Determining personalized treatment by gene expression profiling in metastatic breast carcinoma patients: a pilot study.

PURPOSE: The present study evaluates the massive study of gene expression in metastatic breast carcinoma (MBC) patients using microarray gene expression profiling (MAGE) complemented with conventional sequencing, immunohistochemistry (IHC) and fluorescent "in situ" hybridization (FISH), seeking to optimize the treatment in a subset of heavily pretreated patients and with limited life expectancy. PATIENTS, MATERIAL AND METHODS: MBC patients in hormone therapy progression with survival expectancy of at least 3 months (m) have been included. The MAGE contains gene probes representing genes known to potentially interact with available drugs as cited in the literature. RESULTS: Thirty-nine procedures were performed from October 2010 to April 2016. Within the 30 evaluable procedures, considering all hormonal manipulations as a single line, the patients had received a median of 4 treatment lines prior to MAGE (range 1-7). Progression was observed in 6 cases, stable disease (SD) in 7 cases and partial response (PR) in 16 cases, which implies a clinical benefit rate (SD + PR) of 76%. Actuarial median progression-free survival (PFS) was 6 m (95% CI 2.5-9.5) in patients with clinical benefit. The median overall survival (OS) for the entire series was 11 m (95% CI 2.2-19.8). CONCLUSION: Data presented here indicate that the use of MAGE provides relevant information to establish personalized treatment in frail patients with limited life expectancy in which therapeutic futility is a particularly difficult burden to assume.

ERK1/2 is activated in non-small-cell lung cancer and associated with advanced tumours.

Activation of the ERK1/2 pathway is involved in malignant transformation both in vitro and in vivo. Little is known about the role of activated ERK1/2 in non-small cell lung cancer (NSCLC). The purpose of this study was to characterise the extent of the activation of ERK1/2 by immunohistochemistry in patients with NSCLC, and to determine the relationship of ERK1/2 activation with clinicopathological variables. Specimens from 111 patients with NSCLC (stages I-IV) were stained for P-ERK. Staining for epidermal growth factor receptor (EGFR) and Ki-67 was also performed. In all, 34% of the tumour specimens showed activation for ERK1/2, while normal lung epithelial tissue was consistently negative. There was a strong statistical correlation between nuclear and cytoplasmic P-ERK staining and advanced stages (P<0.05 and P<0.001, respectively), metastatic hilar or mediastinal lymph nodes (P<0.01, P<0.001), and higher T stages (P<0.01, P<0.001). We did not find correlation of nuclear or cytoplasmic P-ERK staining with either EGFR expression or Ki-67 expression. Total ERK1/2 expression was evaluated with a specific ERK1/2 antibody and showed that P-ERK staining was not due to ERK overexpression but rather to hyperactivation of ERK1/2. Patients with a positive P-ERK cytoplasmic staining had a significant lower survival (P<0.05). However, multivariate analysis did not show significant survival difference. Our study indicates that nuclear and cytoplasmic ERK1/2 activation positively correlates with stage, T and lymph node metastases, and thus, is associated with advanced and aggressive NSCLC tumours.

Modulation by acrolein and chloroacetaldehyde of multidrug resistance mediated by the multidrug resistance-associated protein (MRP).

Acrolein (AC) and chloroacetaldehyde (CHA) are metabolites of the non-multidrug resistance cytotoxic drugs cyclophosphamide and ifosfamide. It has previously been reported that both metabolites can induce extensive depletion of glutathione (GSH) in vitro and in vivo and that this depletion occurs at drug concentrations in the micromolar range. A link between the function of the multidrug resistance-associated protein (MRP) and the intracellular concentration of GSH has also been demonstrated. To determine whether AC and CHA can modulate the function of MRP by inducing GSH depletion, we used two human lung cancer cell lines overexpressing MRP: the large cell carcinoma cell line COR-L23/R and the adenocarcinoma cell line MOR/R0.4, along with their respective sensitive parental lines, COR-L23/P and MOR/P. We showed that micromolar concentrations of AC and millimolar concentrations of CHA are able to deplete GSH concentrations in the cell lines studied. In addition, concentrations of 50 micrometer AC and 5 mm CHA could completely reverse the daunorubicin (DNR) and vinblastine accumulation deficit present in COR-L23/R and partially reverse the DNR accumulation deficit in MOR/R0.4. In contrast, AC and CHA did not reverse the drug accumulation deficit in the P-glycoprotein-overexpressing lung cancer cell line H69/LX4. The effect of CHA and AC on drug accumulation was related to the GSH depletion, as we found a concentration-dependent relationship between the GSH levels and the reversal of the accumulation deficit for both AC and CHA. To substantiate further this correlation, we increased cellular GSH content in AC- and CHA-treated cells with the GSH ethyl ester. An increase in cellular GSH levels in CHA- and AC-treated COR-L23/R cells was accompanied by a restoration of the DNR accumulation deficit. No significant effect of the GSH ethyl ester was detected on DNR accumulation in COR-L23/P parental cells. In conclusion, treatment with AC or CHA can reverse the drug accumulation deficit of MRP-overexpressing cells, and this effect appears to be mediated by GSH depletion.