The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up.

BACKGROUND: The role of adjuvant dose-intensive chemotherapy and its efficacy according to baseline features has not yet been established. PATIENTS AND METHODS: Three hundred and forty-four patients were randomized to receive seven courses of standard-dose chemotherapy (SD-CT) or three cycles of dose-intensive epirubicin and cyclophosphamide (epirubicin 200 mg/m(2) plus cyclophosphamide 4 mg/m(2) with filgrastim and progenitor cell support). All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS). This paper updates the results and explores patterns of recurrence according to predicting baseline features. RESULTS: At 8.3-years median follow-up, patients assigned DI-EC had a significantly better DFS compared with those assigned SD-CT [8-year DFS percent 47% and 37%, respectively, hazard ratio (HR) 0.76; 95% confidence interval 0.58-1.00; P = 0.05]. Only patients with estrogen receptor (ER)-positive disease benefited from the DI-EC (HR 0.61; 95% confidence interval 0.39, 0.95; P = 0.03). CONCLUSIONS: After prolonged follow-up, DI-EC significantly improved DFS, but the effect was observed only in patients with ER-positive disease, leading to the hypothesis that efficacy of DI-EC may relate to its endocrine effects. Further studies designed to confirm the importance of endocrine responsiveness in patients treated with dose-intensive chemotherapy are encouraged.

Quick Reads, September 15, 2014

IDPH Quick Reads is an electronic newsletter produced by the Director’s Office at the Iowa Department of Public Health. IDPH Quick Reads are published every three to four weeks.

Quick Reads, October 8, 2014

IDPH Quick Reads is an electronic newsletter produced by the Director’s Office at the Iowa Department of Public Health. IDPH Quick Reads are published every three to four weeks.

Quick Reads, November 20, 2014

IDPH Quick Reads is an electronic newsletter produced by the Director’s Office at the Iowa Department of Public Health. IDPH Quick Reads are published every three to four weeks.

Quick Reads, December 12, 2014

IDPH Quick Reads is an electronic newsletter produced by the Director’s Office at the Iowa Department of Public Health. IDPH Quick Reads are published every three to four weeks.

Quick Reads, January 14, 2015

IDPH Quick Reads is an electronic newsletter produced by the Director’s Office at the Iowa Department of Public Health. IDPH Quick Reads are published every three to four weeks.

Quick Reads, February 16, 2015

IDPH Quick Reads is an electronic newsletter produced by the Director’s Office at the Iowa Department of Public Health. IDPH Quick Reads are published every three to four weeks.

Quick Reads, March 11, 2015

IDPH Quick Reads is an electronic newsletter produced by the Director’s Office at the Iowa Department of Public Health. IDPH Quick Reads are published every three to four weeks.

Optimal CD8 T cell responsiveness is controlled within a defined TCR affinity window

Protective immune responses relyon TCR-mediated recognition of antigenspresented by MHC molecules. Tcells directed against tumor antigensare thought to express TCRs of loweraffinity/avidity than pathogen-specificT lymphocytes. An attractivestrategy to improve anti-tumor T cellresponses is to adoptively transferCD8+ T cells engineered with TCRsof optimized affinity. However, themechanisms that control optimal Tcell activation and responsiveness remainpoorly defined. We aim at characterizingTCR-pMHC binding parametersand downstream signalingevents that regulate T cell functionalityby using an in silico designedpanel of tumor antigen-specific TCRsof incremental affinity for pMHC(Kd100 M- 15 nM).We found that optimalT cell responses (cytokine secretionand target cell killing) occurredwithin a well-defined window ofTCR-pMHC binding affinity (5 M-1 M), while drastic functional declinewas detected in T cells expressingvery low and very high TCRaffinities,which was not caused by any increasein apoptosis. Whole-genomemicroarray analysis revealed that Tcells with optimal TCR affinitieshighly up-regulated transcription ofgenes typical of T cell activation (i.e.IFN-, NF-B and TNFR), while reducedexpression was detected in Tcells of very low or very high TCR affinity.Strikingly, hierarchical clusteringshowed that the latter two variantsclustered together with the un-stimulatedcontrol Tcells.Yet, despite commonclustering, several genes seemedto be differentially expressed, suggestingthat the mechanisms involvedin this "unresponsiveness state" maydiffer between those two variants. Finally,calcium influx assays also demonstratedattenuated responses in Tcells of very high TCR affinity. Ourresults indicate that optimal T cellfunction is tightly controlled within adefinedTCRaffinity window throughvery proximal TCR-mediated mechanisms,possibly at the TCR-pMHCbinding interface. Uncovering themechanisms regulating optimal/maximalT cell function is essential to understandand promote therapeutic designlike adoptive T cell therapy.

Quick Facts, July 2009

An overview of facts concerning the Department of Corrections

Quick Reads, April 7, 2015

IDPH Quick Reads is an electronic newsletter produced by the Director’s Office at the Iowa Department of Public Health. IDPH Quick Reads are published every three to four weeks.

Quick Facts, July 2014

An overview of facts concerning the Department of Corrections

Quick Facts, April 2014

An overview of facts concerning the Department of Corrections

Quick Facts, January 2014

An overview of facts concerning the Department of Corrections