Breast cancer has become one of the most common malignancies among women, with triple-negative breast cancer (TNBC) being considered the most aggressive subtype due to its historically poor prognosis. Looking back at 2024, significant research breakthroughs have emerged in both early-stage and advanced TNBC treatment, covering chemotherapy, targeted therapy, immunotherapy, and antibody-drug conjugates (ADCs). Many of these studies have been led by Chinese researchers, contributing to original findings in the field. In this annual review, Dr. Qiang Liu from Sun Yat-sen Memorial Hospital, Sun Yat-sen University shares the key advancements in systemic therapy for TNBC, showcasing how precision medicine is gradually transforming TNBC treatment and offering patients a brighter future.

Early-Stage TNBC Treatment: Immunotherapy Takes Center Stage

The most remarkable development in early-stage TNBC treatment has been the growing body of evidence supporting immunotherapy, positioning it at the forefront of treatment strategies. The KEYNOTE-522 trial has further reinforced the survival benefits of immunotherapy in this setting.

Chemotherapy

Taxane and anthracycline-based chemotherapy remains the standard neoadjuvant regimen for TNBC, with the addition of platinum agents improving pathologic complete response (pCR) rates. However, it remains uncertain whether this translates into an event-free survival (EFS) benefit. The BR 15-1 PEARLY study, presented at ASCO 2024, evaluated a carboplatin + anthracycline + cyclophosphamide followed by taxane regimen (carboplatin group) compared to the standard anthracycline + cyclophosphamide followed by taxane regimen (control group). Results showed that the carboplatin group had a 32% reduction in EFS events (HR 0.68; 95% CI: 0.50–0.93; P=0.017) and a 7.5% increase in five-year EFS (74.4% vs. 81.9%). This study provided further evidence supporting the inclusion of platinum agents in neoadjuvant chemotherapy for TNBC.

Targeted Therapy

The GeparOLA and OlympiA trials have already demonstrated the benefits of PARP inhibitors (PARPi) in gBRCA-mutated HER2-negative early-stage breast cancer. However, a Phase II/III trial PARTNER, published in Nature in April 2024, explored the use of carboplatin + paclitaxel with or without olaparib as neoadjuvant therapy in gBRCA wild-type TNBC patients, followed by three cycles of anthracycline-based chemotherapy. The results showed no significant differences in pCR (51.1% vs. 52.4%; P=0.753), three-year EFS (80.2% vs. 79.1%; P>0.9), or overall survival (OS) (90% vs. 87.2%; P=0.7) between the two groups. These findings indicate that biomarker status, such as gBRCA mutations, remains crucial when considering early-stage treatment with PARPi.

Immunotherapy

Immune checkpoint inhibitors (ICIs) have transformed early-stage TNBC treatment, marking a significant shift from chemotherapy alone. The Phase III KEYNOTE-522 trial enrolled previously untreated stage II or III TNBC patients, who received neoadjuvant pembrolizumab plus chemotherapy (carboplatin + taxane followed by anthracycline/cyclophosphamide), followed by adjuvant pembrolizumab. The control group received neoadjuvant chemotherapy alone.

Findings published in NEJM in 2022 had already shown significant benefits in pCR (64.8% vs. 51.2%; P<0.001) and three-year EFS (84.5% vs. 76.8%; HR 0.63; 95% CI: 0.48–0.82; P<0.001) favoring the pembrolizumab group. At ESMO 2024, updated data demonstrated a nearly 5% improvement in five-year OS (86.6% vs. 81.7%), with a 34% reduction in the risk of death (HR 0.66; 95% CI: 0.50–0.87; P=0.002). These results confirm that the KEYNOTE-522 neoadjuvant and adjuvant immunotherapy regimen significantly improves survival outcomes in stage II/III TNBC patients.

However, results from the NSABP B-59/GBG-96-GeparDouze trial, presented at SABCS 2024, indicated that adding a PD-L1 inhibitor did not improve survival in TNBC patients, suggesting that the choice of immunotherapy agent may influence efficacy.

A notable study from China, CamRelief, was reported at SABCS 2024 and simultaneously published in JAMA. Led by Professor Zhiming Shao from Fudan University Shanghai Cancer Center, this national, multicenter Phase III trial focused on high-risk early-stage and locally advanced TNBC patients. The study compared neoadjuvant camrelizumab plus chemotherapy (paclitaxel + carboplatin followed by EC chemotherapy) versus chemotherapy alone, followed by adjuvant camrelizumab or standard therapy. The pCR rate was significantly higher in the camrelizumab group than in the chemotherapy-alone group (56.8% vs. 44.7%; P=0.004). Notably, pCR rates were not influenced by PD-L1 expression, lymph node status, or disease stage. This study provides strong clinical evidence supporting the use of a Chinese-developed immunotherapy regimen in TNBC neoadjuvant treatment.

Challenges in Adjuvant Immunotherapy

Despite success in neoadjuvant settings, most trials on intensified adjuvant immunotherapy have failed to show clear benefits. The A-BRAVE trial, presented at ASCO 2024, investigated adjuvant avelumab in early-stage TNBC patients with residual disease after neoadjuvant chemotherapy or high recurrence risk following surgery and adjuvant chemotherapy. Patients were randomized to receive avelumab or observation.

The results showed no significant difference in three-year DFS between the overall population (68.3% vs. 63.2%; HR 0.81; 95% CI: 0.61–1.09; P=0.172) or the non-pCR subgroup (66.9% vs. 60.7%; HR 0.80; 95% CI: 0.58–1.10; P=0.170). However, avelumab significantly improved three-year OS by 8.5% (84.8% vs. 76.3%; HR 0.66; 95% CI: 0.45–0.97; P=0.035).

Subgroup analyses suggested greater survival benefits in patients with PD-L1 expression ≤21%, TILs <10%, or a high residual tumor burden. These findings highlight the importance of patient selection in adjuvant immunotherapy, as not all TNBC patients may benefit equally.

Conclusion

The landscape of early-stage TNBC treatment has evolved significantly, with immunotherapy now playing a central role. The KEYNOTE-522 trial has established pembrolizumab-based neoadjuvant and adjuvant therapy as the new standard of care, providing robust survival benefits. Meanwhile, China’s CamRelief trial has validated a domestically developed immunotherapy regimen, offering an alternative approach.

While PARP inhibitors remain effective in gBRCA-mutated TNBC, their benefit in gBRCA wild-type patients remains uncertain, as demonstrated by the PARTNER trial. The A-BRAVE trial has shown that adjuvant avelumab may provide survival benefits for specific subgroups, highlighting the need for better patient stratification.

As precision medicine advances, TNBC treatment is becoming increasingly individualized, offering hope for better long-term outcomes.

Outstanding Questions in Neoadjuvant Immunotherapy for Breast Cancer

Despite the progress made in neoadjuvant immunotherapy for triple-negative breast cancer (TNBC), many unanswered questions remain. The 2024 CSCO BC Consensus on Clinical Applications of Immunotherapy in Breast Cancer addressed key topics such as patient selection, treatment duration, chemotherapy partners, and predictive biomarkers. As more evidence emerges from clinical trials, these uncertainties will become clearer, providing more refined treatment strategies for early-stage TNBC.

De-Escalation Therapy: Redefining Treatment Approaches

In April and June 2024, JAMA and JAMA Oncology published two pivotal studies exploring chemotherapy-free treatment approaches for early-stage TNBC. The results suggested that for some stage I-II TNBC patients, a treatment strategy that omitted chemotherapy still achieved five-year recurrence-free survival (RFS) rates of 70–80%, particularly in patients with high tumor-infiltrating lymphocytes (TILs). This finding raises the possibility that surgery and radiation alone may be sufficient for a subset of early-stage TNBC patients. However, identifying the right candidates for de-escalation therapy remains a critical clinical challenge.

A soon-to-be-published study on circulating tumor DNA (ctDNA) in early-stage TNBC further supports this concept. The study found that 21.7% of early-stage TNBC patients (including some stage IIIc cases) had undetectable ctDNA throughout treatment, and none of these patients experienced recurrence or metastasis during follow-up. These findings suggest that ctDNA provides a more accurate measure of systemic tumor burden and metastatic risk than traditional TNM staging. Based on these insights, researchers are now designing clinical trials to explore de-escalation strategies that omit or reduce chemotherapy based on ctDNA status, aiming to minimize unnecessary systemic treatment while maintaining excellent long-term outcomes.

Advanced TNBC Treatment: Expanding Innovative Strategies

The standard first-line treatment for PD-L1-positive metastatic TNBC remains immunotherapy combined with chemotherapy. However, 2024 research breakthroughs have introduced new immunotherapy agents, novel chemotherapy regimens, and promising ADC-based therapies, broadening the range of available treatment options.

Immunotherapy Plus Chemotherapy

The KEYNOTE-355 trial established chemo-immunotherapy as the first-line standard for metastatic TNBC. The TORCHLIGHT trial, led by Professor Zefei Jiang from the Oncology Department of the Chinese PLA General Hospital, provided a new first-line treatment option for Chinese TNBC patients.

The study demonstrated that combining toripalimab with albumin-bound paclitaxel significantly prolonged PFS in PD-L1-positive patients (8.4 vs. 5.6 months; HR 0.65; 95% CI: 0.470–0.906; P=0.0102) and reduced the risk of death by 38% (median OS: 32.8 vs. 19.5 months; HR 0.62; 95% CI: 0.414–0.914; P=0.0148). Even in the intent-to-treat (ITT) population, the survival benefit was consistent. The TORCHLIGHT trial results were published in Nature Medicine in January 2024, marking a significant milestone in the treatment of advanced TNBC in China.

Another groundbreaking Chinese-led immunotherapy study, conducted by Academician Binghe Xu and Professor Fei Ma from the Chinese Academy of Medical Sciences Cancer Hospital, explored metronomic chemotherapy plus immunotherapy in a Bayesian adaptive Phase II trial.

This trial randomized patients into five treatment groups:

1. Vinorelbine metronomic chemotherapy (NVB group)
2. Vinorelbine + PD-1 inhibitor (anti-PD1+NVB group)
3. Vinorelbine + cisplatin + PD-1 inhibitor (DDP group)
4. Vinorelbine + bevacizumab + PD-1 inhibitor (BEV group)
5. Vinorelbine + capecitabine + cyclophosphamide + PD-1 inhibitor (VEX group)

Results showed that the VEX (69.7%) and DDP (73.7%) groups had the highest disease control rates (DCR). The VEX group also had the longest median PFS (6.6 months), with subgroup analysis indicating a PFS of up to 9.8 months in TNBC patients. Exploratory analysis of immune cell subsets in peripheral blood suggested that systemic immune status plays a critical role in predicting response to metronomic chemo-immunotherapy. These clinical and translational findings validate VEX as a promising treatment option for advanced TNBC.

At ESMO 2024, the TRIPLE-B trial, a Phase IIb factorial study, investigated the use of chemotherapy based on homologous recombination repair deficiency (HRD) status, combined with atezolizumab. The study found that HRD status was not predictive of chemotherapy response (interaction P=0.1553). Median PFS across different treatment arms was as follows:

• Taxane + atezolizumab: 6.5 months
• Carboplatin + cyclophosphamide + atezolizumab: 5.4 months
• Carboplatin + cyclophosphamide: 5.3 months
• Taxane alone: 4.4 months

ADC and Targeted Therapy: Chinese Innovations in TNBC Treatment

China has made significant progress in antibody-drug conjugates (ADCs) and targeted therapy for TNBC.

At ASCO 2024, Academician Binghe Xu presented results from the Phase III OptiTROP-Breast01 trial, evaluating Trop2 ADC SKB264 (Lucensatuzumab govitecan) in patients with previously treated locally recurrent or metastatic TNBC. The study demonstrated that SKB264 significantly prolonged PFS (6.7 vs. 2.5 months; HR 0.32; 95% CI: 0.22–0.44; P<0.00001) compared to chemotherapy. Although OS data were still immature, there was already a clear survival benefit trend (HR 0.53; 95% CI: 0.36–0.78; P=0.0005).

At ESMO 2024, a Phase III study led by Academician Erwei Song from Sun Yat-sen Memorial Hospital and Professor Huiping Li from Peking University Cancer Hospital explored fluorozaparib (a novel PARP inhibitor) with or without apatinib (VEGFR inhibitor) in gBRCA-mutated HER2-negative advanced breast cancer. The combination therapy significantly improved PFS compared to chemotherapy (11.0 vs. 3.0 months; HR 0.27; 95% CI: 0.17–0.43; P<0.0001), with fluorozaparib monotherapy also showing a PFS benefit (6.7 vs. 3.0 months; HR 0.49; 95% CI: 0.32–0.75; P=0.0004). OS showed a positive trend, with HRs of 0.58 and 0.61 for combination and monotherapy, respectively. These findings indicate that new ADC and targeted therapies may soon reshape TNBC treatment.

Breaking Away from Traditional Subtypes: Toward Personalized Therapy in TNBC

Traditionally, breast cancer has been classified into HR+, HER2+, and TNBC subtypes, with TNBC historically considered a highly heterogeneous “wastebasket” category lacking actionable molecular targets. However, advances in molecular subtyping are enabling more precise, personalized treatments for TNBC.

In 2019, Professor Zhiming Shao proposed the Fudan Subtyping System (FUSCC) for TNBC, dividing it into four subtypes:

1. LAR (luminal androgen receptor subtype)
2. IM (immune-modulatory subtype)
3. BLIS (basal-like immune-suppressed subtype)
4. MES (mesenchymal subtype)

The FUTURE and FUTURE-C-Plus trials provided initial clinical validation, while the FUTURE-SUPER trial, published in Lancet Oncology 2024, was the first randomized umbrella trial assessing subtype-specific precision therapies. Compared to standard chemotherapy (albumin-bound paclitaxel), FUSCC-guided treatment significantly prolonged PFS (11.3 vs. 5.8 months; HR 0.44; 95% CI: 0.30–0.65; P<0.0001). These findings pave the way for clinical adoption of TNBC molecular subtyping, bringing personalized medicine closer to routine practice.