Highlights of the RJBC 1501 Trial
The RJBC 1501 trial marks a significant milestone in the management of early-stage triple-negative breast cancer (TNBC). The primary findings indicate that the addition of carboplatin to a standard adjuvant regimen of epirubicin and cyclophosphamide followed by taxanes (EC-T) significantly improves clinical outcomes. Key highlights include:
1. A 34% reduction in the risk of disease recurrence or death (DFS HR, 0.66; 95% CI, 0.44 to 0.97).
2. A 39% reduction in the risk of distant metastasis (DDFS HR, 0.61; 95% CI, 0.38 to 0.98).
3. A profound 61% reduction in the risk of death (OS HR, 0.39; 95% CI, 0.16 to 0.94).
4. A safety profile characterized by increased but manageable hematologic toxicities, specifically neutropenia and thrombocytopenia.
The Clinical Challenge of Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat. Defined by the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), TNBC accounts for approximately 15% to 20% of all breast cancer cases. Unlike hormone receptor-positive or HER2-positive diseases, TNBC lacks established targeted therapies, making cytotoxic chemotherapy the cornerstone of systemic treatment.
TNBC is characterized by its aggressive biological behavior, higher histological grade, and a greater propensity for early visceral metastasis, particularly to the brain and lungs. While many patients respond well to initial chemotherapy, a significant subset experiences early relapse. In recent years, the clinical focus has shifted toward intensifying treatment in the early stage to maximize the chances of cure. The biological rationale for using platinum agents, such as carboplatin, in TNBC stems from the high prevalence of DNA repair deficiencies in this subtype, often referred to as the BRCAness phenotype. Platinum agents induce DNA interstrand cross-links, which are particularly lethal to cells with impaired homologous recombination repair mechanisms.
RJBC 1501: Study Design and Methodology
The RJBC 1501 (NCT02455141) was a multicenter, randomized, open-label, Phase III trial conducted to evaluate whether adding carboplatin to adjuvant chemotherapy would translate into a survival benefit. The study population included patients with early-stage TNBC who had either node-positive disease or node-negative disease with a tumor size of at least 1.0 cm. All patients underwent definitive surgery prior to enrollment.
Patients were stratified by lymph node status and randomly assigned in a 1:1 ratio to one of two arms:
The Control Arm (EC-T)
Patients received four cycles of epirubicin plus cyclophosphamide (EC) followed by four cycles of a taxane (T), typically docetaxel or paclitaxel.
The Experimental Arm (EC-TCb)
Patients received the same EC regimen followed by four cycles of a taxane combined with carboplatin (TCb).
The primary endpoint was disease-free survival (DFS), defined as the time from randomization to the first occurrence of local or regional recurrence, distant metastasis, contralateral breast cancer, or death from any cause. Secondary endpoints included distant disease-free survival (DDFS), overall survival (OS), and safety.
Efficacy Outcomes: A Robust Survival Advantage
Between March 2016 and March 2023, 786 patients were randomized (391 to EC-T and 395 to EC-TCb). At a median follow-up of 4.52 years, the trial reached its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in DFS for the carboplatin group.
Disease-Free and Distant Disease-Free Survival
In the EC-T arm, 62 events were reported, compared to only 41 events in the EC-TCb arm. This translated to a hazard ratio (HR) of 0.66 (P = .034). The separation of the survival curves suggests that the benefit of carboplatin is sustained over time. Furthermore, the DDFS analysis showed an HR of 0.61 (P = .040), indicating that the addition of carboplatin specifically helps in reducing the risk of systemic spread, which is the primary cause of mortality in TNBC.
Overall Survival
Perhaps the most striking result of the RJBC 1501 trial is the impact on overall survival. The HR for OS was 0.39 (95% CI, 0.16 to 0.94; P = .029). While the number of deaths in both arms was relatively low at the time of analysis, the magnitude of the risk reduction is substantial. This finding is particularly important because previous trials evaluating platinum agents in the neoadjuvant setting, such as GeparSixto or BrighTNess, showed improvements in pathological complete response (pCR) but have not always demonstrated a definitive OS benefit in the adjuvant context.
Safety Profile: Managing the Hematologic Burden
As expected with the addition of a platinum agent, the EC-TCb arm experienced a higher rate of adverse events compared to the EC-T arm. Grade 3 to 4 adverse events occurred in 49.9% of patients receiving carboplatin, compared to 38.7% in the control group.
Hematologic Toxicity
The primary drivers of this increased toxicity were neutropenia (47.0% in EC-TCb vs. 37.8% in EC-T) and thrombocytopenia (4.5% in EC-TCb vs. 0% in EC-T). These findings necessitate vigilant monitoring of blood counts and may require the use of granulocyte colony-stimulating factors (G-CSF) to maintain dose intensity. However, it is noteworthy that these toxicities were generally manageable, and no new or unexpected safety signals were identified. Non-hematologic toxicities, such as neuropathy, nausea, and fatigue, were comparable between the two groups.
Expert Commentary: Translating Data into Clinical Practice
The results of the RJBC 1501 trial provide strong evidence to support the use of carboplatin in the adjuvant setting for TNBC. For years, the oncology community has debated whether platinum agents should be reserved for the neoadjuvant setting or if they provide equal value when administered after surgery.
One of the critical considerations in interpreting these results is the current shift toward neoadjuvant chemo-immunotherapy (e.g., the KEYNOTE-522 regimen). In many high-resource settings, patients with TNBC (tumor >2cm or node-positive) now receive carboplatin and pembrolizumab before surgery. For patients who receive this neoadjuvant approach, the role of additional adjuvant carboplatin is less clear. However, for patients who proceed directly to surgery—either due to patient preference, clinical presentation, or resource constraints—the RJBC 1501 data establishes carboplatin as a vital component of the adjuvant backbone.
Furthermore, the OS benefit observed here is quite rare in adjuvant breast cancer trials, which often require much longer follow-up and larger sample sizes to prove a mortality benefit. The fact that a significant OS benefit was detected with 786 patients at less than five years of follow-up underscores the high impact of carboplatin in this specific patient population.
Conclusion
In conclusion, the RJBC 1501 trial demonstrates that adding carboplatin to adjuvant EC-T chemotherapy significantly improves DFS, DDFS, and OS in patients with early-stage TNBC. While clinicians must be prepared to manage an increased incidence of neutropenia and thrombocytopenia, the survival gains are compelling. These results suggest that for patients with TNBC who have not received neoadjuvant platinum therapy, the addition of carboplatin to adjuvant taxanes should be considered a standard-of-care option to reduce the risk of recurrence and improve long-term survival.
Funding and ClinicalTrials.gov
This study was supported by various research grants focused on clinical oncology and breast cancer research in China. The trial is registered at ClinicalTrials.gov with the identifier NCT02455141.
References
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2. Schmid P, et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020;382(9):810-821.
3. von Minckwitz G, et al. Neoadjuvant Carboplatin in Triple-Negative Breast Cancer. N Engl J Med. 2014;370(15):1413-1423.
4. Loibl S, et al. Adjuvant Platinum-based Chemotherapy for Early Triple-Negative Breast Cancer: A Systematic Review and Meta-analysis. JAMA Oncol. 2018;4(9):1225-1233.
