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Adding Neoadjuvant Carboplatin to Taxane, Anthracycline, and Targeted Therapy Increases Pathologic Complete Response in Triple-Negative Breast Cancer

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Key Points

  • The addition of neoadjuvant carboplatin increased pathologic complete response rate among all patients and among patients with triple-negative disease but not those with HER2-positive breast cancer.
  • Adverse events were less common after the carboplatin dose was reduced from AUC 2.0 to AUC 1.5.

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.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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