ERBB2 and PTPN2 g ene copy numbers as prognostic factors in HER2-positive metastatic breast cancer treated with trastuzumab

Abstract

Trastuzumab has markedly improved the treatment and long-term prognosis of patients with HER2-positive breast cancer. A frequent clinical challenge in patients with relapsing and/or metastatic disease is de novo or acquired trastuzumab resistance, and to date no predictive biomarkers for palliative trastuzumab have been established. In the present study, the prognostic values of factors involved in the HER2-associated PI3K/Akt signalling pathway were explored. The first 46 consecutive patients treated at the Department of Oncology, Linköping University Hospital between 2000 and 2007 with trastuzumab for HER2-positive metastatic breast cancer were retrospectively included. The gene copy number variation and protein expression of several components of the PI3K/Akt pathway were assessed in the tumour tissue and biopsy samples using droplet digital polymerase chain reaction and immunohistochemistry. Patients with tumours displaying a high-grade ERBB2 (HER2) amplification level of ≥6 copies had a significantly improved overall survival hazard ratio [(HR)=0.4; 95%, confidence interval (CI): 0.2-0.9] and progression-free survival (HR=0.3; 95% CI: 0.1-0.7) compared with patients with tumours harbouring fewer ERBB2 copies. High-grade ERBB2 amplification was significantly associated with the development of central nervous system metastases during palliative treatment. Copy gain (≥3 copies) of the gene encoding the tyrosine phosphatase PTPN2 was associated with a shorter overall survival (HR=2.0; 95% CI: 1.0-4.0) and shorter progression-free survival (HR=2.1; 95% CI: 1.0-4.1). In conclusion, high ERBB2 amplification level is a potential positive prognostic factor in trastuzumab-treated HER2-positive metastatic breast cancer, whereas PTPN2 gain is a potential negative prognostic factor. Further studies are warranted on the role of PTPN2 in HER2 signalling.

Keywords: HER2; PI3K; brain metastasis; phosphatase and tensin homolog; protein tyrosine phosphatase non-receptor type 2; ribosomal protein S6 kinase B1.

Figure 1.

Results of the ddPCR analysis for all patients and their distribution. Gene copy number status loss, normal and gain were defined using this distribution bearing in mind a small skewness towards two gene copies due to any non-tumour cells in the sample. (A) PTPN2, (B) MET, (C) CCND1 and (D) RPSKB1.

Figure 2.

Kaplan-Meier curves based on overall survival and progression-free survival. (A) OS for all patients (n=46). (B) PFS for all patients (n=46). (C) OS characterised by low-grade and high-grade ERBB2 amplification. (D) PFS characterised by low-grade and high-grade ERBB2 amplification. (E) OS characterised by PTPN2 gene copy number. (F) PFS characterised by PTPN2 gene copy number.

Figure 3.

Kaplan-Meier curves based on overall survival and progression-free survival in regards to combined protein and GCN PTPN2 status. (A) OS characterised by PTPN2 status. (B) PFS characterised by PTPN2 status. In A and B low PTPN2 status is defined as no PTPN2 gain and low PTPN2 protein expression in IHC (n=9), mixed PTPN2 status is defined as either PTPN2 gain and low protein expression or no PTPN2 gain and high protein expression (n=19) and high PTPN2 status is defined as both PTPN2 gain and high protein expression (n=12). (C) OS characterised by PTPN2 status. (D) PFS characterised by PTPN2 status. In C and D high PTPN2 (n=12) is compared to the low and mixed status combined (n=28) (C, D).