Triple-negative breast cancer (TNBC) accounts for 15% to 20% of BC cases in the U.S. However, despite its lower prevalence, this disease has a more virulent and aggressive course. Adding to this burden, approximately 11% of TNBC patients manifest BRAC1/2 variants, resulting in a dysfunctional BRCA pathway. These variants are associated with abnormal DNA repair and genome-wide instability.
It is for these reasons that the use of platinum-based chemotherapeutic agents is thought to be beneficial since they cause DNA strand breaks leading to apoptosis and cell death. Nonetheless, their role in the management of TNBC has not been firmly established.
The PATTERN (adjuvant Platinum and Taxane in Triple-Negation Breast Cancer), a phase III, multicenter, randomized, open-label clinical trial, examined whether adjunctive therapy with paclitaxel (PCb) and carboplatin was superior to a standard regimen of an anthracycline and docetaxel on survival in women with TNBC.
This study, which was conducted between July 1, 2011, and April 30, 2016, in China, included 647 patients aged 18 to 70 years (mean age 51 years) with pathologically confirmed TNBC. Inclusion criteria included TNBC with regional node-positive or node-negative disease, operable disease, ECOG score <2, adequate hematological, renal, cardiac, and liver function, and tumor diameter >10 mm. Women with metastatic or locally advanced BC, those without TNBC, and those receiving preoperative oncologic therapy were excluded.
A germline variant test of BRAC1/2 was recommended but not required. Using DNA from peripheral blood samples, investigators also examined a set of genes involved in homologous recombination repair (HRR) that had a germline variant in the Chinese population.
Study participants received either six cycles of adjuvant PCb and carboplatin compared with three cycles of standard dose CEF-T (cyclophosphamide, epirubicin and fluorouracil followed by 3 cycles of docetaxel doses of chemotherapeutic agents administered in this study included: PCb 80 mg/m2 and Carboplatin [area under the curve = 2] on Days 1, 8, and 15 every 28 days for 6 cycles or CEF-T (cyclophosphamide 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 every 3 weeks for 3 cycles followed by docetaxel 100 mg/m2 every 3 weeks for 3 cycles).
The primary outcome of the study was disease-free survival (DFS). Secondary outcomes included overall survival (OS), distant DFS (DDFS), relapse-free survival (RFS), overall survival (OS), DFS in patients with germline variants in BRCA1/2 or homologous recombination repair (HRR)-related genes, and toxicity. HRR refers to a cellular mechanism by which double-strand DNA breaks are corrected. BRCA1 and BRCA2 are two proteins involved in this repair process.
A total of 647 women (mean age 51 years) were enrolled in this study, with 325 patients receiving Pcb/carboplatin and 322 patients receiving CEF-T. Patients were stratified based on node status, age, and tumor size. Three-quarters had early stage, node-negative disease. Almost all patients in both groups completed their course of therapy; however, dose reductions were necessary in about 9% of patients in either group. After a median follow-up period of 62 months, those patients who had received Pcb/carboplatin experienced a statistically significantly increased 5-year DFS compared with CEF-T (86.5% vs. 80.3%, HR 0.65 CI, 0.44-0.96). DDFS (92.6% vs. 87.9% in favor of Pcb; HR 0.59; P = .05) and RFS (91.2% vs. 84.4% also in favor of Pcb; HR = 0.54; P = .01) saw similar trends. However, there was no difference in OS between the two treatment groups (HR = 0.71; P = .22). Younger patients and those with high-grade tumors demonstrated greater benefit with Pcb.
Investigators discovered 12 HRR-related genes: ATM, ATR, BARDI, BRCA1, BRCA2, BRIPI, CHEK2, FANCM, PALB2, RADSIC< RADSID, and RECQL. Subgroup analysis revealed no significant difference DFS among patients with and without the BRCA1/2 variant (with the variant: HR 0.44; P = .14 and without the variant: HR 0.68; P = .10). However, there was a difference between with and without the HRR variant (HR 0.39; P = .04) with HRR variants carriers having significantly better DFS with Pcb/carboplatin versus CEF-T. Variants of the 12 genes occurred in 20% of TNBC patients. Out of 521 patients, 120 were carriers for the deleterious HRR genes, including 66 with BRAC1/2 variants (12.7%) and 54 with non–BRAC1/2 variants (10.4%).
The safety profile was consistent with the drugs’ known adverse events with Grade 3/4 neutropenia being the predominant adverse effect, especially in the CEF-T group. In the Pcb/carboplatin group, the most common adverse events were peripheral neuropathy, anemia, and thrombocytopenia.
The authors identified limitations of the study including that it was open-labelled; that CEF-T has fallen out of fallen as the therapeutic option in favor of epirubicin and cyclophosphamide followed by weekly Pcb; that this study was conducted in Chinese patients; that HRR variation or BRAC1/2 subgroups were underpowered; and that some germline variants may have been excluded.
The authors concluded that Pcb/carboplatin is an effective alternative adjuvant chemotherapeutic regimen in patients with operable TNBC. Treatment benefit from the carboplatin-containing regimen was especially noteworthy in patients with defects in homologous recombination and HRR variants. However, more studies are needed to confirm these findings.
It is important for pharmacists to be cognizant of advances in the management of TNBC since therapeutic options are often limited.
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