Genetic predictors of acute toxicities related to radiation therapy following lumpectomy for breast cancer: a case-series study

INTRODUCTION: The cytotoxic effects of radiation therapy are mediated primarily through increased formation of hydroxyl radicals and reactive oxygen species, which can damage cells, proteins and DNA; the glutathione S-transferases (GSTs) function to protect against oxidative stress. We hypothesized that polymorphisms encoding reduced or absent activity in the GSTs might result in greater risk for radiation-associated toxicity. METHODS: Women receiving therapy in radiation units in Germany following lumpectomy for breast cancer (1998–2001) provided a blood sample and completed an epidemiological questionnaire (n = 446). Genotypes were determined using Sequonom MALDI-TOF (GSTA1, GSTP1) and Masscode (GSTM1, GSTT1). Biologically effective radiotherapy dose (BED) was calculated, accounting for differences in fractionation and overall treatment time. Side effects considered were grade 2c and above, as classified using the modified Common Toxicity Criteria. Predictors of toxicity were modelled using Cox regression models in relation to BED, with adjustment for treating clinic, photon field, beam energy and boost method, and potential confounding variables. RESULTS: Low activity GSTP1 genotypes were associated with a greater than twofold increase in risk for acute skin toxicities (adjusted hazard ratio 2.28, 95% confidence interval 1.04–4.99). No associations were noted for the other GST genotypes. CONCLUSION: These data indicate that GSTP1 plays an important role in protecting normal cells from damage associated with radiation therapy. Studies examining the effects of GSTP1 polymorphisms on toxicity, recurrence and survival will further inform individualized therapeutics based on genotypes

Distinct genes related to drug response identified in ER positive and ER negative breast cancer cell lines

Breast cancer patients have different responses to chemotherapeutic treatments. Genes associated with drug response can provide insight to understand the mechanisms of drug resistance, identify promising therapeutic opportunities, and facilitate personalized treatment. Estrogen receptor (ER) positive and ER negative breast cancer have distinct clinical behavior and molecular properties. However, to date, few studies have rigorously assessed drug response genes in them. In this study, our goal was to systematically identify genes associated with multidrug response in ER positive and ER negative breast cancer cell lines. We tested 27 human breast cell lines for response to seven chemotherapeutic agents (cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, gemcitabine, and paclitaxel). We integrated publicly available gene expression profiles of these cell lines with their in vitro drug response patterns, then applied meta-analysis to identify genes related to multidrug response in ER positive and ER negative cells separately. One hundred eighty-eight genes were identified as related to multidrug response in ER positive and 32 genes in ER negative breast cell lines. Of these, only three genes (DBI, TOP2A, and PMVK) were common to both cell types. TOP2A was positively associated with drug response, and DBI was negatively associated with drug response. Interestingly, PMVK was positively associated with drug response in ER positive cells and negatively in ER negative cells. Functional analysis showed that while cell cycle affects drug response in both ER positive and negative cells, most biological processes that are involved in drug response are distinct. A number of signaling pathways that are uniquely enriched in ER positive cells have complex cross talk with ER signaling, while in ER negative cells, enriched pathways are related to metabolic functions. Taken together, our analysis indicates that distinct mechanisms are involved in multidrug response in ER positive and ER negative breast cells. © 2012 Shen et al

Analysis of in vitro chemoresponse assays in endometrioid endometrial adenocarcinoma: an observational ancillary analysis

Abstract Background Chemotherapy plays a role in the treatment of endometrioid endometrial cancer (EEC); however, tumor grade may affect response. Our objective was to evaluate associations between tumor grade and in vitro chemoresponse. Methods We conducted an analysis of primary tumor samples from women with EEC undergoing in vitro chemoresponse testing. Results were classified as sensitive (S), intermediate (I), or resistant (R) to each drug tested. Correlations between tumor grade and response were examined. Results Data was collected from 159 patients: 28 with grade 1 (18%), 52 with grade 2 (32%), and 79 (50%) with grade 3 tumors. Median age of patients was 62 (range 31–92). Most patients were Caucasian (83%) with advanced disease (Stage III: 50.9%; Stage IV: 13.2%). Overall chemoresponse was similar across all grades. Fifty percent, 56 and 51% for grade 1, 2, and 3 tumors, respectively, demonstrated S results to at least 1 agent. There was no association between grade and in vitro response to chemotherapy agents (p > 0.05) except a marginal association between grade and doxorubicin response (p = 0.08). Grade 1 and 2 cancers were more likely to demonstrate R results for doxorubicin compared to grade 3 cancers (G1: 19% vs G2: 25% vs G3: 8%; p = 0.08). In a subset tested for all 7 agents, only one patient tumor was pan-R and 4 were pan-S. Conclusions Based on our data, grades 1–3 EEC have similar in vitro chemoresponse. These findings suggest that chemotherapy may be useful in advanced low grade EECs, but further clinical correlation is needed