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Context: Breast cancer estrogen-receptor (ER) status is useful in predicting benefit from endocrine therapy. It may also help predict which patients benefit from advances in adjuvant chemotherapy.Objective: To compare differences in benefits from adjuvant chemotherapy achieved by patients with ER-negative vs ER-positive tumors.Design, Setting, and Patients: Trial data from the Cancer and Leukemia Group B and US Breast Cancer Intergroup analyzed; patient outcomes by ER status compared using hazards over time and multivariate models. Randomized trials comparing (1): 3 regimens of cyclophosphamide, doxorubicin, and fluorouracil (January 1985 to April 1991); (2) 3 doses of doxorubicin concurrent with cyclophosphamide, with or without subsequent paclitaxel (May 1994 to April 1997); (3) sequential doxorubicin, paclitaxel, and cyclophosphamide with concurrent doxorubicin and cyclophosphamide followed by paclitaxel, and also 3-week vs 2-week cycles (September 1997 to March 1999). A total of 6644 node-positive breast cancer patients received adjuvant treatment.Main Outcome Measures: Disease-free and overall survival.Results: For ER-negative tumors, chemotherapy improvements reduced the relative risk of recurrence by 21%, 25%, and 23% in the 3 studies, respectively, and 55% comparing the lowest dose in the first study with biweekly cycles in the third study. Corresponding relative risk reductions for ER-positive tumors treated with tamoxifen were 9%, 12%, and 8% in the 3 studies, and 26% overall. The overall mortality rate reductions associated with chemotherapy improvements were 55% and 23% among ER-negative and ER-positive patients, respectively. All individual ER-negative comparisons and no ER-positive comparisons were statistically significant. Absolute benefits due to chemotherapy were greater for patients with ER-negative compared with ER-positive tumors: 22.8% more ER-negative patients survived to 5 years disease-free if receiving chemotherapy vs 7.0% for ER-positive patients; corresponding improvements for overall survival were 16.7% vs 4.0%.Conclusion: Among patients with node-positive tumors, ER-negative breast cancer, biweekly doxorubicin/cyclophosphamide plus paclitaxel lowers the rate of recurrence and death by more than 50% in comparison with low-dose cyclophosphamide, doxorubicin, and fluorouracil as used in the first study. [ABSTRACT FROM AUTHOR]

Antibody-based therapy has revitalized the world of cancer therapeutics since rituximab was first approved for the treatment of Non-Hodgkin's Lymphoma. Monoclonal antibodies against cancer antigens have been successful strategies for only a handful of cancer types due to many reasons including lack of antibody specificity and complex nature of tumor milieu which interfere with antibody efficacy. Polyspecific antibodies are promising class of anti-cancer agents which can be directed at multiple tumor antigens to eradicate tumor cells more precisely and effectively. They may overcome some of these limitations and have already changed treatment landscape for some malignancies such as B cell acute lymphoblastic leukemia. Pre-clinical studies and early phase clinical trials have demonstrated that this approach may be an effective strategy even for solid tumors. This review focuses on the development of bispecific and trispecific antibody therapy for the treatment of solid tumor malignancies and highlights the potential they hold for future therapies to come.

Inhibitory ligands on tumor cells and their corresponding receptors on T cells are collectively called immune checkpoint molecules and have emerged as druggable targets that harness endogenous immunity to fight cancer. Immune checkpoint inhibitors targeting CTLA-4, PD-1 and PD-L1 have been developed for the treatment of patients with non-small-cell lung cancer and other malignancies, with impressive clinical activity, durable responses and a favorable toxicity profile. This article reviews the development, current status and future directions for some of these agents. The efficacy and safety data for drugs such as ipilimumab, nivolumab, pembrolizumab, atezolizumab and durvalumab are reviewed, along with combination strategies and response evaluation criteria. The toxicity profiles and predictive biomarkers of response are also discussed.

Background: To examine the effect on cognitive function of adjuvant ovarian function suppression (OFS) for breast cancer., Methods: The Suppression of Ovarian Function (SOFT) trial randomised premenopausal women with hormone receptor-positive breast cancer to 5 years adjuvant endocrine therapy with tamoxifen+OFS, exemestane+OFS or tamoxifen alone. The Co-SOFT substudy assessed objective cognitive function and patient reported outcomes at randomisation (T0), and 1 year later (T1); the primary endpoint was change in global cognitive function, measured by the composite objective cognitive function score. Data were compared for the pooled tamoxifen+OFS and exemestane+OFS groups vs the tamoxifen alone group using the Wilcoxon rank-sum test., Results: Of 86 participants, 74 underwent both T0 and T1 cognitive testing; 54 randomised to OFS+ either tamoxifen (28) or exemestane (26) and 20 randomised to tamoxifen alone. There was no significant difference in the changes in the composite cognitive function scores between the OFS+ tamoxifen or exemestane groups and the tamoxifen group (mean±s.d., -0.21±0.92 vs -0.04±0.49, respectively, P=0.71, effect size=-0.20), regardless of prior chemotherapy status, and adjusting for baseline characteristics., Conclusions: The Co-SOFT study, although limited by small samples size, provides no evidence that adding OFS to adjuvant oral endocrine therapy substantially affects global cognitive function.

There is no available targeted therapy for triple-negative or its more aggressive subtype, basal-like breast cancer. Multiple therapeutic strategies based on translational knowledge have not improved the treatment options for triple negative patients. As understanding of molecular pathways that drive tumor development is rapidly increasing, it is imperative to adapt our treatment strategies to perturbations in molecular pathways driving the malignant process. Basal-like breast cancers over-express EGFR (without mutations or EGFR gene amplifications) and have p53 mutations. While EGFR drives the malignant behavior in triple negative breast cancer (TNBC), anti-EGFR therapies have fallen short of the expected results in clinical trials. Here we bring evidence that the less than optimal results of the anti-EGFR therapies may be explained in part by the increased potency of the EGFR signaling due to increased endosomal recycling. The functional connection between EGFR and endosomal trafficking in TNBC is mutant p53 found in the most aggressive forms of TNBC. Mutant p53 acquires oncogenic functions and binds p63 protein, a member of p53 family with tumor suppressor activities. In the absence of functional p63 there is an upregulation of endosomal recycling EGFR and integrin to the membrane with increased proinvasive abilities of cancer cells. Blocking endosomal trafficking combined with anti-EGFR treatments may result in better clinical outcomes in TNBC., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

For more than 2,000 years, arsenic and its derivatives have shown medical utility. Owing to the toxicities and potential carcinogenicity of arsenicals, their popularity has fluctuated. The exact mechanism of action of therapeutic arsenic is not well characterized but likely to involve apoptosis, generation of reactive oxygen species, inhibition of intracellular transduction pathways, and cell functions. Arsenic trioxide has received approval for use in patients with relapsed acute promyelocytic leukemia for remission induction. Arsenic has additionally shown activity in a range of solid tumors, myelodysplastic syndrome, multiple myeloma, and in autoimmune diseases. The following is a review of the history of arsenic, its cellular metabolism, pharmacology, genetic basis of disposition, associated toxicities, and clinical efficacy.

Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. Although trastuzumab is a very active agent in HER2-overexpressing breast cancer, the majority of patients with metastatic HER2-overexpressing breast cancer who initially respond to trastuzumab develop resistance within 1 year of initiation of treatment and, in the adjuvant setting, progress despite trastuzumab-based therapy. The antibody-drug conjugate trastuzumab-DM1 (T-DM1) was designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent antimicrotubule agent, DM1 (N-methyl-N-[3-mercapto-1-oxopropyl]-l-alanine ester of maytansinol), a maytansine derivative, to HER2-overexpressing breast cancer cells. T-DM1 is the first antibody-drug conjugate with a nonreducible thioether linker in clinical trials. Phase I and II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are awaiting final results; the EMILIA trial is evaluating T-DM1 compared with lapatinib plus capecitabine, and early positive results have been reported. The MARIANNE trial is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Here, we summarize evidence from clinical studies and discuss the potential clinical implications of T-DM1.

Background: The benefit of adding a vena cava filter to anticoagulation in treating cancer patients with venous thromboembolism remains controversial. We initiated this study as the first prospectively randomized trial to evaluate the addition of a vena cava filter placement to anticoagulation with the factor Xa inhibitor fondaparinux sodium in patients with cancer., Methods: Sixty-four patients with deep vein thrombosis (86 %) and/or pulmonary embolism (55 %) were randomly assigned to receive anticoagulation with fondaparinux sodium with or without a vena cava filter. Endpoints included rates of complications by treatment arm, recurrent thromboembolism, complete resolution of thromboembolism, and survival rates., Results: No patient had a recurrent deep vein thrombosis; two (3 %) patients had new pulmonary emboli, one in each randomized cohort. Major bleeding occurred in three patients (5 %). Two patients on the vena cava filter arm (7 %) had complications from the filter. Median survivals were 493 days in the anticoagulation only arm and 266 days for anticoagulation + vena cava filter (p < 0.57). Complete resolution of venous thromboembolism occurred in 51 % of patients within 8 weeks of initiating anticoagulation., Conclusions: No advantage was found for placement of a vena cava filter in addition to anticoagulation with fondaparinux sodium in terms of safety, recurrent thrombosis, recurrent pulmonary embolism, or survival in this prospective randomized trial evaluating anticoagulation plus a vena cava filter in cancer patients. Favorable complete resolution rates of thrombosis were observed on both study arms.

An in-vitro 72-h assay using median effect analysis and curve shift analysis was used to evaluate the utility of potentially clinically useful combinations of agents for synergism or antagonism. Six human breast cancer cell lines, both receptor rich and receptor poor, were studied.Panobinostat (LBH-589), a pan histone deacetylase inhibitor with a multitude of biological effects, exhibits time-dependent synergistic effects in breast cancer cell lines with docetaxel, doxorubicin, or gemcitabine in clinically relevant concentrations. Survivin expression was markedly downregulated in the presence of panobinostat with gemcitabine. Bortezomib, a proteasome inhibitor,markedly enhanced the cytotoxic effects of panobinostat combined with gemcitabine. Panobinostat did not demonstrate universal enhancement of cytotoxic drugs,and therefore, synergy was dependent on the second agent selected. No synergy was noted with anti-Her2 agents in Her2 overexpressing cell lines. Metformin combined with panobinostat demonstrated no synergy in this test system. These effects were confirmed by an apoptosis assay and caspase-3 production. A positive drug interaction was identified. The triplet of panobinostat with either doxorubicin/carboplatin or gemcitabine/carboplatin was especially potent in all cell lines. As all these agents are clinically available, further studies of the potent combinations are warranted.

Although platinum based therapy has improved short term survival of patients with metastatic ovarian cancer, the majority of patients continue to relapse and eventually die of their disease. Currently, a plethora of agents are in development, but how to combine them to enhance efficacy remains largely empiric. We have used short in vitro culture of defined cell lines with application of promising agents and analysis for cell death using a MTT assay to identify potentially useful combinations. Using median effect analysis, curve shift analysis and apoptosis assays, we can identify when agents are synergistic or antagonistic when applied together. Up to three agents can be studied in combination. Using three cell lines: SK-OV3, CaOV-3, and ES-2 (a clear cell tumor), we have identified that panobinostat (LBH-589), a broad histone deacetylase inhibitor in clinical trials, demonstrates global synergy with gemcitabine, with paclitaxel, and additive to synergistic effects with 5'DFUR. The triplet of panobinostat, doxorubicin, and carboplatin is especially synergistic in these cell lines. These effects are cytotoxic and not cytostatic. As all these agents are used clinically, we have identified combinations which warrant further investigation.

The hereditary forms of breast cancer identified by BRCA1 and BRCA2 genes have a defect in homologous DNA repair and demonstrate a dependence on alternate DNA repair processes by base excision repair, which requires poly(ADP-ribose) polymerase 1 (PARP-1). siRNA and deletion mutations demonstrate that interference with PARP-1 function results in enhanced cell death when the malignancy has a defect in homologous recombination. These findings resulted in a plethora of agents in clinical trials that interfere with DNA repair, and these agents offer the potential of being more selective in their effects than classic chemotherapeutic drugs. An electronic search of the National Library of Medicine for published articles written in English used the terms "PARP inhibitors" and "breast cancer" to find prospective, retrospective and review articles. Additional searches were done for articles dealing with mechanism of action. A total of 152 articles dealing with breast cancer and PARP inhibition were identified. PARP inhibition not only affects nonhomologous repair, but also has several other nongenomic functions. Mutational resistance to these agents was seen in preclinical studies. To date, PARP-1 inhibitors were shown to enhance cytotoxic effects of some chemotherapy agents. This new class of agents may offer more therapeutic specificity by exploiting a DNA repair defect seen in some human tumors with initial clinical trials demonstrating antitumor activity. Although PARP inhibitors may offer a therapeutic option for selected malignancies, the long-term effects of these agents have not yet been defined.

Small regulatory ribonucleic acids (RNAs) are recently recognized as being connected with a growing list of common diseases such as: cancer, heart disease, diabetes and inflammation and to date more than 5,000 publications are recorded on PubMed alone. Specific pathways generate each class of RNAs and their activities converge in the process of silence interference. In gastrointestinal malignancies microRNAs are deregulated, sometimes found in higher or lower levels depending on the type of malignancy and stage of the disease, functioning either as tumor suppressors or as oncogenes they interact forming regulatory loops with known transcription factors and signaling pathways. MiRNAs extracted from archived tissue biopsies can be used effectively as diagnostic, prognostic tools and molecular markers because they are stable over time and resistant to RNAse degradation. The distinct physiology of small RNAs may translate in more targeted cancer therapies in the near future., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Amonafide-l-malate (amonafide) is a unique DNA intercalator that maintains activity in the presence of MDR mechanisms, a frequent cause of treatment-failure in secondary AML. 43 patients with relapsed/refractory or secondary AML or CML blast crisis were enrolled into two phase I dose-escalation studies investigating amonafide as monotherapy or in combination with cytarabine. 3/17 patients in the monotherapy trial and 10/26 patients in the combination trial achieved a complete remission. Between both trials responses occurred in 9/20 patients with secondary AML. Both trials demonstrated an acceptable safety profile and significant antileukemic activity in patients with poor-risk AML, especially those with secondary AML., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

The use of cytotoxic therapy in the fit elderly breast cancer patient has been tempered with concerns of age, physical function, and co-morbid illness. In the appropriate patient with biologically aggressive disease, such as receptor poor breast cancer, it is reasonable to consider combination chemotherapy as part of an adjuvant program. If this approach is to be employed, the physician must also consider the patient's co-morbid conditions and status of function in society as potential indicators of toxicity or lack of benefit. In this case, a formal geriatric assessment is of value. A Cancer and Leukemia Group B (CALGB) trial of monotherapy vs combination cytotoxic therapy as adjuvant treatment for localized breast cancer patients over 65 years of age has determined that the combination approach is superior to single agent therapy. In an unplanned analysis of receptor rich and receptor poor tumors, the patients with receptor poor tumors seemed to achieve the greatest benefit from combination cytotoxic therapy. Adjuvant chemotherapy can also be considered for patients with high-risk receptor rich breast cancers. However, the use of chemotherapy in the elderly patient with breast cancer is largely based upon data emerging from trials in younger patients. Studies specifically for patients over 65 years of age are urgently needed in this population to provide evidence-based proof of the current approach.

The Hedgehog (Hh) signaling pathway plays a key role in a variety of processes, such as embryogenesis and maintenance of adult tissue homeostasis. It is also becoming increasingly clear that this pathway can have a crucial role in tumorigenesis. Most recently, the Hh signaling pathway has been implicated in the development and maintenance of breast cancer. Here we review Hh signaling, advances in small molecule and antibody-based inhibitors targeting the Hh pathway, and dysregulation of the Hh signaling pathway in breast cancer.

Background: Cancer patients have an increased incidence of venous thromboembolism (VTE). Inferior vena cava (IVC) filters are used extensively in the US, and more than 40 000 are inserted annually. The impact on survival of cancer patients receiving IVC filters has not been studied., Methods: A retrospective study examined 206 consecutive cancer patients with VTE to compare the effects of IVC filter placement with anticoagulation (AC) therapy on overall survival (OS), as measured from the time of VTE. Patients were classified into 3 treatment groups: AC (n = 62), IVC filter (77), or combination IVC filter + AC (67)., Results: Treatment groups did not differ with respect to age, sex, or albumin levels. Median OS was significantly greater in patients treated with AC (13 months) compared with those treated with IVC filters (2 months) or IVC + AC (3.25 months; P < .0002). IVC patients were 1.9 times more at risk of death than AC only (hazard ratio = .528; 95% confidence interval = .374 to .745). Multivariate analysis revealed that performance status and type of thrombus were not confounders and had no effect on OS., Conclusion: The need for the insertion of an IVC filter projected markedly reduced survival. Patients requiring an IVC filter rather than AC as initial therapy face a 2-fold increase in risk of death. Whether or not this therapeutic procedure has a positive impact on outcome in cancer patients is uncertain. Complications resulting from thrombosis were also analyzed in this cohort. A prospective randomized trial at our institution is addressing this issue.

Background: Hypersensitivity is a well-known complication of the platinum agents cisplatin and carboplatin. Although hypersensitivity to oxaliplatin has been noted, the incidence varies significantly in reports. Risk factors for developing reactions specifically to oxaliplatin have not been evaluated. We report the 5-year incidence of hypersensitivity to oxaliplatin in our clinical program, the patient and disease characteristics associated with its occurrence, and review the literature., Methods: Clinical information on all patients treated with oxaliplatin between September 2002 and August 2007 was retrospectively reviewed. Data from patients who experienced hypersensitivity were compared to patients treated with this agent who did not. Risk factors investigated included age, sex, diagnosis, disease stage, presence of preexisting allergies, chemotherapy received, and use of oxaliplatin in front-line versus salvage therapy., Results: 247 patients received oxaliplatin, with 29 experiencing hypersensitivity, for an incidence of 11.7% (95% CI 7.7-15.8). Grade 3/4 events occurred in 1.6%. Hypersensitivity was associated with younger mean age (54.9 +/- 12.5 vs. 60.4 +/- 12.4 years with reactions vs. those without, p = 0.02), female gender (17.2% of females vs. 6.4% of males, p = 0.01) and with use of oxaliplatin as salvage therapy (23.9% second-line or higher vs. 9.1% front-line, p = 0.01)., Conclusions: Our data demonstrate an incidence of hypersensitivity to oxaliplatin of 11.7%, with grade 3/4 events in 1.6%. As use of this agent becomes more widespread, increased vigilance for this potentially serious complication should be high, especially amongst younger patients, females, and with the use of oxaliplatin as salvage therapy; three newly recognized potential risk factors., (Copyright 2009 S. Karger AG, Basel.)

Epothilones are a new class of antimicrotubule agents currently in clinical trials. Their chemical structures are distinct from taxanes and are more amenable to synthetic modification. Six epothilones have been studied in preclinical and clinical trials: patupilone (epothilone B), ixabepilone (BMS247550), BMS 310705, sagopilone (ZK-EPO), KOS-862 (epothilone D), and KOS-1584. In vitro data have shown increased potency in taxane-sensitive and taxane-resistant cancer cell lines. This enhanced cytotoxic effect has been attributed to epothilone being a poor substrate for p-glycoprotein drug resistance protein and having high affinity to the various beta tubulin isoforms. Phase I clinical data have shown different dose-limiting toxicities for each of the epothilones. These effects are drug specific, dose specific, and schedule of administration specific. While diarrhea and myelosuppression are the dose-limiting toxicities for patupilone and BMS 310705, respectively, neurologic toxicity, as seen with taxanes, is the dose-limiting toxicity of ixabepilone, sagopilone, and KOS-862. In an effort to decrease neurologic toxicity, investigators have modified dosing schedules with limited success. Ixabepilone has the most mature clinical results with published phase II and III data, and regulatory approval for clinical use in the treatment of breast cancer. Ixabepilone has also been combined with other anticancer agents and has regulatory approval in combination with capecitabine for heavily treated breast cancer.

Hsp90 (heat shock protein 90) is a molecular chaperone that modulates the stability and/or transport of a diverse set of critical cellular regulatory, metabolism, organization, and signaling proteins. Binding to Hsp90 is required for normal function of many proteins. In addition, Hsp90 has an extra-cellular function. It is found in two isotypes: alpha which is inducible and beta which is constitutive. Tumor cells frequently over express Hsp90alpha, and Hsp90 is implicated in cancer progression. Hence Hsp90 has emerged as a potential target for cancer treatment. A variety of agents have been found to interfere with Hsp function, mainly by binding to an ATP binding site on the molecule. More recent agents interfere with protein binding or the dimerization of Hsp90 needed for function. Preclinical studies have demonstrated that disruption of the many client proteins chaperoned by Hsp90 is achievable and associated with significant growth inhibition, both in vitro and in tumor xenografts. As a result, agents which interfere with this protein's function are being tested in the clinic as a targeted method of interfering with malignant growth. We review the current clinical status of therapeutic efforts to perturb this pathway and discuss future directions.

Classical chemotherapy has an active, but limited, role in acute leukemia with relapse common in adult patients. Recent evidence has implicated signal transduction pathways in leukemic progression and also in resistance to cytotoxic therapy. We have used a short-term, in-vitro incubation assay with cytotoxic analysis by MTT, confirmed by histone-associated DNA fragmentation, to evaluate both classical and nonclassical combinations of drugs. Isobologram median effect analysis, confirmed by curve shift analysis, was used to identify synergy and antagonism. Fluvastatin, a prenylation inhibitor, demonstrates global enhancement of the effects of classical agents in both AML-193 and KG-1 cell lines. Similarly, the m-TOR inhibitors, RAD-001 (everolimus) and rapamycin, also cause time-dependent global enhancement of cytotoxic agents. At clinically achievable combinations, RAD-001 perturbs the AKT pathway in vitro. The unique combination of fluvastatin and an m-TOR inhibitor was synergistic in both cell lines. These effects were independent of whether or not human plasma was used in the assay system. These studies suggest several novel combinations of agents that need to be evaluated in the management of leukemia.

Breast cancer is the one of leading causes of cancer-related deaths in women within economically developed regions of the world. The heterogeneity of the natural history of breast cancer complicates patient management in that there is tremendous variability in response to treatment and for survival. More recently, several biomarkers (hormone receptor status and HER2 expression) have been added to the risk evaluation and therapeutic assessments. Evolving knowledge of molecular biology and newer techniques, such as genomics and proteomics, offer the potential to better define the biologic nature of the disease process, both for risk and therapy. This review discusses classical as well as new prognostic and predictive techniques. These are leading to a paradigm shift from empirical treatment to an individually tailored approach, which may soon become a realistic option for patients, based on specific molecular profiles.

Hemodialysis complicated by heparin-induced thrombocytopenia (HIT) is a rare event requiring anticoagulation with direct-thrombin inhibitors. Contaminant calcific uremic arteriolopathy (calciphylaxis) further complicates this situation due to the possibility that warfarin anticoagulation may exacerbate skin necrosis. The authors report a patient with renal failure and calciphylaxis who developed HIT after starting hemodialysis. She was successfully treated with Argatroban.

Synuclein gamma (SNCG), previously identified as a breast cancer-specific gene (BCSG1), is highly expressed in breast carcinomas but not in normal epithelium. SNCG regulates many pathways in growth and progression of breast cancer. To determine if SNCG is a biomarker for clinical prognosis of breast cancer, we generated a panel of murine monoclonal antibodies (mAbs) against human SNCG and correlated SNCG protein expression in 358 clinical breast cancer specimens with clinical outcome. A panel of 14 mAbs was characterized by ELISA, immunoprecipitation (IP), Western blot, immunocytochemistry and immunohistochemistry. SNCG protein expression was determined in 438 clinical breast specimens by immunohistochemical analysis using mAb 5C5. Expression of SNCG was strongly correlated with the stage, lymph node involvement, metastasis, tumor size and Her-2 status, but its expression was not associated with ER and PR expression status. While 71.4% of advanced breast cancers were positive for SNCG expression, only 26.8% of Stage I/II breast cancers were positive for SNCG expression and 5.2% of benign hyperplasia expressed SNCG. SNCG protein was not detectable in normal tissue adjacent to breast cancer. After a median follow-up of 64 months, patients with an SNCG-positive tumor had a significantly shorter disease-free survival and overall survival and a high probability of death compared no expression of SNCG. Multivariate analysis demonstrated that SNCG was a strong independent prognostic variable. SNCG is a new unfavorable prognostic marker for breast cancer progression and a potential target for breast cancer treatment., ((c) 2007 Wiley-Liss, Inc.)

The combination of anticancer drugs used in the clinic has been based upon empiricism, and the potential permutations of currently available drugs overwhelm the clinical trials system. Recently, investigators have suggested that the combination of a blockade of vital signal transduction pathways in combination with more standard therapy might enhance anticancer effect. Using a panel of breast cancer cell lines and isobologram median effect analysis, a method of determining synergism or antagonism of drugs, we have investigated in vitro potentially clinically useful combinations of agents with the human cell lines MCF7/wt, MCF7/adr, BT474, and SK-BR-3 grown in log phase. Results were confirmed by curve shift analysis. Cells were exposed to the agent(s) for 72 h and then analyzed for cytotoxicity using a MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyl-tetrazolium bromide) assay. Fluvastatin, an inhibitor of prenylation with excellent tolerability in man, was chosen to disrupt signal transduction pathways and thus potentially enhance the effect of more traditional anticancer agents. Anticancer agents tested were cytotoxics used in the treatment of breast cancer, trastuzumab, and rapamycin as an inhibitor of the AKT pathway. Fluvastatin combined with trastuzumab demonstrates global synergy of cytotoxic effect that is confirmed by apoptosis assay. These effects could only be partially reversed by adding farnesol or geranylgeraniol to restore prenylation. Epirubicin is also synergistic with fluvastatin in three of the four cell lines. Rapamycin, an inhibitor of MTOR, was synergistic with fluvastatin in two of the four cell lines and antagonistic in two other cell lines. The combination of fluvastatin or another inhibitor of prenylation and trastuzumab may be attractive for clinical development as the effect of trastuzumab in Her2/neu positive breast tumors is incomplete as a single agent.

Background: Irinotecan and capecitabine have a broad spectrum of activity in human malignancy and are synergistic in an animal model when irinotecan precedes capecitabine., Patients and Methods: A Phase I design of the combination of irinotecan IV Day 1 with capecitabine on Days 2-8 every 2 weeks was evaluated in 27 adult patients with solid tumors. Two sequential schema were used: Arm A fixed the dose of irinotecan at 100 mg/m(2) and escalated capecitabine in cohorts, and arm B fixed the dose of capecitabine at 750 mg/m(2) PO BID and escalated the dosage of irinotecan., Results: Neutropenia was dose limiting with nausea and diarrhea as the most common nonhematological toxicities. Significant interpatient variation in toxicity occurred despite uniform dosing. No Grade IV toxicities were encountered. Grade III toxicity occurred in first cycle in 15 percent (3/20) patients in arm A and 29 percent (2/7) of patients in arm B. All toxicities were reversible. Repetitive dosing was feasible with prolonged disease stabilization in 8 patients., Conclusions: The suggested Phase II dose of this combination and schedule is irinotecan 100 mg/m(2) and capecitabine 1000 mg/m(2) BID. Some patients tolerated a capecitabine dose as high as 1250 mg/m(2) BID.

Metastatic breast cancer develops in approximately 50% of women diagnosed with breast cancer. The optimal treatment for patients with metastatic breast cancer has yet to be defined, owing to the heterogeneity of this group and the available agents. Patients with metastatic breast cancer often receive single-agent treatment in sequence as it is unclear whether combination therapy with cytotoxic drugs offers an overall disease-free survival benefit and single agents may offer less toxicity. The advantages of combination cytotoxic therapies have included higher response rates. However, such trials have not stratified on rapidity of disease progression or on tumor bulk. In previous studies, docetaxel is one of the few cytotoxic agents to demonstrate a survival benefit in anthracycline-resistant patients and thus it has become a vital component of cytotoxic therapy. Capecitabine is also an important oral drug and has demonstrated activity in patients pretreated with anthracyclines and taxanes. Recent preclinical and clinical trials of this combination have demonstrated an increased time to tumor progression and overall survival benefit. Paclitaxel combined with gemcitabine has been compared with docetaxel plus capecitabine, with similar response rates and survival benefits. As patients on these trials have not received uniform crossover to the other active agent, whether or not the combination therapy offers an advantage for the entire cohort of metastatic patients or may be indicated for specific subgroups remains uncertain. Combination treatments may be preferable to sequential therapy for patients requiring urgent reduction in their tumor burden. Combinations of cytotoxic agents in combination with biological agents are currently being defined.

Targeted therapy for breast carcinoma has achieved a major advance with the use of trastuzumab in Her2/neu-positive tumors. The epidermal growth factor receptor superfamily thus becomes an attractive target for therapeutic agents. As the epidermal growth factor receptor tyrosine kinase family has a conformational binding site, which allows small molecules to interfere with its function, we have explored the effects of a dual kinase (epidermal growth factor receptor-1 and epidermal growth factor receptor-2) inhibitor (GW282974X) with a variety of cytotoxic agents looking for synergistic effects in vitro. Using a median effect model in four breast cancer cell lines in vitro, cytotoxic agents commonly used in treatment of human malignant disease were combined with trastuzumab or one of two epidermal growth factor receptor tyrosine kinase inhibitors in a 72-h culture and then analyzed for cytotoxic effect by 3-[26]-2,5-diphenyl-tetrazolium bromide assay. Combination index values within one standard deviation of unity were considered additive, less than unity as synergistic and more than unity as antagonistic. Synergistic results were confirmed by curve shift analysis and by an enzyme-linked immunosorbent assay measuring apoptosis by cytoplasmic histone-associated DNA fragments. Quantitative real-time polymerase chain reaction analysis was used to measure the expression of three of the critical enzymes in 5'-deoxy-5-fluorouridine metabolism and activity: thymidine phosphorylase, dihydropyrimidine dehydrogenase and thymidine synthase. 5'-Deoxy-5-fluorouridine with GW282974X demonstrated global synergy, both in high and low expressing epidermal growth factor receptor breast cancer cell lines. These results were confirmed by apoptosis assay and cell counts. RNA quantification following treatment with the dual kinase inhibitor suggested reduction in thymidine synthase levels to be a potential mechanism of synergy. The triplet of trastuzumab, GW282974X and 5'-deoxy-5-fluorouridine, and the triplet of GW282974X, epirubicin and 5'-deoxy-5-fluorouridine were highly synergistic in low expression cells (MCF7/wt) and high expression cells (MCF7/adr). These experiments suggest further studies of the dual kinase inhibitor with selected cytotoxics such as 5'-deoxy-5-fluorouridine are warranted.

Objectives: To identify synergistic combinations of clinically available agents with zoledronic acid which would enhance antitumor activity as measured by median effect isobologram analysis and apoptosis assays in vitro., Methods: The interaction of zoledronic acid as a doublet with either carboplatin, cisplatin, 5'DFUR, docetaxel, epirubicin, fluvastatin, gemcitabine, imatinib, paclitaxel, trastuzumab, or vinorelbine was studied in a 72-hour in vitro system using defined human cancer cell lines grown as a monolayer in exponential phase. Drug effect on growth was measured by a standard MTT assay. Median effect isobologram analysis was applied to the results to determine the presence of synergism, additive effects, or antagonism of drug combinations. Synergistic combinations were also assayed by a cytoplasmic histone-associated DNA fragmentation apoptosis assay to verify that the effect was not cytostatic., Results: Zoledronic acid with gemcitabine demonstrated global cytotoxic synergy across 7 of 8 cell lines. Clinically achievable concentrations of fluvastatin with zoledronic acid also demonstrated synergy in 7 of 8 cell lines. All the breast cancer cell lines were sensitive. Zoledronic acid and epirubicin were antagonistic in all 4 breast cell lines studied., Conclusions: Combinations of zoledronic acid with either gemcitabine or fluvastatin may have a therapeutic role in treatment of bone metastasis of selected malignancies., (Copyright 2006 S. Karger AG, Basel.)

Purpose: LY293111, a novel diaryl ether carboxylic acid derivative, is a potent and selective inhibitor of the lipoxygenase pathway either directly through 5'-lipoxygenase or via antagonism of the leukotriene B4 (LTB4) receptor. More recently it has been determined to have peroxisome proliferator activated receptor-gamma agonist (PPARgamma) activity. LY293111 has antineoplastic activity in a variety of preclinical models. The tolerability and pharmacokinetics of LY293111 administered continuously, by mouth, BID for repeat cycles of 21 days was evaluated., Patients and Methods: Thirty-eight patients with advanced solid tumors were treated at five dose levels (200 to 800 mg BID) for a total of 102 cycles., Results: The most common toxicity was diarrhea (76%). One patient at 600 mg BID (n = 11) and two at 800 mg BID (n = 8), experienced dose-limiting grade 3 diarrhea. Dose reductions and/or delays were infrequent. Increases in steady-state maximum plasma concentration (Cmax,ss) and area under the steady-state plasma concentration time curve 0 to 12 hours (AUCtau,ss) on day 8 could be considered to be dose-proportional over the four-fold-dose range. Interpatient variability in Cmax,ss and AUCtau,ss was estimated to be 65% and 71% respectively. There was a small increase in AUC (1.37; 90% CI, 0.85 to 2.21) between single and multiple doses. Two patients with progressive chondrosarcoma and melanoma had stable disease lasting approximately 336 and 168 days, respectively., Conclusion: LY293111 can be administered safely by continuous oral therapy with mild toxicities. Diarrhea is dose-limiting. The recommended phase II dose will be 600 mg BID. The steady-state concentrations in humans exceed relevant levels observed in preclinical models.

Anticancer agents that interfere with microtubulin function are in widespread use in man and have a broad spectrum of activity against both hematological malignancies and solid tumors. The mechanisms of actions of these agents have been better defined during the past decade, indicating that there are distinct binding sites for these agents and that they interfere with microtubulin dynamics (growth and shortening of tubules) at low concentrations and only evoke microtubulin aggregation or dissociation at high concentrations. Tubulin has been recently described in the nucleus of cells and in mitochondria. Downstream events from tubulin binding are believed to be critical events for the generation of apoptosis in the malignant cell. The effects of vinca alkaloids and taxanes are distinct, suggesting that the interference with the tubulin cap by high-affinity binding of effective agents is not the only mechanism of cytotoxic effect, and the low-affinity binding of drug, which distorts microtubulin function, may also be important. The epothilones share some of the binding characteristics of the taxanes and are in clinical trials because of cytoxic activity in taxane resistant cells. Tubulin has additional target sites for anticancer drugs including interference with the binding and function of microtubule associated proteins and interference with motor proteins which are essential for the transport of substances within the cell. Because many of these microtubule associated proteins have an ATP binding site, both computer-aided design and combinatorial chemistry techniques can be used to make agents to interfere with their function analogous to imatinib mesylate (Gleevec). Agents that interfere with the motor protein kinesin are entering clinical trials.

Many cytotoxic agents for the adjuvant treatment of breast cancer are available, but they have produced only modest results, even when the tumor burden is low. This relative lack of efficacy may be attributed, in part, to the nonspecificity of the current regimens. Additionally, there is evidence that the chemotherapy doses used in clinical practice are not optimal, which potentially compromises the outcomes when the thresholds of dose intensity are not reached. Variations in treatment underscore the need to return to the basics of chemotherapy administration: dose, schedule, concentration threshold, and therapeutic index. In patients with metastatic breast cancer a clear dose-response curve has been shown with some agents, including anthracyclines. The E-max model, which in its simplest form assumes a direct relation between the dose of a drug and its effect, may be used to improve dosing in the adjuvant treatment of breast cancer. Consistent with this model, threshold effects have been observed in treatment with both anthracyclines and paclitaxel for breast cancer. There is also evidence that using dose-dense schedules may produce better outcomes with some regimens. Maintaining chemotherapy agents at full dose on schedule is crucial to treatment success, especially in adjuvant therapy. Consequently, treatment practices should use both dose intensity and dose compression to increase the likelihood of positive outcomes in patients with breast cancer.

The arachidonic acid metabolic pathway is currently under active investigation as a promoter of malignancy and several molecules have been synthesized to block either the cyclooxygenase or lipoxygenase branches. LY 293111 is an oral agent known to be a leukotriene B4 antagonist, a 5-lipoxygenase inhibitor and a peroxisome proliferator-activated receptor (PPAR)-gamma agonist with cytotoxic properties in cell lines. We have studied this agent with classical chemotherapeutic agents in a 72-h culture with cell lines using median-effect analysis as a measure of antagonism or synergy. LY 293111 displays global synergy with the active metabolite of irinotecan, SN-38, in the majority of cell lines, synergistic to additive effects with gemcitabine in bladder cancer cell lines, and synergism with 5'-DFUR (the active metabolite of capecitabine) in two breast cancer and one sarcoma cell line. These effects occur at clinically attainable concentrations. The addition of a proteosome inhibitor to the LY 293111 and SN-38 combination markedly enhanced the cytotoxic effects in the sarcoma cell line. As the toxicity of LY 293111 in man is not hematological, this agent may have a role in combination therapy of selected malignancies.

To study the mechanisms of the development of hormone refractory prostate cancer, we established an androgen-independent (AI) prostate cancer cell line derived from hormone-dependent (AD) LNCaP cells. Our previous studies have demonstrated that AI cells are deficient in expression of p21(WAFl/CIP1) (p21) due to overexpressed AR and are resistant to apoptosis. In this study, the induction of p53 and p21 expression by vinorelbine (Navelbine) was compared between AD and AI cells in an attempt to understand the difference(s) in apoptotic signalling pathways in these cells. Using a series of deletion of p21 reporter constructs, we found that vinorelbine mediated p21 induction in a p53-dependent manner in AD cells. In contrast, p21 expression restored by vinorelbine in AI cells was found to be through both p53-dependent and-independent pathways. In the absence of two p53 binding sites, Spl-3 and Spl-4 sites, in the promoter of human p21 gene, were found to be required for vinorelbine-mediated p21 activation. No p21 induction was observed by paclitaxel in AI cells. Exposure of AI cells to paciltaxel followed by vinorelbine produced synergism. Our data, thus, provide a basis for the synergistic combination of vinorelbine and paclitaxel for the treatment of advanced prostate cancer.

Androgens play a critical role not only in the physiological development of the prostate but also in the genesis of prostate cancer. The effects of androgen on the prostate gland and on the other tissues of the body are mediated by activation of the androgen receptor. The androgen receptor is a member of the superfamily of hormone receptors with a DNA-binding site, two zinc finger domains, and a hormone-binding site. Mutations in this receptor can be associated with loss of function or chronic endogeneous activation, depending upon the site of change. Androgens effect a conformal change in the structure of the androgen receptor associated with a change in protein phosphorylation. The androgen receptor can be activated by additional ligands affecting the hormone-binding site besides androgens. Activators and repressors of the androgen receptor modify this protein's function and are very delicately balanced such that disruptions of either function are associated with a disease state. Antiandrogens, which bind to the receptor and thus down-regulate the effects of endogeneous circulating androgens, remain the first line treatment for palliation of advanced prostate cancer. Mutations in the receptor are associated with a change in function of such compounds from antagonist to agonist in vitro. Newer evidence suggests there may be a role of intermittent androgen suppression rather than continuous suppression, perhaps by preventing overgrowth of hormone independent tumor cells. Future research focuses on the development of drugs directed at suppressing the androgen drive of the androgen sensitive clone of the tumor and making the nonsensitive subset more susceptible to cytotoxics.

Microtubulin binding agents such as docetaxel have significant preclinical and clinical activity in the treatment of hormone-refractory prostate cancer. We have previously used median-effect analysis to define both synergistic and antagonistic drug combinations which may be of value in management of human disease. These studies extend our findings in defined prostate cancer cell lines. A semi-automated microtiter culture system was used. Docetaxel was combined with 18 other agents, incubated with DU 145, LnCaP or PC 3 prostate cancer cell lines for 72 h and the cells then incubated with MTT to determine cytotoxic effect. Both doublet and triplet combinations were examined. Synergy and antagonism as measured by the combination index were determined for each combination. The non-mutually exclusive criterion was applied. Docetaxel demonstrated cytotoxic additive effects or synergy with -retinoic acid, cyclosporin A and vinorelbine in all three cell lines. Docetaxel combined with either epirubicin or doxorubicin displayed cytotoxic synergistic effects in hormone-refractory DU 145 and PC 3 cell lines. In contrast, drugs which have been combined clinically to treat hormone-refractory prostate cancer, i.e. cisplatin, carboplatin or etoposide, were antagonistic when combined with docetaxel. We conclude that combinations of docetaxel with either -retinoic acid or vinorelbine may offer an enhanced cytotoxic effect in the management of hormone-refractory prostate cancer and need to be evaluated for therapeutic effect. The combination of docetaxel with an anthracycline was also synergistic in the two hormone-refractory cell lines, DU 145 and PC3, thus suggesting a potential role in advanced disease after endocrine failure. Combinations of docetaxel with platinum or etoposide may lead to subadditive effects in treatment.

Capecitabine (Xeloda) offers a unique mode of action. The drug is currently being combined with other active agents in the treatment of advanced breast cancer. The recent demonstration of improved disease-free and overall survival with the capecitabine/docetaxel (Taxotere) combination, for example, has encouraged investigation of additional capecitabine/taxane regimens and schedules. A unique aspect of the metabolic activation of capecitabine is the ability of several anticancer drugs to upregulate the critical activating enzyme thymidine phosphorylase. These preclinical findings have led to clinical trials of several active agents in combination with capecitabine demonstrating high response rates in early results. In combination studies, capecitabine has been associated with very manageable toxicity. The combination of docetaxel/epirubicin (Ellence)/capecitabine (TEX) has shown particular promise in advanced disease, and should be evaluated in earlier disease. TEX is currently in phase III trials of advanced disease. In preclinical studies, the combination of capecitabine with inhibitors of HER2/neu (or the epidermal growth factor pathway) appears to hold significant promise both in breast cancer treatment and in treatment of other tumors expressing these receptors. Continued evaluation of capecitabine combinations will help to define the roles of this valuable agent, the only oral fluoropyrimidine for treatment of breast cancer available in the United States.

The use of combination chemotherapy is the accepted standard for most human malignancies but little attention has been paid to drug interactions. A combination of drugs may be synergistic, additive, or antagonistic in cytotoxic activity. This study evaluated combinations of agents with docetaxel, one of the most active agents in human breast cancer, using a median effects model to look at synergy or antagonism in vitro as a potential predictor of clinical outcome. Three human breast cancer cell lines, MCF7/wt, MCF7/adr (multiply drug resistant), and BT474 were grown to confluence, plated into 96 well dishes, and incubated with combinations of drugs for 72h. Cytotoxic effect was measured by the MTT assay. Median effect analysis was used to calculate the combination index (CI) with values less than 1 indicating synergism, 1 additive effects, and greater than 1 antagonism. Potentially useful combinations for clinical study which were identified included docetaxel with vinorelbine, docetaxel with dexrazoxane, docetaxel with cis-retinoic acid, docetaxel with disulfiram and either doxorubicin or epirubicin, and docetaxel with dexrazoxane and epirubicin.

Background: Neutropenia is common in patients receiving myelotoxic chemotherapy. Pegfilgrastim, a sustained-duration filgrastim is a once-per-cycle therapy for prophylactic neutrophil support., Patients and Methods: Women, treated with four cycles of doxorubicin/docetaxel chemotherapy every 21 days, received pegfilgrastim or filgrastim 24 h after chemotherapy as a single subcutaneous injection per chemotherapy cycle (pegfilgrastim 30, 60 or 100 microg/kg) or daily subcutaneous injections (filgrastim 5 microg/kg/day). Safety, efficacy and pharmacokinetics were analyzed., Results: The incidence of grade 4 neutropenia in cycle 1 was 95, 90 and 74%, in patients who received pegfilgrastim 30, 60 and 100 microg/kg, respectively, and 76% in patients who received filgrastim. Mean duration of grade 4 neutropenia in cycle 1 was 2.7,2 and 1.3 days for doses of pegfilgrastim, and 1.6 days for filgrastim. The pharmacokinetics of pegfilgrastim were non-linear and dependent on both dose and neutrophil count. Pegfilgrastim serum concentration was sustained until the neutrophil nadir occurred then declined rapidly as neutrophils started to recover, consistent with a self-regulating neutrophil-mediated clearance mechanism. The safety profiles of pegfilgrastim and filgrastim were similar., Conclusions: A single subcutaneous injection of pegfilgrastim 100 microg/kg provided neutrophil support and a safety profile comparable to daily subcutaneous injections of filgrastim during multiple chemotherapy cycles.