Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study.
<h4>Background</h4>In patients with resectable colorectal liver metastases (CRLM), the role of pre- and postoperative systemic therapy continues to be debated. Previous studies have shown that circulating tumor DNA (ctDNA) analysis, as a marker of minimal residual disease, is a powerful...
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Public Library of Science (PLoS)
2021-05-01
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| author | Jeanne Tie Yuxuan Wang Joshua Cohen Lu Li Wei Hong Michael Christie Hui Li Wong Suzanne Kosmider Rachel Wong Benjamin Thomson Julian Choi Adrian Fox Kathryn Field Matthew Burge Jenny Shannon Dusan Kotasek Niall C Tebbutt Christos Karapetis Craig Underhill Andrew Haydon Joy Schaeffer Janine Ptak Cristian Tomasetti Nicholas Papadopoulos Kenneth W Kinzler Bert Vogelstein Peter Gibbs |
| author_facet | Jeanne Tie Yuxuan Wang Joshua Cohen Lu Li Wei Hong Michael Christie Hui Li Wong Suzanne Kosmider Rachel Wong Benjamin Thomson Julian Choi Adrian Fox Kathryn Field Matthew Burge Jenny Shannon Dusan Kotasek Niall C Tebbutt Christos Karapetis Craig Underhill Andrew Haydon Joy Schaeffer Janine Ptak Cristian Tomasetti Nicholas Papadopoulos Kenneth W Kinzler Bert Vogelstein Peter Gibbs |
| author_sort | Jeanne Tie |
| collection | DOAJ |
| description | <h4>Background</h4>In patients with resectable colorectal liver metastases (CRLM), the role of pre- and postoperative systemic therapy continues to be debated. Previous studies have shown that circulating tumor DNA (ctDNA) analysis, as a marker of minimal residual disease, is a powerful prognostic factor in patients with nonmetastatic colorectal cancer (CRC). Serial analysis of ctDNA in patients with resectable CRLM could inform the optimal use of perioperative chemotherapy. Here, we performed a validation study to confirm the prognostic impact of postoperative ctDNA in resectable CRLM observed in a previous discovery study.<h4>Methods and findings</h4>We prospectively collected plasma samples from patients with resectable CRLM, including presurgical and postsurgical samples, serial samples during any pre- or postoperative chemotherapy, and serial samples in follow-up. Via targeted sequencing of 15 genes commonly mutated in CRC, we identified at least 1 somatic mutation in each patient's tumor. We then designed a personalized assay to assess 1 mutation in plasma samples using the Safe-SeqS assay. A total of 380 plasma samples from 54 patients recruited from July 2011 to Dec 2014 were included in our analysis. Twenty-three (43%) patients received neoadjuvant chemotherapy, and 42 patients (78%) received adjuvant chemotherapy after surgery. Median follow-up was 51 months (interquartile range, 31 to 60 months). At least 1 somatic mutation was identified in all patients' tumor tissue. ctDNA was detectable in 46/54 (85%) patients prior to any treatment and 12/49 (24%) patients after surgery. There was a median 40.93-fold (19.10 to 87.73, P < 0.001) decrease in ctDNA mutant allele fraction with neoadjuvant chemotherapy, but ctDNA clearance during neoadjuvant chemotherapy was not associated with a better recurrence-free survival (RFS). Patients with detectable postoperative ctDNA experienced a significantly lower RFS (HR 6.3; 95% CI 2.58 to 15.2; P < 0.001) and overall survival (HR 4.2; 95% CI 1.5 to 11.8; P < 0.001) compared to patients with undetectable ctDNA. For the 11 patients with detectable postoperative ctDNA who had serial ctDNA sampling during adjuvant chemotherapy, ctDNA clearance was observed in 3 patients, 2 of whom remained disease-free. All 8 patients with persistently detectable ctDNA after adjuvant chemotherapy have recurred. End-of-treatment (surgery +/- adjuvant chemotherapy) ctDNA detection was associated with a 5-year RFS of 0% compared to 75.6% for patients with an undetectable end-of-treatment ctDNA (HR 14.9; 95% CI 4.94 to 44.7; P < 0.001). Key limitations of the study include the small sample size and the potential for false-positive findings with multiple hypothesis testing.<h4>Conclusions</h4>We confirmed the prognostic impact of postsurgery and posttreatment ctDNA in patients with resected CRLM. The potential utility of serial ctDNA analysis during adjuvant chemotherapy as an early marker of treatment efficacy was also demonstrated. Further studies are required to define how to optimally integrate ctDNA analyses into decision-making regarding the use and timing of adjuvant therapy for resectable CRLM.<h4>Trial registration</h4>ACTRN12612000345886. |
| format | Article |
| id | doaj-art-5fefae544f494349b57c0bd567ac52e2 |
| institution | OA Journals |
| issn | 1549-1277 1549-1676 |
| language | English |
| publishDate | 2021-05-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Medicine |
| spelling | doaj-art-5fefae544f494349b57c0bd567ac52e22025-08-20T02:00:56ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762021-05-01185e100362010.1371/journal.pmed.1003620Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study.Jeanne TieYuxuan WangJoshua CohenLu LiWei HongMichael ChristieHui Li WongSuzanne KosmiderRachel WongBenjamin ThomsonJulian ChoiAdrian FoxKathryn FieldMatthew BurgeJenny ShannonDusan KotasekNiall C TebbuttChristos KarapetisCraig UnderhillAndrew HaydonJoy SchaefferJanine PtakCristian TomasettiNicholas PapadopoulosKenneth W KinzlerBert VogelsteinPeter Gibbs<h4>Background</h4>In patients with resectable colorectal liver metastases (CRLM), the role of pre- and postoperative systemic therapy continues to be debated. Previous studies have shown that circulating tumor DNA (ctDNA) analysis, as a marker of minimal residual disease, is a powerful prognostic factor in patients with nonmetastatic colorectal cancer (CRC). Serial analysis of ctDNA in patients with resectable CRLM could inform the optimal use of perioperative chemotherapy. Here, we performed a validation study to confirm the prognostic impact of postoperative ctDNA in resectable CRLM observed in a previous discovery study.<h4>Methods and findings</h4>We prospectively collected plasma samples from patients with resectable CRLM, including presurgical and postsurgical samples, serial samples during any pre- or postoperative chemotherapy, and serial samples in follow-up. Via targeted sequencing of 15 genes commonly mutated in CRC, we identified at least 1 somatic mutation in each patient's tumor. We then designed a personalized assay to assess 1 mutation in plasma samples using the Safe-SeqS assay. A total of 380 plasma samples from 54 patients recruited from July 2011 to Dec 2014 were included in our analysis. Twenty-three (43%) patients received neoadjuvant chemotherapy, and 42 patients (78%) received adjuvant chemotherapy after surgery. Median follow-up was 51 months (interquartile range, 31 to 60 months). At least 1 somatic mutation was identified in all patients' tumor tissue. ctDNA was detectable in 46/54 (85%) patients prior to any treatment and 12/49 (24%) patients after surgery. There was a median 40.93-fold (19.10 to 87.73, P < 0.001) decrease in ctDNA mutant allele fraction with neoadjuvant chemotherapy, but ctDNA clearance during neoadjuvant chemotherapy was not associated with a better recurrence-free survival (RFS). Patients with detectable postoperative ctDNA experienced a significantly lower RFS (HR 6.3; 95% CI 2.58 to 15.2; P < 0.001) and overall survival (HR 4.2; 95% CI 1.5 to 11.8; P < 0.001) compared to patients with undetectable ctDNA. For the 11 patients with detectable postoperative ctDNA who had serial ctDNA sampling during adjuvant chemotherapy, ctDNA clearance was observed in 3 patients, 2 of whom remained disease-free. All 8 patients with persistently detectable ctDNA after adjuvant chemotherapy have recurred. End-of-treatment (surgery +/- adjuvant chemotherapy) ctDNA detection was associated with a 5-year RFS of 0% compared to 75.6% for patients with an undetectable end-of-treatment ctDNA (HR 14.9; 95% CI 4.94 to 44.7; P < 0.001). Key limitations of the study include the small sample size and the potential for false-positive findings with multiple hypothesis testing.<h4>Conclusions</h4>We confirmed the prognostic impact of postsurgery and posttreatment ctDNA in patients with resected CRLM. The potential utility of serial ctDNA analysis during adjuvant chemotherapy as an early marker of treatment efficacy was also demonstrated. Further studies are required to define how to optimally integrate ctDNA analyses into decision-making regarding the use and timing of adjuvant therapy for resectable CRLM.<h4>Trial registration</h4>ACTRN12612000345886.https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1003620&type=printable |
| spellingShingle | Jeanne Tie Yuxuan Wang Joshua Cohen Lu Li Wei Hong Michael Christie Hui Li Wong Suzanne Kosmider Rachel Wong Benjamin Thomson Julian Choi Adrian Fox Kathryn Field Matthew Burge Jenny Shannon Dusan Kotasek Niall C Tebbutt Christos Karapetis Craig Underhill Andrew Haydon Joy Schaeffer Janine Ptak Cristian Tomasetti Nicholas Papadopoulos Kenneth W Kinzler Bert Vogelstein Peter Gibbs Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study. PLoS Medicine |
| title | Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study. |
| title_full | Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study. |
| title_fullStr | Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study. |
| title_full_unstemmed | Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study. |
| title_short | Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study. |
| title_sort | circulating tumor dna dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases a prospective cohort study |
| url | https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1003620&type=printable |
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