BRCA1 tumor expression and clinical results in uruguayan patients diagnosed with breast cancer before the age of 40 years old
Keywords:
BREAST NEOPLASMS, BRCA1 GENES, IMMUNOHISTOCHEMISTRY, YOUNG WOMEN
Abstract
BRCA1 mutations are rare in sporadic breast cancer (CM), however their expression at the tumor level is diminished or absent in 30-50% of cases.
Objective: to assess the tumor expression of BRCA1 using immunohistochemistry (IHC) in Uruguayan women diagnosed with BC before the age of 40 years.
Material and methods: patients diagnosed with BC before the age of 40 between. The antibodies used were anti BRCA1 MS110 monoclonal antibodies against the N-terminal end and GLK-2 against the C-terminal. Overall survival (OS) and disease free survival (DFS) were calculated; the curves were developed using the Kaplan-Meier method and the difference in survival was evaluated through the log rank test.
Results: the average age of the 40 patients included was 36 years. The 5-year OS and DFS were 73% and 60% respectively. The expression of BRCA1 with GLK-2 was <10% in 16 of the 40 patients included (40%). The 5-year OS and DFS for patients with <10% expression was 56% vs. 85% for patients with >10% (p=0.015) and 40% vs. 72% (p = 0.034) respectively. The expression of BRCA1 by MS110 was <10% in 11 of the 40 patients included (27.5%). No differences were found in the 5-year OS or DFS based on the expression of this marker.
Conclusion: The loss of BRCA1 expression using GLK-2, which suggests the presence of a truncated protein, was associated with a statistically significantly lower OS and DFS, that the decrease in the BRCA1 protein as determined by GLK2 has an unfavorable prognostic value for young patients with BC.
References
(1) Barrios E, Garau M. Cáncer: magnitud del problema en el mundo y en Uruguay, aspectos epidemiológicos. An Facultad Med (Univ Repúb Urug) 2017; 4(1):9-47.
(2) Barrios E, Garau M, Alonso R, Musetti C. IV Atlas de incidencia del cáncer en el Uruguay 2007-2011. Montevideo: Comisión Honoraria de Lucha Contra el Cáncer, 2014.
(3) Adami H, Malker B, Holmberg L, Persson I, Stone B. The relation between survival and age at diagnosis in breast cancer. N Engl J Med 1986; 315(9):559-63.
(4) Kroman N, Jensen M, Wohlfahrt J, Mouridsen H, Andersen P, Melbye M. Factors influencing the effect of age on prognosis in breast cancer: population based study. BMJ 2000; 320(7233):474-8.
(5) Ahn S, Son B, Kim S, Kim S, Jeong J, Ko S, et al. Poor outcome of hormone receptor-positive breast cancer at very young age is due to tamoxifen resistance: nationwide survival data in Korea—a report from the Korean Breast Cancer Society. J Clin Oncol 2007; 25(17):2360-8.
(6) Francis P. Optimal adjuvant therapy for very young breast cancer patients. Breast 2011; 20(4):297-302. doi:10.1016/j.breast.2011.05.002
(7) Anders C, Hsu D, Broadwater G, Acharya C, Foekens J, Zhang Y, et al. Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression. J Clin Oncol 2008; 26(20):3324-30. doi: 10.1200/JCO.2007.14.2471.
(8) Anders C, Fan C, Parker J, Carey L, Blackwell K, Klauber-DeMore N, et al. Breast carcinomas arising at a young age: unique biology or a surrogate for aggressive intrinsic subtypes? J Clin Oncol 2011; 29(1):e18-20. doi: 10.1200/JCO.2010.28.9199.
(9) Narod S. Breast cancer in young women. Nat Rev Clin Oncol 2012; 9(8):460-70.
(10) Cardoso F, Loibl S, Pagani O, Graziottin A, Panizza P, Martincich L, et al. The European Society of Breast Cancer Specialists recommendations for the management of young women with breast cancer. Eur J Cancer 2012; 48(18):3355-77. doi: 10.1016/j.ejca.2012.10.004.
(11) Malvasio S, Schiavone A, Camejo N, Castillo C, Artgaveytia N, Di Matteo C, et al. Características clínico-patológicas y evolución del cáncer de mama en mujeres uruguayas jóvenes . Rev Méd Urug 2017; 33(2):94-101.
(12) de Sanjosé S, Léoné M, Bérez V, Izquierdo A, Font R, Brunet J, et al. Prevalence of BRCA1 and BRCA2 germline mutations in young breast cancer patients: a population-based study. Int J Cancer 2003; 106(4):588-93.
(13) Newman B, Mu H, Butler L, Millikan R, Moorman P, King M. Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. JAMA 1998; 279(12):915-21.
(14) Frank T, Deffenbaugh A, Reid J, Hulick M, Ward B, Lingenfelter B, et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 2002; 20(6):1480-90.
(15) Delgado L, González A, Fernández G, Cataldi S, Bressac-de Paillerets B, Bombled J, et al. BRCA1 and BRCA2 mutations in Uruguayan breast and breast/ovarian cancer families. Proc Am Soc Clin Oncol 2003; 22: abstr 3510.
(16) Fodor F, Weston A, Bleiweiss I, McCurdy L, Walsh M, Tartter P, et al. Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. Am J Hum Genet 1998; 63(1):45-51.
(17) Thorlacius S, Struewing J, Hartge P, Olafsdottir G, Sigvaldason H, Tryggvadottir L, et al. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 1998; 352(9137):1337-9.
(18) Kurebayashi J, Yamamoto Y, Kurosumi M, Okubo S, Nomura T, Tanaka K, et al. Loss of BRCA1 expression may predict shorter time-to-progression in metastatic breast cancer patients treated with taxanes. Anticancer Res 2006; 26(1B):695-701.
(19) Roldán G, Delgado L, Musé I. Tumoral expression of BRCA1, estrogen receptor alpha and ID4 protein in patients with sporadic breast cancer. Cancer Biol Ther 2006; 5(5):505-10.
(20) Narod S, Foulkes W. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 2004; 4(9):665-76.
(21) Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci 2004; 95(11):866-71.
(22) Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N, et al. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 1999; 91(11):943-9.
(23) Zhang Q, Zhang Q, Cong H, Zhang X. The ectopic expression of BRCA1 is associated with genesis, progression, and prognosis of breast cancer in young patients. Diagn Pathol 2012; 7:181.
(24) Shimizu Y, Luk H, Horio D, Miron P, Griswold M, Iglehart D, et al. BRCA1-IRIS overexpression promotes formation of aggressive breast cancers. PLoS One 2012; 7(4):e34102. doi: 10.1371/journal.pone.0034102.
(25) Madjd Z, Karimi A, Molanae S, Asadi-Lari M. BRCA1 Protein Expression Level and CD44(+)Phenotype in Breast Cancer Patients. Cell J 2011; 13(3):155-62.
(26) Kim D, Jung W, Koo J. The expression of ERCC1, RRM1, and BRCA1 in breast cancer according to the immunohistochemical phenotypes. J Korean Med Sci 2011; 26(3):352-9.
(27) Ansquer Y, Mandelbrot L, Lehy T, Salomon L, Dhainaut C, Madelenat P, et al. Expression of BRCA1, HER-1 (EGFR) and HER-2 in sporadic breast cancer and relationships to other clinicopathological prognostic features. Anticancer Res 2005; 25(6C):4535-41.
(28) Delgado L, Fresco R, Santander G, Aguiar S, Camejo N, Ferrero L, et al. Expresión tumoral de HER-2, receptores de estrógenos y de progesterona y su relación con características clínico-patológicas en pacientes uruguayas con cáncer de mama. Rev Méd Urug 2010; 26(3):145-53.
(29) Blows F, Driver K, Schmidt M, Broeks A, van Leeuwen F, Wesseling J, et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med 2010; 7(5):e1000279. doi: 10.1371/journal.pmed.1000279.
(30) Gutierrez C, Schiff R. HER2: biology, detection, and clinical implications. Arch Pathol Lab Med 2011; 135(1):55-62.
(31) Cancello G, Maisonneuve P, Rotmensz N, Viale G, Mastropasqua M, Pruneri G, et al. Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (<35 years) with operable breast cancer. Ann Oncol 2010; 21(10):1974-81.
(32) Wilson C, Ramos L, Villaseñor M, Anders K, Press M, Clarke K, et al. Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas. Nat Genet 1999; 21(2):236-40.
(33) Li Q, Wei W, Jiang Y, Yang H, Liu J. Promoter methylation and expression changes of BRCA1 in cancerous tissues of patients with sporadic breast cancer. Oncol Lett 2015; 9(4):1807-13.
(34) Yamashita N, Tokunaga E, Kitao H, Hitchins M, Inoue Y, Tanaka K, et al. Epigenetic inactivation of BRCA1 through promoter hypermethylation and its clinical importance in triple-negative breast cancer. Clin Breast Cancer 2015; 15(6):498-504.
(35) Hsu N, Huang Y, Yokoyama K, Chu P, Chen F, Hou M. Methylation of BRCA1 promoter region is associated with unfavorable prognosis in women with early-stage breast cancer. PLoS One 2013; 8(2):e56256. doi: 10.1371/journal.pone.0056256.
(36) Pinto R, De Summa S, Pilato B, Tommasi S. DNA methylation and miRNAs regulation in hereditary breast cancer: epigenetic changes, players in transcriptional and post- transcriptional regulation in hereditary breast cancer. Curr Mol Med 2014; 14(1):45-57.
(37) Zanetti J, Manrique G, Heinzen S, Cancela P, Alonso I, Artagaveytia N. Nivel de ARNm-BRCA1 como factor pronóstico en cáncer de mama esporádico. En: 13º Congreso Uruguayo de Oncología. Montevideo: SOMPU, 2014.
(2) Barrios E, Garau M, Alonso R, Musetti C. IV Atlas de incidencia del cáncer en el Uruguay 2007-2011. Montevideo: Comisión Honoraria de Lucha Contra el Cáncer, 2014.
(3) Adami H, Malker B, Holmberg L, Persson I, Stone B. The relation between survival and age at diagnosis in breast cancer. N Engl J Med 1986; 315(9):559-63.
(4) Kroman N, Jensen M, Wohlfahrt J, Mouridsen H, Andersen P, Melbye M. Factors influencing the effect of age on prognosis in breast cancer: population based study. BMJ 2000; 320(7233):474-8.
(5) Ahn S, Son B, Kim S, Kim S, Jeong J, Ko S, et al. Poor outcome of hormone receptor-positive breast cancer at very young age is due to tamoxifen resistance: nationwide survival data in Korea—a report from the Korean Breast Cancer Society. J Clin Oncol 2007; 25(17):2360-8.
(6) Francis P. Optimal adjuvant therapy for very young breast cancer patients. Breast 2011; 20(4):297-302. doi:10.1016/j.breast.2011.05.002
(7) Anders C, Hsu D, Broadwater G, Acharya C, Foekens J, Zhang Y, et al. Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression. J Clin Oncol 2008; 26(20):3324-30. doi: 10.1200/JCO.2007.14.2471.
(8) Anders C, Fan C, Parker J, Carey L, Blackwell K, Klauber-DeMore N, et al. Breast carcinomas arising at a young age: unique biology or a surrogate for aggressive intrinsic subtypes? J Clin Oncol 2011; 29(1):e18-20. doi: 10.1200/JCO.2010.28.9199.
(9) Narod S. Breast cancer in young women. Nat Rev Clin Oncol 2012; 9(8):460-70.
(10) Cardoso F, Loibl S, Pagani O, Graziottin A, Panizza P, Martincich L, et al. The European Society of Breast Cancer Specialists recommendations for the management of young women with breast cancer. Eur J Cancer 2012; 48(18):3355-77. doi: 10.1016/j.ejca.2012.10.004.
(11) Malvasio S, Schiavone A, Camejo N, Castillo C, Artgaveytia N, Di Matteo C, et al. Características clínico-patológicas y evolución del cáncer de mama en mujeres uruguayas jóvenes . Rev Méd Urug 2017; 33(2):94-101.
(12) de Sanjosé S, Léoné M, Bérez V, Izquierdo A, Font R, Brunet J, et al. Prevalence of BRCA1 and BRCA2 germline mutations in young breast cancer patients: a population-based study. Int J Cancer 2003; 106(4):588-93.
(13) Newman B, Mu H, Butler L, Millikan R, Moorman P, King M. Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. JAMA 1998; 279(12):915-21.
(14) Frank T, Deffenbaugh A, Reid J, Hulick M, Ward B, Lingenfelter B, et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 2002; 20(6):1480-90.
(15) Delgado L, González A, Fernández G, Cataldi S, Bressac-de Paillerets B, Bombled J, et al. BRCA1 and BRCA2 mutations in Uruguayan breast and breast/ovarian cancer families. Proc Am Soc Clin Oncol 2003; 22: abstr 3510.
(16) Fodor F, Weston A, Bleiweiss I, McCurdy L, Walsh M, Tartter P, et al. Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. Am J Hum Genet 1998; 63(1):45-51.
(17) Thorlacius S, Struewing J, Hartge P, Olafsdottir G, Sigvaldason H, Tryggvadottir L, et al. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 1998; 352(9137):1337-9.
(18) Kurebayashi J, Yamamoto Y, Kurosumi M, Okubo S, Nomura T, Tanaka K, et al. Loss of BRCA1 expression may predict shorter time-to-progression in metastatic breast cancer patients treated with taxanes. Anticancer Res 2006; 26(1B):695-701.
(19) Roldán G, Delgado L, Musé I. Tumoral expression of BRCA1, estrogen receptor alpha and ID4 protein in patients with sporadic breast cancer. Cancer Biol Ther 2006; 5(5):505-10.
(20) Narod S, Foulkes W. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 2004; 4(9):665-76.
(21) Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci 2004; 95(11):866-71.
(22) Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N, et al. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 1999; 91(11):943-9.
(23) Zhang Q, Zhang Q, Cong H, Zhang X. The ectopic expression of BRCA1 is associated with genesis, progression, and prognosis of breast cancer in young patients. Diagn Pathol 2012; 7:181.
(24) Shimizu Y, Luk H, Horio D, Miron P, Griswold M, Iglehart D, et al. BRCA1-IRIS overexpression promotes formation of aggressive breast cancers. PLoS One 2012; 7(4):e34102. doi: 10.1371/journal.pone.0034102.
(25) Madjd Z, Karimi A, Molanae S, Asadi-Lari M. BRCA1 Protein Expression Level and CD44(+)Phenotype in Breast Cancer Patients. Cell J 2011; 13(3):155-62.
(26) Kim D, Jung W, Koo J. The expression of ERCC1, RRM1, and BRCA1 in breast cancer according to the immunohistochemical phenotypes. J Korean Med Sci 2011; 26(3):352-9.
(27) Ansquer Y, Mandelbrot L, Lehy T, Salomon L, Dhainaut C, Madelenat P, et al. Expression of BRCA1, HER-1 (EGFR) and HER-2 in sporadic breast cancer and relationships to other clinicopathological prognostic features. Anticancer Res 2005; 25(6C):4535-41.
(28) Delgado L, Fresco R, Santander G, Aguiar S, Camejo N, Ferrero L, et al. Expresión tumoral de HER-2, receptores de estrógenos y de progesterona y su relación con características clínico-patológicas en pacientes uruguayas con cáncer de mama. Rev Méd Urug 2010; 26(3):145-53.
(29) Blows F, Driver K, Schmidt M, Broeks A, van Leeuwen F, Wesseling J, et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med 2010; 7(5):e1000279. doi: 10.1371/journal.pmed.1000279.
(30) Gutierrez C, Schiff R. HER2: biology, detection, and clinical implications. Arch Pathol Lab Med 2011; 135(1):55-62.
(31) Cancello G, Maisonneuve P, Rotmensz N, Viale G, Mastropasqua M, Pruneri G, et al. Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (<35 years) with operable breast cancer. Ann Oncol 2010; 21(10):1974-81.
(32) Wilson C, Ramos L, Villaseñor M, Anders K, Press M, Clarke K, et al. Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas. Nat Genet 1999; 21(2):236-40.
(33) Li Q, Wei W, Jiang Y, Yang H, Liu J. Promoter methylation and expression changes of BRCA1 in cancerous tissues of patients with sporadic breast cancer. Oncol Lett 2015; 9(4):1807-13.
(34) Yamashita N, Tokunaga E, Kitao H, Hitchins M, Inoue Y, Tanaka K, et al. Epigenetic inactivation of BRCA1 through promoter hypermethylation and its clinical importance in triple-negative breast cancer. Clin Breast Cancer 2015; 15(6):498-504.
(35) Hsu N, Huang Y, Yokoyama K, Chu P, Chen F, Hou M. Methylation of BRCA1 promoter region is associated with unfavorable prognosis in women with early-stage breast cancer. PLoS One 2013; 8(2):e56256. doi: 10.1371/journal.pone.0056256.
(36) Pinto R, De Summa S, Pilato B, Tommasi S. DNA methylation and miRNAs regulation in hereditary breast cancer: epigenetic changes, players in transcriptional and post- transcriptional regulation in hereditary breast cancer. Curr Mol Med 2014; 14(1):45-57.
(37) Zanetti J, Manrique G, Heinzen S, Cancela P, Alonso I, Artagaveytia N. Nivel de ARNm-BRCA1 como factor pronóstico en cáncer de mama esporádico. En: 13º Congreso Uruguayo de Oncología. Montevideo: SOMPU, 2014.
Published
2020-03-31
How to Cite
1.
Malvasio S, Camejo N, Di Matteo C, Caserta B, Artagaveytia N, Castillo C, Schiavone A, Notejane R, Alonso I, Delgado L. BRCA1 tumor expression and clinical results in uruguayan patients diagnosed with breast cancer before the age of 40 years old. Rev. Méd. Urug. [Internet]. 2020Mar.31 [cited 2024Nov.25];36(1):49-8. Available from: http://www2.rmu.org.uy/ojsrmu311/index.php/rmu/article/view/497
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