Circulating Tumor DNA is Unreliable to Detect Somatic Gene Alterations in Gastrointestinal Peritoneal Carcinomatosis

Abstract

Introduction Tumor agnostic circulating tumor DNA (ctDNA) is routinely used to guide treatment decisions in gastrointestinal (GI) cancers, especially metastatic cancers. The amount of ctDNA detected in plasma is affected by stage, tumor burden, and tumor vascularization. We hypothesized that peritoneal carcinomatosis (PC) is associated with lower ctDNA levels than other metastatic sites in GI cancers due to the plasma–peritoneal barrier. Methods We conducted a retrospective analysis of patients with stage II–IV GI cancers treated at our institution between 2015 and 2020 with available panel-based ctDNA results (Guardant 360TM). ctDNA analysis was performed on early and pretreatment samples. We compared the reported maximum variant allele frequency (mVAF) of somatic mutations across metastatic sites. Results Of the 279 patients with GI cancers (colorectal, upper GI, pancreaticobiliary), 212 had stage IV disease (PC: n = 61; visceral metastases: n = 138; other metastases: n = 13). Mean mVAF increased with increasing stages of disease (stage II: 3.6 ± 7; stage III: 6.4 ± 10; stage IV: 28.0 ± 51; p < 0.01). Among patients with stage IV disease, PC was associated with lower ctDNA levels independent of primary tumor site (PC only: 12.1%; PC+ visceral metastases: 26.8%; and visceral metastases only: 35.0%; p < 0.01). In a subset of patients (n = 27, matched pair analysis of genomic alterations (GAs) showed fewer GAs were detected in plasma compared with tissue. Conclusions PC of GI origin is associated with significantly lower ctDNA levels compared with visceral metastasis. Caution is warranted when interpreting ctDNA results from patients with PC due to lower sensitivity for detecting actionable mutations.

ASO Author Reflections: Challenges of Circulating Tumor DNA in the Management of Gastrointestinal Peritoneal Carcinomatosis

“…Our study of 279 patients with stages 2-4 GI malignancies found that the amount of plasma ctDNA is significantly lower in GI malignancies with PC than in visceral metastases. 6 The significance of this observation is further enhanced by the fact that the majority of the patients in this study had large volume of peritoneal disease burden, with an average of six intrabdominal regions involved. We also found that plasma ctDNA next-generation sequencing (NGS) showed fewer genomic alterations in patients with GI PC than tissue analysis, with a concordance rate of merely 18%.…”

“…We also found that plasma ctDNA next-generation sequencing (NGS) showed fewer genomic alterations in patients with GI PC than tissue analysis, with a concordance rate of merely 18%. 6 These observations underscore the important biologic differences in the shedding and transport of ctDNA between PC and visceral metastasis. Detection of ctDNA is affected by the anatomy of the peritoneum and peritoneal fluid transport, as well as by the histology of tumors that have a predilection to metastasize to the peritoneum.…”

Plasma Exosome Gene Signature Differentiates Colon Cancer from Healthy Controls

“…Firstgeneration liquid biopsies utilizing cell-free circulating tumor DNA (ctDNA) have shown promise in identification of molecular-residual disease (MRD), somatic gene alterations, and to assess treatment response in CRC; however, there are significant limitations. Specifically, ctDNA has poor sensitivity in mucinous cancers 5 and peritoneal carcinomatosis (PC), 6 with ctDNA detected in only 38-53% of patients with PC. 7,8 We recently reported that ctDNA is detected at significantly lower levels in PC compared with visceral metastasis (VM) and is unreliable to detect somatic gene alterations in gastrointestinal PC.…”

“…7,8 We recently reported that ctDNA is detected at significantly lower levels in PC compared with visceral metastasis (VM) and is unreliable to detect somatic gene alterations in gastrointestinal PC. 6 Due to its dismal prognosis and the only site of disease in 44% of patients with CRC recurrence, 9 there is an urgent need to identify novel blood-based biomarkers that can accurately identify colon cancer regardless of tumor type and metastasis location.…”

Heated Intraperitoneal Chemotherapy for Locally Advanced Colon Cancer—Restarting the Fire

“…A major criticism of previous trials using oxaliplatin for perfusion was the inability to initiate or delay adjuvant chemotherapy after complications secondary to HIPEC. In the HIPECT4 trial, 70.8% of patients received adjuvant chemotherapy within 12 weeks of resection and HIPEC and 68.4% received resection alone; these percentages were even higher when the patients who had pT3N0 disease on final pathology were excluded.…”