Loss of PTEN Immunohistochemical Expression in Patients with Advanced Colorectal Adenocarcinoma: Implications for Targeted Therapy
Rania Bakkar, Russell Broaddus. University of New Mexico School of Medicine, Albuquerque, NM; M.D. Anderson Cancer Center, Houston, TX
Background: The advent of targeted therapy for advanced cancer offers unique challenges to pathologists to devise laboratory assays that are helpful in identifying patients who would benefit most from such therapies. Patients with advanced cancers only have a finite life-span, and targeted therapies are typically expensive. These 2 features highlight the importance of optimal patient selection. PTEN is a negative regulator of the PI3-kinase pathway that is activated in numerous types of cancers, including colorectal cancer. Loss of PTEN expression may potentially be predictive of response to drugs that target the PI3K/AKT/mTOR pathway.
Design: PTEN immunohistochemistry slides from 482 patients enrolled in Phase I clinical trials, which included 83 patients with colorectal adenocarcinoma, were reviewed. We devised a 4-tiered scoring system to accommodate the heterogeneous nature of PTEN expression. Tumors were scored as positive, negative, reduced, and heterogeneous (positive and negative tumor foci). Stromal cells served as a useful internal positive control.
Results: Of the 482 cases reviewed, 46 patients had complete loss of PTEN IHC expression. Colorectal adenocarcinoma had the highest number with PTEN IHC loss (33%; 15/46). Additional colorectal adenocarcinomas had reduced (n=55) or heterogeneous (n=4) PTEN IHC expression which was less than that of PTEN positive cases (n=9) and may thus be amenable to inhibition of this pathway. For 5 of the PTEN IHC negative cases, sufficient tumor DNA was present for PTEN sequencing; no mutations were detected in these 5 cases. Only 3 of the PTEN negative colorectal carcinomas had mutations in KRAS, NRAS, or BRAF. This is important, as activation of the RAS/RAF/MEK pathway is associated with resistance to inhibition of the PI3K/AKT/mTOR pathway.
Conclusions: The 4-tiered scoring system for PTEN IHC identified a relatively high percentage of patients with colorectal adenocarcinoma with PTEN loss. IHC detected PTEN protein loss in cases with no PTEN gene mutation detected. Importantly, the advanced colorectal cancer patients did not have tumors with over-representation of KRAS, NRAS, or BRAF mutations, implying that most patients with PTEN IHC loss would be potential candidates for targeted therapy using inhibitors of the PI3K/AKT/mTOR pathway. This highlights the central role of the pathologist in identifying patients who would benefit most from targeted therapy.
Monday, March 19, 2012 1:00 PM
Poster Session II # 110, Monday Afternoon