Lasofoxifene as a potential treatment for ER+ metastatic breast cancer.

Abstract

1056 Background: Estrogen receptor positive (ER+) metastatic breast cancers (MBC) that express constitutively active somatic ESR1 mutations at Y537S and D538G allow tumors to progress in the presence of approved endocrine therapies. For patients with ER+ MBC, fulvestrant is the first line of treatment. Palbociclib or other CDK4/6 inhibitors are now being included. Preliminary studies show that lasofoxifene, a selective ERα modulator (SERM), was effective in reducing tumor growth in an endocrine resistant xenograph model expressing ERα mutations Y537S or D538G. Additionally, lasofoxifene more effectively inhibited the development of liver and lung metastases than fulvestrant. Lasofoxifene is currently under evaluation in a phase 2 study. Because certain combinations of a hormonal agents like fulvestrant improved efficacy, we investigated the combination of palbociclib and lasofoxifene as a potential therapeutic for mutant ESR1 MBC. We hypothesized that this combination should improve outcome and compared it to a combination with fulvestrant. Methods: We first determined the optimal dose of lasofoxifene in an intraductal (MIND) xenograph model of MCF-7 cells that express active ERα Y537S and D538G. Subsequently, we performed combination studies with lasofoxifene (10mg/kg 5/week SQ) +/- palbociclib (100mg/kg gavage, 5/week) or fulvestrant (5mg/mouse/week, SQ) +/- palbociclib. Results: Lasofoxifene alone was significantly more effective than fulvestrant at inhibiting the metastasis of both MCF7 Y537S and D538G tumors to the lungs and liver. Lasofoxifene + palbociclib was more effective than fulvestrant + palbociclib at reducing primary tumor growth; both combinations demonstrated an increased response. Lasofoxifene + palbociclib was more effective at inhibiting liver metastasis than either drug alone and was more effective than fulvestrant + palbociclib at reducing metastasis to the liver and lung. Structural studies showed that lasofoxifene effectively disrupts the active conformation of the ERα Y537S ligand-binding domain. Conclusions: These results demonstrate that lasofoxifene, in combination with CDK4/6 inhibitors like palbociclib, has promise for treating endocrine therapy resistant ER+ MBC patients whose tumors express activating ESR1 mutations, more effectively than either drug alone.

Overcoming Endocrine Resistance in Breast Cancer

“…While the LBD mutations reduce the potency of fulvestrant (Toy et al, 2017), next-generation oral SERMs or SERDs that target both WT and mutant ER are in clinical development (Table 2) (Fanning and Greene, 2019). For example, GDC-9545 and elacestrant are oral SERDs that have shown preliminary clinical activity in ESR1-mutant MBCs, some of which had progressed on prior SERDs; these agents demonstrated acceptable toxicity profiles (Jhaveri et al, 2020;Kaklamani et al, 2020).…”

“…However, a recent study suggests that fulvestrant and similar ER antagonists suppress ER activity primarily by impairing intra-nuclear ER mobility (Figure 1D) (Guan et al, 2019). A number of oral SERDs, with potentially better pharmacological properties than fulvestrant, are being developed (Fanning and Greene, 2019). In this review, we summarize mechanisms associated with and/or causal to resistance to estrogen suppression, or inactivation of ER by other means (SERMs/SERDs).…”

Genomic Alteration in Metastatic Breast Cancer and Its Treatment

“…Last, information on individual tumor genomic alterations provides the opportunity for patients to participate in molecular-and genetic-driven clinical trials-for instance, multiple clinical trials are ongoing for ESR1mutated breast cancer. 51,52 CLINICAL DETECTION OF GENOMIC ALTERATIONS 53 It is also important to recognize that targeted therapies that are beneficial in a particular disease may not translate to other disease sites.…”