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

Lani · 05-02-2007, 09:36 AM

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.

Adriana Mangus · 05-02-2007, 10:10 AM

Good Lord. I was not aware of it. Thank you for sharing with us.

I guess they(lab,docs,pharmaceutical companies,etc) have to wait to see first if it will work with mice..before beginning any clinical trial. In any event, it's always uplifting and brings a lot of hope to all of us.

Again, thanks for sharing, Joe.

RobinP · 05-02-2007, 10:59 AM

Hi, with the use of these three drugs, Her1,2, and 3 are blocked. Many her2+ are positive for all three.

hutchibk · 05-02-2007, 11:26 AM

All I can say is HURRY! This is such good news if it indeed translates to humans...

Belinda · 05-02-2007, 01:27 PM

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 · 05-02-2007, 02:42 PM

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 · 05-02-2007, 03:01 PM

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 · 05-02-2007, 03:43 PM

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

Joe · 05-02-2007, 03:58 PM

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

Regards
Joe

chrisy · 05-02-2007, 04:49 PM

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!

Lani · 05-02-2007, 11:38 PM

One of the big differences between that abstract and this article is that in the study cited in the ASCO abstract they used not only MCF7 cells transfected with her2 (an artificial construct which may not have any similarity to any naturally occuring tumor) but also BT474
a tumor which naturally occured in the poor person whose cell line was propagated and perpetuated which is her amplified (eg FISH+) and ER+. This human breast cancer cell line was implanted into the rodent,so...

This is as close as it gets to simulating her2+ER+ breast cancer as it occurs in humans.

Estrogen depletion ie, AIs were studied --in the abstract I believe only tamoxifen was studied, which represents a SERM, which blocks the estrogen receptor rather than depleting estrogen.

For all of those (like Jean) wondering what is the best AI, or whether STS and'or 17OH-HSD should also be blocked (aromatase is only one of three enzymes responsible for the formation of estrogen and similar compounds
not only in body fat, muscle and adrenal gland, but also within the breast cancer cells themselves), and worrying about using creams with parabens and other estrogen-like compounds, I thought the following sentence was particularly helpful:

All BT474 tumors treated with pertuzumab, trastuzumab, and gefitinib disappeared rapidly, regardless of endocrine therapy, and no tumor progression was observed for 232 days.

It is the same team of investigators who presented (abstract) and published
(today's article) both. It represents continued work by the lab on the same issue over the years...they have improved the meaningfulness of their study but adding the more representative cancer cell line (BT474), trying to gauge the import of estrogen depletion as well as estrogen receptor blockade (perhaps even addressing ER degradation if I remember correctly and Fulvestrant was addressed--but that might have been another article I read today), and determining that even without removing estrogen or preventing it from having its usual proliferation-inducing effect these three targetted agents sufficed to "cure" this subset of breast cancer which represents about 10% of breast cancers

Genentech makes two of the three drugs and also makes Tarceva, which works similarly to Iressa, but which, unlike Iressa is FDA approved (for another purpose). Let's hope Genentech hops on this bandwagon!

I went again with my friend to this year's Annual Stockholders Meeting (I am not a stockholder). They reported good progress with pertuzumab--
for the passive among us, let's hope and pray...for the activists among us, let's try to use our energies to help push this progress forward!

Lani · 05-02-2007, 11:43 PM

1)sorry I typed ASCO rather than SABCS(San Antonio meeting)

2) that study was different in that it was looking to restore tamoxifen efficacy in tumors that became tamoxifen resistant by developing her2 positivity where they did not have it before. That is very different from her2+ER+ TUMORS WHICH are by their nature relatively tamoxifen resistant from the get-go and which have a very different gene expression profile.

Enough for tonight!

Belinda · 05-03-2007, 02:28 AM

Thank you, again Lani. Your article, and now your interperetation of for us, has helped me pull through a dark post-chemo week. This seems to be the best news going at the moment, and I agree, anything we can do to push it we should. I agree that Gentech needs to get on the bandwagon - it is heartening that the initial research is independent, but to get the funding needed to make this thing really move along will need the drug companies to get on board. And getting trials takes soooooo long... Was there anyone involved in the early Herceptin days? What worked then?

Bx

Christine MH-UK · 05-03-2007, 03:24 AM

I was just wondering how much this combination might cost if it works. Does anyone have any idea?

I saved up for herceptin and would not have gotten it under my circumstances if I had not prepared for it financially, so I always think about this. Ironically, about 1/3 of the way through my treatment, the UK National Health Service decided to fund herceptin, including my herceptin, but I wouldn't have gotten it if I hadn't already been on it.

It might also be useful for people to know so they can be prepared for their copayments.

If I never need this combination then at least I will be well prepared for my old age.

MJo · 05-03-2007, 06:21 AM

As someone who had to stop Herceptin before 12 months due to heart issues, I will be very interested in any side effects on the heart. Otherwise, this is wonderful news.

Lani · 05-03-2007, 08:32 AM

I believe there is a book sometimes available on Amazon about the making of herceptin, which chronicals the history of the discovery, the difficulties finding the right target population to treat (which almost stymied its development) and the parties involved (including Dr. Slamon, of course).

I believe Lily Samuels Tartikoff was terribly helpful in fund-raising (she got Revlon involved) for the early stages of the research.

I haven't read it myself to see how the ideas generated by Dr. Slamon got developed by Genentech into an approvable drug.

Anyone out there who read it?

saleboat · 05-03-2007, 10:14 AM

I read the book and the story is pretty amazing. Scary that Herceptin almost didn't get out of the development phase. One of the take-aways from the book was the power of the advocacy community-- they really rallied to get as many women as possible included in the adjuvent trials, with the well-founded hunch that the drug would be a wonder.

Given the premium that these drugs are commanding, I can imagine that the business development people are all to happy to take bets now on targeted therapy-- at the time Herceptin was developed, it really was out-of-the-box thinking.

Here's a link to the book:
http://www.amazon.com/Her-2-Making-H...8212264&sr=8-1

Jen

Gerri · 05-03-2007, 10:28 AM

I read it (twice) when I began my journey into the world of BC. The name of the book is HER-2: The making of Herceptin, a revolutionary treatment for Breast Cancer, written by Robert Bazell. I found it at my public library. Now with chemo brain in full mode it is hard for me to remember all the specifics but I will try to give a brief summary.

Lily Tartikoff was instrumental in securing the initial funding for Dr. Slamon’s research. He had treated her husband Brandon Tartikoff for Hodgkin’s disease and she was so grateful, that she made it her mission to get him the money he needed to move his research forward (he was having trouble getting funding). She approached the CEO of REVLON and challenged him to do more for women than just make lipstick. The fundraising “Fire & Ice Ball” and the Revlon Run/Walk for Women were a result of this challenge.

The book details the many years of research that went into the discovery of the HER-2 protein and the making of Herceptin. It also tells of how the pharmaceutical companies finally came on board. Most of all, it shows the relentless dedication and passion that Dr. Slamon put into this research, not to mention the brave women who participated in the initial trials.

Belinda · 05-03-2007, 01:48 PM

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 · 05-07-2007, 07:49 PM

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..

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???