ABSTRACT
AIMS: To evaluate the clinicopathological associations and predictive value of the transcription factor NF-κB in a large series of breast cancer patients treated with neoadjuvant chemotherapy. METHODS: A retrospective search of a prospectively maintained database was performed to identify patients. Immunohistochemistry was used to assess the p65 subunit of NF-κB, using nuclear staining as a surrogate of activation. RESULTS: Nuclear NF-κB expression was found in 26.3% (35/133) of cases. Nuclear NF-κB staining was associated with high histological grade (p=0.05), oestrogen receptor (ER) negativity (p=0.01) and higher Ki67 index (p=0.002). Patients with nuclear NF-κB staining had a higher pathological complete response (pCR) rate than those without (26.5% vs 6.0% respectively, p=0.004); there was no significant association with clinical response or outcome. In an exploratory hypothesis-generating analysis, in the ER+/HER2- subgroup (n=43) a significantly lower clinical response rate was observed in those with nuclear NF-κB staining compared with those who had no nuclear NF-κB staining (14.3% vs 61.0%, p=0.038). There were no pCRs in ER+/ HER2- tumours. CONCLUSIONS: Nuclear NF-κB expression is associated with ER negativity, higher Ki67 index and tumour grade. It was also found to be significantly associated with increased pCR but not clinical response to neoadjuvant chemotherapy.
Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Transcription Factor RelA/metabolism , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Nucleus/metabolism , Chemotherapy, Adjuvant , Cytoplasm/metabolism , Female , Humans , Neoplasm Invasiveness , Neoplasm Proteins/metabolism , Neoplasm Staging , Prognosis , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Retrospective Studies , Treatment OutcomeABSTRACT
PURPOSE: To assess the pharmacodynamic effects of nimotuzumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody with intermediate affinity for the receptor, in skin and tumor tissues from head and neck cancer patients. EXPERIMENTAL DESIGN: Pharmacodynamic study in patients with advanced squamous cell carcinoma of the head and neck, unsuitable for chemoradiotherapy, enrolled in a single-center trial. Patients received 8 weekly infusions of nimotuzumab. The first nimotuzumab infusion was administered 1 week before starting radiation, whereas the remaining doses were administered concomitantly with irradiation. Paired biopsies were taken from skin and primary tumors, before (pretherapy) and 1 week (on single-agent therapy) after first infusion. Immunohistochemistry was conducted to assay the effects of nimotuzumab on total and phosphorylated EGFR, phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), p-AKT, and proliferation (Ki-67). RESULTS: Nimotuzumab was well tolerated and there was no evidence of skin rash. Objective response was achieved in 9 of 10 patients. The pharmacodynamic assays showed inhibition of p-EGFR in both skin and tumor (P = 0.042 in skin and P = 0.034 in tumor). No significant changes in p-ERK1/2, p-AKT, or Ki-67 were detected in skin. In addition, lymphocytic infiltrates, folliculitis, or perifolliculitis were not observed. In tumor samples, there was an upregulation of p-AKT (P = 0.043), a reduction in proliferation index (P = 0.012), and a nonsignificant trend toward a decrease of p-ERK1/2 (P = 0.091). CONCLUSIONS: The pharmacodynamic data confirmed the ability of nimotuzumab to decrease EGFR phosphorylation. Downstream effects were observed in tumor cells but not in skin, a finding that may help to explain the lack of skin rash in patients treated with nimotuzumab.