Az egyénre szabott terápia az emlőtumorok közeljövőbeli klinikai szisztémás kezelésének alapja lesz. Ehhez a tumorok hatékonyabb jellemzése, pontosabb prediktív és prognosztikus információk nyerése szükséges, amelyet monogénes (ER, PR, HER-2, stb.), vagy multigénes tesztek alkalmazása tesz lehetővé. Multigénes tesztek segítségével különböző klinikai problémákra tudunk egyidejűleg választ kapni, amely az összköltséget és az időigényt csökkenti. Az általunk ismertetett tesztek a MammaPrint, Oncotype DX, BLN Assay, Theros Breast Cancer Index SM, MapQuant DX, ARUP Breast Bioclassifier, Celera Metastatic Score, eXagen BCtm, Invasive Gene Signature, Wound Response Indicator, Mammostrat, amelyek microarray vagy RT-PCR módszert alkalmaznak a génexpresszió mérésére. Ezek közül kettő (Oncotype DX és MammaPrint) már most az ajánlott diagnosztikus protokollok része. Ma még sok probléma jelentkezik a kereskedelmi forgalomban is kapható tesztekkel kapcsolatban: jellemző a gyenge validáltság, az azonos célra tervezett chipek teljesen eltérő génlistái, az eljárás költségessége és a kiértékeléshez szükséges bioinformatikai módszerek bonyolultsága.
1 Al-Hajj, M, Wicha, MS, Benito-Hernandez, A et al. 2003 Prospective identification of tumorigenic breast cancer cells Proc Natl Acad Sci USA 100 3983–3988.
2 Andre, F, Hatzis, C, Anderson, K et al. 2007 Microtubule-associated protein-tau is a bifunctional predictor of endocrine sensitivity and chemotherapy resistance in estrogen receptor-positive breast cancer Clin Cancer Res 13 2061–2067.
3 Ayers, M, Symmans, WF, Stec, J et al. 2004 Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer J Clin Oncol 22 2284–2293.
4 Bardou, VJ, Arpino, G, Elledge, RM et al. 2003 Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases J Clin Oncol 21 1973–1979.
5 Bast, RC, Jr, Hortobagyi, GN 2004 Individualized care for patients with cancer – a work in progress N Engl J Med 351 2865–2867.
6 Berry, DA, Cirrincione, C, Henderson, IC et al. 2006 Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer JAMA 295 1658–1667.
7 Bhat, KM, Setaluri, V 2007 Microtubule-associated proteins as targets in cancer chemotherapy Clin Cancer Res 13 2849–2854.
8 Bieche, I, Lidereau, R 1995 Genetic alterations in breast cancer Genes Chromosomes Cancer 14 227–251.
9 Blumencranz, P, Whitworth, PW, Deck, K et al. 2007 Scientific Impact Recognition Award. Sentinel node staging for breast cancer: intraoperative molecular pathology overcomes conventional histologic sampling errors Am J Surg 194 426–432.
10 Broyde, A, Boycov, O, Strenov, Y et al. 2009 Role and prognostic significance of the Ki-67 index in non-Hodgkin’s lymphoma Am J Hematol 84 338–343.
11 Bueno-de-Mesquita, JM, Linn, SC, Keijzer, R et al. 2009 Validation of 70-gene prognosis signature in node-negative breast cancer Breast Cancer Res Treat 117 483–495.
12 Carter, P, Presta, L, Gorman, CM et al. 1992 Humanization of an anti-p185HER2 antibody for human cancer therapy Proc Natl Acad Sci USA 89 4285–4289.
13 Chang, HY, Nuyten, DS, Sneddon, JB et al. 2005 Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival Proc Natl Acad Sci USA 102 3738–3743.
14 Chang, HY, Sneddon, JB, Alizadeh, AA et al. 2004 Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds PLoS Biol 2 E7.
15 Cheang, MC, Voduc, D, Bajdik, C et al. 2008 Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype Clin Cancer Res 14 1368–1376.
16 Davis, LM, Harris, C, Tang, L et al. 2007 Amplification patterns of three genomic regions predict distant recurrence in breast carcinoma J Mol Diagn 9 327–336.
17 Debatin, KM, Krammer, PH 2004 Death receptors in chemotherapy and cancer Oncogene 23 2950–2966.
18 Drach, J, Gattringer, C, Glassl, H et al. 1992 The biological and clinical significance of the Ki-67 growth fraction in multiple myeloma Hematol Oncol 10 125–134.
19 Duffy, MJ 2005 Predictive markers in breast and other cancers: a review Clin Chem 51 494–503.
20 Duffy, MJ, McCarthy, K 1998 Matrix metalloproteinases in cancer: prognostic markers and targets for therapy (review) Int J Oncol 12 1343–1348.
21 Dvorak, HF 1986 Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing N Engl J Med 315 1650–1659.
22 Fan, C, Oh, DS, Wessels, L et al. 2006 Concordance among gene-expression-based predictors for breast cancer N Engl J Med 355 560–569.
23 Fodor, SP, Rava, RP, Huang, XC et al. 1993 Multiplexed biochemical assays with biological chips Nature 364 555–556.
24 Gennari, A, Sormani, MP, Pronzato, P et al. 2008 HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials J Natl Cancer Inst 100 14–20.
25 Gerdes, J, Schwab, U, Lemke, H et al. 1983 Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation Int J Cancer 31 13–20.
26 Glas, AM, Floore, A, Delahaye, LJ et al. 2006 Converting a breast cancer microarray signature into a high-throughput diagnostic test BMC Genomics 7 278.
27 Goetz, MP, Suman, VJ, Ingle, JN et al. 2006 A two-gene expression ratio of homeobox 13 and interleukin-17B receptor for prediction of recurrence and survival in women receiving adjuvant tamoxifen Clin Cancer Res 12 2080–2087.
28 Goldhirsch, A, Coates, AS, Gelber, RD et al. 2006 First--select the target: better choice of adjuvant treatments for breast cancer patients Ann Oncol 17 1772–1776.
29 Gong, Y, Yan, K, Lin, F et al. 2007 Determination of oestrogen-receptor status and ERBB2 status of breast carcinoma: a gene-expression profiling study Lancet Oncol 8 203–211.
30 Gralow, JR, Burstein, HJ, Wood, W et al. 2008 Preoperative therapy in invasive breast cancer: pathologic assessment and systemic therapy issues in operable disease J Clin Oncol 26 814–819.
31 Gyorffy, B, Gyorffy, A, Tulassay, Z 2005 A “multiple testing” problémája és a genomiális kísérletekre alkalmazott megoldások Orvosi Hetilap 146 559–563.
32 Habel, LA, Shak, S, Jacobs, MK et al. 2006 A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients Breast Cancer Res 8 R25.
33 Harris, L, Fritsche, H, Mennel, R et al. 2007 American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer J Clin Oncol 25 5287–5312.
34 Harvey, JM, Clark, GM, Osborne, CK et al. 1999 Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer J Clin Oncol 17 1474–1481.
35 Hu, Z, Fan, C, Oh, DS et al. 2006 The molecular portraits of breast tumors are conserved across microarray platforms BMC Genomics 7 96.
36 Iverson, AA, Gillett, C, Cane, P et al. 2009 A single-tube quantitative assay for mRNA levels of hormonal and growth factor receptors in breast cancer specimens J Mol Diagn 11 117–130.
37 Iyer, VR, Eisen, MB, Ross, DT et al. 1999 The transcriptional program in the response of human fibroblasts to serum Science 283 83–87.
38 Janicke, F, Prechtl, A, Thomssen, C et al. 2001 Randomized adjuvant chemotherapy trial in high-risk, lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 J Natl Cancer Inst 93 913–920.
39 Jansen, MP, Sieuwerts, AM, Look, MP et al. 2007 HOXB13-to-IL17BR expression ratio is related with tumor aggressiveness and response to tamoxifen of recurrent breast cancer: a retrospective study J Clin Oncol 25 662–668.
40 Jerevall, PL, Brommesson, S, Strand, C et al. 2008 Exploring the two-gene ratio in breast cancer--independent roles for HOXB13 and IL17BR in prediction of clinical outcome Breast Cancer Res Treat 107 225–234.
41 Kakarala, M, Wicha, MS 2008 Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy J Clin Oncol 26 2813–2820.
42 Liu, R, Wang, X, Chen, GY et al. 2007 The prognostic role of a gene signature from tumorigenic breast-cancer cells N Engl J Med 356 217–226.
43 Loi, S, Haibe-Kains, B, Desmedt, C et al. 2007 Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade J Clin Oncol 25 1239–1246.
44 Look, MP, Putten van, WL, Duffy, MJ et al. 2002 Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients J Natl Cancer Inst 94 116–128.
45 Ma, XJ, Hilsenbeck, SG, Wang, W et al. 2006 The HOXB13:IL17BR expression index is a prognostic factor in early-stage breast cancer J Clin Oncol 24 4611–4619.
46 Ma, XJ, Salunga, R, Dahiya, S et al. 2008 A five-gene molecular grade index and HOXB13:IL17BR are complementary prognostic factors in early stage breast cancer Clin Cancer Res 14 2601–2608.
47 Ma, XJ, Wang, Z, Ryan, PD et al. 2004 A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen Cancer Cell 5 607–616.
48 Mano, MS, Rosa, DD, De, AE et al. 2007 The 17q12-q21 amplicon: Her2 and topoisomerase-IIalpha and their importance to the biology of solid tumours Cancer Treat Rev 33 64–77.
49 Mansel, RE, Goyal, A, Douglas-Jones, A et al. 2009 Detection of breast cancer metastasis in sentinel lymph nodes using intra-operative real time GeneSearch BLN Assay in the operating room: results of the Cardiff study Breast Cancer Res Treat 115 595–600.
50 Miyabe, S, Okabe, M, Nagatsuka, H et al. 2009 Prognostic significance of p27Kip1, Ki-67, and CRTC1-MAML2 fusion transcript in mucoepidermoid carcinoma: a molecular and clinicopathologic study of 101 cases J Oral Maxillofac Surg 67 1432–1441.
51 Molina, R, Barak, V, Dalen van, A et al. 2005 Tumor markers in breast cancer – European Group on Tumor Markers recommendations Tumour Biol 26 281–293.
52 Mook, S, Bonnefoi, H, Pruneri, G et al. 2009 Daily clinical practice of fresh tumour tissue freezing and gene expression profiling; logistics pilot study preceding the MINDACT trial Eur J Cancer 45 1201–1208.
53 Mook, S, Schmidt, MK, Viale, G et al. 2009 The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1–3 positive lymph nodes in an independent validation study Breast Cancer Res Treat 116 295–302.
54 Nielsen, TO, Hsu, FD, Jensen, K et al. 2004 Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma Clin Cancer Res 10 5367–5374.
55 Onitilo, AA, Engel, JM, Greenlee, RT et al. 2009 Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival Clin Med Res 7 4–13.
56 Paik, S, Shak, S, Tang, G et al. 2004 A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer N Engl J Med 351 2817–2826.
57 Paik, S, Tang, G, Shak, S et al. 2006 Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer J Clin Oncol 24 3726–3734.
58 Parker, JS, Mullins, M, Cheang, MC et al. 2009 Supervised risk predictor of breast cancer based on intrinsic subtypes J Clin Oncol 27 1160–1167.
59 Peintinger, F, Anderson, K, Mazouni, C et al. 2007 Thirty-gene pharmacogenomic test correlates with residual cancer burden after preoperative chemotherapy for breast cancer Clin Cancer Res 13 4078–4082.
60 Perou, CM, Sorlie, T, Eisen, MB et al. 2000 Molecular portraits of human breast tumours Nature 406 747–752.
61 Ponti, D, Costa, A, Zaffaroni, N et al. 2005 Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties Cancer Res 65 5506–5511.
62 Pritchard, KI 2009 Are HER2 and TOP2A useful as prognostic or predictive biomarkers for anthracycline-based adjuvant chemotherapy for breast cancer? J Clin Oncol 27 3875–3876.
63 Rhodes, A, Jasani, B, Barnes, DM et al. 2000 Reliability of immunohistochemical demonstration of oestrogen receptors in routine practice: interlaboratory variance in the sensitivity of detection and evaluation of scoring systems J Clin Pathol 53 125–130.
64 Ring, BZ, Seitz, RS, Beck, R et al. 2006 Novel prognostic immunohistochemical biomarker panel for estrogen receptor-positive breast cancer J Clin Oncol 24 3039–3047.
65 Ross, DT, Kim, CY, Tang, G et al. 2008 Chemosensitivity and stratification by a five monoclonal antibody immunohistochemistry test in the NSABP B14 and B20 trials Clin Cancer Res 14 6602–6609.
66 Ross, JS, Hatzis, C, Symmans, WF et al. 2008 Commercialized multigene predictors of clinical outcome for breast cancer Oncologist 13 477–493.
67 Ross, JS, Symmans, WF, Pusztai, L et al. 2007 Standardizing slide-based assays in breast cancer: hormone receptors, HER2, and sentinel lymph nodes Clin Cancer Res 13 2831–2835.
68 Rouzier, R, Rajan, R, Wagner, P et al. 2005 Microtubule-associated protein tau: a marker of paclitaxel sensitivity in breast cancer Proc Natl Acad Sci USA 102 8315–8320.
69 Shi, L, Reid, LH, Jones, WD et al. 2006 The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements Nat Biotechnol 24 1151–1161.
70 Shipitsin, M, Campbell, LL, Argani, P et al. 2007 Molecular definition of breast tumor heterogeneity Cancer Cell 11 259–273.
71 Simon, JA, Szankasi, P, Nguyen, DK et al. 2000 Differential toxicities of anticancer agents among DNA repair and checkpoint mutants of Saccharomyces cerevisiae Cancer Res 60 328–333.
72 Sorlie, T, Perou, CM, Tibshirani, R et al. 2001 Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications Proc Natl Acad Sci USA 98 10869–10874.
73 Sotiriou, C, Neo, SY, McShane, LM et al. 2003 Breast cancer classification and prognosis based on gene expression profiles from a population-based study Proc Natl Acad Sci USA 100 10393–10398.
74 Sotiriou, C, Wirapati, P, Loi, S et al. 2006 Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis J Natl Cancer Inst 98 262–272.
75 Steeg, PS, Zhou, Q 1998 Cyclins and breast cancer Breast Cancer Res Treat 52 17–28.
76 Straver, ME, Glas, AM, Hannemann, J, et al. The 70-gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat 2009.
77 Surowiak, P, Matkowski, R, Materna, V et al. 2005 Elevated metallothionein (MT) expression in invasive ductal breast cancers predicts tamoxifen resistance Histol Histopathol 20 1037–1044.
78 Symmans, WF, Peintinger, F, Hatzis, C et al. 2007 Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy J Clin Oncol 25 4414–4422.
79 Tanner, M, Isola, J, Wiklund, T et al. 2006 Topoisomerase IIalpha gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401 J Clin Oncol 24 2428–2436.
80 Tsai, CM, Chang, KT, Wu, LH et al. 1996 Correlations between intrinsic chemoresistance and HER-2/neu gene expression, p53 gene mutations, and cell proliferation characteristics in non-small cell lung cancer cell lines Cancer Res 56 206–209.
81 Tutt, A, Ashworth, A 2008 Can genetic testing guide treatment in breast cancer Eur J Cancer 44 2774–2780.
82 Tutt, A, Wang, A, Rowland, C et al. 2008 Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature BMC Cancer 8 339.
83 Ueda, T, Aozasa, K, Tsujimoto, M et al. 1989 Prognostic significance of Ki-67 reactivity in soft tissue sarcomas Cancer 63 1607–1611.
84 Veer van ‘t, LJ, Dai, H, Vijver van de, MJ et al. 2003 Expression profiling predicts outcome in breast cancer Breast Cancer Res 5 57–58.
85 Vijver van de, M, He, YD, Veer van ‘t, LJ et al. 2002 A gene-expression signature as a predictor of survival in breast cancer N Engl J Med 347 1999–2009.
86 Weigelt, B, Hu, Z, He, X et al. 2005 Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer Cancer Res 65 9155–9158.
87 Wiechmann, L, Sampson, M, Stempel, M et al. 2009 Presenting features of breast cancer differ by molecular subtype Ann Surg Oncol 16 2705–2710.
88 Wiesner, FG, Magener, A, Fasching, PA et al. 2009 Ki-67 as a prognostic molecular marker in routine clinical use in breast cancer patients Breast 18 135–141.