Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial.

BACKGROUND: At the time of the initial analysis of overall survival (OS) for the Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) randomized, double-blind, phase III trial, approximately 50% of patients had died. A final analysis of OS was subsequently planned for when 75% of patients had died. METHODS: Patients were randomly assigned 1:1 to fulvestrant 500 mg administered as two 5-mL intramuscular injections on days 0, 14, and 28 and every 28 (±3) days thereafter or fulvestrant 250 mg administered as two 5-mL intramuscular injections (one fulvestrant and one placebo [identical in appearance to study drug]) on days 0, 14 (two placebo injections only), and 28 and every 28 (±3) days thereafter. OS was analyzed using an unadjusted log-rank test. No adjustments were made for multiplicity. Serious adverse events (SAEs) and best response to subsequent therapy were also reported. All statistical tests were two-sided. RESULTS: In total, 736 women (median age = 61.0 years) were randomly assigned to fulvestrant 500 mg (n = 362) or 250 mg (n = 374). At the final survival analysis, 554 of 736 (75.3%) patients had died. Median OS was 26.4 months for fulvestrant 500 mg and 22.3 months for 250 mg (hazard ratio = 0.81; 95% confidence interval = 0.69-0.96; nominal P = .02). There were no clinically important differences in SAE profiles between the treatment groups; no clustering of SAEs could be detected in either treatment group. Type of first subsequent therapy and objective responses to first subsequent therapy were well balanced between the two treatment groups. CONCLUSIONS: In patients with locally advanced or metastatic estrogen receptor-positive breast cancer, fulvestrant 500 mg is associated with a 19% reduction in risk of death and a 4.1-month difference in median OS compared with fulvestrant 250 mg. Fulvestrant 500 mg was well tolerated, and no new safety concerns were identified.

Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer.

PURPOSE: We compared fulvestrant 500 mg regimen with the approved dose of fulvestrant 250 mg per month for treatment of postmenopausal women with estrogen receptor-positive advanced breast cancer who experienced progression after prior endocrine therapy. PATIENTS AND METHODS: Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) is a double-blind, parallel-group, multicenter, phase III study. Patients were randomly assigned to fulvestrant 500 mg (500 mg intramuscularly [IM] on day 0, then 500 mg IM on days 14 and 28 and every 28 days thereafter) or 250 mg every 28 days. Primary end point was progression-free survival (PFS). Secondary end points included objective response rate, clinical benefit rate (CBR), duration of clinical benefit (DoCB), overall survival (OS), and quality of life (QOL). RESULTS: PFS was significantly longer for fulvestrant 500 mg (n = 362) than 250 mg (n = 374) (hazard ratio [HR] = 0.80; 95% CI, 0.68 to 0.94; P = .006), corresponding to a 20% reduction in risk of progression. Objective response rate was similar for fulvestrant 500 mg and 250 mg (9.1% v 10.2%, respectively). CBR was 45.6% for fulvestrant 500 mg and 39.6% for fulvestrant 250 mg. DoCB and OS were 16.6 and 25.1 months, respectively, for the 500-mg group, whereas DoCB and OS were 13.9 and 22.8 months, respectively, in the 250-mg group. Fulvestrant 500 mg was well tolerated with no dose-dependent adverse events. QOL was similar for both arms. CONCLUSION: Fulvestrant 500 mg was associated with a statistically significant increase in PFS and not associated with increased toxicity, corresponding to a clinically meaningful improvement in benefit versus risk compared with fulvestrant 250 mg.

Frequency of hemochromatosis gene (HFE) mutations in Russian healthy women and patients with estrogen-dependent cancers.

Possible association between the C282Y and H63D mutations in the HFE gene and estrogen-dependent cancer risk was assessed. Genotyping was performed using PCR amplification followed by digestion of products with specific restrictases. In a population of 260 healthy women (permanent residents of the southwest European Russia), mutant allele frequencies at the C282Y and H63D sites were evaluated as 3.3 and 16.3%, respectively. In patients with breast, ovarian, and endometrial cancer, C282Y frequencies were also low (1.0, 1.3, and 3.8%, respectively), and no cancer risk associated with the C282Y mutation was found. Odds ratios for breast cancer risk associated with the H63D mutation increased significantly with age: 0.5 in women below 48 years old, 1.0 in a range of 48-57 years, and 4.4 in older women (P(trend)=0.002). The latter value was statistically significant (95% CI, 1.4-14.1), indicating that women bearing the H63D mutation may be at an increased breast cancer risk at an age above 57 years. Preliminary results obtained in patients with two other estrogen-dependent malignancies revealed the same tendency to OR increase with age in ovarian cancer patients (P(trend)=0.008), but no age-related OR differences in endometrial cancer patients.