Men with elevated prostate-specific antigen (PSA) and negative prostate biopsies are at risk for prostate cancer. The antiandrogen bicalutamide has a prolonged half-life, thus potentially allowing an ...intermittent administration to retain activity while reducing toxicity. We conducted a phase I-II trial of weekly bicalutamide in men with PSA >4 ng/mL and negative biopsies.
Eighty subjects were nonrandomly assigned to a three-arm trial to either bicalutamide 50 mg/wk (n = 26) or 100 mg/wk (n = 28) or no treatment (n = 26) for 6 months. Blood samples were obtained at 0, 3, and 6 months, and prostate biopsies were repeated after 6 months. The outcome measures were 6-month changes of tissue Ki-67 (primary end point), high-grade prostatic intraepithelial neoplasia (HG-PIN), proliferative inflammatory atrophy, circulating PSA, and sex hormones.
Ki-67 expression was higher in HG-PIN than in normal tissue (10% versus 3%; P < 0.01) but was not modulated by bicalutamide in normal luminal cells. A trend toward an improvement of HG-PIN status was found in treated subjects (26% improved, 60% had no change, 15% worsened) as compared with the no-treatment arm (4% improved, 83% had no change, 13% worsened; P = 0.07). Proliferative inflammatory atrophy prevalence was not reduced by bicalutamide. Bicalutamide reduced PSA by 50% in both arms and raised testosterone and estradiol levels. Asymptomatic breast swelling was noted in 40% of the treated cases.
A weekly administration of bicalutamide seems to be reasonably safe and shows an encouraging signal of activity on HG-PIN prevalence, supporting further studies of this schedule in men at high risk despite the negative primary end-point findings on Ki-67.
Abstract
This abstract is being presented as a short talk in Concurrent Session 5. A full abstract is printed in the Proffered Abstracts section (PR-03) of the Conference Proceedings.
Citation ...Information: Cancer Prev Res 2010;3(12 Suppl):A68.
Abstract
Rationale: Women with breast IEN have an annual risk of invasive disease equal to 8-10 times the general population, thus representing an important target for chemoprevention.
In the ...NSABP-P1 trial, tamoxifen use at 20 mg/day was associated with an 86% reduction of invasive breast cancer in women with previous ADH (RR=0.14, 95% IC, 0.03-0.47) and with a 56% risk reduction in women with previous LCIS (RR=0.44, 0.16-1.06). However, the increased risk of endometrial cancer and of venous thromboembolism, have significantly limited its broad use in chemoprevention.
To improve the risk-benefit ratio, the use of lower doses of the drug has been proposed. Recent trials from our group have shown that a dose of 5 mg/day does not increase endometrial proliferation and is associated with a decrease of the estrogenic activity of tamoxifen on IGF-I, SHBG and antithrombin-III, with a potential decrease of venous thromboembolic events. Moreover, tamoxifen exhibits a high tissue distribution, so that a dose of 5 mg/day attains at the breast tissue level a concentration 10 times higher than that needed to inhibit cell growth in vitro.
The CYP2D6 enzyme mediates oxidation of N-desmethyl tamoxifen to endoxifen, the most active metabolite of tamoxifen. The SNP CYP2D6*4 (1846G>A) allele accounts for 75% of CYP2D6 poor metabolizer phenotype which have been associated with a higher risk to develop a breast event compared to wildtype (Serrano D et al. Pharmacogenomics J. 2010 Mar 23).
Study design and enrollment report: This is a multicenter randomized double-blind placebo-controlled phase III trial with two parallel arms: tamoxifen at daily dose of 5 mg or placebo for a total treatment time of 3 years, to assess the efficacy and the safety of 5 mg/day tamoxifen to reduce breast cancer incidence in women with previous IEN (LIN 2-3 and ER-positive or unknown DIN 1b-3). At present no standard treatment exists to treat these women, particularly in Europe, where tamoxifen is not registered in women with prior DCIS (DIN 2-3). A total of 1400 women will be recruited in 3 years to detect a 50% reduction (Hazard Ratio = 0.5) in the incidence of breast cancer in the tamoxifen arm with an 80% power and a 1-sided 5% alpha level. Secondary endpoints include: incidence of other non-invasive breast disorders (i.e., LIN, ductal atypical hyperplasia), endometrial cancer, clinical bone fractures, cardiovascular events, venous thromboembolic events, and clinically manifest cataract. The pharmacogenetic endpoints include to assess whether CYP2D6 genotype can explain modulation on surrogate biomarkers of tamoxifen efficacy and safety, including circulating IGF-I, hormones, mammographic density, endometrial thickness and hot flashes, but also on clinical events.
As of July 27, 2010, 10 enrolment centers have been activated, n=128 women have been screened and n=44 have been randomized. 58 women refused to participate and 26 women were excluded for the following ineligibility reasons: 6 women for use of raloxifene, tamoxifen or other SERMs; 4 women for ER negative primary breast cancer; 3 women for bilateral mastectomy, 2 for previous thromboembolic events, 2 for age limits and 9 for other reasons. No serious adverse events or suspected unexpected serious adverse reactions were registered.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A70.
Abstract
Background: Prostate cancer (PC) is an ideal target for chemoprevention, with high-grade prostatic intraepithelial neoplasia (HGPIN) as its most likely precursor finasteride, a 5α-reductase ...inhibitor, reduced prostate cancer incidence by 25% in average-risk men. However, a higher proportion of high-grade PC has been noted whose biological significance is unclear. An alternative targeted approach is the use of androgen receptor antagonists such as flutamide. Presurgical window-of-opportunity trials have been proposed as a model to assess the activity of preventive interventions in a cost-effective manner in PC. In this study we test the effect of minimal low-dose flutamide exposure or finasteride in comparison to placebo on biomarkers associated with PC, HGPIN, and normal prostate tissue.
Materials and Methods: This is a prospective randomized phase IIB placebo-controlled double-blind presurgical trial of finasteride 5 mg/day (FIN) vs. flutamide 250 mg/day (FLU) vs. placebo (PLA) in men with PC. Patients with biopsy proven PC, clinical stage ≤T2, candidates to radical retropubic prostatectomy were enrolled. Drugs and placebo were administered for 4 to 6 weeks before surgery. A sample size of 120 patients (40 per arm) was calculated to detect significant differences on change in nuclear area (NA) of epithelial cells between treatment and placebo arms (primary endpoint). To establish a direction of NA change from normal to malignancy a discriminant function derived from differences in morphometric parameters in the pretreatment biopsies between the normal epithelium and the PC tissue was applied to the posttreatment groups. Secondary endpoints include change in proliferation markers (Ki67 labeling index, topoisomerase-IIα), in serum PSA and hormones, safety, and toxicity.
Results: 125 patients were randomized at four cooperating institutions (41 FIN, 42 FLU, and 42 PLA). Mean age and PSA at baseline were 64 years and 8.7 ng/mL, respectively, without differences among arms. There were significant differences in NA and Ki67LI of normal and neoplastic cells both before and after treatment (NA interquartile range: 27-40µ2 in normal tissue, 30-50µ2 in HGPIN and 36-55µ2 in cancer tissue) but no differences were detected among arms.
Image and discriminant analysis performed in a subgroup of patients (16 FIN, 24 FLU, and 20 PLA) showed in the PLA and FLU arms a higher discriminant function score after treatment, with a significant increase of the mean score by 90% and 50%, respectively, meaning that cases treated with placebo or flutamide undergo a statistically significant further progression of karyometric features. Conversely, FIN-treated PC exhibited only a small further progressive change, with a net increase of the mean score by only 8%. LH significantly increased in the FLU arm; PSA and fPSA decreased while T increased significantly in both treatment arms compared to placebo. Treatment was well tolerated.
Conclusion: NA and KI67LI were significantly different among normal, HGPIN and PC tissue and between pre- and posttreatment biopsies. Discriminant analysis detected an inhibition of progressive karyometric pattern in patients treated with finasteride relative to low-dose flutamide and placebo. Our results support the use of nuclear changes as measured by karyometry in presurgical models to assess the activity of preventive agents.
This talk is also presented as Poster A68.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):PR-03.
Abstract
Rationale: Colorectal adenomas are well recognized colorectal cancer (CRC) risk markers, and regression of adenomas through chemopreventive strategies may reduce the incidence of CRC. ...Inflammation and oxidative stress appear to play a crucial role in the development of CRC, and interference with the mechanisms inducing oxidative stress and possibly cancer progression may represent a new strategy in CRC chemoprevention. Colonic cancerous tissue contains high levels of reactive oxygen metabolites (ROM), which may play an important role in the pathogenesis of CRC, and the effects of ROM scavengers are presently being tested for CRC chemoprevention.
Allopurinol, a structural analogue of hypoxanthine inhibiting the action of xantine oxidase (XO), is a ROM scavenger largely employed as an anti-gout agent in clinical practice. Allopurinol use is highly safe, with very uncommon adverse events. Allopurinol was shown to increase survival of patients with advanced CRC, and a recent population-based case-control study showed that its use for at least 5 years was correlated with a diminished risk of developing CRC (Odds Ratio=0.33; 95% CI=0.16-0.71, Rennert G et al. AACR 3rd International Conference on Frontiers in Cancer Prevention Research 2004, Abstract #C88) after adjustment for other known risk factors.
Design: To assess the effects of allopurinol on cell proliferation in both adenomatous and unaffected colonic tissue, we designed a randomized phase I/II, double blind, placebo-controlled, multicenter trial in patients with colorectal adenomatous polyps. After a complete colonoscopy and biopsy of the index polyp, subjects with histologically confirmed adenomas were assigned to either placebo or two doses of allopurinol (100mg or 300mg) and treated for 4-6 weeks before polyp removal. Samples of normal colonic tissue were also collected on both baseline and end-of-study colonoscopy. Treatment effect on cell proliferation was assessed by measuring changes of Ki-67 labeling index (primary endpoint: Ki-67 %change) on both adenomatous and normal colonic tissue. We calculated a total of 75 subjects (25 per arm), required (α = 0.05, 1-β = 0.85, one-sided test) to show a 27% to 40% reduction in Ki-67 LI depending on standard deviation of Ki-67. Secondary endpoints included treatment modulation of biomarkers of oxidative activation (NF-Kb and β-catenin), apoptosis (topoisomerase-II-α, Cox-3, Bcl-2), inflammation (u-CRP) and of circulating IGFs (IGF-1, IGFBP-3).
Preliminary results: The first patient entered the study on May 13th 2006 and the last on May 31th, 2010, for a total study enrolment duration of about 4 years. Enrolment stopped on July 1, 2010, with a total of 73 subjects enrolled.
An interim analysis performed on November 2008 (48 patients enrolled, mean age 62 yrs, mean BMI 25kg/m2) showed a 98% treatment compliance, with only 3 G1 adverse events (1 leg cramps, 1 erythema and 1 skin rush), confirming the high safety of allopurinol. Ki-67 analysis on the first 13 subjects enrolled showed a favourable trend: median Ki-67 expression in normal tissue doubled on placebo compared with a 5% increase in both treatments arms; in adenomas, it increased by 70% on placebo compared with 6% and 12% in the 100 mg and 300 mg allopurinol arm, respectively.
Tissue and serum biomarker analyses on all subjects enrolled are underway and further results will be presented at the conference.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A69.
Abstract
Rationale: The annual risk of invasive disease in women with breast intraepithelial neoplasia (IEN) is about 8–10 times higher than in the general population, thus IEN can be considered an ...important target for chemoprevention strategies. The NSABP-P1 trial showed that women with LCIS randomized to tamoxifen at 20 mg/day reduced their risk of invasive breast cancer by 56% (RR=0.44, 0.16–1.06) and women with previous ADH by 86% (RR=0.14, 95% IC, 0.03–0.47). The issue was the increased risk of endometrial cancer and of venous thromboembolism, which significantly limited tamoxifen broad use in a chemoprevention setting. To improve the risk-benefit ratio, the use of lower doses of the drug has been proposed. Recent trials from our group have shown that a dose of 5 mg/day does not increase endometrial proliferation and is associated with a decrease of the estrogenic activity of tamoxifen on IGF-I, SHBG and antithrombin-III, with a potential decrease of venous thromboembolic events. Moreover, tamoxifen exhibits a high tissue distribution, so that a dose of 5 mg/day attains at the breast tissue level a concentration 10 times higher than that needed to inhibit cell growth in vitro. The CYP2D6 enzyme mediates oxidation of N-desmethyl tamoxifen to endoxifen, the most active metabolite of tamoxifen. The SNP CYP2D6*4 (1846G>A) allele accounts for 75% of CYP2D6 poor metabolizer phenotype which have been associated with a higher risk to develop a breast event compared to wild-type (Serrano D et al. Pharmacogenomics J. 2011;11:100–7).
Study design and enrollment report: We designed a chemoprevention multicenter randomized double-blind placebo-controlled phase III trial to assess the efficacy and safety of tamoxifen at daily dose of 5 mg or placebo for a total treatment duration time of 3 years, to reduce breast cancer incidence in women with previous IEN (LIN 2–3 and ER-positive or unknown DIN 1b-3). At present in Europe no standard treatment exists to treat these patients, since tamoxifen is not registered for women with prior DCIS (DIN 2–3). With an 80% power and a 1-sided 5% alpha level, we calculated a total sample size of 1400 women to detect a 50% reduction in incidence of breast cancer (Hazard Ratio = 0.5) in the tamoxifen arm. Secondary endpoints are: incidence of other non-invasive breast disorders (i.e., LIN, ductal atypical hyperplasia), endometrial cancer, clinical bone fractures, cardiovascular events, venous thromboembolic events and clinically manifest cataract. We planned also a pharmacogenetic sub-study to assess whether CYP2D6 genotype can explain modulation on surrogate biomarkers of tamoxifen efficacy and safety, such as circulating IGF-I, hormones, mammographic density, endometrial thickness and hot flashes, but also clinical events.
As of August 1, 2011, 15 enrolment centers have been activated, n=421 women have been screened and n=166 have been randomized, 181 women refused to participate, 74 women were excluded for ineligibility. Main ineligibility reasons were: ER negative IEN (9 women), cataract (8), previous neoplasms (7), previous use of tamoxifen (6) and age limits (5). Only 1 serious adverse event (venous thrombosis) was registered. No suspected unexpected serious adverse reactions were registered.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A56.
The intracystic electrolyte content is generally used to identify different breast cyst subpopulations: cysts containing high K+ levels have been associated with an increased risk of subsequent ...breast cancer. In order to define whether other biochemical features of breast cyst fluid (BCF) might further explain such an increased risk, we determined the content of epidermal growth factor (EGF), a known mitogenic factor for normal and transformed breast epithelium, in cysts of women with breast cancer or proliferative lesions of the breast (atypical ductal or lobular hyperplasia and proliferative disease without atypia). Median intracystic EGF levels were significantly higher in patients with breast cancer or atypical hyperplasia than in cysts of women without any clinical or instrumental evidence of proliferative disease chosen as controls (p < 0.05 and p < 0.01, respectively). In patients affected by proliferative disease without atypia, intracystic EGF levels were not different either from controls or from the other study groups. No significant difference among groups was observed in the prevalence of Na+/K+ < 3 cysts, this being the most frequently observed type of cysts in all groups except in that with proliferative disease without atypia. No significant difference in EGF levels between cysts ipsilateral or contralateral to the biopsy was observed within each histological group. Our results indicate that EGF levels are higher in cysts aspirated from breasts with an associated proliferative pathology, either benign or neoplastic. The determination of intracystic EGF, combined with that of electrolyte content, might help to identify a subset of patients with gross cystic disease of the breast at potentially higher risk of developing breast cancer.
In recent years, several studies focused on the biochemical analysis of breast cyst fluid composition. It has been shown that breast cysts lined by apocrine epithelium contain higher levels of ...potassium and dehydroepiandrosterone-sulphate as compared to cysts lined by flattened cells, and that women with apocrine cysts are more likely to develop breast cancer. In the present study, we measured the intracystic levels of sodium (Na+), potassium (K+), dehydroepiandrosterone-sulphate (DHEA-S), and epidermal growth factor (EGF), a factor which could play a role in the autocrine or paracrine control of breast cancer cell growth as recently proposed by some investigators. Breast cyst fluids obtained by fine-needle aspiration from 86 women with gross cystic breast disease were assayed. On the basis of the relative intracystic concentrations of Na+ and K+ two main classes of cysts were defined. An arbitrary cut-off value of 3 for the Na+/K+ ratio seemed adequate to separate these two types of cysts. An inverse relationship was found between the Na+/K+ ratio and DHEA-S concentration, median levels of the androgen conjugate being 3615 micrograms/dl in Na+/K+ less than 3 cysts and 480 micrograms/dl in Na+/K+ greater than 3 cysts (P less than 0.001). EGF levels were found to be significantly higher in Na+/K+ less than 3 cysts as compared to Na+/K+ greater than 3 cysts: 103.26 ng/ml versus 57.22 ng/ml, respectively (P less than 0.001). EGF appeared inversely correlated with total protein concentration in the Na+/K+ greater than 3 cysts, while in the Na+/K+ less than 3 cysts high EGF levels were observed independently of total protein content. In addition, a direct correlation was found between EGF and DHEA-S concentrations. On the basis of these results, the hypothesis can be made that EGF, which is measurable in all breast fluids tested and is nearly undetectable in plasma, is actually produced by the epithelium lining the cyst wall, particularly as far as the Na+/K+ less than 3 cysts are concerned. In view of our results this type of cyst, which has been shown to be lined by apocrine epithelium, appears to be characterized by high DHEA-S and EGF levels. It is suggested that the latter finding could provide a clue for understanding the increased risk of subsequent breast cancer in women bearing apocrine cysts.
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