Changes in the gene mutation profiles of circulating tumor DNA detected using CAPP‑Seq in neoadjuvant chemotherapy‑treated advanced ovarian cancer

Abstract

Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) is a novel ultrasensitive next-generation sequencing-based approach that is used to detect circulating tumor DNA (ctDNA). The aim of the present study was to compare the gene mutation profiles and blood tumor mutation burden (bTMB) measured between pre-and post-neoadjuvant chemotherapy (NAC), utilizing CAPP-seq for plasma ctDNA in patients with advanced ovarian cancer. The current study included 10 patients (6 NAC-sensitive and 4 NAC-resistant) clinically diagnosed as having stage III or IV ovarian cancer and were administered NAC between May 2017 and February 2019. The plasma ctDNA samples were collected at pre-and post-NAC, and comprehensive gene mutation analysis was performed using CAPP-seq. In 5 out of 6 NAC-sensitive cases, the variant allele frequency (VAF) of non-synonymous somatic mutations decreased following NAC. In 2 out of the 4 NAC-resistant cases, the VAF of non-synonymous somatic mutations increased, and new somatic mutations emerged following NAC. In regard to TP53 mutation, the rate of TP53 mutation in the NAC-resistant cases was significantly higher compared with NAC-sensitive cases. Finally, the bTMB decreased significantly after NAC treatment in the NAC-sensitive cases, even though there were no significant differences in the pretreatment bTMB levels between the NAC-sensitive and NAC-resistant cases. These results indicated that gene mutation can be profiled and monitored using liquid biopsy-based CAPP-Seq in patients with advanced ovarian cancer with NAC treatment, and TP53 mutation in the ctDNA and bTMB may be novel biomarkers that can be used for patient monitoring during NAC treatment.

Comprehensive Gene Mutation Profiling of Circulating Tumor DNA in Ovarian Cancer: Its Pathological and Prognostic Impact

“…Our analysis showed that the TP53 mutation detected in the ctDNA was the most frequent in whole study cohort (19/51; 37.3%), and in most of the HGSC cases (16/24; 66.7%), which is less than previous tissue DNA studies [ 25 ]. However, the detection rate of TP53 mutation in ctDNA from HGSC patients was reported at about 40–60% in previous ctDNA studies [ 25 , 28 ]. To validate the concordance of genomic alternations between tissue DNA and ctDNA, we analyzed tissue-DNA of 22/24 HGSC patients by focusing on TP53 mutations.…”

“…This study suggested the association of bTMB and clinical outcomes in ovarian cancer for the first time. We reported previously that bTMB might be a new biomarker for monitoring treatment during NAC in advanced ovarian cancers [ 28 ], but the mechanism of the association of bTMB with efficacy of chemotherapy nor immunotherapy remains unclear in ovarian cancer. In our current analysis of bTMB among all the clinical stages and different histological subtypes, although there were no significant differences in the pre-treatment baseline bTMB in each group, or bTMB association with PFS, we could detect some populations of highly mutated tumors in each group ( Figure 5 ), which might be the therapeutic target for anti-PD-L1/PD-1 therapies [ 50 ].…”

“…In our previous study, we showed for the first time the feasibility of ctDNA analysis using CAPP-Seq in gynecological cancers including ovarian cancer, cervical cancer, endometrial cancer, and metastatic colon cancer to the ovary [ 26 , 27 ]. Moreover, we recently demonstrated gene mutation profiles and their monitoring in 10 advanced ovarian cancer patients during neoadjuvant chemotherapy using CAPP-Seq-based liquid biopsy [ 28 ]. However, detailed ctDNA-based gene profiling in individual ovarian cancer patients with various disease stage or histological subtypes has not yet been fully elucidated.…”

Prediction of the treatment response in ovarian cancer: a ctDNA approach

“…These results can be considered as a proof of using ctDNA concept to guide the clinical decisions during the cycles of chemotherapy in ovarian cancers [118]. In addition, Noguchi et al [119] compared the variant allele frequency (VAF) of the measured ctDNA mutations during neoadjuvant chemotherapy in 10 plasma samples. In 5 out of 6 NAC-sensitive cases, the VAF of non-synonymous somatic mutations (TP53, KCAN5, and GJA8) decreased following NAC.…”

Recent Advances in Integrative Multi-Omics Research in Breast and Ovarian Cancer

“…Studies showed that there is an added benefit to adjuvant chemotherapy in the low genomic risk group when compared to patients who did not receive chemotherapy [ 260 , 263 ]. Finally, emerging data supports the role of analyses of circulating tumor DNA in routine clinical care [ 48 , 264 , 265 , 266 , 267 , 268 ]. The FDA recently approved the FoundationOne Liquid CDx test, which is a circulating cell-free DNA (cfDNA) based-assay as a companion diagnostic for treatment of BRCA mutant (germline or somatic) ovarian cancer patients with the PARP inhibitor rucaparib as well as alpelisib treatment of HR+/HER2-, PIK3CA mutated breast cancer patients [ 249 ].…”