Identification of Potential Biomarkers for Clinical Benefit Following Dual Neoadjuvant Anti-HER2 Blockade in HER2-positive/HR-negative Early Breast Cancer

Specific RNA expression signatures were indicators of pathological complete response (pCR) and better invasive disease-free survival (iDFS) after 12 weeks of de-escalated neoadjuvant pertuzumab plus trastuzumab with or without paclitaxel in patients with HER2-positive, hormone receptor (HR)-negative early breast cancer, according to findings presented at the ESMO Breast Cancer Virtual Congress 2021, held 5 to 8 May 2021.

Monika Graeser of the Senologie, Westdeutsche Studiengruppe GmbH in Mönchengladbach, Germany and investigators conducted this study (EudraCT Number: 2011-001462-17) to identify putative associations between biological RNA expression signatures and the presence of stromal tumour infiltrating lymphocytes (sTILs), pCR (ypT0 ypN0) and survival.

The investigators obtained samples from patients participating in the phase II WSG-ADAPT (NCT01779206) study, which enrolled patients with cT1-cT4c, cN0-3 HER2-positive/HR-negative breast cancer. Following randomisation, 92 patients were treated with pertuzumab plus trastuzumab and 42 patients received pertuzumab/trastuzumab plus paclitaxel.

Gene expression signatures were analysed in 117 biopsies obtained at baseline using the NanoString Breast Cancer 360 panel. Baseline sTIL levels were available in 119 and 76 patients had sTIL levels at week 3 of treatment. The impact of standardised gene expression signatures on pCR and iDFS were estimated by logistic and Cox regression, respectively and Spearman correlations were computed.

RNA expression signatures on baseline samples but not baseline sTILS, nor sTILS at 3 weeks neither the change of sTIL levels from baseline to 3 week were predictive of pCR

Favourable biomarkers for pCR included the ERBB2 (odds ratio [OR] 1.7; 95% confidence interval [CI] 1.1-2.7) and oestrogen receptor (ER) pathway signalling signatures (OR 1.7; 95% CI 1.1-2.6) whereas the PTEN signature (OR 0.6; 95% CI 0.4-0.9) was an unfavourable indicator of pCR.

With median follow-up of 60 months, 11 invasive events occurred with pertuzumab/trastuzumab and 2 occurred with pertuzumab/trastuzumab/paclitaxel. No invasive events occurred after pCR was observed.

The evaluation of iDFS revealed that several gene signatures that related to the immune response and ER signalling were favourable markers for iDFS (similar HRs ranging from 0.4 to 0.6).

In addition to these patterns, which were more prominent in the neoadjuvant chemotherapy-free arm, an unfavourable BRCAness signature for iDFS was identified (HR 2.0; 95% CI 1.0-3.8).

The investigators indicated that all of the significant immune response signatures were strongly inter-correlated.

However, the change from baseline in sTILs to treatment week 3 was not significantly associated with pCR or iDFS, although a positive correlation between sTILs in baseline samples an immune response signatures was found.

Dr Carmen Criscitiello of the European Oncology Institute in Milan, Italy who discussed the study results said that in this work, no significant correlation between sTILs and pCR nor iDFS was seen, despite several other did suggest that early TIL evaluation (week 3) may show TIL upregulation, which is a strong determinant of pCR. In this context (7% of patients with no chemotherapy), authors did not confirm that a dynamic assessment of TILs is predictive of pCR/iDFS.  


According to the investigators, this translational analysis of samples from patients in the WSG-ADAPT HER2-positive/HR-negative study suggests distinct (except for ER signalling) gene signatures associated with pCR compared to iDFS.

Immune response signatures can be used to augment morphological data from sTILs. The authors suggested that the potential role of the immune response in preventing recurrence suggests that patients with up-regulated immune response signatures could be candidates for de-escalation concepts in HER2-positive breast cancer.

They study is funded by Hoffmann-La Roche.  


LBA2 – Graeser M, Gluz O, Biehl C, et al. Impact of RNA expression signatures and tumor infiltrating lymphocytes (TILs) for pathological complete response (pCR) and survival after 12 week de-escalated neoadjuvant pertuzumab + trastuzumab ± paclitaxel in the WSG-HER2+/HR- ADAPT trial. ESMO Breast Cancer Virtual Congress 2021 (5-8 May).