Chinese Bulletin of Life Sciences. Over-expression of HER-2/neu and targeted therapy. CHEN Yu-ping

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1 Chinese Bulletin of Life Sciences Vol. 22, No. 1 Jan., (2010) HER-2/neu HER-2/neu HER- 2/neu 20%~30% P185HER2 P185HER2 (Herceptin) HER2/neu HER-2/neu P185HER2 R730.59; R737.9A Over-expression of HER-2/neu and targeted therapy CHEN Yu-ping (Centre of Basic Medical Science, Navy General Hospital of PLA, Beijing , China) Abstract: HER-2/neu oncogene is overexpressed in many kinds of tumors like breast cancer, ovarian cancer, nonsmall-cell lung cancer(nsclc). Overexpression of HER-2/neu has significant effect on tumor occuring and development, it is associated with tumor inversion, metastasis, recuring, poorer prognosis and patient s shortening of life. HER-2/neu is overexpressed in approximately 20%~30% patients with breast cancer. The coding protein P185HER2 of HER-2/neu is a member of the human epidermal growth factor receptor family. Monoclonal antibody of P185HER2(Herceptin) is clinically used as a targeted drug for HER-2/neu overexpressed breast cancer. Key words: HER-2/neu; P185HER2; targeted therapy 2 (human epidermal receptor 2,HER-2/neu), 20%~30% HER-2/neu [1,2] HER-2/neu (trastuzumab Herceptin) [3-5] Herceptin HER-2/neu (overexpression) [6-8] 1 HER-2/neu HER-2/neu c-erbb Slamon Alex 1987 Slamon [9] HER-2/neu HER-2/neu 17q11~21 [10] 4.6 kb k (P185HER2) (receptor tyrosine kinase, * yupingch@sohu.com Tel

2 70 RTK) (EGFR) 82% HER-2/neu P185HER2 P185HER2 shc PLCr GAP P185HER2 EGFR HER-3(or c-erbb-3) HER-4(or c-erbb-4) ( HER-2/neu ) [11] HER-2/neu [9,12] HER-2/neu [13-17] 20%~30% 20% HER-2/neu ( ) P185HER2 26 HER-2/neu 42% HER-2/neu HER-2/neuHER-2/neu HER-2/neu HER-2/neu mrna HER-2/neu HER-1 (EGFR) HER-2 HER-3 HER-4 HER-1(EGFR) α amphiregulin 17 k EGFR HER-3 EGFR HER-1 HER-2 (M2180) HER-3 HER-3 NSCLC HER-3 HER-3 EGFR 3'-OH EGFR/HER-3 PLCr GAP HER-3 HER-2/neu HER-3 HER-4 EGFR 180 k HER-3 EGFR P185HER2 HER-4 EGFR EGFR P185HER2 2HER-2/neu P185HER2 P185HER2 MAPK / P42MAPK(ERK2) P44MAPK(ERK1) P185HER2 MAPK Jun Fos Myc Myb MAPK MAPK P185HER2 PI-3K ( -3 ) 110 k 85 k P185HER2 P85 P185HER2 HER-3 PI-3K PI-3K Ras PI-3K PI-3K Src

3 HER-2/neu 71 Src HER2/neu C-Src 6~8 C-Src P185HER2 PLCr( C-r) ras-gap shc P185HER2 P185HER2 STAT HER-2/neu P185HER2 P185HER2 P185HER2 3 HER-2/neu [18] (1)HER-2 (2)( ER PR HER-2 ) (3)ER (4)ER ER PR HER-2 HER-2/neu HER-2/neu [19] HER-2/neu CMF( 5- ) [20] HER- 2/neu [21-23] ER, HER-2/neu [24-26] ER( ) HER-2/neu 48% HER-2/neu 20% [27] HER-2/neu HER-2 ER HER-2/neu HER-2/neu, 1998 Herceptin FDA Herceptin P185HER2 HER-2/neu HER-2/neu, HER-2/neu HER-2/neu [28] Herceptin HER-2/neu [4,5,18,29,30] Herceptin Herceptin 112 HER-2/neu 23% HER-2/neu 31% [31] Herceptin [32] [33,34] HER-2/neu P185HER2 P185HER2 P185HER2 ( Herceptin) HER-2/neu P185HER2 P185HER2 IgG () P185HER2 HER-2/neu Cr1 PH

4 72 HER-2/neu Fc P185HER2 P185HER2 [ ] [1] Eichler AF, Kuter I, Ryan P, et al. Survival in patients with brain metastases from breast cancer: the importance of HER- 2 status. Cancer, 2008, 112(11): [2] Lee AH, Ellis IO. The Nottingham prognostic index for invasive carcinoma of the breast. Pathol Oncol Res, 2008, 14 (2): [3] RiemerAB, Zielinski CC. Der einsatz von trastuzumab in der adjuvanten und palliativen therapie des mammakarzinoms. [Use of trastuzumab in the therapy of breast cancer]. Ther- Umsch, 2008, 65(4): [4] Ardavanis A, Kountourakis P, Kyriakou F, et al. Trastuzumab plus paclitaxel or docetaxel in HER-2-negative/HER-2 ECDpositive anthracycline- and taxane-refractory advanced breast cancer. Oncologist, 2008, 13(4): [5] Seidman AD, Berry D, Cirrincione C, et al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of cancer and leukemia group B protocol J Clin Oncol, 2008, 26(10): [6] Pothos A, Plastira K, Plastiras A, et al. Comparison of chromogenic in situ hybridisation with fluorescence in situ hybridisation and immunohistochemistry for the assessment of HER-2/neu oncogene in archival material of breast carcinoma. Acta Histochem Cytochem, 2008, 41(3): [7] Graham AD, Faratian D, Rae F, et al. Tissue microarray technology in the routine assessment of HER-2 status in invasive breast cancer: a prospective study of the use of immunohistochemistry and fluorescence in situ hybridization. Histopathology, 2008, 52(7): [8] Nistor A, Watson PH, Pettigrew N, et al. Real-time PCR complements immunohistochemistry in the determination of HER-2/neu status in breast cancer. BMC Clin Pathol, 2006, 6: 2 [9] Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science, 1987, 235(4785) : [10] Grushko TA, Blackwood MA, Schumm PL, et al. Molecular-cytogenetic analysis of HER-2/neu gene in BRCA1- associated breast cancers. Cancer Res, 2002, 62( 5) : [11] Coussens L, Yang- Feng TL, Liao YC, et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science, 1985, 230(4730 ) : [12] Duffy MJ. Predictive markers in breast and other cancers: a review. Clin Chem, 2005, 51: [13] Andrulis IL, Bull SB, Blackstein ME, et al. neu/erbb-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group. J Clin Oncol, 1998, 16: [14] Ro JS, el-naggar A, Ro JY, et al. c-erbb-2 amplification in node-negative human breast cancer. Cancer Res, 1989, 49: [15] Paterson MC, Dietrich KD, Danyluk J, et al. Correlation between c-erbb-2 amplification and risk of recurrent disease in node-negative breast cancer. Cancer Res, 1991, 51: [16] Lovekin C, Ellis IO, Locker A, et al. c-erbb-2 oncoprotein expression in primary and advanced breast cancer. Br J Cancer, 1991, 63: [17] Gullick WJ, Love SB, Wright C, et al. c-erbb-2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes. Br J Cancer, 1991, 63:434-8 [18] Razzak AR, Lin NU, Winer EP. Heterogeneity of breast cancer and implications of adjuvant chemotherapy. Breast Cancer, 2008, 15:31-4 [19] Press MF, Slamon DJ, Flom KJ, et al. Evaluation of HER-2/ neu gene amplification and overexpression: comparison of frequently used assay methods in a molecularly characterized cohort of breast cancer specimens. J Clin Oncol, 2002, 20: [20] Gusterson BA, Gelber RD, Goldhirsch A, et al. Prognostic importance of c-erbb-2 expression in breast cancer. International (Ludwig) Breast Cancer Study Group. J Clin Oncol, 1992, 10: [21] Muss HB, Thor AD, Berry DA, et al. c-erbb-2 expression and response to adjuvant therapy in women with nodepositive early breast cancer. N Engl J Med, 1994, : [22] Paik S, Bryant J, Park C, et al. erbb-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst, 1998, 90: [23] Clark GM. Should selection of adjuvant chemotherapy for patients with breast cancer be based on erbb-2 status? J Natl Cancer Inst, 1998, 90: [24] Carlomagno C, Perrone F, Gallo C, et al. c-erb B2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary lymph node metastases. J Clin Oncol, 1996, 14: [25] Wright C, Nicholson S, Angus B, et al. Relationship between c-erbb-2 protein product expression and response to endocrine therapy in advanced breast cancer. Br J Cancer, 1992, 65: [26] Pegram MD, Pauletti G, Slamon D. HER-2/neu as a predictive marker of response to breast cancer therapy. Breast Cancer Res Treat, 1998, 52:65-77

5 HER-2/neu 73 [27] De Placido S, Carlomagno C, De Laurentiis M, et al. c- erbb2 expression predicts tamoxifen efficacy in breast cancer patients. Breast Cancer Res Treat, 1998, 52( 1~3) : [28] Shak S. Overview of the trastuzumab (Herceptin) anti- HER2 monoclonal antibody clinical program in HER2- overexpressing metastatic breast cancer. Herceptin Multinational Investigator Study Group. Semin Oncol, 1999, 26(4 Suppl 12):71-7 [29] Musolino A, Naldi N, Bortesi B, et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neupositive metastatic breast cancer. J Clin Oncol, 2008, 26(11): [30] Khosravi-Shahi P, Izarzugaza-Peron Y, Encinas-Garcia S, et al. Tratamiento adyuvante en el cancer de mama operable. [Adjuvant treatment of operable breast cancer.]. An-Med- Interna, 2008, 25(1): [31] Pegram MD, Finn RS, Arzoo K, et al. The effect of HER-2/ neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene, 1997, 15( 5) : [32] Kondo N, Ishiguro Y, Kimura M, et al. Antitumor effect of gefitinib on head and neck squamous cell carcinoma enhanced by trastuzumab. Oncol Rep, 2008, 20(2): [33] Mihaljevic A, Buchler P, Harder J, et al. A prospective, nonrandomized phase trial of Trastuzumab and Capecitabine in patients with HER2 expressing metastasized pancreatic cancer. BMC Surg, 2009, 9:1 [34] Stathopoulos GP, Androulakis N, Souglakos J, et al. Present treatment and future expectations in advanced pancreatic cancer. Anticancer Res, 2008, 28(2B):1303-8

Does HER2/neu overexpression in breast cancer influence adjuvant chemotherapy and hormonal therapy choices by Ontario physicians? A physician survey

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