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. 2024 Nov 6;19(1):153.
doi: 10.1186/s13014-024-02540-4.

Dynamics of cell-free tumor DNA correlate with early MRI response during chemoradiotherapy in rectal cancer

Kerstin Clasen  1 , Cihan Gani  2 , Leon Schuetz  3 , Stephan Clasen  4 , Nadja Ballin  3 , Irina Bonzheim  5 , Michael Orth  2 , Stephan Ossowski  3 , Olaf Riess  3 , Maximilian Niyazi  2 , Christopher Schroeder  3 , Olga Kelemen  3
Affiliations

Dynamics of cell-free tumor DNA correlate with early MRI response during chemoradiotherapy in rectal cancer

Kerstin Clasen et al. Radiat Oncol. .

Abstract

Background: In locally advanced rectal cancer, the prediction of tumor response during and after neoadjuvant treatment remains challenging. In terms of organ preservation, adaptive radiotherapy, and intensified (total) neoadjuvant therapies, biomarkers are desirable for patient stratification.

Methods: In 16 patients, weekly blood samples (n = 86) to detect cell-free tumor DNA (ctDNA) during long-course neoadjuvant chemoradiotherapy were analyzed. Data were correlated with initial tumor volumes, MRI response in week 2 and 5 of radiotherapy as well as with pathologic tumor response after resection and outcome parameters.

Results: Most patients showed decreasing ctDNA during the course of radiochemotherapy. However, we found heterogenous dynamics of ctDNA and could identify three groups: (1) decline (2) no clear decline and/or late shedding (3) persistence of ctDNA. In seven patients we could detect significant amounts of ctDNA in week 5 or week 6 of treatment. In our pilot cohort, we did not find significant correlations of ctDNA dynamics with pathologic response or outcome parameters. However, patients with distinct decline of ctDNA had larger tumor volumes prior to treatment, and MRI imaging in week 2 and 5 revealed bigger absolute decrease of tumor volumes. If significant levels of ctDNA were found in week 5 and / or 6, patients showed less absolute tumor volume decrease in week 2 and 5.

Conclusions: Weekly measurement of ctDNA during radiochemotherapy is feasible and might represent a promising biomarker. Bigger initial primary tumors showed different ctDNA shedding profiles compared with smaller primary tumors and correlations of ctDNA dynamics with early imaging response were found.

Keywords: Adaptive radiotherapy; Biomarker; Imaging; Magnetic resonance imaging; NGS; cfDNA; ctDNA.

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Conflict of interest statement

KC, CG and MN report institutional collaborations including financial and non-financial support by Elekta, Philips, Siemens, Dr. Sennewald, PTW Freiburg, Kaiku and Therapanacea. CG reports honoraria and travel support from Elekta outside this work. CS reports institutional grants from Novartis and Illumina as well as research grants from BMS Stiftung Immunonkologie outside the submitted work.

Figures

Fig. 1
Fig. 1
Study design. After diagnosis and endoscopy, all patients had pre-therapeutic magnetic resonance imaging (MRI). MRI imaging was repeated in week 2 and week 5. Radiotherapy (RT) and concomitant chemotherapy (CTX) were administered over 6 weeks. Blood samples for ctDNA monitoring were collected weekly (preferably on Mondays)
Fig. 2
Fig. 2
Dynamics of circulating cell-free tumor DNA (ctDNA) in 16 patients with associated patient features: good versus bad pathologic response (Dworak 1 + 2: bad; 3 + 4 good response) and the occurrence of metastases during follow-up. Patients are grouped accordingly to the respective ctDNA dynamics: green - decline; orange – no clear decline and/or late ctDNA shedding; red - persistence of ctDNA. Each line connects the respective allele frequencies of one particular variant that was tracked over time. Significant proofs of ctDNA (considering all monitored variants in the respective patient) are marked by asterisks (***: p-value < 0.001; **: p-value < 0.01; *: p-value < 0.05)
Fig. 3
Fig. 3
The proof of circulating cell-free tumor DNA (ctDNA) in the liquid biopsies at the end of treatment (week 5 or 6) was not significantly associated with tumor recurrence
Fig. 4
Fig. 4
Correlations of dynamics of circulating cell-free tumor DNA (ctDNA) (“decline” versus “late shedding or persistence”) and the proof of ctDNA at the end of treatment in week 5 / 6 with the pre-therapeutic magnetic resonance imaging (MRI) volumes (tumor volumes pre tx (cc)) (A and B), the absolute tumor volume change in week 2 (C and D) and MRI tumor volume decrease between baseline and week 5 (E and F)
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