Lasofoxifene versus fulvestrant for ER+/HER2- metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial.

BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts. PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. RESULTS: A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (∼5.6 months) versus 16.2 weeks (∼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. CONCLUSIONS: Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.

Effects of river flows on growth of redbreast sunfish Lepomis auritus (Centrarchidae) in Georgia rivers.

Effects of river discharge on growth of redbreast sunfish Lepomis auritus were investigated in nine rivers in Georgia, U.S.A. Fish were aged and annular total length increments (L(Tinc)) estimated from measurements from sectioned sagittal otoliths using the generalized regression model that held for the effects of decreasing L(Tinc) from annual age (X): L(Tinc)=b(o)-b(1)(X) +/-b(i)(D), where b(o), b(1) and b(i) were the regression coefficients for the intercept and slopes and D, discharge, was either a single or multiple measurements of annular or seasonal flow volume or variation in flow volume. For eight of nine rivers, higher or greater variation in flows from April to June was associated with greater L. auritus growth; in the last river, higher flows from January to March were associated with greater fish growth. Across all rivers, L. auritus growth increments were 22, 45 and 36% greater in a wet year v. a dry year at ages 1, 2 and 3 years, respectively. Based on the results of this study, increasing water withdrawals by an additional 30% in five Georgia rivers would reduce the predicted number of L. auritus recruiting to 203 mm (angler preferred size) by 19-62%.

OLGCG: an OPEN LOOK interface to the GCG sequence analysis package.

We have developed a graphical user interface (GUI) to the Genetics Computer Group (GCG) Sequence Analysis Package using the OPEN LOOK interface. The software consists of pulldown menus and window interfaces to the GCG programs. This provides experienced users with methods to expedite the entry of complex commands and inexperienced users easy mouse-driven access to the GCG programs using both IBM-compatible machines and Macintoshes running X server software.

POLLUX: a program for simulated cloning, mutagenesis and database searching of DNA constructs.

Computer support for research in biotechnology has developed rapidly and has provided several tools to aid the researcher. This report describes the capabilities of new computer software developed in this laboratory to aid in the documentation and planning of experiments in molecular biology. The program, POLLUX, provides a graphical medium for the entry, edit and manipulation of DNA constructs and a textual format for display and edit of construct descriptive data. Program operation and procedures are designed to mimic the actual laboratory experiments with respect to capability and the order in which they are performed. Flexible control over the content of the computer-generated displays and program facilities is provided by a mouse-driven menu interface. Programmed facilities for mutagenesis, simulated cloning and searching of the database from networked workstations are described.