Editor’s Note: For hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer patients with no lymph node involvement (N0) and limited high-risk factors, the consensus has been that their risk of recurrence is low, and adjuvant endocrine therapy alone is sufficient. However, with the release of studies like NATALEE, it has become apparent that intensifying treatment for these patients to reduce the risk of recurrence is also necessary. At the 2024 South-North Forum, Prof. Hong Hu from Shenzhen People’s Hospital presented a lecture on “Adjuvant Therapy for HR+/HER2- Breast Cancer: Do N0 Patients with Limited High-Risk Factors Need CDK4/6 Inhibitors?” This article reviews the lecture content.
At the beginning of his lecture, Prof. Hu emphasized that to thoroughly address the question “Adjuvant Therapy for HR+/HER2- Breast Cancer: Do N0 Patients with Limited High-Risk Factors Need CDK4/6 Inhibitors?”, it is necessary to break it down into four sub-questions and answer them one by one: What is the prognosis for HR+/HER2- N0 patients with limited high-risk factors? If their prognosis is poor, will they benefit from adjuvant CDK4/6 inhibitors? If they can benefit, what are the costs? Do current evidence-based medical data support recommending adjuvant CDK4/6 inhibitors for this subgroup?
1. What is the prognosis for HR+/HER2- N0 patients with limited high-risk factors?
Previously, it was believed that HR+/HER2- N0 patients had a good prognosis. However, an EBCTCG meta-analysis showed that this group still has a long-term risk of recurrence and metastasis, with a 20-year distant recurrence risk of 22% and a 20-year breast cancer-related death risk of 15%. Additionally, the risk of recurrence increases with tumor size and histological grade. Therefore, the recurrence risk for this group should not be underestimated.
The 12-year follow-up results of the TAILORx study showed that N0 patients with a recurrence score (RS) of ≥26, even with standard chemotherapy and endocrine therapy, had a 12-year invasive disease-free survival (iDFS) rate of only 65.9%, and a 12-year distant recurrence risk of 19.1%. Hence, for N0 patients with poor prognosis and limited high-risk factors, additional adjuvant treatments beyond chemotherapy and endocrine therapy are needed.
2. Will HR+/HER2- N0 patients with limited high-risk factors benefit from adjuvant CDK4/6 inhibitors?
Prof. Hu stated that before June 2023, his answer to this question would have been negative. Previous randomized controlled trials of adjuvant CDK4/6 inhibitors rarely included this subgroup. The PALLAS study included a small number of N0 patients but yielded negative results. The monarchE study, although positive, did not include any N0 patients.
However, with the release of the NATALEE study data at the 2023 ASCO conference, the situation has changed, giving more hope. The NATALEE study mainly investigated whether 400 mg of ribociclib for three years as adjuvant therapy could improve outcomes in HR+/HER2- breast cancer patients at intermediate to high risk. The study included a broader population, incorporating some T2N0 patients with high-risk factors and T3N0, T4N0 patients.
The final iDFS data from the NATALEE study, presented at the 2023 SABCS conference, showed that the three-year iDFS rates were 90.7% (95% CI: 89.3%-91.8%) in the ribociclib + non-steroidal aromatase inhibitor (NSAI) group and 87.6% (95% CI: 86.1%-88.9%) in the NSAI group, resulting in an absolute benefit of 3.1% for the ribociclib group. The benefits were consistent across all subgroups, including the N0 subgroup, which had an absolute three-year iDFS benefit of 2.6%, similar to that of lymph node-positive patients.
Prof. Hu noted that an absolute three-year iDFS benefit of 2.6% is significant. The SOFT study showed that the benefit of ovarian function suppression (OFS) was not significant in the five-year follow-up but became apparent in the eight-year follow-up, indicating a significant disease-free survival (DFS) benefit. Therefore, although the prognosis for HR+/HER2- N0 patients with limited high-risk factors is poor, they can still achieve better outcomes with adjuvant CDK4/6 inhibitors, and future longer follow-ups may show even greater absolute differences.
3. What are the costs of adjuvant CDK4/6 inhibitors for HR+/HER2- N0 patients with limited high-risk factors?
Prof. Hu pointed out that the safety results of the NATALEE study showed that during the three-year adjuvant treatment with 400 mg ribociclib, patients had good safety and tolerability, with no new safety signals observed. The quality of life of patients in the ribociclib group was not significantly different from that of the control group. Thus, the benefits were achieved without significant costs, and patients tolerated the treatment well.
4. Do current evidence-based medical data support recommending adjuvant CDK4/6 inhibitors for this subgroup?
In the NATALEE study, there were only about 600 N0 patients, accounting for 13.7% of the intention-to-treat (ITT) population. Is this small subgroup sufficient to change clinical practice? Prof. Hu explained that in previous studies, such as the SOFT study, the HER2+ subgroup accounted for only 11.6% of the ITT population, yet the benefit trend of OFS in this subgroup was consistent with the ITT population. Therefore, high-risk premenopausal patients with triple-positive breast cancer are still recommended for OFS in clinical practice.
The OlympiA study indicated that high-risk BRCA-mutated breast cancer patients significantly benefited from adjuvant olaparib treatment. In this study, the HR+/HER2- BRCA-mutated subgroup accounted for only 17.7% of the ITT population, yet the benefit trend of olaparib was consistent with the ITT population. Consequently, in the 2023 St. Gallen consensus, nearly 90% of experts expressed a preference for recommending olaparib in this population.
The DESTINY-Breast04 study was the first Phase III clinical trial targeting HER2-low expressing patients, demonstrating that T-DXd provided clinically meaningful and statistically significant improvements in PFS and OS for HER2-low breast cancer patients, regardless of HR status. In this study, the HR- subgroup included only 58 patients, about 10% of the ITT population, yet the benefit trend of T-DXd was consistent with the ITT population. Therefore, T-DXd was approved for treating adult patients with HER2-low expression (IHC1+ or IHC2+/ISH-) who had unresectable or metastatic breast cancer and had received at least one prior systemic therapy for metastatic disease, or who had disease recurrence during or within six months of completing adjuvant chemotherapy, including a subgroup of triple-negative breast cancer (TNBC) patients.
Prof. Hu emphasized that although the number of N0 patients in the NATALEE study was not large, they were still part of the overall study population, and the benefit trend of CDK4/6 inhibitors was consistent with the ITT population. Therefore, this subgroup should not be excluded from adjuvant CDK4/6 inhibitor treatment. The NATALEE study data have expanded the population eligible for adjuvant CDK4/6 inhibitors by about 30% of early HR+ breast cancer patients, providing a new treatment option for this intermediate-risk group.
In conclusion, Prof. Hu summarized that HR+/HER2- breast cancer patients with limited high-risk factors need CDK4/6 inhibitors in adjuvant therapy. In future clinical practice, for N0 patients who are young, have tumors ≥3.5 cm, histological grade 3, lymphovascular invasion (LVI) positive, and Ki-67 >80%, in addition to chemotherapy and OFS combined with AI, adjuvant CDK4/6 inhibitors should be offered to achieve better outcomes.
Prof. Hong Hu
– Head of Breast Surgery, Shenzhen People’s Hospital
– Doctor of Surgery
– Member, Breast Cancer Professional Committee, Chinese Anti-Cancer Association
– Executive Member, Breast Cancer Integrated Rehabilitation Professional Committee, Chinese Anti-Cancer Association
– Member, Youth Group, Breast Cancer Oncology Branch, Chinese Medical Association
– Member, Youth Expert Committee, Chinese Society of Clinical Oncology (CSCO)
– Vice Chairman, Breast Cancer Prevention and Treatment Professional Committee, Guangdong Preventive Medicine Association
– Member, Breast Disease Committee, Guangdong Medical Association
– Executive Member, Individualized Diagnosis and Treatment and MDT Committee, Beijing Cancer Prevention Society
– Vice Chairman, Youth Committee, Breast Disease Branch, Shenzhen Medical Association
– Editorial Board Member, Clinical Breast Cancer
– Visiting Scholar, Lynn Sage Breast Center, Northwestern Memorial Hospital, USA
– Visiting Scholar, Breast Plastic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research
