Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Hum Pathol. 2021 Sep;115:76-83. doi: 10.1016/j.humpath.2021.06.003. Epub 2021 Jun 19.
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.
卵巢、输卵管和腹膜高级别浆液性癌（HGSCa）的分子发现正在成为潜在的预后指标。化疗反应评分（CRS）已被提议作为接受新辅助化疗（NACT）治疗的 HGSCa 患者的基于组织学的预后因素。尚无研究详细描述 HGSCa 的突变景观与 CRS 之间的关系。本研究使用下一代测序（NGS）解决了这个问题。我们回顾性地确定了 25 例接受 NACT 治疗且有病理学材料可计算 CRS 的 HGSCa。所有病例在 NACT 后均对初次减瘤标本进行 NGS。应用三级 Böhm CRS 对网膜或附件进行评分，并计算为综合评分。计算肿瘤突变负担（TMB）和 TP53 变体等位基因频率（VAF）并进行相关性分析。所有病例均至少有一个突变，最常见的是 TP53（25 例，100%）。其他突变包括 BRCA2（1 例，4%）、ARID1A（2 例，8%）和以下每种情况的 1 例：ERBB2、NTRK3、STK11、NTRK2、TSC1、PIK3CA、NF1、NOTCH3、CDK2、SMAD4 和 PMS2。TMB 范围为 2.58 至 7.75（中位数 3.84）。TMB 与网膜 CRS、R 平方=0.011（P=0.62）；附件 CRS，R 平方=0.005（P=0.74）；或综合 CRS 之间无统计学显著关系，R 平方=0.009（P=0.65）。TP53 VAF 与网膜 CRS（R 平方=0.28，P=0.007）、附件 CRS（R 平方=0.26，P=0.01）和综合 CRS（R 平方=0.33，P=0.0026）之间存在统计学显著相关性。调整幻灯片上存在的肿瘤百分比后，TP53 VAF 得到平均每个细胞的 TP53 突变负荷，结果表明平均每个细胞的 TP53 突变负荷与网膜 CRS（R 平方=0.27，P=0.02）、附件 CRS（R 平方=0.16，P=0.05）和综合 CRS（R 平方=0.23，P=0.02）之间存在统计学显著相关性。总之，NGS 证实了所有 HGSCa 病例均存在 TP53 突变。TMB 与 CRS 无相关性。TP53 VAF 和平均每个细胞的 TP53 突变负荷与 CRS 有显著相关性，无论是在附件还是网膜上分级，还是作为综合评分，这表明在接受 NACT 后分子和组织学发现之间存在一致性。
