Editor’s Note: Endocrine therapy remains one of the standard adjuvant treatments for patients with hormone receptor-positive, HER2-negative (HR+/HER2−) early-stage breast cancer. In recent years, research in this field has made significant progress. A key challenge in clinical practice is how to precisely assess recurrence risk and tailor therapy accordingly. At the recent3rd Shanghai Precision Cancer Research Innovation Summit (SPCRIS), Professor Yang Yu of Zhejiang Cancer Hospital shared valuable insights on the personalized adjuvant treatment of HR+/HER2− early breast cancer.1. Balancing Survival Benefits and Quality of Life in Extended Endocrine Therapy
Oncology Frontier: Extending endocrine therapy can provide survival benefits for patients with HR+/HER2− early breast cancer, but it may also raise concerns about quality of life. Based on your clinical experience, how should we balance these two aspects?
Prof. Yang Yu: Endocrine therapy is a cornerstone of adjuvant treatment for HR+/HER2− early breast cancer. Historical studies have shown that five years of endocrine therapy may be sufficient—for example, five years of tamoxifen can reduce the risk of recurrence by 33% over 15 years. With ongoing research, studies such as aTTom and ATLAS have demonstrated the benefits of extending tamoxifen treatment to ten years. Similarly, sequential therapy has shown long-term survival advantages, as in the MA.17 study, where patients switched from five years of tamoxifen to five years of aromatase inhibitor (AI) therapy. The MA.17R trial further confirmed that 10 years of AI therapy significantly improves disease-free survival.
However, not all patients are suitable for extended therapy. It is most meaningful for those with lymph node involvement or other high-risk features. Therefore, the first step in clinical practice is to accurately identify patients who truly need extended endocrine therapy—namely, those at high risk of recurrence.
At the same time, prolonged endocrine therapy can lead to adverse effects. In premenopausal women treated with 10 years of tamoxifen, side effects like endometrial thickening and increased vaginal discharge may occur, though they are generally manageable. For high-risk patients continuing with AI therapy, more serious concerns such as cardiovascular and bone health issues arise. It’s important to monitor potential toxicities from the outset. For example, lipid profiles should be checked regularly, and any metabolic abnormalities should be addressed promptly with medication. Bone density should also be assessed, not just through measurements but by monitoring for clinical symptoms, with appropriate supportive treatments as needed.
In summary, treatment decisions in breast cancer should balance efficacy and safety. When benefits are clear and side effects are manageable, extending therapy can significantly improve patient outcomes.
2. Individualizing Adjuvant Therapy Based on Risk Stratification
Oncology Frontier: How should adjuvant therapy be personalized for high-risk HR+/HER2− patients based on clinical features such as lymph node status or Ki-67 expression?
Prof. Yang Yu: Risk stratification is essential before initiating adjuvant therapy. Historically, based on the St. Gallen criteria, low-risk patients were defined by several favorable features: HER2-negative, ER-positive, node-negative, Grade 1 histology, Ki-67 < 20%, tumor size < 2 cm, and age over 35. High-risk patients were more narrowly defined—such as those with 1–3 positive axillary lymph nodes and either ER/PR negativity or HER2 positivity, or those with ≥4 positive lymph nodes.
Today, our definition of high risk has broadened. Patients with ≥4 positive lymph nodes (N2/3), or 1–3 nodes with Grade 3 histology, or tumors >5 cm are now considered high risk. For this group, CDK4/6 inhibitors have become an important therapeutic option and are now approved for early-stage adjuvant intensification in the U.S., Europe, and China. This marks a significant advancement for a broader patient population.
From the monarchE to the NATALEE trials, we’ve seen a continuous evolution in our understanding of risk factors. Although the monarchE criteria currently guide our assessment of high-risk patients, future research will likely refine these standards further. The ultimate goal is to ensure that only those who truly need treatment receive it, minimizing both under- and overtreatment. This is the essence of precision medicine.
3. Optimizing Treatment for BRCA-Mutated HR+/HER2− Patients
Oncology Frontier: What benefits can PARP inhibitors offer for patients with high-risk HR+/HER2− early breast cancer who carry BRCA germline mutations?
Prof. Yang Yu: As awareness of hereditary breast cancer increases, more patients are being screened for BRCA mutations. For those with HR+/HER2− tumors, high-risk features, and BRCA mutations, determining the optimal treatment strategy remains a major focus.
In the OlympiA trial, olaparib significantly improved survival in early-stage HR+ patients with ≥4 positive nodes or those who did not achieve a pathological complete response (pCR) after neoadjuvant therapy and had a CPS score ≥3. Since then, monarchE and NATALEE have expanded our treatment landscape. However, several questions remain:
- Are CDK4/6 inhibitors effective in BRCA-mutant patients receiving endocrine therapy?
- Can they be combined with PARP inhibitors?
Exploratory analyses from monarchE suggest that abemaciclib combined with endocrine therapy is beneficial even for BRCA-mutated patients. However, whether it is safe and effective to combine PARP inhibitors with CDK4/6 inhibitors is still unclear due to limited data. Safety concerns must be carefully considered.
The NATALEE study provides new insight by allowing patients who had already received a year of endocrine therapy to enroll. This opens the possibility for a sequential approach—starting with endocrine therapy and a PARP inhibitor, followed by ribociclib later. This treatment strategy aligns better with real-world clinical practice and may offer better outcomes. Nonetheless, more clinical trials are needed to validate this approach and provide clearer guidance.
About Professor Yang Yu
- Department of Breast Surgery, Zhejiang Cancer Hospital
