Perspective
The Distinctive Nature of HER2-Positive Breast Cancers
N Engl J Med 2005; 353:1652-1654October 20, 2005
- Article
Breast cancer is not a single disease but a group of several important tumor subtypes, each with a different natural history and each requiring a different treatment. Overexpression of HER2 (which derives its name from human epidermal growth factor receptor 2) defines one of these unique subtypes. The HER2/neu gene is a member of a family of genes encoding transmembrane receptors for growth factors, including the epidermal growth factor receptor (EGFR), HER2, HER3, and HER4. The intracellular domain of HER2 has tyrosine kinase activity that regulates important aspects of the physiology, growth, and differentiation of cells.1,2 Extracellular domains of the HER2 protein interact with HER family members, allowing HER2 to serve as a coreceptor and to facilitate signal transduction as part of a heterodimer complex that forms after ligand binding. There is no known ligand for HER2 itself, however, suggesting that the primary role of HER2 is to modulate signals after ligand binding to other HER-family receptors.
Amplification of the HER2/neu oncogene and related genetic elements in the amplicon on chromosome 17 causes a marked increase (up to 100 times the usual level) in the expression of HER2 on the surface of breast-tumor cells. The mechanism of the selective amplification of HER2/neu is unknown. Overexpression of HER2 can transform cultured cells into a malignant phenotype and accelerate tumorigenesis. Overexpression of HER2 appears to encourage the formation of receptor homodimers and heterodimers involving HER2, with different signaling properties than seen normally.
HER2 became clinically relevant with the demonstration that HER2-positive breast cancers have a worse prognosis than HER2-negative tumors.3 Between 15 and 20 percent of invasive breast cancers are HER2-positive; amplification of the gene and the resultant overexpression of HER2 occur during the in situ stage of tumor development. After HER2/neu amplification has occurred, the HER2 phenotype is thought to be fixed for the duration of the natural history of the invasive tumor. For this reason, testing for HER2 can be performed on either the primary tumor or a metastatic tumor deposit, generally with similar results.
HER2-positive breast cancers have a distinctive molecular signature, including extensive changes in the patterns of gene expression that distinguish these cancers from other types of breast cancer.4 They also have distinctive clinical features. Population-based studies and retrospective analyses have shown that overexpression of HER2 is an adverse prognostic factor that is associated with poorly differentiated, high-grade tumors, high rates of cell proliferation and lymph-node involvement, and a relative resistance to certain types of chemotherapy. Anthracycline-based adjuvant chemotherapy is particularly beneficial in HER2-positive tumors. Roughly half of HER2-positive breast cancers also express the steroid hormone receptors for estrogen, progesterone, or both. However, in these tumors, the levels of steroid hormone receptors are typically lower than in HER2-negative, hormone-receptor–positive tumors, and for this reason, in part, HER2-positive breast cancer is relatively resistant to tamoxifen. All these factors contribute to the greater risk of recurrence among women with HER2-positive breast cancer than in those with HER2-negative breast cancer. HER2/neu gene amplification is rare outside breast cancer. Tumors other than breast cancer with some degree of HER2 positivity typically express far less HER2 than breast cancers, without evidence of gene amplification.
Trastuzumab, a humanized monoclonal antibody against HER2 created by inserting portions of the antigen-binding site of a mouse monoclonal antibody against HER2 into a human monoclonal antibody, was developed after it had been recognized that HER2 overexpression served as both a marker of aggressive disease and a target for treatment. Because laboratory and clinical studies indicated that the inhibition of cell growth by trastuzumab is limited to HER2-positive cancers, testing tumors for expression of HER2 became integral to the selection of patients for clinical trials of the efficacy of trastuzumab. Because of the success of these trials, HER2 testing became routine in the care of patients with breast cancer, although controversy remains as to the best method of testing.
The studies reported in this issue of the Journal by Piccart-Gebhart and colleagues (pages 1659–1672) and Romond and colleagues (pages 1673–1684) are the culmination of a decade-long adventure in clinical investigation. They show that trastuzumab can dramatically improve outcomes among women with HER2-positive breast cancer. The clinical observations are clear, but the scientific basis for the effects of trastuzumab is uncertain. Laboratory studies and limited data from clinical trials suggest myriad possible mechanisms of action of trastuzumab (see diagram
Interactions between Trastuzumab and Tumor Cells.). After binding to the HER2 protein, trastuzumab contributes to apoptosis, causes down-regulation of surface HER2 expression, alters downstream signaling and regulatory pathways in the cell cycle, suppresses the production of the angiogenic factor vascular endothelial growth factor (VEGF), and potentiates the effects of chemotherapy. There may also be an extracellular effect, possibly in mediating antibody-dependent immune recognition.Trastuzumab appears to have no clinical benefit in HER2-negative breast cancers, in which normal levels of HER2 protein are expressed. This finding suggests that a critical density or threshold of HER2 expression or gene amplification is necessary for trastuzumab to act. Similarly, trastuzumab lacks substantial activity against other non-breast tumors, even if they express moderately elevated HER2 levels. It seems likely that the clinical use of trastuzumab will be narrowly confined to the unique subtype of HER2-positive breast cancer.
A better understanding of the biologic actions of trastuzumab is critical to improving treatments that target HER2. For instance, trials of adjuvant treatment have not determined whether the potentiation of the effect of chemotherapy by trastuzumab warrants concurrent chemotherapy and trastuzumab administration, or whether sequential treatments would be adequate. Similarly, the optimal duration of therapy may depend on how, precisely, trastuzumab works. As yet, there is no defined threshold of HER2 gene amplification that predicts which HER2-positive tumors will respond to treatment. It seems probable that the greater the degree of gene amplification, the greater the potential benefit, but this possibility has not been tested clinically.
Resistance to trastuzumab is now a problem, but we do not understand its mechanism. Strategies to overcome resistance include interference with the coreceptor role of HER2 by blocking interactions with other HER-family receptors or the modulation of related signaling or apoptotic pathways. In vitro models suggest important crosstalk between HER2-driven signal paths and both VEGF-receptor and estrogen-receptor pathways. Clinical trials that use both anti-HER2 and anti-estrogen therapies or an anti-VEGF antibody are under way and may prove fruitful.
The history of HER2 and trastuzumab treatment is a triumphal narrative of translational research. An oncogene, originally discovered in a rat model of chemically induced carcinogenesis, was found to have a sequence that resembled that of a normal cellular gene. The HER2/neu gene, when overexpressed, transforms normal cells into cancer cells. Next, overexpression of the gene was found in human breast cancers, where it was shown to contribute to a poor prognosis. A novel antibody therapy that targets the overabundant HER2 protein was developed, and this antibody now redefines the natural history of the disease and establishes a new standard of treatment for breast cancer. It is a dramatic story that epitomizes the often cited cliché of “bedside to bench to bedside” research.
Like all good stories, this one has a profound lesson: not all breast cancers are the same. Hormone receptors, HER2, and increasingly, genomic profiles distinguish at least four major classes of breast cancer: HER2-positive tumors; HER2-negative, hormone-receptor–positive tumors, which can be divided into two classes, favorable and unfavorable, on the basis of genomic and pathobiologic features; and basal-like tumors that express neither HER2 nor hormone receptors. The growing appreciation of the biologic diversity of breast cancer is forcing treatment into patterns that reflect the underlying biologic features of the tumor, and it challenges us to redefine principles of therapy for each distinctive class of breast cancer.
Source Information
Dr. Burstein is an assistant professor of medicine at the Dana–Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston.
- References
References
1
Yarden Y ,Sliwkowski MX . Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127-137
CrossRef | Web of Science | Medline2
Cho HS ,Mason K ,Ramyar KX , et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 2003;421:756-760
CrossRef | Web of Science | Medline3
Slamon DJ ,Clark GM ,Wong SG ,Levin WJ ,Ullrich A ,McGuire WL . Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-182
CrossRef | Web of Science | Medline4
Perou CM ,Sorlie T ,Eisen MB , et al. Molecular portraits of human breast tumours. Nature 2000;406:747-752
CrossRef | Web of Science | Medline
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1
Zohreh Hojati, Elham Orangi. (2012) HER-2/neu gene amplification assessment in breast cancer patients in Isfahan Province by Real Time PCR, differential PCR and immonohistochemistry. Gene
CrossRef2
Kai Li, Bin Liu. (2012) Polymer encapsulated conjugated polymer nanoparticles for fluorescence bioimaging. Journal of Materials Chemistry
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Sasha Badzek, Vesna Lesko Kelovic, Stjepko Plestina, Ines Humar, Zoran Veir, Zeljko Mihaljevic. (2011) Serum HER2/ECD value in stage I and II early breast cancer – need of a lower cut-off?. Wiener klinische Wochenschrift
CrossRef4
N. Gnaoui, S. Hayah, M. Hassar, R. Saile, H. Benomar. (2011) Récepteurs hormonaux et statut HER2 dans les carcinomes de la glande mammaire. Journal Africain du Cancer / African Journal of Cancer
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Paul HS Shaw, Richard A Adams. (2011) Where now for anti-EGF receptor therapies in colorectal cancer?. Expert Review of Anticancer Therapy 11:10, 1543-1553
CrossRef6
Jamie D. Croxtall, Kate McKeage. (2011) Trastuzumab in HER2-Positive Metastatic Gastric Cancer†. BioDrugs 25:4, 257-259
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Kelli S. Dempsey. (2011) Chemotherapy-Induced Cardiotoxicity in Women. Heart Failure Clinics 7:3, 427-435
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Sylvie Lorenzen, Florian Lordick. (2011) How will human epidermal growth factor receptor 2-neu data impact clinical management of gastric cancer?. Current Opinion in Oncology 23:4, 396-402
CrossRef9
Judith Maresch, Sebastian F. Schoppmann, Christiane M.R. Thallinger, Christoph C. Zielinski, Michael Hejna. (2011) Her-2/neu gene amplification and over-expression in stomach and esophageal adenocarcinoma: From pathology to treatment. Critical Reviews in Oncology/Hematology
CrossRef10
Akiyo Horio, Takashi Fujita, Hironori Hayashi, Masaya Hattori, Naoto Kondou, Mai Yamada, Eri Adachi, Aya Ushio, Naomi Gondou, Aiko Sueta, Yasushi Yatabe, Hiroji Iwata. (2011) High recurrence risk and use of adjuvant trastuzumab in patients with small, HER2-positive, node-negative breast cancers. International Journal of Clinical Oncology
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Metamia Ciampricotti, Kim Vrijland, Cheei-Sing Hau, Tea Pemovska, Chris W Doornebal, Ewoud N Speksnijder, Katharina Wartha, Jos Jonkers, Karin E de Visser. (2011) Development of metastatic HER2+ breast cancer is independent of the adaptive immune system. The Journal of Pathology 224:1, 56-66
CrossRef12
D H Roukos. (2011) Trastuzumab and beyond: sequencing cancer genomes and predicting molecular networks. The Pharmacogenomics Journal 11:2, 81-92
CrossRef13
Guodong Shen, Hui Huang, Anli Zhang, Ting Zhao, Siyi Hu, Liansheng Cheng, Jing Liu, Weihua Xiao, Bin Ling, Qiang Wu, Lihua Song, Wei Wei. (2011) In vivo activity of novel anti-ErbB2 antibody chA21 alone and with Paclitaxel or Trastuzumab in breast and ovarian cancer xenograft models. Cancer Immunology, Immunotherapy 60:3, 339-348
CrossRef14
Paul C. Boutros, Cindy Q. Yao, John D. Watson, Alexander H. Wu, Ivy D. Moffat, Stephenie D. Prokopec, Ashley B. Smith, Allan B. Okey, Raimo Pohjanvirta. (2011) Hepatic transcriptomic responses to TCDD in dioxin-sensitive and dioxin-resistant rats during the onset of toxicity. Toxicology and Applied Pharmacology 251:2, 119-129
CrossRef15
Yan-Xia Shi, Yu-Ting Tan, Zhong-Yu Yuan, Shu-Sen Wang, Rou-Jun Peng, Xin An, Ye Cao, Ying Jin, Xiu-Yu Cai, Yue-Li Sun, Xiao-Yu Teng, Dong-Geng Liu. (2011) Comparison of overall survival between the early use and delayed use of Trastuzumab therapy groups: a retrospective analysis of 128 patients with HER-2-positive advanced breast cancer. Medical Oncology
CrossRef16
George C Zografos, Dimitrios H Roukos. (2011) Innovative biomarker development for personalized medicine in breast cancer care. Biomarkers in Medicine 5:1, 73-78
CrossRef17
Kai Li, Yutao Liu, Kan-Yi Pu, Si-Shen Feng, Ruoyu Zhan, Bin Liu. (2011) Polyhedral Oligomeric Silsesquioxanes-Containing Conjugated Polymer Loaded PLGA Nanoparticles with Trastuzumab (Herceptin) Functionalization for HER2-Positive Cancer Cell Detection. Advanced Functional Materials 21:2, 287-294
CrossRef18
Jamie D. Croxtall, Kate McKeage. (2010) Trastuzumab. Drugs 70:17, 2259-2267
CrossRef19
Xi-Xi Cao, Jing-Da Xu, Xiao-Li Liu, Jia-Wen Xu, Wen-Juan Wang, Qing-Quan Li, Qi Chen, Zu-De Xu, Xiu-Ping Liu. (2010) RACK1: A superior independent predictor for poor clinical outcome in breast cancer. International Journal of Cancer 127:5, 1172-1179
CrossRef20
Cynthia Moreira, Virginia Kaklamani. (2010) Lapatinib and breast cancer: current indications and outlook for the future. Expert Review of Anticancer Therapy 10:8, 1171-1182
CrossRef21
F Martin, S Ladoire, G Mignot, L Apetoh, F Ghiringhelli. (2010) Human FOXP3 and cancer. Oncogene 29:29, 4121-4129
CrossRef22
J. A. Choi, J. W. Lee, H. Kim, E. Y. Kim, J. M. Seo, J. Ko, J. H. Kim. (2010) Pro-survival of estrogen receptor-negative breast cancer cells is regulated by a BLT2-reactive oxygen species-linked signaling pathway. Carcinogenesis 31:4, 543-551
CrossRef23
Michael R. Bleavins, Ramin Rahbari. 2010. Anti-Unicorn Principle: Appropriate Biomarkers Don't Need to be Rare or Hard to Find. .
CrossRef24
Dimitrios H Roukos, Dimosthenis Ziogas. (2010) From tumor size and HER2 status to systems oncology for very early breast cancer treatment. Expert Review of Anticancer Therapy 10:2, 123-128
CrossRef25
Katalin Boér. (2010) A gyógyszeres kezelés szerepe a korai emlőrák kezelésében. Orvosi Hetilap 151:9, 344-353
CrossRef26
Dimitrios H. Roukos. (2010) Targeting Gastric Cancer with Trastuzumab: New Clinical Practice and Innovative Developments to Overcome Resistance. Annals of Surgical Oncology 17:1, 14-17
CrossRef27
Dimitrios H Roukos. (2010) Novel clinico–genome network modeling for revolutionizing genotype–phenotype-based personalized cancer care. Expert Review of Molecular Diagnostics 10:1, 33-48
CrossRef28
Erin M. Goldblatt, Priscilla A. Erickson, Erin R. Gentry, Sergei M. Gryaznov, Brittney-Shea Herbert. (2009) Lipid-conjugated telomerase template antagonists sensitize resistant HER2-positive breast cancer cells to trastuzumab. Breast Cancer Research and Treatment 118:1, 21-32
CrossRef29
X Liu, J Wu, S Zhang, C Li, Q Huang. (2009) Novel strategies to augment genetically delivered immunotoxin molecular therapy for cancer therapy. Cancer Gene Therapy 16:11, 861-872
CrossRef30
Shani Paluch-Shimon, Noa Ben-Baruch, Ido Wolf, Lior Zach, Juri Kopolovic, Anna Kruglikova, Tami Modiano, Ady Yosepovich, Raphael Catane, Bella Kaufman. (2009) Hormone Receptor Expression Is Associated With a Unique Pattern of Metastatic Spread and Increased Survival Among HER2-Overexpressing Breast Cancer Patients. American Journal of Clinical Oncology 32:5, 504-508
CrossRef31
Dimitrios H Roukos, Andreas Tzakos, George Zografos. (2009) Current concerns and challenges regarding tailored anti-angiogenic therapy in cancer. Expert Review of Anticancer Therapy 9:10, 1413-1416
CrossRef32
Jack M. Webster, Rong Zhang, Sanjiv S. Gambhir, Zhen Cheng, Faisal A. Syud. (2009) Engineered Two-Helix Small Proteins for Molecular Recognition. ChemBioChem 10:8, 1293-1296
CrossRef33
Dimitrios H Roukos. (2009) Mea Culpa with cancer-targeted therapy: new thinking and new agents design for novel, causal networks-based, personalized biomedicine. Expert Review of Molecular Diagnostics 9:3, 217-221
CrossRef34
Christine Desmedt, Jeff Sperinde, Fanny Piette, Weidong Huang, Xueguang Jin, Yuping Tan, Virginie Durbecq, Denis Larsimont, Rosa Giuliani, Colombe Chappey, Marc Buyse, John Winslow, Martine Piccart, Christos Sotiriou, Christos Petropoulos, Michael Bates. (2009) Quantitation of HER2 Expression or HER2:HER2 Dimers and Differential Survival in a Cohort of Metastatic Breast Cancer Patients Carefully Selected for Trastuzumab Treatment Primarily by FISH. Diagnostic Molecular Pathology 18:1, 22-29
CrossRef35
Menaka D. S. Lokuhetty, Gayani G. Ranaweera, Manarangi D. M. Wijeratne, Kumudu H. Wickramasinghe, Abdul H. Sheriffdeen. (2009) Profile of Breast Cancer in a Group of Women in a Developing Country in South Asia: Is There a Difference?. World Journal of Surgery 33:3, 455-459
CrossRef36
W. F. Anderson, S. Luo, N. Chatterjee, P. S. Rosenberg, R. K. Matsuno, M. T. Goodman, B. Y. Hernandez, M. Reichman, M. P. Dolled-Filhart, R. M. O’Regan, M. Garcia-Closas, C. M. Perou, I. Jatoi, R. W. Cartun, M. E. Sherman. (2009) Human epidermal growth factor receptor-2 and estrogen receptor expression, a demonstration project using the residual tissue respository of the Surveillance, Epidemiology, and End Results (SEER) program. Breast Cancer Research and Treatment 113:1, 189-196
CrossRef37
M. Chavez-Mac Gregor, A.M. Gonzalez-Angulo. (2009) Poor survival outcomes in HER2-positive breast cancer patients with low-grade, node-negative tumours. Breast Diseases: A Year Book Quarterly 20:4, 373-375
CrossRef38
Michael S. Sabel. 2009. Principles of Adjuvant Chemotherapy for Breast Cancer. , 247-266.
CrossRef39
J.M. Del Casar, A. Martín, C. García, M.D. Corte, A. Alvarez, S. Junquera, L.O. González, M. Bongera, J.L. García-Muñiz, M.T. Allende, F. Vizoso. (2008) Characterization of breast cancer subtypes by quantitative assessment of biological parameters: Relationship with clinicopathological characteristics, biological features and prognosis. European Journal of Obstetrics & Gynecology and Reproductive Biology 141:2, 147-152
CrossRef40
Sabine Classen, Andrea Staratschek-Jox, Joachim L Schultze. (2008) Use of genome-wide high-throughput technologies in biomarker development. Biomarkers in Medicine 2:5, 509-524
CrossRef41
Hyeon‐Man Baek, Jeon‐Hor Chen, Orhan Nalcioglu, Min‐Ying Su. (2008) Choline as a biomarker for cell proliferation: Do the results from proton MR spectroscopy show difference between HER2/neu positive and negative breast cancers?. International Journal of Cancer 123:5, 1219-1221
CrossRef42
Dale O. Kiesewetter, Gabriela Krämer-Marek, Ying Ma, Jacek Capala. (2008) Radiolabeling of HER2-specific Affibody® molecule with F-18. Journal of Fluorine Chemistry 129:9, 799-806
CrossRef43
Clement A. Adebamowo, Ayotunde Famooto, Temidayo O. Ogundiran, Toyin Aniagwu, Chibuzor Nkwodimmah, Effiong E. Akang. (2008) Immunohistochemical and molecular subtypes of breast cancer in Nigeria. Breast Cancer Research and Treatment 110:1, 183-188
CrossRef44
Gabriela Kramer-Marek, Dale O. Kiesewetter, Lucia Martiniova, Elaine Jagoda, Sang Bong Lee, Jacek Capala. (2008) [18F]FBEM-ZHER2:342–Affibody molecule—a new molecular tracer for in vivo monitoring of HER2 expression by positron emission tomography. European Journal of Nuclear Medicine and Molecular Imaging 35:5, 1008-1018
CrossRef45
Primož Drev, Snježana Frković Grazio, Matej Bračko. (2008) Tissue Microarrays for Routine Diagnostic Assessment of HER2 Status in Breast Carcinoma. Applied Immunohistochemistry & Molecular Morphology 16:2, 179-184
CrossRef46
S J L Payne, R L Bowen, J L Jones, C A Wells. (2008) Predictive markers in breast cancer - the present. Histopathology 52:1, 82-90
CrossRef47
Yukyung Jung, Hyo-Jin Park, Pyung-Hwan Kim, Jaewon Lee, Woochan Hyung, Jaemoon Yang, Hyunju Ko, Joo-Hyuk Sohn, Joo-Hang Kim, Yong-Min Huh, Chae-Ok Yun, Seungjoo Haam. (2007) Retargeting of adenoviral gene delivery via Herceptin–PEG–adenovirus conjugates to breast cancer cells. Journal of Controlled Release 123:2, 164-171
CrossRef48
Cynthia Frankel. (2007) Choosing the Appropriate Breast Cancer Therapy for Today's Breast Cancer Patient. Seminars in Oncology Nursing 23, S3-S9
CrossRef49
Iris Grossman. (2007) Routine pharmacogenetic testing in clinical practice: dream or reality?. Pharmacogenomics 8:10, 1449-1459
CrossRef50
William F. Anderson, Bingshu E. Chen, Louise A. Brinton, Susan S. Devesa. (2007) Qualitative age interactions (or effect modification) suggest different cancer pathways for early-onset and late-onset breast cancers. Cancer Causes & Control 18:10, 1187-1198
CrossRef51
Yang Song, George Y. H. Chi. (2007) A method for testing a prespecified subgroup in clinical trials. Statistics in Medicine 26:19, 3535-3549
CrossRef52
Elena F. Brachtel, A. John Iafrate, Eugene J. Mark, Vikram Deshpande. (2007) Cytomorphological correlates of epidermal growth factor receptor mutations in lung carcinoma. Diagnostic Cytopathology 35:5, 257-262
CrossRef53
Mark R. Trusheim, Ernst R. Berndt, Frank L. Douglas. (2007) Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers. Nature Reviews Drug Discovery 6:4, 287-293
CrossRef54
Gianluigi Ferretti, Alessandra Felici, Paola Papaldo, Alessandra Fabi, Francesco Cognetti. (2007) HER2/neu role in breast cancer: from a prognostic foe to a predictive friend. Current Opinion in Obstetrics and Gynecology 19:1, 56-62
CrossRef55
Zsuzsanna Kahán. (2007) Emlőműtéttől a HER2-státuszig, avagy a sebész szerepe a molekulárisan célzott terápiában. Magyar Sebészet (Hungarian Journal of Surgery) 60:1, 506-509
CrossRef56
Christopher C. Benz, Vita Fedele, Fan Xu, Bauke Ylstra, David Ginzinger, Mamie Yu, Dan Moore, Rayna Kneuper Hall, Daynna J. Wolff, Mary L. Disis, Serenella Eppenberger-Castori, Urs Eppenberger, Francesco Schittulli, Stefania Tommasi, Angelo Paradiso, Gary K. Scott, Donna G. Albertson. (2006) Altered promoter usage characterizes monoallelic transcription arising withERBB2 amplification in human breast cancers. Genes, Chromosomes and Cancer 45:11, 983-994
CrossRef57
V Ciocca, A Bombonati, Z Gatalica, M Di Pasquale, A Milos, A Ruiz-Orrico, D Dreher, N Folch, F Monzon, G Santeusanio, C M Perou, P S Bernard, J P Palazzo. (2006) Cytokeratin profiles of male breast cancers. Histopathology 49:4, 365-370
CrossRef58
David G. Hicks, Sarah M. Short, Nichole L. Prescott, Shannon M. Tarr, Kara A. Coleman, Brian J. Yoder, Joseph P. Crowe, Toni K. Choueiri, Andrea E. Dawson, G. Thomas Budd, Raymond R. Tubbs, Graham Casey, Robert J. Weil. (2006) Breast Cancers With Brain Metastases are More Likely to be Estrogen Receptor Negative, Express the Basal Cytokeratin CK5/6, and Overexpress HER2 or EGFR. The American Journal of Surgical Pathology1097-1104
CrossRef59
Siavosh Saatee, Maryam Afrakhteh, Behbood Sadrolhefazi. (2006) High Prevalence of HER-2/neu Overexpression among Iranian Women with Breast Cancer: True or False?. The Breast Journal 12:5, 499-501
CrossRef60
W. F. Anderson, R. Matsuno. (2006) Breast Cancer Heterogeneity: A Mixture of At Least Two Main Types?. JNCI Journal of the National Cancer Institute 98:14, 948-951
CrossRef61
Corina Marx, Crystal Berger, Fan Xu, Cliff Amend, Gary K. Scott, Byron Hann, John W. Park, Christopher C. Benz. (2006) Validated High-Throughput Screening of Drug-Like Small Molecules for Inhibitors of ErbB2 Transcription. ASSAY and Drug Development Technologies 4:3, 273-284
CrossRef62
Dennis A Smith. (2006) Commentary on variability in vitamin K antagonist metabolism. Expert Opinion on Drug Metabolism & Toxicology 2:1, 1-2
CrossRef63
Volker R. Jacobs. (2006) Current Status of Financing and Reimbursement of Trastuzumab (Herceptin<sup>®</sup>) for Adjuvant and Advanced Therapy of Breast Cancer in Germany. Breast Care 1:2, 86-94
CrossRef
