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Editors-in-Chief Toren Finkel National Heart, Lung and Blood Institute, National Institutes of Health, USA Tamas Bartfai Harold L. Dorris Neurological Research Center and The Scripps Research Institute, USA
Breast cancer is the rst human tumor for which targeted therapies have been developed. The most impressive success stories include estrogen receptor pathway downregulators (tamoxifen and aromatase inhibitors) and HER2 antagonists (Herceptin). The development of dozens of other targeted treatments for breast cancer is underway. Unfortunately, some intrinsic features of breast cancer biology compromise the efciency of current therapeutic strategies. Introduction
Breast cancer is the most common malignancy among females affecting approximately one out of ten women. Ageing of population in the industrialized world is the most obvious cause of increased breast cancer occurrence; indeed, the risk of developing breast cancer after 65 years of age is 5.8 times higher than before 65, and 150-fold higher than before 30 years of age. In addition to advanced age, a few dozens of other breast cancer predisposing factors have been identied; however, all these diverse risks can be assigned to either of two major categories: excessive exposure to estrogens and deciency in maintenance of genomic integrity (Fig. 1) [1]. The proliferative effect of estrogens on breast epithelium has been acknowledged for decades. It is suggested since recently, that tumor promotion is not the only mechanism of estrogens action: some of estrogen metabolites were shown to cause DNA damage directly (i.e. contribute in the breast cancer initiation). Selected causes of estrogen overload (e.g. early menarche or late menopause) are at least in part attributed to inherited genetic variations. However, most of determinants of hyperestrogenia are related to the modern, Western lifestyle including low parity, delayed age at rst
*Corresponding author: (E.N. Imyanitov) evgeny@imyanitov.spb.ru 1740-6765/$ 2004 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddmec.2004.09.002
Section Editor: Silvio Gutkind National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
Breast cancer is the most common malignancy among females and affects approximately one in every ten women worldwide. It is the rst human tumor for which targeted therapies have been developed. Some notable successful therapies include tamoxifen, aromatase inhibitors both estrogen receptor pathway downregulators and Herceptin, a HER2 antagonist. However, despite some spectacular examples of prolonged disease remission in selected women, the statistical survival benet in metastatic breast cancer patients is estimated in months and not years. In this article, Evgeny Imyanitov and Kaido Hanson describe the progress of targeted treatments for breast cancer that are already underway, and discuss the particular features of breast cancer biology that compromise the efciency of current therapeutic drugs.
delivery, short duration of breastfeeding, overeating, limited exercise and so on. Interestingly, the obesity correlates with hyperestrogenia and excessive breast cancer risk only after the menopause; in pre-menopausal women, overweight is associated with anovulatory cycles and reduced probability of acquiring breast cancer disease. The adverse impact of oral contraception and hormone replacement therapy has been conrmed in some but not all epidemiological studies. The role of exogenous endocrine disruptors in breast cancer incidence remains to be proven [14]. The second group of breast cancer predisposing properties deciency in maintenance of genomic integrity has been recognized only recently (Fig. 1). There are two lines of supporting arguments: rst, all of the identied breast cancer susceptibility genes contribute to the sensing or repair of DNA damage; second, there is an impressive reproducibility of phenotyping studies demonstrating relationships between breast cancer risk and constitutional chromosomal instability [57]. Unlike lung or bladder cancers, none of environmental carcinogens has been convincingly linked to breast cancer
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Box 1. Challenging the dogmas in breast cancer research: recent unexpected ndings
Viral theory revisited? There are several independent reports claiming that in some groups of patients roughly a third of breast carcinomas contain DNA sequences homologous to the well-known Mouse Mammary Tumor Virus (MMTV); in intriguing accordance with the viral hypothesis, worldwide breast cancer spread appears to parallel the geographical distribution of one species of house mouse, Mus domesticus. If the contribution of viruses in breast cancer etiology will be conrmed, many aspects of breast cancer prevention and treatment will need to be re-analyzed. However, there are also some negative reports on this subject [8,9]. Polyclonal origin of breast cancer? Monoclonal origin of breast cancer is believed to be a wellestablished fact. However, recent data cast some doubt on this condence: at least in some cases, breast cancer lump appears to arise from several independent progenitors, thus supporting the cancer eld theory [42]. Interestingly, stromal cells surrounding breast cancer epithelium also carry somatic mutations, and the spectrum of these genetic alterations is different from those observed in cancer cells [22]. Does all tumor mass possess a danger? Recent experiments show that only a minor, specic fraction of cells forming breast cancer lump is highly tumorigenic [43]. Tumor heterogeneity might compromise the search for new therapeutic targets, as the current approaches are almost always based on the analysis of crude tumor material. The intrinsic resistance of particular intratumoral cell subsets to the treatment might explain a discordance between high frequency of short-term partial tumor responses and low rate of prolonged breast cancer remissions.
etiology. The results of the studies on dietary factors have been inconclusive as well. Contrary to beliefs of many patients, psychological stress is not associated with breast cancer risk [1,2,4]. There are surprisingly few reports in modern scientic literature assessing the relationship between breast trauma and subsequent cancer development. Intriguingly, some recent ndings have resumed the debate on the viral etiology of breast cancer [8,9] (Box 1).
NM_000051) and p53 (GenBank accession number NM_000546) germ-line mutations, predisposing to ataxiatelangiectasia and Li-Fraumeni hereditary syndromes, respectively, can also be considered as breast cancer-associated genetic defects, owing to the increased incidence of breast neoplasia in their heterozygous carriers [5]. There is a growing class of breast cancer-associated genetic variations, which are situated in between rare catastrophic germ-line mutations and frequent normal gene polymorphisms. Some founder mutations can be classied as middlepenetrance polymorphisms, owing to their noticeable occurrence in the population (1%) and modest but clinically meaningful inuence on the breast cancer risk increase. In addition to Jewish founder mutations in BRCA genes, which seem to be somewhat less penetrant than non-founder defects, the examples include CHEK21100delC (GenBank accession number NM_007194) and NBS1657del5 (GenBank accession number NM_002485) [7]. As already mentioned above, all high- and middle-penetrant genes with proven breast cancer-associated signicance participate in various aspects of maintenance of genomic integrity. It is frequently stated that the majority of breast cancer cases are related to the disadvantageous genetic passport (i.e. unfavorable combination of low-penetrant gene polymorphisms). The attempts to link breast cancer risk to polymorphisms in carcinogen metabolizing enzymes have been unsuccessful. There is more hope to detect breast cancer genedisease interactions within the class of hormone metabolizers, based on convincing evidence for heritability of individual features of hormonal portrait coupled with the proven role of hyperestrogenia in breast cancer development. However, no reproducible associations have been revealed over the decade-long research in this eld. Following the success in identifying breast cancer-associated germ-line mutations within genome safeguards in addition to relying on the consistency of the results of phenotyping tests (see the text above and Fig. 1), many breast cancer researchers have recently re-located the efforts to the analysis of DNA repair gene polymorphisms; the outcome of these studies remains to be seen [7].
Figure 1. Breast cancer mechanisms. Two groups of predisposing factors have a major role in breast cancer etiology: excessive breast exposure to estrogens and deciency in maintenance of genomic integrity. During the malignant transformation process, breast epithelial cells accumulate high number of somatic genetic events (mainly gross chromosomal alterations and methylation abnormalities). These DNA alterations activate oncogenes and inactivate tumor suppressor genes, which eventually results in the manifestation of The hallmarks of cancer [21]. Molecular determinants of the most essential tumor properties might serve as potential therapeutic targets.
denitive conclusion [12,14]. Classical type of microsatellite instability does not occur in breast cancer, although it was demonstrated in a small portion of bilateral breast tumors [15]. It was shown recently that many breast carcinomas carry alterations in mitochondrial DNA [16].
Discrete alterations in breast cancer-specic genes can serve both as the triggers of somatic genetic instability and as consequences of increased mutation rate. Hundreds of reports have been devoted to the cataloging of breast cancer-associated genetic abnormalities (e.g. Somatic Mutations
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Gains of genetic material Events of uncertain signicance Losses of heterozygosity (allelic imbalances) reecting either allelic deletion or gain of the remaining allele Inactivating events Losses of genetic material
[12] [18]
[12]
[20] [13]
[12,17]
in Human Cancers Database; http://www.onco-is.com). Conditionally, they can be classied into activating and inactivating events (Table 1). Noticeable frequency of amplications of selected oncogenes [HER2 (also known as ERBB2) (GenBank accession number NM_004448), CCND1 (GenBank accession number NM_053056), C-MYC (GenBank accession number NM_002467)] followed by their overexpression is a distinct feature of breast cancer. In addition to identied oncogenes, there are several other regions in the genome that repeatedly demonstrate extra copies in breast cancer; it remains to be established whether they do contain activated oncogenes or simply reect the background noise of somatic chromosomal instability [12]. Recent developments in expression proling have signicantly enlarged the list of genes overexpressed in breast cancer, however systematic picture of upregulated transcripts has yet to be drawn [17]. In 1990s and early 2000s many researchers tried to locate breast cancer-specic losses of heterozygosity (LOH). However, the attempts to identify new suppressor genes by LOH mapping have largely failed: in addition to enormous variability of LOH patterns due to admixture of non-specic allelic imbalances, it has turned out that conventional PCR allelotyping can not discriminate between inactivating and activating mutations (e.g. loss of the allele versus amplication of the remaining allele) or between homozygous deletion and retention of both gene copies [18,19]. Intragenic mutations are relatively uncommon for breast cancer. The p53
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(GenBank accession number NM_000546) gene is mutated only in 20% of breast carcinomas; mutations in RAS family oncogenes occur in a negligible fraction of breast cancer [20]. The genome-wide approaches led to the identication of dozens breast cancer-associated deletions; there is also a growing list of genes whose transcription is downregulated in breast cancer [12,17]. Frequently, the decreased expression of suppressor genes is associated with the methylation of their promoter regions [13]. However, molecular techniques enabling global mapping of hypermethylated regions are not yet as efcient as expression proling or array-based comparative genomic hybridization. Various combinations of activating and inactivating mutations and epigenetic events lead to the spectrum of properties of tumor cells, which have been dened as The Hallmarks of Cancer in already-classical work of Hanahan and Weinberg [21], and include self-sufciency in growth signals, insensitivity to antigrowth signals, evasion from apoptosis, limitless replicative potential, invasion and metastasis, genomic instability and sustained angiogenesis. Similarly to the progress in understanding of tumor angiogenesis, it is becoming apparent that the contribution of surrounding stroma in tumor growth is not a merely passive process, but, instead, an active and essential component of neoplastic evolution [22,23]. Breast carcinomas share all characteristics of malignancy, with one important reservation: more than 50% of breast cancers retain at least partial dependence from estro-
genic growth stimulation. This benign feature of some breast cancer accounts for remarkable efciency of the antiestrogenic treatment approaches [24]. Although the diversity of molecular portraits of breast cancer is extraordinary, they appear to t into the limited number of distinct disease subsets. Noticeably, many of breast cancer signatures identied by array expression proling tend to group around long-known disease markers, such as estrogen receptor (ER) or HER2 oncogene status [25]. Interestingly, host factors appear to play an essential role in determining the molecular variant of breast cancer pathogenesis [15].
cyclin-dependent cascades, and phosphatidylinositol 3kinase (PI3-K) pathway (AKT, mTOR), which has an essential role in the regulation of cell survival. These molecules are not indeed specic for breast cancer; they do have regulatory functions in normal cells as well, therefore, their targeting possesses a risk of adverse effects. In addition to ER and HERs, there is an increasing attention to the angiogenic pathways triggered by vascular endothelial growth factor (VEGF); these cascades appear to be upregulated in many cancer types, including breast cancer [12,26,28,29].
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Properties of cancer cells as a target Genetic instability and/or Conventional cytostatic high proliferation drugs (anthracyclines, taxanes, alkylating drugs, antimetabolites, vinca alkaloids)
Clinical response can be achieved in more than 8090% cases. However, disadvantages include severe adverse effects, limited duration of response, overlapping spectrum of drug resistance, limited ability to predict response and/or non-response to a given cytostatic compound.
[38]
Molecular targets as tumor-specic anchors for delivery of cytostatic substances Thymidine phosphorylase Capecitabine (Xeloda) On the market Thymidine phosphorylase converts Xeloda to the cytostatic drug, 5-uorouracil; high tumor specicity is attributed to the preferential expression of this enzyme in cancer tissues. Breast cancer-specic antigens Immunoconjugates (with cytotoxic drugs, radioactive isotopes, toxins, attractants of tumor-killing cells) Radioactive iodide Phase III Presumably large spectrum of candidate molecules, since the target does not need to be essential for tumor growth.
Roche
http://www.roche.com
[38]
[39]
Sodiumiodide symporter
Laboratory studies
[40]
Genuine targets (i.e. molecules essential for breast cancer development and maintenance) Estrogen receptor pathway ER pathway downregulators show high efciency combined with good safety prole. However, more than a third of breast cancers are resistant to antiestrogen therapy. Selective estrogen receptor modulators (SERMs) Tamoxifen Toremifene (Fareston) On the market for a long time On the market Almost complete cross-resistance with tamoxifen Almost complete cross-resistance with tamoxifen Many pharmaceutical companies Schering-Plough, Orion http://www.scheringplough.com http://www.orion. http://www.lilly.com [24] [24]
Chemoprevention trials
Eli Lilly
[24]
Vol. 1, No. 2 2004
On the market
AstraZeneca
http://www.astrazeneca.com
[24]
Aromatase inhibitors
Superior when compared with tamoxifen; induce tumor response in a subset of tamoxifen-resistant tumors. However, efcient only in postmenopausal patients. On the market On the market On the market HER2 is activated only in one out of four breast tumors. AstraZeneca Novartis Pzer http://www.astrazeneca.com http://www.novartis.com http://www.pzer.com [24] [24] [24]
Anastrozole (Arimidex) Letrozole (Femara) Exemestane (Aromasin) HER2 (ERBB2) Antibodies Trastuzumab (Herceptin)
On the market
High-efciency combined with good safety prole. Notice that HER2+ tumors represent the most aggressive subset of breast cancer.
Genentech, Roche
http://www.gene.com http://www.roche.com
2C4 (Omnitarg, Pertuzumab) Small molecule inhibitors CP-724714 TAK-165 HER1 (EGFR) ZD1839 (Iressa, Getinib) OSI-774 (Tarceva, Erlotinib)
Phase III
Genentech, Roche
http://www.gene.com http://www.roche.com
[29]
Pzer Takeda
http://www.pzer.com http://www.takeda.com
[29] [29]
[29] [29]
Phase I Phase II Phase II Phase II Phase II Trials on several farnesyltransferase inhibitors have been discontinued due to high-toxicity and lack of clinical effect.
R115777 (Zarnestra, Tipifarnib) Phase II SCH66336 (Sarasar, lonafarnib) CDK kinases Flavopiridol (Alvocidib) Phase III Phase I
http://www.jnj.com
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Table 2 (Continued).
Target Therapy against target UCN-01 CYC202 (Roscovitine) BMS-387032 mTOR kinase CCI-779 (Temsirolimus) RAD001 (Everolimus, Certican) PKC RAF MEK Akt Hsp90 Matrix metalloproteinases BB-2516 (marimastat) BMS-275291 c-Kit and/or PDGFR COX2 STI571 (Gleevec, Glivec, Imatinib) Celecoxib (Celebrex) Phase II Phase II Phase II Phase IIIII COX2 is selectively expressed in tumors, thus COX2 inhibitors have good safety prole. Pzer http://www.pzer.com Bryostatin-1 Bay 43-9006 CI-1040 (PD184352) Perifosine 17-AAG Phase IIIII Phase I Clinical trials on other cancer types Clinical trials on other cancer types Phase II Phase II Phase I High toxicity but limited therapeutic efciency in initial clinical trials Vernalis Bristol-Myers Squibb, Celltech http://www.vernalis.com http://www.bms.com http://www.celltechgroup.com [28] [27] [34] Wyeth Novartis GPC Biotech Onyx, Bayer Pzer Aeterna Zentaris Kosan Biosciences http://www.pzer.com http://www.aeterna.com http://www.kosan.com http://www.wyeth.com http://www.novartis.com [30] [33] [29] [33] [33] [33] [30] Stage of developmenta Phase I Phase II Phase I Advantages and/or disadvantages UCN-01 inhibits several other kinases, including PKC. Who is working on the target Kyowa Hakko Kogyo Cyclacel Bristol-Myers Squibb Website Refs.b [32] [32] [30]
Phase III Laboratory studies Laboratory studies Laboratory studies Inhibition of chemokine receptors might interfere with metastatic process.
Stage of development applies mainly for breast cancer but not for other cancer types; this is especially true for phase II/III trials and already marketed drugs. Notice that some of the already licensed compounds have been approved for the treatment of metastatic breast tumors, but still remain at the stage of clinical trials for the use in adjuvant therapy and/or chemoprevention. b In addition to the literature references indicated in the table, the information was updated using the websites of pharmaceutical companies, Clinical Trials site of the National Cancer Institute (http://www.cancer.gov/clinicaltrials), and the Catalog of FDA Approved Drug Products (http://www.accessdata.fda.gov/scripts/cder/drugsatfda).
Achilles heel of neoplasia. It is probable that the mechanism of action of conventional non-specic cytostatics utilizes this weakness, at least in part. Unfortunately, most of the currently available cytotoxic agents have a low therapeutic index [38].
of action, ER pathway downregulators, HER2 antagonists, selective and, previously, non-selective COX2 inhibitors and so on). Following the logic described above, one would expect higher rate of prolonged breast cancer remissions than the one currently observed. There are several concerns related to the future of breast cancer therapy. With the possible exception of ER, HER2 and COX2, most of the currently considered targets are not truly cancer-specic because they are involved in the functioning of vital human tissues. Not surprisingly, administration of signal transduction modiers (Table 2) often results in noticeable adverse effects, sometimes comparable with toxicities of conventional cytostatics. Interestingly, in attempt to prevent cancer cell from rescuing from target inhibition, some compounds with broader substrate specicity have been recently tested (e.g. pan-HER inhibitor CI-1033, dual HER1HER2 inhibitor GW572016 and CDKsPKC inhibitor UCN-01) (Table 2). Although the relaxed drug specicity might render higher antitumor activity [29], it also increases the risk of undesirable consequences. It is hoped that ongoing efforts in expression array proling will help to increase the list of genuine breast cancer-specic targets. Another group of difculties is related to the tumor ability to evolve over selective pressure of cancer treatment, and inevitably develop drug-resistant phenotype. The intrinsic genomic instability of cancer cells certainly facilitates this process. However, it is not immediately clear whether the treatment-related drug resistance is truly attributed to the adaptive genetic exibility of tumor cell clones, or, vise versa, simply reects the selection of pre-existing fatal cell subsets. In other words, it is difcult to differentiate between tumor evolution and tumor heterogeneity. Although the tumor heterogeneity has been acknowledged for a long time, its extent could have been underestimated. To the great surprise of scientic audience, some of the recent evidence suggests that a notable portion of breast cancer might be polyclonal in their origin, thus supporting the theory of tumor eld [42]. Furthermore, there are experimental data demonstrating that truly dangerous, potentially metastatic cells constitute only a negligible fraction of crude breast cancer lump [43]. Tumor heterogeneity might compromise current efforts of molecular portraying of neoplastic disease, because they are almost always based on the analysis of gross primary tumor mass and, therefore, might miss the targets in the most destructive cancer subclones (Box 1).
Figure 2. The promise of drug combinations. The concept of combined cancer therapy implies that all survival determinants of the tumor cell (depicpted in the center) can be efciently blocked by the individually matched cocktail of signal transduction modiers. The antitumor specicity is warranted if none of normal cells (depicted at the four corners) carries the same set of targets.
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cules occur only in a subset of carcinomas. Overall, the difference between the cancer cell and its normal precursor is much less than that between bacteria and mammalian organisms, which makes the search for the magic bullet against cancer far more complicated than the development of antibacterial therapies [41]. It has been demonstrated that even transformed cells stably retain major lineage-specic molecular markers [44]. In other words, there can be more difference in expression proles between distinct normal tissues than between paired tumor-normal cell counterparts. If this is true, targeted chemical organectomy (i.e. selective ablation of particular cell lineage) can be more achievable than specic elimination of cancer cells [45]. This approach can have a future for the treatment of cancers arising from those organs whose loss is compatible with survival of the host (breast, prostate, ovary and so on). Interestingly, this strategy has some similarities with the bone marrow transplantation, where the rst step includes non-selective elimination of both malignant and normal hemopoietic cell clones. The potential feasibility of the chemical organectomy is difcult to assess, because the comparative cataloging and functional understanding of expression proles of the normal human tissues appears to be less developed compared with the body of data accumulated in the studies of neoplastic disease.
negatively affect the therapeutic index of newly developed compounds. Some alarming data indicate that the most dangerous cell subsets might constitute only a minor portion of primary breast tumor; if it is so, the molecular proling of gross tumor mass might misguide the search for the cancer treatment. Most of current target searches rely on the cataloging of molecules that are upregulated in cancer cells compared with their normal precursors. Because the entire loss of breast epithelium is compatible with survival, it might turn out that the breast-specic molecular targets have advantage over the cancer-specic ones. The feasibility of this concept is difcult to assess, even in theory, as a result of the deciency in systematic understanding of molecular physiology of normal human cells.
Acknowledgements
We thank Ekatherina Kuligina for her invaluable help in the preparation of gures. We apologize to those authors whose articles could not be cited because of space limitations. This work was supported by INTAS (grant 03-51-4234) and RFBR (grant 02-04-49890).
References
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