[show abstract][hide abstract] ABSTRACT: 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 methodsThis 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.ResultsForty 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%).ConclusionsTM is safe and appears to maintain EPCs below baseline in copper-depleted patients. TM may promote tumor dormancy and ultimately prevent relapse.
[show abstract][hide abstract] ABSTRACT: Breast cancer prognosis and breast cancer molecular subtype vary by race/ethnicity. We determined whether the distribution of breast cancer subtypes varies among different Asian ethnic groups. Using immunohistochemical surrogates for the four molecularly defined breast cancer subtypes, we characterized breast cancer subtype for 346 Asian subjects treated at two New York City institutions. We found that Chinese and Japanese had a higher proportion of good-prognosis luminal A cancers (66.7 and 80.0%, respectively) compared to Filipinos and Koreans (48.5 and 47.1%) (P = 0.001). Filipinos had a higher proportion of HER-2/neu positive cancers (45.6%) compared to other ethnic groups (23.6%) (P = 0.002). Koreans had a higher proportion of triple negative cancers (23.5%) compared to other ethnic groups (7.5%) (P = 0.06). The results suggest that differences exist in breast cancer tumor biology among distinct Asian ethnic groups and have implications for cancer care and research. Future studies of breast cancer in Asian-Americans should distinguish among the different ethnic groups.
Journal of Immigrant and Minority Health 01/2012; · 1.16 Impact Factor
[show abstract][hide abstract] ABSTRACT: In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulin-polymerizing agents and to anti-vascular endothelial growth factor-directed therapies. We sought to determine the safety and efficacy of vorinostat plus paclitaxel and bevacizumab as first-line therapy in metastatic breast cancer (MBC), and the biological effects of vorinostat in vivo. For this purpose of this study, 54 patients with measurable disease and no prior chemotherapy for MBC received vorinostat (200 or 300 mg PO BID) on days 1-3, 8-10, and 15-17, plus paclitaxel (90 mg/m(2)) on days 2, 9, 16, and bevacizumab (10 mg/kg) on days 2 and 16 every 28 days. The primary objective of the phase I study was to determine the recommended phase II dose (RPTD) of vorinostat, and for the phase II to detect an improvement of response rate from 40 to 60% (alpha = 0.10, beta = 0.10). No dose limiting toxicities were observed, and the RPTD of vorinostat was 300 mg BID. For the primary efficacy analysis in 44 patients at the RPTD, we observed 24 objective responses (55%, 95% confidence intervals (C.I) 39%, 70%). The adverse event profile was consistent with paclitaxel-bevacizumab, with the exception of increased diarrhea with the addition of vorinostat. Analysis of serial tumor biopsies in seven patients showed increased acetylation of Hsp90 and α-tubulin following vorinostat. Vorinostat induces histone and alpha tubulin acetylation and functional inhibition of Hsp90 in breast cancer in vivo and can be safely combined with paclitaxel and bevacizumab.
Breast Cancer Research and Treatment 12/2011; 132(3):1063-72. · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Animal models have demonstrated the critical role of bone marrow-derived VEGFR1(+) hematopoietic progenitor cells (HPCs) and VEGFR2(+) endothelial progenitor cells (EPCs) in metastatic progression. We explored whether these cells could predict relapse and response in breast cancer (BC) patients. One hundred and thirty-two patients with stages 1-4 BC were enrolled on 2 studies. Circulating CD45(+)/CD34(+)/VEGFR1(+) HPCs and CD45(dim)/CD133(+)/VEGFR2(+) EPCs were assessed from peripheral blood mononuclear cells using flow cytometry. Changes in HPCs and EPCs were analyzed in (1) patients without overt disease that relapsed and (2) metastatic patients according to response by RECIST. At study entry, 102 patients were without evidence of disease and 30 patients had metastatic BC. Seven patients without evidence of BC by exam, labs, and imaging developed recurrence while on study. Median HPC/ml (range) increased from 645.8 (23.5-1,914) to 2,899 (1,176-37,336), P = 0.016, followed by an increase in median EPC/ml from 21.3 (4.7-42.5) to 94.7 (28.2-201.3), P = 0.016, prior to clinical relapse. In metastatic patients with progressive disease, median HPC/ml increased from 1,696 (10-16,470) to 5,124 (374-77,605), P = 0.0009, and median EPC/ml increased from 26 (0-560) to 71 (0-615) prior to progression, P = 0.10. In patients with responding disease, median HPC/ml decreased from 6,147 (912-85,070) to 633 (47-18,065), P = 0.05, and EPC/ml decreased from 46 (0-197) to 23 (0-105), P = 0.41, at response. There were no significant changes in these cells over time in patients with stable disease. Circulating bone marrow-derived HPCs and EPCs predict relapse and disease progression in BC patients.
Breast Cancer Research and Treatment 12/2011; 132(1):235-42. · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Employment status is related to treatment recovery and quality of life in breast cancer survivors, yet little is known about return to work in immigrant and minority survivors. We conducted an exploratory qualitative study using ethnically cohesive focus groups of urban breast cancer survivors who were African-American, African-Caribbean, Chinese, Filipina, Latina, or non-Latina white. We audio- and video-recorded, transcribed, and thematically coded the focus group discussions and we analyzed the coded transcripts within and across ethnic groups. Seven major themes emerged related to the participants' work experiences after diagnosis: normalcy, acceptance, identity, appearance, privacy, lack of flexibility at work, and employer support. Maintaining a sense of normalcy was cited as a benefit of working by survivors in each group. Acceptance of the cancer diagnosis was most common in the Chinese group and in participants who had a family history of breast cancer; those who described this attitude were likely to continue working throughout the treatment period. Appearance was important among all but the Chinese group and was related to privacy, which many thought was necessary to derive the benefit of normalcy at work. Employer support included schedule flexibility, medical confidentiality, and help maintaining a normal work environment, which was particularly important to our study sample. Overall, we found few differences between the different ethnic groups in our study. These results have important implications for the provision of support services to and clinical management of employed women with breast cancer, as well as for further large-scale research in disparities and employment outcomes.
Journal of Community Health 11/2011; 37(4):763-72. · 1.28 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
Annals of Oncology 03/2010; 21(10):2075-80. · 7.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: Eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analog of the marine natural product halichondrin B. This open-label, single-arm, phase II study evaluated efficacy and tolerability of eribulin in heavily pretreated patients with metastatic breast cancer (MBC).
MBC patients who were previously treated with an anthracycline and a taxane received eribulin mesylate (1.4 mg/m(2)) as a 2- to 5-minute intravenous (IV) infusion on days 1, 8, and 15 of a 28-day cycle. Because of neutropenia (at day 15), an alternative regimen of eribulin on days 1 and 8 of a 21-day cycle was administered. The primary end point was overall response rate.
Of the 103 patients treated, the median number of prior chemotherapy regimens was four (range, one to 11 regimens). In the per-protocol population (n = 87), eribulin achieved an independently reviewed objective response rate (all partial responses [PRs]) of 11.5% (95% CI, 5.7 to 20.1) and a clinical benefit rate (PR plus stable disease > or = 6 months) of 17.2% (95% CI, 10.0 to 26.8). The median duration of response was 171 days (5.6 months; range, 44 to 363 days), the median progression-free survival was 79 days (2.6 months; range, 1 to 453 days), and the median overall survival was 275 days (9.0 months; range, 15 to 826 days). The most common drug-related grades 3 to 4 toxicities were as follows: neutropenia, 64%; leukopenia, 18%; fatigue, 5%; peripheral neuropathy, 5%; and febrile neutropenia, 4%.
Eribulin demonstrated activity with manageable tolerability (including infrequent grade 3 and no grade 4 neuropathy) in heavily pretreated patients with MBC when dosed as a short IV infusion on days 1 and 8 of a 21-day cycle.
Journal of Clinical Oncology 04/2009; 27(18):2954-61. · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tumor growth and metastasis is dependent on the formation and assembly of new blood vessels, a process known as neo-angiogenesis. Both pre-existing and circulating vascular cells have been shown to contribute to the assembly of tumor neo-vessels in specific tumors. Mobilization of endothelial progenitor cells (EPCs) from the bone marrow constitutes a crucial step in the formation of de novo blood vessels, and levels of peripheral blood EPCs have been shown to be increased in certain malignant states. However, the role of circulating EPCs in breast cancer is largely unknown. We recruited twenty-five patients with biopsy-proven invasive breast cancer at Weill Cornell Breast Center to participate in a pilot study investigating the correlation of circulating EPCs to extent of disease and initiation of chemotherapy. For each patient, a baseline sample was drawn before systemic treatment, and for seventeen of those patients, a second sample was taken after the first round of chemotherapy. Levels of peripheral blood EPCs, as defined by co-expression of CD133 and VEGFR2, were quantified by flow cytometry. Breast cancer patients with stage III & IV disease had statistically higher levels of circulating EPCs than did patients with stage I & II disease (median = 165,000 EPCs/5 x 10(6)MNCs vs. median = 6,920 EPCs/5 x 10(6)MNCs, respectively, P < 0.0001). In addition, in late-stage patients, levels of EPCs demonstrated a statistically significant drop after initiation of chemotherapy (median = 162,500 EPCs/5 x 10(6)MNCs [pre] vs. median = 117,500 EPCs/5 x 10(6)MNCs [post], P = 0.01). These results suggest that circulating EPCs may serve as a potential tumor biomarker in breast cancer and that EPCs may represent a plausible target for future therapeutic intervention.
Breast Cancer Research and Treatment 02/2008; 107(1):133-8. · 4.47 Impact Factor