Harriet Johansson

Review and meta-analysis on vitamin D receptor polymorphisms and cancer risk

It was suggested that vitamin D levels influence cancer development. The vitamin D receptor (VDR) is a crucial mediator for the cellular effects of vitamin D. Results from previous studies on the association of VDR polymorphisms with different cancer types are somewhat contradictory, and the role of VDR in the etiology of cancer is still equivocal. We therefore performed a meta-analysis on the association between the two most studied VDR polymorphisms (FokI and BsmI) and any cancer site. Up to January 2009, we identified 67 independent studies. We used random-effects models to provide summary odds ratio (SOR) for VDR polymorphisms and cancer. We tested homogeneity of effects across studies and publication bias and explored between-study heterogeneity. When comparing FokI ff with FF carriers, we found a significant increase in skin cancer [SOR; 95% confidence intervals (CIs): 1.30; 1.04-1.61] and breast cancer (SOR; 95%CI: 1.14; 1.03-1.27) risk. For the same genotype comparison, we found a significantly higher risk of cancer when we pooled estimates from cancer sites possibly associated with vitamin D levels (prostate, breast, skin, ovary, non-Hodgkin lymphoma and colorectal). A significant reduction in prostate cancer risk was observed for carriers of BsmI Bb compared with bb genotype (SOR; 95%CI: 0.83; 0.69-0.99). In Caucasian populations, both Bb and BB carriers had a significant reduced risk of cancer at any site. In conclusion, this meta-analysis showed that VDR FokI and BsmI polymorphisms might modulate the risk of cancer of breast, skin and prostate and possibly affect cancer risk at any site in Caucasians.

Dual Effect of Metformin on Breast Cancer Proliferation in a Randomized Presurgical Trial

PURPOSE Metformin is associated with reduced breast cancer risk in observational studies in patients with diabetes, but clinical evidence for antitumor activity is unclear. The change in Ki-67 between pretreatment biopsy and post-treatment surgical specimen has prognostic value and may predict antitumor activity in breast cancer. PATIENTS AND METHODS After tumor biopsy, we randomly allocated 200 nondiabetic women with operable breast cancer to either metformin 850 mg/twice per day (n = 100) or placebo (n = 100). The primary outcome measure was the difference between arms in Ki-67 after 4 weeks adjusted for baseline values. RESULTS Overall, the metformin effect on Ki-67 change relative to placebo was not statistically significant, with a mean proportional increase of 4.0% (95% CI, -5.6% to 14.4%) 4 weeks apart. However, there was a different drug effect depending on insulin resistance (homeostasis model assessment [HOMA] index > 2.8, fasting glucose [mmol/L] × insulin [mU/L]/22.5; P(interaction) = .045), with a nonsignificant mean proportional decrease in Ki-67 of 10.5% (95% CI, -26.1% to 8.4%) in women with HOMA more than 2.8 and a nonsignificant increase of 11.1% (95% CI, -0.6% to 24.2%) with HOMA less than or equal to 2.8. A different effect of metformin according to HOMA index was noted also in luminal B tumors (P(interaction) = .05). Similar trends to drug effect modifications were observed according to body mass index (P = .143), waist/hip girth-ratio (P = .058), moderate alcohol consumption (P = .005), and C-reactive protein (P = .080). CONCLUSION Metformin before surgery did not significantly affect Ki-67 overall, but showed significantly different effects according to insulin resistance, particularly in luminal B tumors. Our findings warrant further studies of metformin in breast cancer with careful consideration to the metabolic characteristics of the study population.

Effect of Transdermal Estradiol and Oral Conjugated Estrogen on C-Reactive Protein in Retinoid-Placebo Trial in Healthy Women

Background—The increase in C-reactive protein (CRP) during oral conjugated equine estrogen (CEE) may explain the initial excess of cardiovascular disease observed in clinical studies. Because the effect of transdermal estradiol (E2) on CRP is unclear, we compared CRP changes after 6 and 12 months of transdermal E2 and oral CEE in a randomized 2×2 retinoid-placebo trial. Methods and Results—A total of 189 postmenopausal women were randomized to 50 &mgr;g/d transdermal E2 and 100 mg BID of the retinoid fenretinide (n=45), 50 &mgr;g/d transdermal E2 and placebo (n=49), 0.625 mg/d oral CEE and 100 mg BID fenretinide (n=46), or 0.625 mg/d oral CEE and placebo (n=49) for 1 year. Sequential medroxyprogesterone acetate was added in each group. Relative to baseline, CRP increased by 10% (95% CI −9% to 33%) and by 48% (95% CI 22% to 78%) after 6 months of transdermal E2 and oral CEE, respectively. The corresponding figures at 12 months were 3% (95% CI −14% to 23%) for transdermal E2 and 64% (95% CI 38% to 96%) for oral CEE. Fenretinide did not change CRP levels at 6 and 12 months relative to placebo. Relative to oral CEE, the mean change in CRP after 12 months of transdermal E2 was −48% (95% CI −85% to −7%, P =0.012), whereas fenretinide was associated with a mean change of −1% (95% CI −34% to 40%, P =0.79) compared with placebo. Conclusions—In contrast to oral CEE, transdermal E2 does not elevate CRP levels up to 12 months of treatment. The implications for early risk of coronary heart disease require further studies.

Randomized double-blind 2 x 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in high-risk premenopausal women.

PURPOSE Tamoxifen and fenretinide are active in reducing premenopausal breast cancer risk and work synergistically in preclinical models. The authors assessed their combination in a two-by-two biomarker trial. PATIENTS AND METHODS A total of 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), or intraepithelial neoplasia (IEN, n = 160), or 5-year Gail risk > or = 1.3% (n = 54) were randomly allocated to either tamoxifen 5 mg/d, fenretinide 200 mg/d, their combination, or placebo. We report data for plasma insulin-like growth factor I (IGF-I), mammographic density, uterine effects, and breast neoplastic events after 5.5 years. RESULTS During the 2-year intervention, tamoxifen significantly lowered IGF-I and mammographic density by 12% and 20%, respectively, fenretinide by 4% and 10% (not significantly), their combination by 20% and 22%, with no evidence for a synergistic interaction. Tamoxifen increased endometrial thickness principally in women becoming postmenopausal, whereas fenretinide decreased endometrial thickness significantly. The annual rate of breast neoplasms (n = 48) was 3.5% +/- 1.0%, 2.1% +/- 0.8%, 4.7% +/- 1.3%, and 5.2% +/- 1.3% in the tamoxifen, fenretinide, combination, and placebo arms, respectively, with hazard ratios (HRs) of 0.70 (95% CI, 0.32 to 1.52), 0.38 (95% CI, 0.15 to 0.90), and 0.96 (95% CI, 0.46 to 1.99) relative to placebo (tamoxifen x fenretinide adverse interaction P = .03). There was no clear association with tumor receptor type. Baseline IGF-I and mammographic density did not predict breast neoplastic events, nor did change in mammographic density. CONCLUSION Despite favorable effects on plasma IGF-I levels and mammographic density, the combination of low-dose tamoxifen plus fenretinide did not reduce breast neoplastic events compared to placebo, whereas both single agents, particularly fenretinide, showed numerical reduction in annual odds of breast neoplasms. Further follow-up is indicated.

Effect of blood tamoxifen concentrations on surrogate biomarkers in a trial of dose reduction in healthy women

PURPOSE Tamoxifen administered at 20 mg/d has been shown to decrease breast cancer incidence in at-risk women by 50%, but toxicity may limit its broad use, particularly in postmenopausal women. Because toxicity may be dose-dependent, we studied the biologic activity of low concentrations of tamoxifen to determine the plausibility of a dose reduction. PATIENTS AND METHODS We measured the blood concentrations of tamoxifen and its main metabolites in a dose titration study in 105 healthy women (placebo, tamoxifen 10 mg on alternate days, tamoxifen 10 mg/d, and tamoxifen 20 mg/d). Drug levels measured after 2 months of treatment were correlated with the changes in surrogate biomarkers of different diseases, including lipid profile, blood cell count, fibrinogen, antithrombin III, osteocalcin, and insulin-like growth factor I, a promising surrogate biomarker of breast cancer. RESULTS The means (+/- SD) for tamoxifen and N-desmethyltamoxifen (metabolite X) concentrations (ng/mL) were dose-related, being, respectively, 0 and 0 with placebo, 26.8 +/- 15.1 and 43.7 +/- 22.5 with 10 mg every other day, 51.2 +/- 24.1 and 90.7 +/- 48.0 with 10 mg/d, and 136.0 +/- 52.7 and 230.6 +/- 75.0 with 20 mg/d of tamoxifen. At variance, the biomarker changes were of comparable magnitude at any drug concentration except for platelet count and triglycerides levels, the latter showing a trend to an increase with increasing tamoxifen concentrations. CONCLUSION An 80% reduction in blood concentrations does not seem to affect the activity of tamoxifen on biomarkers of cardiovascular or breast cancer risk and may in fact have a more favorable safety profile. Additional studies are warranted to determine the most appropriate dose of this agent.

Prognostic significance of Ki-67 labeling index after short-term presurgical tamoxifen in women with ER-positive breast cancer

BACKGROUND Studies have shown that Ki-67 response after short-term neoadjuvant aromatase inhibitors may predict recurrence in postmenopausal breast cancer, whereas its prognostic effect in premenopausal women is unknown. PATIENTS AND METHODS We compared the prognostic and predictive value of baseline and post-treatment Ki-67 in 120 pre- and postmenopausal women with early-stage estrogen receptor-positive breast cancer who participated in a 4-week presurgical trial of tamoxifen. RESULTS After 7.2 years of follow-up, women with post-treatment Ki-67 in the second (14%-19%), third (20%-29%) and top (≥30%) quartiles had a recurrence hazard ratio of 2.92 [95% confidence interval (CI) 0.95-8.96], 4.37 (1.56-12.25) and 6.05 (2.07-17.65), respectively, as compared with those in the bottom quartile (<14%) (P-trend = 0.001). The risk of invasive disease recurrence was 2.2% (95% CI 0.9-5.0) per point increase in baseline Ki-67 (P-trend = 0.076) and 5.0% (95% CI 2.3-7.7) per point increase in post-tamoxifen Ki-67 (P-trend < 0.001). The risk of death was 5.5 (95% CI 1.26-23.16) times higher in patients with post-drug Ki-67 ≥20% than in those with Ki-67 <20% (P-trend = 0.006). CONCLUSIONS Ki-67 response after short-term neoadjuvant tamoxifen is a good predictor of recurrence-free survival and overall survival, further supporting its use as surrogate biomarker to personalize adjuvant treatment and to screen novel drugs cost-effectively.

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

The role of pharmacogenomics and tamoxifen was investigated by analyzing several polymorphisms of cytochrome P450 and SULT1A1 gene in a nested case control study from the Italian Tamoxifen Prevention Trial. This study included 182 Caucasian subjects, 47 breast cancer (BC) cases and 135 matched controls. We used the AmpliChip CYP450 Test to screen 33 alleles of CYP2D6 and 3 of CYP2C19. One more variant for CYP2C19*17 and two single-nucleotide polymorphisms for the gene SULT1A1 were also performed. By using the AmpliChip CYP450 Test, out of 182 subjects, we identified 8 poor metabolizer (PM), 17 intermediate metabolizer (IM), 151 extensive metabolizer (EM) and 3 ultrarapid metabolizer (UM). PM women allocated to the tamoxifen arm showed a higher risk of developing BC compared to the remaining phenotypes (P=0.035). In an exploratory analysis, among 58 women with a CYP2D6*2A allele, 9 BCs were diagnosed in the placebo arm and only 1 in the tamoxifen arm (P=0.0001). CYP2C19 and SULT1A1 polymorphisms did not show any correlation with tamoxifen efficacy. Tamoxifen showed reduced efficacy in CYP2D6 PMs in the chemoprevention setting. Conversely, the CYP2D6*2A allele may be associated with increased efficacy of tamoxifen. These findings support the relevance of pharmaco-genomics in tailoring tamoxifen treatment.

Randomized Dose-Ranging Trial of Tamoxifen at Low Doses in Hormone Replacement Therapy Users

PURPOSE The combination of hormone replacement therapy (HRT) and low-dose tamoxifen may retain the benefits while reducing the risks of either agent. We assessed the optimal biologic dose and schedule of tamoxifen in HRT users using surrogate end point biomarkers and menopausal symptoms. SUBJECTS AND METHODS Two hundred ten current or de novo HRT users were randomly assigned to one of the following four arms: tamoxifen 1 mg/day and placebo/week, placebo/day and tamoxifen 10 mg/week, tamoxifen 5 mg/day and placebo/week, or both placebos for 12 months. The primary end point was the change of plasma insulinlike growth factor 1 (IGF-I) through 12 months, and secondary end points were IGF-I/IGF binding protein-3 (IGFBP-3) ratio, fibrinogen, antithrombin III, C reactive protein, C-telopeptide, mammographic percent density, and endometrial thickness. Endometrial proliferation was assessed by Pipelle biopsy in superficial, deep glandular, and stromal compartments after 12 months. RESULTS Compared with placebo, IGF-I declined in all tamoxifen arms (P = .005), with a greater change on 5 mg/day (P = .019 v 10 mg/week or 1 mg/day). Tamoxifen increased IGFBP-3 and lowered antithrombin-III, C reactive protein, and mammographic density, with greater effects of 5 mg/day. Tamoxifen increased endometrial thickness but not Ki-67 expression, which was lower on 5 mg/day among the three doses. Menopausal symptoms were not significantly worsened by tamoxifen. CONCLUSION Doses of tamoxifen < or = 5 mg/day modulate favorably biomarkers of breast carcinogenesis and cardiovascular risk in HRT users with no increase of endometrial proliferation and menopausal symptoms. A dose of 5 mg/day was the most effective and has been selected for a phase III trial in HRT users.

Effect of Fenretinide and Low-Dose Tamoxifen on Insulin Sensitivity in Premenopausal Women at High Risk for Breast Cancer

The prevalence of metabolic syndrome is increasing along with breast cancer incidence worldwide. Because fenretinide improves insulin action and glucose tolerance in insulin-resistant obese mice and because tamoxifen has shown to regulate several markers involved in metabolic syndrome, we sought to investigate the effect of fenretinide or tamoxifen at low dose on features linked to insulin resistance in premenopausal women at risk for breast cancer. We randomized 235 women to low-dose tamoxifen (5 mg/daily), fenretinide (200 mg/daily), or their combination or placebo for 2 years. We used the homeostasis model assessment (HOMA; fasting insulin x glucose/22.5) to estimate insulin sensitivity. Women were considered to improve insulin sensitivity when they shifted from a HOMA >/=2.8 to <2.8. There was no effect of fenretinide or tamoxifen on HOMA overall, but overweight women (body mass index, >or=25 kg/m(2)) had a 7-fold greater probability to normalize HOMA after 2 years of fenretinide treatment [odds ratio (OR), 7.0; 95% confidence interval (95% CI), 1.2-40.5], with 25% of women improving their insulin sensitivity, whereas tamoxifen decreased insulin sensitivity by almost 7 times compared with subjects not taking tamoxifen (OR, 0.15; 95% CI, 0.03-0.88). In this group only, 5% improved their insulin sensitivity. Interestingly, women with intraepithelial or microinvasive neoplasia had higher HOMA (3.0) than unaffected subjects (2.8; P = 0.07). Fenretinide can positively balance the metabolic profile in overweight premenopausal women and this may favorably affect breast cancer risk. Furthermore, features of the metabolic syndrome should be taken into consideration before proposing tamoxifen for breast cancer prevention. The clinical implications of these results require further investigations.

Preliminary results on safety and activity of a randomized, double-blind, 2 x 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in premenopausal women

PURPOSE To determine whether low-dose tamoxifen and fenretinide have a synergistic effect on surrogate biomarkers, including circulating insulin-like growth factor I (IGF-I) and mammographic density, in premenopausal women at risk for breast cancer and to study drug safety. PATIENTS AND METHODS Premenopausal women (n = 235) were randomly assigned in a double-blind four-arm trial to receive tamoxifen 5 mg/d, fenretinide 200 mg/d, both agents, or placebo for 2 years. The present analysis refers to preliminary data on safety, IGF-I, and breast cancer events. RESULTS Patients were included if they had an excised ductal carcinoma-in-situ (57%), lobular carcinoma-in-situ (13%), minimal invasive breast cancer (7%), or a 5-year Gail risk > or = 1.3% (23%). After a median follow-up of 40 months, there was a reduction of 13%, 2%, 20%, and 1% in IGF-I levels for patients on tamoxifen, fenretinide, tamoxifen plus fenretinide, and placebo, respectively. Recruitment was stopped based on the lack of an interaction on IGF-I levels, which was a primary end point for the study. Thirty-six patients have dropped out of the study, 17 because of adverse events and 19 for various other reasons. One stage I endometrial cancer occurred in a patient on fenretinide, and one optic nerve ischemia and one deep venous thrombosis occurred on tamoxifen. There was no difference in menopausal symptoms, endometrial thickness, polyps, or ovarian cysts among treatment arms. To date, 24 breast cancers have been observed, without differences among arms. CONCLUSION The combination of low-dose tamoxifen and fenretinide is safe but not synergistic in lowering IGF-I levels in premenopausal women. The clinical implications require further follow-up.