Phase IB Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Women with Hormone Receptor-Negative Breast Cancer

Herbert Irving Comprehensive Cancer Center, Columbia University, 161 Fort Washington Ave, 10-1072, New York, NY 10032. .
Cancer Prevention Research (Impact Factor: 4.44). 07/2012; 5(9):1144-54. DOI: 10.1158/1940-6207.CAPR-12-0117
Source: PubMed


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 400 mg (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. Cancer Prev Res; 5(9); 1144-54. ©2012 AACR.

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    • "Numerous in vivo and in vitro studies point to the possibility of using catechins in chemoprevention of cancer. Although its role in breast cancer development in humans is still unclear (Wu and Butler, 2011), there is some positive evidence for catechin intake and the risk and recurrence reduction of breast and other types of cancers (Crew et al., 2012; Johnson et al., 2012; Yu et al., 2013; Yuan et al., 2011) and high consumption of green tea was closely associated with decreased numbers of axillary lymph node metastases among premenopausal stage I and II breast cancer patients (Fujiki et al., 1999). A recent study showed a positive effect of epigallocatechin gallate on breast cancer patients under radiotherapy (Zhang et al., 2012). "
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    • "Although there is a strong interest in using more than one-hundred natural compounds [106] for cancer prevention, none of these dietary agents has been shown to consistently prevent breast cancer. Some of the most promising compounds include catechins (e.g., epigallocatechin gallate (EGCG), green tea extract) [107], curcumin [108], luteolin [109], carotenoids [110], omega-3-fatty acids [111], resveratrol [112–114], soy isoflavones [115, 116], and vitamin D [117, 118]. For example, green tea intake has been associated with reduced incidence of breast cancer, and a recent phase IB dose-escalation trial using 400–800 mg EGCG among women with a history of stage I to III hormone receptor-negative breast cancer demonstrated that this natural compound is well tolerated [107] (Table 2). "
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    • "Therefore, the doses tested in this trial were equivalent to the EGCG content of eight to 24 cups of brewed green tea daily. Five DLTs occurred during this phase I trial (Crew et al., 2012), including indigestion , transaminitis, insomnia, rectal bleeding (all grade 3) and weight gain (grade 2). Based upon these findings, Poly E 600 mg twice daily was defined as the MTD with a DLT rate of 27% (three of 11). "
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    ABSTRACT: Background Observational and experimental data support a potential breast cancer chemopreventive effect of green tea.Methods We conducted an ancillary study using archived blood/urine from a phase IB randomised, placebo-controlled dose escalation trial of an oral green tea extract, Polyphenon E (Poly E), in breast cancer patients. Using an adaptive trial design, women with stage I–III breast cancer who completed adjuvant treatment were randomised to Poly E 400 mg (n = 16), 600 mg (n = 11) and 800 mg (n = 3) twice daily or matching placebo (n = 10) for 6 months. Blood and urine collection occurred at baseline, and at 2, 4 and 6 months. Biological endpoints included growth factor [serum hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)], lipid (serum cholesterol, triglycerides), oxidative damage and inflammatory biomarkers.ResultsFrom July 2007-August 2009, 40 women were enrolled and 34 (26 Poly E, eight placebo) were evaluable for biomarker endpoints. At 2 months, the Poly E group (all dose levels combined) compared to placebo had a significant decrease in mean serum HGF levels (−12.7% versus +6.3%, P = 0.04). This trend persisted at 4 and 6 months but was no longer statistically significant. For the Poly E group, serum VEGF decreased by 11.5% at 2 months (P = 0.02) and 13.9% at 4 months (P = 0.05) but did not differ compared to placebo. At 2 months, there was a trend toward a decrease in serum cholesterol with Poly E (P = 0.08). No significant differences were observed for other biomarkers.Conclusions Our findings suggest potential mechanistic actions of tea polyphenols in growth factor signalling, angiogenesis and lipid metabolism.
    Full-text · Article · Mar 2014 · Journal of Human Nutrition and Dietetics
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