Didier Verhoeven

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.

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 500mg (n = 362) or 250mg (n = 374). At the final survival analysis, 554 of 736 (75.3%) patients had died. Median OS was 26.4 months for fulvestrant 500mg and 22.3 months for 250mg (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 500mg is associated with a 19% reduction in risk of death and a 4.1-month difference in median OS compared with fulvestrant 250mg. Fulvestrant 500mg was well tolerated, and no new safety concerns were identified.

Comparison of cell growth in different parts of breast cancers

This study was performed to answer the question: which parts of breast cancers are active in terms of proliferation as measured by the Ki‐67 antibody and in terms of cell division as measured by the mitotic index. Forty‐six breast samples were studied, including 34 breast cancers and 12 benign conditions. The intraductal component of infiltrating breast cancers showed a significantly lower proliferation index than the infiltrating component. The cells at the periphery of infiltrating tumour strands showed a higher proliferation activity than the cells in the core. These findings suggest that infiltration advances through preferential active growth of the cells at the invasion front.

Desmin-positive stellate cells associated with angiogenesis in a tumour and non-tumour system.

SummaryThe angiogenesis induced after implantation of fragments of the Walker 256 carcinoma was compared with the angiogenesis following implantation of different amounts of Indian ink. Morphologically and chronologically the tumour system showed no difference from the Indian ink system, provided sufficient amounts of ink were implanted. Both systems were characterized by significant macrophage infiltration. The vascular development, which was clearly concentrated in a dense rim around the tumour, remained present when the tumour enlarged, suggesting an acquisition of vasculature by the tumour through vessel incorporation and not vessel ingrowth. Initially, scattered desmin-positive cells, in contact or encircled by collagen IV, were found in the developing angiogenic rim. Later many desmin-positive cells were found around vessels and could be identified by electron microscopy as pericytes. They exhibited close local contacts with endothelial cells. After incorporation of the peritumour vascular rim into the tumour the number of pericytes decreased and their shape became flattened and elongated.

Final analysis of overall survival for the Phase III CONFIRM trial: fulvestrant 500 mg versus 250 mg

Background: The COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) trial (NCT00099437) compared fulvestrant 500 mg with fulvestrant 250 mg in postmenopausal women with locally advanced or metastatic estrogen receptor (ER)-positive breast cancer who had recurred or progressed following prior endocrine therapy. Fulvestrant 500 mg was associated with a statistically significant increase in progression-free survival compared with fulvestrant 250 mg (Di Leo A et al. J Clin Oncol 2010; 28: 4594–4600). At the time of the primary analysis approximately 50% of patients had died. Median overall survival was 25.1 months and 22.8 months for fulvestrant 500 mg and 250 mg, respectively (hazard ratio [HR] 0.84; 95% confidence interval [CI] 0.69, 1.03; p = 0.091). A follow-up analysis of overall survival was subsequently planned for when 75% of patients had died and the results are presented here. Methods: CONFIRM was a randomized, double-blind, parallel-group, multicenter, Phase III study. Patients were randomized 1:1 to either fulvestrant 500 mg (500 mg i.m. on Days 0, 14 and 28 and every 28 days thereafter) or fulvestrant 250 mg (250 mg i.m. every 28 days). After the primary analysis, patients on fulvestrant 250 mg were permitted to switch to 500 mg and all patients were followed up for overall survival, regardless of treatment discontinuation, unless consent was withdrawn. Overall survival was analyzed using an unadjusted log-rank test. No adjustments were made for multiplicity. Serious adverse events (SAEs) were also reported. Results: In total, 736 women (median age 61.0 years) were randomized between February 2005 and August 2007 from 128 centers in 17 countries (fulvestrant 500 mg: n=362; fulvestrant 250 mg: n=374). At time of follow-up analysis, 63 (9.0%) patients were lost to follow-up, 16 (2.2%) patients had withdrawn consent, 103 (14.0%) patients were still ongoing (21 [2.9%] on treatment and 82 [11.1%] not on treatment), and 554 (75.3%) patients had died. Eight (2.1%) patients crossed over from fulvestrant 250 mg to 500 mg. Median overall survival was 26.4 months for fulvestrant 500 mg and 22.3 months for fulvestrant 250 mg (HR 0.81; 95% CI, 0.69, 0.96; nominal p = 0.016). During the treatment period, a total of 32 (8.9%) patients had at least one SAE in the fulvestrant 500 mg and 25 (6.7%) patients in the fulvestrant 250 mg groups, and SAEs that were causally related to study treatment were reported for 6 (1.7%) and 3 (0.8%) patients, respectively. SAEs with an outcome of death were reported for 5 (1.4%) and 6 (1.6%) patients, respectively, during the treatment period. Overall, there were no clinically important differences in the profiles of SAEs between the treatment groups and no clustering of SAEs could be detected in either treatment group. Conclusions: Overall survival data from CONFIRM demonstrate that, in patients with locally advanced or metastatic ER positive breast cancer, fulvestrant 500 mg is associated with a clinically relevant 4.1 month difference in median overall survival and 19% reduction in risk of death compared with fulvestrant 250 mg. There were no new safety concerns associated with the use of fulvestrant 500 mg. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-4.

The presence of a type IV collagen skeleton associated with periductal elastosis in breast cancer.

Using serial sections of frozen and AFA-fixed tissues from 34 breast cancers, we studied the presence of basement membrane material in the areas of elastosis. Various amounts of type IV collagen but not of laminin were demonstrated in areas of periductal elastosis. In some tumors, type IV collagen accumulated beneath the basement membrane. Periductal elastosis in areas of extensive fibrosis showed focal type IV collagen immunoreactivity, indicating remnants of ducts. Interstitial elastosis corresponded with weak type IV collagen reactivity. Each tumor showed type IV collagen immunostaining of the elastotic areas, with various degrees of intensity. Negative crossreactivity of the type IV collagen antibody with elastin was verified in skin biopsies with solar elastosis. Pre-incubation of the antibody with large amounts of elastin demonstrated an identical immunoreactivity. The specificity of the antibody was confirmed by ELISA and by Western blot analysis. To explain the periductal elastosis, we propose the following hypothesis. Excessive production of basement membrane material by the epithelial cells of the ducts leads to formation of a type IV collagen skeleton. This skeleton can act as the matrix for a secondary deposition of elastic material.

Tamoxifen metabolism and efficacy in breast cancer- a prospective multicentre trial

Purpose: Levels of endoxifen, the most active metabolite of tamoxifen, vary by the highly polymorphic cytochrome P450 (CYP) 2D6 enzyme. We prospectively investigated tamoxifen efficacy by serum endoxifen levels and the tamoxifen activity score (TAS). Experimental Design: A prospective observational multicenter study included postmenopausal women with an estrogen receptor–positive breast cancer receiving first-line tamoxifen, 20 mg daily in the neoadjuvant or metastatic setting, recruited between February 2009 and May 2014. The primary endpoint was the objective response rate (ORR) using RECIST criteria 1.0. Secondary endpoints were clinical benefit (CB), progression-free survival (PFS), and tolerability of tamoxifen. The main analysis used logistic regression to relate ORR to serum endoxifen levels after 3 months. Endpoints were also related to other tamoxifen metabolites and to TAS. Results: Endoxifen levels were available for 247 of all 297 patients (83%), of which 209 with target lesions (85%). Median follow-up time for PFS was 32.5 months, and 62% progressed. ORR and CB were 45% and 84%, respectively. ORR was not related to endoxifen, and the OR of ORR was 1.008 per μg/L increase in endoxifen (95% confidence interval, 0.971–1.046; P = 0.56). In general, none of the endpoints was associated with endoxifen levels, tamoxifen metabolites, or TAS. Conclusions: Under the prespecified assumptions, the results from this prospective clinical trial do not suggest therapeutic drug monitoring of endoxifen to be of clinical value in postmenopausal women treated with tamoxifen for breast cancer in the neoadjuvant or metastatic setting. Clin Cancer Res; 24(10); 2312–8. ©2018 AACR.