Androgen receptor, EGFR, and BRCA1 as biomarkers in triple-negative breast cancer: a meta-analysis

Li Zhang, Cheng Fang, Xianqun Xu, Anling Li, Qing Cai, Xinghua Long, Li Zhang, Cheng Fang, Xianqun Xu, Anling Li, Qing Cai, Xinghua Long

Abstract

Objective: More and more evidences demonstrate that androgen receptor (AR), epidermal growth factor receptor (EGFR), and breast cancer susceptibility gene 1 (BRCA1) have unique clinical implications for targeted therapy or prognosis in triple-negative breast cancer (TNBC). Therefore, we conducted a meta-analysis to summarize the possible associations.

Methods: We retrieved published articles about AR, EGFR, and BRCA1 in TNBC from PubMed and EMBASE. The analysis was performed with Rev-Man 5.2 software.

Results: A total of 38 articles were eligible for the meta-analysis. Our study showed that the expression level of EGFR (OR = 6.88, P < 0.00001) and the prevalence of BRCA1 mutation (RR = 5.26, P < 0.00001) were higher in TNBC than non-TNBC. In contrast, the expression level of AR was lower in TNBC than non-TNBC (OR = 0.07, P < 0.00001). In the subgroup related to EGFR expression, the level of EGFR expression was significantly increased in Asians (OR = 9.60) compared with Caucasians (OR = 5.53) for TNBC patients. Additionally, the prevalence of BRCA1 mutation in Asians (RR = 5.43, P < 0.00001) was higher than that in Caucasians (RR = 5.16, P < 0.00001).

Conclusions: The distinct expression of AR and EGFR and the prevalence of BRCA1 mutation indicated that AR, EGFR, and BRCA1 might be unique biomarkers for targeted therapy and prognosis in TNBC.

Figures

Figure 1
Figure 1
Flow diagram of the study.
Figure 2
Figure 2
Forest plot of studies evaluating OR of AR expression in TNBC compared with non-TNBC. The events of TNBC and the events of non-TNBC refer to the number of TNBC patients with positive expression of AR and the number of non-TNBC patients with positive expression of AR, respectively. The squares and horizontal lines correspond to the specific OR and 95% CI for every study. The area of the squares reflects the study specific weight. The diamond stands for the pooled OR and 95% CI.
Figure 3
Figure 3
Forest plot of studies evaluating OR of EGFR expression in TNBC compared with non-TNBC. The events of TNBC and the events of non-TNBC refer to the number of TNBC patients with positive expression of EGFR and the number of non-TNBC patients with positive expression of EGFR, respectively. The squares and horizontal lines correspond to the specific OR and 95% CI for every study. The area of the squares reflects the study specific weight. The diamond stands for the pooled OR and 95% CI.
Figure 4
Figure 4
Forest plot of subgroup related to antibody source evaluating EGFR expression in TNBC compared with non-TNBC.
Figure 5
Figure 5
Forest plot of studies evaluating RR of BRCA1 mutation in TNBC compared with non-TNBC. The events of TNBC and the events of non-TNBC refer to the number of TNBC patients with BRCA1 mutation and the number of non-TNBC patients with BRCA1 mutation, respectively. The squares and horizontal lines correspond to the specific RR and 95% CI for every study. The area of the squares reflects the study specific weight. The diamond stands for the pooled RR and 95% CI.
Figure 6
Figure 6
Forest plot of the subgroup related to race evaluating RR of BRCA1 mutation in TNBC compared with non-TNBC.
Figure 7
Figure 7
Funnel plots for evaluating publication bias for the eligible articles about AR (a), EGFR (b), and BRCA1 (c). As shown in the figures, the funnel plots were almost symmetric and no evidence of publication bias was observed in this analysis.

References

    1. Rakha E. A., El-Sayed M. E., Green A. R., Lee A. H. S., Robertson J. F., Ellis I. O. Prognostic markers in triple-negative breast cancer. Cancer. 2007;109(1):25–32. doi: 10.1002/cncr.22381.
    1. Corkery B., Crown J., Clynes M., O'Donovan N. Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer. Annals of Oncology. 2009;20(5):862–867. doi: 10.1093/annonc/mdn710.
    1. Haffty B. G., Yang Q., Reiss M., et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. Journal of Clinical Oncology. 2006;24(36):5652–5657. doi: 10.1200/JCO.2006.06.5664.
    1. Lehmann B. D., Bauer J. A., Chen X., et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. The Journal of Clinical Investigation. 2011;121(7):2750–2767. doi: 10.1172/JCI45014.
    1. Steward L., Conant L., Gao F., Margenthaler J. A. Predictive factors and patterns of recurrence in patients with triple negative breast cancer. Annals of Surgical Oncology. 2014;21(7):2165–2171. doi: 10.1245/s10434-014-3546-4.
    1. Park J. J., Irvine R. A., Buchanan G., et al. Breast cancer susceptibility gene 1 (BRCA1) is a coactivator of the androgen receptor. Cancer Research. 2000;60(21):5946–5949.
    1. Cuenca-López M. D., Montero J. C., Morales J. C., Prat A., Pandiella A., Ocana A. Phospho-kinase profile of triple negative breast cancer and androgen receptor signaling. BMC Cancer. 2014;14(1):302–311. doi: 10.1186/1471-2407-14-302.
    1. Pristauz G., Petru E., Stacher E., et al. Androgen receptor expression in breast cancer patients tested for BRCA1 and BRCA2 mutations. Histopathology. 2010;57(6):877–884. doi: 10.1111/j.1365-2559.2010.03724.x.
    1. Gucalp A., Traina T. A. Triple-negative breast cancer: role of the androgen receptor. Cancer Journal. 2010;16(1):62–65. doi: 10.1097/PPO.0b013e3181ce4ae1.
    1. Gasparini P., Fassan M., Gascione L., et al. Androgen receptor status is a prognostic marker in non-basal triple negative breast cancers and determines novel therapeutic options. PLOS ONE. 2014;9(2) doi: 10.1371/journal.pone.0088525.e88525
    1. Mrklić I., Pogorelić Z., Ćapkun V., Tomić S. Expression of androgen receptors in triple negative breast carcinomas. Acta Histochemica. 2013;115(4):344–348. doi: 10.1016/j.acthis.2012.09.006.
    1. Sutton L. M., Cao D., Sarode V., et al. Decreased androgen receptor expression is associated with distant metastases in patients with androgen receptor-expressing triple-negative breast carcinoma. The American Journal of Clinical Pathology. 2012;138(4):511–516. doi: 10.1309/AJCP8AVF8FDPTZLH.
    1. Tang D., Xu S., Zhang Q., Zhao W. The expression and clinical significance of the androgen receptor and E-cadherin in triple-negative breast cancer. Medical Oncology. 2012;29(2):526–533. doi: 10.1007/s12032-011-9948-2.
    1. Tang Y., Zhu L., Li Y., et al. Overexpression of epithelial growth factor receptor (EGFR) predicts better response to neo-adjuvant chemotherapy in patients with triple-negative breast cancer. Journal of Translational Medicine. 2012;10(supplement 1, article S4)
    1. Guillamo J.-S., de Boüard S., Valable S., et al. Molecular mechanisms underlying effects of epidermal growth factor receptor inhibition on invasion, proliferation, and angiogenesis in experimental glioma. Clinical Cancer Research. 2009;15(11):3697–3704. doi: 10.1158/1078-0432.CCR-08-2042.
    1. Venkitaraman A. R. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108(2):171–182. doi: 10.1016/S0092-8674(02)00615-3.
    1. Reis-Filho J. S., Tutt A. N. Triple negative tumours: a critical review. Histopathology. 2008;52(1):108–118. doi: 10.1111/j.1365-2559.2007.02889.x.
    1. Atchley D. P., Albarracin C. T., Lopez A., et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. Journal of Clinical Oncology. 2008;26(26):4282–4288. doi: 10.1200/JCO.2008.16.6231.
    1. Musolino A., Bella M. A., Bortesi B., et al. BRCA mutations, molecular markers, and clinical variables in early-onset breast cancer: a population-based study. Breast. 2007;16(3):280–292. doi: 10.1016/j.breast.2006.12.003.
    1. Li W.-F., Hu Z., Rao N.-Y., et al. The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality: two recurrent mutations were identified. Breast Cancer Research and Treatment. 2008;110(1):99–109. doi: 10.1007/s10549-007-9708-3.
    1. Byrski T., Gronwald J., Huzarski T., et al. Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers. Breast Cancer Research and Treatment. 2008;108(2):289–296. doi: 10.1007/s10549-007-9600-1.
    1. Chae B. J., Lee A., Bae J. S., Song B. J., Jung S. S. Expression of nuclear receptor DAX-1 and androgen receptor in human breast cancer. Journal of Surgical Oncology. 2011;103(8):768–772. doi: 10.1002/jso.21861.
    1. Hu R., Dawood S., Holmes M. D., et al. Androgen receptor expression and breast cancer survival in postmenopausal women. Clinical Cancer Research. 2011;17(7):1867–1874. doi: 10.1158/1078-0432.CCR-10-2021.
    1. Koo J. S., Jung W. Clinicopathlogic and immunohistochemical characteristics of triple negative invasive lobular carcinoma. Yonsei Medical Journal. 2011;52(1):89–97. doi: 10.3349/ymj.2011.52.1.89.
    1. Luo X., Shi Y.-X., Li Z.-M., Jiang W.-Q. Expression and clinical significance of androgen receptor in triple negative breast cancer. Chinese Journal of Cancer. 2010;29(6):585–590. doi: 10.5732/cjc.009.10673.
    1. Loibl S., Müller B. M., von Minckwitz G., et al. Androgen receptor expression in primary breast cancer and its predictive and prognostic value in patients treated with neoadjuvant chemotherapy. Breast Cancer Research and Treatment. 2011;130(2):477–487. doi: 10.1007/s10549-011-1715-8.
    1. Micello D., Marando A., Sahnane N., Riva C., Capella C., Sessa F. Androgen receptor is frequently expressed in HER2-positive, ER/PR-negative breast cancers. Virchows Archiv. 2010;457(4):467–476. doi: 10.1007/s00428-010-0964-y.
    1. Niemeier L. A., Dabbs D. J., Beriwal S., Striebel J. M., Bhargava R. Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Modern Pathology. 2010;23(2):205–212. doi: 10.1038/modpathol.2009.159.
    1. Ogawa Y., Hai E., Matsumoto K., et al. Androgen receptor expression in breast cancer: relationship with clinicopathological factors and biomarkers. International Journal of Clinical Oncology. 2008;13(5):431–435. doi: 10.1007/s10147-008-0770-6.
    1. Park S., Koo J., Park H. S., et al. Expression of androgen receptors in primary breast cancer. Annals of Oncology. 2009;21(3):488–492. doi: 10.1093/annonc/mdp510.
    1. Park S., Koo J. S., Kim M. S., et al. Androgen receptor expression is significantly associated with better outcomes in estrogen receptor-positive breast cancers. Annals of Oncology. 2011;22(8):1755–1762. doi: 10.1093/annonc/mdq678.
    1. Peters K. M., Edwards S. L., Nair S. S., et al. Androgen receptor expression predicts breast cancer survival: the role of genetic and epigenetic events. BMC Cancer. 2012;12:132–141. doi: 10.1186/1471-2407-12-132.
    1. Nogi H., Kobayashi T., Suzuki M., et al. EGFR as paradoxical predictor of chemosensitivity and outcome among triple-negative breast cancer. Oncology Reports. 2009;21(2):413–417. doi: 10.3892/or_00000238.
    1. Nozoe T., Mori E., Iguchi T., et al. Immunohistochemical expression of epidermal growth factor receptor in breast cancer. Breast Cancer. 2011;18(1):37–41. doi: 10.1007/s12282-010-0200-2.
    1. Pillai S. K. K., Tay A., Nair S., Leong C.-O. Triple-negative breast cancer is associated with EGFR, CK5/6 and c-KIT expression in Malaysian women. BMC Clinical Pathology. 2012;12, article 18 doi: 10.1186/1472-6890-12-18.
    1. Rydén L., Jirstrom K., Haglund M., Stal O., Fernö M. Epidermal growth factor receptor and vascular endothelial growth factor receptor 2 are specific biomarkers in triple-negative breast cancer. Results from a controlled randomized trial with long-term follow-up. Breast Cancer Research and Treatment. 2010;120(2):491–498. doi: 10.1007/s10549-010-0758-6.
    1. Tan D. S. P., Marchió C., Jones R. L., et al. Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients. Breast Cancer Research and Treatment. 2008;111(1):27–44. doi: 10.1007/s10549-007-9756-8.
    1. Tawfik O., Davis K., Kimler B. F., et al. Clinicopathological characteristics of triple-negative invasive mammary carcinomas in African-American versus Caucasian women. Annals of Clinical and Laboratory Science. 2010;40(4):315–323.
    1. Bayraktar S., Gutierrez-Barrera A. M., Lin H., et al. Outcome of metastatic breast cancer in selected women with or without deleterious BRCA mutations. Clinical and Experimental Metastasis. 2013;30(5):631–642. doi: 10.1007/s10585-013-9567-8.
    1. Chen W., Pan K., Ouyang T., et al. BRCA1 germline mutations and tumor characteristics in Chinese women with familial or early-onset breast cancer. Breast Cancer Research and Treatment. 2009;117(1):55–60. doi: 10.1007/s10549-008-0066-6.
    1. Comen E., Davids M., Kirchhoff T., Hudis C., Offit K., Robson M. Relative contributions of BRCA1 and BRCA2 mutations to “triple-negative” breast cancer in Ashkenazi Women. Breast Cancer Research and Treatment. 2011;129(1):185–190. doi: 10.1007/s10549-011-1433-2.
    1. Kwong A., Wong L. P., Wong H. N., et al. Clinical and pathological characteristics of Chinese patients with BRCA related breast cancer. The HUGO Journal. 2009;3(1):63–76. doi: 10.1007/s11568-010-9136-z.
    1. Lee E., McKean-Cowdin R., Ma H., et al. Characteristics of triple-negative breast cancer in patients with a BRCA1 mutation: results from a population-based study of young women. Journal of Clinical Oncology. 2011;29(33):4373–4380. doi: 10.1200/JCO.2010.33.6446.
    1. Noh J. M., Han B.-K., Choi D. H., et al. Association between BRCA mutation status, pathological findings, and magnetic resonance imaging features in patients with breast cancer at risk for the mutation. Journal of Breast Cancer. 2013;16(3):308–314. doi: 10.4048/jbc.2013.16.3.308.
    1. Ou J., Wu T., Sijmons R., Ni D., Xu W., Upur H. Prevalence of BRCA1 and BRCA2 germline mutations in breast cancer women of multiple ethnic region in Northwest China. Journal of Breast Cancer. 2013;16(1):50–54. doi: 10.4048/jbc.2013.16.1.50.
    1. Phuah S.-Y., Looi L.-M., Hassan N., et al. Triple-negative breast cancer and PTEN (phosphatase and tensin homologue)loss are predictors of BRCA1 germline mutations in women with early-onset and familial breast cancer, but not in women with isolated late-onset breast cancer. Breast Cancer Research. 2012;14(6, article R142) doi: 10.1186/bcr3347.
    1. Xu J., Wang B., Zhang Y., Li R., Wang Y., Zhang S. Clinical implications for BRCA gene mutation in breast cancer. Molecular Biology Reports. 2012;39(3):3097–3102. doi: 10.1007/s11033-011-1073-y.
    1. Yip C.-H., Taib N. A., Choo W. Y., Rampal S., Thong M. K., Teo S. H. Clinical and pathologic differences between BRCA1-, BRCA2-, and non-BRCA-associated breast cancers in a multiracial developing country. World Journal of Surgery. 2009;33(10):2077–2081. doi: 10.1007/s00268-009-0146-8.
    1. Zhang J., Pei R., Pang Z., et al. Prevalence and characterization of BRCA1 and BRCA2 germline mutations in Chinese women with familial breast cancer. Breast Cancer Research and Treatment. 2012;132(2):421–428. doi: 10.1007/s10549-011-1596-x.
    1. Rakha E. A., Elsheikh S. E., Aleskandarany M. A., et al. Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clinical Cancer Research. 2009;15(7):2302–2310. doi: 10.1158/1078-0432.CCR-08-2132.
    1. Higgins J. P. T., Thompson S. G. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine. 2002;21(11):1539–1558. doi: 10.1002/sim.1186.
    1. Higgins J. P. T., Thompson S. G., Deeks J. J., Altman D. G. Measuring inconsistency in meta-analyses. British Medical Journal. 2003;327(7414):557–560. doi: 10.1136/bmj.327.7414.557.
    1. Siroy A., Abdul-Karim F. W., Miedler J., et al. MUC1 is expressed at high frequency in early-stage basal-like triple negative breast cancer. Human Pathology. 2013;44(10):2159–2166. doi: 10.1016/j.humpath.2013.04.010.
    1. Gluz O., Liedtke C., Gottschalk N., Pusztai L., Nitz U., Harbeck N. Triple-negative breast cancer: current status and future directions. Annals of Oncology. 2009;20(12):1913–1927. doi: 10.1093/annonc/mdp492.
    1. Cameron D., Brown J., Dent R., et al. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. The Lancet Oncology. 2013;14(10):933–942. doi: 10.1016/S1470-2045(13)70335-8.
    1. Zhang Z., Wang J., Tacha D. E., et al. Folate receptor α associate with triple-negative breast cancer and poor prognosis. Archives of Pathology & Laboratory Medicine. 2014;138(7):890–895.
    1. Singh J. C., Novik Y., Stein S., et al. Phase 2 trial of everolimus and carboplatin combination in patients with triple negative metastatic breast cancer. Breast Cancer Research. 2014;16(2, article R32) doi: 10.1186/bcr3634.
    1. Ha K., Fiskus W., Choi D. S., et al. Histone deacetylase inhibitor treatment induces “BRCAness” and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells. Oncotarget. 2014;5(14):5637–5650.

Source: PubMed

3
S'abonner