The Promise of Oral SERDs for ER+, HER2- Metastatic Breast Cancer

“Once you’re given a terminal diagnosis, you’re constantly trying to get ahead… You can’t just live your life, because you’re always trying to stay alive a little bit longer.” Amanda M.

Amanda, a mom and registered dental assistant in rural Texas, was diagnosed with metastatic breast cancer (MBC) nearly seven years ago. To receive her treatment at a doctor’s office, she often travels up to three hours, sometimes even booking a hotel room the night before early morning appointments.

This grueling schedule combined with navigating insurance and conducting personal research on emerging therapy options, is exhausting and time-consuming for Amanda and the estimated 168,000 women living with incurable MBC.¹ However, innovative oral treatment options could represent a welcome shift for patients with the potential to offer efficacious treatment in a more manageable way.

Understanding MBC & The Current Treatment Landscape

Estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) is the most common subtype of MBC, with 70 to 80% of all hormone receptor-positive (HR+) breast cancers being ER+. When a cancer cell is ER+, it receives signals from estrogen in the body that trigger cancer cells to grow and divide.² Two of the most common treatments for MBC are endocrine therapy (ET) and aromatase inhibitors (AI).

However, up to 50% of ER+, HER2- MBC patients will develop a mutation in the estrogen receptor 1 (ESR1) gene after exposure to AIs, which changes the shape of the ER protein and leads to estrogen-independent tumor growth, accounting for acquired endocrine resistance in a substantial number of patients with metastatic disease. This mutation makes MBC more difficult to treat with endocrine therapy and is also linked to shorter progression-free survival.³

To help address this treatment resistance, novel therapies have been introduced over time to target ESR1 mutations. Selective estrogen receptor degraders (SERDs) bind to the ER, even when it is mutated, and trigger its degradation through the cell's natural recycling process, preventing the receptor from activating cancer cell growth. Essentially, SERDs "destroy" the mutated estrogen receptor instead of just blocking its activity.

In 2002, a first-generation SERD was approved to treat breast cancer.⁴ While this was a vast improvement at the time, the commonly used SERD is administered via intramuscular injection due to its low bioavailability when taken orally,⁵ which can be an uncomfortable experience for patients and inconvenient since it needs to be given at a doctor’s office. In fact, when MBC patients were surveyed about their treatment experience, 77% reported they would prefer to take a daily oral medication instead of receiving recurring intramuscular injections.⁶

More recently, oral SERDs are becoming a compelling and flexible option for MBC patients that provide a promising alternative to existing ETs. Oral SERDs offer patients flexibility in their treatment regimen by affording them the option to take an oral medication in the comfort and convenience of their own home. An oral option may also eliminate the time and travel burden associated with doctor’s office visits, which often take patients over two hours, hindering their daily life, work and personal obligations.⁶

The Patient Perspective

Amy D., a wife and mother diagnosed with MBC in 2016, noted, “It is hard going in for treatments every month, and I would love to be able to do something at home.” A majority of MBC patients expressed a desire for more flexible treatment options in a recent survey series conducted by Eli Lilly and Company (Lilly). Almost half of patients surveyed reported soreness at the injection site from their current therapy method, while 43% cited this pain as a drawback to treatment and 44% confirmed experiencing anxiety leading up to receiving injections.⁶

Leaders of patient advocacy groups also recognize the impact these medicines can have on patients. “As MBC treatment options evolve, we need to understand that the goal is prolonged survival but also improved symptom management and quality of life,” said Jean Sachs, MSS, MLSP, CEO of Living Beyond Breast Cancer. “People living with MBC already bear the burden of the indefiniteness of their diagnosis, plus the toll it takes on their mental and physical wellbeing as well as their family, friends, and caregivers. Better supporting the MBC community is an essential part of our advocacy work to improve the lives of people impacted by breast cancer.”

Oral SERDs can offer patients a meaningful change as they navigate life with an incurable disease. Lilly’s continuous dedication to helping advance solutions for many of the evolving challenges MBC patients face is evident through the research and development of new treatment options, partnering with organizations that are focused on patient support and wellbeing, and engaging with patients first-hand to understand their cancer experience. People living with MBC deserve treatment plans that may help give them more time and attention to the important things in life, like spending precious time with loved ones and being able to pursue what means the most to them outside of navigating cancer.

References

¹ “Quick Facts on Metastatic Breast Cancer | NIH MedlinePlus Magazine.” MedlinePlus, U.S. National Library of Medicine. Published October 14, 2020. Accessed January 23, 2025. https://magazine.medlineplus.gov/article/quick-facts-on-metastatic-breast-cancer

² “Hormone Receptor-Positive (HR+) Breast Cancer.” Penn Medicine Abramson Cancer Center, National Cancer Institute Comprehensive Cancer Center. Accessed January 23, 2025. https://www.pennmedicine.org/cancer/types-of-cancer/breast-cancer/types-of-breast-cancer/hormone-positive-breast-cancer

³ Raheem, Farah, et al. “Metastatic ER+ Breast Cancer: Mechanisms of Resistance and Future Therapeutic Approaches.” PMC PubMed Central, U.S. National Library of Medicine. Published November 11, 2023. Accessed January 23, 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC10671474/

⁴ Bross, Peter F, et al. “FDA Drug Approval Summaries: Fulvestrant.” PubMed, U.S. National Library of Medicine. Published December 2002. Accessed January 23, 2025. https://pubmed.ncbi.nlm.nih.gov/12490735/

⁵ Liu, Jiawang, et al. “Fulvestrant-3-Boronic Acid (ZB716) Demonstrates Oral Bioavailability and Favorable Pharmacokinetic Profile in Preclinical Adme Studies.” PubMed Central, U.S. National Library of Medicine. Published July 26, 2021. Accessed January 23, 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC8400955/

⁶ “How Treatment Options for Metastatic Breast Cancer Could Improve the Patient Experience.” Making Every Moment Count, Lilly. Published April 2024. Accessed January 23, 2025. https://interactive.4media-group.com/patient-experience-metastatic-breast-cancer-treatment-options