A new report published by the American Cancer Society (ACS) suggests that overall breast cancer mortality rates have, between 1989–2022, declined by 44% overall, translating to 517,900 fewer women dying of the disease during this time. [1] However, despite declining mortality through earlier detection and advancements in treatment, breast cancer remains the second leading cause of cancer death among women overall and the leading cause of cancer death in Black and Hispanic women.
While benefits have mostly been seen in patients with early/localized breast cancer, there remains a substantial need for new approaches that can be used to treat patients whose tumors progress while on the standard of care (SOC) and/or to prevent and treat patients whose disease has a high risk of recurrence.[1]
One approach, independent of the breast cancer subtype, involves reexamining the impact of existing drugs. In doing so, researchers have observed encouraging benefits from the treatment of patients with these available therapies.
For example, researchers at Duke Cancer Institute* research, have found that inhibition of ER-signaling in immune cells increases the efficacy of immunotherapies in disease-relevant animal models of different cancers. They noted that lasofoxifene (Fablyn®), a nonsteroidal selective estrogen receptor modulator (SERM) selectively binds to both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) with high affinity (the IC50 for ERα (1.5 nM) is similar to that of estradiol/estrogen/E2 (4.8 nM)). The drug, used to treat and prevent osteoporosis and vaginal atrophy, increases the efficacy of immunotherapy by promoting the antitumor activity of eosinophils, a type of white blood cell that can influence the efficacy of immune checkpoint blockers.
The findings of their research, suggest that lasofoxifene’ has the potential as a viable immunotherapy combination agent across a broad spectrum of cancer types, were published on September 27, 2024, in the open-access, peer-reviewed journal Science Advances.[2]
“With our Phase 3 ELAINE-3 trial (NCT05696626) currently investigating the combination of lasofoxifene and abemaciclib (Verzenio®; Lilly & Co) in the ESR1-mutated metastatic breast cancer setting, and other data suggesting lasofoxifene’s differentiated and positive influence on the genitourinary syndrome of menopause, sexual function, and bone health, Duke’s research further demonstrates the need to continue examining the drug’s potential as an effective therapy in combination with other treatments to help patients confront cancer,” noted David Portman, MD, founder and Chief Executive Office of Sermonix Pharmaceuticals.
Eosinophils
Eosinophils were recently identified as influential in combating tumor progression. A phenomenon called tumor-associated tissue eosinophilia (TATE) is linked to better outcomes among patients with multiple types of cancer, including colon, esophageal, gastric, oral, melanoma, and liver cancers.[2]
In the article, researchers describe how estrogens not only decrease TATE and the ability of the immune system to attack tumors but also reduce the effectiveness of immunotherapies that are used to treat many types of cancers, including triple-negative breast cancer (TNBC), an aggressive form of the disease that is negative for estrogen, progesterone, and the HER2 receptor proteins.
Earlier studies have demonstrated that in patients diagnosed with TNBC who were eligible for immunotherapy, an increased number of eosinophils in the blood predicted a favorable response to the treatment with immune checkpoint blockade with checkpoint inhibitors. [3] Furthermore, the researchers investigated if tumor eosinophil prevalence could also be a prognostic independent of treatment with immunotherapies. The outcomes showed that higher activity of an intratumoral eosinophil gene signature was associated with a survival advantage in patients with breast cancer
The researchers also found a survival advantage in patients whose tumors expressed higher eosinophil activity measured by the eosinophil peroxidase gene, whose encoded protein is only expressed in eosinophils.
Based on the outcomes, the researchers further investigated the relationships between estrogen deprivation, increased TATE, and decreased growth of tumors in syngeneic cancer models. They found that lasofoxifene was more efficacious than fulvestrant (Faslodex®; AstraZeneca) in reversing the detrimental effects of estrogens on tumor-associated eosinophilia and restoring potency to immunotherapies in a TNBC mouse model.
“Lasofoxifene demonstrated superior efficacy than fulvestrant. It is also a well-tolerated oral therapy in multiple clinical studies, making it a promising regulator of TATE/tumor growth,” said senior author Donald McDonnell, Ph.D., professor in the departments of Medicine, Pharmacology and Cancer Biology, and Cell Biology at Duke University School of Medicine.
“The primary goal of our research is to develop ways to increase the anti-cancer activity of immunotherapies, and we look forward to further studying the lasofoxifene’s potential in this arena,” McDonnell added.
More study results
An unrelated preclinical study conducted by Geoffrey Greene, M.D., Ph.D., chair of the Ben May Department for Cancer Research at the University of Chicago, showed positive effects of oral lasofoxifene in an aromatase inhibitor (AI)-resistant, estrogen receptor-positive (ER+) breast cancer in the absence of ESR1 mutations.[3]
In this study, a mouse model of letrozole-resistant breast cancer without ESR1 mutations, reduced levels of estrogen receptor alpha (ERα), and overexpression of HER2 demonstrated that lasofoxifene alone or combined with palbociclib inhibited primary tumor growth more effectively than fulvestrant. In addition, lasofoxifene plus palbociclib also reduced bone metastases. Based on these outcomes, the researchers believe that lasofoxifene alone or combined with a CDK4/6 inhibitor may offer benefits to patients who have ER-low and HER2-positive, AI-resistant breast cancer, independent of ESR1 mutations.[4]
These findings, published in Breast Cancer Research, formed the basis of a new patent that was issued earlier this year. [4][5]
“This new patent signals Sermonix’s continued momentum toward the broader study of and potential use of lasofoxifene beyond that in the ESR1-mutated setting, including use in earlier lines of therapy in patients with wild-type (WT) ER,” Portman explained.
“There is a great medical need for efficacious and well-tolerated new therapies for this large population of breast cancer patients with WT ER who recur in the adjuvant setting or progress in the advanced setting on aromatase inhibitors. We look forward to investigating lasofoxifene’s potential as an effective therapy option for all hormone-treatment-resistant breast tumors,” Portman concluded.
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Note: * Sermonix licensed patents from Duke covering the use of lasofoxifene in ESR1-mutated breast cancers. It also holds options on additional U.S. patent applications covering the use of lasofoxifene to enhance TATE and the efficacy of immunotherapy in different cancers.
Clinical trials
- Evaluation of Lasofoxifene Versus Fulvestrant in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation – ClinicalTrials.gov ID NCT03781063
- Evaluation of Lasofoxifene Combined With Abemaciclib in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation (ELAINEII) – ClinicalTrials.gov ID NCT04432454
- Evaluation of Lasofoxifene Combined with Abemaciclib Compared with Fulvestrant Combined with Abemaciclib in Locally Advanced or Metastatic ER+/HER2- Breast Cancer with an ESR1 Mutation (ELAINEIII) – ClinicalTrials.gov ID NCT05696626
Highlights of Prescribing Information
Abemaciclib (Verzenio®; Lilly & Co)[Prescribing Information]
Fulvestrant (Faslodex®; AstraZeneca)[Prescription Information]
Reference
[1] , , , et al. Breast cancer statistics 2024. CA Cancer J Clin. 2024; 1–19. doi:10.3322/caac.21863
[2] Artham S, Juras PK, Goyal A, Chakraborty P, Byemerwa J, Liu S, Wardell SE, Chakraborty B, Crowder D, Lim F, Strawser CH, Newlin M, Racioppi A, Dent S, Mirminachi B, Roper J, Perou CM, Chang CY, McDonnell DP. Estrogen signaling suppresses tumor-associated tissue eosinophilia to promote breast tumor growth. Sci Adv. 2024 Sep 27;10(39):eadp2442. doi: 10.1126/sciadv.adp2442. Epub 2024 Sep 27. PMID: 39331714; PMCID: PMC11430468.
[3] Blomberg OS, Spagnuolo L, Garner H, Voorwerk L, Isaeva OI, van Dyk E, Bakker N, Chalabi M, Klaver C, Duijst M, Kersten K, Brüggemann M, Pastoors D, Hau CS, Vrijland K, Raeven EAM, Kaldenbach D, Kos K, Afonina IS, Kaptein P, Hoes L, Theelen WSME, Baas P, Voest EE, Beyaert R, Thommen DS, Wessels LFA, de Visser KE, Kok M. IL-5-producing CD4+ T cells and eosinophils cooperate to enhance response to immune checkpoint blockade in breast cancer. Cancer Cell. 2023 Jan 9;41(1):106-123.e10. doi: 10.1016/j.ccell.2022.11.014. Epub 2022 Dec 15. PMID: 36525971.
[4] Lainé M, Greene ME, Kurleto JD, Bozek G, Leng T, Huggins RJ, Komm BS, Greene GL. Lasofoxifene as a potential treatment for aromatase inhibitor-resistant ER-positive breast cancer. Breast Cancer Res. 2024 Jun 7;26(1):95. doi: 10.1186/s13058-024-01843-4. PMID: 38849889; PMCID: PMC11161925.
[5] Komm BS, Green GK. Lasofoxifene treatment of aromatase-resistant ER+cancer. Patent No: US-12023321-B2. Published on July 2, 2024. Online. Last accessed on October 5, 2024.
Fighting Breast cancer: A quick shot after getting wrapped for the boxing gloves, before the ring comes off and the gloves go on. Photo by Sarah Cervantes on Unsplash. Used with permission
DOI: 10.14229/onco.2024.10.06.001
