Abstract 2052: Genomic and transcriptomic correlates of response to neoadjuvant chemotherapy and survival outcomes in breast cancer

Abstract Background: Neoadjuvant chemotherapy (NAC) is standard for breast cancer treatment, aimed at downgrading tumors and enhancing the feasibility of radical surgery. Pathological complete response (pCR), confirmed through histopathologic examination, is a potential surrogate marker of long-term survival. However, the absence of reliable biomarkers to predict NAC response and prognosis poses a significant challenge, hindering timely treatment adjustments and optimal adjuvant therapy selection. Methods: This study included 73 stage II/III breast cancer patients who underwent NAC followed by curative-intent surgery. We analyzed whole-exome and transcriptome sequencing data from baseline and surgical tumors to identify biomarkers associated with pCR and survival outcomes. Plasma samples were collected at three time points: before NAC (P1), during NAC (P2), and after NAC (P3), to evaluate the predictive value of undetectable circulating tumor DNA (ctDNA) for pCR. Results: TP53, PIK3CA, and TTN mutations were common in breast cancer but were exclusive to surgical samples from non-pCR patients. pCR was associated with baseline mutations in ADGRL3, IFT172, DNHD1, MUC16, TPTE, ABCA13, SULF1, TRANK1, PLEC, and genetic alterations in the HIPPO pathway. At the transcriptional level, pCR tumors exhibited heightened immune activation, characterized by higher fractions of memory B cells and resting NK cells, alongside fewer activated mast cells and cancer-associated fibroblasts. Responding tumors also showed significantly downregulation of pathways related to extracellular matrix organization, PI3K-Akt, and AGE-RAGE signalling compared to non-pCR tumors. Surgical samples from non-pCR tumors exhibited deminished leukocyte-mediated immunity and immune receptor activity, suggesting a potential resistance mechanism to NAC. Undetectable ctDNA at P2 and P3 time points was strongly correlated with pCR (P=0.03 and P=0.001, respectively), with P3 demonstrating slightly better sensitivity (0.90; 95% confidence interval [CI]: 0.55-1.00 vs. 0.80; 95% CI: 0.44-0.97) and specificity (0.63; 95% CI: 0.44-0.80 vs. 0.62; 95% CI: 0.44-0.79). Additionally, baseline USH2A mutations (hazard ratio [HR]: 11.9; 95% CI: 2.8-50.8; P<0.001) and chromosome 8q amplifications in surgical samples (HR: 4.3; 95% CI: 1.1-16.0; P=0.02) were predictive of shorter disease-free survival. Furthermore, elevated NHSL1 expression, while indicative of initial response, was associated with tumor relapse and poor overall survival (P=0.026 and P=0.023, respectively). Conclusions: This study identified key predictive and prognostic biomarkers associated with NAC response and long-term survival in breast cancer, providing valuable insights for developing individualized therapeutic strategies tailored to patient-specific molecular profiles. Citation Format: Menghao Dong, Jian Chen, Nannan Lu, Song Wang, Wenhui Wei, Ziming Wang, Jinnan Wang, Jinguo Zhang, Xinghua Han, Fufeng Wang, Qiuxiang Ou, Haimeng Tang, Xiaopeng Ma, Benjie Shan, Yueyin Pan. Genomic and transcriptomic correlates of response to neoadjuvant chemotherapy and survival outcomes in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2052.