Abstract PD9-06: Peripheral blood gene signatures predict response to neoadjuvant chemotherapy in breast cancer patients
Authors: Axelrod Margaret L , Gonzalez-Ericsson Paula I , Sun Xiaopeng , Bergman Riley E , Donaldson Joshua , Tolaney Sara M , Krop Ian E , Garrido-Castro Ana C , Sanders Melinda E. , Mayer Ingrid A , Balko Justin M 
Published: February 2021

Abstract
Purpose: Neoadjuvant chemotherapy (NAC), the standard of care for a subset of breast cancer patients, is known to have immunologic effects. With emerging data showing improved response rates with anti-PD-1/PD-L1 immunotherapy in combination with chemotherapy, the effects of NAC on systemic and local anti-tumor immunity require further study. Biomarkers of anti-tumor immunity are needed to identify which patients are most likely to respond to immunotherapy. Our previous work has shown that changes in the peripheral blood can be observed over the course of NAC for breast cancer. Peripheral blood biomarkers are attractive because of the relative ease of sampling compared to site of disease. Residual cancer burden (RCB) is a useful surrogate marker of long-term prognosis, as patients who experience a pathologic complete response (pCR) have better outcomes than those with residual disease (RD). Methods: We previously identified an 8 gene signature of cytotoxicity, derived from single cell RNA sequencing of PD-1Hi CD8+ T cells, which are enriched for tumor-reactive T cells. Using a custom NanoString panel, we tested expression of this gene signature in whole blood collected prior to definitive surgery in 88 breast cancer patients (TNBC, n=21; HER2+, n=17; ER+, n= 54; PR+, n=53) across two cohorts (VUMC, n=58; DFCI, n=30), 64 of whom had received NAC (pCR, n=11; RD, n=53). We further investigated peripheral blood gene expression using RNA sequencing (n=58; 34 post-NAC, 24 untreated). Results: In two cohorts of breast cancer patients, expression of the 8 gene signature (FGFBP2 + GNLY + GZMB + GZMH + NKG7 + LAG3 + PDCD1 - HLA-G) was highest in patients with RD who experienced a recurrence within three years compared to those with pCR (p&lt;0.01) or those with the highest RCB (RCB III) compared to those with RCB 0/I/II who did not have a recurrence with three years (p&lt;0.05). RNA sequencing showed higher expression of interferon alpha, interferon gamma, and complement gene sets in patients experiencing a pCR compared to those with RD by gene set enrichment analysis (FDR-corrected q-values &lt; 0.05). Conclusions: Expression of immune-related genes in the peripheral blood may predict response to NAC in breast cancer patients and be a useful biomarker for those who would benefit from additional therapies. These results will be further tested in a large cohort of longitudinal samples from breast cancer patients receiving NAC alone or in combination with pembrolizumab from the I-SPY-2 trial, to determine whether peripheral blood gene signatures can predict response to immunotherapy in breast cancer.
Citation Format: Margaret L Axelrod, Paula I Gonzalez-Ericsson, Xiaopeng Sun, Riley E Bergman, Joshua Donaldson, Sara M Tolaney, Ian E Krop, Ana C Garrido-Castro, Melinda E. Sanders, Ingrid A Mayer, Justin M Balko. Peripheral blood gene signatures predict response to neoadjuvant chemotherapy in breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD9-06.