scholarly journals ctDNA and Adjuvant Therapy for Colorectal Cancer: Time to Re-Invent Our Treatment Paradigm

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 346
Author(s):  
Mahendra Naidoo ◽  
Peter Gibbs ◽  
Jeanne Tie
Keyword(s):  
Colorectal Cancer ◽  
Residual Disease ◽  
Surrogate Endpoint ◽  
Risk Groups ◽  
Recurrence Risk ◽  
Prognostic Impact ◽  
Current Standard ◽  
Curative Intent ◽  
Treatment Benefit ◽  
Ctdna Analysis

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. While there have been significant developments in the treatments for patients with metastatic CRC in recent years, improving outcomes in the adjuvant setting has been more challenging. Recent technological advances in circulating tumour DNA (ctDNA) assay with the ability to detect minimal residual disease (MRD) after curative intent surgery will fundamentally change how we assess recurrence risk and conduct adjuvant trials. Studies in non-metastatic CRC have now demonstrated the prognostic impact of ctDNA analysis after curative intent surgery over and above current standard of care clinicopathological criteria. This ability of ctDNA analysis to stratify patients into low- and very-high-risk groups provides a window of opportunity to personalise adjuvant treatment where escalation/de-escalation of adjuvant systemic therapy could potentially increase cure rates and also reduce treatment-related physical and financial toxicity. Emerging data suggest that conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy may reflect treatment efficacy. This real-time assessment of treatment benefit could be used as a surrogate endpoint for adjuvant novel drug development. Several ctDNA-based randomized adjuvant trials are ongoing internationally to confirm the clinical utility of ctDNA in colorectal cancer.

scholarly journals ctDNA MRD Detection and Personalized Oncogenomic Analysis in Oligometastatic Colorectal Cancer From Plasma and Urine

2021 ◽  
pp. 378-388
Author(s):  
Bruna Pellini ◽  
Nadja Pejovic ◽  
Wenjia Feng ◽  
Noah Earland ◽  
Peter K. Harris ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Residual Disease ◽  
White Blood Cells ◽  
Driver Mutations ◽  
Curative Intent ◽  
Surgical Specimen ◽  
Pik3ca Mutations ◽  
Age Related ◽  
Ctdna Analysis

PURPOSE We hypothesized that circulating tumor DNA (ctDNA) molecular residual disease (MRD) analysis without prior mutational knowledge could be performed after neoadjuvant chemotherapy to assess oligometastatic colorectal cancer (CRC) treated surgically with curative intent. We also investigated urine as an alternative analyte for ctDNA MRD detection in this nongenitourinary setting. PATIENTS AND METHODS We applied AVENIO targeted next-generation sequencing to plasma, tumor, and urine samples acquired on the day of curative-intent surgery from 24 prospectively enrolled patients with oligometastatic CRC. Age-related clonal hematopoiesis was accounted for by removing variants also present in white blood cells. Plasma and urine ctDNA MRD were correlated with tumor cells detected in the surgical specimen, and adjuvant treatment strategies were proposed based on ctDNA-inferred tumor mutational burden (iTMB) and targetable alterations. RESULTS Seventy-one percent of patients were treated with neoadjuvant chemotherapy. Tumor-naive plasma ctDNA analysis detected MRD at a median level of 0.62% with 95% sensitivity and 100% specificity, and 94% and 77% sensitivity when only considering patients treated with neoadjuvant chemotherapy and putative driver mutations, respectively. In urine, ctDNA MRD detection specificity remained high at 100%, but sensitivity decreased to 64% with median levels being 11-fold lower than in plasma ( P < .0001). Personalized ctDNA MRD oncogenomic analysis revealed 81% of patients might have been candidates for adjuvant immunotherapy based on high iTMB or targeted therapy based on actionable PIK3CA mutations. CONCLUSION Tumor-naive plasma ctDNA analysis can sensitively and specifically detect MRD in patients with oligometastatic CRC after neoadjuvant chemotherapy. Urine-based ctDNA MRD detection is also feasible; however, it is less sensitive than plasma because of significantly lower levels. Oligometastatic patients with detectable MRD may benefit from additional personalized treatment based on ctDNA-derived oncogenomic profiling.

scholarly journals Machine learning identifies two autophagy-related genes as markers of recurrence in colorectal cancer

2020 ◽  
Vol 48 (10) ◽  
pp. 030006052095880
Author(s):  
Jianping Wu ◽  
Sulai Liu ◽  
Xiaoming Chen ◽  
Hongfei Xu ◽  
Yaoping Tang
Keyword(s):  
Colorectal Cancer ◽  
Machine Learning ◽  
Protein Interactions ◽  
Early Stage ◽  
Predictive Ability ◽  
Improve Patient Care ◽  
Active Role ◽  
Risk Groups ◽  
Recurrence Risk ◽  
Machine Learning Algorithms

Objective Colorectal cancer (CRC) is the most common cancer worldwide. Patient outcomes following recurrence of CRC are very poor. Therefore, identifying the risk of CRC recurrence at an early stage would improve patient care. Accumulating evidence shows that autophagy plays an active role in tumorigenesis, recurrence, and metastasis. Methods We used machine learning algorithms and two regression models, univariable Cox proportion and least absolute shrinkage and selection operator (LASSO), to identify 26 autophagy-related genes (ARGs) related to CRC recurrence. Results By functional annotation, these ARGs were shown to be enriched in necroptosis and apoptosis pathways. Protein–protein interactions identified SQSTM1, CASP8, HSP80AB1, FADD, and MAPK9 as core genes in CRC autophagy. Of 26 ARGs, BAX and PARP1 were regarded as having the most significant predictive ability of CRC recurrence, with prediction accuracy of 71.1%. Conclusion These results shed light on prediction of CRC recurrence by ARGs. Stratification of patients into recurrence risk groups by testing ARGs would be a valuable tool for early detection of CRC recurrence.

Circulating Tumor DNA as a Biomarker for Outcomes Prediction in Colorectal Cancer Patients

2020 ◽  
Vol 21 ◽  
Author(s):  
Angelica Petrillo ◽  
Massimiliano Salati ◽  
Dario Trapani ◽  
Michele Ghidini
Keyword(s):  
Colorectal Cancer ◽  
Residual Disease ◽  
Early Stage ◽  
Recurrence Risk ◽  
Early Response ◽  
Circulating Tumor Dna ◽  
Response To Treatment ◽  
Molecular Profile ◽  
Liquid Biopsies ◽  
Tissue Biopsy

Abstract:: Circulating tumour DNA (ctDNA) is a novel tool that has being investigated in several types of tumours, includ-ing colorectal cancer (CRC). In fact, the techniques based on liquid biopsies are proposed as appealing non-invasive alter-natives to tissue biopsy, adding more insights into tumour molecular profile, heterogeneity and for cancer detection and monitoring. Additionally, some analysis showed that in CRC patients ctDNA seems to act as biomarker able to predict the outcome (prognostic role) and the response to treatments (predictive role). In particular, in the early stage CRC (stage I-III) it could represent a time marker of adjuvant therapy benefit as well as a marker of minimal residual disease and recurrence risk in addition to the already recognized risk factors. In metastatic CRC, the analysis of molecular tumour profile by ctDNA has shown to have high concordance with the tissue biopsy at diagnosis. Additionally, some studies demonstrated that ctDNA level during the treatment was linked with early response to treatment and prognosis. Finally, the quantitative anal-ysis of ctDNA and copy number alterations may be useful in order to detect resistance to therapy at the time of progression of disease and to help in finding new therapeutic targets.

Use of circulating tumor DNA in colorectal cancer patients to assess tumor burden and response to therapy: An observational study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3528-3528
Author(s):  
Erin L. Symonds ◽  
Susanne Kartin Pedersen ◽  
Bernita Hui Li Yeo ◽  
Hiba Al Naji ◽  
Susan E. Byrne ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Size ◽  
Residual Disease ◽  
Early Stage ◽  
Circulating Tumor Dna ◽  
Tumor Burden ◽  
Post Treatment ◽  
Response To Therapy ◽  
Maximum Diameter ◽  
Curative Intent

3528 Background: Residual disease after treatment for colorectal cancer (CRC) poses a risk for recurrence but imaging and CEA are limited in their capacity to detect residual disease. A simple test is needed for assessing treatment response. This study determined whether levels of methylated BCAT1/IKZF1 DNA in blood correlate with tumor burden and whether post-treatment levels inform efficacy of different treatments for CRC. Methods: Patients with primary CRC had blood collected prior to treatment (n = 282, 59.9% males, median age 68.5y). Cell free DNA (cfDNA) was extracted from plasma and assayed for methylation in BCAT1 and IKZF1. Detection of methylation in either gene deemed a sample positive; levels were expressed as %methylation (average methylation/average cfDNA). Positive patients had additional samples collected post-treatment for early stage CRC (surgery, n = 31), advanced/metastatic CRC (surgery + adjuvant chemotherapy, n = 15), and rectal cancer (neoadjuvant therapy, surgery +/- chemotherapy, n = 6), or following mid-therapy suspension of treatment in advanced CRC (n = 24). Tumor size was expressed as the maximum diameter of the primary (assessed surgically or by MRI). Results: Pretreatment results increased with CRC stage. Positivity by stage was: I, 23.7% (14/59); II, 62.1% (54/87); III, 68.6% (70/102); IV, 85.3% (29/34). Level by stage: I, 0.0%; II, 0.06%; III, 0.07%; IV, 4.07%, p < 0.001). Pretreatment levels correlated significantly with tumor size (r = 0.372, p < 0.001). Post-treatment blood was collected a median 2.4mo (IQR 1.7-3.9) after therapy completion. Positivity decreased after completing treatment (Table), with 88.4% of cases (46/52) becoming ctDNA negative. All cases with complete treatment had a reduction in biomarker levels, whereas in those with incomplete therapy, 54.5% (12/22) remained positive and the pre- and post-treatment levels were not significantly different. Of those positive after treatment, 13 had a further blood sample: 8 had become ctDNA negative and all but one remained disease free. Five remained positive and all had further suspected or confirmed disease. Conclusions: Levels of methylated BCAT1 and IKZF1 DNA in blood correlated with tumor burden; levels became undetectable in the majority of patients following completion of planned curative intent treatment. The methylated ctDNA blood test aids monitoring of responses to therapy and identification of those cases with residual cancer who might benefit from ongoing therapy.[Table: see text]

High Prognostic Impact of Flowcytometric Minimal Residual Disease Detection In Acute Myeloid Leukemia: Prospective Data From the HOVON/SAKK 42a Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 760-760
Author(s):  
Monique Terwijn ◽  
Angèle Kelder ◽  
Wim L.J. van Putten ◽  
Alexander N. Snel ◽  
Vincent H.J. van der elden ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Residual Disease ◽  
Risk Groups ◽  
Prognostic Impact ◽  
Induction Cycle ◽  
Minimal Residual

Abstract Abstract 760 Currently, the most important prognostic factors for acute myeloid leukemia (AML) include molecular aberrancies and karyotype of the leukemic blasts. Although these factors have showed to be of utmost importance in upfront risk stratification in current treatment schedules, the treatment outcome of patients within as such defined risk groups is still quite heterogeneous. Therefore, there is an unmet need for therapy-dependent prognostic factors which can be implemented into risk-adapted treatment strategies. Minimal residual disease (MRD) frequency is such a parameter. MRD cells are considered responsible for the outgrowth of AML after treatment, leading to a relapse in 30–40% of the patients in complete remission (CR). In this study, we are the first to report prospective multicenter data on the prognostic impact of MRD frequency in adult AML. In our retrospective study (N.Feller et al. Leukemia 2004), we explored which cut-off points for percentage of MRD cells would define MRD positive (levels above cut-off, MRD+) patients with a relatively poor prognosis, from MRD negative (levels below cut-off, MRD-) patients who showed a longer overall and relapse-free survival (OS and RFS). In search for the most optimal cut-off level which can be used for clinical purpose in risk stratification-directed therapy, we used these cut-offs to evaluate the prognostic value in the current prospective setting. Diagnosis and follow-up samples were collected of 462 patients treated uniformly according to the HOVON/SAKK42a protocol (www.hovon.nl) and MRD frequency was assessed blindly without knowledge of clinical course. MRD detection was accomplished by immunophenotyping by flow cytometry (FCM) through aberrant expression of markers on AML blasts. Together with the expression of normal immature cell markers and/or myeloid lineage markers, this offers a leukemia associated phenotype (LAP). Each LAP was individually designed for each patient in diagnosis bone marrow (BM) or peripheral blood. Subsequently, BM samples obtained during follow-up were analysed for the presence of LAP-positive cells. MRD frequency was expressed as a percentage of leukocytes. The median MRD frequencies of patients in clinical CR after first induction cycle (n=164), second induction cycle (n=182) and consolidation (n=121) were 0.040%, 0.022% and 0.020%, respectively. The cut-off levels for MRD frequency as defined retrospectively were all significant in the identification of patients with adverse (MRD+) and favourable (MRD-) OS and RFS, respectively. After the first cycle, the most significant cut-off was 0.8%, leading to 17 MRD+ patients who showed a median RFS of only 8.6 months, while 147 MRD- patients had a median RFS of >47 months (p=0.003,A). The relative risk of relapse (RR) was 2.9 (95% c.i. 1.4–6.0, p=0.004). After the second induction cycle, a cut-off level of 0.06% was most significant. Above this cut-off, 49 patients showed a median RFS of 7 months, while 133 MRD- patients showed a RFS of more than 47 months (p<0.00001, fig B). The RR was 3.2 (95% c.i. 2.0–5.0, p<0.00001). After consolidation therapy, 11 MRD+ patients with extremely poor prognosis were identified (median RFS 7.3 months vs. >47 months for 110 MRD- patients, p<0.00001, fig C), with a RR of 10.6 (95% c.i. 4.9–22.8, p<0.00001). Multivariate analysis was performed with conventional prognostic factors for AML: cytogenetic risk groups and time to achieve CR. After every cycle of therapy, MRD frequency was an independent prognostic factor for RFS after all cycles (1st cycle: p=0.010, 2nd cycle and consolidation p<0.00001) and for OS after 1st (p=0.023) and 2nd induction cycle (p=0.010). In this prospective multicenter study, already after first induction cycle, MRD detection by FCM was an independent significant factor in the identification of poor prognostic patients. In future treatment studies, risk stratification, e.g. for allogeneic stem cell transplantation, should not only be based on risk estimation determined at diagnosis, but also on MRD frequency as a therapy-dependent prognostic factor. This work was supported by Netherlands Cancer Foundation KWF. Disclosures: No relevant conflicts of interest to declare.

scholarly journals ctDNA to Guide Adjuvant Therapy in Localized Colorectal Cancer (CRC)

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2869
Author(s):  
Laura Masfarré ◽  
Joana Vidal ◽  
Concepción Fernández-Rodríguez ◽  
Clara Montagut
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Adjuvant Chemotherapy ◽  
Residual Disease ◽  
Early Stage ◽  
Recurrence Risk ◽  
Circulating Tumor Dna ◽  
Key Points ◽  
The Impact ◽  
Critical Overview

Currently, the standard treatment for patients with localized colorectal cancer (CRC) includes surgical resection followed by adjuvant chemotherapy based on clinicopathological features. Recurrence risk stratification in those patients is of utmost importance to guide clinicians to avoid both under- and overtreatment. Recently, the concept of minimal residual disease (MRD) has emerged as the detection of circulating tumor DNA (ctDNA) carrying tumor-specific genomic or epigenomic alterations in the bloodstream of patients after surgery. Emerging studies described how the detection of MRD is a powerful prognostic biomarker to identify patients at higher risk of recurrence and who will potentially benefit the most from a systemic adjuvant treatment. Based on that unprecedented finding, several clinical trials involving stage II and III CRC patients are ongoing evaluating the impact of ctDNA guided treatment by escalating or deescalating adjuvant chemotherapy based on ctDNA MRD detection. This review provides a critical overview of current perspectives of liquid biopsy in early-stage CRC including technical, biological, and clinical key points, as well as ongoing ctDNA-based clinical trials that ultimately aim to improve clinical outcomes of patients with CRC.

scholarly journals Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study

Blood ◽  
2008 ◽  
Vol 111 (12) ◽  
pp. 5477-5485 ◽  
Author(s):  
Michael J. Borowitz ◽  
Meenakshi Devidas ◽  
Stephen P. Hunger ◽  
W. Paul Bowman ◽  
Andrew J. Carroll ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Risk Groups ◽  
Prognostic Impact ◽  
Oncology Group ◽  
Prognostic Information ◽  
Free Survival ◽  
Minimal Residual

Abstract Minimal residual disease (MRD) is an important predictor of relapse in acute lymphoblastic leukemia (ALL), but its relationship to other prognostic variables has not been fully assessed. The Children's Oncology Group studied the prognostic impact of MRD measured by flow cytometry in the peripheral blood at day 8, and in end-induction (day 29) and end-consolidation marrows in 2143 children with precursor B-cell ALL (B-ALL). The presence of MRD in day-8 blood and day-29 marrow MRD was associated with shorter event-free survival (EFS) in all risk groups; even patients with 0.01% to 0.1% day-29 MRD had poor outcome compared with patients negative for MRD patients (59% ± 5% vs 88% ± 1% 5-year EFS). Presence of good prognostic markers TEL-AML1 or trisomies of chromosomes 4 and 10 still provided additional prognostic information, but not in National Cancer Insitute high-risk (NCI HR) patients who were MRD+. The few patients with detectable MRD at end of consolidation fared especially poorly, with only a 43% plus or minus 7% 5-year EFS. Day-29 marrow MRD was the most important prognostic variable in multi-variate analysis. The 12% of patients with all favorable risk factors, including NCI risk group, genetics, and absence of days 8 and 29 MRD, had a 97% plus or minus 1% 5-year EFS with nonintensive therapy. These studies are registered at www.clinicaltrials.gov as NCT00005585, NCT00005596, and NCT00005603.

Improved Outcome in High Risk and Very High Risk ALL by Risk Adapted SCT and in Standard Risk ALL by Intensive Chemotherapy in 713 Adult ALL Patients Treated According to the Prospective GMALL Study 07/2003.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 12-12 ◽  
Author(s):  
Nicola Gökbuget ◽  
Renate Arnold ◽  
Angelika Böhme ◽  
Rainer Fietkau ◽  
Mathias Freund ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Residual Disease ◽  
Univariate Analysis ◽  
Early Death ◽  
Risk Groups ◽  
Prognostic Impact ◽  
Standard Risk ◽  
Very High ◽  
Improved Outcome

Abstract In 2003 the German Multicenter ALL Study Group (GMALL) initiated the trial GMALL 07/2003. Major aims were improvement of outcome by shortened, intensified induction, intensified consolidation, risk adapted and extended SCT indication and minimal residual disease (MRD) based treatment stratification. 8drug-induction was followed by uniform 1st consolidation based on HDARAC and HDMTX. Further treatment was stratified according to the following risk factors (RF): WBC > 30.000 in B-prec. ALL, late CR (>3wks), proB-, earlyT and mature T-ALL, Ph/BCR-ABL and t(4;11)/ALL1-AF4. The risk groups were defined as follows: standard risk (SR, no RF), high risk (HR,>= 1RF) and very high risk (VHR,Ph/BCR-ABL). HR and VHR pts were scheduled for SCT in CR1 with the following priorities: allo sibling, allo matched unrelated and autologous. VHR pts mostly received Imatinib according to different schedules. SR pts received 5 consolidation cycles (HDMTX/ASPx3, VP16/ARAC, CYCLO/ARAC) and reinduction. SR pts with high MRD after consolidation I were allocated to SCT. In the remaining SR pts decision on maintenance therapy was based on MRD. Between 04/03-12/06 713 evaluable (15–55 yrs) pts were included. The median age was 34 yrs. The CR rate after induction was 89% with 5% early death and 6% failure. 50%, 33% and 17% were allocated to SR (N=353), HR (N=235) and VHR (N=117) with similar CR rates of 92%, 88% and 85%. CR rate was not different in pts < vs > 35 yrs (90% vs 89%). 5 year overall survival (OS) was 54% and survival of CR (S-CR) pts was 59%. HR and VHR pts obtained 55% and 49% S-CR at 3 yrs resp. HR subgroups showed different S-CR for early T (58%), mature T (70%), pro B (66%) and other B-lineage ALL (37%). 68% and 71% of HR and VHR pts received SCT in CR1 as scheduled which thus contributed substantially to improved outcome. In SR- ALL S-CR was 69% (68% c/preB, 66% thymicT). The CCR probability was 52% at 3 yrs. CNS prophylaxis was very effective since only 2% of the CR pts had CNS involvement at relapse. Univariate analysis confirmed a significant prognostic impact of immunphenotype, WBC in B-lin ALL, time to CR and Ph/BCR-ABL. WBC was no prognostic factor in T-lin-ALL. Age was highly significant for survival with 64% survival < 35 yrs vs 48% above 35 yrs. In adolescents below 25 years the most favourable survival of 67% was achieved. In standard risk pts below 35 yrs the survival was 73% without SCT in CR1. Overall the study yielded improved CR rates (89%) and survival (54%). Risk adapted SCT indication was feasible (realised in 70% of HR/VHR pts) and lead to improved survival particularly in early/mature T-ALL and pro B-ALL. In standard risk (SR) the survival is favourable, even above 70% in young pts; however, the relapse rate is still high. Further intensification of therapy during the first year seems required. By definition of new risk factors additional SR patients could be allocated to SCT in CR1. There is however no intention to transfer all SR patients to SCT. Future improvement will be attempted by further inclusion of subtype specific and targeted therapies.

Preliminary safety and efficacy of perioperative COI-B (capecitabine, oxaliplatin, irinotecan, and bevacizumab) in patients with borderline resectable or high–recurrence risk colorectal cancer liver metastases (CLM).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 719-719
Author(s):  
Marta Caporale ◽  
Christian Cotsoglou ◽  
Rosa Berenato ◽  
Mauro Scotti ◽  
Maria Di Bartolomeo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Objective Response ◽  
Surrogate Endpoint ◽  
Recurrence Risk ◽  
Pathological Response ◽  
Hepatic Veins ◽  
R0 Resection ◽  
Borderline Resectable ◽  
Poor Prognostic Factor ◽  
Safety And Efficacy

719 Background: FOLFOXIRI and bevacizumab achieves high objective response rate (ORR)/R0 resections in pts with unresectable CLM. Bevacizumab increases pathological response, a surrogate endpoint of survival after CLM resection. COI-B regimen is feasible in pts with advanced colorectal cancer. In this phase II study, we aimed at assessing safety and efficacy of perioperative COI-B for pts with borderline resectable or high recurrence risk CLM. Methods: Inclusion criteria: borderline resectability with portal embolization/2-stage hepatectomy, involvement of > 1 hepatic vein or > 4 segments; and/or at least one poor prognostic factor: > 4 metastases; CEA > 200; synchronicity. Limited resectable extraepatic disease and in situ primary allowed. Primary endpoint: TRG1-3 (Rubbia-Brandt et al) according to Simon 2-stage design (first step 22; target 46 pts); secondary endpoints: ORR; R0 resection; safety; progression-free and overall survival. Pts received bi-weekly irinotecan (180 mg/m2) and bevacizumab (5 mg/Kg) day 1, oxaliplatin (85 mg/m2) day 2 and capecitabine (1000 mg/m2/day b.i.d.) days 2–6; 5 cycles pre-operatively (the last without bevacizumab) and 4 post-operatively. Results: We present preliminary data on the first 25 pts. M/F: 13/12, median age 61 years, synchronous disease 19 (76%), multiple nodules 15 (60%), N+ primary tumour 14 (56%), CEA > 200 4 (16%), extrahepatic disease 1, RAS mutation 15 (60%)/BRAF mutation 0. Involvement ≥ 4 hepatic segments 9 (36%) and involvement of > 1 hepatic veins 4 (16%). ORR was 91% (21 out of 23 evaluable, 2 too early), while 1 SD and 1 PD. Surgery performed in 21 pts (4 awaiting) and R0 resection in 18 (86%). TRG1-2 was observed in 6 (29%), TRG3 in 9 (43%), i.e. pathological response 72% (first step reached). Grade ≥ 3 toxicities: neutropenia 2, diarrhea 2, thrombosis 2. Median follow up 13 months, with only 4 relapses and 1 death. Conclusions: COI-B regimen is a feasible neoadjuvant strategy for borderline resectable or high recurrence risk CLM. This is the first trial to select pathological response as primary surrogate endpoint with encouraging results. Clinical trial information: NCT02086656.

The application of dynamic monitoring of circulating tumor DNA for detecting minimal residual disease and predicting recurrence in colorectal cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15531-e15531
Author(s):  
Hiu Ting Chan ◽  
Satoshi Nagayama ◽  
Yoon Ming Chin ◽  
Masumi Otaki ◽  
Rie Hayashi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Residual Disease ◽  
Circulating Tumor Dna ◽  
Plasma Samples ◽  
Blood Samples ◽  
Clonal Hematopoiesis ◽  
Tumor Tissues ◽  
Ctdna Analysis ◽  
Tumor Dna ◽  
Minimal Residual

e15531 Background: Although the prognosis of colorectal cancer (CRC) has improved in the past decade, a subset of CRC patients may still suffer from relapse due to the progression from minimal residual disease (MRD) after surgical resection. A sensitive and non-invasive method to detect MRD and early diagnosis of recurrence disease is warranted to start therapeutic interventions at an earlier timing and improving the overall survival rate. In this study, we have evaluated the feasibility of circulating tumor DNA (ctDNA) analysis to detect MRD and early detection of recurrence in CRC patients. Methods: Plasma samples were collected prospectively from 38 CRC patients (stage I to IV), who underwent surgical resection. Preoperative blood samples were obtained just before surgery and post-operative samples were collected at multiple time-points to monitor the changes of tumor mutation profiles. Tumor-derived mutations were detected in preoperative blood samples as well as surgically resected-tumor tissues using ultradeep targeted next generation sequencing. Patient-paired peripheral blood cells (PBCs) were sequenced concurrently to exclude clonal hematopoiesis-related mutations. Results: Among the 38 patients, 74 non-synonymous mutations were identified in tumor tissues and 64 mutations in the preoperative plasma samples. Paired PBCs sequencing identified 11 mutations in plasma samples to be clonal hematopoiesis-related mutations. After the exclusion of clonal hematopoiesis-related mutations, 34 (89.5%) of the 38 patients harbors at least one somatic mutation either from tumor tissues or plasma samples to be monitored longitudinally. ctDNA was detectable in 5 of 14 (36%) post-surgical samples of patients who did not receive adjuvant chemotherapy and in 9 of 18 (50%) post-chemotherapy samples. Up to date, 6 patients have been detected with clinical recurrence and ctDNA analysis identified all 6 recurrences before imaging. Serial ctDNA analyses were able to detect disease recurrence up to 6 months before imaging tests. Furthermore, all patients that were ctDNA negative post-operative or post-chemotherapy showed no signs of clinical relapse. Conclusions: Our current results indicate that ctDNA analysis allows the detection of MRD in CRC patients. The integration of ctDNA analysis with current standard monitoring guidelines holds great promise in early detection of recurrence to allow clinical intervention to be applied promptly.

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