© 2004 by Oxford University Press
© 2004 Oxford University Press
IN THIS ISSUE |
10-Year Results of Adjuvant Therapy Trial in Colon Cancer
Investigators from the National Surgical Adjuvant Breast and Bowel Project C-01 trial for patients with colon adenocarcinoma reported in 1988 that, for patients with resected Dukes' stage B and C colon cancer, compared with surgery alone, postoperative chemotherapy with semustine, vincristine, and 5-fluorouracil was associated with better 5-year disease-free and overall survival and that postoperative immunotherapy with bacillus Calmette-Guérin was associated with better 5-year overall survival. Smith et al. (p. 1128) now provide a 10-year update of this trial. They found no difference in 10-year disease-free and overall survival between patients in the chemotherapy group and those in the surgery-alone group. Immunotherapy did not prevent relapse after 10 years but was associated with better overall survival compared with surgery alone. They conclude that the disease-free and overall survival associated with chemotherapy in this patient population is of limited duration, disappearing after 10 years.
In an editorial, Grem (p. 1116) notes that because neither therapeutic regimen is currently in clinical use, appropriate end points for adjuvant colon cancer trials are needed to replace overall survival. Use of 3-year disease-free survival, she writes, would decrease the follow-up before definitive data analysis and allow more timely completion of trials with more rapid implementation of promising new therapies.
Akt Phosphorylation, Gefitinib, and NSCLC
Gefitinib, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has activity against approximately 10% of unselected non–small-cell lung cancer (NSCLC) patients. Phosphatidylinositol 3'-kinase (PI3K)/Akt and Ras/Raf/mitogen-activated protein kinase (MAPK) are downstream mediators of EGFR signaling pathways. Because activation of these pathways is dependent on the phosphorylation status of the components, Cappuzzo et al. (p. 1133) evaluated the association between phosphorylation status of Akt (P-Akt) and MAPK (P-MAPK) and gefitinib activity in patients with advanced NSCLC. The authors found that, of 103 evaluable patients, 51 had tumors that were positive for P-Akt. Patients with P-Akt–positive tumors had a better response rate, disease control rate, and time to progression than patients with P-Akt–negative or P-MAPK–positive tumors. P-Akt positivity, but not P-MAPK positivity, was associated with a reduced risk of disease progression. The authors conclude that gefitinib may be most effective in patients with activated Akt.
In an editorial, Pao et al. (p. 1117) consider recent data on the strong association between EGFR mutations and gefitinib sensitivity in patients with NSCLC and whether phosphorylated Akt has a role in predicting gefitinib sensitivity.
HER-2/neu Amplification and Response to Paclitaxel
Because HER-2/neu overexpression appeared to be associated with improved response to anthracycline-based chemotherapy but its association with taxane-based chemotherapy was unclear, Konecny et al. (p. 1141) analyzed a retrospective subset of patients with metastatic breast cancer participating in a randomized treatment trial to investigate the response of patients with known HER-2/neu status to taxane-based epirubicin–paclitaxel (ET) chemotherapy compared with the response to epirubicin–cyclophosphamide (EC) chemotherapy. They found that HER-2/neu overexpression does not adversely influence response to first-line ET or EC chemotherapy and that a taxane-containing regimen, such as ET, may provide a preferential benef it to patients with tumors that overexpress HER-2/neu.
HDL Cholesterol and Breast Cancer Risk
Low high-density lipoprotein cholesterol (HDL-C) is a component of the increasingly prevalent metabolic syndrome (obesity, glucose intolerance, low HDL-C, high serum triglyerides, and hypertension). To determine if serum HDL-C is associated with breast cancer risk, Furberg et al. (p. 1152) measured it as part of two population-based screening surveys of 38,823 Norwegian women. Among women with a body mass index of 25 kg/m2 or greater, those in the highest quartile of serum HDL-C (above 1.64 mmol/L) had a reduced risk of postmenopausal breast cancer compared with those in the lowest quartile (below 1.20 mmol/L). The authors conclude that low HDL-C, as part of metabolic syndrome, is associated with increased postmenopausal breast cancer risk.
E3 Ubiquitin Ligase Receptor, 
-Catenin, and NF-
B
The ubiquitin–proteasome pathway is important in regulating protein
signaling pathways that are involved in tumorigenesis. -transducin
repeat–containing proteins (-TrCP) are components of the complex
that targets -catenin and IB
for proteasomal degradation,
and thus negatively regulate Wnt/-catenin signaling and positively
regulate NF-B signaling pathways. Ougolkov et al.
(p. 1161) analyzed
expression of -TrCP in colorectal cancers and its association with
-catenin activation. Based on their results, the authors conclude that
increased expression of -TrCP1 is associated with activation of both
-catenin and NF-B, suggesting that the integration of these
signaling pathways by increased -TrCP expression may contribute to an
inhibition of apoptosis and tumor metastasis.
Liposomes, Immune Cell Function, and Neuroblastoma
In neuroblastoma, expression of the c-myb proto-oncogene is linked with cell proliferation and differentiation. Neuroblastomas can be selectively targeted with monoclonal antibodies to the disialoganglioside (GD2) tumor-associated antigen. Liposomes coated with anti-GD2 antibodies (targeted liposomes) and that entrap a c-myb antisense oligonucleotide have antitumor activity. Because antisense oligonucleotides containing CpG motifs can stimulate immune responses, Brignole et al. (p. 1171) evaluated the in vivo effect of CpG-containing c-myb antisense oligonucleotides encapsulated within targeted liposomes. The authors found that tumor-bearing mice injected with these targeted liposomes lived longer than mice in any other treatment group. These liposomes activated macrophages, B cells, and natural killer (NK) cells, although only activated NK cells were associated with antitumor cytotoxic activity. Macrophages were important contributors because ablation of macrophages or NK cells resulted in a loss of in vivo antitumor activity.
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