First Results from FACT – An Open-Label, Randomized Phase III Study Investigating Loading Dose of Fulvestrant Combined with Anastrozole Versus Anastrozole at First Relapse in Hormone Receptor Positive Breast Cancer.
Bibliographic record
Abstract
Abstract Background:Although aromatase inhibitors, including anastrozole (A) have been shown to be effective for treatment of hormone-dependent postmenopausal breast cancer, many patients with advanced disease will develop resistance. Fulvestrant (F) down regulates estrogen receptors in human breast cancer and has similar single agent activity as A and tamoxifen. Fulvestrant demonstrates a dose-response effect and the present standard dosing strategy takes 3-6 months to reach pharmokinetically sufficient drug levels. Combining A with F might counteract resistance by increasing estrogen blockade through different, yet synergistic modes of action A lowering estrogen levels and F antagonizing and down-regulating the estrogen receptor. Here, the combination of F+A vs A was investigated at first relapse in hormone receptor positive breast cancer in the phase III FACT study, by using a loading dose (LD) schedule followed by monthly injections of F, with the aim to overcome some endocrine resistance mechanisms by maximal estrogen blockade and to use F more optimally.Methods:Postmenopausal women, or premenopausal women receiving a GnRH agonist, with ER+ and/or PgR+ disease at first relapse following primary treatment of localized disease, were randomized to F LD (500 mg i.m. day 0, 250 mg day 14 and 28, then 250mg monthly thereafter) + 1 mg A daily, or 1 mg A daily alone at first relapse. The primary endpoint was time to progression (TTP). Secondary endpoints included objective response rate (ORR), clinical benefit rate (ORR + stable disease ≥24 weeks) (CBR), overall survival (OS) and tolerability. With 512 patients, approximately 380 events were required to detect a 3 month increase in TTP (5% two-sided significance level with 80% power).Results:514 patients, 256 in A alone group and 258 in F+A group, were randomized and approximately 2/3 of the full analysis set were either endocrine-naïve patients or patients with recurrence ≥12 month's gap following completion of adjuvant endocrine therapy. The study is mature while disease progression was demonstrated in 78.1% in the A alone group and 77.5% in the F+A combination group (HR 0.99; CI 95% 0.81-1.20, p-value 0.91). Investigator assessed ORR using the RECIST criteria on patients with measurable disease was 33.6% for the A alone group (38/113), and 31.8% for the F+A combination group (41/129) (odds ratio (OR) 0.92; 95% CI 0.54-1.58), respectively. The CBR rates were 55.1% for A and 55.0% for the F+A combination, respectively. F+A is a well-tolerated combination, but with an increased incidence of hot flushes over A alone. A total of 156 patients (61.4%) in the A alone group and 155 (60.5%) in the F+A combination group reported AEs. AEs for both groups were predominantly mild or moderate in intensity, whereas AEs CTC 3 or higher occurred in 16.9% vs 16.4%. 11 deaths due to side effects were recorded in the F+A arm and 5 in the A alone arm. In the investigator&s opinion, none of these AEs were causally related to study treatment.Discussion:Despite convincing preclinical data supporting the combined therapy strategy of fulvestrant plus an aromatase inhibitor, the present prospective, randomized study did not demonstrate any advantage by adding fulvestrant to anastrozole. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 23.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".