The CIRCULATE Trial: Circulating Tumor DNA Based Decision for Adjuvant Treatment in Colon Cancer Stage II Evaluation (AIO-KRK-0217)

Folprecht, Gunnar; Reinacher‐Schick, Anke; Weitz, Jürgen; Lugnier, Céline; Kraeft, Anna-Lena; Wisser, Sarah; Aust, Daniela E.; Weiß, Lukas; Bubnoff, Nikolas von; Kramer, Michael; Thiede, Christian; Tannapfel, Andrea

doi:10.1016/j.clcc.2021.09.005

Cited by 24 publications

(10 citation statements)

References 17 publications

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“…In recent years, the need for non-invasive early cancer detection for diagnosis, minimal residual disease monitoring, prediction, and prognosis has become more and more apparent. The molecular information serving as a systemic fingerprint of cancer dynamics is derived from body fluids through liquid biopsy [ 1 , 2 , 3 , 4 , 5 , 6 ]. Comprehensive target panels are necessary to monitor treatment response on a patient-individual level [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Stringent Base Specific and Optimization-Free Multiplex Mediator Probe ddPCR for the Quantification of Point Mutations in Circulating Tumor DNA

Schlenker

Kipf

Deuter

et al. 2021

Cancers

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There is an increasing demand for optimization-free multiplex assays to rapidly establish comprehensive target panels for cancer monitoring by liquid biopsy. We present the mediator probe (MP) PCR for the quantification of the seven most frequent point mutations and corresponding wild types (KRAS and BRAF) in colorectal carcinoma. Standardized parameters for the digital assay were derived using design of experiments. Without further optimization, the limit of detection (LoD) was determined through spiking experiments with synthetic mutant DNA in human genomic DNA. The limit of blank (LoB) was measured in cfDNA plasma eluates from healthy volunteers. The 2-plex and 4-plex MP ddPCR assays showed a LoB of 0 copies/mL except for 4-plex KRAS G13D (9.82 copies/mL) and 4-plex BRAF V600E (16.29 copies/mL) and allele frequencies of 0.004% ≤ LoD ≤ 0.38% with R2 ≥ 0.98. The quantification of point mutations in patient plasma eluates (18 patients) during follow-up using the 4-plex MP ddPCR showed a comparable performance to the reference assays. The presented multiplex assays need no laborious optimization, as they use the same concentrations and cycling conditions for all targets. This facilitates assay certification, allows a fast and flexible design process, and is thus easily adaptable for individual patient monitoring.

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Section: Introductionmentioning

confidence: 99%

Stringent Base Specific and Optimization-Free Multiplex Mediator Probe ddPCR for the Quantification of Point Mutations in Circulating Tumor DNA

Schlenker

Kipf

Deuter

et al. 2021

Cancers

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“…Additionally, it forecasts how the disease will respond to treatment and perhaps how quickly it will advance, preventing both overtreatment and unnecessary exposure to chemotherapy. Thus, it would also aid in patient follow-up after resection of the primary and occasionally detect early and silent recurrences and some trials are investigating these opening questions ( 125 - 129 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular profiling and patient selection for the multimodal approaches for patients with resectable colorectal liver metastases

Araujo,

Fonseca,

Silva

et al. 2024

Hepatobiliary Surg Nutr

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Colorectal cancer represents the third most common cancer and about 20% are diagnosed with synchronous metastatic disease. From a historical point of view, surgery remains the mainstream treatment for resectable colorectal liver metastases (CRLM). Furthermore, disease outcomes are improving due significant advances in systemic treatments and diagnostic methods. However, the optimal timing for neoadjuvant chemotherapy or upfront surgery for CRLM has not yet been established and remains an open question. Thus, patient selection combining image workouts, time of recurrence, positive lymph nodes, and molecular biomarkers can improve the decision-making process. Nevertheless, molecular profiling is rising as a promising field to be incorporated in the multimodal approach and guide patient selection and sequencing of treatment. Tumor biomakers, genetic profiling, and circulating tumor DNA have been used to offer as much personalized treatment as possible, based on the precision oncology concept of tailored care rather than a guideline-based therapy. This review article discusses the role of molecular pathology and biomarkers as prognostic and predictor factors in the diagnosis and treatment of resectable CRLM.

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“…This high frequency of LP positivity can likely be explained by the fact that most of these patients were treatment naïve—ctDNA levels might accordingly be higher than in stage IV CRC patients under therapy. The use of LP in earlier stages of cancer is currently being investigated in prospective clinical trials such as CIRCULATE (AIO‐KRK‐0217) or COBRA (NRG‐GI005) [10,39–41], for example, to assess the need for adjuvant chemotherapy. Based on the results of these standard‐of‐care LP tests, LP may be suitable to determine the mutational status also in earlier stages, although in these cases cfDNA levels should be assessed in order to minimize the risk of false‐negative test results.…”

Section: Discussionmentioning

confidence: 99%

Liquid profiling of circulating tumor DNA in colorectal cancer: steps needed to achieve its full clinical value as standard care

et al. 2021

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The analysis of circulating tumor DNA (ctDNA) is at the threshold of implementation into standard care for colorectal cancer (CRC) patients. However, data about the clinical utility of liquid profiling (LP), its acceptance by clinicians, and its integration into clinical workflows in real‐world settings remain limited. Here, LP tests requested as part of routine care since 2016 were retrospectively evaluated. Results show restrained request behavior that improved moderately over time, as well as reliable diagnostic performance comparable to translational studies, with an overall agreement of 91.7%. Extremely low ctDNA levels at < 0.1% in over 20% of cases, a high frequency of concomitant driver mutations (in up to 14% of cases), and ctDNA levels reflecting the clinical course of disease were revealed. However, certain limitations hampering successful translation of ctDNA into clinical practice were uncovered, including the lack of clinically relevant ctDNA thresholds, appropriate time points of LP requests, and integrative evaluation of ctDNA, imaging, and clinical findings. In conclusion, these results highlight the potential clinical value of LP for CRC patient management and demonstrate issues that need to be addressed for successful long‐term implementation in clinical workflows.

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The CIRCULATE Trial: Circulating Tumor DNA Based Decision for Adjuvant Treatment in Colon Cancer Stage II Evaluation (AIO-KRK-0217)

Cited by 24 publications

References 17 publications

Stringent Base Specific and Optimization-Free Multiplex Mediator Probe ddPCR for the Quantification of Point Mutations in Circulating Tumor DNA

Stringent Base Specific and Optimization-Free Multiplex Mediator Probe ddPCR for the Quantification of Point Mutations in Circulating Tumor DNA

Molecular profiling and patient selection for the multimodal approaches for patients with resectable colorectal liver metastases

Liquid profiling of circulating tumor DNA in colorectal cancer: steps needed to achieve its full clinical value as standard care

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