In this JCO Precision Oncology Article Insights episode, Fergus Keane provides a summary on "Multi-Institutional Study Evaluating the Role of Circulating Tumor DNA in the Management of Appendiceal Cancers" by Belmont, et al published on May 9th, 2024.

TRANSCRIPT

Fergus Keane: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host, Fergus Keane, an ASCO editorial fellow. Today I will be providing a summary of the article entitled, "Multi-Institutional Study Evaluating the Role of Circulating Tumor DNA in the Management of Appendiceal Cancers" by Dr. Erika Belmont and colleagues.

While appendiceal cancers represent an uncommon diagnosis, the incidence has been rising, with now over 3000 new cases per year diagnosed in the United States. The management of appendiceal cancers includes surgical resection for localized tumors and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy, also known as HIPEC, for select patients with peritoneal metastasis. For patients with higher grade appendiceal cancers, systemic therapy is often included in the treatment paradigm. However, little data pertaining to the optimal treatment regimens exists.

Despite best practice, disease recurrence within three years of surgery will be observed in about 70% of cases of appendiceal cancers. The current conventional methods for surveillance for both detection of recurrence as well as for assessment of response to systemic therapy are using cross sectional imaging and serum tumor markers. These methods are limited and there is a recognition that more accurate biomarkers are required. Circulating tumor DNA, also known as liquid biopsies, refer to shed tumor DNA identified in the plasma. Several ctDNA assays exist, including tumor agnostic assays and tumor informed assays, the latter of which assess presence of personalized tumor derived mutations. The utility of circulating tumor DNA has been studied across several different cancer types and in several different disease settings, for instance in lung cancer and colorectal cancer. However, it has not been well demonstrated to date in appendiceal cancers.

This study aimed to investigate the role of the Signatera ctDNA assay in patients with appendiceal cancer. Specifically, the authors aimed to evaluate factors associated with circulating tumor DNA detection and the association between ctDNA and recurrence free survival after surgery. Their hypothesis was twofold, firstly, that circulating tumor DNA detection would be reduced in patients who received recent systemic therapy, and secondly, that circulating tumor DNA detection after cytoreductive surgery and HIPEC would be associated with a shorter recurrence free survival across all appendiceal cancer grades. The study design was a retrospective review of patients with appendiceal cancers treated at MD Anderson Cancer Center in Texas and the University of Chicago who underwent circulating tumor DNA testing between January 2019 and December 2022. Clinical, pathologic and treatment related information was collected for all patients. Regarding patient treatment, all patients received treatment as per the consensus recommendations at both cancer centers. Diagnostic evaluation was with CT or MRI imaging and serum tumor markers. Diagnostic laparoscopy was performed to evaluate for the presence of peritoneal metastases. The patient treatment plans were determined via MDT tumor board discussions and cytoreductive surgery, and HIPEC was offered with curative intent to eligible patients.

Systemic therapy with 5-FU based doublet or triplet therapy with or without VEGF inhibitors was offered to patients with grade two or three tumors and with a good performance status. HIPEC protocols involved the use of mitomycin C. Postoperative surveillance involved cross sectional imaging and tumor marker evaluation every three months for two years and thereafter every six months if the patients remain disease-free. Circulating tumor DNA testing was offered at the discretion of the treating physician, typically every three months after surgery. The Signatera assay is a personalized, multiplexed, PCR based next generation sequencing platform. Three major analyses were performed. Number one, the frequency of any time ctDNA detection was evaluated in patients with ctDNA assays drawn at the time of radiographic or laparoscopically identifiable disease. Number two, the correlation between preoperative ctDNA levels and intraoperative peritoneal cancer index was evaluated in patients with peritoneal metastases. The third analysis involves the association between circulating tumor DNA presence drawn within one year of optimal resection.

A total of 402 plasma samples were obtained from 94 patients from the two centers. Most patients had grade 2 or 3 appendiceal cancers and 85% underwent surgery. Most patients had peritoneal metastases. 50 patients had circulating tumor DNA assessment in the presence of stage 4 disease, included in this, 13 patients were tested preoperatively, 26 patients who developed recurrence after surgery were included, and 11 patients who did not undergo surgery. In total, circulating tumor DNA was detected in 66% of these patients. The detection frequency was 57.1% in patients with grade 1, 62.5% in patients with grade 2, and 70.4% in patients with grade 3 disease, but this variability did not meet statistical significance. Lower circulating tumor DNA detection was observed in patients who received systemic therapy within six weeks before ctDNA assessment at 43.8% versus 76.5%, and multivariate analysis confirmed this association, demonstrating that recent systemic therapy was associated with an odds ratio of 0.22 versus less recent systemic therapy.

17 patients underwent circulating tumor DNA testing before cytoreductive surgery, and HIPEC and circulating tumor DNA was detected in 23.5% of these cases. No correlation was observed between ctDNA detection and intraoperative PCI index in these patients. Among the 50 patients with ctDNA testing within one year of optimal resection, survival estimates were generated for 36 patients who underwent cytoreductive surgery and HIPEC for grade 2 and 3 appendiceal cancers. The median follow up was 19.6 months. Circulating tumor DNA detection after cytoreductive surgery was associated with a shorter median recurrence free survival of 11.3 months versus not detected in those without ctDNA detection. On multivariate analysis, this was confirmed. The median time interval between surgery and ctDNA detection was 31 weeks. In this cohort of 36 patients, 44.4% or 16 patients developed disease recurrence.

During the surveillance period, ctDNA was elevated in 93.8% of these patients, demonstrating a higher sensitivity than CEA, CA 19-9 or CA 125 tumor markers. Only one patient with disease recurrence had negative ctDNA at that time. Among these 16 patients with disease recurrence, one patient with a positive ctDNA test had their first sample drawn after diagnosis of disease recurrence, and one patient who had extensive adjuvant systemic therapy developed ctDNA negative recurrence. In the remaining 14 patients, circulating tumor DNA detection preceded the diagnosis of recurrence on imaging by a median of 11 weeks.

In summary, this study is a large, retrospective report of tumor-informed circulating tumor DNA testing in patients with appendiceal cancers. This study is one of the first to elucidate the factors associated with circulating tumor DNA detection in this disease and a potential role for circulating tumor DNA as an adjunct tool in the surveillance of patients with this malignancy.

Again, I'm Fergus Keane, a JCO Precision Oncology Editorial Fellow. Thank you for listening to the JCO Precision Oncology Article Insight. Please tune in for the next topic. Don't forget to give us a rating or review, and be sure to subscribe so that you never miss an episode. You can find all ASCO shows at www.asco.org/podcasts.

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