Although first line treatment of breast cancer primarily includes a long-term regimen with an aromatase inhibitor (AI), which today is often combined with a Cyclin-Dependent Kinase (CDK) 4/6 inhibitor, treatment resistance is a relatively common in approximately 20-40% of women treated, and often results in tumor progression and metastatic disease. Resistance is generally associated with activating mutations of the estrogen receptor ESR1.[1][2]

Compelling new data, presented in a poster at the 2021 San Antonio Breast Cancer Symposium (SABCS), held December 7-10, 2021 at the Henry B. Gonzalez Convention Center in San Antonio, TX, suggests that the selective estrogen receptor modulator lasofoxifene (Sermonix Pharmaceuticals) alone, or in combination with a CDK inhibitor, may limit tumor progression in aromatase inhibitor resistant tumors that are characterized by low levels of estrogen receptor (ESR1), elevated HER2 and genetic modifications other than activating ESR1 mutations.[3]

In preclinical models that lasofoxifene more effectively inhibits these tumors’ proliferation and metastases compared to fulvestrant (Faslodex®; AstraZeneca) . However, treatment resistance may not be confined to those with ESR1 activating mutations.

A study performed by a research group at the University of Chicago, employed a model utilizing a metastatic cell line expressing low levels of ESR1 (MCF-7 LTLT-1) which are resistant to aromatase inhibitor treatment, but not as a function of an ESR1 mutation. Lasofoxifene +/- palbociclib (Ibrance®; Pfizer)   was significantly more effective than fulvestrant +/- palbociclib at inhibiting tumor progression, and all treatment combinations inhibited bone metastases except for fulvestrant alone.

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Phase 2 study
The ongoing phase 2 evaluation of lasofoxifene in ESR1 Mutations studies (Evaluation of Lasofoxifene in ESR1 Mutations or ELAINE) include the randomized ELAINE 1 study of lasofoxifene versus fulvestrant and the ELAINE 2 combination study of lasofoxifene with abemaciclib (Verzenio™; Eli Lilly and Company). The program aims to evaluate the safety and efficacy of lasofoxifene as a treatment option for breast cancer patients who develop aromatase inhibitor resistance due to ESR1 mutations.

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“These new pre-clinical data presented at this year’s SABCS move our development program a step further and suggest that lasofoxifene may have activity in non-ESR1-driven mechanisms of resistance as well,” said David Portman, M.D., Sermonix founder and chief executive officer.

“We intend to further evaluate a possible path forward in aromatase inhibitor resistance not due to ESR1 mutations to complement our existing ESR1 mutation-focused programs,” Portman added.

Professor Geoffrey Greene, MD. Ph.D., Chair of Ben May Department of Cancer Research and the Virginia and D. K. Ludwig Professor of Ben May Department of Cancer Research at the University of Chicago. Photo Courtesy: © 2022 The University of Chicago. Used with permission.

“Widespread aromatase inhibitor use and selective pressure in the metastatic setting have together dramatically increased the incidence of endocrine therapy resistance, leading to deteriorating prognosis among these patients,” said professor Geoffrey Greene, MD. Ph.D., Chair of Ben May Department of Cancer Research and the Virginia and D. K. Ludwig Professor of Ben May Department of Cancer Research at the University of Chicago.

“These data, together with Sermonix’s current development program in aromatase inhibitor resistance conferred by ESR1 mutations, suggest that lasofoxifene may have broad clinical utility across a number of resistance mechanisms. If proven in rigorously designed clinical trials, this could represent a significant leap forward in the treatment of metastatic breast cancer.”

These available data support the hypothesis that lasofoxifene or lasofoxifene in combination with a CDK 4/6 inhibitor may effectively limit tumor progression and metastases in aromatase inhibitor resistant tumors not resistant due to an ESR1 mutation.

Clinical trials
Evaluation of Lasofoxifene Versus Fulvestrant in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation – NCT03781063
Evaluation of Lasofoxifene Combined With Abemaciclib in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation (ELAINEII) – NCT04432454

Highlights of Prescribing Information
Fulvestrant (Faslodex®; AstraZeneca) (Prescription Information)
Palbociclib (Ibrance®; Pfizer)(Prescribing Information)

Reference
[1] Lainé M, Fanning SW, Chang YF, Green B, Greene ME, Komm B, Kurleto JD, Phung L, Greene GL. Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer. Breast Cancer Res. 2021 May 12;23(1):54. doi: 10.1186/s13058-021-01431-w. PMID: 33980285; PMCID: PMC8117302.
[2] Pinkerton JV, Conner EA. Beyond estrogen: advances in tissue selective estrogen complexes and selective estrogen receptor modulators. Climacteric. 2019 Apr;22(2):140-147. doi: 10.1080/13697137.2019.1568403. PMID: 30895900.
[3] Laine M, Greene ME, Leng T, Kurleto JD, Li S, Komm B, Greene GL. Lasofoxifene as a potential treatment for aromatase inhibitor resistant ER positive breast cancer. Abstract P4-02-07. Presented at the 2021 San Antonio Breast Cancer Symposium. [Link]

Featured image: Attendees chat during the Career Development Forum. Photo Courtesy: © 2018 – 2021 SABCS/AACR. Used with permission.

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