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`What New Drugs, Biologics, and Treatment Approaches Show Promise
`in Breast Cancer?
`
`The multiplicity ofnew interventions for breast cancer
`will challenge our capability to clinically evaluate them
`
`DR H0R TOBA G YI
`
`A number ofnew agents are being developed concurrently, including cytotoxin s, hormonal agents, and biologic approaches (Table). There are a number ofnew
`anthracyclines, particularly liposomal anthracyclines. There are ongoing clinical trials with liposomal daunorubicin and liposomal doxorubicin. At M.D. Anderson, we
`developed liposomal anarnycin, which is a new anthracycline that is not a p- glycoprotein substrate; in the laboratory, it is effective in doXorubicin- resistant tumors. It is
`unclear whether liposomal daunorubicin or liposomal doxorubicin is more effective than doxorubicin. However, the pharmacokinetics and toxicity profiles of the agents
`certainly difler. Thus, these liposomal agents might create some opportunities for different combinations and scheduling.
`
`A number of antifolates are undergoing clinical trials, although I think that only edatrexate will survive for breast cancer. Other antifolates are currently undergoing
`investigation for Pneumacystis carinii infections and other indications.
`
`The anthrapyrazoles, ofwhich losoxantrone is the best known, continue to be investigated in clinical trials. This agent demonstrates response rates ranging from 50% to
`60%, which are similar to and possibly exceed those ofthe standard anthracyclines. An ongoing clinical trial is comparing losoxant1one/ cyclophosphamide with
`doxorubicin/cyclophosphamide. Other anthrapyrazoles, including teloxantrone, piroxantrone, and CI—958, are also being studied in clinical trials. These other agents
`demonstrate no obvious advantage compared to losoxantrone in preclinical studies.
`
`A large number ofthymidylate synthase inhibitors are in clinical development. Raltitrexed and capecita— bine are completing phase II clinical trials and nearing initiation of
`phase III trials. Uracil/tegafur, S1, and a variety of others coming primarily from Japan are also under evaluation.
`
`A number of agents inhibit the degradation of fluoropyrimidines. For example, Glaxo Wellcome has a compound (776C85) that has just entered phase II trials. There
`are new vinca alkaloids of which vinorelbine is the latest to be approved by the US Food and Drug Administration. However, there are at least two other new vinca
`alkaloids beginning phase I trials, primarily in Europe.
`
`I am aware of one new taxane in clinical trials now and probably several that are approaching phase I trials. We have a hexadecylphosphocholine, miltefosine, that has
`been approved and is commercially available in Germany and other European countries. It is a moderately effective topical agent for local recurrences ofbreast and
`other tumors. Several camptothecin analogues appear to have some activity in breast cancer with reported response rates ranging from 15% to 25%. These include
`irinotecan (CPT- ll), topotecan, and 9-aniinocamptothecin (9-AC).
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`At least two important monoclonal antibodies are directed at growth factors or growth factor receptors in clinical trials, including anti-HER- 2/neu (4D5) and
`antiepiderrnal growth factor receptor (EGFR; C225). There are several other monoclonal antibodies against other components of epithelial cells that also are in clinical
`trials.
`
`At least six different vaccines are being developed against breast cancer. A large number of agents have been developed to reverse MDR- mediated drug resistance,
`and a number of genetic modification approaches are in clinical trial. We have an anti-HER-2/neu transcription repression method that already has accrued five patients
`in a phase I clinical trial. We have a p53 transfer program using a retroviral method. We have also recently completed a phase I study tran sfecting the MDR- gene into
`hematopoietic stem cells to allow posttransplant cytotoxic therapy.1
`
`Thus, there are many ongoing research trials and with the potential number of combinations and permutations, the possibilities are infinite.
`
`DR SLED GE
`
`We have been very interested in another area, angiogenesis inhibitors. When I look in our chemotherapy tool box, it seems we are always waiting for that one
`chemotherapeutic agent to cure breast cancer. I believe we may wait a long time if we seek one particular drug to be the answer. I am impressed with the idea that we
`may be able to subvert the tumors microenvironment rather than just simply kill the tumor. Fascinating data have come from Judah Folkman's group in recent years. 23
`Basically, in the setting of micrometastatic disease, the tumor is already actively dividing but is held in check because it lacks an appropriate vasculature to allow
`growth. The tumor becomes capable of aggressive growth when it is able to induce real blood vessel growth into the tumor microenvironment. This angiogenic activity
`may occur at any point in the life of the tumor.
`
`There are a number of approaches to subvert the tumor microenvironment and shut down the angiogenic process. These include drugs that will block the ligands for
`blood vessel- growth factor receptors, including alphaVbeta3 integrin antagonists. Since alphaVbeta3 integrin is essentially found only on proliferating vascular epithelial
`cells. In the laboratory, one can induce apoptosis in these cells using an antagonist to alphaVbeta3 integrin. This drug will soon be entering clinical trials.
`
`The matrix metalloproteinase inhibitors are important potential inhibitors of the angiogenesis process. The urokinase plasminogen activator family also is another target
`that may be useful in terms of the angiogenic process. Platelet factor 4 is another target that is being evaluated in the angiogenic process. Overall, there are eight or 10
`different parts ofthe angiogenic process that represent potential therapeutic targets.
`
`I believe that lack of knowledge on how to use these novel biologic approaches will be the primary investigational problem. We may have great difficulty testing these
`approaches in our current paradigm of testing drugs in metastatic disease. One cannot really expect that these drugs are going to affect a 2- kg tumor with a firlly
`developed vasculature. However, one could easily rationalize evaluation ofthese agents in a micrometastatic disease setting, which might be similar to giving insulin to a
`diabetic. In other words, these agents may not cure the disease but potentially will allow the disease to be kept in check indefinitely. Thus, knowing how to test these
`agents vsill be a major challenge in the next few years.
`
`Another important treatment approach comes from a different direction than new drugs. Specifically, I think learning how to select the drugs appropriate for each
`individual patient is an important area of research and has been a recurring theme in our discussions. An interesting example ofthis is the anti-HER- 2/neu product. We
`have known for many years that HER-2/neu is a reasonable prognostic factor in breast cancer. In a micrometastatic disease setting, patients who are HER-2/neu-
`positive are more likely to relapse and die than those who are HER-2/neu- negative. As such, HER-2/neu has joined the exhaustive list of prognostic factors in breast
`cancer.
`
`However, the interesting thing about HER- 2/neu is that it may be a predictive as well as prognostic factor. It may define who responds to a particular therapy. In the
`metastatic hormonal therapy setting, for instance, a HER- 2/neu-positive patient is highly unlikely to respond to hormonal therapy, regardless of hormone receptor
`status. In the adjuvant setting, in the spinoff trial from the CALGB trial that evaluated dose intensity, the only patients who benefited from high- dose doxorubicin-based
`
`chemotherapy were patients who were HER-2/neu-positive.4
`
`Thus, in the future, we may be able to use an oncogene such as HER-2/neu or other factors to predict who will benefit from our standard regimens. Theoretically, this
`should allow our standard regimens to be used in patients most likely to benefit and allow us to avoid treating the patients who will experience only toxicity. In the
`future, we may be able to segment our breast cancer population into several different subgroups for whom particular therapies will be most effective. We have always
`done this with hormone receptors, but increasingly I think we are going to do this with these new predictive factors.
`
`DR R0 WINSKY
`
`As far as the classic cytotoxic agents are concerned, the next very active agents that we are testing in San Antonio are the thymidylate synthase inhibitors. As Dr
`Hortobagyi mentioned, at least one or two of these agents, particularly raltitrexed, has demonstrated activity in breast cancer. Other thymidylate synthase inhibitors,
`including ZN9331 1 and LY231514, also are currently undergoing evaluation in breast cancer. These drugs are very different in structure and pharrnacologic activity. I
`think we are going to see a number of trials that attempt to determine the roles of these agents in a number of other tumors.
`
`We are close to evaluating clinically a number of agents directed against proliferative signaling. Two or three compounds will soon begin clinical trials. These
`compounds may prove very exciting and valuable. Another active agent of interest is gemcitabine. We are likely to see increasing evaluation of this drug both alone and
`in combination in a number oftunror types, including breast cancer. For example, we have just completed a phase I trial of gemcitabine plus paclitaxel in which we were
`able to administer both dnrgs using full single-agent doses.
`
`Like Drs Hortobagyi and Sledge, I believe that other exciting drugs on the horizon include epidermal growth factor receptor antagonists, endothelial growth factor
`receptor antagonists, antiangiogenesis agents, and matrix metalloproteinase inhibitors. These drugs have tremendous potential because they are nontoxic and can be
`
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`administered orally for long periods. The problem is going to be disceming the most effective use for these agents because we are unlikely to see significant activity in
`phase I and II clinical trials. Long-terrn adjuvant studies with large patient numbers are required with long follow- up periods in order to truly understand the roles of
`these agents in cancer treatment.
`
`References
`
`1. Hanania EG, Giles RE, Kavanagh J, et al. Results of MDR- 1 vector modification trial indicate that granulocyte/macrophage colony-forming unit cells do not
`contribute to post-transplant hematopoietic recovery following intensive systemic therapy. Proc Natl Acad Sci U S A. 1996;93: 15346- 1535 1 .
`2. Folkman J. Clinical applications of research on angiogenesis. N Engl JMed. 1995;333:1757-1763.
`3. O'Reilly MS, Holmgren L, Shing Y, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma.
`Cell. 1994;79:315-328.
`4. Muss HB, Thor AD, Berry DA, et al. c-3rbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl JMed.
`1994;330:1260-1266.
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