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Dave B.,Methodist Hospital Cancer Center
Breast cancer research : BCR | Year: 2012

Breast cancer relapse, in a large number of patients, after initial response to standard of care therapy warrants development of novel therapies against recurrent and metastatic cancer. Cancer stem cells (CSCs), present in breast tumors while being intrinsically resistant to conventional therapy, have the ability to self renew and cause tumor recurrence. The residual tumors after therapy, with dramatic enrichment of the CSCs, have all the hallmarks of epithelial- mesenchymal transition (EMT). This review will focus on the link between EMT, CSCs and treatment resistance, since a better understanding of these interactions will allow us to effectively target the residual population after therapy.


Crew K.D.,Columbia University | Brown P.,University of Houston | Greenlee H.,Columbia University | Bevers T.B.,University of Houston | And 14 more authors.
Cancer Prevention Research | Year: 2012

Epidemiologic data support an inverse association between green tea intake and breast cancer risk, and numerous experimental studies have shown the antitumor effects of its main component, epigallocatechin gallate (EGCG). We conducted a phase IB dose escalation trial in women with a history of stage I to III hormone receptor-negative breast cancer of an oral green tea extract, polyphenon E (Poly E) 400, 600, 800 twice daily or matching placebo for 6 months. The primary endpoint was to determine the maximum tolerated dose (MTD), defined as the dose that causes 25% dose-limiting toxicity (DLT, grade ≥II). Assignment to dose level was based upon an adaptive design, the continual reassessment method. A mammogram and random core biopsy of the contralateral breast were obtained at baseline and 6 months and serial blood/urine collections every 2 months for biomarker analyses. Forty women were randomized: 10 to placebo, 30 to Poly E (16 at 400 mg, 11 at 600 mg, 3 at 800 mg). There was one DLT at 400mg(grade III rectal bleeding), three DLTs at 600 mg (grade II weight gain, grade III indigestion and insomnia), and one DLT at 800 mg (grade III liver function abnormality). The DLT rate at 600 mg was 27% (3 of 11). Pharmacologic levels of total urinary tea polyphenols were achieved with all three dose levels of Poly E. Using a novel phase I trial design, we determined the MTD for Poly E to be 600 mg twice daily. This study highlights the importance of assessing toxicity for any chemopreventive agent being developed for chronic use in healthy individuals. ©2012 AACR.


Rivera E.,Banner Md Anderson Cancer Center | Chang J.C.,Methodist Hospital Cancer Center | Semiglazov V.,Russian Railways | Burdaeva O.,Arkhangelsk Regional Clinical Oncology Center | And 2 more authors.
Clinical Breast Cancer | Year: 2014

Background As part of a comparative phase II study of eniluracil/5-FU/Lv vs. capecitabine (Xeloda), an oral 5-FU prodrug for MBC, patients with rapid PD during capecitabine therapy crossed over to take eniluracil/5-FU/Lv. Patients and Methods Ten evaluable patients with radiologically documented PD within 70 days of capecitabine treatment were treated with a modified oral weekly eniluracil/5-FU/Lv regimen. Results After switching to eniluracil/5-FU/Lv, 3 (30%) patients had PR. Six (60%) had SD, producing a total of 90% with PR or SD. The median PFS was 140 days (vs. 42.5 days for capecitabine). Four (40%) patients had > 7months PFS. Eniluracil/5-FU/Lv was well tolerated with mild to moderate diarrhea and nausea as the most common side effects. Conclusion These positive efficacy and safety results encourage a larger study in patients with rapid PD during capecitabine treatment. Eniluracil/5-FU/Lv might enable these patients to continue with oral 5-FU rather than switching to the generally less well tolerated intravenous microtubule-interfering agents. In addition, the eniluracil/5-FU/Lv regimen might also provide any overall survival contribution of 5-FU that, for pharmacokinetic reasons, was not provided by capecitabine and would not be provided if these patients progressed directly to the other approved treatments. © 2014 Elsevier Inc. All rights reserved.


Dave B.,Methodist Hospital Cancer Center | Tan N.M.,Methodist Hospital Cancer Center | Chang J.C.,Methodist Hospital Cancer Center
Breast Cancer Research | Year: 2012

Breast cancer relapse, in a large number of patients, after initial response to standard of care therapy warrants development of novel therapies against recurrent and metastatic cancer. Cancer stem cells (CSCs), present in breast tumors while being intrinsically resistant to conventional therapy, have the ability to self renew and cause tumor recurrence. The residual tumors after therapy, with dramatic enrichment of the CSCs, have all the hallmarks of epithelial- mesenchymal transition (EMT). This review will focus on the link between EMT, CSCs and treatment resistance, since a better understanding of these interactions will allow us to effectively target the residual population after therapy. © 2012 BioMed Central Ltd.


Yu K.-D.,Fudan University | Zhu R.,Methodist Hospital Research Institute | Zhan M.,Methodist Hospital Research Institute | Rodriguez A.A.,Methodist Hospital Cancer Center | And 10 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Patients with triple-negative breast cancer (TNBC) and residual disease after neoadjuvant chemotherapy generally have worse outcome; however, some patients with residual tumor after neoadjuvant chemotherapy do not relapse. Wehypothesize that there are subgroups of patients with chemoresistant TNBC with different prognosis. Experimental Design: Forty-nine chemoresistant cases from 111 patients with TNBC treated with neoadjuvant chemotherapy (M.D. Anderson Cancer Center, Houston, TX) constituted the discovery cohort, and 25 chemoresistant samples from 47 neoadjuvant chemotherapy-treated TNBC (The Methodist Hospital, Houston, TX) were chosen for validation. Extended validation was carried out in 269 operable TNBC predicted to be chemoresistant by expression pattern from published datasets. Results: Weestablished a seven-gene prognostic signature using dChip and gene set enrichment analyses. In the independent validation cohort, the classifier predicted correctly with positive predictive value of 75.0% and negative predictive value (i.e., relapse-free survival; RFS) of 76.9% at 3 years. Those predicted to relapse had a HR of 4.67 [95% confidence interval (CI): 1.27-17.15] for relapse in 3 years. In extended validation, patients predicted not to relapse exhibited 3-year RFS of 78.9%, whereas the 3-year RFS was 48.5% for patients predicted to relapse, with HR of 2.61 (95% CI: 1.52-4.49). The TNBC subgroup that predicted to have relatively favorable prognosis was characterized by high expression of "luminal- like" genes [androgen-receptor (AR) and GATA3], whereas the subgroup with worse prognosis was characterized by expression of cancer stem-cell markers. Conclusion: We developed a clinically relevant signature for patients with chemoresistant TNBC. For these women, new therapeutic strategies like targeting AR activation or cancer stem cells may need to be developed. © 2013 AACR.

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