Abstract P3-06-22: Mechanisms behind trastuzumab resistance as neoadjuvant therapy in HER2-positive operable breast cancer

Abstract

Background: The development of trastuzumab has had a major impact in treatment of breast cancer patients with HER2 overexpression. Despite clinical usefulness, intrinsic or acquired resistance to trastuzumab is a common clinical phenomenon. However, the mechanisms of resistance to trastuzumab have not been fully elucidated. Potential mechanisms include aberrant downstream signaling caused by loss of PTEN and/or PIK3CA mutation, alternative signaling from IGF-1R and masking with MUC4. 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. Patients & methods: Patients with operable breast cancer received 12 cycles of weekly paclitaxel (80 mg/m2 IV) plus weekly trastuzumab (4mg/kg loading dose followed by 2 mg/kg IV) for 12 weeks 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. ER and PgR status was assessed using Allred score. For Ki67 labeling index, a total of 400 cells were counted from three consecutive high-power magnifications. PTEN, pIGF-1R and MUC4 expression level was scored semiquantitatively based on staining intensity. PIK3CA mutation status was evaluated by sequencing of PIK3CA exons 9 and 20 using PCR amplification and direct sequencing. pCR was defined as no residual invasive carcinoma in the breast. Results: Thirty-seven patients were enrolled and assessable for clinical and pathologic responses. ER and PgR were positive in 18 (48.6%) and 16 (43.2%) patients, respectively. The overall response rate was 86.5%, including a complete response in 21 patients and a partial response in 11 patients. 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 and pIGF1-R status did not affect the pCR rate. PTEN loss and/or PIK3CA mutation were not significantly associated with pCR rate. pCR rate was significantly correlated with PgR negativity (p = 0.004) and higher Ki67 (p = 0.01). 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. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-22.