© 2005 Oxford University Press
IN THIS ISSUE
Grade Inflation in Prostate CancerOver the last several decades, the survival of men with prostate cancer, by Gleason score, has improved and the reported incidence of low-grade prostate cancer has declined. These changes could reflect the identification of more aggressive tumors; alternatively, they could reflect Gleason score shift, whereby contemporary prostate biopsies are graded higher than they would have been in years past even though their biological characteristics have not changed. In this issue, Albertsen et al. (p. 1248) report that, when a single pathologist reread the biopsy slides of 1858 men who had been diagnosed with prostate cancer a decade earlier, the average Gleason score was increased, from just under 6 to 6.8. As a result, the Gleason score–standardized contemporary prostate cancer mortality rate appeared to be almost 30% lower than the standardized historical rate. The authors conclude that the Gleason score shift over the last decade may be the result of a statistical artifact and not the selective identification of more aggressive tumors.
In an editorial, Thompson et al. (p. 1236) discuss the implications of this "grade inflation" in prostate cancer. In particular, they note that it may contribute to the overtreatment of prostate cancer. For example, biopsies that, in the past, would have received grades consistent with watchful waiting are now receiving grades that indicate a need for more active treatment.
Hormone Receptor Expression and Tamoxifen Resistance
To determine if the tamoxifen resistance and the aggressive phenotype previously observed in estrogen receptor–positive/progesterone receptor–negative (ER+/PR-) breast cancer is associated with epidermal growth factor receptor (HER-1 or HER-2) status, Arpino et al. (p. 1254) compared the clinical and biological features of tumors from 44,819 women with breast cancer. The authors found that the ER+/PR- tumors, which were larger, divided more rapidly, and were more likely to have an abnormal number of chromosomes than the ER+/PR+ tumors, also more often expressed HER-1 and overexpressed HER-2. Recurrence was higher among tamoxifen-treated women with ER+/PRtumors that expressed HER-1 or HER-2 than among women with ER+/PR+ tumors that expressed these growth factor receptors. The authors conclude that the lack of PR expression in ER+ tumors may be a surrogate marker of aberrant growth factor signaling that could contribute to tamoxifen resistance.
In a related editorial, Wilson and Slamon (p. 1238) discuss how the author's findings support new hypotheses in the field regarding ER activity in PR- breast cancer, the role of peptide hormone pathways in steroid hormone–independent breast cancer, and the potential clinical relevance of PR status in ER+ tumors.
Letrozole After Tamoxifen for Receptor-Positive Breast Cancer
Five years of adjuvant tamoxifen treatment improves survival of women with hormone receptor–positive breast cancer. Despite receiving tamoxifen treatment, many women experience new primary tumors and relapses after 5 years. The MA.17 trial showed that the aromatase inhibitor letrozole, given to postmenopausal women after 5 years of tamoxifen, improved disease-free survival to such an extent that the trial was stopped early. In this issue, Goss et al. (p. 1262) present the final efficacy and toxicity results as of the study's unblinding in 2003, including preplanned subset analyses. They confirm the improvement in disease-free survival and demonstrate a statistically significant improvement in distant disease–free survival. Overall survival was not improved in the overall study population but was statistically significantly improved in the approximately 50% of women with lymph node–positive disease. The authors suggest that postmenopausal women completing adjuvant tamoxifen treatment may want to consider extended letrozole therapy.
HIF-1
and Farnesyltransferase Inhibitor SCH66336
Han et al. (p. 1272) examined whether the farnesyltransferase inhibitor SCH66336, which inhibits the growth of non–small-cell lung cancer (NSCLC), also inhibits angiogenesis of aerodigestive tract cancer cells, such as head and neck squamous cell carcinoma (HNSCC) cells. They found that SCH66336 appears to inhibit angiogenic activity of NSCLC and HNSCC cells by decreasing hypoxia- or insulin-like growth factor–stimulated hypoxia-inducible factor 1 (HIF-1) expression, and it inhibits vascular endothelial cell growth factor (VEGF) production by inhibiting the interaction between HIF-1 and heat shock protein Hsp90, resulting in the proteasomal degradation of HIF-1. They conclude that their results provide an important new rationale for the use of farnesyltransferase inhibitors as inhibitors of tumor angiogenesis in aerodigestive cancer.
Phase I Study of OGX-011 in Localized Prostate Cancer
OGX-011 inhibits the expression of the cytoprotective chaperone protein clusterin and enhances drug efficacy in xenograft models. Chi et al. (p. 1287) performed a phase I trial to determine the biologically effective dose of the drug in 25 men with localized prostate cancer who were scheduled to receive a prostatectomy. OGX-011 was administered to successive cohorts of men on days 1, 3, and 5 of the trial and then weekly from days 8–29; anti-androgen therapy was started on day 1. The men experienced no more than grade 1 and 2 toxicities during treatment. A dose-dependent decrease in clusterin expression was observed in the prostate cancer tissue and lymph nodes of the men who underwent prostatectomy on days 30–36 of the trial. The authors conclude that OGX-011 is well tolerated and reduces clusterin expression in primary prostate tumors and that the optimal dose at the schedule used is 640 mg.
Melanoma Risk and Endothelin Receptor B Mutations
To determine whether germline mutations in the endothelin receptor B gene (EDNRB), which is known to be involved in Hirschprung Disease (HSCR), are associated with risk of melanoma, Soufir et al. (p. 1297) sequenced the coding regions of EDNRB of 137 patients with malignant melanoma and of 130 ethnically matched control subjects. EDNRB mutations were identified in four control subjects and in 15 patients, 14 of whom carried mutations previously reported in HSCR, some of which result in loss of gene function. After performing multivariable analysis to adjust for melanoma risk factors, the authors found a direct association between melanoma risk and the presence of EDNRB mutations. They conclude that their data strongly suggest that EDNRB is involved in the predisposition of two different multigenic disorders, HSCR and melanoma.
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