SAN ANTONIO -- Adding carboplatin to presurgery chemotherapy improved disease-free survival for patients with triple-negative breast cancer (TNBC), according to results from the randomized phase II GeparSixto clinical trial presented at the 2015 San Antonio Breast Cancer Symposium, held Dec. 8-12.
"Chemotherapy given to shrink or eliminate a tumor before surgery is called neoadjuvant chemotherapy," said Gunter von Minckwitz, MD, president of the German Breast Group and a professor of gynecology at University of Frankfurt in Germany. "Previously published results from the GeparSixto clinical trial showed that adding carboplatin to anthracycline/taxane-based neoadjuvant chemotherapy increased the proportion of patients with TNBC who had a pathologic complete response [pCR], meaning that they had no residual (invasive or noninvasive) cancer detectable in breast tissue and lymph nodes removed during surgery, from 36.9 percent to 53.2 percent.
"Here we show that the improved pCR rates translated into improved disease-free survival," continued von Minckwitz. "Patients with TNBC who received carboplatin as part of their neoadjuvant chemotherapy regimen were almost half as likely to have had disease relapse at three years after starting treatment compared with those who did not receive carboplatin, and it was those patients who had a pCR who were least likely to have disease relapse."
According to von Minckwitz, these data support the use of carboplatin as a standard part of the neoadjuvant chemotherapy regimens used to treat patients with TNBC.
The researchers enrolled 315 patients with TNBC in GeparSixto, 50 of whom had known germline BRCA gene mutations. All patients received 18 weeks of neoadjuvant chemotherapy consisting of paclitaxel, non-pegylated-liposomal doxorubicin, and bevacizumab and were randomly assigned to concurrently receive weekly carboplatin or nothing extra.
After a median follow-up of three years, disease-free survival for patients assigned to carboplatin was 85.5 percent compared with 76.1 percent for patients assigned no carboplatin.
"We were very excited to see a statistically significant improvement in disease-free survival for patients who received carboplatin because the study is relatively small and would not have been powered to show the effects of carboplatin on survival if the differences had been smaller," said von Minckwitz. "Interestingly, the improvement for disease-free survival was observed predominantly for patients without a germline BRCA mutation, a group where we thought that platinum compounds are not active.
"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 continued. "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."
Among the 129 patients with TNBC who had a pCR, five had disease relapse after a median follow-up of three years, compared with 50 of 162 patients who did not have a pCR.
"These pCR data are important for the research community," said von Minckwitz. "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."
This study was supported by GlaxoSmithKline, Roche, and Teva Pharmaceutical Industries. Von Minckwitz's institution receives research funding from GlaxoSmithKline, Roche, and Teva Pharmaceutical Industries.
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Title: Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto)
Authors: Gunter von Minckwitz1, Sibylle Loibl1, Andeas Schneeweiss2, Christoph T Salat3, Mahdi Rezai4, Dirk-Michael Zahm5, Peter Klare6, Jens-Uwe Blohmer7, Hans Tesch8, Fariba Khandan9, Petar A Fasching10, Christian Jakisch1, Valentina Nekljudova1 and Michael Untch12. 1German Breast Group, Neu-Isenburg, Germany; 2University Hospital Heidelberg, Heidelberg, Germany; 3Hämatologisch-Onkologische Schwerpunktpraxis Salat/Stoetzer, München, Germany; 4Luisenkrankenhaus, Düsseldorf, Germany; SRH Wald-Klinikum Gera, Gera, Germany; 6Praxisklinik Berlin, Berlin, Germany; 7Charité Breast Centre, Berlin, Germany; 8Onkologische Gemeinschaftspraxis am Bethanien-Krankenhaus, Frankfurt, Germany; 9St. Markus Krankenhaus, Frankfurt, Germany; 10University Hospital Erlangen, Erlangen, Germany; 11Sana Klinikumk Offenbach, Offenbach, Germany and 12Helios Klinikum Berlin-Buch, Berlin, Germany.
Introduction: Addition of carboplatin to anthracycline/taxane-based neoadjuvant chemotherapy has shown to improve pathological complete response (pCR; ypT0 ypN0) rates in patients with triple-negative breast cancer in two large phase II studies (GeparSixto: von Minckwitz et al. Lancet Oncol 2014; CALGB 40603: Sikov et al. J Clin Oncol 2015). Participants of the GeparSixto study with triple-negative tumors showed an improvement of pCR rate from 36.9 to 53.2% by the addition of carboplatin (p=0.005); however, no statistically significant difference in pCR rate was observed in the HER2-positive subgroup (36.8 vs 32.8%, respectively). A greater benefit with carboplatin was observed in patients with BRCA mutations or a high homologous recombination deficiency (HRD score) in the tumor (pCR rate of 30% compared to 10% for patients without HRD). So far, it is unknown whether these effects on pCR translate into a survival benefit for the patients. We here report an early survival analysis of the GeparSixto study.
Patients and Methods: In the GeparSixto trial (NCT01426880), patients were treated for 18 weeks with paclitaxel 80mg/m2 q1w and non-pegylated-liposomal doxorubicin (NPLD) 20mg/m2 q1w. Patients with TNBC (N=315) received concurrently bevacizumab 15mg/kg i.v. q2w until surgery. Patients with HER2+ disease (N=273) received concurrently trastuzumab 6(8)mg/kg q3w and lapatinib 750mg daily. All patients were randomized 1:1 to receive concurrently carboplatin AUC 1.5-2.0 q1w vs no carboplatin, stratified by subtype (HER2+ vs TNBC). Carboplatin dose was reduced from AUC 2.0 to 1.5 by an amendment after 330 patients. Primary objective was pCR rate (ypT0 ypN0). Loco-regional invasive recurrence free survival (LRRFS), distant-disease- free survival (DDFS), invasive disease-free survival (IDFS), and overall survival (OS) were secondary objectives.
Results: 595 patients were recruited (8/2011 - 12/2012) in 51 German centers. 296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. So far, 82 events have been reported after a median of 28 months follow-up. Analysis of updated events by treatment arm in the full study population as well as in the TNBC and HRD subgroups will be presented.
Conclusion: Even if the GeparSixto study was not powered to show carboplatin effects on survival, the expected results will help to assess the overall benefit of carboplatin in TNBC and the power of pCR to predict for DFS and OS.
To interview Gunter von Minckwitz, contact Julia Gunther at firstname.lastname@example.org or 267-250-5441.