her2 breast cancer cured (when transplanted in mice) using triple targetted therapy

[Lani]

vs her family:

Combination treatment stymies breast cancer growth [Eureka News Service]
HOUSTON (May 5, 2007)—A combination of three different drugs that block the HER-2 receptor, a critical cellular growth signal for some breast cancers, eradicated aggressive breast tumors in mice and could point the way toward developing better treatments inpatients, said researchers from the Breast Center at Baylor College of Medicine in a report that appears today in the Journal of the National Cancer Institute.
"For the first time, we were able to cure mice of a very aggressive human breast tumor," said Dr. Rachel Schiff, assistant professor in the Breast Center at Baylor College of Medicine and senior author of the report.

In prior such studies, treatment only slowed or delayed the growth of tumors, she said. In this case, the tumors disappear and do not come back, even when treatment is stopped.

The treatment involved is a new approach known as "targeted" therapy because the protein (in this case, HER-2) driving a tumor to grow is first identified in a patient's tumor and then specific drugs are used to block that particular growth pathway in the cells, said Dr. Kent Osborne director of the Breast Center and the Dan L. Duncan Cancer Center with BCM. He is also an investigator on the study.

"When you go after a specific target in a patient's tumor, the treatment is likely to be more effective and less toxic," said Schiff.

The tumors in question - nearly 25 percent of all breast cancers - have high levels of HER-2. While the HER-2 makes the tumors more aggressive, it also provides a target against which new drugs can act.

Previously, treatment for patients with HER-2 positive tumors was less effective.

"Now we have effective treatment, and survival is markedly improved," said Dr. Grazia Arpino, lead investigator of the study and a postdoctoral fellow at BCM.

"These tumors are initially highly sensitive to a drug known as trastuzumab or Herceptin, one of the drugs used in combination in the mouse study and which is approved by the FDA (U.S. Food and Drug Administration) for treatment," said Schiff.

However, the tumor is wily and can sometimes escape the drug's effects, resulting in resistance. Adding two other experimental drugs - gefitinib and pertuzumab — that inhibit HER-2 in different ways can more completely block the growth signals in the tumor, causing it to die.

In one of the tumors studied in this report, blocking the stimulatory effects of estrogen on the tumor was also necessary for optimal treatment, said Schiff. Completely blocking the HER pathway is critical, she said. Leaving out just one of the three drugs was much less effective.

A clinical study using drug combinations in newly diagnosed patients with HER-2 positive breast cancer will start soon under the direction of physicians at BCM's Breast Center, said Osborne.

"We are very excited to see if our laboratory results can be translated to patients with the more aggressive types of breast cancer," he said.

^^^^^^^^^^^^

Treatment of Human Epidermal Growth Factor Receptor 2-Overexpressing Breast Cancer Xenografts With Multiagent HER-Targeted Therapy [Journal of the National Cancer Institute]
Background: Human epidermal growth factor receptor 2 (HER2) is a member of the HER signaling pathway. HER inhibitors partially block HER signaling and tumor growth in preclinical breast cancer models. We investigated whether blockade of all HER homo- and heterodimer pairs by combined treatment with several inhibitors could more effectively inhibit tumor growth in such models.
Methods: Mice carrying xenograft tumors of HER2-overexpressing MCF7/HER2-18 (HER2-transfected) or BT474 (HER2-amplified) cells were treated with estrogen supplementation or estrogen withdrawal, alone or combined with tamoxifen. One to three HER inhibitors (pertuzumab, trastuzumab, or gefitinib) could also be added (n ?8 mice per group). Tumor volumes, HER signaling, and tumor cell proliferation and apoptosis were assessed. Results: were analyzed with the t test or Wilcoxon rank sum test and survival analysis methods. All statistical tests were two-sided.

Results: Median time to tumor progression was 21 days for mice receiving estrogen and 28 days for mice receiving estrogen and pertuzumab (difference = 7 days; P = .001; hazard ratio [HR] of progression in mice receiving estrogen and pertuzumab versus mice receiving estrogen = 0.27, 95% confidence interval [CI] = 0.09 to 0.77). Addition of gefitinib and trastuzumab to estrogen and pertuzumab increased this time to 49 days (difference = 21 days; P = .004; HR of progression = 0.28, 95% CI = 0.10 to 0.76). MCF7/HER2-18 tumors disappeared completely and did not progress (for ?189 days) after combination treatment with pertuzumab, trastuzumab, and gefitinib plus tamoxifen (19 of 20 mice) or plus estrogen withdrawal (14 of 15 mice). Both combination treatments induced apoptosis and blocked HER signaling and proliferation in tumor cells better than any single agent or dual combination. All BT474 tumors treated with pertuzumab, trastuzumab, and gefitinib disappeared rapidly, regardless of endocrine therapy, and no tumor progression was observed for 232 days.

Conclusion: Combined treatment with gefitinib, trastuzumab, and pertuzumab to block signals from all HER homo- and heterodimers inhibited growth of HER2-overexpressing xenografts statistically significantly better than single agents and dual combinations.

[Belinda]

Lani - I adore you! Seriously, I haven't been posting lately, but I truly appreciate your work in sharing new research with us. Thank you! Belindax

[Joe]

I don't quite understand. Another study using the same combination with the same results was released at San Antonio in 2004.

http://www.abstracts2view.com/sabcs/...p?nu=BCS4L_713

Regards
Joe

[Belinda]

Joe - it looks to me like the differnce is that they haven't only focussed on E+ cancers (as they did in the initial study), and that the tumours have been shown to die and not to return - all the more evidence that when the HER2 cancer is isolated, it can be treated successfully. And, good news that they are now intending to start human trials of this combo, eh?


B

[CLTann]

Truly exciting news. Hope the translation to human will confirm the validity in human cancer treatment. Thanks for the posting

[Joe]

The last line in the abstract suggested clinical trials 3 years ago. I will certainly ask this question at ASCO.

Regards
Joe

[chrisy]

Joe, the study your reference is one of my ALL TIME FAVORITES! As I recall, the focus on that one was to restore tamoxifen sensitivity in ER+ cancers. Definitely, do some snoopin and schmoozin around ASCO for news on this!

I agree, finding out if dumb old human BC will also respond can't happen too soon!

[Belinda]

Geri, Jen and Lani - thank you - am going to order the book. Seems like it's never to early to start organising. It's heartening the researchers are continuing their investigations - would be terrible if it ended ecause a PHD was successfully delivered. It's a pity their media release wasn't picked up properly.I am new to this but it seems a shame the big BC orgs aren't channelling the good news stories to the media (we see a lot of rubbish reported here - a couple of weeks ago their was a nonsense story about Neulasta being a new cure for C!).

Have passed on all of this info to an aussie bc forum - would be good ifus aussies could get involved early, we seem to be years behind you US girls in terms of trials and treatments.

Lets keep talking!

B

[fullofbeans]

Lani and all,

I simply cannot get this post out of my mind! Basically it seems so logical in principle to attack all possible pathways at once. I have always considered a cancer cell to be the equivallent of a 'pest' and the only way to deal with a pest is to go hard on it first time round, as to not allow it to develop resistance.

Anyhow, you said "for the activists among us, let's try to use our energies to help push this progress forward!". How can we push these things forward???? as mentioned in 2004 they had already published about the great results of combinaisons of drugs (either er+ or not the principle was already established) was working but nothing much was done since..<!-- / message -->

I have also noticed that unfortunatly that they may consider trial to take place for herceptin virgin only..does that mean that they would leave all of us behind! [how about lapatinib+gefinitib and pertuzumab]

I think that slowing the growth of cancer enough to allow your immune system to deal with it is the way forward.

I feel a need to get involved here.. So how can we push things forwards???

[Lani]

Tarceva is a tyrosine kinase inhibitor of EGFR like IRESSA is. Trying to get different drug companies to cooperate in a clinical trial can be difficult, but perhaps Genentech would be interested in a trial of three of their products.

There is going to be an interesting conference on the biological basis of breast cancer at the end of June with Francisco Esteva, Laszlo Pusztai (sorry about spelling), Carlos Arteaga, Mark Pegram, etc who think deeply about how all the her2 groups interact. It will be held in Santa Monica and will probably be quite
detailed in the molecular biology of breast cancer. These researchers as well as Martine Piccart and Edith Perez as well as George Sledge, Neil Spector and, of course, Dr. Slamon are all truly interested in the multipronged attack necessary in individual breast cancer treatment which is directed and targetted against the molecular "bad actors" driving each particular cancer.

Susan Desmond-Helman(sorry about my spelling--chief scientific officer) and
Pamela Klein (in charge of herceptin) might be good people to ask whether Genentech is interested in starting up such trials

.

Hopefully the length of treatment required with three agents is far shorter than that required with one, or the cost will end up prohibitive.

Am off in the am for Denmark, so may not join back in for a while (until jet lag recovered from and computer setup sorted out)

[Belinda]

Hi Full of Beans. I feel like you do about this. I am going to start with a review of the book mentioned in the posts above. You know, we seem to get a report every day of research advances in BC - yesterday there was a local article on Tykerb. I am blown away that this multi-receptor research hasn't made it into the news at all - it really is an important development, and publicity would help to build awareness, and expectations.

Would love to keep chatting about this.

Would seem that in addition to mutual support, a really good function of this forum could be promotion and collective action. Just not sure how to make that happen.

PS - I have a lot of previous career experience as a trade union activist (early career) and more recently a political and policy adviser to State-level Governments, but in industrial relations, social policy and economics, not in Health. I am thinking a lot about how I can make that experience useful, - not a hard prospect in my own State, but most of the decisions that would need to be influenced are private-sector, international and later national here in Australia - it's a challenge but an interesting one. It's important to find people with energy and/or contacts and/or skills prepared to collaborate to build an international campaign. This site is probably a good place to start.

But, women in all walks of life get BC, so surely there are people who can provide complimentary skills and networks - it is just a matter of finding them.

The reason I want to read the book on the history of herceptin, is that I am just not familiar with the processes required to bring new drugs into the marketplace and into the hands of the women that need them. I think that knowledge will be really important.

At least we can tick the "brains trust" box - Lani is already providing us with the knowledge of the science, which is the ight place to start. (Thank you Lani, again!)

PPS Lani - thanks for your most recent post - the conference sounds good and will no doubt be an important professional network-building event for those very important scientists. Have a safe and productive trip to Denmark.

Belindax

[Belinda]

Well, I finally got Robert Bazell's book - I think it's a very important book. It seems like Herceptin would not be available to us even now were it not for The passionate obsinance of a number of characters, and a whole lot of happenstance. There were so many points at which the process of developing and bringing the drug to market almost went off the rails.

But I am left wondering if it was a freak. The fact that Genentech was a biotech company not a drug company when Trastuzumab was first being explored meant that risks were taken that may not happen in a big pharmaceutical company.

Hopefully not - I know biotech is seen as an 'industry of the future' and I think to be informed and to be able to advocate in the way that many people did for Herceptin (AIDS advocates seemed to be great allies for BC advocates) we need to understand more about biotech companies, and more about how decisions are made about funding for the development of new treatments.

Still exploring.....

[Jean]

What do we do to get it rolling fast!
We as a group (I am sure) would love to help!

Jean

[fullofbeans]

Any news in ASCO regarding the progress on this?

Belinda, just saw your response now and your experience is impressive and you can count me on in term of lobbying! I am French so I am naturally good at this :-)

[Belinda]

Good to be working together!!!! Full of Beans try and read the book, if you haven't already. The historical account of how Herceptin got out there is just the best - and there are loads of lessons. Especially in relation to how important it is to do this work collaboratively.

The copy I have was from my onc nurse - it was a complimentary copy that says 'with compliments of Roche" (who bought genentech). Anyone got any contacts at Roche? This book is more useful than many of the dead trees I was given in the form of pamphlets.

I need to learn more about how this whole system works - maybe we can do this together? Maybe we can get enough HER2 women to share knowledge about how trials work, how products are commercialised....

I am in, but it isn't something I can do alone - I need to also build a network of supoprt in Australia. Maybe we need to be exploring more how this wonderful site and medium can be used as a powerful tool for activism!!!

Should we start by posting anything we know about anything at all that might help or any ideas for getting started?

(F.O.B - lol - French people have a formidable history for taking action to sort out problems....with you on board heads might well roll!!!!!!!)

Bxxxxx

[TSund]

Jean was kind enough to alert me to this thread. I am replying so that I can hear what all of you bright minds are sharing. Thank-you!

Terri
(spouse of Ruth, dx 5/1, completed 2nd of 6 TCH)

[Bev]

Promising news. I am worried that all of us who have done Herceptin already won't be able to access the trio, much like 3 years ago where people who had already done chemo had difficulty obtaining Herceptin. BB

[Belinda]

Bev - I am doing herceptin now - you know what, most of the activists in the Herceptin story were not bc sufferers. I am not sure how trials would work - perhaps someone who knows about trials could help with this question?

BUT what I can share is the thoughts of a dear friend of my husband and I (he was our Best Man) - he has had n-h lymphoma for well over 10 years and has doggedly sought out trials and experimental treatments. He says

"The longer I live, the longer I am going to live".

He means, the longer he stays alive, the longer it is likely that better treatments or even a cure will come through the work of the scientists and the more likely it is that he will live even longer. His aim is to just keep going!

So Bev - the more we work together to bring on the treatments - the more likely we will be able to have access to them, not only in trials but after the trials have given us new treatments, when our previous treatments no longer matter unless they threaten to harm us.

Belindax

[John21]

Very cool. Great post. Let's hope it continues to be researched.

[lilyecuadorian]

make me fell happy and with hope reading this post everytime I wish we know something more about the same .....how we can help ???