anthracyclines to become an adjuvant chemo of the past?

[dlaxague]

Hello all,

Did anyone watch the Project LEAD webcast this evening presented by Dennis Slamon? It was about anthracyclines. Some of it was what he presented at SABCS last year. He has not released the full results yet but much of what he based his discussion on is research that has already been completed.

He admitted that this is a controversial topic but that he does not understand why there is opposition to dropping anthracyclines, because there is not a single study that supports anthracycline efficacy over other chemotherapies. Most recent "others" looked at have been TC and TCH, but CMF has been compared also.

The apparent increased benefit offered by anthracyclines, upon closer analysis, is limited to only HER2+ cancer, and upon even closer analysis, to only HER2+ cancer that also overexpress topo2a (I think he wrote it as TOPO IIa, I'm being lazy). HER2+ cancers overexpress topo2a about 1/3 of the time. HER2 negative (he made mention of HER2 "normal", rather than negative) cancers never overexpress topo2a. So the increased benefit of an anthracycline exists only for a small percent of all breast cancer - 1/3 of the 1/4 of all breast cancer that are HER2+.

Even more important, when Herceptin (and/or probably Tykerb) is used, there is no additional benefit to using an anthracycline (even for topo2a + cancers), and there is significant increase in potential harm, including increasing risk of heart damage and of leukemia.

Bottom line statement by Dr. Slamon was that there is no place today for anthracyclines in adjuvant treatment for anyone, except in countries that do not have access/can't afford Herceptin.

He also stated that epirubicin is not any better than adriamycin. He said that studies that seemed to show that did not compare equivalent doses of the two anthracyclines.

Dr. Slamon said that his results probably would not be released in time for SABCS - he thought more likely ASCO.

The webcast will be archived on the NBCCF's Project LEAD website. I do not know when that will happen.

And lastly, when this information about anthracyclines first came out, many women interpreted it to say that the anthracycline they received for adjuvant treatment "had been for nothing". That is not what this is saying. It is saying that all chemos offer benefit. Anthracyclines offer benefit, they just do not offer any INCREASED benefit over other chemos and they have more serious side effects so they do increase harm. No increased benefit but increased harm = "why are we using this class of drug?"

Debbie Laxague

[Mary Jo]

Hi Debbie,

Thanks for the informative post. Looks like adriamycin may just one day (sooner than later) be a thing of the past for us her2 gals/guys huh? I was one of the lucky?? beneficiaries of this drug. Thankfully, at least at this point, I had no heart issues or any other from this drug and hope it helped me somehow.

Thanks Debbie for taking the time to share this with us.

Love & Peace,

Mary Jo

[Rich66]

Hhmmm...but there's that doxo zol acid info that I posted a while back in Articles section. Well..maybe that means zol after other therapies might do the same?

[AlaskaAngel]

Hi Deb,

Offhand, I wonder too:

1. Big Pharma had an overstock left?

2. It is cheaper than newer drugs?

3. It causes some GI side effects that are fairly immediately obvious, so it seems more "toxic" to some practitioners and ergo, more "effective"?

[Chelee]

Debbie, Thanks for posting this. I knew nothing about any of these chemo drugs when first dx. But my very young new onc choose TCH for me. I asked if there were other options and he said no...I would be treated with "TCH"...period. Later when I found the Her2support board I found everyone here had been treated with AC it seemed. I was very upset because I wondered why I had no say in my treatment options at all when the other her2 women had AC...& many even had DD AC.

Being dx stage IIIA, her2 3+++, 5 positive nodes, Richardson scale 9 of 9...I wanted to be treated as aggressive as possible. I had many tell me TCH was a good choice but it still bothered me that at that time I was pretty much the only one as a stage III'er getting TCH? But now almost 3 yrs out it seems to have been a very good choice...and knock on wood I'm NED and doing great so far.

I know I had two other oncologist tell me after I finished treatment with TCH that I should of had AC..followed by TH. They said they would of never treated me with my dx with just TCH. (That sure didn't make me feel very good after the fact.)

I follow everything I can find on this topic from Dr. Slamon and I have confidence now that this was the best way to go for me. It took time...but I'm good with it now. Thanks so much for your post Debbie...I really appreciate it.

Chelee

[hutchibk]

Thanks DL and I appreciate your translation for me! I had 'big red'/'the red devil', and it definitely lived up to it's reputation... but I am grateful for all of the treatments I have gotten up to this point because they have all played a part in my ongoing existence! It sure is fascinating, though, to watch the progress in the treatments... and to see the potential of what was once thought of as the backbone of bc chemo - get close to being ushered out of the door. Bye Bye Adria. Don't let the door hit 'cha on the way out. LOL

[Christine MH-UK]

I hated anthracyclines and they didn't seem to do that much judging from the MRIs. Nearly five years after diagnosis, I assume that it was the taxotere or herceptin that worked.

Too many women have been rendered ineligible for herceptin because their hearts were damaged by anthracyclines previously.

I suppose that the other oncologists are holding off until they can run a trial that proves this (knowing how conservative they can be).

In general, there needs to be a lot more of this type of research since too many women are getting drugs that don't benefit them and have extreme side effects. Fortunately, I think that medical researchers realise this.

[Mary Anne in TX]

Thank you Debbie!
I can't say I'm sorry to see the red devil go. I can still remember sitting out at the water's edge one morning during adria/taxotere and wondering whether to jump in the water or find a tall building. I couldn't believe my mouth hurt so bad!
But worst of all, my tumor loved the stuff and grew like topsy during the time!
Thanks again for the simple explanation and for making time to watch and share! ma

[chrisy]

Debbie thanks for this posting.

I saw Dr. Slamon in this discussion at SABCS last year (the Alamo advocate panel) - it was very controversial and in fact the discussion got a bit heated! I was so enthralled by the tone of the argument that some of the details got lost! It was almost "Jane, you ignorant slut" (for those who remember when SNL was funny I know I'm dating myself)

So basically his thinking is/was that if you ARE in the small % of people on whom adria would work (Her2+ and TopoII), you would do just as well on Herceptin plus other chemos. If you were not in that small percent, you would get no advantage anyway.

Conclusion in both cases, why suffer the side effects (do harm) if there is no benefit?

Good to see that as our understanding becomes better, we continue to move away from unnecessary toxicity.

[dlaxague]

In the webcast at some point, Dr. Slamon mentioned that there had been a "robust" debate between him and Dr. Buzdar (who thinks anthracyclines have an important place in current treatment). Here's a link posted on the LEADers list, to an article about that debate.

http://www.cancernetwork.com/breast-.../10165/1264037

if that doesn't fit, here's the tinyurl:

http://tinyurl.com/3jzm2h

Debbie, who had adriamycin also, without Herceptin (not available outside of trials then). I'm NED and my heart is fine (knock wood).

[Rich66]

" HER2+ cancers overexpress topo2a about 1/3 of the time. HER2 negative (he made mention of HER2 "normal", rather than negative) cancers never overexpress topo2a."

Hmmm. Does this mean testing for topo2a could be another way to confirm Her2 positivity when FISH results are equivocal? Is topo2 readily testable? I've never heard of it.

[chicagoetc]

How do we know if we overexpress topo2a? [I.e. if we are one of the 1/3 who do benefit from anthracyclines.]

Also maybe not everyone is sure that the anthracyclines are ineffective...?

http://www.cancer.gov/clinicaltrials...hracycline0108

http://cancer-of-breast.blogspot.com...-everyone.html <-probably not that helpful for the discussion here

[dlaxague]

Rich asked: "Hmmm. Does this mean testing for topo2a could be another way to confirm Her2 positivity when FISH results are equivocal? Is topo2 readily testable? I've never heard of it."

Hi Rich,

No, Topo IIa is not another way to confirm HER2 positivity. Some researchers (see slide link, below) have found Topo IIa overexpression or amplification in the absence of HER2+ but Slamon says it only happens when HER2 is positive. If you look at the slides (again, link below), you'll get a visual of how the two genes are adjacent and thus, sometimes (1/3 of the time), similarly altered.

(I did ask (we could type in our questions, or ask them on the phone) if they had found any correlation (why does that word have two "r's" - it just means co-relation, right?) between length of the overexpressed area on the gene and FISH ratios and he said that they had looked at this and the answer was "no".)

He also said something like "at this time, Topo IIa is not a commercially available assay but it can be done" - not sure what the means exactly. Obviously, they're able to test for it to do these studies. Perhaps the standardization of the test is lacking and that would explain why others have gotten different results.

However, if Slamon's right, there is no need or reason to test for Topo IIa because with Herceptin (and probably Tykerb) the response is equal whether anthracyclines are used or not - even for the Topo IIa positive cancers. His point, again, is that the anthracycline would make a difference only in countries without access to Herceptin (and probably Tykerb) and then in only about 8% of all breast cancer.

Here's some more slides and perspectives, including all the ones Slamon used last week. Look at the Buzdar argument also (previous message).

http://clinicaloptions.com/Oncology/...%20Cancer.aspx

Whoa. Let's try tinyurl: http://tinyurl.com/47kmyr

Debbie

[dlaxague]

Your second link didn't work for me. The first one talked of anthracyclines in the absence of Herceptin, as nearly as I could tell from the abstract. And Slamon agrees with that, although he breaks it down further into HER+ AND topo2a+. But now that Herceptin is a standard part of adjuvant treatment for HER2+ bc - even for HER+ and topoIIa+ cancers, anthracylines do not appear to offer additional benefit over Herceptin and a nonanthracyline chemo (TCH for example).

The more that they find and break down these subgroups, the more they are finding that regimens that appeared to offer an advantage to all do not, after all, offer an advantage to many. They offer an advantage to one small subgroup but it's such a strong advantage that in the larger, less-specific group, it appeared to offer an advantage, either because they didn't break it down into subgroups, or more often, because they did not (at that time) even know that the subgroups existed. Does that make sense?

Debbie Laxague

PS: So a question has occurred to me and I haven't let it sit long enough to digest whether it makes sense. Does it make sense to you? "So – we already know that Herceptin “works” for only about half of all HER2+ cancers, for reasons yet unknown (right?). It would not be unreasonable to think that some percentage of those who do not respond to Herceptin would still be Topo2a positive and so alhough they missed Herceptin’s benefit, they could still reap an anthracycline’s improvement in DFS or OS. But it doesn’t look like that’s true, in the studies cited. Is that because we’re getting into such small subgroups that the n’s just aren’t large enough? Or is there some relationship between Topo2a overexpression and Herceptin response?"

[Rich66]

"Some researchers (see slide link, below) have found Topo IIa overexpression or amplification in the absence of HER2+ but Slamon says it only happens when HER2 is positive."

Sounds like some fundamental areas of this research might be unsettled.

I'd like to see how this matches up with the Doxo, Zoledronic acid combo trial as the results come in later this year.
I wish there was a similar trial using taxanes instead.

[chicagoetc]

Debbie, thanks. It sounds like there is an evolving understanding of the best treatments and of what chemo is best for whom. I appreciate you taking the time to post here and to open up a dialogue about this. It makes sense to me that not all chemotherapy regimens work for everyone. Also sounds like the more researchers know...the better for us. Melanie

['lizbeth]

Dako receives FDA approval of TOP2A FISH pharmDx™
15th January 2008

The US Food and Drug Administration has given Dako PMA approval to market its TOP2A FISH pharmDx™ assay. The assay is intended as an adjunct in determining the prognosis for high-risk breast-cancer patients.
Dako, a world-leading provider of cancer-diagnostic solutions, is the first company to receive FDA approval for a TOP2A diagnostic test for breast-cancer patients.
The test, TOP2A FISH pharmDx™, is marketed to assess clinical breast-cancer tissue specimens for changes in the status of the TOP2A. This information aids physicians in evaluating the prognosis for breast-cancer patients, since patients with normal TOP2A status have a better outcome than patients with TOP2A gene amplifications or deletions. TOP2A FISH pharmDx™ provides new prognostic information for additional groups of patients and may serve as an adjunct to existing HER2-testing.
“We are very pleased to announce the FDA approval of our TOP2A FISH pharmDx™ test. The TOP2A FISH pharmDx™ kit adds a new dimension to the way breast cancer will be treated in the future, giving oncologists and pathologists a reliable tool when assessing the disease prognosis for individual patients,” says Patrik Dahlén, CEO and President of Dako.
TOP2A FISH pharmDx™ is part of Dako’s range of pharmacodiagnostic products, and is based on the fluorescence in-situ hybridization (FISH) technique. TOP2A FISH pharmDx™ also has the CE-label within the European Union.
About TOP2A
TOP2A is a molecular target for the pharmacological action of anthracyclines. Anthracycline-based chemotherapy with doxorubicin or epirubicin is one of the most active regimens in breast-cancer treatment. However, these compounds have serious acute and long-term side effects, such as cardiotoxicity and leukemia. The predictive implications of TOP2A amplifications for optimal use of anthracycline therapy have been established for many European patients. It is an area of active research with promising initial results that require confirmation and extension in the context of currently available chemotherapeutic options. Whether TOP2A amplification is an independent predictive marker of response to any type of treatment (chemotherapy or immune-based) has yet to be determined in the United States.
Media contact:
Dako A/S
Anne Thommesen, Corporate Communications, +45 40 63 95 93
You can subscribe to news from Dako online at www.dako.com/news.
Dako, based in Denmark, is a global leader in tissue-based cancer diagnostics. Hospital and research laboratories worldwide use Dako’s know-how, reagents, instruments and software to make precise diagnoses and determine the most effective treatment for patients suffering from cancer. Employing more than 1000 people and operating in more than 70 countries, Dako covers essentially all of the global anatomic pathology markets. Dako is owned by a private equity fund, EQT.www.dako.com

[hutchibk]

Hey Debbie-

here's a question for you - is there any value of finding out one's topo2 status after you are metastatic? would it change anything regarding treatment options?

[dlaxague]

(here's a question for you - is there any value of finding out one's topo2 status after you are metastatic? would it change anything regarding treatment options?)

... and I don't know the answer. Certainly, anthracyclines are used in the metastatic setting. It might be in part that historically, the longterm perspective (heart damage, leukemia) seemed irrelevant for women who were only living a year or two? Now that women with a metastatic diagnosis are living much longer than that, maybe they'll take another look and try to postpone taking the anthracyclines out of that toolbox until they've used up all other options, whether someone is topo IIa+ or not?

Remember that it's not that anthracyclines don't work for everyone - they do (about as much as any other chemo "works"). It's that it appears that they offer that additional small incremental benefit only to Topo IIa positive cancers.

Great question - anyone else have answers?

Debbie Laxague

[Jean]

I just went with a friend whose sister was dx.
with bc...to see her sister's onc. to hear her treatment plan.

she was staged the follow:
Stage 2
1.2 CM tumor
ER positive
Node Positive 1/3
HER 2 Negative
vascular invasion
Do not know the grade
Muga Scan was done and she is 60+

She is a normal weight, does not have any other health issues....she does exercise and she is 65 yrs. old.

The onc. treatment plan is 4 A/C and 4Taxol.
I asked him outside the office when we were alone about TC and he said he wanted to be aggressive
due to the node/and vascular invasion. When I mentioned since she was not Her2 positive...was it
necessary for the A/C. He still felt this was the best treatment.

I have e mailed him this article.

I am a great believer in Dr. Slamon as many on the site already know. He has always been ahead of the pack.
He tested me in 2006 for TOPO 11 and I was neg.
So when he recommended TCH I was confident with it.

I am concerned for her and her treatment - since she
is not HER2 positive. Please share your thoughts.

Thanks,
Jean