Evidence Mounts on Heart Failure After Trastuzumab in Breast Cancer Survivors

[Hopeful]

I posted the above referenced article in the Articles Forum last week. At Michka's suggestion, I am posting the link to it here as well: http://her2support.org/vbulletin/sho...eferrerid=1173

Hopeful

[gdpawel]

There are a number of issues on the subject of Herceptin. In addition to taking this drug for a long time, these kind of individual, targeted oral drugs would be taken in addition to an existing repertoire of chemotherapy mixtures a cancer patient is already taking, instead of taking them alone. Adding even more potential toxicities and thousands of dollars to treatment.

Overt congestive heart failure is a very late and serious manifestation of heart muscle damage. For every patient with frank congestive heart failure, there is probably another two, three, four or five patients with heart muscle damage short of congestive heart failure. The sort of heart muscle damage which can cause fatigue and/or shortness of breath with moderate or mild exertion, which otherwise wouldn't occur.

We don't know what will happen 10 or 20 years from now in women who didn't need any adjuvant therapy at all, who would have been cured by surgery alone. Only a minority of patients who receive adjuvant therapy benefit from it. Adjuvant therapy is worth it if the women have to suffer only short term, temporary toxicity, and if it even slightly reduces the probability that their cancers will come back. But if it produces permanent toxicity, whether "chemo brain" or "heart muscle damage," that is a whole different order of magnitude in terms of risk.

Aside from the issue of congestive heart failure, past studies have suggested a potentially very serious weakness in the drug, the problem with central nervous system (CNS) metastasis. A study from the Dana Farber Cancer Institute identified central nervous system (CNS) metastases in women who receive trastuzumab-based (Herceptin) therapy for metastatic breast carcinoma. Central nervous system disease is defined as one or more brain metastases or leptomeningeal carcinomatosis (carcinomatous meningitis).

Central nervous system metastases was identified in 34% of patients at a median of 16 months after diagnosis of metastatic breast cancer and 6 months from the beginning of Herceptin treatment. Patients receiving Herceptin as first-line therapy for metastatic disease frequently developd brain metastases while responding to or stable on Herceptin. The authors of the study say that efforts to characterize other risk factors for development of CNS disease, optimal screening algorithms, and new treatment strategies may be warranted.

The potential benefits and risks of Herceptin have renewed concerns about the reliability of HER2 testing. Some studies have shown that the test produces false positives as often as 26% of the time, and may also carry some risk of false negatives. Herceptin also doesn't offer any benefit to women with HER2-negative cancer.

Lastly, monoclonal antibodies like Herceptin (and Erbitux) are "large" molecules. These very large molecules don't have a convenient way of getting access to the large majority of cells. Plus, there is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside, which are protected from the drug. The cells may pass small molecules back and forth.

Exciting results have come from studies of multitargeted tyrosine kinase inhibitors,"small" molecules that act on multiple receptors in the cancerous cells, like Tyberb and Sutent. Targeted "small-molecule" therapies ruled at last years annual ASCO meeting of oncologists. The trend is away from the monoclonals to the small molecules, a trend in which a new predictive test may be able to hasten (Cancer 2003 Jun 15;97(12):2972-7).

Rrisk of Heart Failure in Breast cancer Patients After Anthracycline and trastuzumab treatment: A retrospective cohort Study

http://www.oxfordjournals.org/our_jo...wlesdjs317.pdf

Editorial: Herceptin and Congestive Heart Failure

http://www.oxfordjournals.org/our_jo...igerdjs342.pdf

[MJsHusband]

I wonder if the use of TDM1 will have a similar risk since it contains Herceptin?

[gdpawel]

I believe there was one member on the board who commented that a lady who was doing well on the T-DM1 trial, discovered she had 15 brain tumor mets. T-DM1 is a "large molecule" and does not cross the blood-brain barrier (BBB). She thinks on the T-DM1, they should also give the ladies some straight Herceptin, which she thinks will cross the BBB and give a certain amount of protection. The only way for that to happen is a patient may also have to be subjected to an "intrathecal" injection of T-DM1. Herceptin does not cross the BBB because it is a "large molecule" drug. The board member also had a small metastasis to the brain. She stated that she'll be on T-DM1 "indefinitely" or until progression.

The trial found that trastuzumab emtansine (T-DM1) can improve progression-free survival in "some" women with metastatic breast cancer. The final arbiter of clinical approval is overall survival. Median overall survival for patients treated with T-DM1 was not reached. Drug response is not a reliable predictor of overall survival. Median progression-free survival was longer in patients treated with T-DM1 than in those treated with the standard therapy (9.6 vs 6.4 months). The difference reached is statistically significant?

The so-called immunoconjugates or antibody-drug conjugates (ADCs) are unique therapeutics that have become the focus of a plethora of recent and ongoing clinical trials, and for the first time since 2000 when Mylotarg (gemtuzumab ozogamicin) was approved in AML, the FDA gave the green light for another ADC, namely Adcetris (brentuximab vedotin) for the management of Hodgkins Lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL), like its sister agent in HER2-positive breast cancer, T-DM1, and other ADCs.

The ADCs do not work for all patients, T-DM1 is meant to treat only roughly 20 percent of breast cancer cases characterized by an abundance of that protein, and they are not totally free of side effects. And of course, T-DM1 is also likely to be very expensive, costing more than $100,000 for a typical course of treatment. One note: Mylotarg was removed from the market in 2010 after newer studies showed it did not prolong lives and had safety problems. At initial approval, Mylotarg was associated with a serious liver condition called veno-occlusive disease, which can be fatal.

One thing you can definitely say is that T-DM1 is an investigational agent, or just plain experimental.

http://cancerfocus.org/forum/showthread.php?t=3768

[MJsHusband]

I'm hoping for the best for MJ with her Tykerb-only treatment. I wish for her to respond and stay NED without bringing Herceptin back in the picture. We were really disappointed when she had mets with Herceptin in January. These heart risks are a bit scary. I don't know if T-DM1 is the best treatment, but there certainly seems a lot of excitement about getting it.

[gdpawel]

MJsHusband

Exciting results have come from studies of multitargeted tyrosine kinase inhibitors, "small" molecules that act on multiple receptors in the cancerous cells, like Tykerb. Unlike (reversible) Herceptin, which only goes after the Her2 gene, also known as epidermal growth factor receptor (EGFR) type 2, (irreversible) Tykerb goes after Her1 (EGFR) but also Her2 (EGFR type 2). Tykerb irreversibly binds to EGFR and Her2. It works by blocking these receptors, preventing their activation and hopefully inhibiting the unwanted signaling pathways. And Tykerb is a BBB crossing drug.

Best wishes to MJ

Greg

[MJsHusband]

Thanks Greg. I always appreciate your informative posts on here.

MJsHusband(Greg) : )

[hutchibk]

Just wondering if folks on it know to have a knowledgeable cardiologist on board, and are taking either or both Lisinopril or Coreg? (ace inhibitor and if needed a beta blocker)? As well are they execising and eating right? What is their age? Do they have any prior heart issues? Just curious...

It's certainly not everything, at all, but it's a start.

[gdpawel]

Brenda has brought up an extremely important suggestion: having a knowledgeable cardiologist on board. Drs. Douglas L. Mann and Ronald J. Krone, both of the Division of Cardiology, Washington University School of Medicine, St. Louis, put this situation into perspective.

"The management of heart disease in all its forms in patients with cancer in all its forms presents special challenges to the cardiologist. In the war on cancer, the cardiologist is not in the front lines, directly confronting the enemy, but in the role of support and supply, providing the oncologist the ability to keep the warrior strong enough to defeat the enemy. In fighting the war on cancer, there is, like in any war, unwanted 'collateral damage.' There is no 'silver bullet' but, in many ways, a refined shotgun, blasting the tumor while pellets hit other vital organs. The bone marrow, liver, and nervous system get their share of hits; but the heart and vascular system are certainly at risk depending on the weapon used, particularly because the vascular system and blood supply are intimately involved in any treatment delivery. Just as in a war, not only must the enemy be destroyed; but the damage must be contained to permit the rebuilding of the homeland."

http://cancerfocus.org/forum/showthread.php?t=3218
http://cancerfocus.org/forum/showthread.php?t=3711

Greg

[Sheila]

This could be the reason that when I went to the cardiologist a couple weeks ago, he was telling me these issues were discussed at a recent convention of cardiologists, and that treatment with Coreg and or Lisinopril
Should begin BEFORE thenHerceptin and chemo...so as to strengthen the heart before treatment ever begins. he also said most cardiologists prefer the accuracy of Echocardiograms and most Oncolostists seem to order Muga scans....there is usually a size able difference in readings.

[DeenaH]

I have been on herceptin for 2 years now, and have had a cardiologist on board for a year. I get MUGAs every 3 months, and check my triponins every 6 weeks. So far my EF has stayed between 64-72% since my very first chemo. I think checking triponins regularly is important since it can indicate very early heart muscle damage. I'm now on Pertuzumab along with the herceptin plus a little tykerb, so my heart health is always a worry.

[phil]

T DM-1 deserves all the hype its getting, despite Greg P.s' persistent skepticism. Genentech has offerd ot to all pts in EMILIA who got tykerb/xeloda. That tells you something right there. When dealing w/ a her2 cancer that progresses on herceptin, thats extra aggressive -aggressive tx is needed. Tykerb/ xeloda is very often intolerable because of nasty s/e -hand/foot syndrome, g.i. distress and related wt loss. I havent heard of it being prescribed by itself very often, i know it didnt hold Lorraines cancer back more than 6 months or so. And that was w/ xeloda. Have heard of dozens of t dm-1 pts with 1-2 yrs , some 3 + and counting.
In EMILIA i believe 65% of the pts who got t dm-1 were still alive after 2 yrs.
I think t dm-1 will largely supplant tykerb in tx of aggressive, high overexpressed her2 cancer, for a few yrs, until something better comes along. Tyk.'s ability to cross bbb is important, for those whose cancer goes that way. Lorraines goes to her liver area. I am hoping tdm-1 keeps it from going any where else, shes ned on scans since last Nov., 22 months all told so far, and shes far from the only one reporting yrs of stability. The QOL is un-believable, tyk/xel one of the worst for s/e of the 7 or so tx combos she tried.

[gdpawel]

The widespread and inappropriate use of chemotherapy is an obstacle to controlling cancer growth and metastasis in patients. Patients would certainly have a better chance of success had their cancer been "chemo-sensitive" rather than "chemo-resistant," where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most "effective" chemotherapy would be more likely to improve survival. It would seem more prudent to invest the time in using diagnostic technologies for detecting cancer growths, as well as the properties of cells that are destined to metastasize, and match the most "effective" therapeutics to your "individual" cancer cells, not average populations.

[phil]

I am not going to debate too long on the above issue. My focus is on reforming the present cancer drug approval process, and having it reflect the advances in cancer tx in the 21st century. Greg, I hope more effective " individual " cancer screening tests get tested and approved . Quickly. But i say it again, i feel your focus on that issue , your desire to see Rat. Ther. more widely used , is affecting your perspective on related cancer war issues. I dont think you are in the chemo room like we are. I think some of your generalizations about herceptin risks affect that . you are not the only one. FDA officials are similar. If i took your approach with issues , I would be questioning everything the FDA Oncology review division does . I am not. They have kept un-safe drugs off the market , at least gave quick partial appr. to pertuzumab. I am glad that the prevous FDA admin gave accelerated approval to tyk. in 07 ", even tho i feel it is a lesser drug to t dm-1.
These stats on herceptin have to be put in perspective. I am grateful for herceptin , it has saved countless lives . It helped get my wife to t dm-1. even tyk played a small role. My first wife never saw herceptin, in 88-"92. No testing for her2 genethen. Talk about progress , back then adria was the drug everyone pinned thier hope on ! No taxanes even. herceptin by itself cures 20 %, w/ chemo , more. Of course as we see yrs of use , problems become evident. cardiac issues in 30-40 %, doesnt cross bbb in 30-40 %. that stat becomes clearer only because herc has kept so many alive for so long. But we in the chemo room say : without herceptin , whats the percentage of survival , compared to pre-herc. To talk up tykerb, and talk down t dm-1 w/ minimal info on it, is biased on your part .

[gdpawel]

I was in the trenches Phil. I was in the infusion rooms with my wife to know what goes on. I experienced the inappropriate use of chemotherapy to control cancer in patients we met. And those that never showed up again because of it. And I experienced it with my wife. So there is no need to belittle me with that innuendo. Performing laboratory oncology deserves the same degree of professional time and attention as random selection of chemotherapy. In fact, instead of random selection of chemotherapy. There would be a huge advantage for patients to receive a positive/sensitive drug, compared to a negative/resistant drug. The time and energy required to conduct proper "individual" selection pales in comparison to the time, energy and lost opportunities associated with months of ineffective, toxic therapy. I feel your focus on pushing a pharmaceutical company's drug is a disservice to the many that will not be helped by it. The system is overloaded with drugs and underloaded with wisdom and expertise for using them. We are getting an expanding list of treatments which are partially effective in a minority of patients, ineffective in a majority, remarkably effective in a few, while being enormously expensive. Whatever clinical response that has resulted to the average number of patients in a randomized trial is no indication of what will happen to an individual at any particular time. The fastest way to improve things is to match treatment to the patient. Neither would I like to debate this issue too long, but I will defend misrepresentations of my cancer patient advocacy.

[michka]

I asked Hopeful to post on this forum to be sure that everyone watches their heart because it is not always our first priority.
But I don't mean we must stop Herceptin or TDM1 or other drugs because of that. For example we now know that ACs are toxic and sometimes we can avoid them. More and more but not always.
I would love to have tests telling me if a chemo will work for me without having the medical system pay for nothing and maybe having toxic side effects. But we don't have those tests yet.
So Phil and Greg you are both right. Your arguments are good. It is just an open discussion. You are two major contributors to our Group. We need you.
I am so grateful to both of you for sharing all your knowledge with us and fighting on our side. Michka

[phil]

I apologise if you felt I was belittling your personal experience , i know your overall mission is to ease unnecessary suffering . remember i lost awife too, when chemos wer much more rudimentary than now. I agonized over our tx choices did we choose the best tx. ?, etc. in the ned i know we did the best we could w/ what we had at the time. This reminds me of meeting an FDA official , who said " I havent been thru what your wife has, i had prostate cancer txed yrs ago ". I said, " If you have ever sat in an oncologists office, and saw that glowing spot on a scan " then you have been where we are at " But, I stand by my comments about This FDA and I stand by my feed back on some of your statements about percieved shortcomings in drugs like herc., t dm-1, and others . vs the overall survival rate without these drugs .

[gdpawel]

I understand Michka. And I can understand if someone wants to make a case for something, then make that case and back it up. But don't make that case by questioning someone else's integrity. I am an independent cancer patient advocate and have been for numerous years. I am not beholden to any drug company, laboratory, medical equipment manufacturer, insurance carrier, professional organization or hospital group. I get nothing out of my endeavors except the satisfaction of knowing that I've helped to increase the knowledge of informed consent. I get no pay, no lectureships, no junkets, not even any free meals. My point with respect to cell function analysis is to educate patients (even doctors) that such science and technology exists, and might be very valuable. I except Phil's apology and leave it at that. I certainly hope he continues his drug advocacy and hope that he would not impinge on another's credibility. Thanks Phil!

Greg

[Mandamoo]

This has been an interesting thread to follow. I see positives and think that in the current climate both Greg and Phil are correct. It is also different in other countries.

As a patient with stage 4 disease, I have to find treatments within the current system - I can't wait for the culture to change to personalised medicine so I need new treatments to be approved and studied to enable access to options.

So, TDM1 had an impact for 40% (my understanding is this 40% includes partial and complete response), the number kept stable I am not sure of. I believe now that the survival endpoint has also been reached. For me, I've tried to access personalised medicine here in Australia and got very limited results so far (politics yet again) seeing this type of research being stymied by authorities. I was one of those women for whom anthracyclines were useless for and thus progressed from 2b to 4 within months during intensive horrible treatment. So I would sure like to see treatment tailored to the individual but for now I am willing to take my chances on something even if it is effective in 1% - that might be me - I just want the chance to give it a go. As I see it I could die taking it and sure as hell I could die not taking it.

As for the Tykerb - Herceptin debate - surely there is room for both and again this depends upon the individual and I wonder why more research and trials are not happening with Tykerb if it has this potential as a small molecule to cross the BBB and have less cardiotoxicity.

I am about to enter the Teresa trial - maybe I will get TDM1 - maybe I won't - if I draw control we are going to use Tykerb and Herceptin. In Australia these two drugs are not funded to be used together and I will have to pay fully for one of them, even on trial - this is a cost of $50000-$60000 a year.

So for now we have to do the best with what we have, within the current system and hope that knowledge, procedures and medications become more personalised in the future.
Thanks for debating this - it is interesting if somewhat frustrating.

[gdpawel]

Amanda

In regards to the Tykerb - Herceptin debate, what is of particular note is that monoclonal antibodies (like Herceptin) are large molecules that attach to specific proteins on the outside of cancer cells and do not have a convenient way of getting access to a large majority of the targeted cells on the inside, which are protected from the drug. Plus, there is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside. The cells may pass small molecules back and forth. This would be a very good reason Tykerb may be much better than Herceptin.

Tykerb was one of the first oral agents with the potential to compete directly with the IV drugs which is both a high-volume and high-revenue part of office-based practices. Although oral tyrosine kinase inhibitors, like Tykerb, offer patients a well-tolerated, conveniently administered alternative to intravenous (IV) therapy, Decisions Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, found that oncologists were not yet ready to use Tykerb as a replacement for Herceptin. Ninety-one percent of surveyed oncologists stated that intravenous (IV) cancer therapies are more profitable than oral therapies. And fifty-eight percent of oncologists said they would favor IV Herceptin over oral Tykerb because administration of IV drugs remains an important source of income for their practices.

Greg