Our exploratory analyses of this prospective trial strongly suggest that the various breast cancer phenotypes require different chemotherapy approaches and show that even patients with luminal tumors can derive greater benefit from response-guided chemotherapy.
—Gunter von Minckwitz, MD, PhD, and colleagues
In an exploratory analysis of long-term survival data from the GeparTrio trial reported in the Journal of Clinical Oncology, Gunter von Minckwitz, MD, PhD, of the German Breast Group in Neu-Isenburg and the University of Frankfurt, Germany, and colleagues found that response-guided neoadjuvant chemotherapy appears to improve disease-free survival and overall survival and appears to be most effective in hormone receptor–positive tumors.1
In the trial, 2,072 patients with early breast cancer received neoadjuvant therapy with two cycles of TAC (docetaxel, doxorubicin, and cyclophosphamide), with early responders being randomly assigned to an additional four TAC cycles (TAC × 6, n = 704) or an additional six TAC cycles (TAC × 8, n = 686) and early nonresponders being randomly assigned to four more cycles of TAC (TAC × 6, n = 321) or four cycles of NX (vinorelbine/capecitabine, n = 301) before surgery.
TAC was given as docetaxel at 75 mg/m2, doxorubicin at 50 mg/m2, and cyclophosphamide at 500 mg/m2 on day 1 every 3 weeks. NX was given as vinorelbine at 25 mg/m2 on days 1 and 8 plus capecitabine at 1,000 mg/m2 orally twice a day on days 1 to 14 every 3 weeks.
Clinical response was determined preferably by sonography or another clinical method if investigators considered this more appropriate. No patients received trastuzumab during neoadjuvant or adjuvant treatment.
Baseline characteristics were well balanced between patients receiving response-guided chemotherapy (TAC × 8 or TAC-NX) and those receiving conventional chemotherapy (TAC × 6), except for grade, with fewer undifferentiated tumors noted in the response-guided groups. The frequencies of HER2-positive (29.8%) and triple-negative (22.6%) tumors were higher than in the average breast cancer population, reflecting selection of tumors most sensitive to and in need of neoadjuvant chemotherapy.
Disease-Free Survival Improvements
Median follow up was 62 months. Disease-free survival was significantly longer in early responders receiving TAC × 8 than in those receiving TAC × 6 (hazard ratio [HR] = 0.78, P = .026) and in early nonresponders receiving TAC-NX than in those receiving TAC × 6 (HR = 0.59, P = .001). Disease-free survival was similar in the two response-guided groups and shorter in the two groups receiving TAC × 6, particularly in early nonresponders.
Overall, disease-free survival was significantly longer in the response-guided groups than in the conventional groups combined (HR = 0.71, P = .0003). On multivariate analysis, the hazard ratio was unchanged (HR = 0.71, P = .001).
Overall Survival Outcomes
Early responders receiving TAC × 8 had a borderline significant increase in overall survival compared with those receiving TAC × 6 (HR = 0.76, P = .060), whereas nonresponders receiving TAC-NX had no significant improvement compared with those receiving TAC × 6 (HR = 0.85, P = .432). Overall, response-guided therapy was associated with a significant but marginal overall survival benefit vs conventional therapy (HR = 0.79, P = .048).
The investigators speculated that because the treatment effect was mainly observed in hormone receptor–positive patients, 5-year follow-up might have been too short to show more pronounced effects on overall survival, which is longer in such patients.
Disease-free survival was significantly longer after response-guided vs conventional therapy in patients with hormone receptor–positive tumors (HR = 0.56, 95% confidence interval [CI] = 0.44–0.73) and those with HER2-negative tumors (HR = 0.63, 95% CI = 0.49–0.81).
By phenotype, disease-free survival was significantly longer with response-guided therapy in luminal A (hormone receptor–positive, G1 or G2) disease (HR = 0.55, 95% CI = 0.37–0.82), luminal B (hormone
receptor–positive, G3) disease (HR = 0.40, 95% CI = 0.20–0.79), and luminal B (G3; HER2-positive) disease (HR= 0.56, 95% CI = 0.33–0.96), but not in HER2-positive (nonluminal) or triple-negative disease.
Pathologic complete response did not predict many of the observed survival effects, but was significantly predictive of improved disease-free survival in triple-negative (HR = 6.67, P < .001), HER2-positive (nonluminal) (HR = 5.24, P < .001), and luminal B (HER2-negative) tumors (HR = 3.74, P = .018).
Other subgroups with significantly prolonged disease-free survival with response-guided therapy were age ≥ 40 years (HR = 0.73), clinical T stage 1 to 3 (HR = 0.70), clinical tumor size < 40 mm (HR = 0.62) and ≥ 40 mm (HR = 0.79), positive clinical node status (HR = 0.66), ductal or other (nonlobular) histology (HR = 0.73), and tumor grade 3 (HR = 0.65).
The investigators concluded:
This exploratory analysis suggests that response-guided neoadjuvant chemotherapy might improve survival and is most effective in hormone receptor-positive tumors…. The GeparTrio study provides the first demonstration of the advantage of neoadjuvant chemotherapy over adjuvant chemotherapy because response-guided treatment can only be conducted when the tumor is available for the monitoring of response. Our exploratory analyses of this prospective trial strongly suggest that the various breast cancer phenotypes require different chemotherapy approaches and show that even patients with luminal tumors can derive greater benefit from response-guided chemotherapy. These findings must now be prospectively tested but can be used to guide the design of future trials. ■
Disclosure: The study was supported by Amgen, Chugai, Roche, and sanofi-aventis. For full disclosures of the study authors, visit jco.ascopubs.org.
1. von Minckwitz G, Blohmer JU, Costa SD, et al: Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol 31:3623-3630, 2013.
GeparTrio was an innovative phase III trial conducted by the German Breast Group, enrolling over 2,000 women with early breast cancer who were candidates for neoadjuvant chemotherapy. Patients with evidence of early response, defined as reduction in clinical tumor size by 50% or more, following two ...