S3-2: Neoadjuvant Chemotherapy Adapted by Interim Response Improves Overall Survival of Primary Breast Cancer Patients – Results of the GeparTrio Trial.
Authors: G von Minckwitz, JU Blohmer, S Costa, C Denkert, H Eidtmann, W Eiermann, B Gerber, C Hanusch, J Hilfrich, J Huober, C Jackisch, M Kaufmann, S Kümmel, S Paepke, A Schneeweiss, M Untch, DM Zahm, K Mehta, S Loibl
Journal: Cancer Research (2011)

Abstract Background: The GeparTrio phase III trial investigated the concept of interim response-adapted neoadjuvant chemotherapy. Patients with an early response after 2 cycles chemotherapy were considered highly chemo-sensitive and randomized to additional 2 chemotherapy cycles compared to standard treatment. Patients with no early response were considered less chemo-sensitive and randomized to continue with a non-cross-resistant chemotherapy or with standard chemotherapy. Pathological complete response (pCR) rates were different between responders and non-responders but not between the randomized arms (von Minckwitz G, et al JNCI 2008+2008; Huober et al. BCRT 2010). We report here on the results of the secondary endpoints: disease-free (DFS) and overall survival (OS). Patients and Methods: 2072 patients with operable or locally advanced breast cancer were treated with 2 cycles TAC (docetaxel, doxorubicin cyclophosphamide) before interim response assessment. Responders were randomized to additional TACx4 (N=704) or TACx6 (N=686) and non-responders to TACx4 (N=321) or NXx4 (vinorelbine, capecitabine) (N=301). None of the HER2+ patients received Trastuzumab. Endocrine treatment was given postoperatively to ER+ and/or PgR+ patients. We observed 480 recurrences and 302 deaths during median 62 months of follow up. Results: Patients receiving the experimental treatments (TACx8 or TACx2-NXx4) showed a longer DFS (HR 0.71; 95%CI 0.60−0.86, p&amp;lt;0.001) and longer OS (HR 0.79; 95%CI 0.63−0.99, p=0.048) compared to patients receiving standard TACx6 treatment. Treatment effects on DFS were restricted to patients with luminal A (p=0.003), luminal B (HER2−) (p=0.006) and luminal B(HER2+) (p=0.04) tumors. Experimental treatments did not improve outcome in HER2+(non-luminal) (p=1.0) and triple-negative (p=0.5) tumors. Responders showed a significant longer DFS (HR 0.79; 95%CI 0.62−0.97), p=0.026) and a trend towards a longer OS (HR 0.76; 95%CI 0.57−1.01, p=0.061) if they were treated with TACx8 compared to TACx6. Non-responders showed a longer DFS (HR 0.6; 95%CI 0.43−0.82, p=0.001) but not OS (HR 0.85; 95%CI 0.57−1.27, p=0.4) when treated with TACx2-NXx4 compared to TACx6. Results according to phenotypes of responders and non-responders were comparable to the overall comparison. In general, patients with a pCR showed a better DFS if they had triple-negative (p&amp;lt;0.0001), HER2+(non-luminal) (p&amp;lt;0.0001) or luminal B(HER2−) (p=0.004), but not if they had luminal A (p=0.66) or luminal B (HER2+) (0.67) disease. Conclusion: Adapting neoadjuvant chemotherapy according to interim response leads to better DFS and OS and represents therefore a unique advantage over adjuvant treatment. The investigated strategies to improve standard chemotherapy were most effective in the luminal A and B phenotypes. These phenotypes are usually considered less chemo-sensitive and pCR is not a prognostic factor. This might explain why the observed survival advantages could not be predicted by pCR. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S3-2.