Management of hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer patients: First-line therapy

Breast cancer (BC) is the most common cancer in women, ranking as the third leading cause of cancer-related mortality in women in Taiwan.^1–4 Moreover, both incidence and mortality of BC have increased in recent decades in Taiwan, contributing to a big global health problem, significantly impairing body image and damaging psychosocial relationships. Compared to the very poor prognosis of triple-negative BC patients (hormone receptor-negative/human epidermal growth factor receptor two-negative subtype [TNBC, HR-/HER2-BC]), the majority of BC patients belong to the hormone receptor-positive/human epidermal growth factor receptor 2-negative subtype (HR+/HER2-BC), which is believed to be associated with favorable outcomes.^5–8 Conventionally, endocrine therapy (ET), for at least 5 years and up to 10 years, targeting estrogen receptor (ER) signaling pathway in order to inhibit BC growth remains the mainstay treatment choice for HR+/HER2-BC patients either in the early or in advanced setting, which includes different strategies, such as the suppression of estrogen production (gonadotropin-releasing hormone agonist or surgical oophorectomy), aromatase inhibitors (AIs, such as anastrozole or letrozole), or directly blocking the ER signaling pathway through selective estrogen receptor modulators (SERMs, such as tamoxifen) or selective estrogen receptor degraders (SERDs, also called ER antagonist [ERant], such as fulvestrant).⁹ However, a large proportion of patients (more than two-thirds of all BC patients) is noted, and approximately 5% to 10% of HR+/HER2-BC are diagnosed with far-advanced stage (de novo metastatic BC [mBC]), and a minimal one-fifth of diagnosed early-stage HR+/HER2-BC patients then progress to metastatic and disseminated diseases (mBC), which are largely incurable and finally end in cancer-related mortality.^5–8 The aforementioned clinical situations are often called de novo or acquired endocrine resistance, which is always challenging for oncologists. Luckily, advancements of medical technology, particularly through comprehensive genomic profiling (CGP) and next-generation sequencing (NGS) to offer a better understanding of molecular cancer biology in the last few years,^3,6,9–13 have enabled the identification of molecular alterations amenable to precise biomarker-guided targeted therapy, underscoring the urgent need to investigate the mechanisms underlying endocrine resistance and to identify effective strategies to overcome this challenge.^3,6,14,15 Endocrine resistance is complex and involves three major mechanisms, including (1) alterations in the ER (amplifications, fusions, or mutations in the ESR1 gene which encodes ERα); (2) aberrations in regulators of the ER pathway (ie, affecting co-factors, chromatin modifiers, or miRNAs); and (3) changes in other signaling cascades (PIK3CA [phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha] or PIK3CA/AKT [protein kinase B]/mTOR [mammalian target of rapamycin] pathway).^14,15 PIK3C mutations appear to be a very early event, and are present in the primary mBC at baseline, which are often truncal mutations, and they are, most importantly, acquired mutations, having arisen in the context of exposure to AIs, the most important drugs in adjuvant and metastatic settings, and their frequency is approximately 25% to 40% in the advanced setting.¹⁴ ER mutations occur in the most advanced disease and the greatest exposure to estrogen therapy.¹⁴ Therefore, there are some guidelines for molecular testing in these patients that require the identification of PI3K, AKT, PTEN, and ESR mutations to select specific treatment in the refractory/resistance setting, including Dr. Huang’s recommendation published in the August 2025 issue of the Journal of Chinese Medical Association (JCMA).³ Therefore, the recent front-line (1L) standard-of-care (SOC) therapy for HR+/HER2-BC is the combination of ET plus cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (CDK4/6i) and/or PIK3CA inhibitors, regardless of whether prescription is applied to mBC or as adjuvant therapy for high-risk early stage BC,^5,15,16 because the use of novel ET combined with targeted drugs, such as CDK4/6i, which has significantly improved long-term outcome rates (progression-free survival [PFS] and overall survival [OS]).

In this editorial and the following editorial, we will increase the information about the use of CDK4/6is in combination with effective ET as the 1L SOC therapy for HR+/HER2-BC patients. There are three CDK4/6is available in the clinical practice, including palbociclib (Ibrance^®, approved in 2015 in the United States [US]), ribociclib (Kisqali^®, approved in 2017 in the US), and abemaciclib (Verzenio™, approved in 2017 in the US) which have been approved for use in combination with ET, including AIs or ER antagonist, or as a single agent (abemaciclib).¹⁶ CDK4/6is, blocking cell cycle mediated by suppressing the downstream effects of the complex formed by CDK4/6 with cyclin D, and inducing cell cycle arrest in G1 phase, leads to failure to complete the G1–S transition and subsequent DNA synthesis.¹⁵ However, CDK4/6is may have differential efficacy based on variable pharmacodynamics, showing differences in toxicity, half-life, ability to cross the blood-brain barrier (BBB), acquired resistance mechanisms, and ultimate possibility to influence the final efficacy.¹⁵ For example, palbociclib inhibits cell growth and suppresses DNA replication in retinoblastoma tumor suppressor gene (RB) proficient cancer cells. Other examples include that ribociclib and abemaciclib are more selective toward CDK4 over CDK6; abemaciclib has a different chemical structure and additional inhibitory activity toward multiple kinases.¹⁵ An updated meta-analysis has explored the efficacy of three CDK4/6 inhibitors in the management of HR+/HER2-BC patients compared to ET alone.¹⁶ Across the 10 studies comparing different CDK4/6i in the overall population, a total of 1634 patients received palbociclib (the median PFS and OS ranged from 23.4 to 31.0 months and from 38.0 to 58.0 months, respectively), 339 patients received ribociclib (the median PFS ranged from 19.8 to 44.0 months and the median OS ranged from 40.4 to 52.0 months), and 310 patients received abemaciclib (the median PFS ranged from 14.0 to 39.5 months and the median OS was 34.4 months), with similar effectiveness results.¹⁶

ACKNOWLEDGMENTS

This research was supported by grants from the Taipei Veterans General Hospital (V113C-152, V114C-039, and V114B-015) and the Taiwan National Science and Technology Council, Executive Yuan (110-2314-B-075-016 MY3 and 113-2314-B-075-057 MY3), Taipei, Taiwan.

We appreciate the support from the Female Cancer Foun-dation, Taipei, Taiwan.