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 (OS) 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 ROC-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 (PD) after first-line chemotherapy with carboplatin-paclitaxel was 52% in patients with CHFR-high vs. only 19% in those with CHFR-low tumors (p=0.033). Median OS 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 OS (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 OS (p=0.038). Conclusions CHFR expression is a novel predictive marker of response and OS in NSCLC patients treated with taxane-containing chemotherapy.

Molecular characteristics of non-small cell lung cancer with reduced CHFR expression in The Cancer Genome Atlas (TCGA) project

“…We have previously shown that, although CHFR is a frequent target for aberrant promoter hypermethylation in other cancers, such as colon-, gastric-and esophageal cancer[1], epigenetic silencing in NSCLC is much less frequent[4]. The clinical utility of CHFR expression could be through personalization of chemotherapy treatments by selecting patients with CHFR ‘low’ expression to microtubular-targeted therapy while choosing alternative agents such as pemetrexed or gemcitabine for patients with high CHFR expression.…”

“…Previous studies have shown that the percentage of tumors with reduced CHFR expression is approximately 40% (95%CI 26-54%) [4]. In order to determine the best cut-off for ‘high’ vs. ‘low’ CHFR levels, we analyzed the distribution of CHFR expression among adeno- and squamous cell lung cancers.…”

“…Reduced expression or epigenetic silencing of the mitotic checkpoint gene “checkpoint with fork-head and ringfinger domains” (CHFR) has recently been identified as powerful predictor for taxane sensitivity in gastric-, colon and lung cancer[1-3]. Reduced CHFR expression in patients with non-small lung cancer (NSCLC) who received first-line chemotherapy with carboplatin and paclitaxel predicts clinical benefit (81% vs. 48%, p = 0.03) and overall survival (HR = 0.24; 95% CI, 0.1-0.58%; P = 0.002) [4].…”

“…Reduced CHFR expression in patients with non-small lung cancer (NSCLC) who received first-line chemotherapy with carboplatin and paclitaxel predicts clinical benefit (81% vs. 48%, p = 0.03) and overall survival (HR = 0.24; 95% CI, 0.1-0.58%; P = 0.002) [4]. These are important observations since it allows physicians to select patients for microtubular-targeted therapy based on their CHFR expression status, and furthermore, to target CHFR pharmacologically to overcome taxane resistance in patients whose tumors display high CHFR expression.…”

Chemotherapy Outcomes by Histologic Subtypes of Non–Small-Cell Lung Cancer: Analysis of the Southwest Oncology Group Database for Antimicrotubule-Platinum Therapy

“…CHFR is a key regulator of cell entry into mitosis. Immunohistochemical analysis of tumors from 41 patients treated with paclitaxel and carboplatin with or without bevacizumab revealed an association between expression level and treatment response and OS (23). Thirty-two patients (78%) had tumors with nonsquamous histology.…”