Gene expression subtype and p53 mutational status are correlated among neoadjuvantly treated breast cancers in UNC LCCC9819 and I-SPY1 (CALGB 150007/ACRIN 6657)

Abstract

10048 Background: LCCC9819 and I-SPY1 are designed to examine multiple potential predictive markers and assays simultaneously in biopsies from neoadjuvantly treated patients. Both p53 mutation status and molecular ‘intrinsic‘ subtype have been associated with chemosensitivity. In this preliminary analysis, we present the p53 mutation spectra by molecular subtype from patients enrolled in the combined LCCC 9819 and I-SPY1 datasets. Methods: Patients received neoadjuvant anthracycline-based chemotherapy with pre-therapy biopsies. p53 mutation analysis was performed by p53 GeneChip assay for point mutations/1 bp deletions followed by SSCP if GeneChip-negative. Abnormal GeneChip or SSCP were confirmed by sequencing. DNA microarrays used Agilent human microarrays and a common reference strategy approach. Results: 51 patients were treated on LCCC9819 and have available molecular analyses; 87 from I-SPY1. 111 patients have completed p53 mutation analysis, revealing a high proportion (42%) with abnormal p53. Of these, several were in known hotspots, including R175H (4 mutations), R248L (1), R273H (3), and R273C (2). Most were missense mutations (81%), however, there were 8 (17%) null and 1 (2%) silent mutations. Most (91%) mutations were in the DNA binding domain. Molecular subtypes are known on 111 tumors: 22% Luminal A, 22% Luminal B, 3% Normal-like, 23% HER2+/ER−, 27% Basal-like, and 3% unclassified. Among those with both assays complete, we found that p53 mutations differed by subtype (Table). Conclusions: P53 mutations are common in these independent neoadjuvant datasets, and differ in frequency between molecular subtypes, which may have implications for predictive factor identification. Future analyses will include aCGH, cell cycle protein analysis, proteomics, and clinical data including response to chemotherapy. (supported by UNC Breast SPORE-CA58223, NIH M01RR00046, DAMD 17–02–1-0521). [Table: see text] No significant financial relationships to disclose.