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Why Do Some Breast Cancers Stop Responding to Targeted Therapy?

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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
    Gregory D. Pawelski

    Personalized Targeted therapy is still trial-and-error treatment

    Although the theory behind targeted therapy is appealing, the reality is more complex. For example, cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.

    In other words, cancer cells have 'backup systems' that allow them to survive. The result is that the drug does not shrink the tumor as expected. One approach to this problem is to functionally target multiple pathways in a cancer cell.

    Another challenge is to identify which of the targeted treatments will be effective (enzyme inhibitors, proteasome inhibitors, angiogenesis inhibitors, and monoclonal antibodies).

    Targeted therapy is still trial-and-error treatment.

    The functional profiling platform can explore multiple signaling pathways from the same test. It doesn't have to test for each and every signaling pathways there are.

    There are many pathways to altered cellular function. Testing for these pathways, those which identify DNA, or RNA sequences or expression of individual genes or proteins often examine only one component of a much larger, interactive process. In testing for all "known" mutations, if you miss just one, it may be the one that gets through.

    And it's not just only targeted drugs that may be effective as first-line treatment on your individual cancer cells. Cancers share pathways across tumor types. There really is no lung cancer chemos, or breast cancer chemos, or ovarian cancer chemos.

    There are chemos that are sensitive (effective) or there are chemos that are resistant (ineffective) to each and every "individual" cancer patient, not populations. There are chemos that share across tumor types.

    The functional profiling platform has the unique capacity to identify all of the operative mechanisms of response and resistance by gauging the result of drug exposure at its most important level: cell death.

    Finding what targeted therapies would work for what cancers is very difficult. A lot of trial-and-error goes along trying to find out. However, finding the right targeted therapies for the right "individual" cancer cells can be improved by cell-based assays, using functional profiling.

    Identifying DNA expression of individual proteins (that measure of RNA content, like Her2, EGFR, KRAS or ALK) often examine only one component of a much larger, interactive process. Gene (molecular) profiling measures the expression only in the "resting" state, prior to drug exposure. There is no single gene whose expression accurately predicts clinical outcome. Efforts to administer targeted therapies in randomly selected patients often will result in low response rates at significant toxicity and cost.

    All DNA or RNA-type tests are based on "population" research (not individuals). They base their predictions on the fact that a higher percentage of people with similar genetic profiles or specific mutations may tend to respond better to certain drugs. This is not really "personalized" medicine, but a refinement of statistical data.

    Functional profiling measures proteins before and after drug exposure. It measures what happens at the end (the effects on the forest), rather than the status of the individual trees. Molecular profiling is far too limited in scope to encompass the vagaries and complexities of human cancer biology when it comes to drug selection. The endpoints of molecular profiling are gene expression. The endpoints of functional profiling are expression of cell death (both tumor cell death and tumor associated endothelial [capillary] cell death).

    In testing for all "known" mutations, if you miss just one, it may be the one that gets through. And it's not just only targeted drugs that may be effective as first-line treatment on your "individual" cancer cells. Cancers share pathways across tumor types.

    Targeted treatments take advantage of the biologic differences between cancer cells and healthy cells by "targeting" faulty genes or proteins that contribute to the growth and development of cancer. Many times these drugs are combined with chemotherapy, biologic therapy (immunotherapy), or other targeted treatments.

    Clinicians have learned that the same enzymes and pathways are involved in many types of cancer. However, understanding targeted treatments begins with understanding the cancer "cell." In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific pathways that involve various genes and proteins in the cell.

    Cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.

    Targeted therapies are typically not very effective when used singularly or even in combination with conventional chemotherapies. The targets of many of these drugs are so narrow that cancer cells are likely to eventually find ways to bypass them.

    Physicians may have to combine several targeted treatments to try an achieve cures or durable responses for more complicated tumors like those that occur in the breast, colon and lung.

    These targeted therapies produce limited results because they can help a relatively small subgroup of cancer patients. But when they work, they produce very good responses. With targeted therapy, the trick is figuring out which patients will respond. Tests to pinpoint those patients cannot be accomplished with genetic testing.

    All the gene amplification studies, via genetic testing, tell us is whether or not the cancer cells are potentially susceptible to a mechanism/pathway of attack. They don't tell you if one drug is better or worse than another drug which may target a certain mechanism/pathway. Cell-based functional analysis can accomplish this.

    The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one target or pathway, or even a few targets/pathways.

    Literature Citation:

    Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007

    Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)
    Attached Files
    Gregory D. Pawelski


      Breast Cancer Gene Expression Profiling Has Not Achieved Personalized Medicine Yet

      Although ten years of genetic profiling has had an enormous impact on the understanding of breast cancer, progress on individualizing therapy has been rather limited, researchers from the UK and USA reported in The Lancet this week. Specifically, the authors refer to the prognostic and predictive factors associated with personalized medicine, even though genetic profiling offers enormous potential for better prediction of outcomes and optimizing individual patients' treatments.

      At this moment there are no commercially available molecular tests that can predict benefit from a specific therapeutic agent, despite of many prognostic and predictive signatures having been developed. Scientists are still unable to accurately determine prognosis or chemotherapy success in some disease subsets, such as ER-negative and triple negative disease.

      Jorge Reis-Filho from The Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research in London, UK and Lajos Pusztai from the MD Anderson Cancer Center in Texas, USA, set out to determine what progress, if any, had been made over the last ten years regarding microarray analysis (expression profiling) of breast cancers.

      Treatment decisions have usually been based on several clinical factors, such as tumor size and its location, estrogen receptor (ER) status, and whether the cancer has spread to lymph nodes or distant sites in the body.

      The researchers explain: "With these approaches, about 60% of all patients with early-stage breast cancer still receive adjuvant chemotherapy, of which only a small proportion, 2-15% of patients, will ultimately derive benefit, while all remain at risk of toxic side-effects."

      In addition to information provided by clinicopathological features, the introduction of first generation prognostic gene signatures has offered clinically useful prognostics.

      At present, several genomic tests are being used in women with ER-positive disease to help determine the likelihood of cancer recurrence, and which patients' outcome has been sufficiently successful in order to deem chemotherapy unnecessary.

      However, the researchers comment: "Increasingly clear is that the prognostic information offered by these [first generation prognostic] signatures in addition to the information provided by semi-quantitaive analysis of ER, PR, HER2, and Ki67 is limited...and the continued importance of standardized histo-pathological analysis of tumors should be emphasized."

      Using gene signatures to predict which patients may benefit from specific therapies has been less successful, and even though scientists have developed many predictive signatures, some have been based on unreliable data; their usefulness in patients continues to be controversial.

      This could be due to the fact that resistance to chemotherapy is a complex mechanism, as it can be caused by changes in just one or a small number of genes? The likelihood of diverse and often subtle changes resulting in resistance to chemotherapy being reliably identified by standard gene expression profiling is extremely small.

      In a concluding statement the researchers say: "The theoretical knowledge and logistical lessons learned from gene expression profiling studies, however, will prove useful for research aiming to develop the next generation of prognostic and predictive biomarkers."

      References: Prof Jorge S Reis-Filho FRCPath and Prof Lajos Pusztai MD "Gene expression profiling in breast cancer: classification, prognostication, and prediction" The Lancet, Volume 378, Issue 9805, Pages 1812 - 1823, 19 November 2011. doi:10.1016/S0140-6736(11)61539-0

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      Gregory D. Pawelski


        Dermatologic Adverse Events Induced by Molecularly Targeted Cancer Agents

        Dr. Mario Lacouture from Memorial Sloan-Kettering Center Center in New York and his colleagues from the Northwestern University Feinberg School of Medicine in Chicago, have suggested in a new study that painful rashes and other skin-related side effects of newer targeted cancer drugs may jack up treatment costs.

        The average cost of treating each cancer patient who came into a dermatology clinic with skin, hair and nail complaints was almost $2,000, the researchers reported. That included expenses related to doctors' appointments, dermatology medications and lab tests. And some patients with skin problems may have to delay or alter their treatment regimen if side effects are too severe.

        According to Dr. Lacouture, dermatologic side effects including skin irritation and dry skin are the two topmost concerns that patients have that they did not expect during therapy. Patients are prepared to get hair loss, they are prepared to get some nausea and diarrhea, but they aren't expecting to get is all these skin issues.

        Lacouture and his colleagues tracked costs related to skin reactions in 132 patients being treated with targeted cancer-fighting drugs at their dermatology clinic between 2005 and 2008. The majority of those patients had colon or lung cancer and the most common drug treatments included Erbitux (cetuximab) and Tarceva (erlotinib).

        Patients came in with a range of dermatology-related complaints, including painful acne, lesions and blisters on the hands and feet and nail infections. Those conditions cost anywhere from $21 to almost $11,000 to treat, depending on the patient.

        The average total cost of medications, clinic visits, treatment procedures and lab tests such as blood work and wound culturing for each patient was $1,920. Dermatology drugs accounted for the greatest chunk of that, costing an average of about $840 per patient, according to findings published in the Archives of Dermatology.

        Lacouture said that more than half of patients may have skin, hair and nail reactions to newer drugs that treat some of the most fatal types of cancer. That's because along with their cancer-fighting action, the drugs also attack proteins on the skin.

        If skin reactions are severe, especially with certain cancer drugs including Nexavar (sorafenib) for kidney cancer, doctors may have to adjust dosages or take patients off those drugs for a period of time. While most of the extra costs would be covered by patients' insurance, skin problems also mean more time and transportation for appointments and co-payments.

        It adds to the out-of-pocket costs for the patient and to the already ballooning cost of cancer. Those costs should be taken into consideration when evaluating new cancer drugs. The most important thing for patients is to be aware of how common these problems are and know that the sooner they are diagnosed and treated for side effects, the less likely it will interfere with cancer treatment and the quality of life.

        Source: Archives of Dermatology, December 19, 2011.

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        Gregory D. Pawelski