Radiation Oncology Journal

The Korean Society for Radiation Oncology (대한방사선종양학회)
권호 표지

A Study on BRCA1/2 Mutations, Hormone Status and HER-2 Status in Korean Women with Early-onset Breast Cancer

젊은 한국인 유방암 환자에서 BRCA1/2 돌연변이와 호르몬 수용체, HER-2 상태에 관한 연구

  • Choi, Doo-Ho (Departments of Radiation Oncology, Soonchunhyang University College of Medicine) ;
  • Jin, So-Young (Departments of Pathology, Soonchunhyang University College of Medicine) ;
  • Lee, Dong-Wha (Departments of Pathology, Soonchunhyang University College of Medicine) ;
  • Kim, Eun-Seog (Departments of Radiation Oncology, Soonchunhyang University College of Medicine) ;
  • Kim, Yong-Ho (Departments of Radiation Oncology, Soonchunhyang University College of Medicine)
  • 최두호 (순천향대학교 의과대학 방사선종양학교실) ;
  • 진소영 (순천향대학교 의과대학 병리학교실) ;
  • 이동화 (순천향대학교 의과대학 병리학교실) ;
  • 김은석 (순천향대학교 의과대학 방사선종양학교실) ;
  • 김용호 (순천향대학교 의과대학 방사선종양학교실)
  • Published : 2008.03.30
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose: Women with breast cancer diagnosed at an age of 40 years or younger have a greater prevalence of germline BRCA1 and BRCA2 mutations than the prevalence of women with breast cancer diagnosed at older ages. Several immunohistochemical characteristics have been identified in breast cancers from studies of Caucasian women with BRCA1/2 mutations having familial or early-onset breast cancers. The aim of this study is to determine whether early-onset breast cancer in BRCA1 or BRCA2 mutation carriers, who were not selected from a family history, could be distinguished by the use of immunohistochemical methods and could be distinguished from breast cancer in women of a similar age without a germline BRCA1 or BRCA2 mutation. We also analyzed the prognostic difference between BRCA1/2 related and BRCA1/2 non-related patients by the use of univariate and multivariate analysis. Materials and Methods: Breast cancer tissue specimens from Korean women with early-onset breast cancers were studied using a tumor tissue microarray. Immunohistochemical staining of estrogen receptor(ER), progesterone receptor(PR) and HER-2, as well as the histology and grade of these specimens, were compared. The prognostic impact of immunohistochemical and histological factors as well as the BRCA1/2 mutation status was investigated separately. Results: There were 14 cases and 16 deleterious BRCA1/2 mutations among 101 patients tested. A family history(4/14) and bilateral breast cancers(3/9) were high risk factors for BRCA1/2 mutations. BRCA1/2-associated cancers demonstrated more expression of ER-negative(19.4% versus 5.1%, p=0.038) and HER-2 negative than BRCA1/2 negative tumors, especially for tumors with BRCA1 tumors The BRCA1/2 mutation rate for patients with triple negative tumors(negative expression of ER, PR and HER-2) was 24.2%. Tumor size, nodal status, and HER-2 expression status were significantly associated with disease free survival, as determined by univariate and multivariate analysis, but the BRCA1/2 status was not a prognostic factor. Conclusion: Breast cancer that occurs in women with a germline BRCA1 or BRCA2 mutations have recognizable immunohistochemical features, which may be useful in identifying individuals that are more likely to carry germline mutations. Although the BRCA1/2 mutation status was not a prognostic factor in Korean women with early-onset breast cancer, more cases with a longer follow-up period are needed for further study.

목적: 40세 이하의 젊은 여성 유방암 환자는 나이 든 여성 보다 BRCA1과 BRCA2 배선돌연변이의 빈도가 상대적으로 높다. 유방암 가족력이 있거나 젊은 나이에 유방암을 진단받은 백인 여성들의 BRCA1/2 돌연변이 암에 대한 연구에서 면역조직화학적으로 BRCA1/2 돌연변이 음성인 암과 다른 특성이 발견되었다. 이 연구의 목적은 유방암 가족력과 관계없이 젊은 나이에 유방암이 발생한 한국 여성을 대상으로 BRCA1/2 돌연변이 유뮤에 따라, 그리고 BRCA1과 BRCA2 각각의 돌연변이에 따라 면역조직화학적 특성으로 상호간의 구별이 가능한지, 면역조직화학적 검사로 BRCA1/2 돌연변이의 가능성을 알아보는 것이 가능한지를 조사하는데 있으며 BRCA와 관련된 암의 예후인자로서의 역할도 분석하였다. 대상 및 방법: BRCA1/2 검사를 시행한 40세 이하의 한국인 젊은 여성 유방암 환자의 유방암 수술 후 병리조직을 찾아서 조직미세배열법으로 슬라이드를 만들었다. 이 검체들의 병리조직, 등급, 림프절 전이, T 병기, 에스트로겐 수용체, 프로게스테론 수용체 및 HER-2 상태와 BRCA1/2의 관계를 비교하였다. 그리고 이 환자들의 BRCA 돌연변이 상태와 면역조직학적, 병리학적 상태와 예후 인자로서의 역할도 조사하였다. 결과: BRCA1/2 돌연변이를 조사한 101명 중 14명에서 16개의 돌연변이가 있었으며(13.9%), 유방암-난소암 가족력이 있는 경우(4/14, 28.6%), 양측성 유방암이 있는 경우(3/9, 33.3%)에 BRCA1/2 돌연변이 빈도가 높았다. 에스트로겐 수용체 음성인 경우 BRCA1/2 양성이 19.4%(12/62)로 에스트로겐 수용체 양성 비율 5.1%(2/37)에 비해 유의하게 높았고(p=0.038), HER-2 음성인 경우 BRCA1/2 돌연변이 음성 비율이 16.5%(13/79)로 양성 비율 4.5%(1/22)에 비해 높은 경향을 보였으며(p=0.073), 프로게스테론 수용체는 차이가 없었다. 에스트로겐 수용체, 프로게스테론 수용체 및 HER-2 모두 음성인 경우(triple negative)는 BRCA1/2 돌연변이 비율이 24.2%(8/33)로 매우 높았다. 종양의 크기, 림프절 전이 상태, HER-2 상태는 단변량 변수와 다변량 변수 모두에서 무병 생존에 유의한 영향을 미치는 인자 이었으나 BRCA1/2 돌연변이 상태는 무병생존에 유의한 인자가 아니었다. 결론: 면역조직화학적으로 에스트로겐 수용체나 HER-2 음성을 보이는 젊은 유방암 환자에서 BRCA1/2 돌연변이 발생이 유의하게 높았으며, 프로게스테론 수용체까지 모두 음성인 경우 BRCA1/2 돌연변이가 있을 확률이 24.2%로 높아서 유방암 유전자 돌연변이 가능성을 예측하는데 도움을 줄 수 있다. 한국인 젊은 여성 유방암 환자에서 BRCA1/2 돌연변이 상태가 무병생존에 유의한 인자는 아니었으나 좀 더 많은 환자와 긴 추적관찰 기간의 추가적인 연구가 필요하다.

Keywords

References

  1. Ministry of Health and Welfare. Annual report of the Central Cancer Registry in Korea, Seoul. Ministry of Health and Welfare 2001
  2. Cheng SH, Tsou MH, Liu MC, et al. Unique features of breast cancer in Taiwan. Breast Cancer Res Treat 2000;63: 213-223 https://doi.org/10.1023/A:1006468514396
  3. Choi DH, Lee MH, Bale AE, Carter D, Haffty BG. Incidence of BRCA1 and BRCA2 mutations in young Korean breast cancer patients. J Clin Oncol 2004;22:1638-1645 https://doi.org/10.1200/JCO.2004.04.179
  4. Kang HC, Kim IJ, Park JH, et al. Germline mutations of BRCA1 and BRCA2 in Korean breast and/or ovarian cancer families. Hum Mutat 2002;20:235
  5. Ahn SH, Son BH, Yoon KS, et al. BRCA1 and BRCA2 germline mutations in Korean breast cancer patients at high risk of carrying mutations. Cancer Lett 2007;245:90-95 https://doi.org/10.1016/j.canlet.2005.12.031
  6. Park BW, Kim SI, Kim EK, Yang WI, Lee KS. Impact of patients age on the outcome of primary breast cancer. J Surg Oncol 2002;80:12-18 https://doi.org/10.1002/jso.10088
  7. Han W, Kim SW, Park IA, et al. Young age: an independent risk factor for disease free survival in women with operable breast cancer. BMC Cancer 2004;17:82
  8. Loman N, Johannsson O, Bendahl PO, Borg A, Femo M, Olsson H. Steroid receptors in hereditary breast carcinoma s associated with BRCA1or BRCA2 mutations or unknown susceptibility genes. Cancer 1998;83:310-319 https://doi.org/10.1002/(SICI)1097-0142(19980715)83:2<310::AID-CNCR15>3.0.CO;2-W
  9. Armed JE, Trute L, White D, et al. Distinct molecular pathogeneses of early-onset breast cancers in BRCA1 and BRCA2 mutation carriers: a population- based study. Cancer Res 1999;59:2011-2017
  10. Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 1998;4:844-847 https://doi.org/10.1038/nm0798-844
  11. Rimm DL, Camp RL, Charette LA, Costa J, Olsen DA, Reiss M. Tissue microarray: a new technology for amplification of tissue resources. Cancer J 2001;7:24-31
  12. Choi DH, Lee MH, Haffty BG. Is the BRCA germline mutation a prognostic factor in Korean patients with early-onset breast carcinomas? J Korean Soc Ther Radiol Oncol 2003;21:149-157
  13. Choi DH, Lee MH, Haffty BG. Double heterozygotes for non_Caucasian families with mutations in BRCA-1 and BRCA-2 genes. Breast J 2006;12:216-220 https://doi.org/10.1111/j.1075-122X.2006.00245.x
  14. Abeliovich D, Kaduri L, Lerer I, et al. The founder mutations 185delAG, and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarial cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet 1997;60:505-514
  15. Johnnesdottir G, Gudmundsson J, Bergthorsson JT, et al. High prevalence of the 999del5 mutation in Icelandic breast and ovarian Cancer patients. Cancer Res 1996;56:3663-3665
  16. Lakhani SR, Easton DF, Stratton MR. Pathology of familial breast cancer: differences between breast cancers in carries of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium. Lancet 1997;349:1505-1510 https://doi.org/10.1016/S0140-6736(96)10109-4
  17. Johannsson OT, Idvall I, Anderson C, et al. Tumour biological features of BRCA1-induced breast and ovarian cancer. Eur J Cancer 1997;33:362-371 https://doi.org/10.1016/S0959-8049(97)89007-7
  18. Palacious J, Honrado E, Osorio A, et al. Immunohistochemical characteristics defined by tissue microarray of hereditary breast not attributable to BRCA1 or BRCA2 mutations: differences from breast carcinomas arising in BRCA1 and BRCA2 mutation carriers. Clin Cancer Res 2003;9:3606-3614
  19. Lakhani SR, van de Vijver MJ, Jacquemier J, et al. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 2002;20:2310-2318 https://doi.org/10.1200/JCO.2002.09.023
  20. Erola H, Heikkaila P, Tamminen A, Aittomaki K, blomqvist C, Nevanlinna H. Histopathological features of breast tumors in BRCA1, BRCA2 and mutation-negative breast cancer families. Breast Cancer Res 2005;7:R93-100 https://doi.org/10.1186/bcr953
  21. Grushko TA, Blackwood MA, Schumm PL, et al. Molecular-cytogenetic analysis of HER-2/neu gene in BRCA1-associated breast cancers. Cancer Res 2002;62:1481-1488
  22. Han SH, Lee KR, Lee DG, Kim BY, Lee KE, Chung WS. Mutation analysis of BRCA1 and BRCA2 from 793 Korean patients with sporadic breast cancer. Clin Genet 2006;70:496-501 https://doi.org/10.1111/j.1399-0004.2006.00717.x
  23. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumors. Nature 2000;406:747-752 https://doi.org/10.1038/35021093
  24. Adem C, Reynolds C, Soderberg CL, et al. Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers. Cancer 2003;97:1-11 https://doi.org/10.1002/cncr.11048
  25. Hamann U, Sinn HP. Survival and tumor characteristics of German hereditary breast cancer patients. Breast Cancer Res Treat 2000;59:185-192 https://doi.org/10.1023/A:1006350518190
  26. Eerola H, Vahteristo P, Sarantaus L, et al. Survival of breast cancer patients in BRCA1, BRCA2, and non-BRCA1/2 breast cancer families: a relative survival analysis from Finland. Int J Cancer 2001;93:368-372 https://doi.org/10.1002/ijc.1341
  27. EL tamer M, Russo D, Troxel A, et al. Survival and recurrence after breast cancer in BRCA1/2 mutation carriers. Ann Surgical Oncol 2004;11:157-164 https://doi.org/10.1245/ASO.2004.05.018
  28. Brekelmans CT, Seynaeve C, Menke-Pluymers M, et al. Survival and prognostic factors in BRCA1-associated breast cancer. Ann Oncol 2006;17:391-400 https://doi.org/10.1093/annonc/mdj095
  29. Musolino A, Bella MA, Bortesi B et al. BRCA mutations, molecular markers, and clinical variables in early-onset breast cancer: a population-based study. Breast 2007;16:280-292 https://doi.org/10.1016/j.breast.2006.12.003
  30. Brekelmans CT, Tilanus-Linthorst MM, Seynaeve C, et al. Tumour characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1-, and non-BRCA1/2 families as compared to sporadic breast cancer cases. Eur J Cancer 2007;43:867-876 https://doi.org/10.1016/j.ejca.2006.12.009
  31. Kennedy RD, Quinn JE, Mullan PB, Johnston PG, Harkin DP. The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst 2004;96:1659-1668 https://doi.org/10.1093/jnci/djh312