Multiplication of Chromosome 17 Centromere Is Associated with Prognosis in Patients with Invasive Breast Cancers Exhibiting Normal HER2 and TOP2A Status

다국어 초록 (Multilingual Abstract)

Purpose: This study aimed to investigate the clinical significance of chromosome 17 centromere (CEP17) multiplication (increased copy number of CEP17) related to human epidermal growth factor receptor 2 (HER2) and topoisomerase II alpha (TOP2A) status in patients with invasive breast cancer. Methods: We constructed tissue microarrays using 594 invasive breast cancer samples and performed single-color silver-enhanced in situ hybridization (SISH) assay for HER2, TOP2A, and CEP17 to assess for copy number aberrations. The association of CEP17 multiplication with patient survival was analyzed according to HER2 and TOP2A status. Results: Among 567 informative cases, HER2 amplification was noted in 22.8%, TOP2A amplification in 8.3% and TOP2A deletion in 11.1%. CEP17 multiplication was identified in 33.2% and was significantly associated with worse overall survival (OS) (p=0.02) and disease-free survival (DFS) (p=0.02). CEP17 multiplication correlated with patient survival in patients with normal TOP2A or non-amplified HER2 status, but the prognostic significance was lost in those with altered TOP2A or amplified HER2. On multivariate analyses, CEP17 multiplication was an independent prognostic factor for poorer OS (p=0.02)and DFS (p=0.01) in patients with normal TOP2A and non-amplified HER2. Conclusion: CEP17 multiplication was identified as a promising prognostic marker in patients with invasive breast cancer exhibiting either non-amplified HER2 or normal TOP2A status.

참고문헌 (Reference)

1 김태정, "유방암에서 HER2 유전자 증폭 분석에 대한 은제자리부합법과 형광제자리부합법의 비교" 한국유방암학회 12 (12): 295-301, 2009

2 배영경, "유방암에서 HER2 유전자 검사를 위한 자동화 은제자리부합법 검사의 유용성: 형광제자리부합법과 면역조직화학염색과의 비교" 대한병리학회 44 (44): 28-34, 2010

3 Burgess DJ, "Topoisomerase levels determine chemotherapy response in vitro and in vivo" 105 : 9053-9058, 2008

4 O’Malley FP, "Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy" 101 : 644-650, 2009

5 Mukherjee A, "Topo2alpha protein expression predicts response to anthracycline combination neo-adjuvant chemotherapy in locally advanced primary breast cancer" 103 : 1794-1800, 2010

6 Knoop AS, "Retrospective analysis of topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Cooperative Group" 23 : 7483-7490, 2005

7 Bartlett JM, "Predictive markers of anthracycline benefit: a prospectively planned analysis of the UK National Epirubicin Adjuvant Trial (NEAT/ BR9601)" 11 : 266-274, 2010

8 Krishnamurti U, "Poor prognostic significance of unamplified chromosome 17 polysomy in invasive breast carcinoma" 22 : 1044-1048, 2009

9 Elston CW, "Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up" 19 : 403-410, 1991

10 Dhesy-Thind B, "HER2/neu in systemic therapy for women with breast cancer: a systematic review" 109 : 209-229, 2008

11 Gennari A, "HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials" 100 : 14-20, 2008

12 Pritchard KI, "HER2 and responsiveness of breast cancer to adjuvant chemotherapy" 354 : 2103-2111, 2006

13 Järvinen TA, "HER-2/neu and topoisomerase IIalpha in breast cancer" 78 : 299-311, 2003

14 Marchiò C, "Does chromosome 17 centromere copy number predict polysomy in breast cancer? A fluorescence in situ hybridization and microarray- based CGH analysis" 219 : 16-24, 2009

15 Cardoso F, "Correlation between complete response to anthracycline-based chemotherapy and topoisomerase II-alpha gene amplification and protein overexpression in locally advanced/metastatic breast cancer" 24 : 201-209, 2004

16 Dietel M, "Comparison of automated silver enhanced in situ hybridisation (SISH) and fluorescence ISH (FISH) for the validation of HER2 gene status in breast carcinoma according to the guidelines of the American Society of Clinical Oncology and the College of American Pathologists" 451 : 19-25, 2007

17 Jun Kang, "Comparison of Silver-Enhanced in situ Hybridization and Fluorescence in situ Hybridization for HER2 Gene Status in Breast Carcinomas" 한국유방암학회 12 (12): 235-240, 2009

18 Yeh IT, "Clinical validation of an array CGH test for HER2 status in breast cancer reveals that polysomy 17 is a rare event" 22 : 1169-1175, 2009

19 Watters AD, "Chromosome 17 aneusomy is associated with poor prognostic factors in invasive breast carcinoma" 77 : 109-114, 2003

20 Järvinen TA, "Characterization of topoisomerase II alpha gene amplification and deletion in breast cancer" 26 : 142-150, 1999

21 정규원, "Cancer Statistics in Korea: Incidence, Mortality and Survival in 2006-2007" 대한의학회 25 (25): 1113-1121, 2010

22 Reinholz MM, "Breast cancer and aneusomy 17: implications for carcinogenesis and therapeutic response" 10 : 267-277, 2009

23 Viale G, "Be precise! The need to consider the mechanisms for CEP17 copy number changes in breast cancer" 219 : 1-2, 2009

24 Konecny GE, "Association between HER2, TOP2A, and response to anthracyclinebased preoperative chemotherapy in high-risk primary breast cancer" 120 : 481-489, 2010

25 Järvinen TA, "Amplification and deletion of topoisomerase IIalpha associate with ErbB-2 amplification and affect sensitivity to topoisomerase II inhibitor doxorubicin in breast cancer" 156 : 839-847, 2000

26 Hammond ME, "American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer" 28 : 2784-2795, 2010

27 Wolff AC, "American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer" 25 : 118-145, 2007

28 Slamon DJ, "Alterations in the TOP2A and HER2 genes: association with adjuvant anthracycline sensitivity in human breast cancers" 101 : 615-618, 2009