Editor's Note: Breast cancer is the most common malignancy among women worldwide, with approximately 5% to 10% of patients carrying BRCA gene mutations. These patients often present with more advanced disease, face a higher risk of recurrence, and have poorer prognoses. For patients with germline BRCA-mutated (gBRCA) triple-negative breast cancer (TNBC), platinum-based chemotherapy remains the standard treatment but offers limited survival benefits and comes with significant side effects. Meanwhile, for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer patients, endocrine therapy combined with CDK4/6 inhibitors is the first-line standard treatment. However, the optimal therapy after progression on CDK4/6 inhibitors is still unclear. In this era of precision medicine, there is a pressing need for more effective treatments for gBRCA-mutated HER2-negative breast cancer. At the 2024 Cross-Strait Breast Cancer Forum and the Annual Academic Conference of the Fujian Medical Association Breast Disease Branch, Oncology Frontier invited Dr. Huiping Li from Peking University Cancer Hospital to discuss the latest progress in precision treatment for BRCA-mutated breast cancer.

Oncology Frontier: What are the characteristics of BRCA mutations in Chinese breast cancer patients, and how do these mutations impact patient survival?

Dr. Huiping Li: BRCA mutations are commonly observed in both breast and ovarian cancers. In breast cancer, BRCA mutations are more prevalent in triple-negative breast cancer (TNBC), accounting for about 10% of cases. Additionally, 5% to 6% of hormone receptor-positive (HR+) breast cancer patients also carry BRCA mutations. Therefore, BRCA mutations are not limited to TNBC; a portion of HR+ patients also present with these mutations. Moreover, BRCA mutations are more frequently found in younger women.

BRCA mutations impair the gene’s normal tumor-suppressing function, increasing cancer risk. For healthy individuals with BRCA mutations, the risk of developing breast cancer is significantly higher. However, for breast cancer patients with BRCA mutations, large clinical studies have shown no significant difference in disease-free survival (DFS) compared to patients without the mutation.

Oncology Frontier: With rapid advancements in targeted therapy, what major breakthroughs have been made internationally in treating BRCA-mutated breast cancer?

Dr. Huiping Li: Since BRCA mutations are highly specific genetic alterations, numerous targeted therapies have been developed internationally to address this mutation. Among these, poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as innovative targeted treatments. PARP inhibitors exploit synthetic lethality to target tumors with DNA repair deficiencies, significantly improving the prognosis for breast cancers related to germline BRCA1/2 (gBRCA1/2) mutations. Even with BRCA mutations, PARP inhibitors can induce tumor cell death, making them highly specific therapies for BRCA-mutated cancers.

Several PARP inhibitors, such as olaparib, talazoparib, and niraparib, have been approved internationally for breast cancer treatment. Notably, on December 1, 2024, the domestically developed PARP inhibitor fuzuloparib received approval in China for a new indication: as monotherapy or in combination with apatinib for neoadjuvant, adjuvant, or metastatic treatment in adult HER2-negative breast cancer patients with germline BRCA mutations who have previously undergone chemotherapy. This marks the first domestically approved PARP inhibitor in China. The availability of these drugs has provided significant treatment opportunities for patients with BRCA-mutated breast cancer, and China continues to actively develop multiple PARP inhibitors targeting BRCA mutations.

Oncology Frontier: China’s innovative drug development is progressing rapidly. What specific advancements have been made in treating BRCA-mutated breast cancer?

Dr. Huiping Li: The approval of fuzuloparib for new indications was primarily based on the outstanding results of the FABULOUS study. This nationwide multicenter clinical trial was jointly led by Academician Erwei Song from Sun Yat-sen Memorial Hospital and myself, in collaboration with 59 clinical research centers across China. The study aimed to evaluate the efficacy and safety of fuzuloparib alone and in combination with apatinib in treating HER2-negative breast cancer patients with gBRCA mutations, compared to investigator-chosen chemotherapy regimens.

Early studies showed that fuzuloparib had significant efficacy in BRCA-mutated breast and ovarian cancer patients, while apatinib demonstrated notable tumor-shrinking effects in breast cancer patients with chest wall metastases. This prompted us to explore the potential of combining fuzuloparib with apatinib. The study results revealed that the median progression-free survival (PFS) for the combination therapy reached 11 months, significantly longer than fuzuloparib monotherapy (6.7 months) and chemotherapy (3 months). Compared to the chemotherapy group, the risk of disease recurrence was reduced by 73% in the combination group and by 51% in the monotherapy group.

Although overall survival (OS) data are not yet mature, a survival benefit trend was observed with both fuzuloparib monotherapy and the combination therapy compared to chemotherapy. In terms of safety, the treatments were generally well-tolerated.

The success of the FABULOUS study not only confirmed the significant efficacy of fuzuloparib alone or combined with apatinib in treating BRCA-mutated HER2-negative breast cancer but also provided a valuable reference for future treatment strategies.

Oncology Frontier: How can we enhance early screening and diagnosis for BRCA-mutated breast cancer patients to improve survival outcomes?

Dr. Huiping Li: BRCA mutations are relatively common in younger women. For early-stage breast cancer patients with high-risk features—such as TNBC with high-risk clinical and pathological factors—BRCA testing is recommended. BRCA mutations occur in about 10% of TNBC cases. The OlympiA study has confirmed that olaparib can significantly reduce the risk of recurrence and death in early high-risk, HER2-negative breast cancer patients carrying gBRCA mutations.

For advanced breast cancer patients, BRCA testing is advised upon disease recurrence or metastasis. Genetic testing should not be limited to BRCA but should also include other genes like PIK3CA. Early genetic testing enables personalized treatment planning. With approved drugs now available, patients with detected BRCA mutations can receive fuzuloparib monotherapy or combination therapy with apatinib for better outcomes.

Therefore, after a breast cancer diagnosis, patients with high-risk factors—such as extensive lymph node involvement or large tumors—should undergo BRCA testing. Regardless of the metastasis status, BRCA testing should be performed upon recurrence to promptly determine the treatment strategy. Early use of PARP inhibitors, such as the domestically developed fuzuloparib, offers a valuable treatment opportunity for patients.

Dr. Huiping Li

• Director, Department of Breast Medical Oncology, Peking University Cancer Hospital
• Chief Physician, Professor, Doctoral Supervisor, MD
• Two years of study at MD Anderson Cancer Center, University of Texas, USA
• Chair, Breast Cancer Committee, Chinese Medical Women’s Association
• Vice Chair, Breast Group, Chinese Medical Association
• Executive Member, Breast Cancer Committee, Chinese Anti-Cancer Association
• Vice Chair, Clinical Oncology Committee, Chinese Medical Women’s Association
• Co-Chair and Lead Author, Chinese Consensus Guidelines for Advanced Breast Cancer
• Associate Editor of Breast Cancer Research and Treatment