CHFR protein expression predicts outcomes to taxane-based first line therapy in metastatic NSCLC.

Abstract

PURPOSE:

Currently, there is no clinically validated test for the prediction of response to tubulin-targeting agents in non-small cell lung cancer (NSCLC). Here, we investigated the significance of nuclear expression of the mitotic checkpoint gene checkpoint with forkhead and ringfinger domains (CHFR) as predictor of response and overall survival with taxane-based first-line chemotherapy in advanced stage NSCLC.

METHODS:

We studied a cohort of 41 patients (median age 63 years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. CHFR expression by immunohistochemistry (score 0-4) was correlated with clinical outcome using chi-square test and Cox proportional models. A cutoff score of "3" was determined by receiver operator characteristics analysis for "low" CHFR expression. Results were validated in an additional 20 patients who received taxane-based chemotherapy at Emory University Hospital and the Atlanta VAMC.

RESULTS:

High expression (score = 4) of CHFR is strongly associated with adverse outcomes: the risk for progressive disease after first-line chemotherapy with carboplatin-paclitaxel was 52% in patients with CHFR-high versus only 19% in those with CHFR-low tumors (P = 0.033). Median overall survival was strongly correlated with CHFR expression status (CHFR low: 9.9 months; CHFR high: 6.2 months; P = 0.002). After multivariate adjustment, reduced CHFR expression remained a powerful predictor of improved overall survival (HR = 0.24; 95% CI, 0.1-0.58%; P = 0.002). In the validation set, low CHFR expression was associated with higher likelihood of clinical benefit (P = 0.03) and improved overall survival (P = 0.038).

CONCLUSIONS:

CHFR expression is a novel predictive marker of response and overall survival in NSCLC patients treated with taxane-containing chemotherapy.

• Authors: Rathi N Pillai, Seth A Brodie, Gabriel L Sica, You Shaojin, Ge Li, Dana C Nickleach, Liu Yuan, Vijay A Varma, Dacian Bonta, James G Herman, Malcom V Brock, Maria J A Ribeiro, Suresh S Ramalingam, Taofeek K Owonikoko, Fadlo R Khuri, Johann C Brandes
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 6 Pg. 1603-11 (Mar 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23386692 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Biomarkers, Tumor
• Bridged-Ring Compounds
• Cell Cycle Proteins
• Neoplasm Proteins
• Poly-ADP-Ribose Binding Proteins
• Taxoids
• taxane
• CHFR protein, human
• Ubiquitin-Protein Ligases

Topics

• Adult
• Aged
• Biomarkers, Tumor (genetics)
• Bridged-Ring Compounds (administration & dosage)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cell Cycle Proteins (genetics)
• DNA Methylation (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (drug therapy, genetics, pathology)
• Male
• Middle Aged
• Neoplasm Metastasis (drug therapy, genetics, pathology)
• Neoplasm Proteins (genetics)
• Poly-ADP-Ribose Binding Proteins
• Prognosis
• Taxoids (administration & dosage)
• Ubiquitin-Protein Ligases