A Meta-Analysis of Gene Expression Profiling Studies Identifies Clinically Relevant Oncogenic Pathways in Basal-Like Breast Cancer.
Authors: M. Ignatiadis, P. Bedard, B. Haibe-Kains, B. Haibe-Kains, S. Singhal, S. Loi, C. Criscitiello, C. Desmedt, G. Bontempi, M. Piccart, M. Piccart, C. Sotiriou, C. Sotiriou
Journal: Cancer Research (2009)

Abstract Background: Basal-like breast cancer is characterized by an increased risk of early distant relapse.Adjuvant cytotoxic chemotherapy is the only treatment option available. Understanding the biological heterogeneity of basal-like breast cancer may lead to improved targeted therapies.Methods: 957 systemically untreated patients with early breast cancer were identified from 4 large publicly available datasets. Among these patients, 192 were basal-like according to the “intrinsic gene set” (Sorlie PNAS 2003) and 212 were ER-/HER2- according to “subtype clustering model” (Desmedt CCR 2008). We calculated the hazard ratio (HR) for distant metastasis-free survival for several published gene signatures and biologically relevant single genes.Results: There was a significant overlap between the two classifications, with 190 (99%) cases of basal-like breast cancers identified also as ER-/HER2- (p&amp;lt;0.001). Among the 192 patients with basal-like breast cancer, 62% were T1, 93% were node-negative, 87% were grade 3 tumors. At a median follow-up of 7.3-years, 31% experienced a distant relapse. First generation gene signatures were not prognostic in basal-like tumors.Summary of Univariate HRs for Distant Metastasis-Free Survival in basal-like breast cancer (N=192) HR (95% CI)P-valueFirst Generation Prognostic SignaturesONCOTYPE (Paik NEJM 2004)1.31 (0.43-3.95)0.6270-gene signature (Van't Veer Nature2002)1.81 (0.72-4.55)0.20GGI (Sotiriou JNCI 2006)0.89 (0.40-1.97)0.77Pathway Specific SignaturesSRC (Bild Nature 2006)0.60 (0.37-1.00)0.05RAS (Bild Nature 2006)0.88 (0.53-1.45)0.63MYC (Bild Nature 2006)1.07 (0.68-1.70)0.75E2F3 (Bild Nature 2006)1.46 (0.91-2.37)0.12Stroma (Farmer Nat Med 2009 )1.85 (1.08-3.21)0.03Immune Response (Teschendorff Genome Biol 2007)0.46 (0.28-0.75)&amp;lt;0.01IGF1 Pathway (Creighton JCO 2008)0.55 (0.29-1.03)0.06PI3K mutant-like (Loi AACR 2009)0.54 (0.28-1.02)0.06Androgen Pathway (Doane Oncogene 2006)1.11 (0.47-2.64)0.79BRCA1 mutant-like (Van't Veer Nature 2002)0.41 (0.21-0.82)0.01Single Gene ExpressionPARP1 mRNA0.87 (0.55-1.37)0.55c-KIT mRNA1.42 (0.91-2.25)0.12EGFR mRNA0.80 (0.41-1.58)0.53GRB7 mRNA (Sparano ASCO 2009)1.11 (0.52-2.39)0.78 An activated stroma signature was associated with a poorer prognosis, whereas signatures reflecting BRCA1 loss, enhanced immune response, down-regulation of mTOR signaling and an activated SRC pathway were all associated with better prognosis in basal-like tumors. Intriguingly, an activated IGF1 signaling, known to be associated with poorer prognosis in ER-positive tumors (Creighton JCO 2008), was associated with better prognosis in basal-like cancers particularly those with an activated androgen pathway signaling (HR 0.26, p&amp;lt;0.01).Conclusion: Nearly all genomically ER- /HER2- tumors are basal-like. Basal-like breast cancer is heterogeneous with distinct oncogenic pathways associated with long term outcome. Trials with novel agents in basal-like breast cancer should account for this biological heterogeneity. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 106.