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Carboplatin plus neoadjuvant chemotherapy improves DFS in triple-negative breast cancer
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SAN ANTONIO — The addition of carboplatin to neoadjuvant taxane- or anthracycline-based chemotherapy extended DFS among patients with triple-negative breast cancer, according to results of the phase 2 GeparSixto trial presented at San Antonio Breast Cancer Symposium.
“GeparSixto supports the use of carboplatin as part of neoadjuvant treatments in all patients with triple-negative breast cancer,” Gunter von Minckwitz, MD, president of the German Breast Group and professor of gynecology at University of Frankfurt in Germany, said during a press conference. “In addition, the DFS effect of carboplatin was correctly predicted by its extensive effect on pathologic complete response, and this trial is therefore supporting the surrogacy of pathologic complete response.”
Gunter von Minckwitz
The GeparSixto study included 595 patients with triple-negative or HER-2–positive breast cancer treated at 51 German centers.
All patients received weekly paclitaxel 80 mg/m2 weekly and weekly nonpegylated liposomal doxorubicin 20 mg/m2 for 18 weeks.
The 315 patients with triple-negative disease received concurrent bevacizumab (Avastin, Genentech) every 2 weeks until surgery. The 273 patients with HER-2–positive disease received concurrent trastuzumab (Herceptin, Genentech) every 3 weeks, plus lapatinib (Tykerb, Novartis) daily.
Researchers randomly assigned half of the patients to a weekly schedule of carboplatin. The initial dose was area under the curve (AUC) 2, but investigators reduced the dose to AUC 1.5 after enrollment of 330 patients to improve tolerability.
Pathologic complete response (pCR) — defined as no residual cancer detectable in breast tissue or lymph nodes removed during surgery — in all patients served as the primary endpoint.
Results showed the addition of carboplatin increased pathologic complete response rates in the overall population (43.7% vs. 36.9%), but the difference did not reach statistical significance. Carboplatin appeared associated with a statistically significant increase in pCR rate among patients with triple-negative disease (53.2% vs. 36.9%; OR = 1.94; P = .005) but not among patients with HER-2–positive disease (32.8% vs. 36.8%; OR = .84; P for interaction = .015).
In the current analysis, von Minckwitz and colleagues assessed whether the improvement in pCR observed among carboplatin-treated patients translated into a survival benefit.
Median follow-up was 3 years.
Researchers reported no DFS advantage with carboplatin in the overall population (84.7% vs. 81%; HR = 0.81; 95% CI, 0.54-1.21).
When researchers assessed outcomes by subtype, they determined carboplatin was associated with a statistically significant increase in 3-year DFS among patients with triple-negative breast cancer (85.5% vs. 76.1%; HR = 0.56; 95% CI, 0.33-0.96) but not those with HER-2–positive disease (83.4% vs. 86.7%; HR = 1.33; 95% CI, 0.71-2.48; P for interaction = .046).
Von Minckwitz and colleagues were surprised to discover pCR rates among carboplatin-treated patients were considerably higher among those with germline BRCA wild-type disease (OR = 2.09; 95% CI, 1.24-3.53) than those with germline BRCA mutations (OR = 1.6; 95% CI, 0.52-4.93).
“Further studies are needed to investigate this, however, because there were only 50 patients who had a germline BRCA mutation in our study,” von Minckwitz said in a press release. “We might in this group just not see an existing effect of carboplatin, or it could be there is no extra effect because of the high sensitivity of these patients to the other agents given.”
The DFS analysis showed carboplatin conferred a benefit to patients with BRCA wild-type disease, whereas patients with BRCA mutations derived no obvious benefit from carboplatin.
The results are important for the research community, von Minckwitz said.
“They show that the effect of carboplatin on disease-free survival was correctly predicted by its effect on pCR, and they add to the evidence that suggests that pCR can be a surrogate for clinical benefit if the effects of an investigational agent on pCR are large,” he said. – by Mark Leiser
Reference:
von Minckwitz G, et al. Abstract S2-04. Presented at: San Antonio Breast Cancer Symposium; Dec. 8-12, 2015; San Antonio.
Disclosure: Von Minckwitz reports research funding to his institution from GlaxoSmithKline, Roche and Teva. See the abstract for a full list of all researchers’ relevant financial disclosures.
Perspective
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Alberto J. Montero
Two studies were presented at the San Antonio Breast Cancer Symposium — the GeparSixto trial, and the smaller phase 2 CALGB/Alliance 40603 trial — that evaluated carboplatin as neoadjuvant therapy in triple-negative breast cancer.The bottom takeaway point is that although the GeparSixto trial showed an improvement in DFS in patients with triple-negative breast cancer who received carboplatin — about a 9% improvement — the fact that it utilized a non-standard arm of chemotherapy makes it very difficult to apply that into regular practice for breast cancer in the U.S. Based on these results, it is still too premature to use carboplatin — it can be used on an individualized basis, perhaps in a patient with a very high risk for recurrence and stage III breast cancer. Otherwise, this is not a practice-changing study, yet.
Perspective
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Debu Tripathy, MD
An update of the GeparSixto study now shows a DFS benefit from the addition of neoadjuvant carboplatin to anthracycline/taxane chemotherapy in triple-negative breast cancer. The 3-year DFS benefit was nearly 10 percentage points (85.8% vs. 76.1%), equating to an HR of 0.56 (95% CI, 0.33-0.96). An improvement in pathologic complete response rate had previously been shown in the GeparSixto, as well. In contrast, the HER-2–positive cohort did not show an advantage in either pathologic complete response rate or DFS with the addition of carboplatin to this chemotherapy backbone given with HER-2–directed therapy. Additionally, there was a statistically significant interaction between the use of platinum and subtype (HER-2–positive vs. triple-negative breast cancer) in DFS outcome. The researchers concluded that this trial “supports the use of carboplatin as part of neoadjuvant treatment of all patients with triple-negative breast cancer.” Are we then to make platinum therapy a new standard of care for triple-negative breast cancer in the neoadjuvant setting?It is important to first examine the full landscape of platinum therapies for triple-negative breast cancer. Although platinum therapies are clearly active in triple-negative breast cancer, in the metastatic setting, the TNT randomized trial showed equivalence of carboplatin to docetaxel as single-agent therapy in BRCA wild-type cases, whereas platinum was better in regard to DFS and response rate in BRCA mutation carriers. This is in keeping with other studies that showed deficiency in double strand DNA repair may sensitize to therapy with DNA-damaging agents, but that not all triple-negative breast cancer cases share that phenotype.
Additionally, the CALBG 40603 trial — which assessed the addition of carboplatin to a more standard chemotherapy regimen of weekly paclitaxel followed by doxorubicin plus cyclophosphamide — also showed an improvement in pathologic complete response rate but no difference in DFS. In contrast, the GeparSixto trial used a nonconventional chemotherapy regimen of liposomal doxorubicin and weekly paclitaxel without an alkylating agent. Therefore, it is possible that the improvement in DFS was not specific for platinum, but rather the inclusion of an alkylator.
Two phase 3 randomized trials underway the United States (NCT02445391 and NCT 02488967) are testing the addition of platinum for triple-negative breast cancer in the neoadjuvant setting for patients with residual disease at surgery, as well as in the adjuvant setting for higher-risk patients. These studies and others of similar design ultimately will be needed to set a new standard.
Finally, the CREATE-X study of post-neoadjuvant capecitabine, also presented at San Antonio Breast Cancer Symposium, demonstrated an improvement DFS and OS in HER-2–negative cases with residual disease, with an apparent stronger effect in the hormone receptor-negative subset. The publication of these results ultimately may inform new recommendations, at least in the short term.
References:
Lee S-J. Abstract S1-07.Sikov WM, et al. Abstract S2-05.
Telli ML, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.57.0085.
Tutt A, et al. Abstract S3-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 9-13, 2014; San Antonio, Texas.
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