Oleg Gluz1,2,3, Ulrike Nitz1,2, Cornelia Liedtke4, Matthias Christgen5, Eva-Maria Grischke6, Helmut Forstbauer7, Michael Braun8, Mathias Warm9, John Hackmann10, Christoph Uleer11, Bahriye Aktas12,13, Claudia Schumacher14, Nikola Bangemann15, Christoph Lindner15,16, Sherko Kuemmel17, Michael Clemens18, Jochem Potenberg19, Peter Staib20, Andreas Kohls21, Raquel von Schumann2, Ronald Kates1, Ronald Kates1, Johannes Schumacher22, Rachel Wuerstlein23, Hans Heinrich Kreipe5, Nadia Harbeck1,23. 1. Moenchengladabach, West German Study Group. 2. Moenchengladbach, Breast Center Niederrhein, Evangelical Hospital Johanniter Bethesda. 3. University Clinics Cologne. 4. Department of Gynecology and Obstetrics, University Clinics Schleswig-Holstein/Campus Luebeck. 5. Institute of Pathology, Medical School Hannover. 6. Department of Gynecology and Obstetrics, University Clinics Tuebingen. 7. Oncology Practice Network Troisdorf. 8. Breast Center, Rotkreuz Clinics Munich. 9. Breast Center, City Hospital of Cologne Holweide. 10. Breast Center, Marien-Hospital Witten. 11. Gynecologic Oncologic Practice Hildesheim. 12. Department of Gynecology and Obstetrics, University Clinics Essen. 13. Department of Gynecology, University Hospital Leipzig. 14. Breast Center, St. Elisabeth Hospital Cologne. 15. Clinic of Gynecology, Charité University Clinics Berlin. 16. Department of Gynecology and Obstetrics, Agaplesion Diakonie Clinic. 17. Clinics Essen-Mitte, Breast Center. 18. Department of Oncology, Clinics Mutterhaus Trier. 19. Department of Oncology, Evangelical Waldkrankenhaus Berlin. 20. Department of Oncology, St. Antonius Hospital. 21. Department of Gynecology and Obstetrics, Evangelical Hospital Ludwigsfelde. 22. Statitistics, Palleos Healthcare. 23. Breast Center, University of Munich (LMU) and CCCLMU, Munich, Germany.
Abstract
Background: Pathological complete response (pCR) is associated with improved prognosis in triple-negative breast cancer (TNBC). The optimal chemotherapy regimen is unclear. Weekly nab-paclitaxel vs conventional paclitaxel or addition of carboplatin to anthracycline-taxane results in higher pCR rates with uncertain survival impact. We evaluated carboplatin vs gemcitabine with a nab-paclitaxel backbone as a short 12-week A-free regimen with a focus on early response. Methods:Patients with TNBC (estrogen receptor/progesterone receptor < 1%, human epidermal growth factor receptor 2-negative, cT1c-cT4c, cN0/+) were randomly assigned to A: nab-paclitaxel 125 mg/m2/gemcitabine 1000 mg/m2 d1,8 three times weekly (q3w); vs B: nab-paclitaxel 125 mg/m2/carboplatin AUC2 day 1,8 q3w. The trial was powered for a pCR (ypT0/is ypN0) comparison by therapy arm and early response (defined as Ki-67 decrease >30% or < 500 invasive tumor cells in the three-week serial biopsy). All statistical tests were two-sided. Results: A total of 336 patients were enrolled (48 centers, arms A/B: n = 182/154). The median age was 50 years. At baseline (A vs B), 62.6% and 62.9% had cT2-4c tumors; 86.8% and 90.9% completed therapy per protocol, respectively. pCR favored arm B (28.7%, 95% CI = 0.22 to 0.36, vs 45.9%, 95% CI = 0.38 to 0.54; 95% CI(dBA) = 6.2% to 27.9%, P = .002) and was lower in nonresponders than in early responders (19.5% vs 44.4%, P < .001) or in patients with unclassifiable early response (50.0%). The nab-paclitaxel/gemcitabine was associated with more frequent dose reductions (20.6% vs 11.9%, P = .04), treatment-related serious adverse events (11.1% vs 5.3%, P = .07), grade 3-4 infections (7.2% vs 2.6%, P = .07), and grade 3-4 ALAT elevations (11.7 vs 3.3%, P = .01). Conclusions: This first large randomized trial suggests high efficacy and excellent tolerability of a neoadjuvant nab-paclitaxel/carboplatin regimen, superior to nab-paclitaxel/gemcitabine in TNBC. De-escalation of further chemotherapy in patients with early pCR after a short anthracycline-free regimen is a promising field of future research. Early necrotic morphological changes and/or proliferation decrease after the first therapy cycle seem to be associated with subsequent pCR.
RCT Entities:
Background: Pathological complete response (pCR) is associated with improved prognosis in triple-negative breast cancer (TNBC). The optimal chemotherapy regimen is unclear. Weekly nab-paclitaxel vs conventional paclitaxel or addition of carboplatin to anthracycline-taxane results in higher pCR rates with uncertain survival impact. We evaluated carboplatin vs gemcitabine with a nab-paclitaxel backbone as a short 12-week A-free regimen with a focus on early response. Methods:Patients with TNBC (estrogen receptor/progesterone receptor < 1%, human epidermal growth factor receptor 2-negative, cT1c-cT4c, cN0/+) were randomly assigned to A: nab-paclitaxel 125 mg/m2/gemcitabine 1000 mg/m2 d1,8 three times weekly (q3w); vs B: nab-paclitaxel 125 mg/m2/carboplatin AUC2 day 1,8 q3w. The trial was powered for a pCR (ypT0/is ypN0) comparison by therapy arm and early response (defined as Ki-67 decrease >30% or < 500 invasive tumor cells in the three-week serial biopsy). All statistical tests were two-sided. Results: A total of 336 patients were enrolled (48 centers, arms A/B: n = 182/154). The median age was 50 years. At baseline (A vs B), 62.6% and 62.9% had cT2-4c tumors; 86.8% and 90.9% completed therapy per protocol, respectively. pCR favored arm B (28.7%, 95% CI = 0.22 to 0.36, vs 45.9%, 95% CI = 0.38 to 0.54; 95% CI(dBA) = 6.2% to 27.9%, P = .002) and was lower in nonresponders than in early responders (19.5% vs 44.4%, P < .001) or in patients with unclassifiable early response (50.0%). The nab-paclitaxel/gemcitabine was associated with more frequent dose reductions (20.6% vs 11.9%, P = .04), treatment-related serious adverse events (11.1% vs 5.3%, P = .07), grade 3-4 infections (7.2% vs 2.6%, P = .07), and grade 3-4 ALAT elevations (11.7 vs 3.3%, P = .01). Conclusions: This first large randomized trial suggests high efficacy and excellent tolerability of a neoadjuvant nab-paclitaxel/carboplatin regimen, superior to nab-paclitaxel/gemcitabine in TNBC. De-escalation of further chemotherapy in patients with early pCR after a short anthracycline-free regimen is a promising field of future research. Early necrotic morphological changes and/or proliferation decrease after the first therapy cycle seem to be associated with subsequent pCR.
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