Potential for Early Intervention in 1L HR+/HER2- Advanced Breast Cancer

Announcer:
You’re listening to ReachMD. This medical industry feature titled “Potential for Early Intervention in 1L HR+/HER2- Advanced Breast Cancer” is sponsored by AstraZeneca.

Dr Wander:
Intervening at the earliest emergence of ESR1 mutations during first-line endocrine treatment might address the endocrine resistance mechanism proactively, before the cancer becomes harder to treat.

It could be like taking your car to the mechanic when the ‘check engine’ light comes on, before any serious damage occurs. Or fixing a leaky faucet before it causes a flood in your house.

Hi, I’m Doctor Seth Wander. I’d like to share my perspectives as a medical oncologist.

Let’s review the evidence that supports early intervention:

• Patient experiences on aromatase inhibitors,
• Efficacy declining from the first- to second-line treatment setting,
• Quality of life—declining from the first- to second-line setting and having no difference between regimens in the second-line setting,
• The interplay of quality of life and survival outcomes,
• Attrition rates, and

Links between ESR1 mutations, clinical progression, tumor complexity, and efficacy outcomes.

The first line of evidence supporting early intervention involves patient experiences on aromatase inhibitors. The standard first-line treatment for hormone receptor-positive, HER2-negative advanced breast cancer is a regimen that includes an aromatase inhibitor and a CDK4/6 inhibitor. Although effective, this combination does have some limitations. Patients taking an AI may have mixed experiences regarding adverse reactions, tolerability, and quality of life.

For example, AI-induced musculoskeletal syndrome is well documented, causing symptoms such as arthralgia, myalgia, arthritis, and stiffness, and potentially leading to discontinuation of aromatase inhibitors. Therefore, hope remains that innovation of endocrine therapy combinations might be an effective strategy to improve patient outcomes and experiences before their first clinical progression.

Another line of evidence is efficacy declining from the first- to the second-line setting. The combination of an AI plus a CDK4/6 inhibitor may yield 25 to 28 months of median progression-free survival in the first-line setting, but disease progression is inevitable and treatment efficacy outcomes decline in the second-line setting. After 6 months of treatment with a first-line regimen, about 85 percent of women have cancer that is progression-free.

But in the second-line setting with FDA-approved monotherapies, only about 42 percent of women have cancer that still responds to treatment at 6 months. This steep decline in the second-line setting highlights the importance of maximizing time on treatment before the first clinical progression. Next up is quality of life declining from the first- to second-line treatment setting and having no difference between regimens in the second-line.

With the standard first-line regimen, there is generally an adequate quality of life for patients, but like efficacy, quality of life may also worsen after patients move to second-line therapy. Such deterioration can involve increased depression, as well as declines in functional and physical well-being.

And in the second-line setting, 2 clinical trials using validated assessment methods showed that oral SERD monotherapy did not provide a clinically meaningful difference in quality of life or delay deterioration when compared with the control arm. Therefore, extending the duration and benefit of first-line treatment while delaying resistance is crucial for the well-being of patients.

Another line of evidence is the interplay between quality of life and survival outcomes. Surprisingly, measures for quality of life might capture more than just how patients feel during routine daily activities. In a systematic review and meta-analysis of more than 44,000 patients with solid tumors, higher scores in global health status and quality of life were associated with improved overall survival. These quality-of-life measures also offered independent prognostic information for overall survival across cancer types.

Next, let’s discuss attrition rates. One approach to maximizing treatment outcomes might be to use the most effective treatments as early as possible. About 1 in 5 women never make it to second-line therapy. And women who develop visceral crisis or have rapidly progressing disease may only have chemotherapy as their next treatment option instead of endocrine therapy.

Based on medical records from 199 women with HER2-negative metastatic disease across 3 cancer centers in the US, 20% did not receive second-line treatment due to death, disease progression, adverse reactions, or even financial reasons. Likewise, two studies of more than 3,400 women with hormone receptor-positive, HER2-negative metastatic disease in Europe showed similar attrition rates, with seventeen to eighteen percent who didn’t receive second-line treatment. To fully understand the current clinical situation with attrition rates and to aid in clinical decision-making about sequencing therapies, larger multicenter studies need to be completed across the US.

Finally, there are links between ESR1 mutations, clinical progression, tumor complexity, and efficacy outcomes. Because aromatase inhibitors have no direct effect on the estrogen receptor, ESR1 mutations may emerge that make the estrogen receptor active, even in the absence of estrogen. This is a well characterized and widely accepted resistance mechanism.

As the exposure to aromatase inhibitors increases, the rate of ESR1 mutations also increases in the metastatic setting. To illustrate this, the rate of ESR1 mutations is about 5% at diagnosis of advanced breast cancer and may increase to as much as 50% after progression on an AI regimen in the first-line metastatic setting. This increasing rate of ESR1 mutations signals that the cancer is at risk of progression.

For example, a study of 104 women with hormone receptor-positive metastatic breast cancer showed about a 3-fold increase in the risk of disease progression within 6 months of detecting an ESR1 mutation.

In addition, the emergence of ESR1 mutations is associated with increased genetic complexity, including a high rate of polyclonal ESR1 mutations and potentially other mutations. And most importantly, patients with ESR1 mutations have shorter progression-free survival and overall survival than those without ESR1 mutations detected during first-line treatment, as shown by these real-world results when the subgroup with ESR1 mutations is compared to the subgroup without ESR1 mutations detected.

These increases in tumor and mutational burden over time may be responsible for some of the limitations of current second-line therapies. This leads us to a potential approach to early intervention. A potential way to address that ‘check engine’ light, or fix that leaky faucet. To help patients have the best chance of extending the benefit of first-line AI plus CDK4/6 inhibitor regimens, it may be critical to detect emerging endocrine resistance as early as possible. One approach would be to integrate ctDNA monitoring for ESR1 mutations with routine blood work. The hope is that an approach like this may lead to personalized treatments with improved patient outcomes. The right intervention for the right patient, at the right time.

For hormone receptor-positive, HER2-negative advanced breast cancer, proactive intervention could occur at the earliest emergence of ESR1 mutations during first-line endocrine treatment, which may help address this mechanism of endocrine resistance, before the cancer becomes harder to treat.

Announcer:
This program was sponsored by AstraZeneca. If you missed any part of this discussion, visit Industry Features on ReachMD.com, where you can Be Part of the Knowledge.

References:

1. Allouchery V, Beaussire L, Perdrix A, et al. Circulating ESR1 mutations at the end of aromatase inhibitor adjuvant treatment and after relapse in breast cancer patients. Breast Cancer Res. 2018;20(1):40.
2. Amaro CP, Batra A, Lupichuk S. First-line treatment with a cyclin-dependent kinase 4/6 inhibitor plus an aromatase inhibitor for metastatic breast cancer in Alberta. Curr Oncol. 2021;28(3):2270-2280.
3. Andrikopoulou A, Fiste O, Liontos M, Dimopoulos MA, Zagouri F. Aromatase and CDK4/6 inhibitor-induced musculoskeletal symptoms: a systematic review. Cancers (Basel). 2021;13(3):465.
4. Barrios CH. Treatment post-CDK4/6 inhibitors: single agent endocrine therapy. Presented at: San Antonio Breast Cancer Symposium (SABCS) 2023; December 5-9, 2023; San Antonio, TX.
5. Basile D, Gerratana L, Corvaja C, et al. First- and second-line treatment strategies for hormone-receptor (HR)-positive HER2-negative metastatic breast cancer: A real-world study. Breast. 2021;57:104-112.
6. Bhave MA, Quintanilha JCF, Tukachinsky H, et al. Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) metastatic breast cancer: prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice. Breast Cancer Res Treat. 2024;207(3):599-609.
7. Bidard FC, Hardy-Bessard AC, Dalenc F, et al. Lancet Oncol. 2022;23(11):1367-1377.
8. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD Trial. J Clin Oncol. 2022;40(28):3246-3256.
9. Brett JO, Spring LM, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23(1):85.
10. Campone M, De Laurentiis M, Jhaveri K, et al; VERITAC-2 study group. Vepdegestrant, a PROTAC estrogen receptor degrader, in advanced breast cancer. N Engl J Med. 2025;393(6):556-568.
11. Chaudhary N, Chibly AM, Collier A, et al. CDK4/6i-treated HR+/HER2- breast cancer tumors show higher ESR1 mutation prevalence and more altered genomic landscape. NPJ Breast Cancer. 2024;10(1):15.
12. Clatot F, Perdrix A, Augusto L, et al. Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor. Oncotarget. 2016;7(46):74448-74459.
13. Clatot F, Perdrix A, Beaussire L, et al. Risk of early progression according to circulating ESR1 mutation, CA-15.3 and cfDNA increases under first-line anti-aromatase treatment in metastatic breast cancer. Breast Cancer Res. 2020;22(1):56. doi:10.1186/s13058-020-01290-x
14. Cortes J, Bidard FC, Bardia A, et al. EMERALD trial analysis of patient-reported outcomes (PROs) in patients with ER+/HER2– advanced or metastatic breast cancer (mBC) comparing oral elacestrant vs standard of care (SoC) endocrine therapy [abstract]. Presented at: 2023 ESMO Breast Cancer Annual Congress, May 11-13, 2025; Berlin, Germany.
15. Curigliano G, O’Shaughnessy J, Bidard FC, et al. Patient-reported outcomes (PROs) in patients with ER+, HER2- advanced breast cancer (ABC) treated with imlunestrant, investigator's choice standard endocrine therapy, or imlunestrant + abemaciclib: Results from the phase Ill EMBER-3 trial. Presented at: 2025 ASCO Annual Meeting, May 30-June 3, 2025; Chicago, IL.
16. Fribbens C, Garcia Murillas I, Beaney M, et al. Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer. Ann Oncol. 2018;29(1):145-153.
17. Gelmon K, Villarreal-Garza C, Aubel D, et al. Improving the quality of life of people with advanced breast cancer: a global expert review and call-to-action for 2025-2035 (goal 3). Breast. 2025;84:104603. doi:10.1016/j.breast.2025.104603
18. Harbeck N, Dieras V, Gelmon KA, et al. Effect of palbociclib plus letrozole on patient-reported health-related quality of life: extended follow-up of the PALOMA-2 trial. ESMO Open. 2025;10(4):104497. doi:10.1016/j.esmoop.2025.104497
19. Hartkopf AD, Walter CB, Kolberg HC, et al. Attrition in the first three therapy lines in patients with advanced breast cancer in the German real-world PRAEGNANT registry. Geburtshilfe Frauenheilkd. 2024;84(5):459-469.
20. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29(7):1541-1547.
21. Huang RS, Chen D, Benour A, et al. Patient-reported outcomes as prognostic indicators for overall survival in cancer: a systematic review and meta-analysis. JAMA Oncol. 2025;11(11):1303-1312.
22. Jhaveri KL, Neven P, Casalnuovo ML, et al; EMBER-3 study group. Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med. 2025;392(12):1189-1202.
23. Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019;5:5. doi:10.1038/s41523-018-0097-z
24. Kalinsky K, Bianchini G, Hamilton E, et al. J Clin Oncol. 2025;43(9):1101-1112.
25. Kalinsky K, Accordino MK, Chiuzan C, et al. Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: MAINTAIN trial. J Clin Oncol. 2023;41(24):4004-4013.
26. Living Beyond Breast Cancer. Metastatic breast cancer to the bones. Accessed January 12, 2026. https://www.lbbc.org/about-breast-cancer/types-breast-cancer/metastatic-breast-cancer/bone-metastases
27. Living Beyond Breast Cancer. Testing and precision medicine. Accessed January 12, 2026. https://www.lbbc.org/about-breast-cancer/testing
28. Lloyd MR, Brett JO, Carmeli A, et al. CDK4/6 inhibitor efficacy in ESR1-mutant metastatic breast cancer. NEJM Evid. 2024;3(5):EVIDoa2300231.
29. Lloyd MR, Spring LM, Bardia A, Wander SA. Mechanisms of resistance to CDK4/6 blockade in advanced hormone receptor-positive, HER2-negative Breast cancer and emerging therapeutic opportunities. Clin Cancer Res. 2022;28(5):821-830.
30. Lloyd MR, Wander SA, Hamilton E, Razavi P, Bardia A. Next-generation selective estrogen receptor degraders and other novel endocrine therapies for management of metastatic hormone receptor-positive breast cancer: current and emerging role. Ther Adv Med Oncol. 2022;14:17588359221113694.
31. Marschner N, Zacharias S, Lordick F, et al. Association of disease progression with health-related quality of life among adults with breast, lung, pancreatic, and colorectal cancer. JAMA Netw Open. 2020;3(3):e200643.
32. Mayer EL, Ren Y, Wagle N, et al. Presented at: 2022 San Antonio Breast Cancer Symposium, December 6-10, 2022; San Antonio, TX. Abstract GS3-06.
33. Meisel JL, Pham T, Chen C, Kris A, Roose J. Real-world treatment patterns and clinical outcomes in patients with emerging estrogen receptor 1 (ESR1)-mutated ER+ metastatic breast cancer in the U.S., 2018-2024. Presented at: 2025 San Antonio Breast Cancer Symposium, December 9-12, 2025; San Antonio, TX. Poster PS2-02-04.
34. National Cancer Institute (NCI). Breast cancer treatment (PDQ^®)–health professional version. Updated April 25, 2025. Accessed April 1, 2026. https://www.cancer.gov/types/breast/hp/breast-treatment-pdq
35. Patel R, Klein P, Tiersten A, Sparano JA. An emerging generation of endocrine therapies in breast cancer: a clinical perspective. NPJ Breast Cancer. 2023;9(1):20. doi:10.1038/s41523-023-00523-4
36. Razavi P, Chang MT, Xu G, et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell. 2018;34(3):427-438.e6. doi:10.1016/j.ccell.2018.08.008
37. Rugo HS, Finn RS, Diéras V, et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat. 2019;174(3):719-729.
38. Rugo HS, Lerebours F, Ciruelos E, et al. Lancet Oncol. 2024;25(12):e629-e638.
39. Sonke GS, van Ommen-Nijhof A, Wortelboer N, et al; SONIA Study Consortium. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024;636(8042):474-480.
40. Stanciu IM, Nitipir C. Real-world quality-of-life data in metastatic breast cancer patients treated with CDK4/6 inhibitors using four assessment tools. Cancers (Basel). 2025;17(5):818. doi:10.3390/cancers17050818
41. Tan CJ, Willis C, Au T, et al. Treatment discontinuation among patients with stage IV HER2-negative breast cancer: a multisite study in the United States. Presented at: 42^nd Annual Miami Breast Cancer Conference, March 6-9, 2025; Miami, FL.
42. Turner N, Huang-Bartlett C, Kalinsky K, et al. Future Oncol. 2023;19(8):559-573.
43. Turner NC, Oliveira M, Howell SJ, et al [supplementary appendix]. N Engl J Med. 2023;388(22):2058-2070.
44. Turner NC, Swift C, Kilburn L, et al. Clin Cancer Res. 2020;26(19):5172-5177.
45. Zhang K, Hong R, Xu F, et al. Clinical value of circulating ESR1 mutations for patients with metastatic breast cancer: a meta-analysis. Cancer Manag Res. 2018;10:2573-2580.

©2026 AstraZeneca. All rights reserved. US-112907 Last Updated 6/26