TP53 variant allele frequency correlates with the chemotherapy response score in ovarian/fallopian tube/peritoneal high-grade serous carcinoma

Molecular findings in ovarian, fallopian tube, and peritoneal high-grade serous carcinoma (HGSCa) are emerging as potential prognostic indicators. The chemotherapy response score (CRS) has been proposed as a histologic-based prognostic factor in patients with HGSCa treated with neoadjuvant chemotherapy (NACT). No study details the relationship between the mutational landscape of HGSCa and the CRS. This study addresses this issue using next-generation sequencing (NGS). We retrospectively identified 25 HGSCas treated with NACT and pathology material available to calculate the CRS. All cases had NGS on the primary debulking specimen post-NACT. The three-tier Böhm CRS was applied to the omentum or adnexa and calculated as a combined score. Tumor mutation burden (TMB) and TP53 variant allele frequency (VAF) were calculated and used in correlative analysis. All cases had at least one mutation, most commonly TP53 (25 cases, 100%). Other mutations were BRCA2 (one case, 4%), ARID1A (two cases, 8%), and 1 (4%) of each of the following: ERBB2, NTRK3, STK11, NTRK2, TSC1, PIK3CA, NF1, NOTCH3, CDK2, SMAD4, and PMS2. TMB ranged from 2.58 to 7.75 (median 3.84). There was no statistically significant relationship between the TMB and omental CRS, R-squared = 0.011 (P = 0.62); adnexal CRS, R-squared = 0.005 (P = 0.74); or with the combined CRS, R-squared = 0.009 (P = 0.65). Statistically significant correlation was found between the TP53 VAF and the omental CRS (R-squared = 0.28, P = 0.007), adnexal CRS (R-squared = 0.26, P = 0.01), and the combined CRS (R-squared = 0.33, P = 0.0026). The TP53 VAF was adjusted for percent of tumor present on the slide resulting in an average per cell TP53 mutational load, resulting in similar results with a statistically significant correlation between the average per cell TP53 mutational load and the omental CRS (R-squared = 0.27, P = 0.02), adnexal CRS (R-squared = 0.16, P = 0.05), and the combined CRS (R-squared = 0.23, P = 0.02). In summary, NGS confirmed TP53 mutations in all cases of HGSCa. TMB showed no correlation with the CRS. TP53 VAF and average per cell TP53 mutational load showed significant correlation with the CRS, whether graded on the adnexa or omentum or as a combined score, indicating concordance between molecular and histological findings following NACT.