PTK (protein tyrosine kinase)-6 and HER2 and 4, but not HER1 and 3 predict long-term survival in breast carcinomas

Abstract

The HER receptors are of therapeutic and prognostic significance in breast cancer, and their function is modulated by cytoplasmic tyrosine kinases like PTK6 (brk). We performed a retrospective study on archival breast cancer samples from patients with long follow-up and compared the protein expression between individual HERs and between HERs and the PTK6. Univariate and multivariate analyses were used to study the prognostic value of parameters. Metastases-free survival of patients for longer than 240 months was inversely associated (P< or =0.05) with nodal status, tumour size, and oestrogen receptor status, but was also directly associated with high protein expression levels of HER4 and PTK6 in Kaplan-Meier analysis. In multivariate analysis for metastases-free survival of >240 months, the stepwise selected parameters were tumour size (relative risk 3.1), PTK6 expression (0.4), and number of positive lymph nodes (1.2). Furthermore, we demonstrated a timedependence of the prognostic value attributed to the parameters. The HER receptors (HER2,4), but not PTK6, were independent prognostic markers for metastases-free survival at 60 months, whereas at 240 months PTK6 is the strongest prognostic marker. We demonstrate that PTK6 is a prognostic marker of metastases-free survival in breast cancer, and is independent of the classical morphological and molecular markers of lymph node involvement, tumour size, and HER2 status.

Figure 1

Representative examples of PTK6 IHC (objective magnification × 40) in normal breast epithelium (A), and in breast carcinomas classified as 1+ (B), 2+ (C), and 3+ (D).

Figure 2

Kaplan–Meier curves for an event-free (distant recurrence) survival of patients of >240 months, with low (0/1+) vs high (2+/3+) protein expression of HER4 (A) and PTK6 (B). The individual groups are: HER4: low=42 patients, 55% remain event-free; high=52 patients, 75% event-free. PTK6: low=33 patients, 48% event-free; high=56 patients, 80% event-free.

Figure 3

Kaplan–Meier curves for the event-free (distant recurrence) survival of patients of >240 months. Grouping of patients according to their multivariate PF resulted in three different risk groups: low PF (−1.63 to ⩽0.4): 21 patients, 91% remain event-free; medium (0.4 to ⩽1.5): 31 patients, 71% event-free; high PF (1.5–3.24): 28 patients, only 43% event-free. In addition, the overall event-free survival of all patients is plotted in grey.