Help with explaining treatment to general population
 

Hi All -

I may be doing an interview soon where I will be asked the patient's perspective on getting into clinical trials. As many of you know, I am heavily pretreated and am extremely interested in the TDM1 trials. Also, like many of my friends here on this board I like to be a very educated consumer and advocate. I wanted to find out if someone has an easy definition of how the various Her2 treatments work to target Her2 breast cancer. Specifically how is it thought that Herceptin, Tykerb, and Pertuzimab work differently / together to slow down/ stop Her2 disease? If you have an analogy that is easy to understand please share. In my real job I pride myself at making difficult concepts easy to understand…

My goal will be to put a face on a population of heavily pretreated patients with a desire for access to these newest trial drugs. To show that Stage IV breast cancer patients can look and act like anyone else with some luck and access to the latest treatments. To show that we are a very educated population that speaks about cancer without hesitation and with hope. To demonstrate that as patients we are active participants in this quest to find a cure for cancer. I also want to make my son proud and let him know that I am doing my best to stay healthy with Stage IV.

Knowledge is power and we have to be our own advocates. Thank you for sharing your knowledge.

Love, Hope, Peace, Carolyn

Hi Carolyn! I'm sure that your son is already very, very proud of you. I know you will receive many answers and the help that you seek. You have my thoughts and prayers.

Found this from a page on <Breastcancer.org> dated Oct. 10, 2008

Andrew Seidman, M.D.: Currently, the only agent that has been shown to improve the effectiveness of conventional therapy in Herceptin resistant breast cancer is Tykerb, or lapatinib, based on the trial we spoke of earlier. Another promising agent reported by my colleague Dr. Shanu Modi at the ASCO meeting this spring is an agent known as 17AAG. This is also known as KOS-953. This novel agent inhibits a molecule known as heat-shock protein 90 and causes degradation of the HER2 receptor. Dr. Modi reported responses with this agent in combination with Herceptin in patients whose cancer had recently progressed on other chemotherapy with Herceptin. There is also data from Dr. Storniolo from the San Antonio Breast Cancer Symposium in December 2005 demonstrating the role for Tykerb and this might perhaps in the future be observed with other tyrosine kinase inhibitors. We have also studied Cox-2 inhibitors, such as Celebrex (chemical name: celecoxib), based on laboratory evidence, but unfortunately found no evidence that this strategy had any effectiveness in Herceptin-resistant breast cancer. Other strategies under investigation include tumor vaccines, the agent pertuzimab, which is a monoclonal antibody targeting a different portion of the HER2 receptor than Herceptin, among others.

One of the heros of HER2 research is Dr. Kent Osborne at the Breast Center at Baylor College of Medicine in Houston. He spoke at length at SABCS in 2007 about all of the questions you just mentioned, and I think I actually understood it. LOL. Here some links explaining the HER family of proteins and the pathways that must be shut off with multiple targeted agents.

Hope it helps!

http://www.bcrfcure.org/action_0809g...s_osborne.html

http://sabcs.cancernetwork.com/displ...le/10171/46323

Project 1: Targeting the HER2 Pathway: Mechanisms of Resistance and Strategies to Overcome Them

Rachel Schiff, Ph.D., Project Leader
C. Kent Osborne, M.D., Project Co-Leader
Trastuzumab has proven to be a very effective therapy for HER2-positive breast cancer, but de novo or acquired resistance limits its long-term value. New observations from our laboratory suggest several hypotheses on the mechanisms of resistance to trastuzumab and other therapies targeting the HER network. First, our results suggest that this resistance might stem from incomplete blockade of the signals generated from the various HER-family dimer pairs in the network input layer. Using a limited number of HER2-overexpressing xenograft models we have found that combined drug therapies designed to more completely block these heterodimers can overcome resistance to single agents and are even capable of eradicating many of these tumors in mice. Our preclinical models and preliminary patient data also suggest alternative mechanisms for resistance to HER-directed therapy that involve the estrogen receptor in some tumors and the MUC4 mucins in others.
Here we propose a series of preclinical studies and an early phase clinical trial to begin to test these hypotheses. Specifically we will: 1) Confirm our preliminary data that resistance to single-agent HER-targeted therapy can be overcome by various combinations of trastuzumab, lapatinib, and pertuzumab, designed to more completely block signaling from the HER network input layer, in a large panel of HER2-amplified breast cancer cell lines, and to identify and establish models resistant to these single and combined antiHER2 drugs for later studies; 2) Determine using these various preclinical HER2-positive models whether upregulation of ER or ER signaling to an alternative survival pathway can be induced by HER blockade as a resistance mechanism, and whether simultaneous targeting of ER and HER2 is then necessary for optimal treatment; 3) Investigate whether upregulation of MUC4 causes resistance to HER-targeted therapy in our preclinical in vivo model system, thereby providing a new potential diagnostic and treatment target to investigate in human samples; 4) Lead a multi-institutional phase 2 neoadjuvant clinical trial of lapatinib combined with trastuzumab, with serial tissue sampling to assess molecular mechanisms of action and resistance, in order to begin to translate our exciting preclinical findings to patients. This work will facilitate new strategies to circumvent resistance to HER-targeted therapy for improved patient survival.

Understandy your point...trying to keep it simple.
 

Maybe some of this will be of some use?

Her2 breast cancer stands for
Human Epidermal growth factor Receptor 2
It is a gene inside the cell and carries the information for making Her2 protein. The Her2 protein is also called the Receptor and would be on the surface of normal cells. In normal cells the her2 protein sends growth signals from outside the cell to inside the cell.

In Her2 breast cancer the cells have an abnormally high number of Her2 genes per cell. This is called Her2 overexpression. Too much Her2 protein causes cancer cells to grow and divide more quickly.

Antibodies produced by our bodies immune cells, are part of the body's normal defense against abnormal cells.

Herceptin works by interfering with one of the ways in which breast cancer cells divide and grow. Herceptin blocks the process by attaching itself to the Her2 protein so that the epidermal growth factor cannot reach the breast cancer cells. This stops the cells from dividing and growing. Herceptin also works by attracting the body’s own immune cells to help destroy the cancer cells.

Herceptin on its own causes a shrinkage of the cancer in a few women and stops it growing in others. Usually however it given alongside chemotherapy drugs, particularly, taxol or taxotere.


Herceptin is designed to specifically target cancer cells and not attack normal cells. A monocolonal antibody which specifically targets HER2 proteins on breast cancer cells is proving to be an effecitve treatment for some women with HER2 positive breast cancer.

Can I just say, "I love you man?" and mean men and women??? I just went for a swim with my son and his friends and I survived full on water cannon attacks... to come back and read these responses. Wow, thanks so much for these thoughtful answers.

I plan to read them in greater detail tomorrow when I am fresh. Too much BC reading for bed does not make for a good night's sleep for me. But the support just fills my spirit.

Bill - What can I say, I feel healthier just looking at you and the Kale.

Jackie, I got 3 months out of Herceptin and Tykerb alone... it was the first time my doctor had seen this. I was going to go the Heat Shock Protein trial but it has been suspended for now. Thanks for the information.

Brenda, Thank you. I agree Kent Osborne is amazing. I plan to spend some time reviewing the links that you sent. The excerpt seemed fairly easy to understand.

Jean - That is right KISS theory - keep it simple. I like one of the most obvious points that your statement makes in the fact that these are targeted therapies.

If I get the chance to speak, my role will be to just put a face on "one" person's excitement about these new trials. Even so, I have a tendency to over-prepare for anything I do... so here I go. Thanks for all of the support and wisdom.

Love, Hope, Peace, Carolyn

Ha, had to chuckle...Carolyn...you requested easy definition...and I did think of the KISS theory (as KISS is in my e mail) I have found in training and getting people on board with new programs nothing works better!

Best of Luck,
Jean

Target for medication, Her2 is more pronounced at cancer site. The toxin is active during time that cell replicates, with cancer cells that’s normally much more frequent than with normal, healthy cells.
If cancer consists of numerous pathways used to supply nutrition and discard wastes, I visualize it somewhat like lair of prairie dogs with multitude of access-egress tunnels.

Trastuzumab locates the her2 target and enters the cancer, where the linker (MCC) breaks down and releases a very potent DM1 toxin that explodes like an earthquake trying to cave in as many tunnels as possible. Depending on strength of burrow, destruction of nest could be total, significant, or minimal. Overall damage to domain factors in how long it will be out-of-service, i.e. it's the measurement of drug's effectiveness.

Hope that this analogy is helpful.

Maybe should have used "moles" in veggie garden for analogy; purpose of this post however is to flag that new t-dm1 trial has been listed.http://www.clinicaltrials.gov/ct2/sh...m=t-dm1&rank=2

Take my face with you! I also wanted to go on TDM1 but found out that first I have to get worse so I can have measurable disease in either soft tissue or an organ. Apparently my sternum mets (or any bone mets) don't "count". So, I had to do more rads in effort to control the sternum.

Thanks for all the effort to properly explain and represent. When you are fortunate enough to be a stage four survivor, it is compelling to want the WORLD to take notice!

Blessings,
Flori