Good morning everybody. I take the warm pleasure of welcoming you here today and I am so impressed that you all got up so very early this morning. People travel from all different time zones so I appreciate you all getting here and spending the morning having breakfast with us and hopefully getting a tremendous amount of education to take back to your centers.
I just like to take a moment to welcome everybody to the educational symposium. It’s entitled the evolution of targeted therapies for the treatment of breast cancer. This educational activity is cosponsored by the Post Graduate Institute of Medicine or PIM and the Institute of Medical Education and Research or IMER. We would like to give a big hand to IMER because they are the ones who set all this up today.
I would also like to take a moment to give a tremendous amount of thanks and gratitude to Genentech who sponsored this unrestricted educational grant for us. I’d like to thank Genentech very much. They have always been so proactive in their education of nurses way back when in 1998 with Herceptin was first FDA approved for the treatment of breast cancer. I always applaud and appreciate their efforts in terms of nursing education.
This symposium is designated for a maximum of 2.0 contact hours. In order to receive credit you must complete the evaluation form that is found in the back of your syllabus. At the end of the program, there will be IMER staff at each of the doorways and they will collect the evaluation forms and they will send you a certificate in the mail. It will take about three to four weeks to actually receive that certificate and just a warning or caution, I’ve been the recipient of trying to read peoples’ addressed when they are printing them for the mail away to receive your certificate, so please make sure your handwriting is legible so that they can get an accurate address for you.
There will be a Q&A session at the conclusion of this program. Please write your questions. There are Q&A cards on each of the tables and the IMER staff will walk around at the end of each lecture. They will collect the questions and the last 15 minutes of the program the answers will be collated and responded to by each of our panel recipients.
In addition to that there is a value added service of attending this program in twofold: one is that Fran Palmieri and myself will be at the IMER both at the Civic Center this morning immediately following the program. If your questions don’t get answered or you have something that comes up while you are walking around the conference, we will be there for about half an hour to 45 minutes. We will be happy to spend some time speaking with you, talking about the latest trends in targeted therapy for breast cancer.
The second value added part of this symposium is if you still have more questions or you go back to your sites and you realize that there are questions or things came up, in the back of your syllabus is an e-mail address for IMER online, I think it’s 125_IMER.com. You can send questions to there. Those questions will be forwarded to the panel recipients and you’ll receive a response from us in the very quick future, so there will be a very quick turnaround.
I’d like to just ask you if you could all turn off your cellphones or place them on vibration. I’d appreciate your time and participation for this program. I’d like to take a moment to just review the syllabus to make sure everybody has one at their tableside. In the syllabus, in the opening pages, is the faculty as well as their disclosure information and abstracts for each of their presentations, their slide content with room for notes for you all and then at the back again, as I said, there are appendices. Because there is so much information about breast cancer and targeted therapies we couldn’t possibly include all of it in our presentation today so we wanted to make sure that you had handouts that you could take back to your centers and incorporate into educational programs for your nurses or your patients as you’re going forward.
This is very important, again, evaluation at the back will help you in getting your CEUs and it’s 2.0 contact hours for nurses.
There will be an audio response system, which I will talk about in just a moment but I’d like to take a moment to introduce our panel. At first, I’d like to introduce Fran Palmieri or Frances Palmieri. She is a clinical nurse specialist. She is currently the nurse manger of the multidisciplinary breast clinic and coordinator of the breast cancer program at the Mayo Clinic in Jacksonville, Florida.
In this capacity, she has oversight within the breast cancer program for patient education as well as staff education, research activities, clinical management. Ms Palmieri
has developed and managed various ongoing educational and research programs both at Mayo Clinic and within the North Central Cancer Treatment Group, or the NCCTG.
She develops and oversees many NCC Mayo Clinic research programs and serves as a liaison to the NCCTG Cooperative Group Research Nursing Board. Not only is Fran an excellent speaker and a true advocate for breast cancer, she is certainly a very good friend of mine and I’d like to take a moment just to welcome her.
Maria Theodoulou is also going to be here today. Her plane arrived late last evening so she is just taking a few minutes to get herself together this morning. She will be talking on targeted therapies and the treatment of breast cancer. Maria is an associate attending physician in the Department of Medicine at Memorial Hospital for Cancer and Allied Diseases. Dr. Theodoulou is an expert in the use of targeted therapies in the treatment of breast cancer. She is leading multicenter trials, studying the effectiveness of novel chemotherapy agents as well as the use of novel biologics alone and in combination with standard treatments to achieve a more potent response with locally advanced and late stage disease, so improving efficacy and hopefully reducing toxicity in both early and late stage breast cancer.
I haven’t had much time to introduce myself in all the housekeeping tips. My name is Maureen Major. I am also a clinical nurse specialist. I work at Memorial Sloan-Kettering Cancer Center at the Evelyn H. Lauder Breast Center. I have been there for about ten years. I work in a collaborate practice model with a medical oncologist. My primary focus is disease management, patient education, and supportive care for patients undergoing the medical management of breast cancer both early stage and late stage treatment.
I’d like to take this time to just talk a little bit about the audio response system. If you see at each of your chairs there is a little hand-held device. This is a hand-held device that will enable us to interactively speak with you during our presentation. The audio response system allows you to interactively respond to questions that are presented during the program. We will now do a simulated test in order to familiarize ourselves with the system. I will pose a question and you may choose an answer by pressing the corresponding letter on the keypad.
How knowledgeable are you on the subject of targeted therapies for the treatment of breast cancer?
Very. I’m here for an update on this topic.
Somewhat. I need more information to feel comfortable caring for patients with breast cancer, receiving targeted therapies.
Not at all. This is the first educational program I have attended on this topic.
You have to punch in the keypad, A, B, or C, depending on what knowledge level you have.
I don’t know if anybody has had the opportunity to ever present to such a wonderful audience like this but you do feel a little bit like you’re on jeopardy. The answer overwhelmingly 62% of our audience said that they need more information to feel comfortable caring for the patients with breast cancer receiving targeted therapies. I think 28% are here for an update on the topic.
There has been a tremendous amount of research data that has been represented since ASCO 2005 on targeted therapies in both early and late stage breast cancer and our goal today is really to talk to you about that specific data and how it pertains to our patients with breast cancer. Again, the educational objectives will be contained within the syllabus that you have in front of you.
Okay, my specific topic is to talk about the evolution of targeted therapies for the treatment of breast cancer and I’m going to be targeting cellular pathways. It’s really the scientific foundation for the rest of the discussion and why the drugs we use are being used and effective in the treatment of breast cancer.
What we know about cancer is that the initial development of cancer is to a very large extent related to the overwhelming loss of growth constraints that govern the patterns and behavior of normal cells through activation of oncogenes and inactivation of tumor suppression genes, cells forget the rules that govern growth and development and become progressively less dependent on external growth factors and less responsive to cell cycle controls.
Cancer cell growth also requires stimulation of angiogenesis or development of tumor vasculature, which provides nourishment for cell growth and rapid expansion of tumor burden. Progression of malignancy involves tumor cells developing the ability to invade surrounding tissue and to answer channels that affect metastases such as the lymphatic system. Certainly, the cancer cell is a very complicated system and really all of these entry points within the cell have an important part in cell growth.
There are many molecular events that occur in cancer development. Again, we have growth factors that sit on the surface cell membranes and they interact with things that are circulating in our system such as growth factors. These growth factors attach to receptors. They communicate information into the nucleus of the cell and they tell that cell to grow and multiply and divide depending on what’s going on.
We also have angiogenesis, which is again the development of blood vessels to feed and nourish tumor cells. If we can interrupt and target chemotherapy, the real goal of targeted therapy unlike chemotherapy, which destroys healthy cells and cancer cells. Targeted therapy is really specifically looking to alter the molecular event that occurs in cancer cell growth.
The primary focus of our discussion today is really to talk about the human epidermal growth factor or HER2 as its target in breast cancer. What we know about targeted therapy is while trastuzumab or Herceptin was the first targeted in early stage in metastatic breast cancer, there have been multiple FDA approved agents that are targeting different vehicles within this molecular makeup of cancer cel growth. But today, our specific focus is just on HER2 and breast cancer.
What is the HER2 system or the human epidural growth factor receptor? They are all normal proteins that regulate cell growth and differentiation and survival. Growth factors bind with specific receptors located on the surface cell membrane and they initiate the transmission of signals to the cell nucleus. This signaling process is called signal transduction and is carried through the tyrosine kinase pathway. The tyrosine kinase pathway in the center of the cell the growth factor attaches to the receptor and transmits through the signal transduction into the nucleus of the cell. It’s a complex tyrosine kinase pathway as a complex series of intracellular events that result in altered cell activity and gene expression.
Epidermal growth factor receptors and factors are found in many tissues including breast tissue. When over produced they are associated with a poor prognosis and serve as a prognostic marker for tumor relapse and decreased survival.
The human epidermal growth factor is really family of four receptors. They are transmembrane proteins and they all have different properties HER1, HER2, HER3, HER4 are all involved with cell proliferation and survival. The HER family are all extracellular as well as intracellular capabilities and allow growth factors to bind with the ligand and activate signal transduction or communication to the nucleus of the cell through the tyrosine kinase protein pathway.
HER2 is the first in the epidermal growth factor family to be specifically targeted for cancer therapy. Trastuzumab is a specific monoclonal antibody that targets HER2 and is indicated for HER2 positive metastatic breast cancer.
HER1 or the epidermal growth factor is another very promising target in solid tumor cancer treatment and there are many other epidermal growth factor medications coming down the line waiting in clinical trials or awaiting for FDA approval. We are also looking to interact with that tyrosine kinase pathway to inhibit the communication between the receptor and the nucleus of the cell.
The HER2 receptor is commonly found in many different types of tissues but in certain breast cancers between 20 to 30% of all breast cancers target the overexpression of the HER2 protein. It elicits survival changes and elicits protein development on the surface cell membrane. If you look at this slide, remember there are normal cells that produce HER2 protein but in a HER2 overexpressing breast cancer there are multiple receptors found on the surface cell membrane. This communicates information into the nucleus of the cell where were typically find multiple gene copies of the HER2 protein. In a normal cell, there are 2-3 copies of the gene protein in the nucleus of the cell. In HER2 overexpressing breast cancer there are multiple HER2 genes found in that nucleus of the cell.
HER2 overexpression can very often lead to communication with HER1, HER3, and HER4 so HER2 overexpression can lead to communication with the other growth factor receptors on that surface cell membrane. What that can lead to is increased cell proliferation, increased cell migration and again, resistance to apoptosis.
What does this mean for us and our patients? We are trying to understand visually what happens with a patient who is HER2 normal breast cancer patient. That means that they have a few receptors on the surface cell membrane and a normal gene content or gene array within the nucleus of the cell.
A patient who overexpressed HER2 has multiple receptors on that surface cell membrane and multiple gene copy within the nucleus of the cell so there is rapid communication between the growth factor receptor and the gene telling that cell to grow, multiple, and divide a very quick pace so we have excessive cellular division and multiplication in patients what we see typically in a patient who overexpresses HER2 protein.
What does that translate to us with our patients who clinically present with a HER2 overexpression in their breast cancer? If you look at the left hand of your slides, these patients tend to have much more aggressive disease if you think about it. The gene is telling the cells to grow, multiple, and divide at a very quick rate so you have very aggressive disease. Patients tend to relapse faster following adjuvant therapy. They tend to have shorter survival when they are diagnosed with metastatic disease. There is some clinical evidence to support the use of anthracyclines in early stage breast cancer with patients that are HER2 positive. Typically, these are patients that present with a poor prognostic factor. At time of surgery, they have high positive nodal involvement. In the nuclear content of the cell they have high S-phase and high nuclear grade. Approximately 50% of these patients are HER2 negative. Therefore, these are the patients that have worse prognostic indicators going into adjuvant therapy.
If you look at the survival curve on the right hand side, clearly patients that are HER2 normal have a much longer survival than patients that are HER2 positive. HER2 positive patients tend to have a much more aggressive treatment style. That was the historical perspective of HER2 positive overexpression.
What we found as time has gone on and science has brought new medications to the bedside, that perhaps this curve, this survival curve has changed a bit and what we are seeing is that our patients with HER2 positive overexpressing breast cancer and metastatic disease are living longer with much better qualities of life with new medications to target that HER2 receptor.
Trastuzumab is a monoclonal antibody. It was FDA approved in 1998. It targets HER2 overexpressing cells. What it does is that it results in tumor cell inhibition or death. It is a multipronged approach. If you think about it, trastuzumab or Herceptin is a monoclonal antibody so it attaches to that receptor almost like a fork and it can shut down that growth factor so there is no communication to the nucleus of the cell reducing cell division. It can also by interacting as a monoclonal antibody, interacting with that receptor on the surface cell membrane, sends out a signal to our immune system to come fight and destroy the cell.
We think that it reduces an antiangiogenic agent so it reduces the tumor vasculature, which increases the cell nutrients going to that abnormal cancer cell and finally we know by combining trastuzumab with chemotherapy we can potentially improve the efficacy of a chemotherapy agent.
Again, trastuzumab was approved in 1998. It was approved for metastatic breast cancer in first line treatment combined with paclitaxel for metastatic breast cancer in patients that are HER2 positive. The response rate in paclitaxel plus Herceptin was a 41% response rate. When we look at the pivotal trial of our patients that were enrolled, there were 454 women enrolled in the pivotal trial, half of those women got chemotherapy either AC or Taxol. The other women got a combination of AC plus Herceptin or Taxol plus Herceptin.
Lets just breakout chemotherapy alone versus combination therapy. When we look at response rate 32% for single agent therapy, chemotherapy alone versus combination of 50%. Time to tumor progression was improved with combination therapy from 4.6 months to 7.4 months and finally when we look at overall survival improved from 21 months for single agent chemotherapy combination biologic and chemotherapy improved to 26 months. This is a marked advantage with patients with HER2 overexpressing cancer.
What about single agent therapy? It was also FDA approved in 1998 as second-line treatment for metastatic breast cancer in patients that were HER2 positive. The response rate for that was 15%, which is standard when we get to second, third, and fourth-line treatment for patients getting chemotherapy, the response rate is anywhere from 12 to 19%. This falls in line with that finding.
When we talk about Herceptin or trastuzumab what is it exactly, what is a monoclonal antibody? Again, it is a Y-type device and there is constant, which is an FC portion, the FAB portion is altered in Herceptin or trastuzumab. It is humanized, so there is 98% human monoclonal antibody, 2% is murine content.
Testing is vital. It is very important for us to accurately test our patients because we know that patients respond to Herceptin we need to identify those candidates that would be appropriate for this treatment. HER2 testing provides vital information not only to identify patients clinically but also prognostically to help us decide the best treatments for our patients.
There are two types of testing: We can look at overexpression on the surface cell membrane of protein expression of that receptor. We can also look at gene amplification in the nucleus of the cell. Both ASCO and NCCN recommend testing at time of surgery. From 1998 onward most of our patients that have had surgical resections for breast cancer have had testing. We can go back to metastatic sites and get accurate HER2 testing or you can back to initial pathology.
FISH testing looked at gene content within the nucleus of the cell and it’s called fluorescence in situ hybridization, normal is anything less than 2. Amplification of gene expression is anything greater than 2 and those patients are considered HER2 positive.
Immunohistochemistry chemical staining looks at IHC expression on the surface cell negative. Negative HER2 status is 0 or 1+, 3+ is considered HER2 positive and the patient who becomes and IHC of 2 means that additional testing is needed to accurately determine its actual response to treatment.
We know that because we looked at concordance data for that pivotal trial and we went back. All the patients were IHC tested on the pivotal trial. They went back and performed testing with fluorescence in situ hybridization looking at the gene amplification.
If you look at the 2+ group, they would be considered negative on the clinical trial although they are 24% gene amplification in that patient population. In the clinical trial, patients based on IHC were considered negative whereas with FISH testing they are considered positive and would be appropriate candidates for Herceptin administration.
What we know about testing is that IHC and fluorescence in situ hybridization are effective, but FISH sensitivity is more superior. IHC testing is about 50% to 90% compared with FISH.
Lets look at angiogenesis as a target for breast cancer cell growth. We are moving into metastatic disease right now.
What is angiogenesis? It’s the process by which capillary sprout existing blood vessels through a variety of conditions. Some of them are normal like in our menstrual cycle and with wound healing, normal angiogenesis.
However, what we see in tumor cells is that they have an abnormal vasculature. They supply the tumor burden with additional nutrients and they cause vascularization, growth, and metastases of breast cancer cells.
Typically, we have a small tumor. It’s nonvascular. It doesn’t have any impact on capillary vessels and these cells can lie dormant and not have any cell growth.
In tumor angiogenesis what you see is that there are growth factor receptors that are stimulated, are circulating throughout the body. They are released from the tumor cell and they cause the vasculature to grow capillaries. If you see what happens here, that cell grows, multiples, and divides, and therefore, metastasis can occur.
We know that there are several factors that are in line with angiogenesis. The two most common ones that we have been looking at is VEGF or vascular endothelial growth factor and platelet derivative growth factor in angiogenesis. VEGF increases vascular permeability with the tumor cell, endothelial cell proliferation, invasion migration, and most importantly survival because there is new blood cell formation to that of normal cell.
With the platelet derivative growth factor, it recruits pericytes to newly formed blood vessels providing structure for that abnormal vasculature. It also releases the VEGF factor into the system and stimulates autocrine growth in some tumors. What we know is that new blood vessels form because of these two factors. If we can possibly inhibit either one of those, perhaps we can slow down angiogenesis.
We know that VEGF one of the factors that parlays in this is very overexpressed in most tumor cells, specifically breast cancer.
When we inhibit that, if we can inhibit angiogenesis with some type of an agent, we can reduce tumor burden and perhaps slow down the course of disease progression.
Some targets that we are looking at in terms of vascular endothelial growth factor are bevacizumab, which is also known as Avastin. It is a monoclonal antibody and there is some data that was reported in 2005 to show that it does have an impact on early metastatic breast cancer. Again, it is a recombinant monoclonal antibody. It binds to the VEGF ligand. It is already FDA approved in combination with IV 5FU for the first line treatment of metastatic colorectal cancer.
Kathy Miller and her group at ASCO reported on some data that supports the use of bevacizumab in metastatic breast cancer in combination with paclitaxel, significantly improves disease-free survival, increases objective response, and again longer followup is needed to assess survival.
Again, hope for the future targeted therapy is here to stay. It’s very important for us in terms of understanding pathways so that we can communicate this information to our patients.
When we look at mortality rate for breast cancer you can see that it is slowly starting to dwindle down. Our hope is that we can take our agents that are very effective in the treatment of metastatic disease and parlay that into early stage breast cancer treatment and perhaps improve upon mortality rate.
I would like to introduce Maria Theodoulou who has joined us and she will be speaking specifically on targeted therapies. Thank you.
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