Then again,
so were videotapes

Then again,
so were flip phones

Then again, so were personal computers

For HR+/HER2- metastatic breast cancer (mBC)

IN THE '90s, AROMATASE INHIBITORS WERE STATE
OF THE ART

While 1L SOC has advanced to include CDK4/6i, aromatase inhibitors (AIs) have remained the most used endocrine therapy (ET) backbone since their introduction over 2 decades ago. How can we modernize our understanding of what’s limiting patients’ time on their 1L ET backbone?1-3

Time on 1L Time on 1L

TIME ON 1L IS KEY FOR PATIENTS4-12

1L treatment response is critical as outcomes worsen in later lines, elevating the need for modern approaches for ETs in 1L.

Why time on 1L matters
First Line Icon First Line Icon

AI use may limit ET efficacy in 1L13-15

AIs may leave the estrogen receptor intact and susceptible to estrogen-independent activation and resistance.1,16,17

Uncover limitations of AIs
Stagnation in 1L ET Stagnation in 1L ET

>2 decades of innovation
stagnation in 1L ET1,3,18

1L ET backbone in HR+/HER2- mBC has had little innovation in 20 years, yet cancer keeps evolving.

Time to rethink 1L approach?

1L=first line; CDK4/6i=cyclin-dependent kinase 4/6 inhibitor; HER2-=human epidermal growth factor receptor 2-negative; HR+=hormone receptor-positive; SOC=standard of care.

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  2. Hanker AB, Sudhan DR, Arteaga CL. Overcoming endocrine resistance in breast cancer. Cancer Cell. 2020;37(4):496-513. doi:10.1016/j.ccell.2020.03.009
  3. Zanotti G, Hunger M, Perkins JJ, Horblyuk R, Martin M. Treatment patterns and real world clinical outcomes in ER+/HER2- post-menopausal metastatic breast cancer patients in the United States. BMC Cancer. 2017;17(1):393. doi:10.1186/s12885-017-3379-1
  4. Yamamura J, Kamigaki S, Tsujie M, et al. Response to first-line recurrence treatment influences survival in hormone receptor-positive, HER2-negative breast cancer: a multicenter study. In Vivo. 2019;33(1):281-287. doi:10.21873/invivo.11473
  5. Matikas A, Kotsakis A, Perraki M, et al. Objective response to first-line treatment as a predictor of overall survival in metastatic breast cancer: a retrospective analysis from two centers over a 25-year period. Breast Care (Basel). 2022;17(3):264-271. doi:10.1159/000519729
  6. 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. doi:10.1200/JCO.22.02392
  7. 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
  8. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936. doi:10.1056/NEJMoa1607303
  9. Mayer EL, Ren Y, Wagle N, et al. PACE: a randomized phase II study of fulvestrant, palbociclib, and avelumab after progression on cyclin-dependent kinase 4/6 inhibitor and aromatase inhibitor for hormone receptor-positive/human epidermal growth factor receptor-negative metastatic breast cancer. J Clin Oncol. 2024;42(17):2050-2060. doi:10.1200/JCO.23.01940
  10. Llombart-Cussac A, Harper-Wynne C, Perello A, et al. Second-line endocrine therapy (ET) with or without palbociclib (P) maintenance in patients (pts) with hormone receptor-positive (HR[+])/human epidermal growth factor receptor 2-negative (HER2[-]) advanced breast cancer (ABC): PALMIRA trial. J Clin Oncol. 2023;41(16_suppl):1001. doi:10.1200/JCO.2023.41.16_suppl.1001
  11. Kalinsky K, Bianchini G, Hamilton E, et al. Abemaciclib plus fulvestrant in advanced breast cancer after progression on CDK4/6 inhibition: results from the phase 3 postMONARCH trial. J Clin Oncol. 2025;43(9):1101-1112. doi:10.1200/JCO-24-02086
  12. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131
  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. Chen S, Masri S, Wang X, Phung S, Yuan YC, Wu X. What do we know about the mechanisms of aromatase inhibitor resistance? J Steroid Biochem Mol Biol. 2006;102(1-5):232-240. doi:10.1016/j.jsbmb.2006.09.012
  15. Bidard FC, Hardy-Bessard AC, Dalenc F, et al. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2022;23(11):1367-1377. doi:10.1016/S1470-2045(22)00555-1
  16. Hernando C, Ortega-Morillo B, Tapia M, et al. Oral selective estrogen receptor degraders (SERDs) as a novel breast cancer therapy: present and future from a clinical perspective. Int J Mol Sci. 2021;22(15):7812. doi:10.3390/ijms22157812
  17. Will M, Liang J, Metcalfe C, Chandarlapaty S. Therapeutic resistance to anti-oestrogen therapy in breast cancer. Nat Rev Cancer. 2023;23(10):673-685. doi:10.1038/s41568-023-00604-3
  18. Pejerrey SM, Dustin D, Kim JA, Gu G, Rechoum Y, Fuqua SAW. The impact of ESR1 mutations on the treatment of metastatic breast cancer. Horm Cancer. 2018;9(4):215-228. doi:10.1007/s12672-017-0306-5