Mv Cobham

Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse

BACKGROUND Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. This study explores the effect of tetrathiomolybdate (TM), an anti-angiogenic copper chelator, on EPCs in patients at high risk for breast cancer recurrence. PATIENTS AND METHODS This phase 2 study enrolled breast cancer patients with stage 3 and stage 4 without evidence of disease (NED), and stage 2 if triple-negative. TM 100 mg orally was administered to maintain ceruloplasmin <17 mg/dl for 2 years or until relapse. The primary end point was change in EPCs. RESULTS Forty patients (28 stage 2/3, 12 stage 4 NED) were enrolled. Seventy-five percent patients achieved the copper depletion target by 1 month. Ninety-one percent of triple-negative patients copper-depleted compared with 41% luminal subtypes. In copper-depleted patients only, there was a significant reduction in EPCs/ml by 27 (P = 0.04). Six patients relapsed while on study, of which only one patient had EPCs maintained below baseline. The 10-month relapse-free survival was 85.0% (95% CI 74.6%-96.8%). Only grade 3/4 toxicity was hematologic: neutropenia (3.1% of cycles), febrile neutropenia (0.2%), and anemia (0.2%). CONCLUSIONS TM is safe and appears to maintain EPCs below baseline in copper-depleted patients. TM may promote tumor dormancy and ultimately prevent relapse.

Phase 1/2 clinical trial of interferon α2b and weekly liposome-encapsulated all-trans retinoic acid in patients with advanced renal cell carcinoma

To evaluate the feasibility, efficacy, and biologic effects of weekly liposome-encapsulated all-trans retinoic acid (ATRA-IV) plus interferon α2b (IFN) in patients with advanced renal cell carcinoma (RCC). Twenty-six patients with metastatic RCC were treated on a phase 1/2 trial with weekly ATRA-IV and IFN SQ daily 5 d/wk. Twelve patients received ATRA-IV at three dose levels (60, 75, and 90 mg/m2) according to phase 1 methodology, and 14 additional patients received 90 mg/m2. Response was assessed according to an intention-to-treat analysis. Serum retinoic acid (RA) concentrations were assayed and peripheral blood mononuclear cell mRNA expression of RA and IFN-inducible genes (RARα, RARβ2, IRF1, CRABP2, and TRAIL) were examined. No dose limiting toxicities occurred at 60 mg/m2; grade 3 leukopenia affected 1/6 patients at 75 mg/m2, whereas 3 patients received 90 mg/m2 without a dose limiting toxicities. Fourteen additional patients received 90 mg/m2 ATRA-IV without grade 3/4 toxicity. Five of 26 (19%) patients achieved a major response, with a median duration of 14 months (range 9 to 23); 9 additional patients (41%) demonstrated stable disease or minor response lasting ≥4 months. No significant differences in serum (RA) after ATRA infusion were detected between weeks 1 and 8 of treatment. Peripheral blood mononuclear cell mRNA expression did not correlate with clinical response. The addition of weekly ATRA-IV to IFN therapy is feasible and well tolerated, resulting in sustainable increased serum (RA). This regimen demonstrates antitumor activity in metastatic RCC, and suggests ATRA-IV augments IFN therapy.

Ixabepilone-induced mitochondria and sensory axon loss in breast cancer patients.

We sought to define the clinical and ultrastructure effects of ixabepilone (Ix), a microtubule‐stabilizing chemotherapy agent on cutaneous sensory nerves and to investigate a potential mitochondrial toxicity mechanism.

Influencing the Tumor Microenvironment: A Phase II Study of Copper Depletion Using Tetrathiomolybdate in Patients with Breast Cancer at High Risk for Recurrence and in Preclinical Models of Lung Metastases

Purpose: Bone marrow–derived progenitor cells, including VEGFR2+ endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models. Experimental Design: Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition. Results: Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P < 0.001). Two-year EFS for patients with stage II–III and stage IV NED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 50% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012). Conclusions: Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted. Clin Cancer Res; 23(3); 666–76. ©2016 AACR.

Ixabepilone: a new treatment option for the management of taxane-resistant metastatic breast cancer

Ixabepilone (Ixempra®; Bristol-Myers Squibb) is a novel microtubule stabilizing agent recently approved for the treatment of metastatic breast cancer (MBC). This article focuses on considerations for ixabepilone administration and adverse event (AE) management, drawing from the biomedical literature indexed in PubMed, published abstracts from the American Society of Clinical Oncology annual meetings, and the manufacturer’s prescribing information for ixabepilone. Administered as monotherapy or in combination with capecitabine in clinical studies, ixabepilone demonstrated positive clinical response rates, prolonged progression-free survival, and a favorable safety profile in patients with MBC. Treatment-related AEs were predictable and manageable with dose modification, treatment interruption, and active management. As ixabepilone undergoes development in earlier lines of breast cancer therapy and in other solid tumors, oncology nurses will encounter more and more patients receiving ixabepilone therapy. If nurses are acquainted with the unique management strategies associated with ixabepilone treatment, as detailed herein, patients are more likely to receive the full benefit of therapy.

Phase I trial of ixabepilone plus pegylated liposomal doxorubicin in patients with adenocarcinoma of breast or ovary

BACKGROUND Ixabepilone is a semisynthetic epothilone B analogue that is active in taxane-resistant cell lines and has shown activity in patients with refractory breast and ovarian cancer. We carried out a phase I trial of ixabepilone plus pegylated liposomal doxorubicin (PLD) in patients with advanced taxane-pretreated ovarian and breast cancer. METHODS Patients with recurrent ovarian or breast carcinoma received PLD every 3 or 4 weeks plus five different dose schemas of ixabepilone in cohorts of three to six patients. RESULTS Thirty patients received a total of 142 treatment cycles of the PLD-ixabepilone combination. The recommended phase II dose and schedule of ixabepilone was 16 mg/m(2) on days 1, 8, and 15 plus PLD 30 mg/m(2) given on day 1, repeated every 4 weeks. Hand-foot syndrome and mucositis were dose limiting when both ixabepilone and PLD were given every 3 or 4 weeks. Objective responses were observed in 3 of 13 patients (23%) with breast cancer and 5 of 17 patients (29%) with ovarian cancer. CONCLUSION Ixabepilone may be safely combined with PLD, but tolerability is highly dependent upon the scheduling of both agents. This combination demonstrated efficacy in patients with breast and ovarian cancer and merits further evaluation in these settings.

Abstract P6-05-06: Association of HER2/neu single nucleotide polymorphism with trastuzumab-related cardiotoxicity

Background: Treatment with trastuzumab prolongs overall survival when given to patients (pts) with Her2/neu+ breast cancer (BC). The primary toxicity of trastuzumab is cardiotoxicity and the incidence is estimated at 2-4% in the adjuvant setting. The mechanism for trastuzumab-induced cardiotoxicity is not known. Although Her2neu expression is usually not seen on cardiac myocytes, its expression has been shown to be upregulated after chemotherapy. Trastuzumab is a monoclonal antibody that binds to the extracellular domain of Her2/neu. We hypothesized that single nucleotide polymorphisms (SNPs) in the Her2/neu receptor may play a role in trastuzumab associated cardiotoxicity. Methods: 140 pts with BC who were treated with chemotherapy and trastuzumab were enrolled into an IRB approved protocol at the Weill Cornell Medical College between July 2008 and March 2013. Cardiotoxicity was defined as either symptomatic CHF, or a decline in LVEF of 15% (or if LVEF Results: 140 subjects (29 with cardiotoxicity and 111 without) had 11 SNPs sequenced. Median age of subjects was 56 years (range: 32-85), mean baseline LVEF was 65% (±6%). 16.4% of subjects had hypertension (HTN). 80% of patients were Caucasian, 10% East Asian, 7.1% African American, 2.9% South Asian. There were two SNPs for which there was variation seen among subjects: rs 1136201 (corresponding to codon 655) and rs61552325 (codon 1170). The frequencies of the codon 655 polymorphisms were: AA (Ile/Ile) 67.9%, AG (Ile/Val) 29.3%, and GG (Val/Val) 2.9%. The frequencies of the codon 1170 polymorphisms were: CC (Pro/Pro) 20.7%, GC (Ala/Pro) 45.7%, and GG (Ala/Ala) 33.6%. There was no association observed between the codon 655 polymorphism and cardiotoxicity (p = 0.96). A significant association between cardiotoxicity and the codon 1170 polymorphism was observed, with subjects having cardiotoxicity being more likely to carry the CC allele compared with subjects without cardiotoxicity (34.5% vs 17.1%, p = 0.04). This association persisted after multivariable adjustment for age, race, and HTN status (adjusted OR = 2.60, 95% CI = 1.02-6.62, p = 0.046). Conclusion: In this study, the Her2/neu 1170 Pro/Pro polymorphism was associated with trastuzumab cardiotoxicity. If confirmed in a larger series, this polymorphism could be used to identify pts who may be at increased risk for cardiotoxicity and who may benefit from treatments associated with less cardiotoxicity. Furthermore, the Her2/neu 1170 SNP has previously been implicated as a minor histocompatibility antigen, and our findings raise the possibility that immune mediated mechanisms may play a role in trastuzumab related cardiotoxicity. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-06.

Abstract P1-15-07: Ixabepilone-associated peripheral neuropathy in metastatic breast cancer patients and its effects on the ultrastructure of neurons

Background: Peripheral neuropathy is a dose-limiting toxicity of most microtubule-stabilizing chemotherapeutic agents. Ixabepilone, a semisynthetic analog of the natural epothilone B, has activity in a wide range of tumors including taxane-resistant disease. In this study, we sought to understand the effect of ixabepilone on the development of peripheral neuropathy both clinically and its effect at the ultrastructural level of the peripheral nerves and circulating factors over time. Parallel studies in animal models of neuropathy were performed at the same time (Proc AACR 2010 Abstract 4184). Methods: This open-label, non-randomized phase II study enrolled 14 patients with metastatic breast cancer. Ixabepilone was administered by 2 schedules: the FDA approved dose of 40 mg/m 2 every 3 weeks (q3w) and 16 mg/m 2 on day 1, 8, and 15 of a 28-day cycle (weekly). Five controls, 2 with residual taxane-associated peripheral neuropathy and 3 with no prior chemotherapy or peripheral neuropathy, were also accrued. The primary objectives were to characterize the natural history of ixabepilone-associated peripheral neuropathy using the Total Neuropathy Score Clinical (TNSc) assessment tool prior to each cycle and to correlate changes in the ultrastructure of dermal myelinated nerve fibers via a 3 mm punch biopsy of an area 10 cm above the lateral malleolus every 2 cycles with electron microscopy (EM), as well as circulating factors (both inflammatory and neurotrophic) considered to be important in the pathogenesis of chemotherapy-induced peripheral neuropathy. Secondary objectives included progression-free survival (PFS) and non-neurologic toxicity. Results: 14 patients were enrolled and were equally divided between the 2 schedules of ixabepilone chemotherapy. There were no differences in baseline characteristics between the two groups. Mean age was 54 years (range 32–71). Mean number of previous chemotherapy regimens was 3.5 (range 0–8). 57% of patients had received a taxane in the adjuvant setting and 64% in the metastatic setting. The mean neuropathy score (TNSc) at baseline was 4.6 (range 1–11). At a mean cumulative dose of 185 mg/m 2 , the TNSc with ixabepilone q3w schedule was 3.7 points higher/worse (95% CI: 2.2–5.3, p = 0.03) than the mean score observed in patients on the weekly schedule. The sensory component was most significantly affected, predominantly numbness. In 3 patients, the chemotherapy schedule was changed from every 3 weeks to weekly due to > grade 2 toxicity at a mean cumulative dose of 107 mg/m 2 , and TNSc decreased/improved by 2.7 points. PFS in patients on q3w ixabepilone was 133 days (range 28–280) and in patients on weekly ixabepilone was 179 days (range 66–336), nonsignificant. Evaluation of EM and circulating factors is ongoing. Conclusions: Weekly ixabepilone appears to have a more favorable neurotoxicity profile compared to the standard q3w schedule. Integration of the EM data and the circulating factor data are underway and will be presented. Ixabepilone-associated peripheral neuropathy may improve in patients switched to weekly ixabepilone without compromising efficacy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-07.

Abstract P6-11-04: Targeting the tumor microenvironment: tetrathiomolybdate decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse.

Background: Bone marrow-derived endothelial progenitor cells (EPCs) constitute an important part of the tumor microenvironment and are critical for metastatic progression in preclinical models and breast cancer patients (Jain et al, Breast Cancer Res Treat, 2012). Tetrathiomolybdate (TM), a copper-depleting compound inhibits angiogenesis, tumor growth, and metastasis. This study explores the effect of TM on EPCs in patients at high risk for breast cancer recurrence. Methods: This phase II study enrolled stage 3, 4 without evidence of disease (NED), and any node-positive triple negative breast cancer patient. Only concomitant hormone therapy was allowed. Patients received induction TM 180 mg daily at baseline followed by an equal or lower daily dose (median 100 mg, range 0–140) to maintain ceruloplasmin (Cp) level Results: 50 patients (33 adjuvant, 17 Stage 4 NED, and 22 triple negative) were enrolled. In the first 40 patients enrolled who had received at least 24 months of TM, EPC and Cp data were available for analysis. Of these 40 patients, 1 patient did not take TM due to patient preference, and 736 cycles of TM (average 18.9 per patient) were administered. Median age was 50 years (range 29–66). Median number of tumor size and positive lymph nodes among adjuvant patients were 3.5 cm (range 1.2–7) and 9 (range 0–42), respectively. Of the patients receiving hormone therapy, 11 patients were on tamoxifen and 16 patients were on an aromatase inhibitor. Median baseline Cp level was 30 mg/dL (range 20–47). 71% patients adequately copper depleted at month 1 to a mean Cp of 14.8 mg/dL. A larger proportion of triple negative patients copper depleted (82%) compared to hormone receptor positive subtypes (47%) and HER2/neu positive subtypes (67%). Median EPCs/ml decreased from baseline to last dose by 16 in patients that achieved the copper depletion target, p = 0.014. Conversely, in patients that did not copper deplete, median EPCs/ml increased by 136, p = 0.005. Of the 50 patients on study, 7 patients relapsed in which a significant increase in EPCs preceded an objective clinical relapse and a tumor marker rise by a median of 1 month. Only grade 3/4 toxicity was hematologic, occurred in 49 cycles (6.7%), and resolved in 5–13 days with TM held and resumed at a lower dose. Conclusions: TM is a well-tolerated oral copper chelator that may contribute to maintaining EPCs below baseline in copper-depleted patients. Molecular subtype may impact on the ability to copper deplete. EPCs may have potential as a surrogate marker for early relapse and as a therapeutic target for interrupting the metastatic progression. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-04.

Abstract 2699: Phase II study evaluating the effect of tetrathiomolybdate on circulating endothelial progenitor cells in patients with high risk for breast cancer recurrence

Background: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. Tetrathiomolybdate (TM), a copper-depleting compound inhibits angiogenesis and maintains tumor dormancy. This study explores the effect of TM on EPCs in patients (pts) at high risk for breast cancer (BC) recurrence. Methods: This phase II study enrolled Stage 3, 4 without evidence of disease (NED), and any node-positive triple negative (TN) BC pts. Only concomitant hormonal therapy was allowed. Pts received induction TM 180 mg daily at baseline (with exception of one pt) followed by an equal or lower daily dose (median 100mg, range 0-140) to maintain ceruloplasmin (Cp) level Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2699. doi:1538-7445.AM2012-2699