[1913] 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.

Summary of KRAS, NRAS, and BRAF mutations in 46 cancers with IHC loss of PTEN
 Total tested# Mutations (% tested)Mutation typeTumor type
NRAS172 (12%)Exon 2, codon 13; Exon 3, codon 61Uterus endometrioid adenocarcinoma; Skin melanoma
KRAS285 (18%)Exon 2, codons 12 (x3) and 13 (x2)Colon adenocarcinoma (x2); Uterus endometrioid adenocarcinoma; Uterus serous carcinoma; Pancreas adenocarcinoma
BRAF351 (3%)Exon 15, codon 594Colon adenocarcinoma

Conclusions: Although approximately 10% of patients with advanced cancers have tumors with PTEN IHC loss, and therefore activation of the PI3K/AKT/MTOR signaling pathway, 17% of these have mutations either in KRAS, NRAS or BRAF. Such mutations may provide tumor resistance to inhibition of this important signaling pathway. Identification of possible mediators of targeted therapy resistance is important, as patients with advanced cancers have a finite, limited life-span, and targeted therapies are typically expensive.
Category: Pathobiology

Wednesday, March 21, 2012 9:30 AM

Poster Session V # 259, Wednesday Morning


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