Circulating tumor DNA as a biomarker to guide therapy in post-operative locally advanced rectal cancer: the best option?

e15125 Background: Neoadjuvant radiochemotherapy (RCT) is rapidly becoming the preferred treatment for patients diagnosed with late-stage locally advanced rectal cancer (LARC). Presently, tumor regression grades (TRG) is used to characterize treatment responsiveness; patients with low TRG scores have been shown to receive no benefit from surgery. To-date, however, there exists no reliable method for identifying low TRG-scoring patients without surgery. Here we propose the use of circulating tumor DNA (ctDNA) to identify low TRG-scoring patients to reduce overtreatment and improve quality of life. Methods: 30 LARC patients undergoing neoadjuvant RCT were prospectively enrolled in our study. Plasma was collected before treatment, immediately preceding cycle 3 chemotherapy, and 2 weeks following cycle 4 chemotherapy. Tumor tissue was also collected before treatment start. CtDNA and tumor DNA were sequenced using Accu-Act, a 61-gene NGS panel. Tumor response was classified as TRG1-5 according to Mandard classification system. Somatic mutation profiles were correlated with tumor response. The accuracy of ctDNA and tumor DNA in predicting TRG scores was calculated using the change of allele frequency. The predictive value of ctDNA was also compared to that of standard CEA and CA199 assays. Patients with CEA and CA199 scores below threshold were also considered for evaluation. Results: 18 of the 30 LARC patients enrolled had complete ctDNA profiling test among whom 13 had already undergone surgery. 17 somatic mutations were identified from the 10 patients with TRG scores of either 1, 2, or 3. Predictive accuracy of pretreatment ctDNA profiling was 70%, compared to that of CEA analysis (66%) and CA199 analysis (50%). TRG prediction using ctDNA successfully evaluated half of patients for whom CEA analysis failed to predict the change in tumor burden. Conclusions: Our findings suggest ctDNA mutation profiling may be a powerful tool for predicting TRG in LARC patients undergoing RCT. Further studies are needed to validate the utility of ctDNA in identifying patients who can be spared from unnecessary surgical treatment in LARC. Clinical trial information: NCT02031939.

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Clinical impact of pre-surgery circulating tumor DNA after total neoadjuvant treatment in locally advanced rectal cancer: a biomarker study from the GEMCAD1402 Trial

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-20-4769 ◽

2021 ◽

pp. clincanres.4769.2020

Author(s):

Joana Vidal ◽

David Casadevall ◽

Beatriz Bellosillo ◽

Carles Pericay ◽

Rocio Garcia-Carbonero ◽

...

Keyword(s):

Rectal Cancer ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Advanced Rectal Cancer ◽

Circulating Tumor Dna ◽

Locally Advanced Rectal Cancer ◽

Clinical Impact ◽

Tumor Dna

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Circulating Tumor DNA Predicts Pathologic and Clinical Outcomes Following Neoadjuvant Chemoradiation and Surgery for Patients With Locally Advanced Rectal Cancer

JCO Precision Oncology ◽

10.1200/po.20.00220 ◽

2021 ◽

pp. 123-132

Author(s):

Susan G. R. McDuff ◽

Karin M. Hardiman ◽

Peter J. Ulintz ◽

Aparna R. Parikh ◽

Hui Zheng ◽

...

Keyword(s):

Rectal Cancer ◽

Predictive Value ◽

Surgical Outcome ◽

Locally Advanced ◽

Advanced Rectal Cancer ◽

Circulating Tumor Dna ◽

Locally Advanced Rectal Cancer ◽

Neoadjuvant Chemoradiation ◽

Node Negative ◽

Tumor Dna

PURPOSE This study was designed to assess the ability of perioperative circulating tumor DNA (ctDNA) to predict surgical outcome and recurrence following neoadjuvant chemoradiation for locally advanced rectal cancer (LARC). MATERIALS AND METHODS Twenty-nine patients with newly diagnosed LARC treated between January 2014 and February 2018 were enrolled. Patients received long-course neoadjuvant chemoradiation prior to surgery. Plasma ctDNA was collected at baseline, preoperatively, and postoperatively. Next-generation sequencing was used to identify mutations in the primary tumor, and mutation-specific droplet digital polymerase chain reaction was used to assess mutation fraction in ctDNA. RESULTS The median age was 54 years. The overall margin-negative, node-negative resection rate was 73% and was significantly higher among patients with undetectable preoperative ctDNA (n = 17, 88%) versus patients with detectable preoperative ctDNA (n = 9, 44%; P = .028). Undetectable ctDNA was also associated with more favorable neoadjuvant rectal scores (univariate linear regression, P = .029). Recurrence-free survival (RFS) was calculated for the subset (n = 19) who both underwent surgery and had postoperative ctDNA available. At a median follow-up of 20 months, patients with detectable postoperative ctDNA experienced poorer RFS (hazard ratio, 11.56; P = .007). All patients (4 of 4) with detectable postoperative ctDNA recurred (positive predictive value = 100%), whereas only 2 of 15 patients with undetectable ctDNA recurred (negative predictive value = 87%). CONCLUSION Among patients treated with neoadjuvant chemoradiation for LARC, patients with undetectable preoperative ctDNA were more likely to have a favorable surgical outcome as measured by the rate of margin-negative, node-negative resections and neoadjuvant rectal score. Furthermore, we have confirmed prior reports indicating that detectable postoperative ctDNA is associated with worse RFS. Future prospective study is needed to assess the potential for ctDNA to assist with personalizing treatment for LARC.

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