SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. The American Cancer Society estimates that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.
Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival (OS) of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers.
Neoadjuvant chemotherapy is the preferred treatment approach in this group of patients and can potentially increase the likelihood of tumor resectability and breast conservation. Further, a pathological Complete Response (pCR) after neoadjuvant chemotherapy can result in a longer Event-Free Survival and Overall Survival. Pathological Complete Response is therefore used as an end point for clinical testing of neoadjuvant treatment in patients with early TNBC.
Conventionally, TNBC has been treated with cytotoxic chemotherapy regimens incorporating anthracyclines and taxanes, which remain foundational despite ongoing exploration of novel agents. The role of immune checkpoint inhibitors such as Pembrolizumab (KEYTRUDA®) has expanded into neoadjuvant settings, in addition to its consistent Progression Free Survival (PFS) and Overall Survival (OS) benefits in advanced TNBC. Recent studies have investigated the addition of platinum agents due to their ability to induce DNA damage and apoptosis in tumors with defective DNA repair mechanisms, such as those seen in BRCA-mutated breast cancer. Triple-Negative Breast Cancers that do not harbor BRCA1/2 mutations show defects in the DNA repair mechanism, similar to BRCA1/2 mutant TNBC, and are called BRCAness. Platinum agents have shown promise in increasing the pCR rate when combined with standard taxane and anthracycline regimens in neoadjuvant settings, potentially enhancing outcomes for patients who otherwise face high recurrence risks. The importance of achieving pCR has been underscored by studies like the CTNeoBC pooled analysis, which demonstrated significantly improved survival outcomes in TNBC patients who achieved pCR, compared to those with residual disease. This has prompted the exploration of combination therapies aimed at maximizing response rates and minimizing residual disease burden.
PEARLY is a randomized, multicenter, open-label, Phase III trial in which anthracyclines followed by taxane was compared with anthracyclines followed by taxane plus Carboplatin as (neo)adjuvant therapy in patients with TNBC. Patients with Stage II or III TNBC who need adjuvant or neoadjuvant chemotherapy were included. Any prior systemic therapy for breast cancer was not allowed. In this study, 868 patients (N=868) were randomized 1:1 to either standard arm treatment, which consisted of Doxorubicin 60 mg/m2 IV along with Cyclophosphamide 600 mg/m2 IV every 3 weeks for 4 cycles followed by taxane treatment (Paclitaxel 80 mg/m2 IV weekly for 12 doses or Docetaxel 75mg/m2 IV every 3 weeks for 4 cycles), or experimental group in which Carboplatin AUC5 IV every 3 weeks for 4 cycles was added during taxane treatment. Patients were stratified based on the nodal status (N0 versus N+), treatment setting (neoadjuvant versus adjuvant), and BRCA mutation status (positive versus negative). Patients with bilateral, metastatic, and inflammatory breast cancer were excluded. The Primary objective was to evaluate 5-year Event Free Survival (EFS) rate in the enrolled patients. Secondary objectives included Overall Survival (OS), Distant Recurrence-Free Survival (DRFS), pathologic Complete Response (pCR), and tolerability.
At a median follow up of 51.1 months, Carboplatin significantly improved the 5-year EFS compared to the control arm (HR 0.68; P=0.017). The 5-year EFS rates were increased from 74.4% to 81.9% with the addition of Carboplatin, demonstrating a 7.5% absolute difference in EFS rates. Subgroup analysis showed consistent benefits across various patient subgroups. Secondary endpoints such as OS and DRFS showed favorable trends in the Carboplatin group, although OS data were not mature at the time of reporting. Grade 3 or more treatment-related Adverse Event rates were 74.6% in the Carboplatin group and 56.7% in the control group, but were generally manageable.
In conclusion, the PEARLY trial demonstrated that the addition of Carboplatin to standard anthracycline followed by taxane therapy significantly improved Event-Free Survival in early-stage Triple-Negative Breast Cancer. These findings suggest that Carboplatin has a role in enhancing treatment outcomes in TNBC, particularly by reducing the risk of recurrence. Further research and longer-term follow-up are necessary to fully validate these results and refine treatment strategies for this challenging subtype of breast cancer.
A randomized, multicenter, open-label, phase III trial comparing anthracyclines followed by taxane versus anthracyclines followed by taxane plus carboplatin as (neo) adjuvant therapy in patients with early triple-negative breast cancer: Korean Cancer Study Group BR 15-1 PEARLY trial. Sohn J, Kim GM, Jung KH, et al. Journal of Clinical Oncology. Volume 42, Number 17_suppl. https://doi.org/10.1200/JCO.2024.42.17_suppl.LBA502
