Focus on breast cancer.

Abstract

Breast cancer is the most frequent malignancy among women in Western countries, with an incidence rate in the U.S. of 111 cases per 100,000 woman-years (wy) and a mortality rate of 24 deaths per 100,000 wy (Howe et al., 2001Howe H.L. Wingo P.A. Thun M.J. Ries L.A.G. Rosenberg H.M. Feigal E.G. Edwards B.K. Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends.J. Natl. Cancer Inst. 2001; 93: 824-842Crossref PubMed Scopus (647) Google Scholar). There are an estimated 1 million new cases per year in the world, with up to 5-fold lower incidence in Eastern Asia than in Western countries, a variation probably related to environmental rather than genetic factors (Probst-Hensch et al., 2000Probst-Hensch N.M. Pike M.C. McKean-Cordin R. Stanczyk F.Z. Kolonel L.N. Henderson B.E. Ethnic differences in post-menopausal plasma estrogen levels: high estrone levels in Japanese–American women despite low weight.Br. J. Cancer. 2000; 82: 1867-1870Crossref PubMed Scopus (44) Google Scholar). Established risk factors for breast cancer include:•Age. Breast cancer incidence rates double about every 10 years, reaching an incidence of 500 cases per 100,000 wy at age 70.•Increased hormone exposure, with early menarche, late menopause, alcohol consumption, postmenopausal obesity, and hormonal replacement therapy being associated with increased risk, and young age at first pregnancy, prolonged lactation, and physical exercise being associated with a reduced risk (Feigelson and Henderson, 2001Feigelson H.S. Henderson B.E. The epidemiology of breast cancer.in: Bonnadona G. Hortobagyi G.N. Gianni A.M. Breast cancer: A Clinical Guide to Therapy. Martin Dunitz Ltd, London2001Google Scholar).•Family history of breast cancer. Risk ratios increase with increasing numbers of affected first-degree relatives. Breast cancer incidence rates peaked in the late eighties, and have been stable thereafter. On the other hand, mortality has been decreasing, with an encouraging 3.4% annual decrease from 1995 through 1998 (Howe et al., 2001Howe H.L. Wingo P.A. Thun M.J. Ries L.A.G. Rosenberg H.M. Feigal E.G. Edwards B.K. Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends.J. Natl. Cancer Inst. 2001; 93: 824-842Crossref PubMed Scopus (647) Google Scholar, Peto et al., 2000Peto R. Borecham J. Clarke M. Davies C. Beral V. UK and USA breast cancer deaths down 25% in year 2000 at ages 20–69 years.Lancet. 2000; 355: 1822Abstract Full Text Full Text PDF PubMed Scopus (531) Google Scholar). This decrease in mortality may be the result of widespread mammography screening and the implementation of adjuvant therapy with tamoxifen and polychemotherapy (EBCT, 1998aEBCT Tamoxifen for early breast cancer: An overview of the randomised trials.Lancet. 1998; 351: 1451-1467Abstract Full Text Full Text PDF PubMed Scopus (3842) Google Scholar, EBCT, 1998bEBCT Polychemotherapy for early breast cancer: An overview of the randomised trials.Lancet. 1998; 352: 930-942Abstract Full Text Full Text PDF PubMed Scopus (2020) Google Scholar). Breast cancer is an heterogeneous disease, and its clinical signs and symptoms depend largely on whether the disease is confined to the breast or has metastasized to adjacent or distant parts of the body. Frequent sites of metastasis include the skin, lymph nodes, contralateral breast, bones, lungs, liver, and the central nervous system. The evaluation of a breast cancer patient at the time of initial presentation includes a pathological examination of the tumor and an evaluation of the extent of disease. The pathological examination includes assessment of histologic type and grade, tumor size, axillary lymph nodes status, and hormone receptor and ErbB2 receptor status. The evaluation of the extent of disease—or clinical staging—requires a physical exam and, if clinically indicated, a selected utilization of imaging techniques ranging from conventional roentograms of the chest, abdominal sonograms, and bone radionuclide scans to more complex computed tomography (CT) scans, magnetic resonance imaging (MRI), and functional imaging such as positron emission tomography (PET). Extensive utilization of imaging techniques for initial staging and follow-up is not indicated since it does not improve survival. The extension of the disease is documented with the TNM staging system, in which T refers to the tumor, N to nodes and M to metastases (AJCC, 1997AJCC Cancer Staging Manual. 5th edition. Lippincott-Raven, Philadelphia1997Google Scholar). This clinical staging system, ranging from stage I (early and localized) to stage IV (metastatic) disease, is utilized to estimate the prognosis and to select the treatment for individual patients as well as to compare the results from different treatment programs. The primary therapy of localized—early stage I and II—breast cancer is either breast-conserving surgery and radiation therapy or mastectomy with or without reconstruction. Systemic adjuvant therapies designed to eradicate clinically undetectable microscopic deposits of cancer cells that may have spread from the primary tumor result in decreased recurrences and improved survival (EBCT, 1998aEBCT Tamoxifen for early breast cancer: An overview of the randomised trials.Lancet. 1998; 351: 1451-1467Abstract Full Text Full Text PDF PubMed Scopus (3842) Google Scholar, EBCT, 1998bEBCT Polychemotherapy for early breast cancer: An overview of the randomised trials.Lancet. 1998; 352: 930-942Abstract Full Text Full Text PDF PubMed Scopus (2020) Google Scholar). Adjuvant therapies include chemotherapy and hormonal therapy. Chemotherapy is usually given for 4 to 6 months in combination with different agents (polychemotherapy); the drugs most frequently used are alkylating agents (cyclophosphamide), anthracyclins (doxorubicin), antimetabolites (5-fluorouracil), and antimicrotubule agents (such as paclitaxel and docetaxel) (Norton, 2001Norton L. Theoretical concepts and the emerging role of taxanes in adjuvant therapy.Oncologist. 2001; 6: 30-35Crossref PubMed Scopus (104) Google Scholar). Adjuvant hormonal therapy with tamoxifen is beneficial in patients whose tumors express estrogen and/or progesterone receptors (EBCT, 1998aEBCT Tamoxifen for early breast cancer: An overview of the randomised trials.Lancet. 1998; 351: 1451-1467Abstract Full Text Full Text PDF PubMed Scopus (3842) Google Scholar). In addition, adjuvant radiation therapy provides a better local control and may enhance survival (EBCT, 2000EBCT Favourable and unfavourable effects on long-term survival of radiation therapy for early breast cancer: an overview of the randomized trials.Lancet. 2000; 355: 1757-1770Abstract Full Text Full Text PDF PubMed Scopus (1165) Google Scholar). In advanced disease, in addition to the agents used in the adjuvant setting, new active cytotoxic agents include vinca alkaloids (vinorelbine), pyrimidine analogs (gemcitabine), and new antimetabolites (capecitabine) (Hortobagyi, 2000Hortobagyi G.N. Developments in chemotherapy of breast cancer.Cancer. 2000; 88: 3073-3079Crossref PubMed Google Scholar). In the hormonal therapy front, tamoxifen is a selective estrogen receptor modulator (SERM) that binds to the estrogen receptor and has antiestrogenic activity in the breast and estrogenic-like activity in the endometrium, bone, and lipid metabolism (Jordan, 2001Jordan V.C. Selective estrogen receptor modulation: A personal perspective.Cancer Res. 2001; 61: 5683-5687PubMed Google Scholar). New SERMs with a more desirable tissue selectivity are being evaluated, as well as pure antiestrogens that result in programmed early receptor destruction (Jordan, 2001Jordan V.C. Selective estrogen receptor modulation: A personal perspective.Cancer Res. 2001; 61: 5683-5687PubMed Google Scholar). Aromatase inhibitors that prevent the peripheral tissue conversion of adrenal androgens into estrogen have recently been shown to be superior to tamoxifen and are being incorporated into first line therapy of advanced disease (Nabholtz et al., 2000Nabholtz J.M. Buzdar A. Pollak M. Harwin W. Burton G. Mangalik A. Steinberg M. Webster A. von Euler M. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial.J. Clin. Oncol. 2000; 18: 3758-3767Crossref PubMed Scopus (932) Google Scholar). Breast cancer results from genetic and environmental factors leading to the accumulation of mutations in essential genes. Genes involved in the hereditary and familial forms of breast cancer include BRCA1, BRCA2, P53, PTEN, and STK11/LKB1 (Nathanson et al., 2001Nathanson K.L. Wooster R. Weber B.L. Breast cancer genetics: What we know and what we need.Nat. Med. 2001; 7: 552-556Crossref PubMed Scopus (350) Google Scholar). The 2 BRCA genes appear to serve as important regulators of cell-cycle “checkpoint control” mechanisms, involving cell-cycle arrest, apoptosis, and DNA repair. However, germline mutations of BRCA1 and BRCA2 and of these other genes account for only 15%–20% of breast cancer that clusters in families and less than 5% of breast cancer overall, and it is likely that breast cancer susceptibility may be dictated by a larger number of low penetrance mutations. The most common genetic abnormalities in the progression of both sporadic and familial breast cancers are losses of heterozygosity (LOH) at multiple loci resulting in the uncovering of the functional consequences of mutations in alleles of tumor suppressor genes. In addition to the mentioned BRCA and P53 genes, LOH on 13q, 9p, and 16q are known to involve the Rb (retinoblastoma gene), CDKN2 (encoding the p16 protein), and CDH1 (encoding the E-cadherin protein), respectively (Dickson and Lippman, 2001Dickson R.B. Lippman M.E. Cancer of the Breast. Molecular Biology of Breast Cancer.in: DeVita V.T.J. Hellman S. Rosenberg S.A. Principles and Practice of Oncology. Lippincott Williams and Wilkins, Philadelphia2001: 1633-1645Google Scholar). The second most common type of cytogenetic alteration is the amplification of genes, such as ErB2, c-myc, and cyclin D1 (Dickson and Lippman, 2001Dickson R.B. Lippman M.E. Cancer of the Breast. Molecular Biology of Breast Cancer.in: DeVita V.T.J. Hellman S. Rosenberg S.A. Principles and Practice of Oncology. Lippincott Williams and Wilkins, Philadelphia2001: 1633-1645Google Scholar). The role of certain receptors in breast cancer has been extensively studied, since they are either established or potential targets for therapy. The estrogen receptors are nuclear receptors that modulate transcription of target genes that play a role in the onset and progression of disease; coactivating and corepressive proteins interact with these receptors and play a critical role in the initiation of transcription (Elledge and Fuqua, 2000Elledge R.M. Fuqua S.A.W. Estrogen and progesterone receptors.in: Harris J.R. Lippman M.E. Morrow M. Osborne C.K. Diseases of the Breast. Lippincott Williams and Wilkins, Philadelphia2000: 471Google Scholar). Activation of tyrosine kinase receptors does also result in malignant transformation and tumor proliferation. Good examples of tyrosine kinase receptors in breast cancer are the epidermal growth factor (EGF) family of growth factors receptors, including the ErbB2 receptor, and the insulin-like growth factors and their receptors (Dickson and Lippman, 2001Dickson R.B. Lippman M.E. Cancer of the Breast. Molecular Biology of Breast Cancer.in: DeVita V.T.J. Hellman S. Rosenberg S.A. Principles and Practice of Oncology. Lippincott Williams and Wilkins, Philadelphia2001: 1633-1645Google Scholar). Early detection of breast cancer is a clear priority since cure rates are greater the earlier the clinical stage at diagnosis. Screening mammography, despite an ongoing debate (Olsen and Gotzsche, 2001Olsen O. Gotzsche P. Cochrane review on screening for breast cancer with mammography.Lancet. 2001; 358: 1340-1342Abstract Full Text Full Text PDF PubMed Scopus (607) Google Scholar), is currently the best available tool for early detection, and reduces breast cancer mortality rates by about 16% for women 40–49 years old and 25%–30% for women 50–69 years old (Kerlikowske, 1997Kerlikowske K. Efficacy of screening mamography among women aged 40 to 49 years and 50 to 60 years: comparison of relative and absolute benefit.J. Natl. Cancer Inst. Monogr. 1997; 22: 79-86PubMed Google Scholar). New directions include the development of improved imaging techniques such as digital mammography and MRI. MRI may be more accurate than mammography in breast cancer surveillance of women with a hereditary risk of breast cancer (Stoutjesdijk et al., 2001Stoutjesdijk M.J. Boetes C. Jager G.J. Beex L. Bult P. Hendriks J.H. Laheij R.J. Massuger L. van Die L.E. Wobbes T. Barentsz J.O. Magnetic resonance imaging and mammography in women with a hereditary risk of breast cancer.J. Natl. Cancer Inst. 2001; 93: 1095-1102Crossref PubMed Scopus (289) Google Scholar). PET scanning is a functional imaging technique based on the enhanced glucose consumption by malignant cells. 18F-deoxyglucose is given intravenously and is taken up preferentially by the tumor, allowing the accurate characterization of primary tumors and axillary and mediastinal lymph nodes, and also the detection of distant metastases, all in a single whole-body examination (Czernin and Phelps, 2001Czernin J. Phelps M.E. Positron emission tomography scanning: Current and future applications.Annu. Rev. Med. 2001; 53: 89-112Crossref Scopus (268) Google Scholar). PET scanning also seems well-suited to predict therapy outcome in patients with locally advanced breast cancer (Czernin and Phelps, 2001Czernin J. Phelps M.E. Positron emission tomography scanning: Current and future applications.Annu. Rev. Med. 2001; 53: 89-112Crossref Scopus (268) Google Scholar). The current pathologic classification and staging system are suboptimal, since patients with identical tumor types and stage of disease have markedly different responses to therapy and overall outcomes. The limitations of the current system stem from its inability to take into account biological determinants of prognosis. As a result, many patients who would have been cured by surgery and radiation therapy alone will receive unnecessary cytototoxic therapy. Over the last two decades, the routine determination of estrogen receptor and other key proteins such as ErbB2 has provided evidence that breast cancer represents several distinct subtypes (Figure 1). The advent of microarray technology with high throughput and parallel analysis of thousands of genes is allowing the linking of expression profiles to clinical outcome and response to therapy (van't Veer et al., 2002van't Veer L.J. Dai H. van de Vijver M.J. He Y.D. Hart A.A.M. Mao M. Peterse H.L. van der Kooy K. Marton M.J. Witteveen A.T. Schreiber G.J. Kerkhoven R.M. Roberts C. Linsley P.S. Bernards R. Friend S.H. Gene expression profiling predicts clinical outcome of breast cancer.Nature. 2002; 415: 530-536Crossref PubMed Scopus (7474) Google Scholar); if the predictive value of functional genomics is confirmed, it will be possible to accurately predict which tumors will relapse and to choose therapy accordingly (Ince and Weinberg, 2002Ince T.A. Weinberg R.A. Functional genomics and the breast cancer problem.Cancer Cell. 2002; 1: 15-17Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). Another important implication is that molecular profiling may lead to the identification of new targets for therapy. The majority of cytotoxic agents were developed solely on the basis of their preclinical activity. However, an increased knowledge of their mechanism(s) of action is allowing the development of improved cytotoxic agents. As an example, doxorubicin inhibits topoisomerase functions, and more specific topoisomerase inhibitors are being developed; the stimulation by taxanes of tubulin polymerization has lead to the identification in tubulin polymerization screens of epothilones, active agents on taxane-refractory breast cancer (Gibbs, 2000Gibbs J.B. Mechanism-based target identification and drug discovery in cancer res.Science. 2000; 287: 1969-1973Crossref PubMed Scopus (432) Google Scholar). In parallel, agents against a series of molecular targets that dictate malignant growth are being developed. This approach is illustrated by agents directed at the EGF receptor family of growth factor receptors (Figure 2). Trastuzumab, a humanized monoclonal antibody directed at the ErbB2 receptor, is the first of this new class of agents, and is active and improves survival in patients with ErbB2 amplification (Slamon et al., 2001Slamon D.J. Leyland-Jones B. Shak S. Fuchs H. Paton V. Bajamonde A. Fleming T. Eiermann W. Wolter J. Pegram M. et al.Concurrent administration of anti-HER-2 monoclonal antibody and first-line chemotherapy for HER2-overexpresing metastatic breast cancer: A phase III, multinational, randomized, conrolled trial.N. Engl. J. Med. 2001; 344: 783-792Crossref PubMed Scopus (8958) Google Scholar). Small molecules that inhibit receptor kinase activation have shown tolerability at doses that fully inhibit receptor function in vivo (Albanell et al., 2002Albanell J. Rojo F. Averbuch S. Feyereislova A. Mascaro J.M. Herbst R. LoRusso P. Rischin D. Sauleda S. Gee J. et al.Pharmacodynamic studies of the EGF receptor inhibitor ZD1839 (‘Iressa’) in skin from cancer patients: Histopathological and molecular consequences of receptor inhibition.J. Clin. Oncol. 2002; 20: 110-124Crossref PubMed Scopus (512) Google Scholar). These agents are active in preclinical breast cancer models, and phase II clinical trials in breast cancer are ongoing. Downstream substrates of cell surface receptors being explored as targets for therapy include the members of the Ras-Raf-MAP-kinase pathway, involved in cell proliferation, and the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway that plays an important role in survival (Figure 2). Clinical responses in breast cancer have been observed with anti-RAS agents and with mTOR inhibitors. Agents are also being developed against apoptosis-regulating pathways, such as BCL-2 antisense oligonucleotides (Chen et al., 2000Chen H.X. Marshall J.L. Trocky N. Ling Y. Baidas S. Rizvi N. Bhargava P. Lippman M. Yang D. Hayes D.F. A phase I study of BCL-2 antisense G3139 (Genta) and weekly docetaxel in patients with advanced breast cancer and other solid tumors.Proc. Am. Soc. Clin. Onc. 2000; 19: A692Google Scholar), proteasome inhibitors (Adams et al., 1999Adams J. Palombella V. Sausville E. Johnson J. Destree A. Lazarus D. Maas J. Pien C. Prakash S. Elliott P. Proteasome inhibitors: a novel class of potent and effective antitumor agents.Cancer Res. 1999; 59: 2615-2622PubMed Google Scholar), and inhibitors of cyclin-dependent kinases (Senderowicz, 2000Senderowicz A.M. Small molecule modulators of cyclin-dependent kinases for cancer therapy.Oncogene. 2000; 19: 6600-6606Crossref PubMed Scopus (114) Google Scholar). Interactions between breast cancer cells and their surrounding environment are determinant for breast cancer progression, as exemplified by the tumor's requirement for sustained angiogenesis. Antiangiogenic agents include monoclonal antibodies targeting the vascular endothelial growth factor (VEGF), its receptors (anti-Flk-1 antibodies), and receptor tyrosine kinase inhibitors. Clinical responses in advanced breast cancer have been documented with anti-VEGF antibodies (Sledge et al., 2000Sledge G. Miller K. Novotny W. Gaudreault J. Ash M. Cobleigh M. A phase II trial of single-agent rhumab VEGF (recombinant humanized monoclonal antibody to vascular endothelial cell growth factor) in patients with relapsed metastatic breast cancer.Proc. Am. Soc. Clin. Onc. 2000; 19: A5Google Scholar). It may be oversimplistic to expect that interfering with a single molecular target may reverse a malignant phenotype that is the result of the accumulation of multiple successive genetic events. Thus, identification of the several key drivers in a given tumor will hopefully lead to individualized treatment in which several targeted agents will be combined—tailored combination polytargeted therapy—in a rational way, rather the current empiric administration of combination polychemotherapy. In addition, as with trastuzumab and paclitaxel (Baselga et al., 1998Baselga J. Norton L. Albanell J. Kim Y.M. Mendelsohn J. Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts.Cancer Res. 1998; 58: 2825-2831PubMed Google Scholar, Slamon et al., 2001Slamon D.J. Leyland-Jones B. Shak S. Fuchs H. Paton V. Bajamonde A. Fleming T. Eiermann W. Wolter J. Pegram M. et al.Concurrent administration of anti-HER-2 monoclonal antibody and first-line chemotherapy for HER2-overexpresing metastatic breast cancer: A phase III, multinational, randomized, conrolled trial.N. Engl. J. Med. 2001; 344: 783-792Crossref PubMed Scopus (8958) Google Scholar), it is expected that molecular targeting agents and cytotoxic agents will be given together in a successful partnership. Significant advances have been made in the field of breast cancer prevention in patients with increased risk. Studies with two different SERMs, tamoxifen and raloxifen, have demonstrated reductions in breast cancer close to 50%. (Cummings et al., 1999Cummings S.R. Eckert S. Krueger K.A. Grady D. Powles T.J. Cauley J.A. Norton L. Nickelsen T. Bjarnason N.H. Morrow M. et al.The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the more randomized trial.JAMA. 1999; 281: 2189-2197Crossref PubMed Scopus (1809) Google Scholar, Fisher et al., 1998Fisher B. Constantino J.P. Wickerham D.L. Redmond C.K. Kavanah M. Cronin W.M. Vogel V. Robidoux A. Dimitrov N. Atkins J. et al.Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel project P-1 study.J. Natl. Cancer Inst. 1998; 90: 1371-1388Crossref PubMed Scopus (4714) Google Scholar). For women with germline BRCA1 and BRCA2 mutations, current management guidelines appear to reduce the risk of breast and ovarian cancer by at least 60% and 90%, respectively (Eisen et al., 2000Eisen A. Rebbeck T.R. Wood W.C. Weber B.L. Prophylactic surgery in women with a hereditary predisposition to breast and ovarian cancer.J. Clin. Oncol. 2000; 18: 1980-1995PubMed Google Scholar). In a similar fashion, it is anticipated that further advances in the identification of patients with enhanced breast cancer susceptibility will allow the successful implementation of prevention strategies. In the last two decades, major advances have been made in our understanding and treatment of breast cancer that have resulted in a decline in breast cancer mortality. To accelerate this process, research efforts need to be directed to a series of areas, including breast cancer genetics and study of populations at risk for genetic predisposition, identification of new targets for therapy and drug development programs, molecular profiling of breast tumors, and finally, improved screening and better diagnostic tools to facilitate early detection and prevention programs. However, for these advances to translate into benefit for patients, strategies to accelerate their clinical applicability have to be promoted. We would like to acknowledge Fredi Rojo for his assistance in the preparation of the figures.