaguely recall concerns that brain tumour rates with herceptin might be higher in absolute terms.

The answer is probably we don't yet have the figures for early BC treatment.

The earlier post on fats is the result of trying to put a lot into a small space in terms that were comprehensible. It is based on reading and the thoughts largely of others, albeit often in little snippets here and there. The connection of cancer with the reproductive pathways and evolutionary pathways is not new but is on the edges. The more one reads on fats the more their importance and functionality is evident. Anybody who has read in this area will have got the jist of what I was saying even if they held very different view points.

I apologise for the typos etc my touch typing is not all it should be (A Mavis Beacon CD student) and I have no access to a spell check in the version of posting engine I have access to. I can be a bit word blind and suscribe to the view of a famous news paper editor that getting the general message out is the most important element.

Thank all

RB