Abstract P3-09-05: Predictive markers of response to durvalumab concurrent with nab-paclitaxel and dose dense doxorubicin cyclophosphamide (ddAC) neoadjuvant therapy for triple negative breast cancer (TNBC)
Authors: Blenman Kim RM , Li Xiaotong , Marczyk Michal , O'Meara Tess , Yaghoobi Vesal , Gunasekharan Vignesh , Park Tristen , Rimm David , Pusztai Lajos 
Published: March 2020

Background: The goal of this analysis was to identify immune cell types and mRNA expression signatures that are associated with pathologic complete response (pCR: ypT0/N0) to neoadjuvant durvalumab concurrent with weekly nab-paclitaxel (100 mg/m2) x 12 followed by ddAC x 4 chemotherapy in stage I-III triple negative breast cancer (TNBC).

Methods: Pre-treatment core needle biopsies were obtained from 57 patients (n=25 pCR, n=32 residual disease (RD)) who participated in Phase I/II clinical trial (NCT02489448) for RNA sequencing and histology assessment. Formalin-fixed paraffin-embedded (FFPE) core biopsies were stained by immunofluorescence for CD8, CD68 and cytokeratin, images were acquired on the Vectra-Polaris system and analyzed using InForm software with the adaptive segmentation into three compartments: Tumor, Stroma, and All (Tumor + Stroma). Correlation between immune cell density in the tissue compartments and pCR was assessed. RNA was extracted from core biopsies collected into RNAlater and poly-A enriched mRNAs were sequenced on Illumina platform using NovaSeq paired-end, 100bp fragments, with a depth of 50 million reads. Six specimens failed QC due to insufficient tumor cells in the sample. Correlation between pCR and immune markers and previously published immune, proliferation and DNA damage response deficiency (DDRD) gene signatures were assessed using logistic regression. Due to high overlap of genes across signatures, no multiple testing correction was done. Differentially expressed genes were found using DESeq2 R package with Benjamini-Hochberg correction for multiple testing. Broadside, an interaction mining tool, was used to extract sets of combinations of genes associated with pathologic response.

Results: In cases with pCR, we detected significantly higher overall CD8 cell density and a trend for higher CD8 in tumor and stroma compartments. There was no significant difference in CD68 cell density between response groups. At the RNA level, high expression of DDRD, IFNγ, T-cell, B-cell, dendritic cell, M1 macrophage signatures and the tumor inflammation gene signature were significantly associated with higher rate of pCR. High expression of epithelial mesenchymal transition and TGFβ and IL8/VEGF gene signatures were associated with higher rate of residual disease. Proliferation gene signatures were not associated with response in this TNBC population. At individual gene level, the highest pCR predictive value was observed for the STAT1 + PCF11 and LAMP3 + SDR39U1 doublets.

Conclusion: High CD8 cell density, high expression of a broad range of immune gene expression signatures and DNA damage response deficiency are associated with greater sensitivity to neoadjuvant anti-PD-L1 and chemotherapy.

Citation Format: Kim RM Blenman, Xiaotong Li, Michal Marczyk, Tess O'Meara, Vesal Yaghoobi, Vignesh Gunasekharan, Tristen Park, David Rimm, Lajos Pusztai. Predictive markers of response to durvalumab concurrent with nab-paclitaxel and dose dense doxorubicin cyclophosphamide (ddAC) neoadjuvant therapy for triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-05.