Nocturnal increase of concentration of circulating tumor DNA in metastatic colorectal cancer patients with disease control but not with progressive disease

Nocturnal increase of concentration of circulating tumor DNA in metastatic colorectal cancer patients with disease control but not with progressive disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Nocturnal increase of concentration of circulating tumor DNA in metastatic colorectal cancer patients with disease control but not with progressive disease Ekaterina S. Kuligina, Aleksandr S. Martianov, Liliya S. Baboshkina, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7761150/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract The utility of liquid biopsy in clinical oncology is often compromised by low concentration of tumor-derived fragments. Recent study demonstrated a nocturnal peak in the amount circulating tumor cells during the deep sleep phase (~ 4 a.m.). This study questioned whether the same peak is characteristic of circulating tumor DNA (ctDNA). Plasma samples were collected from 19 RAS/RAF-mutated colorectal cancer (CRC) patients at 12 p.m. (day 1), 4 a.m. (night), and 12 p.m. (day 2). 14 subjects provided a single triplet for the study, and 5 patients underwent the above procedure twice or thrice. KRAS, NRAS , and BRAF mutations in plasma were quantified via ddPCR. RAS/RAF mutations (> 10 copies/mL) were detected in at least one plasma sample in 20/25 (80%) triplets. Among these, 15 showed detectable ctDNA at all timepoints, with intra-individual variation ranging from 1.7% to 74.8%. In five triplets, ctDNA was undetectable during daytime but present at night. Overall, 7 of 9 triplets collected at the time of disease control exhibited a night peak in ctDNA concentration, while all 10 triplets obtained during tumor progression showed other patterns of ctDNA changes (p = 0.005, Fisher’s exact test). These findings demonstrate that ctDNA level is a subject of circadian variations in a subset of cancer patients. circulating tumor DNA (ctDNA) circadian rhythms individual dynamics driver mutations individual variability colorectal cancer Figures Figure 1 Figure 2 Introduction The analysis of circulating tumor DNA (ctDNA) is commonly utilized in clinical oncology. It allows for early cancer diagnosis, genomic tumor profiling, and monitoring of the disease course [ 1 , 2 ]. Practical use of ctDNA tests is complicated because many tumors shed into the bloodstream vanishingly low amounts of DNA [ 3 ]. Significant efforts have been invested in the identification of factors which influence the performance of ctDNA assays. Larger tumors and those exhibiting acute inflammation, necrosis, or high mitotic index, typically release more ctDNA [ 4 , 5 ]. Elevated ctDNA levels are more common in patients with disease progression and aggressive cancer subtypes [ 6 , 7 ]. Oncogenic pathway activation (e.g., STK11, TP53, KRAS, EGFR ), epithelial-mesenchymal transition, hypoxia, and cell-cycle dysregulation are also linked to increased DNA shedding [ 4 , 8 , 9 ]. Treatment-resistant tumors are among the most prolific shedders of ctDNA [ 10 , 11 ]. In low-shedding tumors or early-stage cancers with minimal tumor burden, enhancing the sensitivity of liquid biopsy (LB) remains a key priority. Despite advances in droplet digital PCR (ddPCR) and deep sequencing, 20–35% of cancer patients remain ctDNA-negative despite a significant tumor burden [ 12 – 14 ]. Strategies to transiently stimulate ctDNA release - e.g., irradiation, ultrasound - are explored but often impractical for patients [ 15 – 17 ]. Recent study demonstrated that circulating tumor cells (CTCs) peak during sleep, with implications for liquid biopsy timing [ 18 ]. Indeed, in breast cancer patients the amount of CTCs was markedly elevated at night (4 a.m.), and these nocturnally released CTCs showed greater metastatic potential [ 19 , 20 ]. We previously observed a non-significant trend toward higher ctDNA levels in the afternoon versus morning samples in cancer patients [ 7 ]. This study questioned whether blood-take at 4 a.m. has a potential of increasing the sensitivity of ctDNA detection. Methodology Patients: Patients with locally advanced or metastatic colorectal cancer (CRC), who were treated in the N.N. Petrov Institute of Oncology (St. Petersburg) or St. Luke's Clinical Hospital (St. Petersburg) between June 2024 and February 2025, were invited to participate in the study. All patients provided informed consent. The study was approved by the local Ethics Committee. Eligible participants had tumors positive for the most common KRAS, NRAS , or BRAF somatic mutations as determined by the analysis of paraffin-embedded tumor tissues. Clinical characteristics of the patients are presented in Table 1 . Serial plasma samples were collected over two consecutive days at three timepoints: 12 p.m. (1st day), 4 a.m. (night), and 12 p.m. (2nd day). Plasma Processing and ctDNA Isolation: Blood samples (10 mL) were drawn into GBM scf-DNA tubes (Gradbiomed, Russia). Plasma was separated by one-step centrifugation at 400 g for 10 minutes at room temperature. Cell-free DNA was extracted from 3–5 mL of plasma using the QIAamp Circulating Nucleic Acid kit (Qiagen, the Netherlands), following the manufacturer's instructions, and dissolved in 50–60 µL of water. ddPCR and ctDNA Quantification: KRAS, NRAS , or BRAF mutant allele fractions in plasma samples were measured by ddPCR using the QX200 System (Bio-Rad), as described previously [ 7 , 16 ]. ddPCR reactions were performed with 2 X ddPCR supermix for probes (no dUTP; Bio-Rad, USA), the appropriate mutation detection kit (Supplementary Table 1S), and 2–3 µL of template DNA in a 22–23 µL of total reaction volume. Data were analyzed using QuantaSoft Software version 1.7.4, with duplicate analyses performed and merged for each sample. Thresholds were manually set based on predefined assay optimization criteria. The absolute number of tumor-derived mutated DNA copies per mL of initial plasma (Cmut) was calculated as: С mut = [Concentration (mut copies/µL) × V reaction × V dilution ] / [V template × V plasma ] Where: Concentration - number of «mutated» droplets per 1 µL of ddPCR reaction; V reaction - total ddPCR reaction volume, µL; V template - volume of ctDNA aliquot taken into ddPCR, µL; V dilution - total volume of diluted ctDNA sample collected from the plasma, µL; V plasma - initial volume of processed plasma, mL. Wild-type (wt) fragment concentrations were not considered for the data interpretation, given that non-mutated circulating DNA may derive both from blood cells and non-tumor epithelial cells, and, therefore, these results have limited relevance to the aim of this study [ 21 ]. The analysis focused only on the concentrations of mutant DNA copies. The raw data, including the concentration of wt-ccfDNA at all timepoints, are available in Supplementary Table 3S. Statistics: Intra-individual variance was assessed using the coefficient of variation (CV%) = standard deviation / mean. To analyze the relationship between ctDNA content and blood collection time, the following variables were evaluated for paired measurements (1st day vs. night; 1st day 1 vs. 2nd day; night vs. 2nd day): Percentage change (%) = 100% × (final Cmut – initial Cmut) / initial Cmut Quantitative data were reported as mean and 95% CI or median and range. Wilcoxon signed-rank test and Mann–Whitney U test were used for median comparisons. Fisher's exact test was used for categorical variables. A p-value < 0.05 was considered statistically significant. Analyses were performed using IBM SPSS v.23. Table 1 Patient characteristics. CT – chemotherapy; Metastatic sites: hep – hepatic, lympn - lymph node; pulm – pulmonary; per – peritoneal. Lab Code Mutation Gender Age Date of the 1st blood take Diagnosis TNM Disease status at the time of the 1st blood draw* Therapy Pt-1.1 KRAS G13D female 69 29.03.2024 Adenocarcinoma of sigmoid colon, low-grade T3N1M1 (hep) nd 1st cycle of the first-line CT (FOLFOX) Pt-1.2 KRAS G13D female 69 04.05.2024 Adenocarcinoma of sigmoid colon, low-grade T3N1M1 (hep) Stable 3rd cycle of the first-line CT (FOLFOX + bevacizumab) Pt-2.1 KRAS G12D male 49 28.04.2024 Adenocarcinoma of rectum, low-grade T3N2M1 (hep) Stable Radiotherapy; 1st cycle of the first-line CT (FOLFOX) Pt-2.2 KRAS G12D male 49 27.05.2024 Adenocarcinoma of rectum, low-grade T3N2M1 (hep) Stable 2nd cycle of the first-line CT (FOLFOX) Pt-2.3 KRAS G12D male 49 14.01.2025 Adenocarcinoma of rectum, low-grade T3N2M1 (hep) Progressing 5th cycle of the second-line CT (FOLFIRI + bevacizumab); Pt-3 KRAS G13D male 69 27.06.2024 Adenocarcinoma of sigmoid colon, low-grade T4bN1M1 (hep) Progressing 10th cycle of the first-line CT (FOLFOX) Pt-4 KRAS G12D female 31 15.08.2024 Adenocarcinoma of colon, low-grade T2NxM1 (hep, per, pulm) Progressing 1st cycle of the third-line CT (FOLFIRI + bevacizumab) Pt-5 KRAS G12D male 75 21.08.2024 Adenocarcinoma of ascending colon, low-grade; DLBCL TxN0M1 (hep, pulm) Progressing R-CHOP** Pt-6.1 BRAF V600E male 52 03.11.2024 Adenocarcinoma of hepatic flexure of the colon, high-grade T4bN2bM1 (hep, per) Progressing 1st cycle of the first-line CT (FOLFOX) Pt-6.2 BRAF V600E male 52 28.01.2025 Adenocarcinoma of hepatic flexure of the colon, high-grade T4bN2bM1 (hep, per) Stable 5th cycle of the first-line CT (FOLFOX + bevacizumab) Pt-7 KRAS G12D male 71 17.01.2025 Adenocarcinoma of sigmoid colon, low-grade T2N1M1 (hep, per) Progressing 1st cycle of the first-line CT (FOLFOX + bevacizumab) Pt-8 KRAS Q61R male 55 20.01.2025 Adenocarcinoma of colon, low-grade T3N1M1b (hep, pulm) Progressing 4th cycle of the first-line CT (FOLFOX + bevacizumab) Pt-9 KRAS G12D female 72 24.01.2025 Adenocarcinoma of colon, high-grade T4aN2aM1c (per) Stable 10th cycle of the first-line CT (5-fluorouracil + bevacizumab) Pt-10.1 KRAS G12D female 52 27.01.2025 Adenocarcinoma of rectum, low-grade T3N1M0 Progressing 1st cycle of the first-line CT (FOLFIRI + bevacizumab) Pt-10.2 KRAS G12D female 52 27.02.2025 Adenocarcinoma of rectum, low-grade T3N1M0 Stable 2st cycle of the first-line CT (FOLFIRI + bevacizumab) Pt-11.1 KRAS A146V male 63 26.11.2024 Adenocarcinoma of ascending colon, low-grade TxNxM1 (hep, pulm) Progressing 1st cycle of the first-line CT (5-fluorouracil) Pt-11.2 KRAS A146V male 63 15.01.2025 Adenocarcinoma of ascending colon, low-grade TxNxM1 (hep, pulm) Stable 4st cycle of the first-line CT (FOLFOX + bevacizumab) Pt-12 KRAS G13D female 67 05.02.2025 Adenocarcinoma of cecum, low-grade T2N0M1 (hep) Progressing 1st cycle of the first-line CT (FOLFOX + bevacizumab) Pt-13 KRAS A146T female 48 07.02.2025 Adenocarcinoma of rectosigmoid junction, low-grade T4aN2aM1a (hep) Stable 6th cycle of the second-line CT (FOLFOX + bevacizumab) Pt-14 KRAS G12S female 59 07.02.2025 Adenocarcinoma of sigmoid colon, low-grade T3NxM1c (hep, per, pulm) Stable 9th cycle of the second-line CT (FOLFIRI + ramucirumab) Pt-15 KRAS A146T female 67 27.01.2025 Adenocarcinoma of rectum, low-grade T4aN2bM1b (hep, pulm) Stable 3rd cycle of the first-line CT (5-fluorouracil + bevacizumab) Pt-16 KRAS G13D male 66 28.04.2024 Adenocarcinoma of sigmoid colon, low-grade T3N1M1a (hep, lympn) nd 2nd cycle of the first-line CT (FOLFOX + bevacizumab) Pt-17 NRAS Q61K female 72 16.05.2024 Adenocarcinoma of ascending colon, low-grade T4bN0M0 Stable 8th cycle of the first-line CT (FOLFIRI + bevacizumab) Pt-18 KRAS G12С male 72 28.06.2024 Adenocarcinoma of rectum, low-grade T3N0M1 (hep) Progressing 2nd cycle of the first-line CT (FOLFOX) Pt-19 KRAS G12C male 63 21.01.2025 Adenocarcinoma of sigmoid colon, low-grade T4bN0M1 (hep) Progressing 1st cycle of the third-line CT (bevacizumab) *Progression criteria were defined as follows: a) ≥ 20% increase in target lesion size, any increase in non-target lesions, or the appearance of new tumor foci (progressive disease, PD, RECIST 1.1), as documented by CT, MRI, or PET imaging; b) peritoneal carcinomatosis was confirmed by imaging (CT, MRI, or PET) and/or biopsy; c) high tumor budding grade was assessed on H&E-stained slides; tumor buds may exhibit features of epithelial–mesenchymal transition (EMT) [ 22 ]. ** Patient 5 completed the fourth cycle of R-CHOP therapy for diffuse large B-cell lymphoma (DLBCL) two months prior to the first blood draw. CT - chemotherapy Results Twenty-five triplets of plasma samples were collected from 19 individuals. Four patients (Pt-1, Pt-6, Pt-10, Pt-11) participated twice (with intervals of 4–12 weeks), and one patient (Pt-2) participated three times (with intervals of 4 and 33 weeks) (Fig. 1 ). Due to the evolving clinical context and varying time intervals, all 25 triplets were analyzed as independent cases. At the time of blood collection, 12 patients exhibited clinical or radiological signs of tumor progression, while 11 showed no signs of progression and were classified as “stable”; in two cases, the disease status could not be assessed (Table 1 , detailed clinical information is provided in Supplementary Table 3S) At least one "ctDNA-positive" sample with detectable RAS/RAF mutations ( ≥ 10 copies·mL − 1 ) was found in 20/25 (80%) triplets. The remaining five triplets were plasma-negative across all timepoints and, therefore, excluded from the analysis (Fig. 1 ). C mut ranged from 10 to 103,250 copies·mL − 1 (Table 2 ). The probability of ctDNA detection did not correlate with age, gender, primary tumor size, prior surgery for primary tumor resection, or location of metastatic sites (Supplementary Table 2S). A borderline association was observed with lymph node involvement [N+: 12/14 (86%) vs. N0: 2/5 (14%), p = 0.084, Mann-Whitney U test]. Among 20 plasma-positive patients, 15 showed measurable ctDNA across the entire triplet, with intra-individual CV% ranging from 1.7 to 74.8 (Table 2 ; Supplementary Table S3). Five triplets (Pt-1.2, Pt-7, Pt-12, Pt-13, Pt-14) were ctDNA-negative in at least one noontime draw but consistently positive at night (mean nocturnal Cmut ± 95% CI: 14,254 ± 10,331 copies·mL − 1 ). Mean noontime Cmut was slightly lower (13,919 ± 8,263 copies·mL − 1 ), with no significant difference (p = 0.726, Mann-Whitney U; p = 0.312, Wilcoxon test). The fluctuations of intra-individual RAS/RAF + ctDNA within ± 25% have been interpreted as random [ 16 ]. Personal ctDNA kinetics over day-night-day cycles revealed five distinct temporal patterns (Fig. 2 ): Night peak: 1st day-to-night increase – maximum C mut at night – night-to-2nd day decrease, n = 8 (Pt-1.1, Pt-1.2, Pt-2.1, Pt-2.2, Pt-6.2, Pt-10.2, Pt-11.2, Pt-14); Night drop: 1st day-to-night decrease – minimum C mut at night – night-to-2nd day increase, n = 2 (Pt-2.3, Pt-8); Uptrend: 1st day-to-night stable/increase – night-to-2nd day stable/increase – maximum C mut at 2nd day, n = 3 (Pt-3, Pt-9, Pt-11.1); Downtrend: 1st day-to-night stable/decreasing – night-to-2nd day stable/decreasing – minimum C mut at 2nd day, n = 5 (Pt-4, Pt-6.1, Pt-7, Pt-12, Pt-13); Quasi-constant levels at three timepoints, n = 2 (Pt-5, Pt-10.1). Notably, after stratifying the triplets by the disease status at the moment of blood take, 7/9 patients without pronounced signs of tumor progression exhibited a "night peak," while all 10 progressing cases followed other patterns. No "night peak" was observed in patients with the disease progression (p = 0.005, Fisher's exact test; Fig. 2 ). Interestingly, patients who donated triplet sample for the study more than once demonstrated different patterns of ctDNA concentration depending on the disease status. For example, patient Pt-2 displayed a “night peak” in the first and second monitoring rounds, both conducted during the disease control. At the third time point (33 weeks later), the clinical situation had deteriorated, with Cmut reaching 103,250 copies/µL plasma; the day–night–day profile showed a “night drop”. Patients Pt-6, Pt-10 and Pt-11 entered the study with disease progression, showing downtrend, uptrend, and quasi-constant profiles, respectively. After stabilization, each shifted to a “night peak” pattern (Table 2 ; Fig. 2 ). Table 2 . ddPCR measurement of mutated ctDNA content in plasma of CRC patients in three consecutive time points: 12 p.m. (1 st day) - 4 a.m. (night) - 12 p.m. (2 nd day) LabCode Mutation 12 p.m. (1 st day) ddPCR mut/wt 12 p.m. (1 st day) Cmut* 4 a.m. (night) ddPCR mut/wt 4 a.m. (night) Cmut 12 p.m. (2 nd day) ddPCR mut/wt 12 p.m. (2 nd day) Cmut % change night - 1 st day % change 2 nd day - night CV% 2 nd day to 1 st day Pattern day-night-day Tumor status Pt-1.1 KRAS G13D 5/105 33 10/78 162 7/64 53 391 - 6 7 32.9% night peak Nd Pt-1.2 KRAS G13D 1/52 33 2/60 55 0/31 0 68 -100 141.4% night peak Stable Pt-2.1 KRAS G12D 319/280 5705 791/704 14000 539/390 8050 145 - 4 3 24.1% night peak Stable Pt-2.2 KRAS G12D 459/419 7140 846/773 14455 497/466 8190 102 -43 9.7% night peak Stable Pt-2.3 KRAS G12D 4803/3927 103250 4237/4120 71750 5244/5075 95900 -31 34 5.2% night drop Progressing Pt-3 KRAS G13D 73/5333 1855 117/931 2984 259/734 6020 61 102 74.8% uptrend Progressing Pt-4 KRAS G12D 1888/5455 31290 1229/3650 22575 1143/6826 21070 -28 -7 27.6% downtrend Progressing Pt-5 KRAS G12D 84/1381 2100 87/3052 2053 77/262 1885 -2 -8 7.6% constant Progressing Pt-6.1 BRAF V600E 2968/2516 86333 2885/2362 65800 925/735 26040 -24 -60 75.9% downtrend Progressing Pt-6.2 BRAF V600E 3/243 19 4/289 31 3/936 12 63 -61 31.9% night peak Stable Pt-7 KRAS G12D 2/272 35 1/400 14 0/262 0 -60 -100 141.4% downtrend Progressing Pt-8 KRAS Q61R 84/463 900 8/105 76 29/156 788 -92 937 9.4% night drop Progressing Pt-9 KRAS G12D 11/497 77 10/519 59 19/723 165 -23 180 27.4% uptrend Stable Pt-10.1 KRAS G12D 105/341 1050 119/518 1024 94/296 1076 -3 5 1.7% constant Progressing Pt-10.2 KRAS G12D 40/446 463 114/843 875 63/243 413 89 -53 8.1% night peak Stable Pt-11.1 KRAS A146V 774/507 21811 1357/431 33416 1255/596 48263 53 44 53.4% uptrend Progressing Pt-11.2 KRAS A146V 2020/1421 43750 2628/1286 55650 1704/1382 32865 27 -41 20.1% night peak Stable Pt-12 KRAS G13D 5/632 24 3/662 10 0/403 0 -63 -100 141.4% downtrend Progressing Pt-13 KRAS A146T 5/12645 74 2/703 28 1/133 0 -62 -100 141.4% downtrend Stable Pt-14 KRAS G12S 0/909 0 6/357 60 2/5242 25 inf -58 141.4% night peak Stable Pt-15 KRAS A146T 0/419 0 0/445 0 0/542 0 0 0 0 Stable Pt-16 KRAS G13D 0/70 0 0/121 0 0/93 0 0 0 0 Nd Pt-17 NRAS Q61K 0/100 0 0/75 0 0/121 0 0 0 0 Stable Pt-18 KRAS G12С 0/5030 0 0/4647 0 0/2808 0 0 0 0 Progressing Pt-19 KRAS G12C 0/509 0 0/1422 0 0/4264 0 0 0 0 Progressing Notes: Concentration С mut = mut copies ctDNA/µL of plasma; Percentage change (%) = 100% x (final C mut – 1 st day C mut )/(1 st day C mut ); Δ C mut = final C mut – initial C mut ; Coefficient of Variation CV% = Standard deviation/Mean; >25% increase (red) or decrease (blue) of the plasma ctDNA concentration was taken as a significant change; fluctuations within < 25% were assumed as insignificant; gray boxes – uninformative plasma-negative triplets. Discussion This study demonstrates that plasma ctDNA levels exhibit some intra-individual circadian variations, with a 4 a.m. peak observed in patients with the tumor disease control. The results align with prior reports on nocturnal surges in CTC in breast cancer patients and suggest that liquid biopsy results are modulated by circadian rhythms or sleep-related physiological changes [ 18 , 19 ]. Diamantopoulou et al. [ 18 ] reported 2- to 34-fold higher CTC levels at night in breast cancer patients, with increased metastatic potential of CTCs released during sleep [ 20 ]. While rhythmic patterns in CTC dynamics are recognized, a direct link to ctDNA remains unproven. The prevailing view holds that cancer cells continuously release DNA into the bloodstream during tumor progression [ 23 ]. However, emerging evidence shows that ctDNA levels can fluctuate considerably within short timeframes [ 7 , 24 , 25 ]. In lung cancer patients, Hojbjerg et al. [ 26 ] observed ctDNA variations of up to 53% day-to-day and 27% hour-to-hour, as determined by digital PCR. Our findings, together with prior reports, indicate that ctDNA dynamics may be modulated by circadian rhythms, which govern a broad range of physiological functions, including metabolism, hormonal signaling, immune surveillance, tumor cell apoptosis or necrosis, etc. [ 27 – 30 ]. In particular, hormones such as melatonin, insulin, and cortisol, known to follow circadian cycles, may influence the release and clearance of tumor-derived analytes [ 29 ]. Disruption of melatonin during sleep deprivation has been associated with increased oxidative stress, epithelial-to-mesenchymal transition, impaired DNA repair, and enhanced cancer cell migration, particularly in night-shift workers [ 31 , 32 ]. Circadian changes in immune function - reflected by shifts in inflammation, immune cell distribution, and tissue trafficking - may also affect tumor-host interactions and ctDNA shedding [ 28 , 33 , 34 ]. In addition, circadian regulation of hepatic metabolism can influence circulating metabolite levels, potentially affecting ccfDNA degradation [ 30 , 35 , 36 ]. Interestingly, ctDNA circadian rhythms observed in our study were clearly associated with non-progressing status of the tumor disease. This relationship was evident both when comparisons involved different patients and when same patients provided blood for the study while being at different points of the course of cancer disease. Perhaps, failure of the host organism to control tumor growth is associated with a number of pathological processes (inflammation, neovascularization, metabolic changes etc.) (Table 2 ). The biological basis of nocturnal ctDNA enrichment remains poorly understood. One possibility is that circadian rhythms modulate tumor biology, leading to transient surges in DNA release from tumor foci [ 37 , 38 ]. Alternatively, the peak may reflect increased decay of CTCs during deep-sleep phase [ 18 , 19 , 39 ]. A third possibility is that it arises from circadian fluctuations in the activity of ccfDNA clearance pathways, including nuclease-mediated degradation [ 40 , 41 ] and uptake by liver-resident Kupffer cells and spleen macrophages [ 42 , 43 ]. Moreover, the activity, toxicity and tumor-killing effects of many antitumor agents, including chemotherapeutic agents, targeted therapies, and immunotherapies, are strongly influenced by circadian rhythms [ 44 , 45 ]. Several limitations of this study need to be considered. The sample size (n = 19) was limited due to the logistical challenges of 4 a.m. blood draws. The small cohort size, single-night sampling, and exclusive focus on colorectal cancer limit the generalizability of our findings. Although five patients were sampled more than once, each triplet was analyzed independently. Future studies should aim to include other tumor types (e.g., lung, breast) to differentiate tumor site–specific effects from broader circadian regulatory mechanisms. Additionally, longitudinal, multi-day sampling combined with integrated clinical and circadian biomarker data would provide a more comprehensive understanding. We also acknowledge potential biases in ctDNA dynamics introduced by chemotherapy. Nearly all patients were hospitalized in connection with the initiation of a new chemotherapy cycle and received their respective drug regimens on the day of the first blood collection. The interval between drug administration and the nocturnal blood draw ranged from 12 to 40 hours (Supplementary Table 3S). We assessed whether nocturnal ctDNA concentrations correlated with the time since prior drug administration; no such association was observed. Conclusion Colorectal cancer patients, which experience disease controls at the time of bloodtakes, demonstrate nocturnal peaks of ctDNA concentration. Biological basis of this phenomenon deserves investigation. In addition, the obtained data suggest that circadian rhythms may affect the sensitivity of liquid biopsy. Abbreviations AI/ML Artificial Intelligence/Machine Learning ccfDNA circulating cell-free DNA Cmut Concentration number of «mutated» DNA fragments in plasma CRC colorectal cancer CT chemotherapy CTC circulating tumor cells ctDNA circulating tumor DNA CV% coefficient of variation ddPCR droplet digital PCR LB liquid biopsy PD progressive disease SD stable disease Wt Wild-type Declarations The authors have no relevant financial or non-financial interests to disclose. Acknowledgements Not applicable. Clinical trial number Not applicable. Funding This study was supported by Russian Science Foundation (RSF) grant № 23-15-00461 Ethics declarations All patients provided informed consent. The study was approved by the local Ethics Committee. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Data availability All data generated or analyzed during this study are included in this published article [and its supplementary information files]. Supplementary Information Supplementary Tables 1-3 (xlsx, 481Kb). 1S: ddPCR assays for mutation detection; 2S: Association between the results of plasma tumor DNA test and clinical characteristics of the patients; 3S: ddPCR measurement of mutated ctDNA content in plasma of CRC patients in three consecutive time points: 12 p.m. (1 st day) - 4 a.m. (night) - 12 p.m. (2 nd day). Author information Authors and Affiliations: Department of Tumor Growth Biology, N.N. Petrov National Medical Research Center of Oncology, Ministry of Public Health of the Russian Federation, 197758, Saint Petersburg, Russia. Ekaterina S. Kuligina, Aleksandr S. Martianov, Liliya S. Baboshkina, Arina S Perevalova, Anastasia N Ershova, Tatiana A. Laidus, Gulfiia M. Teletaeva, Evgeny N. Imyanitov Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 194100, Saint Petersburg, Russia. Aleksandr S. Martianov, Tatiana A. Laidus, Evgeny N. Imyanitov Department of clinical oncology, Pavlov First Saint Petersburg State Medical University, 197022, Saint Petersburg, Russia. Aram A. Musaelyan Department of Antitumor Drug Therapy, St. Luke Clinical Hospital, 194044, Saint Petersburg, Russia. Ekaterina M. Anokhina Contributions: Conception and design: Ekaterina S. Kuligina, and Evgeny N. Imyanitov. Development of methodology: Aleksandr S. Martianov, Tatiana A. Laidus, Arina S. Perevalova, Anastasia N. Ershova. Acquisition of data: Liliya S. Baboshkina, Aram A. Musaelyan, Ekaterina M. Anokhina, Gulfiia M. Teletaeva. Analysis and interpretation of data: Ekaterina S. Kuligina, Aleksandr S. Martianov. Writing, review, and/or revision of the manuscript: Ekaterina S. Kuligina and Evgeny N. Imyanitov. Study supervision: Evgeny N. Imyanitov. Corresponding author Correspondence to Ekaterina S. Kuligina [email protected] References Aredo JV, Jamali A, Zhu J, et al. Liquid Biopsy Approaches for Cancer Characterization, Residual Disease Detection, and Therapy Monitoring. Am Soc Clin Oncol Educ Book. 2025;45(3):e481114. 10.1200/EDBK-25-481114 . Zhang D, Jahanfar S, Rabinowitz JB, Dower J, Song F, Wu CH, et al. Role of circulating tumor DNA in early-stage triple-negative breast cancer: a systematic review and meta-analysis. Breast Cancer Res. 2025;27(1):38. 10.1186/s13058-025-01986-y . Fusco N, Venetis K, Pepe F, Shetty O, Farinas SC, Heeke S, et al. 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1","display":"","copyAsset":false,"role":"figure","size":1809308,"visible":true,"origin":"","legend":"\u003cp\u003eThe workflow: serial “day-night-day” measurement of mutated ctDNA concentration in CRC patients. Tumor status: P - progressing (tumor growth and/or new foci documented by CT, MRI, or PET scanning and/or clinical evaluation); S – “stable” tumors without signs of progression.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7761150/v1/75554f8f17e489b572f86258.jpeg"},{"id":97923478,"identity":"8c92e381-eff7-4d5d-8d81-9307266bcc2e","added_by":"auto","created_at":"2025-12-10 20:13:15","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":912920,"visible":true,"origin":"","legend":"\u003cp\u003eIndividual day-to-night dynamics of mutated ctDNA concentration in plasma of CRC patients: association with disease status\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7761150/v1/03df7e410c46579a9499b0c9.jpeg"},{"id":98621960,"identity":"23a159c6-c402-4693-8dcd-d8ca7d65b654","added_by":"auto","created_at":"2025-12-19 16:39:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4028644,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7761150/v1/346cd0d7-512f-47fa-a9b0-6495a44901c0.pdf"},{"id":97923471,"identity":"22eef9ec-63a6-4483-8487-26d74a82a29b","added_by":"auto","created_at":"2025-12-10 20:13:02","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":471202,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7761150/v1/08cb9e8dc73559d2e31bf708.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Nocturnal increase of concentration of circulating tumor DNA in metastatic colorectal cancer patients with disease control but not with progressive disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe analysis of circulating tumor DNA (ctDNA) is commonly utilized in clinical oncology. It allows for early cancer diagnosis, genomic tumor profiling, and monitoring of the disease course [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Practical use of ctDNA tests is complicated because many tumors shed into the bloodstream vanishingly low amounts of DNA [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Significant efforts have been invested in the identification of factors which influence the performance of ctDNA assays. Larger tumors and those exhibiting acute inflammation, necrosis, or high mitotic index, typically release more ctDNA [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Elevated ctDNA levels are more common in patients with disease progression and aggressive cancer subtypes [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Oncogenic pathway activation (e.g., \u003cem\u003eSTK11, TP53, KRAS, EGFR\u003c/em\u003e), epithelial-mesenchymal transition, hypoxia, and cell-cycle dysregulation are also linked to increased DNA shedding [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Treatment-resistant tumors are among the most prolific shedders of ctDNA [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn low-shedding tumors or early-stage cancers with minimal tumor burden, enhancing the sensitivity of liquid biopsy (LB) remains a key priority. Despite advances in droplet digital PCR (ddPCR) and deep sequencing, 20\u0026ndash;35% of cancer patients remain ctDNA-negative despite a significant tumor burden [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Strategies to transiently stimulate ctDNA release - e.g., irradiation, ultrasound - are explored but often impractical for patients [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRecent study demonstrated that circulating tumor cells (CTCs) peak during sleep, with implications for liquid biopsy timing [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Indeed, in breast cancer patients the amount of CTCs was markedly elevated at night (4 a.m.), and these nocturnally released CTCs showed greater metastatic potential [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. We previously observed a non-significant trend toward higher ctDNA levels in the afternoon versus morning samples in cancer patients [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This study questioned whether blood-take at 4 a.m. has a potential of increasing the sensitivity of ctDNA detection.\u003c/p\u003e"},{"header":"Methodology","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatients:\u003c/h2\u003e\u003cp\u003ePatients with locally advanced or metastatic colorectal cancer (CRC), who were treated in the N.N. Petrov Institute of Oncology (St. Petersburg) or St. Luke's Clinical Hospital (St. Petersburg) between June 2024 and February 2025, were invited to participate in the study. All patients provided informed consent. The study was approved by the local Ethics Committee. Eligible participants had tumors positive for the most common \u003cem\u003eKRAS, NRAS\u003c/em\u003e, or \u003cem\u003eBRAF\u003c/em\u003e somatic mutations as determined by the analysis of paraffin-embedded tumor tissues. Clinical characteristics of the patients are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Serial plasma samples were collected over two consecutive days at three timepoints: 12 p.m. (1st day), 4 a.m. (night), and 12 p.m. (2nd day).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePlasma Processing and ctDNA Isolation:\u003c/h3\u003e\n\u003cp\u003eBlood samples (10 mL) were drawn into GBM scf-DNA tubes (Gradbiomed, Russia). Plasma was separated by one-step centrifugation at 400 g for 10 minutes at room temperature. Cell-free DNA was extracted from 3\u0026ndash;5 mL of plasma using the QIAamp Circulating Nucleic Acid kit (Qiagen, the Netherlands), following the manufacturer's instructions, and dissolved in 50\u0026ndash;60 \u0026micro;L of water.\u003c/p\u003e\n\u003ch3\u003eddPCR and ctDNA Quantification:\u003c/h3\u003e\n\u003cp\u003e\u003cem\u003eKRAS, NRAS\u003c/em\u003e, or \u003cem\u003eBRAF\u003c/em\u003e mutant allele fractions in plasma samples were measured by ddPCR using the QX200 System (Bio-Rad), as described previously [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. ddPCR reactions were performed with 2\u003csup\u003eX\u003c/sup\u003e ddPCR supermix for probes (no dUTP; Bio-Rad, USA), the appropriate mutation detection kit (Supplementary Table\u0026nbsp;1S), and 2\u0026ndash;3 \u0026micro;L of template DNA in a 22\u0026ndash;23 \u0026micro;L of total reaction volume. Data were analyzed using QuantaSoft Software version 1.7.4, with duplicate analyses performed and merged for each sample. Thresholds were manually set based on predefined assay optimization criteria.\u003c/p\u003e\u003cp\u003eThe absolute number of tumor-derived mutated DNA copies per mL of initial plasma (Cmut) was calculated as:\u003c/p\u003e\u003cp\u003eС\u003csub\u003emut\u003c/sub\u003e = [Concentration (mut copies/\u0026micro;L) \u0026times; V\u003csub\u003ereaction\u003c/sub\u003e \u0026times; V\u003csub\u003edilution\u003c/sub\u003e] / [V\u003csub\u003etemplate\u003c/sub\u003e \u0026times; V\u003csub\u003eplasma\u003c/sub\u003e]\u003c/p\u003e\u003cp\u003eWhere:\u003c/p\u003e\u003cp\u003eConcentration - number of \u0026laquo;mutated\u0026raquo; droplets per 1 \u0026micro;L of ddPCR reaction;\u003c/p\u003e\u003cp\u003eV\u003csub\u003ereaction\u003c/sub\u003e - total ddPCR reaction volume, \u0026micro;L;\u003c/p\u003e\u003cp\u003eV\u003csub\u003etemplate\u003c/sub\u003e - volume of ctDNA aliquot taken into ddPCR, \u0026micro;L;\u003c/p\u003e\u003cp\u003eV\u003csub\u003edilution\u003c/sub\u003e - total volume of diluted ctDNA sample collected from the plasma, \u0026micro;L;\u003c/p\u003e\u003cp\u003eV\u003csub\u003eplasma\u003c/sub\u003e - initial volume of processed plasma, mL.\u003c/p\u003e\u003cp\u003eWild-type (wt) fragment concentrations were not considered for the data interpretation, given that non-mutated circulating DNA may derive both from blood cells and non-tumor epithelial cells, and, therefore, these results have limited relevance to the aim of this study [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The analysis focused only on the concentrations of mutant DNA copies. The raw data, including the concentration of wt-ccfDNA at all timepoints, are available in Supplementary Table\u0026nbsp;3S.\u003c/p\u003e\n\u003ch3\u003eStatistics:\u003c/h3\u003e\n\u003cp\u003eIntra-individual variance was assessed using the coefficient of variation (CV%)\u0026thinsp;=\u0026thinsp;standard deviation / mean. To analyze the relationship between ctDNA content and blood collection time, the following variables were evaluated for paired measurements (1st day vs. night; 1st day 1 vs. 2nd day; night vs. 2nd day): Percentage change (%)\u0026thinsp;=\u0026thinsp;100% \u0026times; (final Cmut \u0026ndash; initial Cmut) / initial Cmut\u003c/p\u003e\u003cp\u003eQuantitative data were reported as mean and 95% CI or median and range. Wilcoxon signed-rank test and Mann\u0026ndash;Whitney U test were used for median comparisons. Fisher's exact test was used for categorical variables. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Analyses were performed using IBM SPSS v.23.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient characteristics. CT \u0026ndash; chemotherapy; Metastatic sites: hep \u0026ndash; hepatic, lympn - lymph node; pulm \u0026ndash; pulmonary; per \u0026ndash; peritoneal.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLab\u003c/p\u003e\u003cp\u003eCode\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMutation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGender\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDate of the 1st blood take\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDiagnosis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTNM\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDisease status at the time of the 1st blood draw*\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eTherapy\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-1.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G13D\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e29.03.2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of sigmoid colon, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT3N1M1\u003c/p\u003e\u003cp\u003e(hep)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003end\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1st cycle of the first-line CT (FOLFOX)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G13D\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e04.05.2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of sigmoid colon, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT3N1M1\u003c/p\u003e\u003cp\u003e(hep)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eStable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e3rd cycle of the first-line CT (FOLFOX\u0026thinsp;+\u0026thinsp;bevacizumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-2.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G12D\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e28.04.2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of rectum,\u003c/p\u003e\u003cp\u003elow-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT3N2M1\u003c/p\u003e\u003cp\u003e(hep)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eStable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eRadiotherapy; 1st cycle of the first-line CT (FOLFOX)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-2.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G12D\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e27.05.2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of rectum,\u003c/p\u003e\u003cp\u003elow-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT3N2M1\u003c/p\u003e\u003cp\u003e(hep)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eStable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e2nd cycle of the first-line CT (FOLFOX)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-2.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G12D\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e14.01.2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of rectum,\u003c/p\u003e\u003cp\u003elow-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT3N2M1\u003c/p\u003e\u003cp\u003e(hep)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProgressing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e5th cycle of the second-line CT (FOLFIRI\u0026thinsp;+\u0026thinsp;bevacizumab);\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G13D\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e27.06.2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of sigmoid colon, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT4bN1M1\u003c/p\u003e\u003cp\u003e(hep)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProgressing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e10th cycle of the first-line CT (FOLFOX)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G12D\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e15.08.2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of colon, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT2NxM1\u003c/p\u003e\u003cp\u003e(hep, per, pulm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProgressing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1st cycle of the third-line CT (FOLFIRI\u0026thinsp;+\u0026thinsp;bevacizumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G12D\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e21.08.2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of ascending colon, low-grade; DLBCL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTxN0M1\u003c/p\u003e\u003cp\u003e(hep, pulm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProgressing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eR-CHOP**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-6.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eBRAF V600E\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e03.11.2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of hepatic flexure of the colon, high-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT4bN2bM1\u003c/p\u003e\u003cp\u003e(hep, per)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProgressing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1st cycle of the first-line CT (FOLFOX)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-6.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eBRAF V600E\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e28.01.2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of hepatic flexure of the colon, high-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT4bN2bM1\u003c/p\u003e\u003cp\u003e(hep, per)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eStable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e5th cycle of the first-line CT (FOLFOX\u0026thinsp;+\u0026thinsp;bevacizumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G12D\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e17.01.2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of sigmoid colon, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT2N1M1\u003c/p\u003e\u003cp\u003e(hep, per)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProgressing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1st cycle of the first-line CT (FOLFOX\u0026thinsp;+\u0026thinsp;bevacizumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS Q61R\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20.01.2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of colon, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT3N1M1b\u003c/p\u003e\u003cp\u003e(hep, pulm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProgressing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e4th cycle of the first-line CT (FOLFOX\u0026thinsp;+\u0026thinsp;bevacizumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G12D\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e24.01.2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of colon, high-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT4aN2aM1c\u003c/p\u003e\u003cp\u003e(per)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eStable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e10th cycle of the first-line CT (5-fluorouracil\u0026thinsp;+\u0026thinsp;bevacizumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-10.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G12D\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e27.01.2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of rectum, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT3N1M0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProgressing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1st cycle of the first-line CT (FOLFIRI\u0026thinsp;+\u0026thinsp;bevacizumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-10.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G12D\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003e52\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e27.02.2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of rectum, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT3N1M0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eStable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e2st cycle of the first-line CT (FOLFIRI\u0026thinsp;+\u0026thinsp;bevacizumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-11.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS A146V\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e26.11.2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of ascending colon, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTxNxM1\u003c/p\u003e\u003cp\u003e(hep, pulm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProgressing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1st cycle of the first-line CT (5-fluorouracil)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-11.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS A146V\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e15.01.2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of ascending colon, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTxNxM1\u003c/p\u003e\u003cp\u003e(hep, pulm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eStable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e4st cycle of the first-line CT (FOLFOX\u0026thinsp;+\u0026thinsp;bevacizumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G13D\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e05.02.2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of cecum, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT2N0M1\u003c/p\u003e\u003cp\u003e(hep)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProgressing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1st cycle of the first-line CT (FOLFOX\u0026thinsp;+\u0026thinsp;bevacizumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS A146T\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e07.02.2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of rectosigmoid junction, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT4aN2aM1a\u003c/p\u003e\u003cp\u003e(hep)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eStable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e6th cycle of the second-line CT (FOLFOX\u0026thinsp;+\u0026thinsp;bevacizumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G12S\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e07.02.2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of sigmoid colon, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT3NxM1c\u003c/p\u003e\u003cp\u003e(hep, per, pulm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eStable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e9th cycle of the second-line CT (FOLFIRI\u0026thinsp;+\u0026thinsp;ramucirumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS A146T\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e27.01.2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of rectum, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT4aN2bM1b\u003c/p\u003e\u003cp\u003e(hep, pulm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eStable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e3rd cycle of the first-line CT (5-fluorouracil\u0026thinsp;+\u0026thinsp;bevacizumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G13D\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e28.04.2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of sigmoid colon, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT3N1M1a\u003c/p\u003e\u003cp\u003e(hep, lympn)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003end\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e2nd cycle of the first-line CT (FOLFOX\u0026thinsp;+\u0026thinsp;bevacizumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eNRAS Q61K\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e16.05.2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of ascending colon, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT4bN0M0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eStable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e8th cycle of the first-line CT (FOLFIRI\u0026thinsp;+\u0026thinsp;bevacizumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G12С\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e28.06.2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of rectum, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT3N0M1\u003c/p\u003e\u003cp\u003e(hep)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProgressing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e2nd cycle of the first-line CT (FOLFOX)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt-19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS G12C\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e21.01.2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdenocarcinoma of sigmoid colon, low-grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eT4bN0M1\u003c/p\u003e\u003cp\u003e(hep)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProgressing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1st cycle of the third-line CT (bevacizumab)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003e*Progression criteria were defined as follows: a)\u0026thinsp;\u0026ge;\u0026thinsp;20% increase in target lesion size, any increase in non-target lesions, or the appearance of new tumor foci (progressive disease, PD, RECIST 1.1), as documented by CT, MRI, or PET imaging; b) peritoneal carcinomatosis was confirmed by imaging (CT, MRI, or PET) and/or biopsy; c) high tumor budding grade was assessed on H\u0026amp;E-stained slides; tumor buds may exhibit features of epithelial\u0026ndash;mesenchymal transition (EMT) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. ** Patient 5 completed the fourth cycle of R-CHOP therapy for diffuse large B-cell lymphoma (DLBCL) two months prior to the first blood draw. CT - chemotherapy\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eTwenty-five triplets of plasma samples were collected from 19 individuals. Four patients (Pt-1, Pt-6, Pt-10, Pt-11) participated twice (with intervals of 4\u0026ndash;12 weeks), and one patient (Pt-2) participated three times (with intervals of 4 and 33 weeks) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Due to the evolving clinical context and varying time intervals, all 25 triplets were analyzed as independent cases. At the time of blood collection, 12 patients exhibited clinical or radiological signs of tumor progression, while 11 showed no signs of progression and were classified as \u0026ldquo;stable\u0026rdquo;; in two cases, the disease status could not be assessed (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, detailed clinical information is provided in Supplementary Table\u0026nbsp;3S)\u003c/p\u003e\u003cp\u003eAt least one \"ctDNA-positive\" sample with detectable \u003cem\u003eRAS/RAF\u003c/em\u003e mutations (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;10 copies\u0026middot;mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) was found in 20/25 (80%) triplets. The remaining five triplets were plasma-negative across all timepoints and, therefore, excluded from the analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). C\u003csub\u003emut\u003c/sub\u003e ranged from 10 to 103,250 copies\u0026middot;mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The probability of ctDNA detection did not correlate with age, gender, primary tumor size, prior surgery for primary tumor resection, or location of metastatic sites (Supplementary Table\u0026nbsp;2S). A borderline association was observed with lymph node involvement [N+: 12/14 (86%) vs. N0: 2/5 (14%), p\u0026thinsp;=\u0026thinsp;0.084, Mann-Whitney U test].\u003c/p\u003e\u003cp\u003eAmong 20 plasma-positive patients, 15 showed measurable ctDNA across the entire triplet, with intra-individual CV% ranging from 1.7 to 74.8 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; Supplementary Table S3). Five triplets (Pt-1.2, Pt-7, Pt-12, Pt-13, Pt-14) were ctDNA-negative in at least one noontime draw but consistently positive at night (mean nocturnal Cmut\u0026thinsp;\u0026plusmn;\u0026thinsp;95% CI: 14,254\u0026thinsp;\u0026plusmn;\u0026thinsp;10,331 copies\u0026middot;mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e). Mean noontime Cmut was slightly lower (13,919\u0026thinsp;\u0026plusmn;\u0026thinsp;8,263 copies\u0026middot;mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e), with no significant difference (p\u0026thinsp;=\u0026thinsp;0.726, Mann-Whitney U; p\u0026thinsp;=\u0026thinsp;0.312, Wilcoxon test).\u003c/p\u003e\u003cp\u003eThe fluctuations of intra-individual \u003cem\u003eRAS/RAF\u003c/em\u003e\u0026thinsp;+\u0026thinsp;ctDNA within \u0026plusmn;\u0026thinsp;25% have been interpreted as random [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Personal ctDNA kinetics over day-night-day cycles revealed five distinct temporal patterns (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e):\u003c/p\u003e\u003cp\u003e\u003col style=\"list-style-type:lower-roman;\"\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eNight peak: 1st day-to-night increase \u0026ndash; maximum C mut at night \u0026ndash; night-to-2nd day decrease, n\u0026thinsp;=\u0026thinsp;8 (Pt-1.1, Pt-1.2, Pt-2.1, Pt-2.2, Pt-6.2, Pt-10.2, Pt-11.2, Pt-14);\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eNight drop: 1st day-to-night decrease \u0026ndash; minimum C mut at night \u0026ndash; night-to-2nd day increase, n\u0026thinsp;=\u0026thinsp;2 (Pt-2.3, Pt-8);\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eUptrend: 1st day-to-night stable/increase \u0026ndash; night-to-2nd day stable/increase \u0026ndash; maximum C \u003csub\u003emut\u003c/sub\u003e at 2nd day, n\u0026thinsp;=\u0026thinsp;3 (Pt-3, Pt-9, Pt-11.1);\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eDowntrend: 1st day-to-night stable/decreasing \u0026ndash; night-to-2nd day stable/decreasing \u0026ndash; minimum C\u003csub\u003emut\u003c/sub\u003e at 2nd day, n\u0026thinsp;=\u0026thinsp;5 (Pt-4, Pt-6.1, Pt-7, Pt-12, Pt-13);\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eQuasi-constant levels at three timepoints, n\u0026thinsp;=\u0026thinsp;2 (Pt-5, Pt-10.1).\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003eNotably, after stratifying the triplets by the disease status at the moment of blood take, 7/9 patients without pronounced signs of tumor progression exhibited a \"night peak,\" while all 10 progressing cases followed other patterns. No \"night peak\" was observed in patients with the disease progression (p\u0026thinsp;=\u0026thinsp;0.005, Fisher's exact test; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eInterestingly, patients who donated triplet sample for the study more than once demonstrated different patterns of ctDNA concentration depending on the disease status. For example, patient Pt-2 displayed a \u0026ldquo;night peak\u0026rdquo; in the first and second monitoring rounds, both conducted during the disease control. At the third time point (33 weeks later), the clinical situation had deteriorated, with Cmut reaching 103,250 copies/\u0026micro;L plasma; the day\u0026ndash;night\u0026ndash;day profile showed a \u0026ldquo;night drop\u0026rdquo;. Patients Pt-6, Pt-10 and Pt-11 entered the study with disease progression, showing downtrend, uptrend, and quasi-constant profiles, respectively. After stabilization, each shifted to a \u0026ldquo;night peak\u0026rdquo; pattern (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. ddPCR measurement of mutated ctDNA content in plasma of CRC patients in three consecutive time points: 12 p.m. (1\u003csup\u003est\u0026nbsp;\u003c/sup\u003eday) - 4 a.m. (night) - 12 p.m. (2\u003csup\u003end\u003c/sup\u003e day)\u003c/p\u003e\n\u003ctable style=\"border: none;width:737.6pt;margin-left:4.9pt;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47.5pt;border: 1pt solid windowtext;background: rgb(191, 191, 191);padding: 0cm 5.4pt;height: 44.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003eLabCode\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73.65pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: rgb(191, 191, 191);padding: 0cm 5.4pt;height: 44.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003eMutation\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53.6pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: rgb(191, 191, 191);padding: 0cm 5.4pt;height: 44.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family: \"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;12 p.m. (1\u003csup\u003est\u003c/sup\u003e day) \u0026nbsp;ddPCR\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family: \"Times New Roman\",serif;color:black;'\u003emut/wt\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52.55pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: rgb(191, 191, 191);padding: 0cm 5.4pt;height: 44.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family: \"Times New Roman\",serif;color:black;'\u003e12 p.m. \u0026nbsp;\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family: \"Times New Roman\",serif;color:black;'\u003e(1\u003csup\u003est\u003c/sup\u003e day) Cmut*\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53.6pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: rgb(191, 191, 191);padding: 0cm 5.4pt;height: 44.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family: \"Times New Roman\",serif;color:black;'\u003e4 a.m. (night) ddPCR\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family: \"Times New Roman\",serif;color:black;'\u003emut/wt\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 55.3pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: rgb(191, 191, 191);padding: 0cm 5.4pt;height: 44.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e4 a.m. (night) Cmut\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53.6pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: rgb(191, 191, 191);padding: 0cm 5.4pt;height: 44.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family: \"Times New Roman\",serif;color:black;'\u003e12 p.m. (2\u003csup\u003end\u003c/sup\u003e day) ddPCR\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family: \"Times New Roman\",serif;color:black;'\u003emut/wt\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.25pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: rgb(191, 191, 191);padding: 0cm 5.4pt;height: 44.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family: \"Times New Roman\",serif;color:black;'\u003e12 p.m. (2\u003csup\u003end\u003c/sup\u003e day) Cmut\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45.75pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: rgb(191, 191, 191);padding: 0cm 5.4pt;height: 44.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e% change night - 1\u003csup\u003est\u003c/sup\u003e day\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.7pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: rgb(191, 191, 191);padding: 0cm 5.4pt;height: 44.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family: \"Times New Roman\",serif;color:black;'\u003e% change 2\u003csup\u003end\u003c/sup\u003e day - night\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.75pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: rgb(191, 191, 191);padding: 0cm 5.4pt;height: 44.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family: \"Times New Roman\",serif;color:black;'\u003eCV% 2\u003csup\u003end\u003c/sup\u003e day to 1\u003csup\u003est\u003c/sup\u003e day\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.85pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: rgb(191, 191, 191);padding: 0cm 5.4pt;height: 44.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003ePattern day-night-day\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95.5pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: rgb(191, 191, 191);padding: 0cm 5.4pt;height: 44.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003eTumor status\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47.5pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;background: white;padding: 0cm 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003ePt-1.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73.65pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: white;padding: 0cm 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cem\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003eKRAS G13D\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.6pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 5.4pt 0cm 5.4pt;height:14.25pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e5/105\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 5.4pt 0cm 5.4pt;height:14.25pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e33\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.6pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 5.4pt 0cm 5.4pt;height:14.25pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e10/78\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:55.3pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 5.4pt 0cm 5.4pt;height:14.25pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e162\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background: white;padding:0cm 5.4pt 0cm 5.4pt;height:14.25pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e7/64\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 5.4pt 0cm 5.4pt;height:14.25pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e53\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:45.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 5.4pt 0cm 5.4pt;height:14.25pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:red;'\u003e391\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:46.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 5.4pt 0cm 5.4pt;height:14.25pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:#2506E2;'\u003e-\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:#2506E2;'\u003e6\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:#2506E2;'\u003e7\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:46.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 5.4pt 0cm 5.4pt;height:14.25pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e32.9%\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.85pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FBDAD7;padding:0cm 5.4pt 0cm 5.4pt;height:14.25pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003enight peak\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;height:14.25pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003eNd\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47.5pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;background: white;padding: 0cm 5.4pt;height: 15pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003ePt-1.2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73.65pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: white;padding: 0cm 5.4pt;height: 15pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cem\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003eKRAS G13D\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.6pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 5.4pt 0cm 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e1/52\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 5.4pt 0cm 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan 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style=\"width:53.6pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 5.4pt 0cm 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e459/419\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 5.4pt 0cm 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New 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style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003eProgressing\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47.5pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;background: white;padding: 0cm 5.4pt;height: 15pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003ePt-5\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73.65pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: white;padding: 0cm 5.4pt;height: 15pt;vertical-align: bottom;\"\u003e\n \u003cp 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1.0pt;background:white;padding:0cm 5.4pt 0cm 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e2100\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.6pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 5.4pt 0cm 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e87/3052\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd 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5.4pt 0cm 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e7.6%\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.85pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 5.4pt 0cm 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style='font-size:13px;font-family: \"Times New Roman\",serif;color:black;'\u003econstant\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 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style=\"width: 53.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 14.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/542\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 14.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan 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style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/100\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 14.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 14.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/75\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 55.3pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 14.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid 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style=\"width:45.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#D9D9D9;padding:0cm 5.4pt 0cm 5.4pt;height:14.25pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:46.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#D9D9D9;padding:0cm 5.4pt 0cm 5.4pt;height:14.25pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New 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style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#D9D9D9;padding:0cm 5.4pt 0cm 5.4pt;height:14.25pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003eStable\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47.5pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 9.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003ePt-18\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73.65pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 9.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cem\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003eKRAS G12С\u0026nbsp;\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 9.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/5030\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 9.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 9.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4647\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 55.3pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 9.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 9.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/2808\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 9.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:45.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#D9D9D9;padding:0cm 5.4pt 0cm 5.4pt;height:9.9pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:46.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#D9D9D9;padding:0cm 5.4pt 0cm 5.4pt;height:9.9pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:46.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#D9D9D9;padding:0cm 5.4pt 0cm 5.4pt;height:9.9pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.85pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#D9D9D9;padding:0cm 5.4pt 0cm 5.4pt;height:9.9pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#D9D9D9;padding:0cm 5.4pt 0cm 5.4pt;height:9.9pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003eProgressing\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47.5pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 8.7pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003ePt-19\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73.65pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 8.7pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cem\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003eKRAS G12C\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 8.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/509\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 8.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 8.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/1422\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 55.3pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 8.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 8.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4264\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(217, 217, 217);padding: 0cm 5.4pt;height: 8.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:45.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#D9D9D9;padding:0cm 5.4pt 0cm 5.4pt;height:8.7pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:46.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#D9D9D9;padding:0cm 5.4pt 0cm 5.4pt;height:8.7pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:46.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#D9D9D9;padding:0cm 5.4pt 0cm 5.4pt;height:8.7pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.85pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#D9D9D9;padding:0cm 5.4pt 0cm 5.4pt;height:8.7pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#D9D9D9;padding:0cm 5.4pt 0cm 5.4pt;height:8.7pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;color:black;'\u003eProgressing\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNotes: Concentration С\u003csub\u003emut\u0026nbsp;\u003c/sub\u003e= mut copies ctDNA/\u0026micro;L of plasma; Percentage change (%) = 100% x (final C\u003csub\u003emut\u0026nbsp;\u003c/sub\u003e\u0026ndash; 1\u003csup\u003est\u003c/sup\u003e day C\u003csub\u003emut\u0026nbsp;\u003c/sub\u003e)/(1\u003csup\u003est\u003c/sup\u003e day C\u003csub\u003emut\u003c/sub\u003e); \u0026Delta; C\u003csub\u003emut\u003c/sub\u003e = final C\u003csub\u003emut\u003c/sub\u003e \u0026ndash; initial C\u003csub\u003emut\u003c/sub\u003e; Coefficient of Variation CV% = \u0026nbsp;Standard deviation/Mean; \u0026gt;25% increase (red) or decrease (blue) of the plasma ctDNA concentration was taken as a significant change; fluctuations within \u003cu\u003e\u0026lt;\u003c/u\u003e 25% were assumed as insignificant; gray boxes \u0026ndash; uninformative plasma-negative triplets.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study demonstrates that plasma ctDNA levels exhibit some intra-individual circadian variations, with a 4 a.m. peak observed in patients with the tumor disease control. The results align with prior reports on nocturnal surges in CTC in breast cancer patients and suggest that liquid biopsy results are modulated by circadian rhythms or sleep-related physiological changes [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Diamantopoulou et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] reported 2- to 34-fold higher CTC levels at night in breast cancer patients, with increased metastatic potential of CTCs released during sleep [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. While rhythmic patterns in CTC dynamics are recognized, a direct link to ctDNA remains unproven. The prevailing view holds that cancer cells continuously release DNA into the bloodstream during tumor progression [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. However, emerging evidence shows that ctDNA levels can fluctuate considerably within short timeframes [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In lung cancer patients, Hojbjerg et al. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] observed ctDNA variations of up to 53% day-to-day and 27% hour-to-hour, as determined by digital PCR.\u003c/p\u003e\u003cp\u003eOur findings, together with prior reports, indicate that ctDNA dynamics may be modulated by circadian rhythms, which govern a broad range of physiological functions, including metabolism, hormonal signaling, immune surveillance, tumor cell apoptosis or necrosis, etc. [\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In particular, hormones such as melatonin, insulin, and cortisol, known to follow circadian cycles, may influence the release and clearance of tumor-derived analytes [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Disruption of melatonin during sleep deprivation has been associated with increased oxidative stress, epithelial-to-mesenchymal transition, impaired DNA repair, and enhanced cancer cell migration, particularly in night-shift workers [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Circadian changes in immune function - reflected by shifts in inflammation, immune cell distribution, and tissue trafficking - may also affect tumor-host interactions and ctDNA shedding [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. In addition, circadian regulation of hepatic metabolism can influence circulating metabolite levels, potentially affecting ccfDNA degradation [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eInterestingly, ctDNA circadian rhythms observed in our study were clearly associated with non-progressing status of the tumor disease. This relationship was evident both when comparisons involved different patients and when same patients provided blood for the study while being at different points of the course of cancer disease. Perhaps, failure of the host organism to control tumor growth is associated with a number of pathological processes (inflammation, neovascularization, metabolic changes etc.) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe biological basis of nocturnal ctDNA enrichment remains poorly understood. One possibility is that circadian rhythms modulate tumor biology, leading to transient surges in DNA release from tumor foci [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Alternatively, the peak may reflect increased decay of CTCs during deep-sleep phase [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. A third possibility is that it arises from circadian fluctuations in the activity of ccfDNA clearance pathways, including nuclease-mediated degradation [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] and uptake by liver-resident Kupffer cells and spleen macrophages [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Moreover, the activity, toxicity and tumor-killing effects of many antitumor agents, including chemotherapeutic agents, targeted therapies, and immunotherapies, are strongly influenced by circadian rhythms [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSeveral limitations of this study need to be considered. The sample size (n\u0026thinsp;=\u0026thinsp;19) was limited due to the logistical challenges of 4 a.m. blood draws. The small cohort size, single-night sampling, and exclusive focus on colorectal cancer limit the generalizability of our findings. Although five patients were sampled more than once, each triplet was analyzed independently. Future studies should aim to include other tumor types (e.g., lung, breast) to differentiate tumor site\u0026ndash;specific effects from broader circadian regulatory mechanisms. Additionally, longitudinal, multi-day sampling combined with integrated clinical and circadian biomarker data would provide a more comprehensive understanding. We also acknowledge potential biases in ctDNA dynamics introduced by chemotherapy. Nearly all patients were hospitalized in connection with the initiation of a new chemotherapy cycle and received their respective drug regimens on the day of the first blood collection. The interval between drug administration and the nocturnal blood draw ranged from 12 to 40 hours (Supplementary Table\u0026nbsp;3S). We assessed whether nocturnal ctDNA concentrations correlated with the time since prior drug administration; no such association was observed.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eColorectal cancer patients, which experience disease controls at the time of bloodtakes, demonstrate nocturnal peaks of ctDNA concentration. Biological basis of this phenomenon deserves investigation. In addition, the obtained data suggest that circadian rhythms may affect the sensitivity of liquid biopsy.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAI/ML\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eArtificial Intelligence/Machine Learning\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eccfDNA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecirculating cell-free DNA\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCmut\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eConcentration number of \u0026laquo;mutated\u0026raquo; DNA fragments in plasma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCRC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecolorectal cancer\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003echemotherapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCTC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecirculating tumor cells\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ectDNA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecirculating tumor DNA\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCV%\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecoefficient of variation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eddPCR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003edroplet digital PCR\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLB\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eliquid biopsy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eprogressive disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003estable disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eWt\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eWild-type\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Russian Science Foundation (RSF) grant № 23-15-00461\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients provided informed consent. The study was approved by the local Ethics Committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupplementary Tables 1-3 (xlsx, 481Kb). 1S: ddPCR assays for mutation detection; 2S: Association between the results of plasma tumor DNA test and clinical characteristics of the patients; 3S: ddPCR measurement of mutated ctDNA content in plasma of CRC patients in three consecutive time points: 12 p.m. (1\u003csup\u003est\u003c/sup\u003e day) - 4 a.m. (night) - 12 p.m. (2\u003csup\u003end\u003c/sup\u003e day). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors and Affiliations:\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepartment of Tumor Growth Biology, N.N. Petrov National Medical Research Center of Oncology, Ministry of Public Health of the Russian Federation, 197758, Saint Petersburg, Russia.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEkaterina S. Kuligina, Aleksandr S. Martianov, Liliya S. Baboshkina, Arina S Perevalova, \u0026nbsp; Anastasia N Ershova, Tatiana A. Laidus,\u0026nbsp;Gulfiia M. Teletaeva, Evgeny N. Imyanitov\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepartment of Medical Genetics, St.-Petersburg Pediatric Medical University, 194100, Saint Petersburg, Russia.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAleksandr S. Martianov, Tatiana A. Laidus, Evgeny N. Imyanitov\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepartment of clinical oncology, Pavlov First Saint Petersburg State Medical University, 197022, Saint Petersburg, Russia.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAram A. Musaelyan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepartment of Antitumor Drug Therapy, St. Luke Clinical Hospital, 194044, Saint Petersburg, Russia.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEkaterina M. Anokhina\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design: Ekaterina S. Kuligina, and Evgeny N. Imyanitov. Development of methodology: Aleksandr S. Martianov, Tatiana A. Laidus, Arina S. Perevalova, \u0026nbsp; Anastasia N. Ershova. Acquisition of data: Liliya S. Baboshkina, Aram A. Musaelyan, Ekaterina M. Anokhina, Gulfiia M. Teletaeva. Analysis and interpretation of data: Ekaterina S. Kuligina, Aleksandr S. Martianov. Writing, review, and/or revision of the manuscript: Ekaterina S. Kuligina and Evgeny N. Imyanitov. Study supervision: Evgeny N. Imyanitov.\u003c/p\u003e\n\u003cp\u003eCorresponding author\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCorrespondence to Ekaterina S. 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Lancet Oncol. 2022;23:e129\u0026ndash;43. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S1470-2045(21)00639-2\u003c/span\u003e\u003cspan address=\"10.1016/S1470-2045(21)00639-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-gastrointestinal-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijgc","sideBox":"Learn more about [Journal of Gastrointestinal Cancer](https://www.springer.com/journal/12029)","snPcode":"12029","submissionUrl":"https://submission.nature.com/new-submission/12029/3","title":"Journal of Gastrointestinal Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"circulating tumor DNA (ctDNA), circadian rhythms, individual dynamics, driver mutations, individual variability, colorectal cancer","lastPublishedDoi":"10.21203/rs.3.rs-7761150/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7761150/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe utility of liquid biopsy in clinical oncology is often compromised by low concentration of tumor-derived fragments. Recent study demonstrated a nocturnal peak in the amount circulating tumor cells during the deep sleep phase (~\u0026thinsp;4 a.m.). This study questioned whether the same peak is characteristic of circulating tumor DNA (ctDNA).\u003c/p\u003e\u003cp\u003ePlasma samples were collected from 19 RAS/RAF-mutated colorectal cancer (CRC) patients at 12 p.m. (day 1), 4 a.m. (night), and 12 p.m. (day 2). 14 subjects provided a single triplet for the study, and 5 patients underwent the above procedure twice or thrice. \u003cem\u003eKRAS, NRAS\u003c/em\u003e, and \u003cem\u003eBRAF\u003c/em\u003e mutations in plasma were quantified via ddPCR.\u003c/p\u003e\u003cp\u003e\u003cem\u003eRAS/RAF\u003c/em\u003e mutations (\u0026gt;\u0026thinsp;10 copies/mL) were detected in at least one plasma sample in 20/25 (80%) triplets. Among these, 15 showed detectable ctDNA at all timepoints, with intra-individual variation ranging from 1.7% to 74.8%. In five triplets, ctDNA was undetectable during daytime but present at night. Overall, 7 of 9 triplets collected at the time of disease control exhibited a night peak in ctDNA concentration, while all 10 triplets obtained during tumor progression showed other patterns of ctDNA changes (p\u0026thinsp;=\u0026thinsp;0.005, Fisher\u0026rsquo;s exact test).\u003c/p\u003e\u003cp\u003eThese findings demonstrate that ctDNA level is a subject of circadian variations in a subset of cancer patients.\u003c/p\u003e","manuscriptTitle":"Nocturnal increase of concentration of circulating tumor DNA in metastatic colorectal cancer patients with disease control but not with progressive disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-10 20:12:57","doi":"10.21203/rs.3.rs-7761150/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-02T01:52:58+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-23T20:11:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"49145581634340498071375721624510254867","date":"2025-12-03T14:48:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"227722243097306688430348620036234930980","date":"2025-12-03T08:58:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"235013607666656879681144044605994989082","date":"2025-10-13T11:00:49+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-07T17:19:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-07T17:17:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-07T07:36:16+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Gastrointestinal Cancer","date":"2025-10-01T15:54:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-gastrointestinal-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijgc","sideBox":"Learn more about [Journal of Gastrointestinal Cancer](https://www.springer.com/journal/12029)","snPcode":"12029","submissionUrl":"https://submission.nature.com/new-submission/12029/3","title":"Journal of Gastrointestinal Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ae617353-8144-47eb-8a9c-a01c5512142a","owner":[],"postedDate":"December 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-05T01:08:44+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-10 20:12:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7761150","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7761150","identity":"rs-7761150","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}