Preoperative Circulating Tumor DNA in Patients with Peritoneal Carcinomatosis is an Independent Predictor of Progression-Free Survival

Our plain-English summary of Preoperative Circulating Tumor DNA in Patients with Peritoneal Carcinomatosis is an Independent Predictor of Progression-Free Survival, by J.M. Baumgartner, V.M. Raymond, R.B. Lanman, et al (Annals of Surgical Oncology, 2018).

The study

• Authors: J.M. Baumgartner, V.M. Raymond, R.B. Lanman, L. Tran, K.J. Kelly, A.M. Lowy, R. Kurzrock
• Journal: Annals of Surgical Oncology
• Published: 2018;25(8):2400-2408
• Cited by: 63 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Next-generation sequencing (NGS) is a useful tool for detecting genomic alterations in circulating tumor DNA (ctDNA). To date, most ctDNA tests have been performed on patients with widely metastatic disease. Patients with peritoneal carcinomatosis (metastases) present unique prognostic and therapeutic challenges. We therefore explored preoperative ctDNA in patients with peritoneal metastases undergoing surgery.

Methods: Patients referred for surgical resection of peritoneal metastases underwent preoperative blood-derived ctDNA analysis (clinical-grade NGS [68-73 genes]). ctDNA was quantified as the percentage of altered circulating cell-free DNA (% cfDNA).

Results: Eighty patients had ctDNA testing: 46 (57.5%) women; median age 55.5 years. The following diagnoses were included: 59 patients (73.8%), appendix cancer; 11 (13.8%), colorectal; five (6.3%), peritoneal mesothelioma; two (2.5%), small bowel; one (1.3%) each of cholangiocarcinoma, ovarian, and testicular cancer. Thirty-one patients (38.8%) had detectable preoperative ctDNA alterations, most frequently in the following genes: TP53 (25.8% of all alterations detected) and KRAS (11.3%). Among 15 patients with tissue DNA NGS, 33.3% also had ctDNA alterations (overall concordance = 96.7%). Patients with high ctDNA quantities (≥ 0.25% cfDNA, n = 25) had a shorter progression-free survival (PFS) than those with lower ctDNA quantities (n = 55; 7.8 vs. 15.0 months; hazard ratio 3.23, 95% confidence interval 1.43-7.28, p = 0.005 univariate, p = 0.044 multivariate).

Conclusions: A significant proportion of patients with peritoneal metastases referred for surgical intervention have detectable ctDNA alterations preoperatively. Patients with high levels of ctDNA have a worse prognosis independent of histologic grade.

In plain English

This prospective study at the University of California San Diego tested preoperative blood for circulating tumor DNA (ctDNA) shed by tumors. It included 80 consecutive patients referred between May 2015 and January 2017 with cancer spread to the abdominal lining (peritoneal metastases). Most had appendix (59) or colorectal (11) cancer; five had peritoneal mesothelioma. The study did not examine asbestos exposure. Detectable ctDNA alterations were found in 31 of 80 patients (38.8%), including 2 of 5 with mesothelioma. The most commonly altered genes were TP53 and KRAS. The 25 patients with higher ctDNA (0.25% or more of cell-free DNA) had median progression-free survival of 7.8 months (95% CI 3.6 to 12.0), versus 15.0 months (95% CI 11.8 to 18.3) for the 55 with lower levels. This association remained after accounting for tumor grade (hazard ratio 2.36, 95% CI 1.02 to 5.45, p = 0.044). Mesothelioma cases were excluded from grade analyses, with no separate survival results. The authors concluded that patients with high preoperative ctDNA have a worse prognosis. They noted modest sample size, a single institution and incomplete follow-up.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Prospective study of preoperative blood ctDNA testing in patients undergoing surgery for peritoneal metastases
• Who was studied: 80 consecutive patients who had ctDNA analyzed and underwent surgery for peritoneal metastases. They had been referred to the UCSD peritoneal malignancy program for consideration of surgery from 20 May 2015 to 1 January 2017. Diagnoses: 59 appendix cancer, 11 colorectal, 5 peritoneal mesothelioma, 2 small bowel, and 1 each of cholangiocarcinoma, ovarian and testicular cancer. 46 were women; median age was 55.5 years.
• Exposure: No asbestos or other environmental exposure was studied. The factor examined was the preoperative level of circulating tumor DNA, measured as the percentage of altered cell-free DNA (% cfDNA). Patients were split into high (0.25% or more) and low (below 0.25%) groups.
• Main results:
  • Detectable preoperative ctDNA alterations were found in 31 of 80 patients (38.8%).
  • Among the 5 patients with malignant mesothelioma, 2 (40.0%) had detectable ctDNA alterations.
  • The most commonly altered genes were TP53 (16 alterations, 25.8% of all alterations) and KRAS (7, 11.3%).
  • Median progression-free survival was 15.0 months (95% CI 11.8 to 18.3) in the 55 patients with low ctDNA levels and 7.8 months (95% CI 3.6 to 12.0) in the 25 with high levels.
  • High ctDNA predicted worse progression-free survival on univariate analysis (HR 3.23, 95% CI 1.43 to 7.28, p = 0.005) and on multivariate analysis (HR 2.36, 95% CI 1.02 to 5.45, p = 0.044).
  • High-grade histology also remained an independent predictor of worse progression-free survival on multivariate analysis (HR 3.30, p = 0.009).
  • In 15 patients who also had tumor tissue sequencing, 5 had alterations in the blood. Among those 5, overall, positive and negative concordance with tissue was 96.7%, 35.3% and 96.6%.
  • Mesothelioma cases were excluded from the tumor grade analyses.
• The authors' conclusion: The authors concluded that ctDNA alterations are detectable in many patients having surgery for peritoneal metastases and that patients with high preoperative ctDNA levels have a worse prognosis. They called ctDNA a promising method for prognosis that merits more study.
• Limitations the authors state:
  • Modest sample size, a single institution, and incomplete follow-up due to referral patterns.
  • Not all patients had tissue genetic profiling for comparison with ctDNA.
  • DNA in the blood may come from sources other than the tumor being studied, such as a second cancer or clonal hematopoiesis.

Topics

Medical terms in this study, explained in our Lexicon: Progression-Free Survival, Next-Generation Sequencing (NGS), ctDNA, Surgical Resection, Peritoneal Mesothelioma, Hazard Ratio, confidence interval, Prognosis.

Related studies

• Tumor-specific genetic variants can be detected in circulating cell-free DNA of malignant pleural mesothelioma patients — M. Hylebos, K. Op de Beeck, et al. (2018)
• Preoperative computed tomography does not predict resectability in peritoneal carcinomatosis — J.D. Rivard, W.J. Temple, et al. (2014)
• Preoperative Thrombocytosis Predicts Shortened Survival in Patients with Malignant Peritoneal Mesothelioma Undergoing Operative Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy — Y.C. Li, T. Khashab, et al. (2017)
• High Wilms' tumour gene (WT1) expression and low mitotic count are independent predictors of survival in diffuse peritoneal mesothelioma — A. Scattone, G. Serio, et al. (2012)
• Malignant Peritoneal Mesothelioma: National Practice Patterns, Outcomes, and Predictors of Survival — V. Verma, R.L. Sleightholm, et al. (2018)
• Progression free survival rate at 9 and 18 weeks predict overall survival in patients with malignant pleural mesothelioma: an individual patient pooled analysis of 10 European Organisation for Research and Treatment of Cancer Lung Cancer Group studies and an independent study validation — B. Hasan, L. Greillier, et al. (2014)

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