Purpose: To identify proteomic and genomic alterations in residual disease (RD) for human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer (BC) after preoperative trastuzumab (H), lapatinib (L), or both (H+L) in combination with chemotherapy.
Patients and methods: Patients with stage II/III HER2+ BC (n = 100) were randomly assigned to preoperative treatment with H versus L 1,250mg versus H+L (L: 750 to 1,000 mg) plus 5-fluorouracil, epirubicin, and cyclophosphamide, followed by weekly paclitaxel. After receiving institutional review board-approved informed consent, targeted next-generation sequencing was performed on 20 patients' formalin-fixed paraffin embedded tumors to characterize genomic alterations across 287 cancer-related genes. Reverse phase protein array (RPPA) analysis was performed on both the baseline biopsy and RD specimens, when available.
Results: Two of 20 RD tissues were HER2 negative per next-generation sequencing; one sample had insufficient tissue. Of six pretreatment biopsy specimens, four were comutated with TP53 and PIK3CA. Of 17 HER2+ RD, seven specimens (41%) had PIK3CA mutations always comutated with TP53, and four (24%) also had concurrent CDK12 amplification. Overall, CDK12 amplification was observed in eight of the 17 (47%) HER2+ RD specimens. A total of 12 RD specimens (71%) had TP53 mutations. Although prevalence of individual TP53 and PIK3CA mutations was only modestly higher than published estimates for those in HER2+ primary BCs (55% and 32% for TP53 and PIK3CA, respectively), prevalence of these as comutations appeared higher (41%), compared with less than 10% in several series. On RPPA analysis of the RD tissue with comutations, the strongest Spearman ρ correlations were limited to EGFR and phospho-AKT (ρ, 0.999; P = .019) and phospho-mTOR and phospho-S6 ribosomal protein (ρ, 0.994; P = .048).
Conclusion: HER2-amplified RD tissue after preoperative H, L, or H+L plus chemotherapy was enriched for PIK3CA and TP53 comutations, and the RD tissue demonstrated activation of EGFR/AKT/mTOR signaling on RPPA.