Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Karolinska University Hospital Solna, Stockholm, Sweden.

Immunotherapy is being increasingly utilized for adjuvant treatment for breast cancer (BC). We have previously described immune functions during primary therapy for BC. The present study describes immune recovery patterns during long-term, unmaintained follow-up after completion of adjuvant therapy.A group of patients with primary BC had been treated with adjuvant radio-chemotherapy (RT + CT) 5-fluorouracil, epirubicin and cyclophosphamide (FEC) (n = 21) and another group with radiotherapy (RT) (n = 20) alone. Immunological testing of NK and T-cell functions was performed initially at the end of adjuvant treatment and repeated after 2, 6 and 12 months. NK cell cytotoxicity was significantly higher (P < 0.05) at all time-points in patients than in age-matched controls and did not differ between the two treatments groups during one year observation. In contrast, lower numbers of CD4 T-cells and lower expression of CD28 on T-cells was observed particularly in RT + CT patients and did not normalize during the observation period. The numbers of T(reg) cells (CD4(+)CD25(high)) were low in the RT + CT group during follow-up, as well as expression of TCRxi, Zap70, p56(lck), P59(fyn) and PI3 k in CD4(+) cells. In contrast, expression of intracellular cytokines (IFN-gamma, IL-2, IL-4) in CD4 and CD8 T cells were significantly higher in RT + CT patients than in the RT group and the difference increased during follow-up. In conclusion, NK-cell cytotoxicity increased during unmaintained long-term follow-up whereas CD4 and regulatory T cells as well as signal transduction molecules remained low following adjuvant radio-chemotherapy.

Share This

Sarah Cannon Research Institute, Nashville, TN 37203, USA. Howard.Burris@scresearch.net

The epothilones constitute a novel class of microtubule inhibitors that act like the taxanes by hyperstabilizing tubulin polymerization, thus disrupting functioning of the mitotic spindle. Natural epothilones produced by myxobacteria, and second- or third-generation partially or fully synthesized analogs, have been explored as cancer chemotherapy agents to replace or follow the taxanes. For those epothilones that have gone on to clinical development (epothilone B, ixabepilone, BMS-310705, ZK-EPO, KOS-862, and KOS-1584), preclinical investigations in breast cancer models are reviewed. All of these epothilones improve upon the cytotoxic activity of paclitaxel in various human breast cancer cell lines in vitro, but are also highly active in lines that are resistant to paclitaxel. Comparable antitumor activity has been demonstrated against nude mouse xenografts of paclitaxel-sensitive and -resistant breast cancer lines. Additionally, some analogs have reduced toxicity or increased water solubility that may permit oral administration, while others with enhanced tissue penetration show promise in animal models of breast cancer brain or bone metastasis and may provide benefits in patients with poor-prognosis advanced breast cancer.

Share This

Division of Hematology/Oncology, Weill Cancer Medical College of Cornell University, New York, NY 20021. ltv2001@med.cornell.edu

Standard cytotoxic chemotherapy of locally cancer advanced or metastatic breast cancer includes the microtubule-stabilizing taxanes, but like other cytotoxic drugs their effectiveness is compromised by resistance that is either inherent or develops during treatment. Epothilones, which also stabilize microtubules but by a different mechanism, are in clinical development primarily to overcome taxane or multidrug resistance, based on potent preclinical antitumor activity against resistant tumor lines. Ixabepilone is the best-studied epothilone clinically and is active in cancer patients with metastatic breast cancer that has been pretreated with, or had established resistance to, taxanes and/or anthracyclines. In a phase III trial in patients with anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer, adding ixabepilone to capecitabine significantly improved progression-free survival and the overall response rate compared with capecitabine alone. The primary toxicities associated with ixabepilone treatment are neuropathy and neutropenia, but both are generally manageable. Other epothilones currently in clinical studies are KOS-862, patupilone, ZK-EPO, BMS-310705, and KOS-1584, which have all shown activity in patients with pretreated or resistant metastatic breast cancer.

Share This

The University of breast cancer Texas MD Anderson Cancer Center, Houston, TX 77030, USA. festeva@mdanderson.org

Despite the recent trend toward treatment of early stage breast cancer aggressively with anthracyclines and taxanes, nearly half of those women will have metastatic recurrence. Moreover, because of the increasing prior exposure to these drugs, far more women facing first-line therapy for recurrent disease will now have developed anthracycline- and taxane-refractory metastatic breast cancer (ATRMBC), presenting a major therapeutic challenge. A number of established drugs are showing promise in this setting: capecitabine alone or combined with lapatinib; gemcitabine; vinorelbine; and oxaliplatin. At the same time, a variety of new drugs are emerging for potential use in ATRMBC. Among the drugs in clinical development that have shown promising activity include novel classes of compounds (camptothecins and epothilones), newer members of established classes (pemetrexed and vinflunine), and breast cancer agents with novel mechanisms of action (the mitosis inhibitor E7389 and the ascidian-derived anticancer compound trabectedin). Several molecularly targeted agents are also being evaluated in ATRMBC, including interleukin-2 receptor-binding denileukin diftitox, and 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), which inhibits the protein chaperone heat shock protein 90.

Share This

From the 1Department of Adult Health, School of Nursing, Indiana University; and 2Department of Psychology, School of Science, Indiana University-Purdue University, Indianapolis, IN.

OBJECTIVE:: To evaluate relationships among different measures of hot flashes, perceived hot flash interference, and associated outcomes (positive affect, negative affect) while controlling potential covariates. DESIGN:: Breast cancer survivors (N = 236) provided demographic data, objective hot flash frequency data via sternal skin conductance monitoring, prospective diary-based hot flash frequency and severity data, and questionnaire data via the Hot Flash Related Daily Interference Scale and the Positive and Negative Affect Scale. RESULTS:: Objective hot flash frequency and subjective hot flash severity emerged as separate factors in the structural equation model. Subjective hot flash frequency was associated with a high degree of unexplained variance (error) and seemed to be a potentially less accurate measure of either frequency or severity. Objective frequency was directly related to greater positive affect. In contrast, greater hot flash severity was (1) directly related to greater perceived hot flash interference and (2) indirectly related to more negative affect and lower positive affect through interference. CONCLUSIONS:: Findings provide a theoretical basis for selecting among symptom measures and anticipating how interventions aimed at different hot flash measures might affect perceived hot flash interference or associated outcomes. Because objective hot flash frequency and subjective hot flash severity seemed to measure different dimensions, measuring both may provide a more comprehensive picture of women’s symptom experiences.

Share This