Gene expression signatures, stromal tumor infiltrating lymphocytes (sTILs), and change in tumor cellularity to predict pathological complete response (pCR) after 12 week de-escalated neoadjuvant endocrine therapy (ET) vs paclitaxel + dual HER2 blockade in the WSG-TP-II trial.

Monika Karla Graeser West German Study Group, Moenchengladbach, Germany info_outline Monika Karla Graeser, Oleg Gluz, Ulrike Nitz, Claudia Biehl, Angela Berg, Matthias Christgen, Sherko Kuemmel, Johannes Holtschmidt, Johannes Schumacher, Andreas D. Hartkopf, Jochem Potenberg, Kerstin Luedtke-Heckenkamp, Marianne Just, Christian Schem, Christine zu Eulenburg, Timo Schinkoethe, Rachel Wuerstlein, Ronald E. Kates, Hans Heinrich Kreipe, Nadia Harbeck

Authors Monika Karla Graeser West German Study Group, Moenchengladbach, Germany info_outline Monika Karla Graeser, Oleg Gluz, Ulrike Nitz, Claudia Biehl, Angela Berg, Matthias Christgen, Sherko Kuemmel, Johannes Holtschmidt, Johannes Schumacher, Andreas D. Hartkopf, Jochem Potenberg, Kerstin Luedtke-Heckenkamp, Marianne Just, Christian Schem, Christine zu Eulenburg, Timo Schinkoethe, Rachel Wuerstlein, Ronald E. Kates, Hans Heinrich Kreipe, Nadia Harbeck Organizations West German Study Group, Moenchengladbach, Germany, Klinikum Dortmund gGmbH, Dortmund, Germany, Medical School Hannover, Hannover, Germany, St. Elisabeth-Krankenhaus Köln-Hohenlind, Cologne, Germany, Palleos Healthcare GmbH, Wiesbaden, Germany, University Hospital Tübingen, Tübingen, Germany, Ev. Waldkrankenhaus Spandau, Berlin, Germany, Niels-Stensen-Kliniken, Georgsmarienhütte, Germany, Oncological Specialist Practice Bielefeld, Bielefeld, Germany, Mammazentrum Hamburg – Brustklinik am Krankenhaus Jerusalem, Hamburg, Germany, CANKADO Service GmbH, Kirchheim Bei München, Germany Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Roche Pharma AG Background: There are limited data on predictive biomarkers for de-escalated ET or chemotherapy with dual anti-HER2 blockade in HR+/HER2+ early breast cancer (BC). In this translational pre-planned project of the WSG-TP-II phase II-trial (NCT03272477), we aimed to identify associations of gene expression signatures and sTILs with pCR. Methods: Patients with cT1c-cT4c, cN0-3 centrally confirmed HR+/HER2+ BC were randomized to 12 weeks of standard ET (n = 100) or paclitaxel (Pac; n = 107). All patients received trastuzumab + pertuzumab (T+P) q3w as neoadjuvant and adjuvant treatment. Gene expression signatures were analyzed using NanoString BC360 panel in baseline biopsies (T+P+ET: n = 72; T+P+Pac: n = 78). sTILs were analyzed in 93 (T+P+ET) and 97 patients (T+P+Pac) at baseline and in 65 (T+P+ET) and 57 patients (T+P+Pac) at week 3. Impacts of standardized BC360 gene expression signatures and sTILs on pCR (ypT0/is ypN0; primary endpoint) expressed in odds ratios (OR) were estimated by logistic regression analysis. Results: pCR rate in patients with BC360 analysis was 39.3% (T+P+ET: 23.6%; T+P+Pac: 53.9%). Overall, ERBB2 (OR 2.37; 95%CI 1.55, 3.62) and cytotoxic cells signature (OR 1.42; 95%CI 1.02, 1.99) were favorable for pCR, while apoptosis (OR 0.64; 95%CI 0.44, 0.92), estrogen receptor 1 (OR 0.60; 95%CI 0.42, 0.85), estrogen receptor signaling (OR 0.64; 95%CI 0.45, 0.91), and progesterone receptor (OR 0.67; 95%CI 0.47, 0.94) signatures were unfavorable. Analyzing by treatment arm, a similar pattern was observed in the T+P+Pac arm (ERBB2: OR 2.01; apoptosis: OR 0.59; estrogen- and progesterone-related signatures: OR 0.41-0.58), but not in the T+P+ET arm where only ERBB2 was prognostic for pCR (OR 7.24; 95%CI 2.12, 24.05). Baseline ≥30% sTIL levels (vs < 30% sTILs; n = 16 vs n = 174) were associated with pCR (OR 5.16; 95%CI 1.60, 16.66); significance was not achieved in either trial arm. Compared to < 30% sTILs (n = 90), low tumor cellularity at week 3 precluding sTILs analysis ( < 500 invasive tumor cells, n = 22), but not ≥30% sTILs (n = 10), was prognostic for pCR in all patients (OR 9.47; 95%CI 2.94, 30.50) and in individual trial arms (OR 6.00-11.79). Conclusions: This hypothesis-generating translational results suggest that gene expression signatures (particularly ERBB2), baseline sTILs, and low tumor cellularity at week 3 predict pCR after ET + double HER2 blockade. Future neoadjuvant trials are needed to prospectively test the use of baseline gene expression and sTILs analysis, and early on-treatment cellularity measurement to select patients with HR+/HER2+ tumors for de-escalated endocrine-therapy-based approaches. Clinical trial information: NCT03272477.