Resistance prediction in high-grade serous ovarian carcinoma with neoadjuvant chemotherapy using data-independent acquisition proteomics and an ovary-specific spectral library

High-grade serous ovarian carcinoma (HGSOC) is the most common subtype of ovarian cancer with 5-year survival rates below 40%. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is recommended for patients with advanced-stage HGSOC unsuitable for primary debulking surgery (PDS). However, about 40% of patients receiving this treatment exhibited chemoresistance of uncertain molecular mechanisms and predictability. Here, we built a high-quality ovary-specific spectral library containing 130 735 peptides and 10 696 proteins on Orbitrap instruments. Compared to a published DIA pan-human spectral library (DPHL), this spectral library provides 10% more ovary-specific and 3% more ovary-enriched proteins. This library was then applied to analyze data-independent acquisition (DIA) data of tissue samples from an HGSOC cohort treated with NACT, leading to 10 070 quantified proteins, which is 9.73% more than that with DPHL. We further established a six-protein classifier by parallel reaction monitoring (PRM) to effectively predict the resistance to additional chemotherapy after IDS (Log-rank test, P = 0.002). The classifier was validated with 57 patients from an independent clinical center (P = 0.014). Thus, we have developed an ovary-specific spectral library for targeted proteome analysis, and propose a six-protein classifier that could potentially predict chemoresistance in HGSOC patients after NACT-IDS treatment.

Automated summary

High-grade serous ovarian carcinoma (HGSOC) is a common subtype of ovarian cancer with low survival rates. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is recommended for advanced-stage HGSOC patients. However, a significant number of patients exhibit chemoresistance with unknown mechanisms.