Risk Of Recurrence In Stage Research Articles

Surgical Approach and Recurrence Risk in Struma Ovarii: A Retrospective and Systematic Analysis.

Struma ovarii (SO) represents a rare subset of ovarian germ cell tumors, with approximately 5% transforming into malignant SO (MSO). This study retrospectively analyzed clinical data from 23 SO patients treated at the Cancer Hospital of the Chinese Academy of Medical Sciences between January 2013 and December 2023, including 17 benign SO (BSO) and 6 MSO cases. Additionally, a systematic review of 164 cases of MSO confined to the ovary, reported in the literature from 1946 to 2024, was conducted. Data on pathological type, treatment, and prognosis were extracted, and univariate and multivariate Cox regression analyses were performed to identify risk factors for recurrence in stage I MSO. The median age at diagnosis was higher for BSO compared to MSO (58 vs. 42.5 years), with 70.6% of patients being postmenopausal. BSO commonly presented with abdominal distension or mass, with more than half having ascites, while MSO patients were asymptomatic and lacked ascites. Cox regression analyses revealed that ovarian cystectomy was adversely associated with recurrence risk in stage I MSO, likely due to surgically induced capsular rent and potential tumor spillage. Significantly lower recurrence risks were observed in patients who underwent unilateral or bilateral salpingo-oophorectomy (HR = 0.36, P = 0.019; HR = 0.19, P = 0.004, respectively). This study highlights the importance of the surgical approach in the management of stage I MSO. A thorough preoperative discussion of the benefits and risks of different surgical approaches is recommended for patients desiring fertility preservation. Postoperative adjuvant therapy has not been shown to have a significant impact on prognosis. For the treatment of recurrent MSO, selecting appropriate surgical and adjuvant therapeutic strategies is essential to improve the long-term prognosis of MSO patients.

Residual circulating tumor DNA after adjuvant chemotherapy effectively predicts recurrence of stage II-III gastric cancer.

Circulating tumor DNA (ctDNA) is a promising biomarker for predicting relapse in multiple solid cancers. However, the predictive value of ctDNA for disease recurrence remains indefinite in locoregional gastric cancer (GC). Here, we aimed to evaluate the predictive value of ctDNA in this context. From 2016 to 2019, 100 patients with stage II/III resectable GC were recruited in this prospective cohort study (NCT02887612). Primary tumors were collected during surgical resection, and plasma samples were collected perioperatively and within 3 months after adjuvant chemotherapy (ACT). Somatic variants were captured via a targeted sequencing panel of 425 cancer-related genes. The plasma was defined as ctDNA-positive only if one or more variants detected in the plasma were presented in at least 2% of the primary tumors. Compared with ctDNA-negative patients, patients with positive postoperative ctDNA had moderately higher risk of recurrence [hazard ratio (HR) = 2.74, 95% confidence interval (CI) = 1.37-5.48; P = 0.003], while patients with positive post-ACT ctDNA showed remarkably higher risk (HR = 14.99, 95% CI = 3.08-72.96; P < 0.001). Multivariate analyses indicated that both postoperative and post-ACT ctDNA positivity were independent predictors of recurrence-free survival (RFS). Moreover, post-ACT ctDNA achieved better predictive performance (sensitivity, 77.8%; specificity, 90.6%) than both postoperative ctDNA and serial cancer antigen. A comprehensive model incorporating ctDNA for recurrence risk prediction showed a higher C-index (0.78; 95% CI = 0.71-0.84) than the model without ctDNA (0.71; 95% CI = 0.64-0.79; P = 0.009). Residual ctDNA after ACT effectively predicts high recurrence risk in stage II/III GC, and the combination of tissue-based and circulating tumor features could achieve better risk prediction.

Predictive models of recurrence from transcriptomic signatures of the tumor microenvironment and cell cycle in stage III colon cancer from PETACC-8 and IDEA France trials.

3523 Background: The objective of this work was to establish predictive models of the risk of recurrence in stage III colon cancer (CC) based on transcriptomic signatures of the tumor microenvironment (TME) and cell cycle from the PETACC-8 (training set) and IDEA- France (validation set) trials. Methods: 3'RNAseq was performed in 1733 patients from the PETACC-8 trial (85%) and 1263 patients from the IDEA-France trial (63%). 4 transcriptomic signatures were analyzed: a signature reflecting T-cells infiltration named "Immunoscore-Like", a signature reflecting M2 macrophage infiltration named "M2-like", the expression of CXCL13 (reflecting B cells infiltration) and a score based on the Oncotype DX® Colon Cancer RS using the same formula from the stromal score and the cell cycle score, named “Oncotype DX Like”. In the 1st multivariate model, we analyzed the 4 signatures separately with a dichotomization into "high" and "low" with the best cut point value for the prediction of time to recurrence (TTR) in PETACC-8 trial. In the 2nd multivariate model, we defined a score named “IPS” (Immune Proliferative Stromal), corresponding to the number of deleterious signatures (“high” or “low” depending on the signatures), ranging from 0 to 4. Results: The 1st multivariate model, built from PETACC-8 trial, showed that these 4 signatures were significantly associated with TTR with a protective effect of Immunoscore Like and CXCL13 "high" (HR: 0.66, p = 0.003 and 0.60, p &lt; 0.001 respectively) and a deleterious effect of M2 Like and Oncotype Like “high” (HR: 1.28, p = 0.05 and HR: 1.37, p = 0.01, respectively), independently of known prognostic factors, with a C-index of 0.73. This model was applied to the IDEA-France cohort by calculating a predictive score for each patient, with TTR significantly different depending on the quartile of this score with a 3-year TTR ranging from 55% for the lowest quartile to 90% for the highest quartile (p &lt; 0.001). In the 2nd model, in the 2 cohorts, IPS score was independently associated with TTR with a HR increasing with the IPS score, independently of T and N stage and intra-tumoral CMS heterogeneity (Table). Conclusions: Using transcriptomic data of patients with stage III CC from 2 large-scale adjuvant trials, two predictive models based on signatures of the TME and the cell cycle, provide important information in addition to known prognostic factors for patient stratification on risk of recurrence. Beyond T and N stage, for the decision of adjuvant chemotherapy in stage III CC, the combination of these different variables could be exploited in the future for personalized care (de-escalation, intensification). [Table: see text]

Investigation of Microbial Translocation, TLR and VDR Gene Polymorphisms, and Recurrence Risk in Stage III Colorectal Cancer Patients.

Simple SummaryGut microbial dysbiosis and microbial passage into the peripheral blood leads to colorectal cancer (CRC) and disease progression. Toll-like (TLR) and vitamin D (VDR) receptors play important role in the immune modulation and polymorphisms that may increase CRC risk. The aim of the current study was to demonstrate the prognostic value of microbial DNA fragments in the blood of stage III CRC patients and correlate such microbial detection to TLR/VDR polymorphisms. TLR/VDR polymorphisms and presence of microbial DNA in CRC patients highlight their role in cancer development and progression.Gut microbial dysbiosis and microbial passage into the peripheral blood leads to colorectal cancer (CRC) and disease progression. Toll-like (TLR) and vitamin D (VDR) receptors play important role in the immune modulation and polymorphisms that may increase CRC risk and death rates. The aim of the current study was to demonstrate the prognostic value of microbial DNA fragments in the blood of stage III CRC patients and correlate such microbial detection to TLR/VDR polymorphisms. Peripheral blood was collected from 132 patients for the detection of microbial DNA fragments, and TLR/VDR gene polymorphisms. In the detection of various microbial DNA fragments, TLR and VDR polymorphisms was significantly higher compared to healthy group. Homozygous individuals of either TLR or VDR polymorphisms had significantly higher detection rates of microbial DNA fragments. Mutational and MSI status were significantly correlated with TLR9 and VDR polymorphisms. Significantly shorter disease-free survival was associated with patients with BRAF mutated tumors and ApaI polymorphisms, whereas shorter overall survival was associated with the detection of C. albicans. The detection of B. fragilis, as demonstrated by the multivariate analysis, is an independent poor prognostic factor for shorter disease-free survival. TLR/VDR genetic variants were significantly correlated with the detection of microbial fragments in the blood, and this in turn is significantly associated with tumorigenesis and disease progression.

Predictive Value of Circulating Tumor Cells Based on Subtraction Enrichment for Recurrence Risk in Stage II Colorectal Cancer.

Current guidelines recommend adjuvant chemotherapy (ACT) for stage II colorectal cancer (CRC) patients by using clinical high risk factors, with which circulating tumor cells (CTCs) were not considered. Here, an assessment to detect CTCs based on subtraction enrichment mediated by magnetic beads conjugated with CD45, immunofluorescence staining of CK, and fluorescence in situ hybridization of CEP8 is established. Both CEP8- and CK-positive CTCs have the potential to improve the risk stratification of stage II CRC patients. Patients with preoperative CTCs of ≥4 had a significantly higher recurrence risk than those with preoperative CTCs of <4 in two external validation cohorts (P < 0.0001). In the subgroup with clinical high risk, when preoperative CTCs were <4, patients did not benefit from ACT (P = 0.5764); however, when preoperative CTCs were ≥4, patients received benefit from ACT (P = 0.0064). Additionally, regardless of clinical risk status and preoperative CTC levels, if postoperative CTC levels were ≥4 for more than three consecutive time points (monitoring time interval, 2-6 months), the recurrence rate was 100%. Our findings suggested that the subtraction enrichment of CTCs could provide a reliable method to stratify the recurrence risk and make therapeutic decisions after surgery in stage II CRC patients.

Abstract 5115: Combine high risk factors with circulating tumor DNA (ctDNA) to assist adjuvant chemotherapy (ACT) decision in Stage II colorectal cancer (CRC)

Abstract Background: Approximately 10% to 15% have residual disease after surgery in patients with stage II CRC. Identification of this high-risk population and treatment with ACT could potentially reduce their risk of recurrence. However, the relative contribution of the factors used to define high risk stage II disease needs better understanding, although post-surgical ctDNA has been studied as a marker for an elevated risk of recurrence in stage I-III colorectal cancer. Methods: Individual data from 3 early colorectal cancer clinical studies(Tie, 2016;Reinert, 2019; Chen, 2021) that included information on high-risk factors and post-surgical ctDNA status were collected and reanalysed for 595 patients with or without ACT. Results: In stage II CRC patients with ctDNA-negative not treated with ACT form the Tie cohort, with high-risk status (n=42) showed a significantly reduced recurrence-free survival (RFS) compared to those with low-risk status(n=122) [HR, 3.283; 95%CI, 1.398 to 14.18; P = 0.0116], but in the ctDNA-negative patients with high-risk status, ACT (n=32) or not did not affect the RFS(P=0.1758). It meant false negatives of ctDNA made for bias of survival analysis results. Interestingly, in other two cohorts of stage II CRC patients with ctDNA-negative not treated with ACT, high-risk status showed no difference in RFS compared to low-risk status (p=0.3429 and 0.3173, respectively). In addition to the low sample size, the contribution of defined high-risk factors in prognosis was worth exploring which meant pseudo high-risk status also affect survival analysis results. And there were big differences in the high-risk factors included in the three cohorts especially in ctDNA-negative patients, such as the proportion of lymph nodes (LN) yield &amp;lt;12 seemed higher in Tie cohort. Conclutions: It was not enough to predict recurrence depend on ctDNA status alone for stage II CRC. Different risk factors might have different prognostic weights so that different combinations of post-surgical ctDNA status and risk factors might be used to make more accurate ACT decision. Citation Format: Xie Gui Yuan, Liu Miao, Huang Meng Li. Combine high risk factors with circulating tumor DNA (ctDNA) to assist adjuvant chemotherapy (ACT) decision in Stage II colorectal cancer (CRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5115.

Circulating tumor DNA is a potential prognostic risk factor of recurrence in patients with hepatocellular carcinoma treated by liver transplantation.

e16196 Background: Liver transplantation (LT) is one of the most effective therapeutic strategies for hepatocellular carcinoma (HCC), however, tumour recurrence after LT often leads to poor outcomes. At present, clinical characteristic profile, imaging diagnosis as well as level of serum biomarkers prior to LT could predict the prognosis in HCC patients treated by LT. However, the sensitivity and specificity of these biomarkers are limited, highlighting the crucial need to identify novel biomarkers. Previous clinical studies have shown that postoperative circulating tumor DNA (ctDNA) can be used as a predictive biomarker for the risk of recurrence in stage I-III solid tumor. This study aimed at investigating the relationship between the level of ctDNA and the probability of recurrence in HCC patients treated by LT. Methods: HCC patients receiving LT treatment were enrolled. Peripheral blood samples before LT and available matched tissue samples were collected. Targeted sequencing of 328 cancer-related genes were conducted. The clinicopathologic data of the patients was retrospectively analyzed. The predictive efficiency for recurrence after LT of different clinicopathologic parameters and ctDNA were accessed. Results: A total of 45 patients were enrolled, including 42 males (93%) and 3 females (7%), with a median age of 51 (range 31-76 years). Thirty-five patients (78%) had detectable ctDNA before LT while gene alterations were identified in tumor tissue of all the patients. Larger tumor size (&gt; 5cm), cirrhosis, portal vein tumor thrombus (PVTT) and elevated AFP level (≥400ng/ml) prior to LT were associated with higher percentage of positive ctDNA (94% vs 73%, 84% vs 75%, 88% vs 79%, 88% vs 76%, respectively). Patients with micro-vessel invasion (MVI) had higher ctDNA abundance (maxVAF, P &lt; 0.05). Interestingly, after over 3 years’ follow-up, clinical factors including MVI, PVTT, BCLC stage, maximum tumor diameter and serum AFP failed to predict disease free survival (DFS) and overall survival (OS). In contrast, the recurrence rate was remarkably augmented (48.6% vs 0%) and the median DFS was significantly decreased (390 days vs not reached, p&lt; 0.05) in patients with detectable ctDNA. Conclusions: In conclusion, ctDNA could be a potential biomarker to sensitively predict the recurrence in patients with HCC treated by LT, which may help to improve the post-transplant management of these patients.

Recurrence risk stratification model for patients with stage I-III colorectal cancer based on clinicopathological and postoperative ctDNA predictors.

e15511 Background: The aim of this study was to propose a new kind of recurrence risk classification and further establish a prognostic model for resected stage I-III colorectal cancer (CRC). Methods: From 2017 to 2020, 142 patients diagnosed with stage I-III CRC at Peking University Shougang Hospital were recruited for this study. Tissues and paired white blood cells were analyzed with a 733-gene NGS panel, and peripheral plasma obtained 7-10 days after surgery was analyzed with a 127-gene ultra-deep target panel in a CLIA-certified laboratory. The relationship between the postoperative ctDNA status, clinicopathological features and recurrence-free survival (RFS) was identified by log-rank test and Cox regression analysis. Results: In total, 108 patients successfully completed both tissue and postoperative plasma NGS tests, of which 17 patients were postoperatively positive for ctDNA (tumor-informed, ≥1 somatic mutation). Postoperative ctDNA positivity was independently associated with poorer RFS (HR = 8.4, P &lt; 0.0001). Postoperative recurrence rates were significantly higher in ctDNA-positive patients than ctDNA-negative patients (76.5% vs 16.5%, P &lt; 0.0001). Univariate analysis showed that, in addition to ctDNA status, stage, vascular invasion, neural invasion, and preoperative CEA were all significantly associated with worse RFS (P &lt; 0.05). Furthermore, in a COX regression model, the contribution of these clinicopathological factors to RFS has been adjusted. The model showed good discrimination [the concordance index (c-index): 0.811] of recurrence. Clinically high-risk groups according to clinicopathological risk model had significantly poorer RFS than low-risk groups (HR = 10.6, P &lt; 0.001). In the clinicopathological high-risk group, ctDNA-positive patients can still further differentiate the higher risk of recurrence (HR = 3.7, P = 0.0012). There were similar trends in the clinicopathological low-risk group (HR = 6.1, P = 0.066). Combining the clinicopathological model and ctDNA, patients with either clinicopathological high-risk or ctDNA-positive had a significantly poorer RFS, compared with both clinicopathological low-risk and ctDNA-negative (HR = 12.9, P &lt; 0.0001). Conclusions: Postoperative ctDNA can independently predict the risk of recurrence in stage I-III CRC. Combining clinicopathological factors and ctDNA showed superiority for recurrence risk stratification over either alone. This recurrence risk stratification model may serve as a useful clinical tool to help clinicians determine individualized treatment plans for stage I-III CRC patients. However, the model still needs further external cohort validation.

Microbial translocation, toll-like and vitamin D receptor polymorphisms in blood and risk of recurrence in stage III colorectal cancer.

3531 Background: Microbial translocation from the intestinal lumen into the blood circulation is significantly linked to intestinal dysbiosis; thus, leading to colorectal cancer (CRC), disease progression and decreased survival. Toll-like (TLRs) and vitamin D receptors (VDRs) play essential role in immunity and gut microbiome determination. Polymorphisms in such receptors have been associated with increased CRC incidence risk and mortality. The aim was to evaluate the microbial translocation in the blood of stage III CRC patients and correlate the presence of TLR and VDR genetic variants with microbial DNA fragments at risk of CRC development and progression. Methods: A total of 132 stage III CRC patients and 100 healthy donors were enrolled in the study. Peripheral blood DNA was analyzed using PCR for the amplification of microbial DNA encoding 16S rRNA, β-galactosidase gene of Escherichia coli, glutamine synthase of Bacteroides fragilis, and 5.8S rRNA of Candida albicans. Moreover, DNA from patients and controls was analyzed using PCR and PCR-RFLP for genotyping functional polymorphisms of both TLR (TLR2, TLR4, TLR9) and VDR ( TaqI, ApaI, FokI and BsmI) genes. Results: Median age of patients was 62 years, 59.8% were males, 92.7% had a colon/sigmoid tumor, 24.4% had a right colon tumor and 99.2% had a good performance status. Microbial DNA fragments from 16S rRNA, E. coli, B. fragilis, and C. albicans were detected in 43.2%, 20.5%, 31.8% and 36.4% of patients, respectively. Significantly higher rates of all microbial fragments, but E. coli, were detected in the group of patients in comparison to healthy donors ( p &lt; 0.001). Similarly, higher rates of both TLR and VDR genetic variants were detected in CRC patients compared to healthy donors ( p &lt; 0.001). Moreover, individuals with homozygous mutant alleles of either TLR or VDR polymorphisms had significantly higher detection rates of microbial DNA fragments. KRAS, BRAF and MSI status were significantly correlated with TLR9 genetic variants ( p= 0.001, p= 0.013 and p= 0.011, respectively) and MSI status was significantly correlated with all four VDR polymorphisms ( TaqI, p= 0.044; ApaI, p= 0.037; FokI, p= 0.002 and BsmI, p&lt; 0.001). Cox regression analysis revealed that BRAF mutations, histology type and ApaI genetic variants are significantly associated with shorter disease-free survival (DFS). C. albicans detection is significantly associated with shorter overall survival, and B. fragilis is an independent poor prognostic factor for decreased DFS (HR = 33.85; p = 0.018). Conclusions: The detection of higher frequencies of the TLR/ VDR genetic variants was correlated with significantly higher detection rates of microbial DNA fragments. The detection of these TLR/VDR polymorphisms and microbial DNA fragments in CRC patients highlighted their role in cancer development, progression, and patients’ survival.

Circulating tumor DNA and recurrence risk in stage II-III gastric cancer.

4054 Background: Circulating tumor DNA (ctDNA) is a promising biomarker for detecting molecular residual disease (MRD) and relapse after definitive treatment in multiple solid cancers. However, the significance of ctDNA is rarely clarified in locoregional gastric cancer (GC). Here, we conducted a prospective and observational study to evaluate the utility of ctDNA in predicting the recurrence risk of GC. Methods: From October 2016 to June 2019, 100 patients with stage II/III resectable GC were recruited in this study (NCT02887612). Primary tumors and plasma samples were collected perioperatively and after adjuvant chemotherapy (ACT). Somatic variants were captured via a targeted sequencing panel of 425 cancer-related genes. The plasma of patients was defined as ctDNA positive only if one or more variants detected in the plasma presented in at least 2% of the primary tumors. All the patients received curative-intent standard-of-care therapy. Results: Preoperative ctDNA was detectable in 38 (38.0%) patients but showed limited value for predicting recurrence. After surgery (median days, 4), the plasma of 25 (25.0%) patients were still ctDNA positive and they had higher recurrence risk than the non-positive patients (hazard ratio [HR], 2.74 (95% CI: 1.37–5.48); P = 0.003). Forty-one patients had evaluable plasma after ACT and 10 (24.4%) of them who were ctDNA positive had remarkably higher recurrence and death risk compared with ctDNA-negative patients (recurrence-free survival [RFS] HR = 14.99 (95% CI: 3.08–72.96); P &lt; 0.001; overall survival HR, 11.88 (95% CI: 2.38–59.24); P &lt; 0.001). In particular, post-ACT ctDNA achieved better predictive performance (sensitivity, 77.8%; specificity, 90.6%) than both postoperative ctDNA and post-treatment tumor biomarkers (i.e., CEA, CA199, and CA72-4). In all multivariate analyses, ctDNA positivity was an independent factor of RFS. Patients with ERBB4 mutation in their primary tumors had poorer RFS compared to those were ERBB4 wildtype (HR = 3.46 (95% CI: 1.32–9.03); P = 0.007). A comprehensive model incorporating ctDNA status for recurrence risk prediction showed a higher concordance index (0.78; 95%CI, 0.71–0.84) than the model without ctDNA status (0.71; 95%CI, 0.64–0.79; P = 0.009). Conclusions: Postoperative and post-ACT ctDNA was associated with MRD and high risk of relapse in patients with stage II/III GC and can be utilized to guide GC management in post-surgical settings.

Copy number aberration burden on circulating tumor DNA predicts recurrence risk after neoadjuvant chemotherapy in patients with triple-negative breast cancer: Post-hoc analysis of phase III PEARLY trial.

603 Background: Our previous study reported prognostic significance of copy number aberration (CNA) burden on low-pass whole genome sequencing (LP-WGS) based circulating tumor DNA (ctDNA) analysis in metastatic breast cancer patients. Here, we report the prognostic value of ctDNA CNA burden measured before neoadjuvant chemotherapy in stage II-III triple-negative breast cancer (TNBC) patients enrolled in phase III PEARLY trial (NCT02441933, BIG Supporter Study BIG 19-01, KCSG BR15-01). Methods: The PEARLY trial was performed as a randomized, open-label, multicenter, phase III study to test the efficacy and safety of adding carboplatin to (neo)adjuvant chemotherapy in patients with stage II-III TNBC. Patients were randomized in a 1:1 ratio to receive 4 cycles of AC followed by the taxane or taxane plus carboplatin (AUC 5, tri-weekly 4 cycles) as neoadjuvant or adjuvant therapy. This post-hoc baseline ctDNA analysis (before neoadjuvant chemotherapy) included only the neoadjuvant patient cohort with available baseline ctDNA results (n = 465, median follow-up 16.8 months), while it was blinded for randomization information (carboplatin or not). We used "I-score" method to estimate CNA burden of ctDNA by LP-WGS to be matched with disease-free survival (DFS) after primary surgery. Results: The baseline ctDNA I-score level was positively associated with clinical T and N stage, while baseline I-score was not different between patients with pathologic complete response (pCR) and non-pCR. We listed 465 patients in the order in which they underwent primary surgery, and then alternated patients to be assigned to exploratory cohort (n =232) and validation cohort (n = 233). The DFS was significantly shorter in high I-score (I-score ≥ 7.81) patients compared with low I-score (I-score &lt; 7.81) patients in exploratory cohort. The high I-score independently predicted poor DFS adjusted for clinical T stage, clinical N stage, and pCR status (hazard ratio [HR] 3.88, p = 0.003). In the validation cohort, high I-score was validated to be associated poorer DFS, and multivariate Cox analysis validated the independent prognostic impact of I-score on DFS (HR 2.04 , p = 0.050). The high baseline I-score patients showed shorter DFS both in pCR-positive and pCR-negative patients. The 12-month DFS rate for pCR (+)/Low I-score patients was 98%, whereas that of pCR(-)/High I-score patients was 61.3 % in the validation cohort. Conclusions: The baseline ctDNA CNA burden on LP-WGS before neoadjuvant chemotherapy robustly predicts recurrence risk in stage II-III TNBC patients. The ctDNA I-score showed prognostic value independently from pCR status, suggesting ctDNA I-score can serve as a useful clinical determinant for escalating or de-escalating (neo)adjuvant strategy in TNBC patients. Clinical trial information: NCT02441933.

Pembrolizumab reduces recurrence risk in stage II melanoma.

Pembrolizumab reduces recurrence risk in stage II melanoma.

Tumor-associated macrophages and risk of recurrence in stage III colorectal cancer.

Tumor‐associated macrophages (TAMs) have a unique favorable effect on the prognosis of colorectal cancer (CRC), although their association with stage‐specific outcomes remains unclear. We assessed the densities of CD68+ and CD163+ TAMs at the invasive front of resected CRC stage III CRC from 236 patients, 165 of whom received post‐surgical FOLFOX treatment, and their relationship with disease‐free survival (DFS). Associations between macrophage mRNAs and clinical outcome were investigated in silico in 59 stage III CRC and FOLFOX‐treated patients from The Cancer Genome Atlas (TCGA). Biological interactions of SW480 and HT29 cells and macrophages with FOLFOX were tested in co‐culture models. Low TAM densities were associated with shorter DFS among patients receiving FOLFOX (CD68+, p = 0.0001; CD163+, p = 0.0008) but not among those who were untreated. By multivariate Cox analysis, only low TAM (CD68+, p = 0.001; CD163+, p = 0.002) and nodal status (CD68+, p = 0.009; CD163+, p = 0.007) maintained an independent predictive value. In the TCGA cohort, high CD68 mRNA levels were associated with better outcome (p = 0.02). Macrophages enhanced FOLFOX cytotoxicity on CRC cells (p < 0.01), and drugs oriented macrophage polarization from M2‐ to M1‐phenotype. Low TAM densities identify stage III CRC patients at higher risk of recurrence after adjuvant therapy, and macrophages can augment the chemo‐sensitivity of micro‐metastases.

A validated nomogram integrating baseline peripheral T-lymphocyte subsets and NK cells for predicting survival in stage I-IIIA non-small cell lung cancer after resection.

BackgroundAccurately predicting the risk of recurrence in stage I–IIIA non-small cell lung cancer (NSCLC) after resection is critical in the treatment process. This study aimed to establish a novel nomogram to identify patients with a risk of disease progression in stage I–IIIA lung cancer based on clinical characteristics, peripheral T-lymphocyte subsets, and CD16+56 natural killer (NK) cells.MethodsA total of 306 NSCLC patients from Shanghai Municipal Hospital of Traditional Chinese Medicine between 2010 and 2020 who met the inclusion and exclusion criteria between January 2011 and December 2020 were retrospectively reviewed. Patients were randomly assigned to the training cohort (206 patients) and the validation cohort (100 patients). A nomogram model was developed based on the results of multivariate Cox regression in the training cohort. The optimal cut-off values were determined by X-tile software. The bootstrap method was used to validate the nomogram. Receiver operating characteristics curves (ROC) and the area under the ROC curve (AUC) were used to compare prognostic factors. The concordance index (C-index) was calculated to determine the accuracy of the nomogram in predicting disease-free survival (DFS).ResultsGender, drinking history, TNM stage, and CD4+T/CD8+T were independent factors for DFS and were integrated into the model, while CD16+56 NK cells were not proven to be significant independent factors for DFS. The calibration curves for probability of 3- and 5-year DFS showed excellent agreement between predicted and actual survival. The C-index for the nomogram to predict DFS was 0.839 in the training cohort. The nomogram showed an excellent predictive performance in the training cohort (3-/5-year AUC: 0.860/0.847) and in the validation cohort (3-/5-year AUC: 0.726/0.748).ConclusionsWe developed a prognostic model which provided individual prediction of DFS for stage I–IIIA NSCLC patients after resection. This practical prognostic tool may help oncologists in clinical treatment planning.

Tumor enhancement ratio on preoperative abdominal contrast-enhanced CT scan for predicting recurrence risk in stage II colon cancer.

The identification of high recurrence risk stage II colon cancer patients was critical to adjuvant chemotherapy decision. However, current definition of high-risk features remains inadequate. This study aimed to construct a model for predicting recurrence risk based on tumor enhancement ratio (TER) on abdominal contrast-enhanced CT scan. 282 stage II colon cancer patients were included and randomly divided into training and validation sets in the ratio of 7:3. TER was calculated using maximum tumor attenuation value in contrast-enhanced CT scan divided by the minimum. Kaplan-Meier survival analyses were adopted to evaluate the prognostic value of variables. A model based on TER was built to predict recurrence risk through the LASSO Cox model. The recurrence risk score of patients was calculated based on this model. The optimal cut-off value of TER was 1.83 derived from the time-dependent ROC (tdROC) curve. Patients with high-TER showed increasingly poorer disease-free survival (DFS) in both training (p < 0.001) and validation (p < 0.001) sets. A model was built based on TER demonstrated satisfactory performance to recurrence risk prediction (C-index: 0.784 in the training set and 0.725 in the validation set). Patients were regrouped into modified high-risk and non-high risk according to recurrence risk score (cut-off value: 1.75) and a significant DFS difference was observed (training set: p < 0.001; validation set: p < 0.001). TER can serve as a high-risk feature of stage II colon cancer. And a model based on TER provided a new approach to assess recurrence risk of stage II disease.

Circulating Tumor Cells for Stratification of Recurrence Risk in Stage II Colorectal Cancer: A Multicenter Cohort Study

Circulating Tumor Cells for Stratification of Recurrence Risk in Stage II Colorectal Cancer: A Multicenter Cohort Study

Development and clinical validation of a novel six-gene signature for accurately predicting the recurrence risk of patients with stage II/III colorectal cancer

BackgroundA large number of patients with stage II/III colorectal cancer (CRC) have a high recurrence rate after radical resection. We aimed to develop a novel tool to stratify patients with different recurrence-risk for optimizing decision-making in post-operative surveillance and therapeutic regimens.MethodsWe retrospectively enrolled four independent cohorts from the Gene Expression Omnibus and 66 CRC tissues from our hospital. The initial signature discovery was conducted in GSE143985 (n = 91). This was followed by independent validation of this signature in GSE17536 (n = 111), GSE29621 (n = 40), and GSE92921 (n = 59). Further experimental validation using qRT-PCR assays (n = 66) was performed to ensure the robustness and clinical feasible of this signature.ResultsWe developed a novel recurrence-related signature consisting of six genes. This signature was validated to be significantly associated with dismal recurrence-free survival in five cohorts GSE143985 (HR: 4.296 [2.612–7.065], P < 0.0001), GSE17536 (HR: 2.354 [1.662–3.334], P < 0.0001), GSE29621 (HR: 3.934 [1.622–9.539], P = 0.0024), GSE92921 (HR: 7.080 [2.011–24.924], P = 0.0023), and qPCR assays (HR: 3.654 [2.217–6.020], P < 0.0001). This signature was also proven to be an independent recurrent factor. More importantly, this signature displayed excellent discrimination and calibration in predicting the recurrence-risk at 1–5 years, with most AUCs were above 0.9, average C-index for the five cohorts was 0.8795, and near-perfect calibration.ConclusionsWe discovered and experimental validated a novel gene signature with stable and powerful performance for identifying patients at high recurrence-risk in stage II/III CRC.

Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by a Five Circulating Tumor DNA Methylation Signature in Colorectal Cancer

Purpose: To develop a circulating tumor DNA (ctDNA) methylation signature for early detection of metastatic relapse and surveillance of therapeutic efficacy in stage III CRC. Perimental design: The deferentially methylated locations (DMLs) between 52 normal intestinal mucosa and 134 stage III CRC tissue and between plasma from 96 stage I/II CRC patients and 73 stage IV CRC patients were detected by high-throughput targeted methylation sequencing. CtDNA methylation signature was established by random forest with DMLs shared by plasma and tissue samples. This signature was then applied to predict the risk of metastatic disease recurrence in blood samples from 50 stage III CRC patients and dynamic monitor the recurrence risk in serial blood samples from 4 CRC patients. Results: 2237 and 1185 hypermethylation markers were identified in CRC tissue and plasma from stage IV CRC patients, respectively. Our signature achieved the sensitivity of 84.21% and specificity of 81.81% in distinguishing late CRC from early CRC in the validation cohort. Moreover, this signature yielded high sensitivity (87.5%) and specificity (94.12%) for predicting metastatic disease relapse in a cohort of 50 stage III CRC patients, and could be an independent risk factor for relapse in those patients (HR, 18.7; 95% CI, 5.3-66.2; P = 9.86e-6). The analyses of serial blood samples of CRC showed that this model was more sensitive to monitor treatment response than imaging examination and serum carcinoembryonic antigen (CEA). Conclusions: We identify a ctDNA methylation signature for stratifying risk of recurrence in stage III CRC and non-invasively monitoring treatment response.Statement of translational relevanceWe successfully developed a ctDNA methylation signature for risk assessment of metastatic disease recurrence in stage III CRC patients and surveillance of therapeutic efficacy of CRC. Funding: This work was supported by the National Key R&D program of China (2017YFC1309002), National Natural Science Foundation of China (81672821, 81872041, 81773101, 81802306, 81903002), Natural Science Foundation Key program of Guangdong Province of China (2018B0303110017), Natural Science Foundation of Guangdong Province of China (2018A030310457, 2019A1515011436), Science and Technology Planning Project of Guangdong Province, China (2017B020226005). Declaration of Interest: The authors Jianbing Fan, Xia Li are employees of AnchorDx Medical Co., Ltd., a company that focuses on the development of next generation sequencing diagnostic products for cancer detection using liquid biopsy. All other authors declare no competing financial interest. Ethical Approval: It was approved by the Human Research Ethical Review Board in Southern Hospital of Southern Medical University and Southern Theater General Hospital of Chinese people's Liberation Army.

CT-Based Radiomics Signature: A Potential Biomarker for Predicting Postoperative Recurrence Risk in Stage II Colorectal Cancer.

Objective: To evaluate whether a radiomics signature could improve stratification of postoperative risk and prediction of chemotherapy benefit in stage II colorectal cancer (CRC) patients.Material and Methods: This retrospective study enrolled 299 stage II CRC patients from January 2010 to December 2015. Based on preoperative portal venous-phase CT scans, radiomics features were generated and selected to build a radiomics score (Rad-score) using the Least Absolute Shrinkage and Selection Operator (LASSO) method. The minority group was balanced by the synthetic minority over-sampling technique (SMOTE). Predictive models were built with the Rad-score and clinicopathological factors, and the area under the curve (AUC) was used to evaluate their performance. A nomogram was also constructed for predicting 3-year disease-free survival (DFS). The performance of the nomogram was assessed with a concordance index (C-index) and calibration plots.Results: Overall, 114 features were selected to construct the Rad-score, which was significantly associated with the 3-year DFS. Multivariate analysis demonstrated that the Rad-score, CA724 level, mismatch repair status, and perineural invasion were independent predictors of recurrence. Results showed that the Rad-score can classify patients into high-risk and low-risk groups in the training cohort (AUC 0.886) and the validation cohort (AUC 0.874). On this basis, a nomogram that integrated the Rad-score and clinical variables demonstrated superior performance (AUC 0.954, 0.906) than the clinical model alone (AUC 0.765, 0.705) in the training and validation cohorts, respectively. The C-index of the nomogram was 0.872, and the performance was acceptable.Conclusion: Our radiomics-based model can reliably predict recurrence risk in stage II CRC patients and potentially provide complementary prognostic value to the traditional clinicopathological risk factors for better identification of patients who are most likely to benefit from adjuvant therapy. The proposed nomogram promises to be an effective tool for personalized postoperative surveillance for stage II CRC patients.

Completeness and accuracy of the registration of recurrences in the Swedish Colorectal Cancer Registry (SCRCR) and an update of recurrence risk in colon cancer

Background The completeness and accuracy of the registration of synchronous metastases and recurrences in the Swedish Colorectal Cancer Registry has not been investigated. Knowing how accurate these parameters are in the registry is a prerequisite to adequately measure the current recurrence risk. Methods All charts for patients diagnosed with stage I–III colorectal cancer (CRC) in two regions were reviewed. In one of the regions, all registrations of synchronous metastases were similarly investigated. After the database had been corrected, recurrence risk in colon cancer was calculated stratified by risk group as suggested by ESMO in 2020. Results In patients operated upon more than five years ago (N = 1235), there were 20 (1.6%) recurrences not reported. In more recent patients, more recurrences were unreported (4.0%). Few synchronous metastases were wrongly registered (3.6%) and, likewise, few synchronous metastases were not registered (about 1%). The five-year recurrence risk in stage II was 6% for low-risk, 11% for intermediate risk, and 23% for high-risk colon cancer patients. In stage III, it was 25% in low- and 45% in high-risk patients. Incorporation of risk factors in stage III modified the risks substantially even if this is not considered by ESMO. Adjuvant chemotherapy lowered the risk in stage III but not to any relevant extent in stage II. Conclusion The registration of recurrences in the registry after 5 years is accurate to between 1 and 2% but less accurate earlier. A small number of unreported recurrences and falsely reported recurrences were discovered in the chart review. The recurrence risk in this validated and updated patient series matches what has been recently reported, except for the risk of recurrence in stage II low risk colon cancers which seem to be even a few percentage points lower (6 vs. 9%).