Adding Neoadjuvant Carboplatin to Taxane, Anthracycline, and Targeted Therapy Increases Pathologic Complete Response in Triple-Negative Breast Cancer
Preclinical data suggest that triple-negative breast cancer is sensitive to interstrand crosslinking agents and that the combination of a taxane, trastuzumab (Herceptin), and a platinum may have synergistic effects in HER2-positive breast cancer. In a randomized phase II trial (GeparSixto, German Breast Group 66) reported in The Lancet Oncology, von Minckwitz et al found that adding neoadjuvant carboplatin to regimens consisting of a taxane, an anthracycline, and a targeted therapy improved pathologic complete response rate in patients with triple-negative or HER2-positive breast cancer, with the benefit appearing to be limited to patients with triple-negative disease.
Study Details
In the study, 588 patients with previously untreated, nonmetastatic, stage II or III triple-negative or HER2-positive breast cancer were randomly assigned to receive treatment with (n = 296) or without (n = 293) once weekly carboplatin at area under the curve (AUC) = 2.0 for the first 329 patients and 1.5 in the remainder after an interim safety analysis. All patients were treated for 18 weeks with paclitaxel (80 mg/m² once a week) and nonpegylated liposomal doxorubicin (20 mg/m² once a week). Patients with triple-negative breast cancer received simultaneous bevacizumab (Avastin) (15 mg/kg IV every 3 weeks), and those with HER2-positive disease received simultaneous trastuzumab (8 mg/kg initial dose followed by 6 mg/kg IV every 3 weeks) and lapatinib (Tykerb) (750 mg daily).
The primary endpoint was the proportion of patients who achieved a pathologic complete response (ypT0, ypN0), with a P value of 0.2 considered significant for the primary endpoint (0.05 for all other endpoints).
In total, 315 patients had triple-negative breast cancer, including 158 in the carboplatin group and 157 in the no carboplatin group, and 273 had HER2-positive disease, including 137 in the carboplatin group and 136 in the no carboplatin group.
Improved Response Rate
Among all patients, pathologic complete response occurred in 43.7% of patients in the carboplatin group vs 36.9% of patients in the no carboplatin group (odds ratio [OR] = 1.33, P = .107). After adjustment for age, clinical tumor and nodal stage, sonographic tumor size, grade, and biologic subtype, the odds ratio remained significant at 1.39 (P = .068). The odds ratio was higher in patients receiving carboplatin AUC 1.5 (n = 131; 1.93, 95% confidence interval [CI] = 1.16–3.21) than in those receiving AUC 2.0 (n = 164; 1.01, 95% CI = 0.652–1.57; P = .059 for interaction).
Benefit Limited to Triple-Negative Disease
Among patients with triple-negative breast cancer, pathologic complete response rates were 53.2% vs 36.9% (P = .005). Among those with HER2-positive disease, pathologic complete response rates were 32.8% vs 36.8% (P = .581). The test for interaction between the subgroups was significant (P = .015).
Adverse Events
Grade 3 or higher hematologic and nonhematologic adverse events that were significantly more common (all P < .05) in the carboplatin group consisted of neutropenia (65% vs 27%), anemia (15% vs < 1%), thrombocytopenia (14% vs < 1%), diarrhea (17% vs 11%), nausea (10% vs 4%), and anorexia (8% vs 3%). The frequency of grade 3 or 4 hematologic and nonhematologic adverse events decreased from 82% to 70% and from 78% to 59%, respectively, after the dose of carboplatin was reduced from AUC 2.0 to 1.5.
Treatment discontinuation was more common in the carboplatin vs no carboplatin group among patients with triple-negative disease (49% vs 36%, P = .023) but not in those with HER2-positive disease (47% vs 43%, P = .543). Treatment discontinuation was more common in carboplatin patients receiving AUC 2.0 than in those receiving AUC 1.5 (53% vs 41%). Dose reduction of any drug occurred in 69% of the carboplatin group and 55% of the no carboplatin group.
The investigators concluded, “The addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increases the proportion of patients achieving a pathological complete response. This regimen seems to increase responses in patients with triple-negative breast cancer, but not in those with HER2-positive breast cancer.
Gunter von Minckwitz, MD, of the German Breast Group Forschungs GmbH, Neu-Isenburg, is the corresponding author for The Lancet Oncology article.
The study was funded by GlaxoSmithKline, Roche, and Teva. For full disclosures of the study authors, visit www.thelancet.com.
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