Authors
Sierra Mi Li
City of Hope, Duarte, CA
Sierra Mi Li , Xiwei Wu , Paul Henry Frankel , Harry Gao , Guihua Sun , Femke De Snoo , John Rossi , Emily Wang , Paul Roepman , Yun Yen , Justine Peeters , Lisette Stork , George Somlo
Organizations
City of Hope, Duarte, CA, Agendia NV, Amsterdam, Netherlands
Research Funding
Pharmaceutical/Biotech Company
Background: GEP may predict for pathologic complete response (pCR). Correlation between miRs, GEP, and pCR may reveal novel targets. Methods: Patients (pts) with HER2- BC were randomized to receive docetaxel, doxorubicin, cyclophosphamide (TAC, arm A) or A and C given every 2 weeks x 4, followed by carboplatin and nab-paclitaxel (arm B). Pts with HER2+ BC received NT per arm B, with trastuzumab added (arm C). Core biopsies were snap-frozen prior to NT, and RNA extracted for gene array analysis (Agilent 44K microarray) and deep sequence miRNA analysis (Solexa/Illumina platform). HER2 testing by IHC [3+] or FISH and/or gene array was carried out (Blueprint). MiRs were measured in 72 of 119 enrolled pts. Of 882 miRNAs reported by Solexa sequencing, 487 were assessed (observed at raw counts > 10 in at least 3 pts). TargetScan was used to obtain miRNA targets and negative correlation between miR and mRNA expression was applied. Results: In 44 HER2- cases, we found 17 miRs differentially expressed between pts who achieved pCR vs. pts who did not (< pCR), 13 with predicted targets by TargetScan (TS). We found 28 canonical pathways (including Embryonic Cell, EGF signaling, Estrogen-dependent signaling) affected by the identified miRs, and inclusive of 74 target mRNAs identified (Agilent) and correlating with pCR. The top overexpressed miRs are 31 [gene targets: FZD4]; 18a [IGF1, ALDH5A1]; 19a [PIK3R, IGF1]) and 3 lowest expressors are miR-190b [MMP1]; 29c [FOS, WNT5B]; 342-3p [BMP7]. Among the 28 HER2+ cases there were 14 miRNAs differentially expressed between BCs with pCR vs <pCR, and 8 had predicted targets from TS. We found 10 canonical pathways (including p53, HER-2, PTEN) affected by miRs, which included 44 target mRNAs (Agilent) correlating with pCR. The most overexpressed miRs are miR-708 [gene target: RRM2B; 193a-p5 [BMPR1B, RPRM] ; 92b [CCNE2, DKK2]. The lowest expressors are: miR-30a [FZD1, SMAD1, TP63]; miR-450-5p [FOXO1, WINT5A, ERBB2]; miR-497 [PIK3R1, FGFR1, FOXO1]. Conclusions: Combined assessment of miRNA and gene expression patterns is feasible, and may yield information leading to individualized and improved NT.