p53 Mutation Correlates with Molecular Profile and Outperforms p53 Immunohistochemistry (IHC) in Predicting Response to Neo-Adjuvant Chemotherapy in Operable Early Stage Breast Cancer (ESBC)
JS Ross, CM Perou, E Slodkowska, MS Ross, AB Boguniewicz, EF McKenna, HJ Lawrence, M Royce, S Gluck. Albany Medical College, Albany, NY; U North Carolina, Chapel Hill, NC; XeNa Trialists and Roche Molecular Systems, Pleasanton, CA; U New Mexico, Albuquerque, NM; Miami U, Miami, FL
Background: The XeNa Phase II muticenter trial of neoadjuvant capecitabine, docetaxel +/- trastuzumab enrolled 157 patients with ESBC (T2-T3, N0-N1). The primary endpoint was the rate of pathologic complete response (pCR) and near-complete response (npCR). A secondary endpoint was to evaluate the association between p53 alterations with standard biomarkers, molecular profiling and response to chemotherapy.
Design: p53 mutation status was determined by a microarray-based resequencing assay (ACHIP) (AmpliChip p53 Roche Molecular Systems, Pleasanton, CA); and by standard IHC staining for p53 protein using the Bp-53-11 antibody (Ventana, Tucson, AZ). Gene expression profiling for breast cancer subtypes was performed using a new 50-gene centroid-based method (PAM50).
Results: 78/157 (50%) of cases had p53 mutations (70% missense, 17% nonsense, 11% frame shift and 1% splice site). In 78/120 (65%) cases IHC was concordant with ACHIP. IHC was negative in 16/60 samples (27%) which had ACHIP mutations with 10/16 (63%) featuring non-missense mutations likely to result in no detectable p53 protein. IHC was positive in 26/60 cases (43%) which were ACHIP wild type. P53 mutations were highest in Basal-like (75%) and HER2-enriched (57%) molecular subtypes. P53 IHC varied little with molecular subtypes (35 to 50%) and did not correlate with ACHIP status. The rate of pCR and npCR was significantly higher in cases with ACHIP p53 mutations (20/58 - 35%) than in cases without mutations (7/52 - 13%; p = 0.014; 2-tailed Fisher's Exact Test), and this was apparent in both HER2+ and HER2- cases. IHC results did not predict treatment response (18% pCR and npCR in IHC-negative cases vs. 27% in IHC-positive cases; p = 0.35). PAM50 expression subtype (p<0.001), ER- (p=0.0001) and HER2+ (p=0.0004) status also predicted for pCR and npCR.
Conclusions: P53 mutations are frequent in Basal-like and HER2-enriched subtypes and predict pCR and npCR for this regimen. IHC lacks sensitivity and specificity for p53 mutations and does not predict therapy response. In addition to ER-/HER2+ status, the new PAM50 expression profiling subtypes correlated with p53 mutation status and also predicted therapy response.
Wednesday, March 11, 2009 1:00 PM
Poster Session VI # 17, Wednesday Afternoon