Peripheral Circulating Tumor DNA Detection Predicts Poor Outcomes After Liver Resection for Metastatic Colorectal Cancer

Narayan, Raja R.; Goldman, Debra A.; Gönen, Mithat; Reichel, Jonathan; Huberman, Kety; Raj, Sandeep; Viale, Agnès; Kemeny, Nancy E.; Allen, Peter J.; Balachandran, Vinod P.; D’Angelica, Michael I.; DeMatteo, Ronald P.; Drebin, Jeffrey A.; Jarnagin, William R.; Kingham, T. Peter

doi:10.1245/s10434-019-07201-5

Cited by 30 publications

(30 citation statements)

References 44 publications

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“…Inclusion of adjunct tools, such as immunoscore, 36 a robust and validated test of the host immune reaction measuring CD3+ and CD8+ T-cell densities within the tumour and/or detection of ctDNA may be considered for determination of the risk of recurrence. 37,38 To our knowledge, this is the first study determining the influence of RAS mutations on overall survival from the perspective of the age of onset in RAS-driven colorectal cancer liver resections.…”

Section: Discussionmentioning

confidence: 98%

The prognostic impact of RAS on overall survival following liver resection in early versus late-onset colorectal cancer patients

et al. 2020

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Background The impact of molecular aberrations on survival after resection of colorectal liver metastases (CLM) in patients with early-age-onset (EOCRC) versus late-age-onset colorectal cancer (LOCRC) is unknown. Methods Patients who underwent liver resection for CLM with known RAS, BRAF and MSI status were retrospectively studied. The prognostic impact of RAS mutations by age was analysed with age as a categorical variable and a continuous variable. Results The study included 573 patients, 192 with EOCRC and 381 with LOCRC. The younger the age of onset of CRC, the greater the negative impact on overall survival of RAS mutations in the LOCRC, EOCRC, and ≤40 years (hazard ratio (HR), 1.64 (95% confidence interval (CI), 1.23–2.20), 2.03 (95% CI, 1.30–3.17), and 2.97 (95% CI, 1.44–6.14), respectively. Age-specific mortality risk and linear regression analysis also demonstrated that RAS mutations had a greater impact on survival in EOCRC than in LOCRC (slope: −4.07, 95% CI −8.10 to 0.04, P = 0.047, R2 = 0.08). Conclusion Among patients undergoing CLM resection, RAS mutations have a greater negative influence on survival in patients with EOCRC, more so in patients ≤40 years, than in patients with LOCRC and should be considered as a prognostic factor in multidisciplinary treatment planning.

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Section: Discussionmentioning

confidence: 98%

The prognostic impact of RAS on overall survival following liver resection in early versus late-onset colorectal cancer patients

et al. 2020

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“…In this study we focused on the analysis of ctDNA, considering the higher detection rate of ctDNA compared to CTCs in patients with metastatic CRC [40] . Limited data is available on the value of ctDNA in patients with CRLM [40] , [41] , [42] . Narayan et al.…”

Section: Discussionmentioning

confidence: 99%

Postoperative circulating tumour DNA is associated with pathologic response and recurrence-free survival after resection of colorectal cancer liver metastases

et al. 2021

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Background Recurrence rates after resection of colorectal cancer liver metastases (CRLM) are high and correlate with worse survival. Postoperative circulating tumour DNA (ctDNA) is a promising prognostic biomarker. Focusing on patients with resected CRLM, this study aimed to evaluate the association between the detection of postoperative ctDNA, pathologic response and recurrence-free survival (RFS). Methods Twenty-three patients were selected from an ongoing phase-3 trial who underwent resection of RAS -mutant CRLM after induction systemic treatment. CtDNA analysis was performed by droplet digital PCR using blood samples collected at baseline, before and after resection. Pathologic response of CRLM was determined via the Tumour Regression Grading system. Findings With a median follow-up of 19.6 months, the median RFS for patients with detectable ( N = 6, [26%]) and undetectable ( N = 17, [74%]) postoperative ctDNA was 4.8 versus 12.1 months, respectively. Among 21 patients with available tumour tissue, pathologic response in patients with detectable compared to undetectable postoperative ctDNA was found in one of six (17%) and 15 of 15 (100%) patients, respectively ( p < 0.001). In univariable Cox regression analyses both postoperative detectable ctDNA (HR = 3.3, 95%CI = 1.1–9.6, p = 0.03) and pathologic non-response (HR = 4.6, 95%CI = 1.4–15, p = 0.01) were associated with poorer RFS and were strongly correlated ( r = 0.88, p < 0.001). After adjusting for clinical characteristics in pairwise multivariable analyses, postoperative ctDNA status remained associated with RFS. Interpretation The detection of postoperative ctDNA after secondary resection of CRLM is a promising prognostic factor for RFS and appeared to be highly correlated with pathologic response.

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“…Finally, in patients referred to surgery for LM resection, persistently detectable ctDNA levels before surgery was associated with short post-surgical OS, suggesting that LM were not fully responding to therapy and/or that extra-hepatic micro-metastases were present. A study by Narayan and colleagues [27] in 59 metastatic CRC patients who underwent LM resection found an association between worse disease-specific survival and the detection of circulating mutant TP53 copies during surgery (but not with ctDNA). However, blood samples were only obtained during and after surgery.…”

Section: Discussionmentioning

confidence: 99%

Circulating Tumor Cells and Circulating Tumor DNA Detection in Potentially Resectable Metastatic Colorectal Cancer: A Prospective Ancillary Study to the Unicancer Prodige-14 Trial

Bidard

Kiavue

Ychou

et al. 2019

Cells

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The management of patients with colorectal cancer (CRC) and potentially resectable liver metastases (LM) requires quick assessment of mutational status and of response to pre-operative systemic therapy. In a prospective phase II trial (NCT01442935), we investigated the clinical validity of circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) detection. CRC patients with potentially resectable LM were treated with first-line triplet or doublet chemotherapy combined with targeted therapy. CTC (Cellsearch®) and Kirsten RAt Sarcoma (KRAS) ctDNA (droplet digital polymerase chain reaction (PCR)) levels were assessed at inclusion, after 4 weeks of therapy and before LM surgery. 153 patients were enrolled. The proportion of patients with high CTC counts (≥3 CTC/7.5mL) decreased during therapy: 19% (25/132) at baseline, 3% (3/108) at week 4 and 0/57 before surgery. ctDNA detection sensitivity at baseline was 91% (N=42/46) and also decreased during treatment. Interestingly, persistently detectable KRAS ctDNA (p = 0.01) at 4 weeks was associated with a lower R0/R1 LM resection rate. Among patients who had a R0/R1 LM resection, those with detectable ctDNA levels before liver surgery had a shorter overall survival (p < 0.001). In CRC patients with limited metastatic spread, ctDNA could be used as liquid biopsy tool. Therefore, ctDNA detection could help to select patients eligible for LM resection.

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Peripheral Circulating Tumor DNA Detection Predicts Poor Outcomes After Liver Resection for Metastatic Colorectal Cancer

Cited by 30 publications

References 44 publications

The prognostic impact of RAS on overall survival following liver resection in early versus late-onset colorectal cancer patients

The prognostic impact of RAS on overall survival following liver resection in early versus late-onset colorectal cancer patients

Postoperative circulating tumour DNA is associated with pathologic response and recurrence-free survival after resection of colorectal cancer liver metastases

Circulating Tumor Cells and Circulating Tumor DNA Detection in Potentially Resectable Metastatic Colorectal Cancer: A Prospective Ancillary Study to the Unicancer Prodige-14 Trial

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