Abstract P6-01-20: Luminal androgen receptor subtype and M2 macrophage signatures strongly associate with low pathological complete response rates and poor outcomes in patients with triple negative breast cancer receiving neoadjuvant chemotherapy
Authors: Meisel Jane , Douglass Eugene , Kalinsky Kevin , Griffiths Lyra M. , Li Zaibo , Li Xiaoxian 
Published: March 2023

Background: Triple negative breast cancers (TNBC) are a heterogeneous group of cancers and it is difficult to predict which patients will respond to neoadjuvant chemotherapies (NACT). Achieving pathologic complete response (pCR) to NACT is prognostically favorable, whereas lack of pCR is associated with high rates of recurrence and death from TNBC. Currently, there is no universally accepted biomarker to predict TNBC response to NACT. Methods: We analyzed 25 in-house TNBC biopsies that were treated with neoadjuvant adriamycin (A), cyclophosphamide (C) and paclitaxel (T) and 31 residual TNBC after NACT-ACT using RNA-seq data from macro-dissected tumor tissues from formalin fixed paraffin embedded (FFPE) blocks. Raw reads were mapped to the Human reference genome GRCH38 using the kallisto aligner v0.46.1. Immune infiltrate fractions were estimated using the Cibersort algorithm derived from the LM22 gene-signature matrix of 22 hematopoietic cell types. TNBCtype-4 classification of samples was determined calculating the enrichment of gene-sets for: Luminal Androgen Receptor (LAR), Basal-like 1 and 2 (BL1, BL2), Mesenchymal(M). Overall immune-infiltrate analysis and cancer-intrinsic subtyping were conducted independently on each transcriptional profile. Results were validated by running our novel analyzing protocol in independent cohorts including 182 TNBC cases treated with NACT-ACT from a published Vanderbilt cohort and 179 TNBC cases from the TCGA database. Results: Twenty one (68%) of the 31 residual TNBC after neoadjuvant ACT were luminal androgen receptor (LAR) subtype and significantly enriched in M2 macrophage signature. The LAR subtype and monocyte or M2 macrophage signaturesstrongly associated with lack of pCR in the 25 TNBC biopsy cases and 182 Vanderbilt TNBC cases treated with NACT-ACT. Survival analysis of 179 TNBC cases from the TCGA database showed a significant association of LAR subtype and M2 macrophage signature with worse survival. Conclusions: We developed a novel RNA-seq analyzing protocol that combines tumor subtype and immune profile. The LAR subtype and M2 macrophage signatures strongly associated with lack of pCR and worse survival in TNBC patients when treated with NACT-ACT. Both tumor subtype and immune profile should be considered in biomarker development and further studied in specimens from patients treated with modern chemoimmunotherapy regimens.

Citation Format: Jane Meisel, Eugene Douglass, Kevin Kalinsky, Lyra M. Griffiths, Zaibo Li, Xiaoxian Li. Luminal androgen receptor subtype and M2 macrophage signatures strongly associate with low pathological complete response rates and poor outcomes in patients with triple negative breast cancer receiving neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-20.