Identification of Risk Molecular Subtype of Colon Cancer with Lymphovascular Invasion

2021 ◽  
Vol 16 ◽  
Author(s):  
Qing Jin ◽  
Binhua Liang ◽  
Xiujie Chen ◽  
Huiwen Liu
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Molecular Basis ◽  
Lymphovascular Invasion ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Tumor Stage ◽  
Stage Ii ◽  
Genetic Mutations

Background: Although surgical resection generally yields excellent outcomes, a part of colon cancer patients still have relapse or metastasis after surgery. Adjuvant chemotherapy in tumor stage III has been demonstrated to eradicate micrometastasis and improve survival, whereas the benefits of adjuvant chemotherapy in tumor stage II remain controversial. The leading cause is the lack of understanding of the molecular basis of underlying metastatic mechanisms. Objective: The aim of this study was to identify molecular subtype(s) of colon cancer with a high risk for metastasis and provide potential biomarkers for prognostic prediction in tumor stage II. Method: Based on the assumption that colon cancer evolves due to the stepwise accumulation of a series of genetic mutations, we performed a systematic investigation on the molecular basis of colon cancer by applying restart random walk on the PPI network. To compare the functional similarity of patients, we extracted mutation-propagating modules of each patient and calculated their enrichment score in 50 hallmark gene sets. According to the functional similarity matrix, we classified colon cancers with positive lymphovascular invasion and the prognosis of molecular subtypes. We determined the molecular characteristics of subtypes by conducting an enrichment analysis of subtype-specific genetic mutations. Additionally, we identified potential biomarkers for predicting patients with a high risk for metastasis in stage II through differential analysis of miRNA expression profile of subtypes. Then, we used two independent data sets to construct a random forest classifier and performed 10-fold cross-validation of miRNA biomarkers. Results: Firstly, we identified two molecular subtypes of colon cancer with positive lymphovascular invasion as well as their associated biological characteristics: LVI1=Canonical subtype (110, 85%); LVI2=Metastatic subtype (20, 15%). Secondly, we identified 11 miRNA biomarkers for predicting patients with a high risk for metastasis in tumor stage II. Conclusion: Our findings put forward a detailed classification of colon cancer and provided risk biomarkers for stage II patients to determine whether to take adjuvant chemotherapy after surgery.

Evaluating the prognostic significance of lymphovascular invasion in stage II and III colon cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 685-685 ◽  
Author(s):  
Dorotea Mutabdzic ◽  
Shalana BL O'Brien ◽  
Elizabeth A. Handorf ◽  
Karthik Devarajan ◽  
Sanjay S. Reddy ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Lymph Node ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Lymphovascular Invasion ◽  
Lymph Node Involvement ◽  
Stage Ii ◽  
Stage Iii ◽  
Node Involvement

685 Background: Presence of lymphovascular invasion (LVI) is known to be a predictor of lymph node involvement in colon adenocarcinoma (CA). Lymph node involvement is associated with poorer prognosis necessitating adjuvant therapy. While some studies have suggested that LVI is a predictor of worse overall survival in early stage colon cancer, the significance of LVI on prognosis has not been tested in a comprehensive North American data set. Methods: Patients with stage II and III CA with LVI data available and those who received predefined standard of care treatment were identified from the National Cancer Data Base (NCDB) from 2011 to 2015. The relationship between LVI and overall survival was tested using Kaplan-Meier survival curves and Cox proportional hazards regression analysis after adjusting for relevant clinical and demographic variables. Hazard ratios and 95% confidence intervals are reported along with median overall survival (OS) where available. Results: The dataset included 93,070 patients with stage II and 66,701 patients with stage III CA. The proportion of patients with LVI was 13% in stage II and 47% in stage III CA. After adjusting for age, sex, gender, race, comorbidities, socioeconomic status, T, and N stage, LVI was associated with worse OS in stage II, HR 1.2 (1.15-1.25, p < 0.001), and in stage III, HR 1.25 (1.21-1.30, p < 0.001), CA. Median OS was 6.51 years with LVI versus. 6.85 years without LVI in stage II compared with 6.57 years with LVI versus not reached without LVI in stage III CA. Of the stage II patients with LVI, 20% received adjuvant chemotherapy (CT) and median OS was 6.91 years for those who did versus 6.07 years for those who did not receive CT. Conclusions: Our data suggest that LVI is an important predictor of OS in stage II and III CA. There is evidence that adjuvant chemotherapy improves OS in advanced CA but there remains uncertainty as to the benefit in stage II. Despite this uncertainty, guidelines suggest consideration of adjuvant CT in patients with high-risk stage II disease. Our data support the recommendation that LVI be considered a high-risk feature in stage II disease. Further studies are necessary to examine whether the type or duration of CT should differ for patients with CA and LVI.

Development and validation of a robust prognostic and predictive signature for colorectal cancer (CRC) patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4036-4036
Author(s):  
A. M. Glas ◽  
P. Roepman ◽  
R. Salazar ◽  
G. Capella ◽  
V. Moreno ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Cancer Patients ◽  
Gene Signature ◽  
Low Risk ◽  
Stage Ii ◽  
Significant Difference ◽  
Independent Cohort

4036 Background: Between 25 and 35% of stage II CRC patients will experience a recurrence of their disease and may benefit from adjuvant chemotherapy. Official guidelines give suggestions but no clear recommendation for best risk stratification. Here we describe the development a robust signature that predicts disease relapse and can assist in treatment decisions. Methods: Fresh frozen tumor tissues from 180 patients with stage I, II and III colorectal cancer undergoing surgery were analyzed using high density Agilent 44K oligonucleotide arrays. Median FU was 70.2 months; 85% of patients did not receive adjuvant chemotherapy. Unsupervised hierarchical clustering based on full-genome gene expression measurement indicated the existence of 3 main colon molecular subclasses. Survival analysis of the 3 classes showed that subtype C (n= 27) had a poor outcome and subtype A (n= 48) good outcome. Only the intermediate group B (n=104) was used to develop a signature by using a cross validation procedure to score all genes for their association with 5-yr distant metastasis free survival (DMFS) and subsequently applied to all samples (n=180). The obtained gene signature was further validated on an independent cohort of 178 stage II + III colon samples. Results: A set of 38 prognosis related gene probes showed robust DMFS association in over 50% of all iterations in the Training Set of 180 samples. The gene signature was validated on an independent cohort of 178 samples from stage II + III colon cancer patients. The profile classified 61% of the validation samples as low-risk and 39% as high-risk. The low- and high-risk samples showed a significant difference in DMFS with a HR of 3.19 (P= 8.5e-4). Five-year DMFS rates were 89% (95%CI 83–95) for low-risk and 62% (95%CI 50–77) for high-risk samples. Moreover, the profile showed a significant performance within stage II (P=0.0058) and III (P=0.036) only samples. The performance of the profile was significant for both untreated (P=0.0082) and treated patients (P=0.016) suggesting that its power is independent of treatment benefits. Conclusions: ColoPrint is able to predict the prognosis of stage II and III colon cancer patients and facilitates the identification of patients who would benefit from adjuvant chemotherapy. [Table: see text]

Genomic classifiers (ColoPrint/MSI-Print) predict outcome and chemotherapy benefit in stage II and III colon cancer patients.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 378-378 ◽  
Author(s):  
Scott Kopetz ◽  
Zhi-Qin Jiang ◽  
Michael J. Overman ◽  
Christa Dreezen ◽  
Sun Tian ◽  
...  
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Cancer Patients ◽  
Additional Treatment ◽  
Low Risk ◽  
Stage Ii ◽  
High Risk Patients ◽  
Risk Patients

378 Background: Although the benefit of chemotherapy in stage II and III colon cancer patients is significant, many patients might not need adjuvant chemotherapy because they have a good prognosis even without additional treatment. ColoPrint is a gene expression classifier that distinguish patients with low or high risk of disease relapse. It was developed using whole genome expression data and has been validated in public datasets, independent European patient cohorts and technical studies (Salazar 2011 JCO, Maak 2012 Ann Surg). Methods: In this study, the commercial ColoPrint test was validated in stage II (n=96) and III patients (n=95) treated at the MD Anderson Cancer Center from 2003 to 2009. Frozen tissue specimen, clinical parameters, MSI-status and follow-up data (median follow-up 64 months) were available. The 64-gene MSI-signature developed to identify patients with deficient mismatch repair system (Tian 2012 J Path) was evaluated for its accuracy to identify MSI patients and also for prognosis. Results: In this cohort, ColoPrint classified 56% of stage II and III patients as being at low risk. The 3-year Relapse-Free-Survival (RFS) was 90.6% for Low Risk and 78.4% for High Risk patients with a HR of 2.33 (p=0.025). In uni-and multivariate analysis ColoPrint and stage were the only significant factors to predict outcome. The MSI-signature classified 47 patients (24.6%) as MSI-H and most MSI-H patients were ColoPrint low risk (81%). Patients who were ColoPrint low risk and MSI-H by signature had the best outcome with a 3-year RFS of 95% while patients with ColoPrint high risk had a worse outcome independently of the MSI-status. Low risk ColoPrint patients had a good outcome independent of stage or chemotherapy treatment (90.1% 3-year RFS for treated patients, 91.4% for untreated patients) while ColoPrint high risk patients treated with adjuvant chemotherapy had 3-year RFS of 84%, compared to 70.1% 3-year RFS in untreated patients (p=0.026). Conclusions: The combination of ColoPrint and MSI-Print improves the prognostic accuracy in stage II and stage III patients and may help the identification of patients at higher risk who are more likely to benefit from additional treatment

Clinical impact of diverting ileostomy on the dose intensity of adjuvant chemotherapy for colorectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 867-867
Author(s):  
Shusuke Yagi ◽  
Eiji Shinozaki ◽  
Keisho Chin ◽  
Mitsukuni Suenaga ◽  
Daisuke Takahari ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Dose Intensity ◽  
Clinical Impact ◽  
Stage Ii ◽  
Stage Iii ◽  
Diverting Ileostomy ◽  
Grade 3

867 Background: CAPOX as adjuvant chemotherapy is a standard care option for stage III and high risk stage II colorectal cancer(CRC). And then chemotherapy induced diarrhea (CID) is known as one of the dose-limiting toxicities for CAPOX. Although diverting ileostomy is useful for preventing serious complications of high risk anastomosis, it is well recognized that high ileostomy output is hard to manage. Furthermore, the effect of diverting ileostomy on CID of adjuvant chemotherapy is unclear. In this study, we addressed the clinical impact of diverting ileostomy on the dose intensity of adjuvant chemotherapy for CRC. Methods: Patients who diagnosed with stage III colon cancer and stage II or III rectal cancer after curative surgery and received CAPOX as adjuvant chemotherapy during 2011- 2014 were reviewed retrospectively. We investigated the relationship between diverting ileostomy and dose intensity, toxicities and disease-free survival (DFS). Results: 112 patients (median age 60 years, 52% male, 69% colon cancer, 63% stage III, median follow-up 47 months) were enrolled in this study. Of 112 patients, 100 patients were received chemotherapy without ileostomy (non-ileostomy group: NIG) and 12 patients were received chemotherapy with ileostomy (ileostomy group: IG). 112 Patients received 870 chemotherapy cycles. All treatment related grade 3/4 adverse events were documented in 39% of patients in NIG and 33% of patients in IG (P = 0.77). Grade 3/4 of CID occurred in 8% of patients in NIG and 8% of patients in IG (P = 1). Grade 3/4 of neutropenia were recognized in 21% of patients in NIG and 17% of patients in IG (P = 1). Average relative dose intensity (RDI) in NIG were 75.7% and 85.8% for capecitabine and oxaliplatin, respectively. Average RDI of capecitabine and oxaliplatin in IG were 76.1% and 82.7%, respectively. Significant difference of RDI of capecitabine and oxaliplatin were not shown in comparison between NIG and IG (P = 0.93, P = 0.63). The 3-year DFS rate was 85.0% in NIG and 75.0% in IG. The HR for DFS for NIG compared to IG was 1.709 (95% CI, 0.49 to 5.95; P = 0.40). Conclusions: The presence of diverting ileostomy does not affect RDI of CAPOX as adjuvant chemotherapy.

American Society of Clinical Oncology Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer

2004 ◽  
Vol 22 (16) ◽  
pp. 3408-3419 ◽  
Author(s):  
Al B. Benson ◽  
Deborah Schrag ◽  
Mark R. Somerfield ◽  
Alfred M. Cohen ◽  
Alvaro T. Figueredo ◽  
...  
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Clinical Oncology ◽  
Meta Analysis ◽  
Indirect Evidence ◽  
Stage Ii ◽  
Prognostic Features ◽  
American Society ◽  
Stage Ii Colon Cancer

Purpose To address whether all medically fit patients with curatively resected stage II colon cancer should be offered adjuvant chemotherapy as part of routine clinical practice, to identify patients with poor prognosis characteristics, and to describe strategies for oncologists to use to discuss adjuvant chemotherapy in practice. Methods An American Society of Clinical Oncology Panel, in collaboration with the Cancer Care Ontario Practice Guideline Initiative, reviewed pertinent information from the literature through May 2003. Results A literature-based meta-analysis found no evidence of a statistically significant survival benefit of adjuvant chemotherapy for stage II patients. Recommendations The routine use of adjuvant chemotherapy for medically fit patients with stage II colon cancer is not recommended. However, there are populations of patients with stage II disease that could be considered for adjuvant therapy, including patients with inadequately sampled nodes, T4 lesions, perforation, or poorly differentiated histology. Conclusion Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease. The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences. Patients with stage II disease should be encouraged to participate in randomized trials.

Tumor sidedness and intrinsic subtypes in patients with stage II/III colon cancer: Analysis of NSABP C-07 (NRG Oncology).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3514-3514 ◽  
Author(s):  
S. Rim Kim ◽  
Nan Song ◽  
Greg Yothers ◽  
Patrick Gavin ◽  
Carmen Joseph Allegra ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Therapy Response ◽  
Stage Ii ◽  
Intrinsic Subtypes ◽  
Treatment Benefit ◽  
Cancer Subtypes ◽  
Metastatic Setting

3514 Background: The predictive value of tumor sidedness in colorectal cancer is currently of interest especially in metastatic setting for anti-EGFR therapy response. We tested whether intrinsic molecular subtype classification predictive of treatment benefit in stage II/III colon cancer is an independent novel marker in association with tumor sidedness. Methods: All available cases included in the NSABP/NRG C-07 trial for which we had both gene expression data and anatomical data (n=1603) were used to determine the molecular subtypes using the following classifiers; the Colorectal Cancer Assigner (CRCA), the Colon Cancer Subtypes (CCS) and the Consensus Molecular Subtypes (CMS). Frequency of tumor sidedness in each subtype and recurrence-free survival were analyzed. Results: Intrinsic subtypes were differentially distributed in right- and left-colon tumors with the exception of the stem-like or CMS4 (mesenchymal) subtype (Table 1). Sidedness was not associated with prognosis (p=0.82, HR: 1.022 [CI: 0.851-1.227]) or prediction of patients with greater benefit from oxaliplatin when combined with 5-Fu+LV (interaction p=0.484). Conclusions: Although tumor sidedness is associated with distribution of intrinsic subtypes in stage II/III colon cancer, it is not predictive of survival benefit from oxaliplatin in C-07. Support: -180868, -180822, U24-CA196067; HI13C2162; PA DOH; Sanofi-Synthelabo Clinical trial information: NCT00004931. [Table: see text]

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