Impact of RNA Signatures on pCR and Survival after 12-Week Neoadjuvant Pertuzumab plus Trastuzumab with or without Paclitaxel in the WSG-ADAPT HER2+/HR− Trial
Clinical Cancer Research, December 2022
Monika Graeser, Oleg Gluz, Claudia Biehl, Daniel Ulbrich-Gebauer, Matthias Christgen, Jenci Palatty, Sherko Kuemmel, Eva-Maria Grischke, Doris Augustin, Michael Braun, Jochem Potenberg, Rachel Wuerstlein, Katja Krauss, Claudia Schumacher, Helmut Forstbauer, Toralf Reimer, Andrea Stefek, Hans Holger Fischer, Enrico Pelz, Christine zu Eulenburg, Ronald Kates, Hua Ni, Cornelia Kolberg-Liedtke, Friedrich Feuerhake, Hans Heinrich Kreipe, Ulrike Nitz, Nadia Harbeck
TTo identify associations of biological signatures and stromal tumor infiltrating lymphocytes (sTILs) with pathological complete response (pCR, ypT0 ypN0) and survival in the phase II WSG-ADAPT HER2+/HR- trial (NCT01817452). Patients with cT1-cT4c, cN0-3 HER2+/HR- early breast cancer (EBC) were randomized to pertuzumab+trastuzumab (P+T, n=92) or P+T+paclitaxel (n=42). Gene expression signatures were analyzed in baseline (BL) biopsies using NanoString Breast Cancer 360 panel (n=117); BL and on-treatment (week 3) sTIL levels were available in 119 and 76 patients, respectively. Impacts of standardized gene expression signatures on pCR and invasive disease-free survival (iDFS) were estimated by logistic and Cox regression. In all patients, ERBB2 (OR 1.70; 95%CI 1.08-2.67) and estrogen receptor (ER) pathway signaling signatures (OR 1.72; 95%CI 1.13-2.61) were favorable, while PTENsignature (OR 0.57; 95%CI 0.38-0.87) was unfavorable for pCR. After 60 months median follow-up, 13 invasive events occurred (P+T: n=11, P+T+paclitaxel: n=2), none following pCR. Gene signatures related to immune response (IR) and ER signaling were favorable for iDFS, all with similar HR about 0.43-0.55. These patterns were even more prominent in the neoadjuvant chemotherapy-free group, where additionally BRCAness signature was unfavorable (HR 2.00; 95%CI 1.04-3.84). IR signatures were strongly intercorrelated. sTILs (BL/week 3/change) were not associated with pCR or iDFS, though BL-sTILs correlated positively with IR signatures. Distinct gene signatures were associated with pCR vs iDFS in HER2+/HR- EBC. The potential role of IR in preventing recurrence suggests that patients with up-regulated IR signatures could be candidates for de-escalation concepts in HER2+ EBC.
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