Weekly vs Every-3-Week Carboplatin with Weekly Paclitaxel in Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: A Retrospective Analysis

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Introduction

Breast cancers are typically categorized by their expression of estrogen and progesterone receptors (ER, PR) and the presence or absence of human epidermal growth factor receptor 2 (HER2) gene amplification.1 Those without any of these markers are referred to as triple-negative breast cancers (TNBC), which accounts for approximately 10–15% of all breast cancers. TNBC is more common in women who carry germline mutations in BRCA1, comprising 70–80% of breast cancers that develop in such patients, though BRCA mutations are detected in less than 20% of patients diagnosed with TNBC, and is seen more commonly in women of African or Hispanic descent. This subtype is associated with a worse prognosis and, when diagnosed without overt metastatic disease, a higher risk of early relapse. In the absence of molecular targets that guide treatment of other breast cancer subtypes, current optimal treatment for non-metastatic TNBC is cytotoxic chemotherapy, typically sequential or concurrent administration of an anthracycline-based regimen such as doxorubicin or epirubicin and cyclophosphamide (AC or EC) and a taxane [2, 3]. With regard to the choice of taxane and dosing schedule, the E1199 study demonstrated that weekly paclitaxel was more effective than either every 3-week paclitaxel or weekly or every 3-week docetaxel following AC as adjuvant therapy for node-positive TNBC.2

Gene expression analysis reveals heterogeneity within TNBC, with one group of investigators identifying at least six subtypes that appear to differ by response to treatment.3 However, one characteristic shared by a majority of TNBC, whether associated with an identifiable BRCA mutation or not, is impairment of DNA repair by homologous recombination, also referred to as homologous recombination deficiency (HRD).4 While this defect presumably plays a role in development of the malignancy, it also renders the cancer cells more vulnerable to DNA-damaging chemotherapeutic agents. While many of the agents used to treat TNBC target DNA (excluding the taxanes), employing platinum-based antineoplastic therapies, which create DNA crosslinks that can lead to double-stranded DNA breaks, has been of particular interest.

Read more  Prospects of Immunotherapy for Triple-Negative Breast Cancer

In patients with non-metastatic TNBC, achievement of a pathologic complete response (pCR) with neoadjuvant chemotherapy (NACT), usually defined as the absence of residual invasive disease in the breast and sampled axillary nodes (ypT0/isN0), is associated with large improvements in long-term outcomes compared to patients with residual invasive disease. In a recently updated meta-analysis, TNBC patients who attained pCR were found to have an 82% improvement in event-free survival (EFS) and an 80% improvement in overall survival (OS) compared to patients with residual invasive disease at surgery.5–10 However, in large, multicenter neoadjuvant trials, sequential administration of weekly paclitaxel and AC or EC typically yields pCRs in less than one-third of patients.11–15 As a result, clinical trials have investigated a variety of approaches to try to increase the pCR rate in TNBC, including several studies that focused on incorporation of platinum agents, more commonly carboplatin, into NACT for TNBC. These studies have demonstrated significantly improved pCR rates (~50–60%) with the addition of carboplatin, and one trial has reported significant improvement in disease-free survival among patients treated with carboplatin compared to those who did not receive this agent.11,12,16,17

Given the compelling evidence supporting the inclusion of carboplatin into NACT regimens, clinical trials have included both weekly or every 3-week carboplatin regimen, but a direct comparison between these two dosing schedules on achieving a pCR has not been studied in a randomized trial. Thus, our current study aims to evaluate pCR rates in TNBC associated with the neoadjuvant use of weekly carboplatin dosing (with an area-under-the-curve (AUC) of 2) versus every 3-week dosing (AUC of 6) at two institutions to compare their efficacy in real-world settings.

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About the Author: Tung Chi