Adjuvant hormonal therapy is administered to all early stage ER+ breast cancers, and has led to significantly improved survival. Unfortunately, a subset of ER+ breast cancers suffer early relapse despite hormonal therapy. To identify molecular markers associated with early relapse in ER+ breast cancer, an outlier analysis method was applied to a published gene expression dataset of 268 ER+ early-stage breast cancers treated with tamoxifen alone. Increased expression of sets of genes that clustered in chromosomal locations consistent with the presence of amplicons at 8q24.3, 8p11.2, 17q12 (HER2 locus) and 17q21.33-q25.1 were each found to be independent markers for early disease recurrence. Distant metastasis free survival (DMFS) after 10 years for cases with any amplicon (DMFS = 56.1%, 95% CI = 48.3–63.9%) was significantly lower (P = 0.0016) than cases without any of the amplicons (DMFS = 87%, 95% CI = 76.3% –97.7%). The association between presence of chromosomal amplifications in these regions and poor outcome in ER+ breast cancers was independent of histologic grade and was confirmed in independent clinical datasets. A separate validation using a FISH-based assay to detect the amplicons at 8q24.3, 8p11.2, and 17q21.33-q25.1 in a set of 36 early stage ER+/HER2- breast cancers treated with tamoxifen suggests that the presence of these amplicons are indeed predictive of early recurrence. We conclude that these amplicons may serve as prognostic markers of early relapse in ER+ breast cancer, and may identify novel therapeutic targets for poor prognosis ER+ breast cancers.
References
[1]
Clarke M, Collins R, Davies C, Godwin J, Gray R, et al. (1998) Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351: 1451–1467.
[2]
Clarke M, Collins R, Darby S, Davies C, Evans V, et al. (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365: 1687–1717. doi. pp. 10.1016/S0140–6736(05)66544-0.
[3]
Hurvitz SA, Pietras RJ (2008) Rational management of endocrine resistance in breast cancer: a comprehensive review of estrogen receptor biology, treatment options, and future directions. Cancer 113: 2385–2397. doi:10.1002/cncr.23875.
[4]
Gnant M, Dubsky P, Fitzal F, Blaha P, Schoppmann S, et al. (2009) Maintaining bone density in patients undergoing treatment for breast cancer: is there an adjuvant benefit? Clin Breast Cancer 9 Suppl 1: S18–27. doi:10.3816/CBC.2009.s.002.
[5]
Rastelli F, Crispino S (2008) Factors predictive of response to hormone therapy in breast cancer. Tumori 94: 370–383.
[6]
Ma CX, Sanchez CG, Ellis MJ (2009) Predicting endocrine therapy responsiveness in breast cancer. Oncology (Williston Park, NY) 23: 133–142.
[7]
Paik S, Shak S, Tang G, Kim C, Baker J, et al. (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. The New England journal of medicine 351: 2817–2826. doi:10.1056/NEJMoa041588.
[8]
Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, et al. (2006) Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. Journal of the National Cancer Institute 98: 262–272. doi:10.1093/jnci/djj052.
[9]
Alexe G, Dalgin GS, Ramaswamy R, Delisi C, Bhanot G (2007) Data perturbation independent diagnosis and validation of breast cancer subtypes using clustering and patterns. Cancer informatics 2: 243–274.
[10]
Alexe G, Dalgin GS, Scanfeld D, Tamayo P, Mesirov JP, et al. (2007) High expression of lymphocyte-associated genes in node-negative HER2+ breast cancers correlates with lower recurrence rates. Cancer research 67: 10669-10676. doi. pp. 10.1158/0008–5472.CAN-07–0539.
[11]
Dalgin GS, Alexe G, Scanfeld D, Tamayo P, Mesirov JP, et al. (2007) Portraits of breast cancer progression. BMC bioinformatics 8: 291. doi. pp. 10.1186/1471–2105-8-291.
[12]
Loi S, Haibe-Kains B, Desmedt C, Lallemand F, Tutt AM, et al. (2007) Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 25: 1239–1246. doi:10.1200/JCO.2006.07.1522.
[13]
Cheang MCU, Chia SK, Voduc D, Gao D, Leung S, et al. (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. Journal of the National Cancer Institute 101: 736–750. doi:10.1093/jnci/djp082.
[14]
Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, et al. (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proceedings of the National Academy of Sciences of the United States of America 98: 10869–10874. doi:10.1073/pnas.191367098.
[15]
Osborne CK, Schiff R (2011) Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 62: 233–247. doi. pp. 10.1146/annurev–med-070909-182917.
[16]
Osborne CK, Shou J, Massarweh S, Schiff R (2005) Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res 11: 865s–70s.
[17]
Arpino G, Wiechmann L, Osborne CK, Schiff R (2008) Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocrine reviews 29: 217–233. doi. pp. 10.1210/er.2006–0045.
[18]
Arpino G, Green SJ, Allred DC, Lew D, Martino S, et al. (2004) HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a southwest oncology group study. Clinical cancer research: an official journal of the American Association for Cancer Research 10: 5670–5676. doi. pp. 10.1158/1078–0432.CCR-04-0110.
[19]
Naylor T, Greshock J, Wang Y, Colligon T, Yu QC, et al. (2005) High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization. Breast cancer research: BCR 7: R1186–98. doi:10.1186/bcr1356.
[20]
Naume B, Zhao X, Synnestvedt M, Borgen E, Russnes HG, et al. (2007) Presence of bone marrow micrometastasis is associated with different recurrence risk within molecular subtypes of breast cancer. Mol Oncol 1: 160–171. doi:10.1016/j.molonc.2007.03.004.
[21]
Loi S, Haibe-Kains B, Desmedt C, Wirapati P, Lallemand F, et al. (2008) Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen. BMC genomics 9: 239. doi. pp. 10.1186/1471–2164-9-239.
[22]
The Gene Ontology project in 2008 (2008) Nucleic acids research 36: D440–4.
[23]
Borg A, Baldetorp B, Fern？ M, Killander D, Olsson H, et al. (1994) ERBB2 amplification is associated with tamoxifen resistance in steroid-receptor positive breast cancer. Cancer letters 81: 137–144.
[24]
Kallioniemi A, Kallioniemi O-P, Piper J, Tanner M, Stokke T, et al. (1994) Detection and Mapping of Amplified DNA Sequences in Breast Cancer by Comparative Genomic Hybridization. Proceedings of the National Academy of Sciences of the United States of America 91: 2156–2160.
[25]
Parssinen J, Kuukasjarvi T, Karhu R, Kallioniemi A (2007) High-level amplification at 17q23 leads to coordinated overexpression of multiple adjacent genes in breast cancer. British Journal of Cancer 96: 1258–1264. doi:10.1038/sj.bjc.6603692.
[26]
Orsetti B, Courjal F, Cuny M, Rodriguez C, Theillet C (1999) 17q21-q25 aberrations in breast cancer: combined allelotyping and CGH analysis reveals 5 regions of allelic imbalance among which two correspond to DNA amplification. Oncogene 18: 6262–6270. doi:10.1038/sj.onc.1203006.
[27]
Gelsi-Boyer V, Orsetti B, Cervera N, Finetti P, Sircoulomb F, et al. (2005) Comprehensive profiling of 8p11-12 amplification in breast cancer. Molecular cancer research: MCR 3: 655–667. doi. pp. 10.1158/1541–7786.MCR-05-0128.
[28]
Cingoz S, Altungoz O, Canda T, Saydam S, Aksakoglu G, et al. (2003) DNA copy number changes detected by comparative genomic hybridization and their association with clinicopathologic parameters in breast tumors. Cancer genetics and cytogenetics 145: 108–114.
[29]
Bernard-Pierrot I, Gruel N, Stransky N, Vincent-Salomon A, Reyal F, et al. (2008) Characterization of the recurrent 8p11-12 amplicon identifies PPAPDC1B, a phosphatase protein, as a new therapeutic target in breast cancer. Cancer research 68: 7165-7175. doi. pp. 10.1158/0008–5472.CAN-08-1360.
[30]
Stec I, van Ommen GJ, den Dunnen JT (2001) WHSC1L1, on human chromosome 8p11.2, closely resembles WHSC1 and maps to a duplicated region shared with 4p16.3. Genomics 76: 5–8.
[31]
De Paepe P, Baens M, van Krieken H, Verhasselt B, Stul M, et al. (2003) ALK activation by the CLTC-ALK fusion is a recurrent event in large B-cell lymphoma. Blood 102: 2638–2641.
[32]
Argani P, Lui MY, Couturier J, Bouvier R, Fournet J-C, et al. (2003) A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23). Oncogene 22: 5374–5378.
[33]
Patel AS, Murphy KM, Hawkins AL, Cohen JS, Long PP, et al. (2007) RANBP2 and CLTC are involved in ALK rearrangements in inflammatory myofibroblastic tumors. Cancer genetics and cytogenetics 176: 107–114.
[34]
Dai C, Whitesell L, Rogers AB, Lindquist S (2007) Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130: 1005–1018.
[35]
Streicher KL, Yang ZQ, Ethier SP (2007) Transforming function of the LSM1 oncogene in human breast cancers with the 8p11–12 amplicon. Oncogene: 2104–2114. doi:10.1038/sj.onc.1210002.
[36]
Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, et al. (2010) FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer research 70: 2085-2094. doi. pp. 10.1158/0008–5472.CAN-09-3746.
[37]
Gy？rffy B, Sch？fer R (2008) Meta-analysis of gene expression profiles related to relapse-free survival in 1,079 breast cancer patients. Breast Cancer Res Treat 118: 433–441. doi. pp. 10.1007/s10549–008-0242-8.
[38]
Jonsson G, Staaf J, Vallon-Christersson J, Ringner M, Holm K, et al. (2010) Genomic subtypes of breast cancer identified by array comparative genomic hybridization display distinct molecular and clinical characteristics. Breast cancer research: BCR 12: R42. doi:10.1186/bcr2596.
[39]
Venkatraman ES, Olshen AB (2007) A faster circular binary segmentation algorithm for the analysis of array CGH data. Bioinformatics (Oxford, England) 23: 657–663. doi:10.1093/bioinformatics/btl646.
[40]
Beroukhim R, Getz G, Nghiemphu L, Barretina J, Hsueh T, et al. (2007) Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proceedings of the National Academy of Sciences of the United States of America 104: 20007–20012. doi:10.1073/pnas.0710052104.
[41]
Fan C, Oh DS, Wessels L, Weigelt B, Nuyten DSA, et al. (2006) Concordance among gene-expression-based predictors for breast cancer. N Engl J Med 355: 560–569. doi:10.1056/NEJMoa052933.
[42]
Singh L, Wilson AJ, Baum M, Whimster WF, Birch IH, et al. (1988) The relationship between histological grade, oestrogen receptor status, events and survival at 8 years in the NATO (‘Nolvadex’) trial. Br J Cancer 57: 612–614.
[43]
Lockwood WW, Chari R, Coe BP, Thu KL, Garnis C, et al. (2010) Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma. PLoS Med 7: e1000315. doi:10.1371/journal.pmed.1000315.
[44]
Butt AJ, McNeil CM, Musgrove EA, Sutherland RL (2005) Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E. Endocrine-related cancer 12: 47–59. doi:10.1677/erc.1.00993.
[45]
Frasor J, Chang EC, Komm B, Lin C-Y, Vega VB, et al. (2006) Gene Expression Preferentially Regulated by Tamoxifen in Breast Cancer Cells and Correlations with Clinical Outcome. Cancer Research 66: 7334–7340. doi. pp. 10.1158/0008–5472.CAN-05-4269.
[46]
Bergamaschi A, Christensen BL, Katzenellenbogen BS (2011) Reversal of endocrine resistance in breast cancer: interrelationships among 14-3-3ζ, FOXM1, and a gene signature associated with mitosis. Breast Cancer Res 13: R70. doi:10.1186/bcr2913.
[47]
He B, Feng Q, Mukherjee A, Lonard DM, DeMayo FJ, et al. (2008) A repressive role for prohibitin in estrogen signaling. Mol Endocrinol 22: 344–360. doi. pp. 10.1210/me.2007–0400.
[48]
Ishii Y, Waxman S, Germain D (2008) Tamoxifen Stimulates the Growth of Cyclin D1–Overexpressing Breast Cancer Cells by Promoting the Activation of Signal Transducer and Activator of Transcription 3. Cancer Research 68: 852–860. doi. pp. 10.1158/0008–5472.CAN-07-2879.
[49]
Karlsson E, Ahnstrom Waltersson M, Bostner J, Perez-Tenorio G, Olsson B, et al (2009) Comprehensive Genomic and Transcriptomic Analysis of the 11q13 Amplicon in Breast Cancer. Cancer Res 69: 5166. doi. pp. 10.1158/0008–5472.SABCS-09-5166.
[50]
Bautista S, Theillet C (1998) CCND1 and FGFR1 coamplification results in the colocalization of 11q13 and 8p12 sequences in breast tumor nuclei. Genes, chromosomes & cancer 22: 268–277.
[51]
Kwek SS, Roy R, Zhou H, Climent J, Martinez-Climent JA, et al. (2009) Co-amplified genes at 8p12 and 11q13 in breast tumors cooperate with two major pathways in oncogenesis. Oncogene 28: 1892–1903. doi:10.1038/onc.2009.34.
[52]
Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, et al. (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science (New York, NY) 310: 644–648. doi:10.1126/science.1117679.
[53]
Fisher RA (1922) On the Interpretation of χ2 from Contingency Tables, and the Calculation of P. Journal of the Royal Statistical Society 85: 87–94. doi:10.2307/2340521.
[54]
Benjamini Y, Hochberg Y (1995) Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society Series B (Methodological) 57: 289–300.
[55]
Wiedswang G, Borgen E, K？resen R, Kvalheim G, Nesland JM, et al. (2003) Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. J Clin Oncol 21: 3469–3478. doi:10.1200/JCO.2003.02.009.
