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. 2016 Jul 6;8(346):346ra92.
doi: 10.1126/scitranslmed.aaf6219.

Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer

Jeanne Tie  1 , Yuxuan Wang  2 , Cristian Tomasetti  3 , Lu Li  4 , Simeon Springer  2 , Isaac Kinde  5 , Natalie Silliman  2 , Mark Tacey  6 , Hui-Li Wong  7 , Michael Christie  8 , Suzanne Kosmider  9 , Iain Skinner  9 , Rachel Wong  10 , Malcolm Steel  11 , Ben Tran  12 , Jayesh Desai  7 , Ian Jones  13 , Andrew Haydon  14 , Theresa Hayes  15 , Tim J Price  16 , Robert L Strausberg  17 , Luis A Diaz Jr  2 , Nickolas Papadopoulos  2 , Kenneth W Kinzler  2 , Bert Vogelstein  18 , Peter Gibbs  19
Affiliations

Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer

Jeanne Tie et al. Sci Transl Med. .

Abstract

Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify patients at the highest risk of recurrence and help inform adjuvant treatment decisions. We used massively parallel sequencing-based assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer. In patients not treated with adjuvant chemotherapy, ctDNA was detected postoperatively in 14 of 178 (7.9%) patients, 11 (79%) of whom had recurred at a median follow-up of 27 months; recurrence occurred in only 16 (9.8 %) of 164 patients with negative ctDNA [hazard ratio (HR), 18; 95% confidence interval (CI), 7.9 to 40; P < 0.001]. In patients treated with chemotherapy, the presence of ctDNA after completion of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8 to 68; P = 0.001). ctDNA detection after stage II colon cancer resection provides direct evidence of residual disease and identifies patients at very high risk of recurrence.

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Conflict of interest statement

Competing interests: K.W.K., N.P, L.A.D., and B.V. are founders of PapGene and Personal Genome Diagnostics and members of the Scientific Advisory Boards of Morphotek and Sysmex-Inostics. I.K. is an employee of PapGene. These companies and others have licensed patent applications on genetic technologies from Johns Hopkins, some of which result in royalty payments to K.W.K., N.P., L.A.D., B.V., and I.K. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies.

Figures

Fig. 1
Fig. 1
Patient enrolment and sample collection
Fig. 2
Fig. 2. RFS in patients not treated with adjuvant chemotherapy
(A) Kaplan-Meier estimates of RFS for all patients not treated with adjuvant chemotherapy, stratified by postoperative ctDNA status. (B) Kaplan-Meier estimates of RFS in the same patients, stratified by clinicopathologic characteristics. (C) Kaplan-Meier estimates of RFS stratified by postoperative ctDNA status in patients with low-risk clinicopathologic characteristics. (D) Kaplan-Meier estimates of RFS stratified by postoperative ctDNA status in patients with high-risk clinicopathologic characteristics. The high-risk group is defined as those having mismatch repair–proficient (pMMR) tumors with at least one of the following poor prognostic features: T4, LN yield <12, LVI, and poor tumor differentiation. The low-risk group is defined as those with no poor prognostic features.
Fig. 3
Fig. 3. ctDNA status before, during, and after adjuvant chemotherapy
(A to F) ctDNA concentrations (% mutant alleles) for the six patients with positive postoperative ctDNA who subsequently received adjuvant chemotherapy. The blue shaded box indicates the period during which adjuvant chemotherapy was administered. The dotted line indicates the time of radiologic recurrence or last follow-up (if recurrence-free). The ctDNA status of patients represented in (A) and (B) initially became negative, then became positive again at the completion of adjuvant chemotherapy; both patients subsequently suffered a radiologic recurrence. Note that CEAs were not elevated in either patient at any time point. (C to F) Four patients whose ctDNA became negative after completion of chemotherapy. Three of these patients (patients C, D, and F) remained radiologic recurrence-free at their last follow-up visit. (G) Kaplan-Meier estimates of RFS according to post-chemotherapy ctDNA status in patients treated with adjuvant chemotherapy. ND, not detected; NE, not elevated.
Fig. 4
Fig. 4. Serial ctDNA status up to radiological recurrence
(A) Serial ctDNA measurements up to the time of radiological recurrence for the nine patients who were not treated with adjuvant chemotherapy and who were ctDNA-positive postoperatively. (B) Scatter plot of the lead time to radiological recurrence for ctDNA detection and CEA elevation, with the error bars representing the median and IQR.
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