P1-06-19: Absence or Low Levels of c-JunNH2 – Terminal Protein Kinase (JNK) Mitogen Activated Protein Kinase (MAPK) Is Related to a Luminal B Subtype and an Impaired Survival in Patients with an ER Positive Breast Cancer Treated with Adjuvant Tamoxifen.
Authors: Linderholm BK , Sanchez-Chavez B , Hellborg H , Johansson UM , Lewensohn R , Viktorsson K , Kanter L 
Published: June 2012

Abstract
Background: Resistance to endocrine therapy is a clinical problem and is not explained by lack or loss of the oestrogen receptor (ER). Up-regulation of several receptor tyrosine kinases have been correlated to diminished effect of endocrine treatment. More contradictory are the role of downstream mitogen activated protein kinases (MAPK's).
Patients and Methods: We performed a tissue micro array (TMA's) on patients that originate from an earlier presented population of 404 patients with a steroid receptor positive BC subjected to tamoxifen as only adjuvant systemic treatment. Material from 120 patients was available for the TMA. JNK, p38 and ERK was determined by use of immunohistochemistry and scored 0, +1, +2, +3. Patients were grouped into two categories for statistical analyses.
Results: Absence or low JNK was statistically significantly correlated with HER2+ (p=0.018), a Luminal B like subtype (ER+, high proliferation and/or HER2+) (p=0.007), shorter relapse-free (p= 0.0494) and breast cancer corrected survival (p=0.0458). High ERK was more frequent among node-negative patients (p=0.00469) and more frequent in relapse-free patients; RFS (p= 0.225); BCCS (p= 0.0705). High expression of p38 was associated with p38 previously determined by ELISA (p=0.085) and HER2+ (p=0.094), however not reaching statistical significance. High p38 was related to increased relapses within the first years but the difference vanished with longer follow-up time; RFS (p=0.486) and BCCS (p= 0.589). JNK remained as an independent marker of RFS in a Cox proportional multivariate analysis (HR=2.19; 95%CI=1.14−11.41; p=0.029), together with nodal status (HR=3.6; 95%CI=1.44−8.81; p=0.006) and histological grade (HR=3.1; 95%CI=1.29−7.56; p=0.011).
Discussion: Our data on ERK and p38 is concordant with results from previous published studies. Two studies have shown ERK expression, determined by IHC to be correlated with “good prognosis features” as smaller tumour size, absence of nodal metastasis, lower proliferation and a favourable outcome after adjuvant tamoxifen (Svensson et. al. 2005, Bergqvist et. al. 2006). Higher p38 determined by use of an ELISA has been suggested as a marker of early relapses i.e. intrinsic resistance, although methodological problems must be taken into account (Linderholm et. al. 2011). By use of IHC we could confirm that patients with higher expression of p38 actually had significantly more relapses within early follow-up. JNK was the MAPK with the most pronounced effect on survival. Absent or low expression was significantly correlated with an impaired survival in both uni- and multivariate analyses, a finding to our very best knowledge not described before. Low JNK was actually found more frequently in patients with a HER2 positive or Luminal B like BC (ER+, high proliferation rate or HER2+).
Conclusions: Our results suggest that MAPK's can be evaluated by IHC on TMA's. Absence/low JNK was significantly correlated with an impaired survival and a Luminal B like subtype. Confirming studies in large preferable randomised patient populations are warranted.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-19.