Recent Developments in Breast Cancer Therapy
`
`Gabriel N. Hortobagyi, Mien-Chie Hung, and Aman U. Buzdar
`
`Overthe past three decades conceptual approaches to
`breast cancer have led to improvements in locore-
`gional therapy and early diagnosis. Systematic screen-
`ing programs with mammographyreduce disease-spe-
`cific mortality by 25% to 30%, while many patients with
`early breast cancer receive optimal breast-conserving
`treatments. Our increased understanding of the biol-
`ogy of breast cancer helped develop successful adjuvant
`systemic therapies (cytotoxic and hormonal) that, in
`turn, reduce mortality by 15% to 25%. Newer therapeu-
`tic interventions are under intensive investigation.
`While continued progress in cytotoxic therapy is evi-
`dent (taxanes, vinorelbine, gemcitabine, new antifo-
`lates, liposomal anthracyclines, etc), there is increasing
`interest in targeting growth factors and their recep-
`tors. Thus, a monoclonal antibody directed to the ex-
`tracellular domain of the HER-2/neu oncoprotein was
`recently approved by the Food Drug Administration
`based on evidence of antitumor activity as a single
`agent and in combination with cytotoxic therapy. A
`similar approach against the epidermal growth factor
`receptor is under evaluation in clinical trials. Various
`methods ofinhibiting intracellular signal transduction
`also arein clinical development. These include tyrosine
`kinase inhibition, dominant negative mutantinhibitors
`of GRB-2, farnesyl transferase inhibition and vaccines
`directed against various epitopes expressed by mam-
`mary cancercells. Angiogenesis and the enzymete-
`lomerase are other targets underintense scrutiny since
`they are integrally involved with metastases and cellu-
`lar immortality, both common characteristics of the
`malignantcell. These lines of investigation are likely to
`provide innovative therapeutic interventions, which
`may improve the specificity and therapeutic index of
`anticancer treatments.
`Semin Oncol 26 (suppl 12):11-20. Copyright © 1999 by
`W.B. Saunders Company.
`
`To. LAST THREE decades have witnessed
`
`definite progress in the diagnosis and man-
`agement of breast cancer. This progress can be
`measured both in conceptual and practical terms.
`Experimental evidence suggested that primary
`breast cancer was often associated with systemic
`micrometastasis at the time of clinical diagnosis.!
`These observations led to a new paradigm and
`eventually caused a departure from the Halstedian
`approach to the treatment of primary breast can-
`cer.!3-6 The practical consequences were the de-
`velopment of breast-conserving therapy and adju-
`vant systemic treatment. A number of randomized
`trials have documented that breast-conserving
`therapy and total mastectomy produce equivalent
`local and systemic control rates.’-? Furthermore, it
`
`Seminars in Oncology, Vol 26, No 4, Supp! 12 (August), 1999: pp 11-20
`
`has been established that the addition of adjuvant
`hormonal or cytotoxic therapy reduces the inci-
`dence of recurrence and death when combined
`with appropriate locoregional treatments.!°!!
`The observation of an inverse correlation be-
`tweenclinical or pathologic stage at diagnosis and
`long-term outcome led to increased emphasis on
`the earlier diagnosis of primary breast cancer.!2-!4
`The logical conclusion was the institution of sys-
`tematic screening programs using mammography.
`Randomized trials of screening mammography
`have demonstrated a 30% decrease in breast can-
`cer mortality.!5!9 Incremental progress over the
`last three decades has included technical improve-
`ments in radiation therapy and the development
`of new cytotoxic agents. Both have resulted in
`increased efficacy of the respective therapeutic
`modalities.
`Perhaps the most dramatic conceptual develop-
`ment was the identification of the first specific
`therapeutic target,
`the estrogen receptor, over
`three decades ago.?° Its discovery was part of the
`evolution of endocrine interventions for the man-
`agement of breast cancer. The identification of
`steroid hormonalreceptors and the understanding
`of their signal transduction pathway led not only
`to more specific and better-tolerated hormonal
`therapy but, more importantly, also to the under-
`standing that the identification of specific targets
`
`From the Departments of Breast Medical Oncology and Tumor
`Biology, The University of Texas M.D. Anderson Cancer Center,
`Houston, TX.
`Drs Hortobagyi and Buzdar have received research support and
`honoraria from Bristol-Myers Squibb. Dr Hortobagyi has received
`research support from Amgen and Millenium. He has received
`honoraria from Eli Lilly, Genentech, Novartis, Rhéne-Poulenc
`Rorer, and is an Advisory Board member to Bristol-Myers Squibb,
`Genentech, Novartis, and Rhéne-Poulenc Rorer. Dr Hung has
`received research support,
`is an Advisory Board member, and is a
`stockholder of Targeted Genetics. Dr Buzdar has received research
`support from Eli Lilly, Zeneca, and Novartis and honoraria from
`Zeneca.
`Supported in part by the Nellie B. Connally Breast Cancer
`Research Foundation.
`Address correspondence and reprint requests to Gabriel N. Hor-
`tobagyi, MD, FACP, Department of Breast Medical Oncology,
`The University of Texas M.D. Anderson Cancer Center, Box 56,
`1515 Holcombe Blvd, Houston, TX 77030.
`Copyright © 1999 by W.B. Saunders Company
`0093-7754/99/2604- 1206
`
`(cid:43)(cid:82)(cid:86)(cid:83)(cid:76)(cid:85)(cid:68)(cid:3)(cid:89)(cid:17)(cid:3)(cid:42)(cid:72)(cid:81)(cid:72)(cid:81)(cid:87)(cid:72)(cid:70)(cid:75)(cid:3)
`Hospira v. Genentech
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`IPR2017-00805
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`Genentech Exhibit 2062
`
`

`

`12
`
`represents the most important direction in trans-
`lational research.It is likely that research directed
`toward specific targets will result in important con-
`ceptual and incremental developments in the
`management of breast and other cancers.
`Progress in cell biology, including a better un-
`derstanding of the cell cycle, signal transduction,
`and gene expression, as well as the rapid develop-
`ment of our knowledge concerning molecular bi-
`ology and genetics, set the stage for a variety of
`innovative research approaches in oncology. Table
`1 shows a numberof research directions that have
`resulted in treatments currently under clinical
`evaluation. Surgery, radiation therapy, chemother-
`apy, and hormonaltherapy will continue to be the
`mainstay of the treatment of breast cancer for the
`next 5 to 10 years. However, novel therapeutic
`interventions will play an increasingly important
`tole and will enhance or replace some of our
`currently used standard interventions.
`
`IMPROVEMENTS IN CYTOTOXIC
`THERAPY
`
`Over the past decade, a number of new and
`effective cytotoxic agents have become available
`for the treatment of breast cancer (Table 2).2!-23
`Perhaps the most active among these were the
`taxanes (paclitaxel and docetaxel)?+25 because
`they represent a new class of drugs with a new and
`well-defined mechanism of antitumor activity and
`their clinical efficacy matches or exceeds that of
`the anthracyclines, previously the most effective
`agents against breast cancer.?629 Other effective
`novel agents represent new analogs of previously
`available drugs. For instance, vinorelbine is a nor-
`vinca alkaloid related to vinblastine.2°3! Gemcit-
`abine is a purine analog with broad-spectrum an-
`titumor activity against solid tumors.3234 The
`anthrapyrazoles are derived from the anthra-
`cenediones and, more distantly, from the anthra-
`cyclines.35-38 Several new antifols3?-43 and thymi-
`dylate synthase inhibitors*+-46 are currently under
`clinical evaluation. Many of these agents have
`completed phaseII evaluation and are currently in
`phase III trials. The taxanes and vinorelbine are
`under phase III clinical evaluation in adjuvant
`therapy as part of curative, multidisciplinary man-
`agementof primary breast cancer. These and other
`novel agents at earlier stages of development could
`result in incremental improvements in our ability
`to cure primary breast carcinoma and to palliate
`
`HORTOBAGYI, HUNG, AND BUZDAR
`
`
`
`Improvements in cytotoxic therapy
`Improved utilization of existing agents
`Optimization of delivery: pharmacokinetically designed
`administration schedule
`
`Evaluation of dose-intensive treatment regimens
`Biochemical modulation
`
`Prevention or reversal of drug resistance
`New cytotoxic agents
`Development of new cytotoxic agents with novel
`mechanismsof action
`
`Development of analogues with improved therapeutic
`ratio
`
`Immunologic strategies
`Monoclonal antibodies
`
`Immunoconjugates
`With cytotoxic agents
`With natural or synthetic toxins
`With radioactive agents
`Fusion molecules
`Vaccines
`
`
`
`
`Cellular therapy
`Cytokine therapy
`Biological therapy
`Estrogen receptor pathway-directed therapy
`Antiestrogens, selective estrogen receptor modulators
`Aromatase inhibitors
`
`LHRH agonists
`Retinoids
`
`Peptide growth factor receptor-directed therapy
`Anti-epidermal growth factor receptor antibodies
`Anti-HER-2/neu antibodies
`
`Signal transduction inhibition
`Tyrosine kinase inhibitors
`Farnesyl transferase inhibitors (ras inhibitors)
`Antisense therapy
`Dominant negative mutant inhibitors
`Angiogenesis inhibition
`Telomerase inhibition
`
`Osteoclast inhibitory treatment
`Bisphosphonates
`Gallium nitrate
`Inhibition of metastatic cascade
`
`Matrix metalloproteinase inhibitors
`Angiogenesis inhibition
`Adhesion factor-directed therapies
`Gene therapy
`Transcriptional downregulation (eg, E1A)
`Wild-type gene replacement or substitution (eg, p53)
`Insertion of suicide genes
`Dietary interventions
`Limiting total caloric intake
`Limiting fat intake
`Micronutrients
`
`Alternative therapies
`
`Abbreviation: LHRH; luteinizing hormone-releasing hormone.
`
`

`

`RECENT DEVELOPMENTS IN BREAST CANCER THERAPY
`
`13
`
`metastatic breast cancer and cure primary breast
`carcinoma.
`Another approach to improving cytotoxic ther-
`apy is to use effective agents in new strategies
`based on alternative hypotheses. One hypothesis
`proposes that dose intensity is an importantdeter-
`minantof antitumoractivity.4’ Testing of the dose
`intensity hypothesis has taken several forms. In
`one, single-agent therapy at maximally tolerated
`doses is used sequentially, in contradistinction to
`the more traditional simultaneous combination
`chemotherapy approach.485° While there are en-
`thusiastic proponents of this approach, it remains
`to be demonstrated that this approach is therapeu-
`tically superior or that it is associated with im-
`proved quality of life compared with the tradi-
`tional combination chemotherapy programs.
`A second approach to dose intensification is the
`use of high-dose, marrow-ablative doses of cyto-
`toxic therapy, usually with alkylating agents.>!
`The development of improved harvesting tech-
`niques and re-infusion of autologous hematopoi-
`etic stem cells in combination with hematopoietic
`
`growth factors made the use of these regimens
`possible, with reduced morbidity and mortality
`rates. While preliminary data from uncontrolled
`trials were encouraging,°*early results from well-
`controlled, prospective, randomizedtrials are dis-
`appointing.
`A third approach to dose intensification is the
`utilization of standard or moderately higher-than-
`standard doses of chemotherapy administered at
`more frequent intervals (dose density).>+ This ap-
`proachis also under investigation in appropriately
`designed prospective randomized trials. Whether
`dose-intense regimenswill improve treatment out-
`comes depends on the results of these multiple
`controlled clinicaltrials.
`Another approach to enhancingtheefficacy of
`cytotoxic therapy is to better understand mecha-
`nisms of drug resistance and to evaluatestrategies
`to reverse or prevent the establishment of drug
`resistance.?55-5?7 An example ofthis strategy is the
`utilization of calcium channel blockers or other
`agents to compete with the P-glycoprotein, the
`most representative example of multidrug resis-
`tance. While this approach has been successful in
`experimental systems and limited preclinical trials
`for the past several decades, there is no evidence
`that it prevents or reverses drug resistance in pa-
`tients with breast cancer.>? Other approaches to
`interfere with drug resistance mechanisms include
`monoclonal antibodies to the P-glycoprotein,*®
`biochemical modulation (folinic acid for 5-flu-
`orouracil, for example),®*! or the developmentof
`analogs that specifically bypass
`the molecular
`mechanism of resistance for that family of com-
`pounds.38 Of course, the concept of combination
`chemotherapy was originally developed to prevent
`the developmentof drug resistance by using drugs
`with different (complementary) mechanismsofac-
`tion.
`
`IMMUNOLOGIC APPROACHES
`
`For many years, the development of a “magic
`bullet” has been the major goal of research in
`oncology. Better understanding of the immune
`system, technologic developments that led to our
`increased ability to evaluate a numberof different
`aspects of the immuneresponse, and the develop-
`ment of monoclonal antibodies have transformed
`our approach to immunetherapy. From the modest
`beginnings with nonspecific immunotherapy in
`the late 1960s and 1970s, today we have a large
`
`
`
`
`Table 2. New Cytotoxic Agents With Demonstrated
`Efficacy Against Breast Cancer
`
`
`
` Anthracyclines
`Liposomal doxorubicin (TLC D-99)
`Liposomal doxorubicin (Doxil, Sequus Pharmaceuticals Inc,
`Menlo Park, CA)
`Anthrapyrazoles
`Losoxantrone
`Teloxantrone
`Antifols
`Edatrexate
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Nucleoside analogues
`Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis,
`IN}
`Taxanes
`
`Docetaxel (Taxotere; Rhéne-PoulencRover, Antony,
`France)
`Paclitaxel (Taxol; Bristol-Myers Squibb Oncology,
`Princeton, NJ)
`Thymidylate synthetase inhibitors
`Capecitabine (Xeloda, Rocho Pharmaceuticals, Nutley, NJ)
`Eniluracil
`
`Uracil/ftorafur (UFT, Bristol-Myers Squibb, Princeton, NJ)
`UFT/leucovorin (Orzel, Bristol-Myers Squibb, Princeton,
`N))
`Vinca alkaloids
`
`Vinorelbine (Navelbine; Glaxo Wellcome, Inc, Research
`Triangle Park, NC)
`
`
`
`
`
`

`

`14
`
`HORTOBAGYI, HUNG, AND BUZDAR
`
`number of diagnostic tests based on monoclonal
`antibodies with high specificity to better-defined
`epitopes. These developments are reflected in the
`availability of tumor markers, such as carcinoem-
`bryonic antigen, CA-15-3, CA-27-29, and oth-
`ers.®2-64 In addition to increased diagnostic ability,
`immunologic interventions also can be exploited
`for therapy. A large number of monoclonal anti-
`bodies against specific aspects of the normal breast
`or breast cancer cells have been described in the
`literature.-72,
`In general
`terms,
`single-agent
`monoclonal antibody therapy for metastatic breast
`cancer has been disappointing.”3-75
`In recent years, immunologic therapy has con-
`centrated more on the development of immuno-
`conjugates. Immunoconjugates, in which the an-
`tibody is bound to a cytotoxic agent, radionuclide,
`or natural or synthetic toxin, are underclinical
`evaluation.”©79 Substantial challenges remain in
`the development of a functional and relatively
`nontoxic immunoconjugate for breast cancer. Per-
`haps the most recent example of the unsuccessful
`development of an immunoconjugate was
`the
`BR96-doxorubicin molecule.76808! While this im-
`munoconjugate worked well in preclinical studies,
`in clinical trials it was associated with severe gas-
`trointestinal toxicity secondary to cross-reactivity
`of the antibody with gastric mucosa. Because of
`this dose-limiting toxicity, further evaluation of
`this immunoconjugate was halted. Other immuno-
`conjugates are at various stages of preclinical
`and/or clinical development.
`There is considerable interest (and effort) in the
`development of antitumor vaccines.82-84 Some of
`these efforts are directed toward the product of the
`MUC-1 gene; others target carcinoembryonic
`antigen-expressing cells, while still others use the
`STn antigen®* as the putative target.84 A number
`of vaccines directed against these antigens are in
`phase I/II clinical development. Even more so-
`phisticated technology has gone into the develop-
`ment of vaccines based on sensitization of cyto-
`toxic T cells, the development of dendritic cells
`with known specificity,8? and the engineering of
`vaccines by identifying specific small peptides in
`the target antigen.®?
`
`BIOLOGICAL THERAPY
`
`the only
`Immunologic approaches are not
`Improved
`means for targeting malignant tissue.
`understanding in the molecular biology of normal
`
`and malignantcells has resulted in the identifica-
`tion of specific molecular genetic abnormali-
`ties®>88 and the consequences of such abnormali-
`ties,8°89-91
`the identification of autocrine and
`paracrine growth factors??-°4 and their specific re-
`ceptors,3-°> and the characterization of the intra-
`cellular signal transduction pathway that leads to
`the effector function of each growth factor. In
`addition to our increased understanding of the
`endocrine system, which is intimately invoived in
`the developmentof the normalbreast and strongly
`inculpated in the process of malignant transforma-
`tion, we have started to understand the close in-
`teraction between cancer cells and supporting
`stroma. This is a symbiotic relationship.
`
`Hormonal Therapy
`Over the last three decades, the traditional ap-
`proaches to hormonal therapy have been com-
`pletely replaced by novel synthetic agents.°© The
`major ablative surgical procedures, such as bilat-
`eral adrenalectomy or hypophysectomy, are no
`longer in use.?’ Instead, aromatase inhibition,%8
`antiestrogens,?? and progestins®©!!0! have been
`introduced. The experience with the new aro-
`matase inhibitors (anastrozole, letrozole) indicates
`that they are more effective than older aromatase
`inhibitors and progestins, producing prolonged ob-
`jective responses. While surgical oophorectomy
`and radiation for gonadal ablation are still used in
`some institutions, antiestrogens and luteinizing
`hormone-releasing hormone analogs have largely
`supplanted surgical ablation in the clinical man-
`agement of this disease. The recent development
`of selective estrogen receptor modulators!®2-!05
`promises to deliver antiestrogens with higher spec-
`ificity and more limited adverse effects over nor-
`mal tissue. It is likely that other hormonal agents
`with increasing specificity and more limited tox-
`icity will become the standard approach to the
`managementof metastatic and primary breast can-
`cer. One example of the evolution of endocrine
`intervention in breast cancer is the development
`of raloxifene,!°!96 a selective estrogen receptor
`modulator recently approved for the management
`of osteoporosis. Reanalysis of the osteoporosis tri-
`als showed a secondary benefit: a nearly 50% re-
`duction in the incidence of breast cancers for
`raloxifene-treated patients in placebo-controlled,
`randomized trials. The preliminary results of the
`breast cancer prevention trial conducted by the
`
`

`

`RECENT DEVELOPMENTS IN BREAST CANCER THERAPY
`
`iS
`
`National Surgical Breast and Bowel Project, dem-
`onstrated that the administration of tamoxifen
`therapy for 5 years to women at high risk for
`developing primary breast cancer was associated
`with a 45% reduction in the developmentofclin-
`ically detectable breast cancers.!°? This reduction
`was observed for both invasive and noninvasive
`breast cancers, but was also associated with a mod-
`est increase in the incidence of endometrial cancer
`and thromboembolic phenomena. Overall, how-
`ever, benefits exceeded risks. While tamoxifen
`might not be the ideal chemopreventive agent for
`breast cancer, conceptually this is an enormously
`importantfirst step in the development of other
`chemopreventive strategies, perhaps with an im-
`proved therapeutic index.
`
`Therapies Directed to Other Growth Factors
`Many of the growth factors induced by steroid
`hormoneaction are described in Table 3. Perhaps
`the best-characterized family of growth factors is
`the epidermal growth factor family.°* Four closely
`related growth factor receptors (HER-1, HER-2,
`HER-3, and HER-4) have been the object of con-
`siderable interest to many research laboratories.
`The identification of their ligands and theclarifi-
`cation of the downstream signal
`transduction
`pathways
`represent
`a major
`conceptual
`ad-
`vance.94:108.109 The understanding of the signal
`transduction pathwayis important because several
`steps in this pathway are currently being targeted
`for
`therapeutic intervention. Examples of such
`therapeutic intervention are shown in Table 1.
`Recent reports have demonstrated that a mono-
`clonal antibody directed against the extracellular
`domain of the HER-2/neu oncoprotein results in
`
`"fable 3, SteroidHormone-inducedGrowthFactors
`
`
`Growth-Stimulatory
`
`Growth-Inhibitory
`
`(basic fibroblast growth factor)
`
`Transforming growth
`factor-B
`Mammastatin
`
`Epidermal growth factor
`
`Transforming growth factor-a
`Insulin-like growth factor |
`Insulin-like growth factorIl
`Platelet-derived growth factor
`Heparin-binding growth factor |
`(acid fibroblast growth factor)
`Heparin-binding growth factor Il
`
`objective regression of established metastatic tu-
`mors in 10% to 20% of patients.!!° This antibody,
`in association with cytotoxic therapy, signiftcantly
`increases response rate, time to progression, and
`survival of patients treated with this combina-
`tion.!!! Similar data were obtained in preclinical
`models
`using
`another monoclonal
`antibody
`against the epidermal growth factor receptor. !12:113
`Clinical trials with both antibodies currently are
`in progress.
`
`Signal Transduction Inhibition
`The intracellular domains of all four HER te-
`ceptors havetyrosine kinase activity and a number
`of compoundswith tyrosine kinase inhibitory ac-
`tivity have been identified.!!+-115 Some of these are
`natural products, while others were synthesized
`based on expanding knowledge of the molecular
`structure of tyrosine kinase. Further downstream,
`several of the docking molecules have been tar-
`geted for therapeutic intervention. GRB-2 is being
`targeted with small peptides and dominant nega-
`tive mutantinhibitors.!!6 RAS activation is abro-
`gated with the use of farnesyl transferase inhibi-
`tors. 117,118
`
`Gene Therapy
`Ourgroup has developed a genetic modification
`strategy for
`transcriptional downregulation of
`HER-2. In preclinical studies, this approach pro-
`duced a dramatic downregulation of HER-2119:120
`and prolongationofsurvivalof animals with trans-
`planted HER-2—overexpressing tumors.!21.122 Our
`limited experience with the initial phase I trial
`demonstrated the proof of principle, both with
`clear expression of the transfected gene in the
`target tissue and the downregulation of HER-2
`expression in cancer cells.!23 Furthermore, de-
`creases in tumor cell count and tumor marker
`concentration were also observed in several pa-
`tients.!23 Other gene therapy approaches havetar-
`geted p53 mutations!24 or have used external ac-
`tivation of suicide genes.125.126
`
`Angiogenesis
`The pioneering work by Folkman!2? and oth-
`ers!28.129 demonstrated that primary or metastatic
`tumors cannot grow above 2 to 4 mm without the
`development of neovascularity. To survive, suc-
`cessful tumor deposits secrete mediators that en-
`hance the development of tumorvascularity from
`
`

`

`16
`
`HORTOBAGYI, HUNG, AND BUZDAR
`
`neighboring normalcapillaries. There are a num-
`ber of critical steps in the angiogenesis pathway
`and several of these have been targeted for inter-
`vention.!3°-134 While over 20 substances with pu-
`tative antiangiogenesis effect are in preclinical or
`clinical development, a few have reached phase II
`or phaseIII clinical trials, and there are anecdotal
`reports of objective responses with some of these
`agents.!9!-134 Tt
`is anticipated that the major ap-
`plication of these angiogenesis inhibitors will be as
`adjuvant
`to rapid cytoreductive interventions,
`such as surgery, radiotherapy, or chemotherapy.
`
`Telomerase Inhibition
`
`During normalcellular replication, the terminal
`portion of each chromosomeis gradually short-
`ened, and with each cell division is shortened
`further. After reaching a critical length, chromo-
`somalreplication is no longer possible, and cellular
`senescence and death follow. Telomerase is an
`enzyme that preserves the length of chromosomes
`and therefore theoretically confers immortality on
`the cell. It has been shown that this enzyme is
`inactive or absent in most mature, normal human
`cells, while it
`is active or overactive in many
`malignantcells.!35-'36 Telomerase activity was re-
`ported to correlate with prognosis in breast can-
`cer.!37.138 Therefore, it has been hypothesized that
`inhibition or inactivation of telomerase might be
`one way to limit the number of divisions of the
`cancer cell, eventually causing cell death.!35-139
`The developmentof successful telomerase inhibi-
`tors is an attractive hypothesis, but practical ac-
`complishments in this area have been limited.
`
`Osteoclast Inhibitory Therapy
`
`Bone metastases are the most commonsites of
`distant spread of breast cancer and several other
`common human malignancies.!4° Bone metastases
`are also a frequent source of morbidity and can
`lead to catastrophic complications. Traditional an-
`ticancer therapies have had limited activity and
`success in controlling bone metastases. Over the
`last two decades, it has been demonstrated thatall
`lytic bone metastases and bone-related complica-
`tions, such as hypercalcemia, osteoporosis, and
`Paget’s disease, are the direct or indirect conse-
`quence of osteoclast hyperactivity.!40142 A num-
`ber of osteoclast inhibitors have been developed.
`Among them, the bisphosphonates probably have
`been the most successful group of compounds.!42-!45
`
`They inhibit osteoclast activity as well as recruit-
`ment of osteoclast precursors, and also interfere
`with differentiation of osteoclast precursors. Clin-
`ical studies have demonstrated that bisphospho-
`nates are the treatment of choice for hypercalce-
`mia of malignancy and Paget’s disease of the bone.
`Bisphosphonatesare also successful in the preven-
`tion and managementof osteoporosis. In patients
`with osteolytic bone metastases, bisphosphonate
`therapy producespain relief, reduction in analgesic
`requirements, and delay as well as reduction in the
`frequency of skeletal-related events, such as frac-
`tures, hypercalcemia, and spinal cord compres-
`sion./46-149 These drugs reduce the need for specific
`bone-related interventions, such as radiation ther-
`apy or orthopedic surgery. Pamidronate was re-
`cently shown to be an effective second-generation
`bisphosphonate and monthly administrations of
`this bisphosphonate have produced a 30% to 40%
`reduction in skeletal-related events, with reduc-
`tion in pain, analgesic requirements, and preser-
`vation of quality oflife.
`
`CONCLUSIONS
`
`Much progress has been made in our under-
`standing of the process of malignant transforma-
`tion. Expansion of our knowledge in molecular
`biology, molecular genetics,
`immunology, metas-
`tases, and angiogenesis, as well as the clinical
`behavior of primary and metastatic breast cancer,
`have led to the identification of many noveltar-
`gets. Applied research presents us with a large
`numberof potential tools with which to intervene
`in the management of metastatic disease and,
`more recently, in the prevention of primary breast
`cancer. Additional research will
`likely identify
`critical steps in the process of malignant transfor-
`mation that could expand our options for primary
`prevention of breast cancer. For the short term,
`chemotherapy, hormonetherapy, and locoregional
`treatments will continue to be the mainstay of
`treatment for patients with primary and metastatic
`breast cancer. Specific molecular
`interventions
`will have an increasing role and may eventually
`teplace some of the therapies used today.
`
`ACKNOWLEDGMENT
`
`The authors thank Lisa Chaput for her assistance in the
`preparation of this manuscript.
`
`

`

`RECENT DEVELOPMENTS IN BREAST CANCER THERAPY
`
`\7
`
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