Evaluation of Circulating Tumor DNA in Patients with Ovarian Cancer Harboring Somatic <i>PIK3CA</i> or <i>KRAS</i> Mutations

Abstract

Purpose Circulating tumor DNA (ctDNA) is an attractive source for liquid biopsy to understand molecular phenotypes of a tumor non-invasively, which is also expected to be both a diagnostic and prognostic marker. PIK3CA and KRAS are among the most frequently mutated genes in epithelial ovarian cancer (EOC). In addition, their hotspot mutations have already been identified and are ready for a highly sensitive analysis. Our aim is to clarify the significance of PIK3CA and KRAS mutations in the plasma of EOC patients as tumor-informed ctDNA. Methods We screened 306 patients with ovarian tumors for somatic PIK3CA or KRAS mutations. A total of 85 EOC patients had somatic PIK3CA and/or KRAS mutations, and the corresponding mutations were subsequently analyzed using a droplet digital polymerase chain reaction in their plasma. Results The detection rates for ctDNA were 27% in EOC patients. Advanced stage and positive peritoneal cytology were associated with higher frequency of ctDNA detection. Preoperative ctDNA detection was found to be an indicator of outcomes, and multivariate analysis revealed that ctDNA remained an independent risk factor for recurrence (p=0.010). Moreover, we assessed the mutation frequency in matched plasma before surgery and at recurrence from 17 patients, and found six patients had higher mutation rates in cell-free DNA at recurrence compared to that at primary diagnosis. Conclusion The presence of ctDNA at diagnosis was an indicator for recurrence, which suggests potential tumor spread even when tumors were localized at the time of diagnosis.

Identification and clinical significance of somatic oncogenic mutations in epithelial ovarian cancer

“…PIK3CA encodes a lipid kinase involved in multiple signaling pathways that influence cellular functions such as growth, death, and proliferation. PIK3CA mutations occur in about 13% of solid tumors [ 18 ], and in our study, they occurred in 27.5% (22/80) of the EOC, which was similar to a recent study [ 19 ]. As for histological subtypes of EOC, PIK3CA mutation is rare in HG-SC and MC, although may be seen in up to 40% of CCC and EC [ 20 ], similar to our results (Table 2 ).…”

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 ].…”

Circulating tumor DNA: a noninvasive biomarker for tracking ovarian cancer

“… WGS 89 NR PFS, HR=3.31, 95% CI 1.33-9.13, p=0.011 HGSOC (III-IV) 46 plasma BRCA1/2 [ 55 ] CAPP-Seq NR NR NR HGSOC III or IV (1 mucinous carcinoma III) 10 Blood (8.5 ml) TP53 (60%), YAP2, SLITRK5, RET, GRM1, FAT1, LRRTM1, BRINP2, CDH9 and GRM1, etc. [ 56 ] ddPCR 37.3 NR OS (p=0.017); PFS (p<0.001) EOCs (I-IV) 85 Plasma (0.5 ml) PIK3CA or KRAS [ 57 ] MSP 70.6 Sp=50%, Sn=90.0% NR EOCs (I- III) 17 Plasma CNV [ 52 ] Targeted-NGS TP53=96 NR PFS, HR=0.12 (p<0.0001) EOCs (96% HGSOC) 97 Blood (9 ml); Plasma (2-3 ml) BRAC1, BRAC2, TP53 [ 58 ] Targeted-NGS 100 for TP53 and variable for the other genes NR PFS (p<0.01) HGSOC (II-IV) 12 Blood (5-6 ml); Plasma (1-2 ml) CNV and >500 cancer related genes including TP53, PTEN, BRCA2, etc. [ 59 ] Targeted-NGS ~90% for onlyTP53;100 for all mutant genes Sp=100%; Sn=74-75% OS (p=0.025); PFS (p<0.001) EOCs (II and III) 10 drugresistant recurrent; 11 drugsensitive recurrent Plasma (1 ml) NV and mutant genes including TP53, BRCA1, NOTCH2, DNMT3A, etc.…”

“…It is important that ctDNA exists as 150-200 base pairs short fragments that are able to perform PCR-based and NGS-based analyses, thereby probing the mono-mutations within cancer using allele-specific assays. Ogasawara et al [ 57 ] obtained approximately 30% mutation rates of targeted ctDNA (i.e., KRAS or PIK3CA ) from the patients with an ovarian tumor using ddPCR. Of note, Forshew et al .…”

“…After a surgical resection, it is difficult to distinguish between patients actually achieving remission from those having minimal residual disease. A few studies have demonstrated the ctDNA analysis can prognosticate disease recurrence and minimal residual tumor and may predict progression or response to treatment more rapidly than imaging or CA-125 [ 57 , 94 , 95 ]. Pereira et al [ 94 ] indicated that the utility of personalized ctDNA can identify the presence of residual tumor.…”