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Why Do Some Breast Cancers Stop Responding to Targeted Therapy?
Targeted therapy halts the growth of certain cancers by zeroing in on a signaling molecule critical to the survival of those cancer cells. The drugs are effective in about 10-15% of patients. The drugs work specifically in patients whose cancers contain mutations in a gene that encodes the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) or some other pathway.
The EGFR stands at the origin of a major signaling pathway involved in the growth of breast cancer. Two of the four receptors in this pathway, epidermal growth factor receptor type 1 (HER1) and epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu or ErbB2), are promising targets for new treatments. In about 20% of patients with breast cancer, the tumor overexpresses HER2. Herceptin, a humanized monoclonal antibody that targets the extracellular domain of HER2, is effective as adjuvant therapy and as treatment for metastatic disease in patients with HER2-positive breast cancer. Tykerb, an orally administered small-molecule inhibitor of the tyrosine kinase domains of HER1 and HER2, has antitumor activity when used as a single agent in patients with HER2-positive inflammatory breast cancer or HER2-positive breast cancer with central nervous system (CNS) metastases that are refractory to Herceptin. This finding is important because HER2-positive tumors frequently spread to the CNS, where the tumor is sheltered from Herceptin and most chemotherapeutic agents. Other targeted therapies also show great promise in the treatment of breast cancer. Avastin is a monoclonal antibody against the vascular endothelial growth factor (VEGF). Tumors can be effectively controlled by targeting the network of blood vessels that feed them. Tumor growth is dependent on angiogenesis. Angiogenesis is dependent on VEGF. Avastin directly binds to VEGF to directly inhibit angiogenesis. Within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF. Although these targeted therapies are initially effective in certain subsets of patients, the drugs eventually stop working, and the tumors begin to grow again. This is called acquired or secondary resistance. This is different from primary resistance, which means that the drugs never work at all. The change of a single base in DNA that encodes the mutant protein has been shown to cause drug resistance. Initially, tumors have the kinds of mutations in the EGFR or VEGF gene that were previously associated with responsiveness to these drugs. But, sometime tumors grow despite continued therapy because an additional mutation in the gene, strongly implies that the second mutation was the cause of drug resistance. Biochemical studies have shown that this second mutation, which was the same as before, could confer resistance to the EGFR or VEGF mutants normally sensitive to these drugs. It is especially interesting to note that the mutation is strictly analogous to a mutation that can make it tumor resistant. For example, mutations in a gene called KRAS, which encodes a signaling protein activated by EGFR, are found in 15 to 30 percent of certain cancers. The presence of a mutated KRAS gene in a biopsy sample is associated with primary resistance to drugs. Tumor cells from patients who develop secondary resistance to a drug like Tarceva after an initial response on therapy did not have mutations in KRAS. Rather, these tumor cells had new mutations in EGFR. This further indicates that secondary resistance is very different from primary resistance. All the EGFR/VEGF mutation or amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if one drug is better or worse than some other drug which may target this. There are differences. The drug has to get inside the cells in order to target anything. EGFR/VEGF-targeted drugs are poorly-predicted by measuring the ostansible targets, but can be well-predicted by measuring the effect of the drug on the "function" of live cells. Literature Citation: PLoS Medicine, February 22, 2005 Eur J Clin Invest 37 (suppl. 1):60, 2007 |
This posted article is 3 years old.
If you look at the presentations of Dr. Kent Osborne from SABCS in Dec '07 and more recently in Miami, (http://www.cancerconf.com/media/2008.../WEB/index.htm -cannot be viewed with Firefox browser) then you might find the answer to your question about why there is a resistance to individual targeted therapies, at least in the metastatic setting. If I understand correctly, it appears through recent research that it takes a double or triple targeted approach to close down all of the pathways and alternate pathways that HER1,2,3 and 4 fueled cancers find to use when only one targeted treatment is used... one targeted treatment can only turn off or close one to two pathways, and that leaves other pathways for the cancer to take advantage of. That is why there are current trials in the metastatic setting for combining Herceptin with Tykerb, and also combining Herceptin with the new 'mab', pertuzamab, and a complimentary chemo. |
Logical Implications of Tumor Cell Evolution
Thank you for the link to Dr. Osborne's presentation at the Miami Breast Cancer Conference in Orlando. The underlying assumption in this presentation has been that the pathways of tumor cells can be known in sufficient detail to control cancer. This assumption is embedded in the approach described in this and other presentations in the past.
Sequencing the genome of cancer cells is explicitly based upon this assumption, an assumption that just so happens to be false. The assumption that the pathways of tumor cells can be known in a patient with metastatic cancer is logically inconsistent with the reality of tumor cell evolution. The problem is that a patient with metastatic cancer can have billions of unknown cancer cells disseminated throughout the body at unknown locations. Each cancer cell can be different. And the cancer cells that are present change and evolve with time. The required target for the consistent and specific control of cancer is the set of all malignant cells that could evolve. Targeting a lesser set will fail. It may act to change the course, but not the flow of tumor cell evolution. It must have the ability to kill or inactivate all malignant cells in the patient (one malignant cell that excapes could multiply and cause progressive disease). It must have the ability to target cancer cells without harming normal cells or causing toxicity to the patient, and target properties of cancer that can be known, or accurately predicted. The consistent and specific control of cancer will require a set of drugs, given in combination, targeted to patterns of normal cellular machinery related to proliferation and invasiveness. A sufficient number of independent methods of cell killing must be employed so that it is too improbable for cancer cells to evolve that can escape death or inactivation. It must examine functional aspects of every cell in the body and must do so for a prolonged period of time. Today, we have the ability to take a cancer specimen, analyze it, and follow those genetic changes that influence particular pathways, then use two, three, four or more targeted therapies, perhaps simultaneously, and be able to completely interrupt the flow of the cancer process. Given the current state of the art, in vitro drug resistance and sensitivity testing could be of significant clinical value to this premise. If in vitro drug resistance can demonstrate the presence of cancer cells that are resistant to a drug combination, then it would be rational to use alternative therapy. If in vitro drug sensitivity can demonstrate which drug combinations would be synergistic to cell death in all cancer cells present, then it would be rational to use the drugs indicated in the assay. Functional profiling assays can assess the activity of a drug combination upon combined effect of all cellular processes, using combined metabolic (cell metabolism) and morphologic (structure) endpoints, at the cell population level, measuring the interaction of the entire genome. Functional, cell culture-based assays are vastly more informative for virtually all drugs than marker-based tests, including multi-gene tests. Functional assays are the best available tests in the world for anti-vascular drugs, such as Avastin, Sutent, Nexavar, Tarceva, Iressa, Tykerb, Gleevec, Tamoxifen, Thalidomide, etc., both as single agents and in combination with each other and with traditional cytotoxic agents. Functional assays can provide more valuable information today than will be provided with marker and genomic-based assays ten years from now. It simultaneously tests for direct anti-tumor activity and for anti-vascular activity against the microvascular present within the three-dimensional tumor cell clusters. A number of cell culture assay labs across the country have data from tens of thousands of fresh human tumor specimens, representing virtually all types of human solid and hematologic neoplasms. Cell culture assay labs have the database necessary to define sensitivity and resistance for virtually all of the currently available drugs in virtually all types of human solid and hematologic neoplasms. Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007 Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117 "Cure: Scientific, Social, and Organizational Requirements for the Specific Cure of Cancer" A. Glazier, et al. |
***prior to this post, Maryanne had posted a question to GD...)
Maryanne- GD's point/agenda in this thread appears to be to advocate for the the belief/theories held by and proposed by Dr. Larry Weisenthal of the Weisenthal Cancer Group. http://www.weisenthal.org/ Dr. Weisenthal is the doctor who developed the EGFRx Assay Cell Culture test that GW has been referring to. I don't know if GW has a connection to Dr. Weisenthal, but GW is not a patient or a doc, he is an advocate who has devoted his time to hours and hours of research in recent years. I certainly respect the hours of research and the knowledge brought forth by GW, as knowledge is power. But in the interest of full disclosure, I thought it would be prudent to post the basis of the info he has been providing on this thread. |
In the interest of full disclosure and allaying the fears of some paranoid people, I was a spouse/caregiver to a cancer patient. I became intensely interested in cancer medicine by virtue of working through, enduring and surviving my wife's illness. My college educaton and experience helped me to gather knowledge by virtue of voluminous reading and hundreds of hours of past and ongoing personal communication with noted authorities in the field. This includes surgeons, medical oncologists, radiation oncologists, clinical researchers, and the like.
Although retired, privately, I've been a student of cell function analysis. I do not have any financial conflicts of interest raising the awareness of this technology. On the internet, my point with respect to this systematic procedure is to educate patients that such techniques exist, and might be very valuable. 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. To paraphrase Martin Luther King Jr.: "A scientific communication should be judged on the quality of its content and only secondarily, or not at all, on the qualifications of its author. I hope I allayed your fears hutchibk. Don't forget to give credit to all of the other fine assay labs: http://www.rational-t.com/ http://weisenthalcancer.com/ http://www.precisiontherapeutics.com/ http://www.anticancer.com/ |
I am certainly not paranoid my friend, and never had any fears that you needed to allay. But I find it important to know where people are coming from, and what might be their basis for being here if they are not a HER2 breast cancer patient or caregiver. Especially when they are sharing info that is somewhat technical beyond the average participant's understanding (me included). Consider me 'in-tune with my skeptical eye' perhaps. (oh, and I am the daughter of a spy, in case that helps explain anything)
But now I am more curious. Where does your specific interest in HER2 survivors come from? Like I mentioned before, I respect the hours of research and knowledge brought forth here by you. But, I am curious how you found our subset to be of particular interest to you? |
For your added inquiry hutchibk (I don't know, it must come from your parent), I've been a student of cell function analysis, a very exciting and thought-provoking science, for over six years now. The technique spans over all solid and non-solid tumors. Besides my spouse, I've intimately experienced the trials and tribulations of numerous relatives and good friends with all sorts of cancers (breast and prostate cancers being some of the most recent). I do have a no-nonsense, sometimes harsh but honest writing style. Cancer patients need informed opinion, whether with good, bad or indifferent consequences.
If more people researched how and why they are being treated by orthodox cancer therapies, then I believe there would be a movement (which I think there has) to have more effective and less toxic treatments available. Ideally, we would conduct such research before the treatments are administered, but we usually don't have the luxury of time to learn what the oncologists are not telling us when it matters most. The quality of life must be considered as a major decision point in cancer care. Don't cut short the readers of this or some of the other cancer discussion boards. They are a lot more intelligent than you expect. Dr. Ronald DePinho, director of the Center for Applied Cancer Science at the Dana-Farber Cancer Institute and a lead researcher, argues for quick movement to clinical trials that combine three or more "targeted" drugs for cancers to shut down all the malfunctioning growth switches. Dr. Len Lichtenfeld, deputy chief medical officer for the American Cancer Society, in a response about the Cancer Genome Project, says that we're going to be able to take a cancer specimen, analyze it, and follow those genetic changes that influence particular pathways, then we'll use one, two, three or more "targeted" therapies, perhaps simultaneously, and be able to completely interrupt the flow of the cancer process. Cancer researcher and former oncology fellow at Johns Hopkins, Dr. Arnold Glazier, says in his book, "Cure: Scientific, Social, and Organizational Requirements for the Specific Cure of Cancer, will require multiple drugs administered in combination targeted to abnormal patterns of normal cellular machinery that effect or reflect malignant behavior. It means finding the patterns of malignant cells and develop a set of 5 to 10 drugs in order to cure or control cancer. I've pointed out in my thread, the belief/theories of all three of these doctors, not just those of Dr. Larry Weisenthal, or Dr. Robert Nagourney, or any of the other physician/scientists of cell culture assays. The last paper Dr. Weisenthal has published was in 2007, "Eur J Clin Invest 37 (suppl. 1):60, 2007" (European Journal of Clinical Investigation). |
(*** GD edited and removed his full name from the end of the above post, which he was so proud to share at the time. If anyone would like more info and to read blogs on the web regarding his activism, feel free to contact me...***)
GD - You didn't answer why you are interested in our subset and this forum, which is primarily used by Her2 patients/caregivers for support. If your purpose is to push a movement or agenda, then maybe this is not an appropriate place. Many of us are fighting for our lives, for moments, hours, days, months and hopefully years of continued survival... speaking for myself, that takes all of the energy I have. To try and recruit us to join in a movement to change the culture of oncology is perhaps out of our emotional range, as we are living in real-time treatment and may not have the luxury to wait while our doctors learn to use or embrace what you are passionately researching and fighting for. I would assume that you might understand the real-time aspect of this, losing your wife to ovarian cancer. Perhaps your beliefs and agenda would be better supported in the blogoshere of the web, in the meeting rooms of advocates, and in the offices of doctors who like you have the energy to embark on the long, arduous task of changing a system, a culture, a profession. Perhaps honorable and deeply caring in your passion, perhaps important and logical is much of your sharing, it does disturb me that your posts consistently share a subtle degree of fear-mongering about many of the drugs and treatments that many of us are finding great success with and tolerating well. It is not fair if you come here with that agenda. If you are here for a reason other than just sharing helpful research, please reconsider where you take your activism and who the audience is. I don't pretend to speak for everyone here, but I am not a fan of outsider activism on the forums here. Speaking for myself, I prefer to choose who I get my "informed opinion" from (in reference to your opinion that "Cancer patients need informed opinion, whether with good, bad or indifferent consequences.") I am not cutting anyone short of learning from your posts. If they want to read what you post, absolutely more power to them. I read it and find some of it informative and interesting. My opinion is, however, that we should be apprised of who you are and what your reason is for posting on our forums. Full disclosure is important when a mysterious participant is sharing "opinion" and "conclusions" - I want to know who you are and why I should heed your opinion or conclusions. I have read your contributions in multiple blogs, etc. on the web, so I have a more general picture of your opinions, positions and agendas. Others here probably haven't had the luxury of that info. I feel it is necessary to find out why you are here and why you feel you need to share your opinions with us, as you are not one of us... Thanks for listening. |
My posts to you have nothing to do with paranoia or fear, GD. As a matter of fact, I would characterize them as more "Healthy Skepticism" (sound familiar?) than anything else. I am a smart independent thinker who leads my life with an eye of justified suspicion when mysterious and evasive characters attempt to sell me on something. You show yourself to be disingenuous by attempting to be sarcastic/clever, yet you continue to evade my questions. Were you to answer what your interest is in us, it might allay my suspicions.
Remember, you have come into our house, and you do not share our particular disease or complications from it. Yet you wish to share your opinions and conclusions and agenda. I find that rather curious. I have not picked a fight with you, I have asked why you have chosen to participate in our particular forum. Should be easy enough for you to answer, yet you evade. Are you here simply to share info? Or are you here to share your opinions and conclusions that fit your beliefs? Are you here to scare? Are you here to recruit? Are you here because of a passion for HER2 patients? As I stated above and fully stand by: "Full disclosure is important when a mysterious participant is sharing "opinion" and "conclusions"... As I said, I am not soley familiar with you from this forum. You are a well-documented activist who seeks to challenge and change the culture of pharma companies, the culture of clinical oncology, the culture of research and trials, the culture of cancer treatments, the culture of the FDA and of ASCO. Not that yours is not an honorable plight, however patients in real-time treatment may not be your most appropriate target audience. (I read alot, and the web is an interesting place...) |
No you haven't.
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Anyone who might be interested, I can share some of the info I have come across in my web reading.
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(**** this is in response to a post by GD about why Maryanne's posts disappeared, which he appeared to find suspicious... and now his post regarding that has apparently been deleted by him.)
To my knowledge, the only one who can delete posts is the originator of the post or the moderator of the board at the behest of the originator of the post. |
Valid question
I think the original question has great validity and meaning on this forum.
Can we get back to addressing that question?? As Brenda says, there are many of us here fighting for our lives in real time who want to know why the "dart board" method of throwing drugs at the tumors does not work. Understanding how cancer cells grow and divide is crucial to an effective treatment. Perhaps all the answers are not known, but in trying to forge ahead on this subject we need all the GOOD information we can get. Just last evening Christine and I were talking about how we felt and had to deal with so much unknown when we had our cancers come roaring back way before there was any support for us and when the knowledge was very thin on HER2. This forum is not a scientific one, but a certain amount of science is needed for those of us who are able to devote some brain cells to it. That is why we have the Articles of Interest area of this web site. In our fight, most of us want to be able to follow our onc's thinking on where we go next when there is progression. Some onc's are more thoughtful than others and it is clear that some also have a hidden agenda. We need to be able to discern these things. Keep up the discussion, but try to keep it on the subject, please. |
I would never have learned as much good information here as I have over time without being able to see and evaluate for myself the contributions of a wide variety of individuals with varying backgrounds. Cancer is very complicated, but being able to consider the open, nonpersonal, polite exchange of interpretations of the process is basic to making any genuine choices about them. Let's do get back to focusing on the question that was raised and providing information to discuss it.
AlaskaAngel |
I have no idea what sets hutchibk off. It was suggested that maybe it's being grounded in the minute, perhaps by necessity as she indicated. Sometimes it is difficult to express on public forums for fear of reprisals (one form or another). Perhaps some do not wish to fuel the arguments with hutchibk. Neither do I. But I will not be subjugated by manipulative indeuendos.
A good person told me that although this board is pretty much considered a board of adults (with a higher threshold than some other boards), there are some less mature people participating who seem determined to take on any discussion as a personal issue, and make it personal. I certainly don't know what the motivation for it is. But all I can say is "lighten up" hutchibk! |
Hi,
I am going to be off subject a little bit. Could you tell me how to post a long article? I did not see the 'copy' and 'paste' button. And every time I typed ove a page, I got kicked out of the site. Is it some setting on my computer that needs to be changed? 'Agenda' is a strong word. I feel like this is a wonderful site for all of us. Anytime anybody that is not interested in a message, he/she can just start another thread or check on another one. I still think it is healthy and necessary for us to feel safe/free to express ourself here 'out in the open'. |
Jackie07
What I use is to frequently tap the "preview post" button, which then gives you a preview, and then continue, as it seems to hold onto what I've already typed. Try it. AlaskaAngel |
Thank you, 'Angel', I'll try that. (Be ready, it's going to be 'long')
I did some research on the links on GD's posting. First, they are all '.com's. One thing we have to remember is that any web address ends with '.com' is a commercial site. Commercial sites exit because they want to make money. They are not 'non-profit' (that will be the ones ending with '.org') nor are they government site (ends with '.gov') So, we do need to be aware of their 'agenda'. A better place to go for information is the database provided by the National Institute of Health - National Cancer Institute - National... Use a web search engine like Yahoo or Google, and type in "PubMed", that is the best medical database in the world. And it is paid for by our tax dollars. The governement (and many foundations) invest quite a bit money - though never enough - on cancer research. When something was discovered, drug companies start making new drug, going through clinical trial ...we all know that. It might be 5-10 years before a 'miracle' drug is invented (discovered). The doctor who has a lab (the 2nd link on GD's last posting) has not published any research article since at least 2002. And the $3500.00 his lab requires (by the way, he has decided not to accept Medicare/Medicaid?which further tells us his 'agenda' :) - Perhaps he just wanted to have freedom to do his own research. But the fact that he has not published anything since at least 2002 tells us something. However, he may well publish one next week to surprise us.) to do the functional analysis (assay) is reasonable. However, isn't that what we paid our oncologists for? Our oncologists are supposed to be the ones to have read all those research articles, gone to all those seminars, and treat us with the state-of-the-art medicine/procedure. They know us personally (if they don't, we need to force them to :) and they know our medical history and current condition. They are supposed to weigh all the information available and give us the best options out there. They are the one to counsel us, to walk with us... We are desperate. Doctors are desperate. Family members are desperate. Scientists are desperate. Everyone involved in this battle are looking for something to cure our cancer. And it is a long battle. I feel very, very privileged to be here with all the wonderful fighters. You give me hope and inspiration; you provide fellowship. But we've got to remember we are just a support group. We can exchange information, we can provide our opinions. But our ultimate goal is to support each other. That's what we do best. And let's continue doing it. (End of my speech - blame Angel, she's the one showed me how to type long message...:) |
That was a great post, Jackie :)
I wish we had a little clapping emoticon |
Civility, and Analysis of Information
Jackie, I'm told that somewhere recently in time, another "Angel" has posted, so unless I'm allowed to let that one take the "blame" we better keep the "Alaska" in the name for accuracy's sake. Anyway, I'm glad the tactic seems to have worked okay. Thanks for keeping discussion civil and bright.
It IS important to consider the source for information as one way to consider its value. One of the best aspects of the forums here is that information from a wide variety of sources is available for consideration. I can go through the list of sources mentioned, and then read Robert Bazell's "The Making of Herceptin" and understand that revolutonary concepts can still come very close to never being fully developed by "the system" of respectable sources. The source of information is only one factor of many to take into account in evaluating whether the information is meaningful, accurate, or useful. Even questionable information is valuable simply because it often creates the opportunity for further discussion and development of sharper questions and clearer understanding. I would recommend to you "The Truth About the Drug Companies", by Marcia Angell, M.D. as one resource that looks at the interrelationships between .com's, .edu's, and governmental agencies in the development of information. What would be most conclusive in discussing anyone's contribution here would be intelligent analysis and discussion of the actual concepts provided. Other than the first few posts on this thread, I'm still looking for any information either supporting or refuting the actual concepts that were presented. I'm not ready to throw out the concepts based solely on sources, or on personalities. Respectfully, AlaskaAngel |
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