168 Background: Despite clinical usefulness of trastuzumab, intrinsic or acquired resistance to trastuzumab is a common clinical phenomenon. However, the mechanisms of resistance to trastuzumab have not been fully elucidated. The objective of this study was to determine the possible mechanisms of resistance to trastuzumab as neoadjuvant therapy in women with HER2-overexpressing operable breast cancer. Methods: Patients with operable breast cancer received 12 cycles of weekly paclitaxel plus weekly trastuzumab before surgery. All tumors were HER2-positive by immunohistochemistry (IHC) or fluorescence in situ hybridization. Expressions of ER, PgR, Ki67, PTEN, phosphorylated IGF-1R (pIGF-1R) and MUC4 were performed by IHC in core needle biopsy samples at baseline. PIK3CA mutation status was evaluated by sequencing of PIK3CA exons 9 and 20 using PCR amplification and direct sequencing. Results: Thirty-seven patients were enrolled and assessable for clinical and pathologic responses. The pCR rate was 48.6% (18/37). Negative, moderate and strong membranous expression of MUC4 was observed in 3 (8.1%), 18 (48.6%) and 12 (32.4%) patients, respectively. Membranous staining for pIGF1-R was negative in 24 (64.9%) patients. PTEN loss was observed in 33.3% (8/24) of the tumor examined. PIK3CA sequence analysis of the 13 tumors identified 2 mutations in exon 20 and 2 mutations in exon 9, corresponding to a PIK3CA mutation frequency of 30.8%. MUC4 status did not affect the pCR rate. Although membranous pIGF1-R expression did not affect pCR rate in hormone receptor-positive patients (66.7% vs. 50.0%), hormone receptor-positive patients with positive membranous pIGF1-R tended to show higher pCR rate compared with negative pIGF1-R (41.2% vs. 0%). PTEN loss and/or PIK3CA mutation were not significantly associated with pCR rate. Conclusions: These data indicate that aberrant downstream signaling caused by loss of PTEN and/or PIK3CA mutation, alternative signaling from IGF-1R and masking with MUC4 were not important mechanisms of resistance to trastuzumab.
Chemotherapy and Mechanisms of Resistance in Breast Cancer
