In the evolving landscape of breast cancer treatment, the management of HR+ advanced breast cancer remains a central focus. During the Northern China Breast Cancer Salon – Annual Progress Review, Dr. Zhanhong Chen from Zhejiang Cancer Hospital delivered an in-depth analysis on the stratified treatment approach for HR+ advanced breast cancer. Following the meeting, Oncology Frontier invited Professor Chen to discuss key topics, including the optimal timing for CDK4/6 inhibitor use and the future development of novel targeted therapies.

Reevaluating the Timing of CDK4/6 Inhibitor Use in HR+ Advanced Breast Cancer

Oncology Frontier: CDK4/6 inhibitors combined with endocrine therapy (ET) have become the preferred first-line treatment for HR+ advanced breast cancer. However, the SONIA study, published in Nature this year, suggested that using CDK4/6 inhibitors in the first-line setting offers no significant statistical or clinical survival benefit compared to their use in the second-line setting. Moreover, first-line use was associated with higher medical costs and increased adverse events. How do you interpret this study? What are your views on the timing of CDK4/6 inhibitor administration?

Dr. Zhanhong Chen: This is a crucial topic for discussion. Currently, CDK4/6 inhibitors plus ET are the standard first-line treatment for HR+ advanced breast cancer. A key question is whether these inhibitors should be used immediately in the first line or reserved for second-line treatment upon disease progression on ET alone. The SONIA study indeed reported negative findings, showing no significant difference in progression-free survival (PFS) or overall survival (OS) between first- and second-line CDK4/6 inhibitor use.

However, a single clinical trial should not be the sole determinant of treatment decisions. In the SONIA study, two distinct scenarios were analyzed. One group received fulvestrant plus a CDK4/6 inhibitor after progressing on a nonsteroidal aromatase inhibitor (AI)—a commonly used strategy in clinical practice. In this setting, CDK4/6 inhibitors combined with fulvestrant serve as a standard second-line option, making this an effective treatment sequence.

The other group received a nonsteroidal AI plus a CDK4/6 inhibitor in the first-line setting, and upon progression, received fulvestrant monotherapy in the second line. This approach raises concerns, as fulvestrant monotherapy is rarely used alone after CDK4/6 inhibitor progression in clinical practice. Instead, second-line options often include a different targeted agent combined with ET. Other alternatives include cross-line use of CDK4/6 inhibitors, selective estrogen receptor degraders (SERDs), antibody-drug conjugates (ADCs), or chemotherapy. Therefore, the SONIA study does not align fully with real-world treatment decisions, and its findings should not lead to an immediate change in clinical practice.

Another factor to consider is that over 90% of patients in the SONIA study received palbociclib. The reported OS for first-line CDK4/6 inhibitor use was 45.9 months, which may not be representative of all CDK4/6 inhibitors. For instance, in the MONALEESA-2 trial, ribociclib achieved an OS of 63.9 months, and in monarchE, OS exceeded five years. Differences in CDK4/6 inhibitors may influence survival outcomes, and results from one agent should not be generalized to all.

Additionally, the study highlighted adverse event (AE) profiles. While first-line CDK4/6 inhibitor therapy was associated with higher AEs, this can be attributed to treatment duration. Patients in the first-line arm received CDK4/6 inhibitors for a median of 24.6 months, whereas those in the second-line arm received them for only 8.4 months. Naturally, a longer treatment duration leads to a higher incidence of AEs. This discrepancy underscores the need for careful interpretation of AE data. Given these factors, I do not believe that the SONIA study should alter the current position of CDK4/6 inhibitors as the preferred first-line option.

That said, we must also reflect on individualized treatment strategies. Certain patient groups may benefit from delaying CDK4/6 inhibitor use. For example, patients who had a prolonged response to adjuvant ET, whose tumors retain similar biological characteristics upon recurrence, and who remain highly endocrine-sensitive may be suitable candidates for ET monotherapy, particularly if they are elderly or have poor tolerance to treatment-related toxicities such as bone marrow suppression.

Future directions should focus on identifying biomarkers to refine patient selection. RNA-based biomarkers, advanced PET imaging techniques, and circulating tumor DNA (ctDNA) analysis may help optimize treatment sequencing and personalize therapy. These areas represent important avenues for future research.

Personalized Second-Line Therapy Selection for HR+ Advanced Breast Cancer

Oncology Frontier: In your lecture, you discussed the importance of stratified treatment for HR+ advanced breast cancer. For patients who progress on first-line CDK4/6 inhibitor plus endocrine therapy, how should treatment decisions be made based on this stratification approach?

Dr. Zhanhong Chen: Stratification is more important than simply dividing treatments into different lines, as we make treatment decisions based on precision medicine throughout the entire course of therapy. Factors such as PAM pathway activation, ESR1 mutations, and BRCA mutations play a crucial role in determining the next steps.

For certain patients—such as those who relapse within a year of stopping adjuvant endocrine therapy and have a PI3K mutation—we may opt for a second-line treatment strategy even though they theoretically qualify for first-line therapy. The INAVO120 study provides strong evidence for this approach. In this patient group, adding inavolisib to CDK4/6 inhibitor plus ET significantly improved outcomes. With a median follow-up of 21.3 months, the inavolisib group had a median progression-free survival (PFS) of 15.0 months compared to 7.3 months in the placebo group (HR=0.43).

For patients with ESR1 mutations, oral selective estrogen receptor degraders (SERDs) are an effective choice. The EMERALD study enrolled 478 patients, including 222 with ESR1 mutations who had received prior ET plus CDK4/6 inhibitors for at least 12 months. In this subgroup, elacestrant achieved a median PFS of 8.6 months, significantly outperforming standard-of-care endocrine therapy (mPFS=1.9 months, HR=0.41, 95% CI: 0.26–0.63, P<0.014).

Additionally, at the 2024 San Antonio Breast Cancer Symposium (SABCS), the EMBER-3 study confirmed the efficacy of the oral SERD imlunestrant in ESR1-mutant patients, with imlunestrant plus abemaciclib achieving a PFS of 11.1 months. These findings reinforce that oral SERD therapy, with or without CDK4/6 inhibitors, represents a strong option for ESR1-mutant patients.

For PIK3CA-mutant patients, the SOLAR-1 and BYLieve trials confirmed the efficacy of alpelisib. However, the CAPItello-291 trial demonstrated that patients with PIK3CA, AKT, or PTEN alterations could benefit from the AKT inhibitor capivasertib, suggesting a broader treatment population. Patients with PAM pathway mutations may benefit more from AKT inhibitors, while PI3K inhibitors remain an excellent choice for PIK3CA-only mutations.

For patients with BRCA mutations, the OlympiAD study confirmed the superiority of olaparib over physician’s choice chemotherapy (including capecitabine).

For patients without BRCA mutations or PAM pathway activation, alternative targeted approaches should be considered. Options include HDAC inhibitors (entinostat or chidamide) combined with endocrine therapy. The postMONARCH study also demonstrated the efficacy of cross-line therapy with abemaciclib plus fulvestrant. Overall, second-line treatment decisions should be based on precise biomarker-driven strategies, utilizing a combination of endocrine therapy and targeted agents.

The Future Role of Novel Targeted Therapies and ADCs in HR+ Advanced Breast Cancer

Oncology Frontier: With the continuous development of novel targeted therapies and ADCs, treatment options for HR+ advanced breast cancer are expanding. How do you see emerging agents, such as the PI3K inhibitor inavolisib and the AKT inhibitor capivasertib, shaping the future treatment landscape?

Dr. Zhanhong Chen: In HR+ advanced breast cancer, treatment selection depends on specific genetic alterations. For PIK3CA-mutant patients, PI3K inhibitors remain the primary option. For AKT-mutant patients, AKT inhibitors may be more effective.

The CAPItello-291 trial demonstrated that AKT inhibitors benefit a broader patient population, including those with PIK3CA, AKT1, or PTEN mutations, showing positive results in both the intention-to-treat (ITT) population and those with AKT pathway alterations. In contrast, PI3K inhibitors are only effective in PIK3CA-mutant patients, and do not work in AKT-mutant cases. Notably, PIK3CA-mutant cells remain sensitive to AKT inhibitors, while AKT-mutant cells are resistant to PI3K inhibitors, highlighting the mechanistic differences between these two drug classes.

The INAVO120 study further suggested that in endocrine-resistant, PIK3CA-mutant patients, PI3K inhibitors could be considered even as a first-line treatment, particularly when combined with CDK4/6 inhibitors and ET. This regimen showed superior efficacy compared to CDK4/6 inhibitors plus ET alone, allowing treatment escalation to reverse or delay endocrine resistance.

It is important to emphasize that these studies specifically targeted patients with endocrine resistance and relevant genetic mutations (PIK3CA or AKT). As a result, their applicable patient populations are distinct. Both drugs are expected to enter the Chinese market in 2025, offering new therapeutic options for patients.

About the Expert

• Zhanhong Chen Chief Physician, Master’s Supervisor Deputy Director of the Breast Oncology Department, Zhejiang Cancer Hospital Director of the Breast Cancer Ward Expert, Breast Cancer Group, National Committee for Clinical Application of Anticancer Drugs Executive Member, Integrative Oncology and Cardio-Oncology Committee, Chinese Anti-Cancer Association Executive Member, Breast Cancer Committee, Chinese Female Doctors Association Executive Member, Breast Disease Committee, China Health Promotion Foundation Member, Breast Cancer Expert Committee, Chinese Society of Clinical Oncology (CSCO) Member, Breast Cancer Guidelines Committee, CSCO Member, Breast Cancer Group, Chinese Medical Doctor Association Oncology Division Chair, Tumor Cardio-Oncology Committee, Zhejiang Anti-Cancer Association Chair, Breast Cancer Diagnosis and Treatment Committee, Zhejiang Mathematical Medicine Association Chair-Elect, Breast Cancer Clinical Trials Committee, Zhejiang Mathematical Medicine Association Vice Chair, Tumor Immunology and Biotherapy Committee, Zhejiang Immunology Society Member, Breast Cancer Committee, Zhejiang Anti-Cancer Association Member, Oncology Committee, Zhejiang Anti-Cancer Association