Impact of PTEN protein expression on benefit from adjuvant trastuzumab in early-stage human epidermal growth factor receptor 2-positive breast cancer in the North Central Cancer Treatment Group N9831 trial

Abstract

Purpose: It has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) -positive trial-North Central Cancer Treatment Group (NCCTG) N9831.

Patients and methods: The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years.

Results: Of 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ(2) P < .001) and nodal positivity (χ(2) P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47).

Conclusion: In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.

Fig 1.

PTEN staining distribution for overall patient cohort.

Fig 2.

Representative PTEN staining. Immunohistochemical score of (A) 0, no cytoplasmic staining; (B) 1+, weak staining; (C) 2+, moderate staining; and (D) 3+, strong staining.

Fig 3.

Kaplan-Meier curves of disease-free survival by treatment arm. (A) Negative (0), (B) positive (1, 2, or 3+), (C) negative (0 or 1+), and (D) positive (2 or 3+) PTEN cytoplasmic staining. AC, doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² once every 3 weeks × 4; T, paclitaxel 80 mg/m²/wk × 12 weeks; H, trastuzumab 4 mg/kg loading + 2 mg/kg/wk × 52 weeks; HR, hazard ratio.

Fig A1.

Schema for North Central Cancer Treatment Group (NCCTG) N9831 trial incorporating trastuzumab in adjuvant therapy. FISH, fluorescent in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; q3w, once every 3 weeks.

Fig A2.

Patient flow diagram.

Fig A3.

(A) PTEN variability in normal (left) and malignant (right) breast epithelium. Cell signaling anti-PTEN antibody 1:250, diaminobenzidine (DAB), ×100. (B) PTEN lost, positive endothelial internal control. Cell signaling anti-PTEN antibody 1:250, DAB, ×200. (C) PTEN lost, positive normal breast internal control. Cell signaling anti-PTEN antibody 1:250, DAB, ×200.

Fig A4.

Forest plot: comparison of disease-free survival between concurrent trastuzumab and chemotherapy alone (arm C v arm A) within PTEN cytoplasmic staining subgroups.