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Circulating tumor DNA (ctDNA) utilizing a high-sensitivity panel to detect minimal residual disease post liver hepatectomy and predict disease recurrence
Michael J. Overman, Jean-Nicolas Vauthey, Thomas A. Aloia, Claudius Conrad, Yun Shin Chun, Allan Andresson Lima Pereira, et al.
Editorial comment from Dr Cremolini
The potential interest of the quantitative and qualitative evaluation of cfDNA in liquid biopsy is a field of interest in many solid malignancies. With regard to colorectal cancer, the potential application of liquid biopsy has been mainly focused on the early identification of mechanisms of acquired resistance to anti-EGFRs, but in spite of interesting and promising proof-of-concept findings, their way toward clinical practice has been halted by the lack of high levels of evidence. These works, commented in the poster discussion session, highlight another potential application of cfDNA in colorectal cancer, focusing on its prognostic impact in locally advanced rectal cancer and in patients undergoing radical resection of their liver metastases. The detection of cfDNA after neoadjuvant chemoradiotherapy or after rectal surgery predicts relapse with high specificity, independently of the exposure to adjuvant chemotherapy and the histopathological complete response. Similarly, the detection of cfDNA after liver metastases’ surgical resection predicts both relapse free and overall survival. These findings continue and corroborate previous results achieved by Tie et al. (Sci Transl Med 2016), evidencing the ability of cfDNA in unveiling the minimal residual disease following resection of stage II colorectal cancer. A currently ongoing clinical trial in stage II resected patients (where tools able to estimate the risk of relapse are extremely needed) incorporates results of cfDNA as decision drivers to administer or not adjuvant chemotherapy.
Preliminary data suggests that ctDNA can serve as a marker of minimal residual disease following colorectal cancer (CRC) tumor resection. Applicability of current ctDNA testing is limited by the requirement of sequencing known individual tumor mutations. We explored the applicability of a multi-gene panel ctDNA detection technology in CRC.
Plasma was prospectively collected from CRC patients (pts) undergoing hepatic resections with curative intent between 1/2013 to 9/2016. In a blinded manner 5ml of preoperative (preop) and immediate post-operative (postop) plasma were tested using a novel 30kb ctDNA digital sequencing panel (Guardant Health) covering SNVs in 21 genes and indels in 9 genes based on the landscape of genomic alterations in ctDNA from over 10,000 advanced cancer pts with a high theoretical sensitivity (96%) for CRC. Median unique molecule coverage for this study is 9000 for cfDNA inputs ranging from 10 – 150 ng (media input preop = 27 ng, median input postop = 49 ng) with 120,000X sequencing depth on an IIlumina HiSeq2500.
A total of 54 pts underwent liver metastectomies with curative intent with a median follow-up of 33 months. Preop blood was a median of 49 days from last systemic chemotherapy and 3 days prior to surgery; postop blood was a median of 17 days after resection. Tumor mutations from standard of care hotspot multigene panel testing (at MDACC) were identified in 46 of 54 pts (85%). Preop ctDNA mutation detection rate was 80% (43/54) and 44% (24/54) in postop setting, with postop median allele frequency of 0.16% (range 0.01% to 20%). In pts with a minimum of 1 year follow up, sensitivity of postop ctDNA for residual disease was 58% (95%CI; 41%-74%), and specificity was 100% (66%-100%). In 43 patients who underwent successful resection of all visible disease, postop detection of ctDNA significantly correlated with RFS (P = 0.002, HR 3.1; 95% CI 1.7-9.1) with 2-year RFS of 0% vs. 47%. Recurrence was detected in ctDNA a median of 5.1 months prior to radiographic recurrence.
The detection of postop ctDNA using an NGS panel-based approach is feasible and is associated with a very high rate of disease recurrence
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