Abstract 5738: Transcriptomic profiles of response to neoadjuvant chemotherapy in patients with high-grade serous ovarian cancer
Authors: Lee Sanghoon , Zhao Li , Fleming Nicole D. , Celestino Joseph , Hajek Richard A. , Morgan Margaret B. , Liu Yan , Westin Shannon N. , Jazaeri Amir A. , Liu Jinsong , Zhang Jianhua , Futreal P Andrew , Sood Anil K. 
Published: June 2022

Background: High-grade serous ovarian cancer (HGSC) is the most aggressive epithelial ovarian cancer, exhibiting tumor heterogeneity, molecular abnormality, and variable clinical outcomes. The heterogeneity and apparent adaptability of the HGSC genome under selective pressure by chemotherapy likely explain the high rates of drug resistance in HGSC. However, the underlying mechanisms of drug resistance are not well understood. Following our previous findings of significant distinct molecular and cellular characteristics in pre-treatment tumor samples from highly clinically annotated HGSC patients who received neoadjuvant chemotherapy (NACT), we examined post-treatment transcriptomic changes associated with excellent or poor responders to NACT in HGSC patients.

Methods: Thirty tumor tissues (pre- and post-treatment) after 3 to 4 cycles of NACT were collected from HGSC patients at interval cytoreductive debulking surgery from the following groups: excellent response to NACT with carboplatin/paclitaxel (post-ER, n=8); poor response to NACT (post-PR, n=8). Primary or metastatic sites for each patient were obtained (n=13, post-ER; n=17, post-PR) and subjected to RNA sequencing. The downstream bioinformatics analysis was then performed and compared with the data from the matched pre-NACT samples from the same patients (Lee et al., Cell Reports, 2020).

Results: We identified a total of 9,764 upregulated and 2,762 downregulated differentially expressed genes (DEGs, absolute log2FC &gt;=2, adj-p&lt;0.05) in the post-NACT samples vs the pre-NACT samples in the ER group. In contrast, 11,246 upregulated and 1,320 downregulated DEGs were found in the NACT-PR group. Ovarian cancer-related genes, including KRAS, NRAS, BRCA1/2, RB1, NF1, MLH1, PIK3CA, MSH2, AKT1, and NOTCH3 were differentially expressed in post-NACT vs pre-NACT in both ER and PR groups. TP53 was exclusively upregulated in post-ER vs pre-ER, and GABRA6 was exclusively upregulated in post-PR vs pre-PR. In signaling pathway analysis, apoptosis and DNA repair-related pathways were exclusively downregulated in post-ER vs pre-ER. Interestingly, the percentage of immune cells − CD8 and macrophages M0 were significantly elevated in post-ER (p&lt;0.05), while γδ T cells and activated dendritic cells were significantly decreased in the post-ER (p&lt;0.05), not in the PR. Neutrophil cells were significantly lower in post-PR vs pre-PR, but not in ER group. We also found that the level of ESR1 decreased significantly in post-ER vs post-PR (p&lt;0.05). The level of PAX8 significantly increased in post-PR vs post-ER (p&lt;0.05).

Conclusions: Our transcriptomic analysis revealed distinct transcripts changes in post-NACT vs pre-NACT tumor tissues from HGSC patients with excellent or poor response to the NACT. These findings could enhance treatment decision-making and rationale for developing alternative therapies for patients with HGSC.

Citation Format: Sanghoon Lee, Li Zhao, Nicole D. Fleming, Joseph Celestino, Richard A. Hajek, Margaret B. Morgan, Yan Liu, Shannon N. Westin, Amir A. Jazaeri, Jinsong Liu, Jianhua Zhang, P Andrew Futreal, Anil K. Sood. Transcriptomic profiles of response to neoadjuvant chemotherapy in patients with high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5738.