Abstract and Introduction
Abstract
Background: Endocrine therapy remains the mainstay of treatment for estrogen receptor-positive (ER+) breast cancer. Constitutively active mutations in the ligand binding domain of ERα render tumors resistant to endocrine agents. Breast cancers with the two most common ERα mutations, Y537S and D538G, have low sensitivity to fulvestrant inhibition, a typical second-line endocrine therapy. Lasofoxifene is a selective estrogen receptor modulator with benefits on bone health and breast cancer prevention potential. This study investigated the anti-tumor activity of lasofoxifene in breast cancer xenografts expressing Y537S and D538G ERα mutants. The combination of lasofoxifene with palbociclib, a CDK4/6 inhibitor, was also evaluated.
Methods: Luciferase-GFP tagged MCF7 cells bearing wild-type, Y537S, or D538G ERα were injected into the mammary ducts of NSG mice (MIND model), which were subsequently treated with lasofoxifene or fulvestrant as single agents or in combination with palbociclib. Tumor growth and metastasis were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis.
Results: As a monotherapy, lasofoxifene was more effective than fulvestrant at inhibiting primary tumor growth and reducing metastases. Adding palbociclib improved the effectiveness of both lasofoxifene and fulvestrant for tumor suppression and metastasis prevention at four distal sites (lung, liver, bone, and brain), with the combination of lasofoxifene/palbociclib being generally more potent than that of fulvestrant/palbociclib. X-ray crystallography of the ERα ligand binding domain (LBD) shows that lasofoxifene stabilizes an antagonist conformation of both wild-type and Y537S LBD. The ability of lasofoxifene to promote an antagonist conformation of Y537S, combined with its long half-life and bioavailability, likely contributes to the observed potent inhibition of primary tumor growth and metastasis of MCF7 Y537S cells.
Conclusions: We report for the first time the anti-tumor activity of lasofoxifene in mouse models of endocrine therapy-resistant breast cancer. The results demonstrate the potential of using lasofoxifene as an effective therapy for women with advanced or metastatic ER+ breast cancers expressing the most common constitutively active ERα mutations.
Introduction
Breast cancer is the most common cause of cancer mortality in women worldwide.[1] Approximately 80% of breast cancers are estrogen receptor positive (ER+).[2] Evidence suggests that estrogen receptor alpha (ERα, encoded by ESR1), a member of the nuclear receptor family of transcription factors, is involved in the initiation and progression of ER+ breast tumors.[3] Estradiol (E2) binding to the ER causes receptor dimerization to its active form for coactivator binding, leading to enhanced proliferation and survival of breast epithelial cells through the transcriptional modulation of genes.[3,4]
Endocrine therapy that inhibits ERα activity remains the mainstay of treatment for ER+ breast cancer. Tamoxifen, a selective estrogen receptor modulator (SERM), acts as a partial antagonist for ERα, and aromatase inhibitors (AIs) inhibit estrogen production.[3] However, a number of patients either are de novo resistant to these therapies[5] or become resistant after prolonged exposure to these drugs,[6] and experience cancer recurrence in the 5 to 20 years following treatment completion.[7] Fulvestrant (FUL), the only approved selective estrogen receptor down regulator (SERD), has been shown to be effective in treating endocrine therapy-resistant tumors,[8] but the challenges of drug resistance remain even for FUL.[9]
Several mechanisms have been suggested for endocrine-therapy resistance.[4,6] One important mechanism involves acquired ESR1 mutations under the selective pressure of endocrine therapy treatments, especially aromatase inhibitors. The ESR1 mutations are detected almost exclusively in the ligand binding domain (LBD), which includes the major transcriptional activating function-2 (AF2).[3] In patients with metastatic ER+ breast cancer, these mutations have been observed at a frequency of 10–40%, but are rarely detected in primary tumors.[10–12] The two most common ESR1 mutations are Y537S and D538G, located at the N-terminus of helix 12 (H12), a key structural regulator of coactivator recruitment in the LBD of ERα.[10–13] The conformational changes in H12 caused by these mutations give rise to a constitutively active receptor that can interact with coactivators, independent of ligand, and has reduced affinity for agonists and antagonists, thereby conferring reduced sensitivity of the mutants to endocrine drugs such as tamoxifen or FUL.[10–14] Additionally, allele-specific neomorphic properties found in these mutants could also contribute to cancer metastasis.[15] These limitations prompted the search for new treatment strategies that would be effective against breast cancers expressing known ERα mutants, including a SERM that might also alleviate postmenopausal symptoms related to estrogen loss, while inhibiting breast cancer progression. Raloxifene is the only SERM other than tamoxifen currently approved for reducing invasive breast cancer risk in postmenopausal women.[16] Bazedoxifene, a third-generation SERM, has shown potential anti-tumor effects in animal models with therapy-resistant breast cancer.[17,18]
Lasofoxifene (LAS), also a third-generation SERM, was developed to treat postmenopausal vaginal atrophy and osteoporosis[19] and approved but not used in Europe for osteoporosis treatment in postmenopausal women at increased risk of fracture.[20] In the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) trial, 5 years of LAS was associated with reduced risk of 79% for total breast cancers and 83% for invasive ER+ breast cancer and had beneficial effects on vertebral and non-vertebral fractures, coronary heart disease events, and stroke.[21] A network meta-analysis of randomized controlled trials on breast cancer chemoprevention agents showed that similar to raloxifene, LAS elicited a better benefit-risk profile than tamoxifen and AIs.[22] However, LAS has not been tested as a therapeutic option for progressive breast cancer. A recent cell-based study showed that the antagonist activity of LAS on ER+ breast cancer cells was not affected by the expression level of activating ERα mutants relative to wild-type (WT) ERα, a property not observed for other agents tested, including tamoxifen, bazedoxifene, raloxifene, and FUL.[23]
The objective of these studies was to investigate the potential benefit of LAS on endocrine-resistant ER+ metastatic breast cancer (MBC) in human-derived xenograft models harboring Y537S and D538G ESR1 mutations, the most commonly observed ERα mutations. In addition, effectiveness on tumor inhibition by LAS combined with palbociclib (PAL), a CDK4/6 inhibitor that blocks cell-cycle progression and has been shown to enhance the efficacy of endocrine agents,[24,25] was evaluated. Notably, LAS alone or in combination with PAL was an effective inhibitor of tumor growth in the MCF7 Y537S ERα+ MBC xenograft model. Additionally, the LAS/PAL combinations were notably more effective than the FUL/PAL combinations at inhibiting tumor growth and metastasis to the lung, liver, brain, and long bones. Structural analyses showed that LAS stabilizes an antagonist conformation of both WT and Y537S ERα LBDs.
— Update: 14-03-2023 — cohaitungchi.com found an additional article Lasofoxifene Plus Abemaciclib Induces Response in Previously Treated ER+/HER2–/ESR1+ Metastatic Breast Cancer from the website www.cancernetwork.com for the keyword lasofoxifene breast cancer.
Results of the phase 2 ELAINEII trial (NCT04432454) indicated acceptable tolerability and a favorable risk-benefit ratio with lasofoxifene in combination with abemaciclib (Verzenio) for pre and postmenopausal women with previously treated locally advanced or metastatic estrogen receptor (ER)–positive, HER2-negative breast cancer and mutant ESR1, according to data presented in a poster at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.
In a group of patients who had progressed on 1 or 2 prior lines of therapy, the objective response rate (ORR) was 50% (95% CI, 29.0%-71.0%) with a 24-week clinical benefit rate (CBR) of 69.0% (95% CI, 50.8%-82.7%). The censored median progression-free survival (PFS) was 55.7 weeks (95% CI, 32.0-not evaluable), or about 13 months.
“This clinically meaningful efficacy of [lasofoxifene plus abemaciclib] may offer a significant benefit than currently available therapies, with a differentiated profile from intra-muscular or oral SERDs [selective estrogen degraders], particularly in this patient population, and warrants further study,” the authors of the post who were led by Senthil Damodaran, MD, PhD, of the MD Anderson Cancer Center in Houston, wrote in their conclusion.
Long-term endocrine therapy administration can lead to treatment resistance caused by acquired ESR1 mutations. Lasofoxifene has shown activity against ESR1 mutations alone or in combination with CDK4/6 inhibition vs fulvestrant in preclinical studies. Similarly, abemaciclib has been shown to have activity in patients with metastatic breast cancer who have progressive disease on prior CDK4/6 inhibitors.
The open-label, single-arm multicenter ELAINEII study evaluated lasofoxifene plus abemaciclib in patients at least 18 years of age with ER-positive, HER2-negative metastatic breast cancer, and acquired ESR1 mutations on circulating tumor DNA (ctDNA). All patients (n = 29) had progressed on 1 or 2 prior lines of therapy, 1 of which could have been chemotherapy. Patients were given oral lasofoxifene at 5 mg daily plus abemaciclib at 150 mg twice daily until disease progression, toxicity, withdrawal, or death. The primary end point was safety and tolerability, with secondary outcome measures of PFS, CBR, ORR, duration of response (DOR), and time to response (TTR).
Among patients with measurable target lesions, 9 (50%) had partial responses (PRs). The median time to PR was 169 days with a median response duration of 164 days. Out of 4 patients who had previously progressed while receiving abemaciclib, 3 had significant clinical responses of PR in 1 and stable disease in 2. Two out of 3 patients who received prior fulvestrant plus alpelisib (Piqray) had clinical benefit.
ESR1 mutant allele fractions by ctDNA were screened at baseline and at 4 weeks using SafeSEQ next-generation sequencing technology. Initially, 47 ESR1 mutant variants were detected at baseline. After 4 weeks of treatment, 68% of these were undetectable and 23% were reduced, whereas only 9% were increased.
“Undetectable and reduced levels of ESR1 [mutant allele frequency with lasofoxifene plus abemaciclib] is consistent with target engagement and may correlate with clinical response,” wrote the investigators.
The most common adverse effects (AEs) reported were diarrhea, nausea, fatigue, and white blood cell decrease, which were mostly grade 1/2 severity. The most frequent treatment-emergent AEs attributable to lasofoxifene specifically were muscle spasms and hot flashes.
Two patients developed deep vein thrombosis (DVT) and pulmonary embolism (PE), with one case of DVT occurring after knee surgery and the other DVT and both PEs emerging on routine surveillance. Both patients were successfully treated with anticoagulants and continued the study treatment.
Lasofoxifene dose reductions were not reported whereas the dose of abemaciclib was reduced to 100 mg twice daily in 5 patients, mostly due to AEs.
Patients had a median age of 60 years (range, 35-79) and were mostly White (86.2%). More than half (62.1%) had measurable disease on presentation. Prior therapies included chemotherapy in 25 patients (86.2%), chemotherapy in the metastatic setting for 14 (48.3%), CDK4/6 inhibitor therapy in 28 (96.6%), everolimus (Afinitor) in 4 (13.8%), and alpelisib in 3 (10.3%). All patients had received some sort of prior endocrine therapy, including aromatase inhibitors (96.6%), fulvestrant (79.3%), and tamoxifen (41.4%). The median number of prior therapies was 2, and the median duration of prior CDK4/6 inhibitor was 2 years. Most patients (86.2%) had received the CDK 4/6 inhibitor palbociclib (Ibrance).
Results of the phase 1 ELAINEI trial will inform the activity of single-agent lasofoxifene and are expected for presentation at a medical meeting in the second half of 2022.
References
Damodaran S, Plourde PV, Moore HCF, et al. Open-label, phase 2, multicenter study of lasofoxifene (LAS) combined with abemaciclib (Abema) for treating pre- and postmenopausal women with locally advanced or metastatic ER+/HER2− breast cancer and an ESR1 mutation after progression on prior therapies. J Clin Oncol. 2022;40(suppl 16):1022. doi:10.1200/JCO.2022.40.16_suppl.1022
— Update: 15-03-2023 — cohaitungchi.com found an additional article Lasofoxifene Improves Responses Vs Fulvestrant in ESR1-Mutated, ER+/HER2- Metastatic Breast Cancer from the website www.onclive.com for the keyword lasofoxifene breast cancer.
Single-agent lasofoxifene did not produce a statistically significant improvement in progression-free survival (PFS) vs fulvestrant (Faslodex) for patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer harboring ESR1 mutations, according to data from the phase 2 ELAINE 1 trial (NCT03781063).
However, investigators determined that the nonsteroidal selective estrogen receptor modulator (SERM) elicited a benefit in objective response rate (ORR) and clinical benefit rate.
Findings presented at the ESMO 2022 Congress showed that patients treated with lasofoxifene (n = 52) achieved a median PFS of 6.04 months (95% CI, 2.82-8.04) compared with 4.04 months (95% CI, 2.93-6.04) for patients who received fulvestrant (n = 51; HR, 0.699; 95% CI, 0.445-1.125; P = .138). The 6- and 12-month PFS rates in the lasofoxifene arm were 53.4% and 30.7%, respectively, vs 37.9% and 14.1%, respectively, in the fulvestrant arm (P = .138).
“Lasofoxifene did not statistically improve PFS, but we did see numerically superior outcomes in all of these primary and secondary areas, such as PFS and ORR,” lead study author Matthew P. Goetz, MD, a professor of oncology and pharmacology and a consultant in the Division of Medical Oncology in the Department of Oncology at Mayo Clinic, said in a presentation of the data.
Read more Triple negative breast cancer: the kiss of death
ESR1 mutations in patients with ER-positive, HER2-negative breast cancer are associated with endocrine resistance, metastases, and poor prognosis. Selective estrogen degraders, such as fulvestrant, have displayed limited efficacy in this patient population.
Lasofoxifene is a third-generation oral SERM that improved tumor growth inhibition and metastases reduction vs fulvestrant in preclinical models. Additionally, the combination of lasofoxifene and abemaciclib (Verzenio) produced an ORR of 50% and a median PFS of 13.9 months in patients ER-positive, HER2-negative metastatic breast cancer harboring ESR1 mutations following treatment with a CDK4/6 inhibitor in the phase 2 ELAINE 2 trial (NCT04432454).
ELAINE 1 evaluated lasofoxifene monotherapy vs fulvestrant in patients with ESR1-mutated, ER-positive/HER2-negative metastatic breast cancer who progressed on prior aromatase inhibitors (AIs) plus a CDK4/6 inhibitor.
The trial randomly assigned patients to 5 mg of oral lasofoxifene 500 mg of fulvestrant as an intramuscular injection on days 1, 15, and 29, then every 4 weeks thereafter. Treatment continued until progression, death, unacceptable toxicity, or withdrawal.
The primary end point of the trial was PFS. Secondary end points included ORR, clinical benefit rate, overall survival, and safety.
The median age in the lasofoxifene arm and the fulvestrant arm was 61.6 years (range, 33-84) and 60.1 years (range, 38-82), respectively. The majority of patients had measurable disease (73.1% and 64.7% in the lasofoxifene and fulvestrant arms, respectively) and visceral disease (67.3% and 64.7%). Rates of prior chemotherapy in the metastatic setting were 5.8% and 5.9% in the lasofoxifene and fulvestrant groups, respectively.
All patients received prior treatment with an AI and CDK4/6 inhibitor, and the median duration of treatment with an AI and CDK4/6 inhibitor was 2.5 years and 2.2 years in the lasofoxifene and fulvestrant arms, respectively. All patients had an ESR1 mutation, and ESR1 Y537S mutations were reported in 40% and 47% of patients in the lasofoxifene and fulvestrant groups, respectively.
At data cutoff, 4 patients in the lasofoxifene arm were ongoing treatment, compared with 2 in the fulvestrant arm. Forty-three patients in each arm stopped treatment due to disease progression.
Additional data showed lasofoxifene elicited an ORR of 13.2% compared with 2.9% for fulvestrant (P = .12). In the lasofoxifene arm, 1 patient achieved a complete response with a duration of 18 months. Four patients had partial responses (PRs) with a median duration of 13.75 months. One patient in the fulvestrant arm achieved a PR with a duration of 16 months.
The clinical benefit rate after 24 weeks in the lasofoxifene group was 36.5% vs 21.6% in the fulvestrant group (P = .12).
An exploratory circulating tumor DNA (ctDNA) analysis assessed the baseline and 8-week ctDNA samples of 61 patients for ESR1-mutant allele fraction. The median relative change for all variants in the lasofoxifene arm was –87.1% compared with –14.7% in the fulvestrant arm. In patients with ESR1 Y537S mutations, the median mutant allele fraction change was –89% in the lasofoxifene arm and –82% in the fulvestrant arm.
Regarding safety, most adverse effects (AEs) were grade 1/2 and no thrombotic AEs were reported. The most common treatment-emergent AEs of any grade were nausea (27.5% and 18.8% in the lasofoxifene and fulvestrant arms, respectively), fatigue (23.5% and 37.5%), arthralgia (21.6% and 22.9%), hot flush (21.6% and 10.4%), constipation (15.7% and 12.5%), dizziness (15.7% and 4.2%), hypertension (15.7% and 14.6%), and cough (15.7% and 10.4%).
One patient in the lasofoxifene arm discontinued treatment due to AEs.
Investigators are planning a phase 3 trial to evaluate the combination of lasofoxifene and abemaciclib, based on findings from ELAINE 1 and ELAINE 2. “In terms of monotherapy, a larger trial is going to be needed to determine if lasofoxifene can be an alternative to fulvestrant,” Goetz concluded.
Reference
Goetz MP, Plourde P, Stover DG, et al. Open-label, randomized study of lasofoxifene (LAS) vs fulvestrant (Fulv) for women with locally advanced/metastatic ER+/HER2- breast cancer (mBC), an estrogen receptor 1 (ESR1) mutation, and disease progression on aromatase (AI) and cyclin-dependent kinase 4/6 (CDK4/6i) inhibitors. Ann Oncol. 2022;33(suppl_7):S808-S869. doi:10.1016/annonc/annonc1089
