Abstract RF2-01: Prognostic Markers in Residual Tumors after neoadjuvant chemotherapy (NACT) for Early Triple-negative Breast Cancer (TNBC) - a Pooled Analysis from nine Neoadjuvant GBG/AGO-B Trials

Abstract Background: Residual invasive disease after NACT for TNBC is associated with high recurrence rates and poor overall survival (OS). The assessment of pathologic complete response (pCR) vs. non-pCR in early breast cancer is not consistently linked to OS. For instance, it does not address partial responses or favourable changes in tumor biology during NACT. Therefore, we investigated proliferation (Ki67) and tumor-infiltrating lymphocytes (TILs) in invasive residual tumor (RT) for improved prediction of outcome. Study Design: Pts with TNBC treated with anthracycline/taxane-containing NACT in nine GBG/AGO-B trials (GeparTrio, GeparQuattro, GeparQuinto, GeparSixto, GeparSepto, GeparOcto, GeparNuevo, GeparOla, and GeparX) were included. Of 3017 pts with TNBC enrolled, 1505 had ypT>0/is and 640 had prospectively collected RT-samples for evaluation of TILs and Ki67. Endpoints were distant disease-free survival (DDFS; primary endpoint) and OS (both as land-mark analysis). Results: Of the 640 pts included, most had cT2 (57.6%), 36.9% had cN+ with 61.6% having stage II disease. At baseline (BL), 93.4% of tumors had Ki67>15% (median 51%), the median for TILs at BL was 20%. After treatment, 54% of RTs had Ki67>15% (median 18%) with a median absolute change in Ki67 of -27.5% compared to BL. Median TILs in RT were 20% with a median change of +5% compared to BL. In pts with ypT1, ypN0 at surgery Ki67 was lower and TILs were higher in RT compared to pts with >ypT1y, pN0 at surgery with no correlation with ypN status. Ki67 >15% vs ≤15% in RT was associated with worse DDFS (HR 1.71; 95% CI 1.33-2.21; p<0.0001) and OS (HR 2.02; 95% CI 1.51-2.71; p<0.001) with a significant increase in risk for DDFS/OS events by 9.4%/10.7% for each 10% of Ki67 increase in RT. TILs in RT were associated with a 6.3%/8.7% significant reduction in risk for DDFS/OS events for each 10% increased TIL level at surgery. When combining Ki67 and TILs in the RT, pts with Ki67≤15% and TILs ≥50% had the best and those with Ki67>15% and TILs ≤10% had the worst DDFS (HR 3.62 95% CI 2.00-6.52; p<0.0001) and OS (HR 7.57 95% CI 3.19-17.94; p<0.0001). 5y survival rates in the 4 groups Ki67≤15% and TILs ≥50%; Ki67≤15% and TILs <50%; Ki67>15% and TILs >10%; Ki67>15% and TILs <10% were: DDFS 83.7% (74.5-94.1); 66.3% (60.1-73.1); 55.8% (49.9-62.4); 42.4% (32.2-55.8) and OS 92.1% (84.9-99.9); 75% (69.3-81.2); 61.5% (55.6-67.9); 48% (37.4-61.7). The combination of Ki67 and TILs remained significant in different multivariate models for DDFS and OS with clinical and pathological tumor stage. Pts with limited residual disease (ypT1, ypN0) had meaningfully improved DDFS (HR 0.33; 95% CI 0.24-0.45; p<0.0001) and OS (HR 0.25; 95% CI 0.17-0.37; p<0.0001) compared to pts with >ypT1ypN0. Amongst pts with ypT1, ypN0, those with Ki67>15% in RT trended towards worse DDFS (HR 1.48; 95% CI 0.88-2.48; p=0.14) and OS (HR 1.93; 95% CI 0.99-3.76; p=0.055) compared to Ki67 ≤15%. In the bivariate model including limited residual disease (ypT1, ypN0), Ki67 ≤15% remained an independent predictor of DDFS and OS. Amongst pts with ypT1ypN0 those with Ki67≤15% and TILS≥50% in RT had numerically better survival compared to pts with ypT1, ypN0 not meeting these criteria (5y DDFS rates: 87.5% (76.7-99.9) vs 76.1% (70.3-82.4); 5y OS rates: 96.8% (90.8-100) vs 82.7% (77.3-88.4). Conclusion: Our results suggest that the combined assessment of Ki67 and TILs in residual disease after NACT for TNBC could contribute to prediction of prognosis as well as to improved personalized selection of post-neoadjuvant therapy strategies. Low Ki67 in RT was prognostic for superior DDFS and OS especially when combined with moderate-strong TILs in RT. Amongst pts with ypT1, ypN0, those with low Ki67 and strong TILs in RT had the highest 5yr survival rates. Citation Format: J. Holtschmidt, A. Schneeweiss, N. Frickel, N. Filmann, M. Untch, A. Hartkopf, V. Müller, C. Solbach, M. van Mackelenbergh, J. Blohmer, K. Lübbe, T. Karn, F. Holms, P. A. Fasching, P. Jank, M. Darsow, F. Marmé, M. Braun, E. Stickeler, R. Weide, T. Fehm, C. Schem, A. Eidmann, B. Felder, S. Loibl, C. Denkert. Prognostic Markers in Residual Tumors after neoadjuvant chemotherapy (NACT) for Early Triple-negative Breast Cancer (TNBC) - a Pooled Analysis from nine Neoadjuvant GBG/AGO-B Trials [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF2-01.