Concurrent KRAS, NRAS, and BRAF Mutations in Cancers with PTEN Loss by Immunohistochemistry: Experience with 464 Patients Referred for Phase I Clinical Trials
Rania Bakkar, Russell Broaddus. University of New Mexico School of Medicine, Albuquerque, NM; M.D. Anderson Cancer Center, Houston, TX
Background: Pathologists play a central role in identifying patients who would benefit most from targeted therapy. Cancer patients with tumors with activated PI3K signaling are potentially eligible for treatment with PI3K/AKT/mTOR inhibitors. PTEN acts as the key inhibitor of this pathway, and we have shown that its expresssion can be judged accurately by immunohistochemistry. It has been shown that inhibitors of the PI3K/AKT/mTOR pathway may lose their potential effectiveness if the tumor has a KRAS or BRAF mutation, as either can result in activation of the RAS/RAF/MEK pathway.
Design: PTEN IHC was evaluated in 464 cancers from patients referred for Phase I clinical trials of targeted therapy. Many cancer types were represented in this population. The most common was colorectal adenocarcinoma (18%), followed by ovarian/peritoneal high grade serous carcinoma (11%), melanoma (7%), lung carcinoma (7%), and uterine carcinoma (6%). Tumors were scored as positive, negative, reduced, and heterogeneous (positive and negative tumor foci). Stromal cells served as an internal positive control for IHC. Sequenom was used to detect concurrent mutations in KRAS, NRAS, and BRAF.
Results: Negative PTEN IHC expression was observed in 46 cases (10% of patients). The majority of these patients had either colorectal adenocarcinoma (15/46, 33%) or uterine carcinoma (10/46, 22%). Mutations of KRAS], NRAS, and BRAF were detected in 8 cases (see table). No tumor had mutation in more than one gene.
|Total tested||# Mutations (% tested)||Mutation type||Tumor type|
|NRAS||17||2 (12%)||Exon 2, codon 13; Exon 3, codon 61||Uterus endometrioid adenocarcinoma; Skin melanoma|
|KRAS||28||5 (18%)||Exon 2, codons 12 (x3) and 13 (x2)||Colon adenocarcinoma (x2); Uterus endometrioid adenocarcinoma; Uterus serous carcinoma; Pancreas adenocarcinoma|
|BRAF||35||1 (3%)||Exon 15, codon 594||Colon adenocarcinoma|