Editor's Note: Hormone receptor (HR)-positive breast cancer accounts for approximately 70% of all breast cancer cases. From the early exploration of ovarian ablation more than a century ago, to tamoxifen ushering in the era of endocrine therapy, and then to CDK4/6 inhibitor-based combinations reshaping the treatment landscape of advanced disease, each major therapeutic breakthrough has profoundly altered the survival trajectory of patients. However, treatment resistance remains a major clinical challenge. The discovery of resistance mechanisms such as PI3K/AKT/mTOR pathway alterations and ESR1 mutations has subsequently driven the development of increasingly precise targeted strategies. The 2026 Northern Breast Cancer Forum was successfully held in Qingdao from July 25 to 26. During the meeting, Oncology Frontier interviewed Prof. Yunjiang Liu from the Fourth Hospital of Hebei Medical University, who provided an in-depth overview of the major milestones in HR-positive breast cancer treatment, precision strategies following CDK4/6 inhibitor resistance, and the new opportunities created by domestically developed innovative therapies.Oncology Frontier: HR-positive breast cancer is the most common subtype of breast cancer. From tamoxifen initiating the era of endocrine therapy, to the development of aromatase inhibitors, and then to CDK4/6 inhibitor plus endocrine therapy becoming the first-line standard, which milestones do you believe have truly transformed the diagnosis and treatment of HR-positive breast cancer?
Prof. Yunjiang Liu: HR-positive breast cancer accounts for approximately 70% of all breast cancer cases. Its growth is largely dependent on estrogen signaling, making blockade of this pathway one of the fundamental strategies for controlling the disease. Endocrine therapy has therefore remained a cornerstone of treatment for this subtype.
This therapeutic concept can be traced back to the 1890s. More than a century ago, surgeons discovered that removing the ovaries and thereby eliminating a major source of estrogen could effectively control disease in some patients. This can be regarded as the first milestone in the history of HR-positive breast cancer treatment.
As research into endocrine therapy progressed, the close relationship between estrogen and breast cancer development became increasingly clear. In the 1940s, estrogen was explored as a treatment for postmenopausal patients with advanced breast cancer. In the 1970s, tamoxifen (TAM) began to be investigated in breast cancer, and in 1978 it received FDA approval for adjuvant endocrine therapy in early breast cancer. The development and clinical application of endocrine agents represented by tamoxifen therefore constituted the second major milestone in the treatment of HR-positive breast cancer.
Subsequently, aromatase inhibitors (AIs), selective estrogen receptor degraders (SERDs), and other endocrine therapies were introduced into the treatment of HR-positive breast cancer. AIs have now evolved into third-generation agents, although resistance and other challenges remain. Therefore, combining endocrine therapy with other targeted agents to further improve efficacy and overcome resistance has become a major research direction.
The emergence of CDK4/6 inhibitors marked the arrival of the third major milestone and once again reshaped the treatment landscape of HR-positive/HER2-negative advanced breast cancer. CDK4/6 inhibitors combined with endocrine therapy have significantly prolonged progression-free survival (PFS) and are now recommended by major clinical guidelines as a standard treatment option for this population. Although combination therapy can cause certain adverse events, these are generally manageable compared with chemotherapy and other treatment approaches.
From the introduction of endocrine therapies such as tamoxifen, to extending the duration of adjuvant endocrine therapy from two years to five years and subsequently to ten years, long-term outcomes for patients have improved substantially. The emergence of CDK4/6 inhibitors has further enhanced the efficacy of endocrine-based treatment, benefiting both patients with early-stage and advanced breast cancer. In particular, adjuvant CDK4/6 inhibitor therapy can significantly reduce the risk of early recurrence in patients with early breast cancer at intermediate or high risk of recurrence. Taken together, these three developments undoubtedly represent landmark milestones in the evolution of endocrine therapy for HR-positive breast cancer.
Oncology Frontier: CDK4/6 inhibitor plus endocrine therapy has become the first-line standard for HR-positive/HER2-negative advanced breast cancer, but resistance remains a major clinical challenge. Activation of the PI3K/AKT/mTOR pathway and ESR1 mutations are two important mechanisms of resistance. What treatment strategies are currently available for patients who progress following CDK4/6 inhibitor-based therapy?
Prof. Yunjiang Liu: Tumors exhibit both temporal and spatial heterogeneity, and genetic alterations can emerge under treatment pressure. This is an important reason why resistance to CDK4/6 inhibitors develops. The mechanisms of resistance include alterations in the PI3K/AKT/mTOR pathway, ESR1 mutations, and interactions and cross-talk among multiple signaling pathways. Among these mechanisms, alterations in the PI3K pathway may represent an early event in some patients.
For patients who develop resistance, we should prioritize genomic testing and use the results to guide precision treatment. Specifically, for patients with PIK3CA mutations, the PI3K inhibitor inavolisib may be considered; for patients with AKT1 alterations, an AKT inhibitor such as capivasertib may be an option. Everolimus, an mTOR inhibitor, is another treatment option. For patients with ESR1 mutations, fulvestrant or newer oral SERDs may be considered. These agents may also have important potential applications in adjuvant treatment of early breast cancer in the future.
For patients with HER2-low or HER2-ultralow expression, ADCs such as T-DXd may be considered. Several Chinese pharmaceutical companies are also conducting clinical studies in this area, and we look forward to domestically developed ADCs demonstrating similarly meaningful efficacy. For patients with HER2-zero disease, Trop-2-directed ADCs such as sacituzumab govitecan or datopotamab deruxtecan (Dato-DXd) may provide treatment options. Once resistance develops to these targeted approaches, chemotherapy remains an option in later lines.
Overall, when treating patients after CDK4/6 inhibitor resistance, we should make every effort to identify the underlying resistance mechanism and determine whether there is an actionable target. Treatment should then be individualized according to the patient’s previous treatment history and physical condition. While prolonging PFS, we must also pay close attention to treatment-related toxicity and preserve patients’ quality of life.
Oncology Frontier: In recent years, several important advances have emerged in HR-positive breast cancer. The global first-in-class CDK2/4/6 inhibitor dalpiciclib? has received approval for first-line treatment, China’s independently developed CDK4/6 inhibitor dalpiciclib has been approved for adjuvant treatment of high-risk early breast cancer, and several oral SERDs have generated encouraging results in patients with ESR1 mutations. How do you evaluate the impact of these breakthroughs on the treatment landscape of HR-positive breast cancer?
Prof. Yunjiang Liu: Globally, breast cancer remains one of the most commonly diagnosed solid tumors. Although the incidence in China is lower than that in many Western countries, the country’s large population means that the absolute number of breast cancer patients remains substantial. Encouragingly, Chinese patients now have access to an increasingly broad range of treatment options, driven in part by the rapid development and approval of domestically developed anticancer therapies such as dalpiciclib and other innovative agents.
HR-positive breast cancer continues to account for a large proportion of breast cancer cases. As we discussed when considering the mechanisms of CDK4/6 inhibitor resistance, activation of CDK2 can serve as an important compensatory mechanism through which tumor cells bypass CDK4/6 inhibition and maintain cell-cycle progression. Therefore, CDK2 inhibition represents a potentially important strategy for overcoming resistance to CDK4/6 inhibitors. However, the clinical efficacy of these emerging approaches still needs to be confirmed through substantial clinical data and real-world evidence.
At the same time, Chinese pharmaceutical companies are actively developing increasingly precise targeted agents, including inhibitors targeting CDK2, CDK4, and even CDK9. Research has shown that inhibition of CDK6 may contribute to adverse events such as myelosuppression. Therefore, in the era of precision treatment, greater target selectivity may potentially reduce off-target toxicity while improving therapeutic efficacy.
We sincerely hope that the continued development of innovative therapies in China will bring more effective and better-tolerated treatment options to breast cancer patients, both in China and around the world.
Prof. Yunjiang Liu
