P2-11-06: PTEN Loss in Asian Triple Negative Breast Cancer Is a Frequent Event Associated with Basal Markers, Tumour Grade and Younger Age of Onset.
Authors: S Dean, A Rhodes, J Holly, C Perks, L-M Looi, KS Mun, NA Taib, CH Yip
Journal: Cancer Research (2011)

Abstract Triple negative (TN) breast cancers are defined by their lack of expression of hormone receptors and HER2 and account for approximately 15% of all breast cancers. They are highly aggressive tumors for which there is currently no effective targeted therapy. PTEN is a tumor suppressor gene that shows loss or mutation in many types of cancer. PTEN functions by deactivating Akt signaling so cell growth is inhibited and apoptosis is promoted. PTEN has also been found to have an important role in DNA repair. Cancers with PTEN loss have been shown to be sensitive to PARP inhibitors that prevent DNA repair and result in tumor cell death. In unselected breast cancer cohorts with the expected frequency of HER2 and hormone receptor positive cases, its loss appears to be a relatively rare event. Insulin-like growth factor binding protein-2 (IGFBP-2) regulates the anti-apoptotic and mitogenic effects of insulin like growth factors (IGF's) -I and -II and can also exert its own intrinsic effects on cell function; in vitro cell line models have shown that IGFBP-2 down regulates PTEN expression by interacting with the β-integrin receptor. The purpose of the current study was to investigate the extent of PTEN loss in an Asian series of TN breast cancers also to determine the association of PTEN loss with IGFBP2 expression and clinicopathological features. 122 TN breast carcinomas from the University of Malaya Medical Centre were immunohistochemically (IHC) stained for CK5/6, CK14, PTEN and IGFBP-2. The basal-like phenotype was defined as positivity for either one or both of CK5/6 and CK14, in invasive tumour cells. A modified Allred scoring system was used to assess the IGFBP-2 staining. PTEN was assessed for loss in both the cytoplasm and the nuclei; the surrounding stromal tissue and normal ducts had to be positive for the case to be assessable. Expression of basal CKs were present in the majority of cases, with 72.5% and 70.4% of TN cases staining positively for CK5/6 and CK14, respectively. Loss of nuclear and cytoplasmic IHC staining for PTEN occurred in 44.9% of TN cases. In those cases with PTEN loss, 88.4% were positive for CK5/6 compared to only 66% for cases without PTEN loss. (p=0.011). The median age of patients with tumors showing PTEN loss were 48 years old, compared with 56 years in those without PTEN loss (p=0.007). Of the cases showing PTEN loss, 35/40 (87.5%) were Grade 3 tumors; in comparison 28/46 (60.9%) of tumors without PTEN loss were Grade 3 (p=0.008). With respect to IGFBP2, 26.5% of cases were positive using the cut-off score of 6 or greater. However, there was no significant association between PTEN loss and IGFBP2 expression (p= 0.542). Complete PTEN loss was a frequent event in a cohort of nearly one hundred TN breast cancers; this was significantly associated with younger age. PTEN loss can be readily and reliably assessed by an optimised IHC assay and validated PTEN antibody. The extent of PTEN loss occurring in TN breast cancers may well reflect a defect in DNA double strand repair and therefore, along with other suitable markers, may prove to be a valuable assay to identify those patients with TN breast cancers that are most likely to respond well to PARP inhibitors. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-11-06.