Editor’s Note: The 47th San Antonio Breast Cancer Symposium (SABCS), held from December 10–13, 2024, in San Antonio, USA, showcased the latest research, clinical practices, and technological innovations in breast cancer. In this special installment of the “Highlights Series,” hosted by Prof. Yongmei Yin of Jiangsu Provincial People’s Hospital, Prof. Qiang Liu from the Sun Yat-sen Memorial Hospital joins us live from SABCS to present significant immunotherapy findings unveiled on the final day of the conference (December 13). These include updates on the ZEST, CamRelief, NSABP B-59/GBG-96-GeparDouze, A-BRAVE, and BreastImmune-03 studies for triple-negative breast cancer (TNBC), as well as insights into HER2-positive breast cancer from the NRG-BR004 and neoHIP trials.

01 ZEST Study: Exploring and Reflecting on Niraparib for MRD-Directed Therapy in Breast Cancer

Prof. Qiang Liu: The first study I’d like to discuss is the ZEST trial (Abstract GS3-01). ZEST (NCT04915755) is the first Phase III randomized, double-blind clinical trial targeting minimal residual disease (MRD) in breast cancer. It aimed to evaluate whether intensified therapy with niraparib could improve disease-free survival (DFS) in patients with circulating tumor DNA (ctDNA)-positive status but no radiographic recurrence after completing primary treatment. Unfortunately, the ZEST trial failed to meet its primary endpoint and was terminated early.

Eligible participants were patients with Stage I–III TNBC or BRCA-mutated HER2-negative breast cancer. Despite screening 2,746 patients and monitoring ctDNA in 1,901, only 8% (147 patients) were ctDNA-positive. Alarmingly, half of these ctDNA-positive patients (73 cases) had already developed radiographic metastases at the time of ctDNA detection and were excluded from randomization. Ultimately, only 40 patients were randomized.

In this cohort, 18 patients received niraparib, and 22 received a placebo. Of these, 90% had TNBC, while the remaining 10% had BRCA-mutated HR-positive breast cancer. At data cutoff, 6 patients in the niraparib arm and 4 in the placebo arm were still undergoing treatment without radiographic recurrence. Median DFS was 11.4 months (95% CI: 5.7–18.2) in the niraparib group compared to 5.4 months (95% CI: 2.8–9.3) in the placebo group, with an HR of 0.64 (95% CI: 0.30–1.39).

Key Reasons for Failure:

1. Late Timing of ctDNA Monitoring: Although the study utilized Natera’s personalized gene panel for frequent monitoring every 2–3 months, the initial ctDNA assessment occurred within six months post-treatment. This timing may have been too late, as over half of the ctDNA-positive patients already exhibited radiographic metastases at the first detection.
2. Low-Risk Patient Inclusion: Among enrolled patients, 25.6% had Stage I disease, 40.9% had Stage II, and 30.7% had Stage III. Additionally, more than 60% were lymph node-negative. These characteristics made it difficult to identify high-risk, ctDNA-positive patients, with only 2.3% of Stage I patients being ctDNA-positive.
3. Mismatch of Therapy and Tumor Genomics: The trial focused on somatic BRCA mutations rather than germline BRCA mutations. While somatic mutations may respond to PARP inhibitors, their distribution and proportion in tumor cells were not clearly delineated. If the mutation was not a clonal driver, niraparib’s efficacy could be limited.

Although the ZEST trial did not succeed, it offers critical lessons. Future ctDNA research must refine monitoring schedules, focus on high-risk cohorts, and target actionable genomic alterations. As the Chinese proverb goes, “Failure is the mother of success.” We hope that insights from ZEST will guide the development of MRD-directed trials that can truly transform clinical practice.

02 CamRelief Study: Camrelizumab Plus Chemotherapy Significantly Boosts pCR Rates in TNBC

In this session, two key studies on immunotherapy were presented. One of them, the CamRelief study (Abstract GS3-06), was introduced by Prof. Zhiming Shao from Fudan University Shanghai Cancer Center. This randomized, double-blind Phase III clinical trial (NCT04613674) aimed to assess the efficacy and safety of camrelizumab combined with chemotherapy in patients with early-stage or locally advanced triple-negative breast cancer (TNBC). The study successfully demonstrated the significant efficacy of camrelizumab, a domestically developed PD-1 inhibitor, in combination with a four-drug chemotherapy regimen as neoadjuvant therapy.

A total of 441 patients were randomized and treated (camrelizumab arm: n=222; placebo arm: n=219). With a median follow-up of 14.4 months, the results showed that the pathological complete response (pCR) rate in the camrelizumab plus chemotherapy group was 56.8% (95% CI: 50.0–63.4), compared to 44.7% (95% CI: 38.0–51.6) in the placebo plus chemotherapy group. The difference in pCR rates was 12.2% (95% CI: 3.3–21.2; one-sided P=0.0038). The benefits of pCR were observed across all subgroups, regardless of PD-L1 expression, lymph node status, or baseline disease stage.

The CamRelief study demonstrated that adding camrelizumab to platinum-based intensified neoadjuvant chemotherapy significantly improves pCR rates in early or locally advanced TNBC, with manageable safety profiles. While long-term survival data require further follow-up, the results provide new treatment options and hope for TNBC patients. Notably, these findings were simultaneously published in JAMA.

03 NSABP B-59/GBG-96-GeparDouze Study: Atezolizumab Falls Short of Expectations in TNBC Treatment

Before Prof. Zhiming Shao’s presentation, Prof. Charles Geyer from the United States presented the findings of the NSABP B-59/GBG-96-GeparDouze study (Abstract GS3-05). This trial evaluated the addition of atezolizumab to a neoadjuvant chemotherapy (NAC) regimen comprising sequential paclitaxel and carboplatin followed by AC or EC, with atezolizumab also used as adjuvant therapy for one year in patients with Stage II/III TNBC. The primary endpoint was event-free survival (EFS), with secondary endpoints including pCR, overall survival (OS), and safety.

Despite enrolling 1,550 patients who were randomized 1:1 into atezolizumab and placebo groups, the final results were unexpectedly negative. The four-year EFS rates were 81.9% in the atezolizumab arm and 85.2% in the placebo arm (HR=0.8; 95% CI: 0.62–1.03; Log-rank P=0.08).

Potential Reasons for Failure:

1. Mechanistic Differences Between PD-L1 and PD-1 Antibodies: PD-L1 inhibitors like atezolizumab and PD-1 inhibitors differ in their mechanisms of action, potentially leading to varying efficacy in breast cancer treatment. Evidence from several studies suggests that PD-1 inhibitors may outperform PD-L1 inhibitors in TNBC.
2. Patient Population Characteristics: A significant proportion of patients in the GeparDouze study were PD-L1-negative, in contrast to the KEYNOTE-522 study, where most participants were PD-L1-positive. This discrepancy may have influenced the outcomes.

Interestingly, subgroup analyses in the GeparDouze study showed significant benefits for patients with lymph node positivity and Stage III disease. However, these findings from subgroup analyses cannot overturn the overall negative conclusion.

04 A-BRAVE Study: Biomarker Analysis for Enhanced Efficacy

The A-BRAVE study is a pivotal Phase III, multicenter, randomized clinical trial evaluating one year of avelumab adjuvant intensification therapy versus observation in early-stage, high-risk triple-negative breast cancer (TNBC) patients. Last year, the overall findings of the study were published, showing that avelumab improved overall survival (OS) and distant disease-free survival (DDFS) but did not significantly extend disease-free survival (DFS). This year, the focus was on biomarker analysis from the study (Abstract RF3-02).

In the A-BRAVE trial, patients were categorized into two subgroups: Group A comprised high-risk patients who underwent surgery followed by adjuvant chemotherapy (17.8%), while Group B included patients who had residual disease after neoadjuvant chemotherapy (non-pCR), accounting for 82% of the cohort. The biomarker analysis revealed significant associations between PD-L1 expression levels and the benefits derived from avelumab. Specifically, for every 1% increase in PD-L1 expression, improvements in DFS, DDFS, and OS were observed. However, among patients with PD-L1 expression greater than 21% (15% of the total cohort), avelumab did not show substantial benefits. In contrast, patients with PD-L1 levels ≤21% experienced more pronounced benefits from avelumab adjuvant therapy.

Additionally, for Group B (non-pCR patients post-neoadjuvant chemotherapy), residual cancer burden (RCB) was identified as a critical factor influencing avelumab efficacy. RCB grade strongly correlated with three-year DFS, with higher RCB grades predicting poorer prognosis. Notably, avelumab provided greater benefits to patients with higher RCB grades.

Another significant biomarker was tumor-infiltrating lymphocytes (TILs). In specimens from post-neoadjuvant chemotherapy patients, TIL proportions below 10% were associated with more significant benefits from avelumab, albeit with a worse overall prognosis. Conversely, patients with TILs ≥10% had better three-year DFS outcomes but derived less benefit from avelumab. This suggests that TILs levels may also serve as a predictive marker for avelumab efficacy.

In summary, the biomarker analysis from the A-BRAVE study provides valuable insights into which TNBC patients are more likely to benefit from avelumab as adjuvant intensification therapy. These findings are instrumental in guiding clinical decisions and optimizing treatment strategies.

05 BreastImmune-03 Study: NIVO+IPI Combination Shows No Advantage

For TNBC patients with residual disease (non-pCR) following neoadjuvant chemotherapy, the BreastImmune-03 study evaluated the efficacy of post-surgical immunotherapy. This study compared nivolumab plus ipilimumab (NIVO+IPI) with eight cycles of capecitabine in patients with RCB II or III disease. Between July 2019 and October 2021, 95 patients from 17 centers in France were enrolled and randomized into two groups: 50 patients in the capecitabine group and 45 in the NIVO+IPI group (median age: 47 years [range 29–82], ECOG PS 0: 80%, RCB III: 40%). Unfortunately, the trial was prematurely terminated due to treatment-related adverse events.

The six-month postoperative NIVO+IPI combination therapy did not demonstrate improved clinical outcomes for patients with RCB II–III TNBC compared to capecitabine. This lack of advantage underscores the need for alternative therapeutic approaches in this high-risk population.

The findings of BreastImmune-03 provide valuable lessons for future studies and highlight the challenges of identifying effective post-neoadjuvant therapies for TNBC patients with residual disease.

06 Targeted and Immunotherapy for HER2-Positive Breast Cancer: Uncertain Results

The NRG-BR004 study is a clinical trial targeting first-line treatment for HER2-positive advanced breast cancer patients. Currently, the taxane-based dual-targeted therapy with trastuzumab and pertuzumab (THP regimen) is the standard treatment, playing a crucial role in managing HER2-positive advanced breast cancer. However, the NRG-BR004 study sought to further explore the potential of immunotherapy, particularly whether the addition of atezolizumab could provide additional benefits to patients.

Unfortunately, the results of the NRG-BR004 study did not meet expectations. The study aimed to compare the efficacy difference between the THP regimen combined with atezolizumab and a placebo group, with progression-free survival (PFS) as the primary endpoint. Although patient characteristics in the trial were well-balanced, the study terminated enrollment prematurely in May 2022 due to higher mortality in the atezolizumab group. Final results showed that the PFS in the atezolizumab-THP group did not significantly surpass the placebo-THP group. Specifically, the two-year PFS was 54.0% for the atezolizumab-THP group versus 45.6% for the placebo-THP group (HR 0.73, 95% CI: 0.49–1.09, P=0.12). These results did not achieve statistical significance.

Additionally, the study also evaluated overall survival (OS) and overall response rate (ORR), but no significant advantages were found in the atezolizumab group. For OS, the three-year survival rate was 86.4% in the atezolizumab-THP group and 81.7% in the placebo-THP group (HR 0.8, 95% CI: 0.39–1.63, P=0.53), which also did not reach statistical significance.

The neoHIP Study

The neoHIP study is a multicenter, Phase II, open-label clinical trial targeting early-stage HER2-positive breast cancer. It explored the efficacy and safety of neoadjuvant therapies, comparing three groups: (A) THP, (B) THP plus pembrolizumab, and (C) TH plus pembrolizumab. The study enrolled patients aged ≥18 years with untreated Stage II-III HER2-positive breast cancer, stratified randomly based on clinical lymph node status (positive or negative) and hormone receptor status (positive or negative). The primary endpoint was pathological complete response (pCR; ypT0/Tis ypN0), with secondary endpoints including pCR rates defined by ypT0ypN0 and ypT0/Tis, residual cancer burden (RCB), event-free survival (EFS), and safety.

Between January 4, 2019, and March 25, 2024, the study enrolled 138 untreated Stage II-III HER2-positive breast cancer patients: 58 in Group A, 58 in Group B, and 22 in Group C (Group C enrollment was discontinued after a pre-specified interim efficacy analysis). Results showed that the pCR rate was 48.3% in Group A and 67.2% in Group B. These findings indicate that dual-targeted therapy combined with immunotherapy significantly improves efficacy. This underscores that, in just 12 weeks of targeted therapy and chemotherapy, adding immunotherapy can significantly enhance treatment outcomes for these patients.

The neoHIP study provides new directions and insights into the treatment of early-stage HER2-positive breast cancer and lays a solid foundation for future research. Based on the findings from the neoHIP study, more studies combining dual-targeted therapy with immunotherapy, particularly PD-1 inhibitors, may emerge in the future. Moreover, the study highlights the critical role of dual-targeted therapy in neoadjuvant treatment, demonstrating its indispensability even when combined with immunotherapy.

Professor Liu Qiang: That concludes my presentation today.

Professor Yin Yongmei: Thank you, Professor Liu Qiang, for your excellent presentation, providing us with the key research findings on the final day of the SABCS conference regarding advancements in immunotherapy. From Professor Liu’s insights, we saw the ZEST study demonstrate the potential of ctDNA in monitoring treatment responses and recurrence risks in breast cancer patients. The research reported by Professor Shao Zhiming revealed that adding camrelizumab to neoadjuvant chemotherapy significantly improved pCR rates in high-risk early or locally advanced triple-negative breast cancer.

Through an in-depth analysis of the A-BRAVE study, we observed the efficacy of avelumab as adjuvant therapy for high-risk triple-negative breast cancer. However, the negative results from atezolizumab-related studies, such as NSABP B-59/GBG-96-GeparDouze and NRG-BR004, have prompted deeper reflections on immunotherapy. These studies have not only enriched our understanding of breast cancer treatment but also provided valuable guidance and inspiration for future clinical practice in immunotherapy.

Once again, thank you to Professor Liu Qiang for the wonderful presentation and to all the experts and scholars who participated in and supported “Outlook Broadcast.” Let us look forward to the next brilliant chapter in the field of breast cancer research. See you at the next SABCS conference!

Professor  Yongmei Yin

• Vice President, Jiangsu Province People’s Hospital
• Professor, Chief Physician, Doctoral Supervisor
• Vice President, Chinese Society of Clinical Oncology (CSCO)
• Secretary General, CSCO Breast Cancer Expert Committee
• Chairperson, CSCO Patient Education Expert Committee
• Deputy Director, CSCO Smart Medicine Professional Committee
• Standing Member, Breast Cancer Specialty Committee, China Anti-Cancer Association (CBCS)

Professor Qiang Liu

• Professor, Chief Physician, Researcher, Doctoral Supervisor
• Director of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University
• Executive Vice President of Yixian Breast Tumor Hospital, Director of the Breast Tumor Center, and Chief of Breast Surgery
• Member of ESO-ESMO International Consensus Panel on Young Breast Cancer
• Standing Member and Deputy Secretary General, CSCO Breast Cancer Expert Committee
• Standing Member, Breast Cancer Specialty Committee, China Anti-Cancer Association
• Standing Member, Tumor Molecular Medicine Specialty Committee, China Anti-Cancer Association
• Chairperson, Guangdong Medical Association Breast Disease Branch
• Deputy Editor-in-Chief, Chinese Journal of General Surgery; Associate Editor-in-Chief, Chinese Journal of Endocrine Surgery
• PhD in Surgery, National University of Singapore; former lecturer at Harvard University’s Dana-Farber Cancer Institute
• Principal investigator of multiple national-level major projects, including National Natural Science Foundation key projects and international collaboration initiatives
• Pioneered the application of liquid biopsy and immune combination therapy for breast cancer in China and initiated and developed the country’s first expert consensus on the diagnosis and treatment of young breast cancer
• Honored with the title of “Outstanding Exemplary Physician of the Nation” by People’s Daily in 2020
• Specializes in the diagnosis, surgery, and comprehensive treatment of breast cancer, with expertise in challenging breast-conserving surgeries, individualized precision treatment for young breast cancer patients, and triple-negative breast cancer.