Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance).

Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals, there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel-induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genotype and patient information from the paclitaxel arm of CALGB 40101 (Alliance), a phase III clinical trial evaluating adjuvant therapies for breast cancer in women, we estimated the variance in maximum grade and dose at first instance of sensory peripheral neuropathy. Our results suggest that paclitaxel-induced neuropathy has a heritable component, driven in part by genes involved in axon outgrowth. Disruption of axon outgrowth may be one of the mechanisms by which paclitaxel treatment results in sensory peripheral neuropathy in susceptible patients.

CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations.

The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

The interplay between gastric cancer cell lines and PBMCs mediated by the CC chemokine RANTES plays an important role in tumor progression.

In the present study, we investigated the effect of the RANTES-mediated interaction between gastric carcinoma cell lines and peripheral blood mononuclear cells (PBMCs) in tumor progression. RANTES production in PBMCs stimulated by highly metastatic cancer cell line-conditioned supernatants was higher than in those stimulated by a less metastatic gastric cancer cell line-conditioned supernatant. RANTES receptors were expressed in PBMCs, but not in those cancer cell lines; therefore it was suggested that RANTES might affect PBMCs but not cancer cells. Matrix metalloproteinase (MMP)-9 expression in PBMCs was examined. Similar to RANTES production, MMP-9 expression in PBMCs stimulated by highly metastatic cell line-conditioned supernatants was higher than in that stimulated by a less metastatic cell line-conditioned supernatant. Invasion assays of gastric cancer cell lines were performed. Cancer cells cultured with PBMCs invaded into Matrigel more frequently than those without PBMCs. This invasive activity was highly inhibited by an anti-RANTES antibody. These results suggest that tumor cells can acquire the potential for invasion by cooperating with PBMCs and RANTES plays an important role in the interplay between tumor cells and PBMCs. It is thus thought that RANTES might be a candidate molecular target in the therapeutic strategy for gastric cancers.

Prediction of sensitivity of esophageal tumors to adjuvant chemotherapy by cDNA microarray analysis of gene-expression profiles.

We applied cDNA microarray analyses of 9216 genes to establish a genetic method for predicting the outcome of adjuvant chemotherapy to esophageal cancers. We analyzed expression profiles of 20 esophageal cancer tissues from patients who were treated with the same adjuvant chemotherapy after removal of tumor by operation, and we attempted to find genes associated with the duration of survival after surgery. By comparing expression profiles of those cancer tissues, we identified by statistical analysis 52 genes that were likely to be correlated with prognosis and possibly with sensitivity/resistance to the anticancer drugs. We also developed a drug response score based on the differential expression of these genes, and we found a significant correlation between the drug response score and individual patients' prognoses. Our results indicated that this scoring system, based on microarray analysis of selected genes, is likely to have great potential for predicting the prognosis of individual cancer patients with the adjuvant chemotherapy.

Tubular adenoma of the breast in a 73-year-old woman.

A 73-year-old woman presenting with a right breast mass is described. The patient underwent lumpectomy under a diagnosis of breast cancer. However, histopathologically the surgical specimen was tubular adenoma of the breast. This is a rare benign tumor that is difficult to differentiate from breast cancer clinically, especially in elderly patients. We describe two reported cases of tubular adenoma in patients older than 65-years in Japan, as well as the present case.