P3-05-01: Gene Profiling of Histopathologically Characterized Apocrine Breast Cancers

Background Breast cancer is currently classified in 3 groups based on estrogen receptor alpha (ER) and human epidermal growth factor receptor 2 (HER2/ERBB2) gene expression: one basal-like (ER-ERBB2-), one HER2−enriched (ERBB2+) and one luminal (ER+). Yet, in transcriptome-based classifications, ER-ERBB2+ group partially overlaps with more recently defined ER-AR+ (androgen receptor positive) group. This type was named molecular apocrine, in reference to the histopathologically characterized apocrine carcinomas (H-Apo), in which a marked activation of AR signaling was demonstrated with a distinct proteomic signature. H-Apo tumors correspond to 1% of invasive breast carcinomas and are clearly morphological distinct from other AR+ tumors. However, no specific H-Apo transcriptome signature has been reported for this sub-group. In an effort to better characterize those tumors, we have performed a meta-analysis of genomic data, focusing on the ER- AR+ breast subset. Samples and Methods: Chips were from Affymetrix array generations HG-U133. 258 profiles were unpublished and 1145 were from published or in press data. Gene expression was carried out after GC-RMA normalization. Unsupervised hierarchical clustering and other statistical analysis were performed with R software. Results: 160 of the 1403 investigated tumors were ER-AR+. An unsupervised hierarchical clustering clearly identified a small subgroup of 14 closely tumors expressing high transcripts levels of PIP, HPGD, ACSM1, AR, SDR5A1, HS3DB1. This profile was very similar to the proteomic signature previously described for the H-Apo tumors. In addition, the pathology report, although available only for 4 of those14 tumors, described them as typical apocrine carcinomas. Taken together, these data suggested that this cluster was the H-Apo subgroup. Unexpectedly, when using the transcriptomic PAM50 classification, 13 were classified as Luminal and only 1 as HER2−enriched, although the 14 tumors were all ER-negative. CGH analysis with Agilent 244K chips was carried out with 25 ER- AR+ tumors, of which 5 were H-Apo carcinomas. Importantly, those 5 H-Apo tumors exhibited fewer DNA lesions than the other ER-AR+ apocrine tumors (17% copy number alterations in H-Apo group versus 41%, p=0.02). More CGH data are currently under investigations and will be discussed. Discussion: The histopathologically characterized apocrine carcinomas (H-Apo) display transcriptomic signs of active androgen metabolism and fewer DNA lesions than others molecular apocrine tumors. This could suggest that molecular apocrine and H-apocrine tumor derive from the same cell of origin, but that only H-Apo retains morphological apocrine features, possibly due to the presence of fewer genetic lesions. In any case, the prominent androgen signaling activation warrants functional assays of anti-androgen in these breast cancer subtypes. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-05-01.