12-Gene Recurrence Score Assay Stratifies the Recurrence Risk in Stage II/III Colon Cancer With Surgery Alone: The SUNRISE Study

2016 ◽  
Vol 34 (24) ◽  
pp. 2906-2913 ◽  
Author(s):  
Takeharu Yamanaka ◽  
Eiji Oki ◽  
Kentaro Yamazaki ◽  
Kensei Yamaguchi ◽  
Kei Muro ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Risk Group ◽  
Recurrence Score ◽  
Recurrence Risk ◽  
High Risk Group ◽  
Stage Ii ◽  
Stage Iii ◽  
Stage Iiia ◽  
Resected Stage ◽  
Stage Ii Colon Cancer

Purpose The 12-gene Recurrence Score assay has been validated in resected stage II colon cancer treated with or without chemotherapy and resected stage III disease treated with chemotherapy. This study evaluated the 12-gene Recurrence Score assay for stage II and III colon cancer without chemotherapy to reveal the natural course of recurrence risk in stage III disease. Methods A cohort-sampling design was used. From 1,487 consecutive patients with stage II to III disease who had surgery alone, 630 patients were sampled for inclusion with a 1:2 ratio of recurrence and nonrecurrence. Sampling was stratified by stage (II v III). The assay was performed on formalin-fixed, paraffin-embedded primary cancer tissue. Association of the Recurrence Score result with recurrence-free interval (RFI) was assessed by using weighted Cox proportional hazards regression. Results Overall, 597 of 630 patients were analyzable—247 patients had stage II, and 350 had stage III colon cancer. The continuous Recurrence Score was significantly associated with RFI after adjustment for disease stage (hazard ratio for a 25-unit increase in Recurrence Score, 2.05; 95% CI, 1.47 to 2.86; P < .001). With respect to prespecified subgroups, as defined by low (< 30), intermediate (30 to 40), and high (≥ 41) Recurrence Score risk groups, patients with stage II disease in the high-risk group had a 5-year risk of recurrence similar to patients with stage IIIA to IIIB disease in the low-risk group (19% v 20%), whereas patients with stage IIIA to IIIB disease in the high-risk group had a recurrence risk similar to that of patients with stage IIIC disease in the low-risk group (approximately 38%). Conclusion To our knowledge, this study provides the first validation of the 12-gene Recurrence Score assay in stage III colon cancer without chemotherapy and showed the heterogeneity of recurrence risks in stage III as well as in stage II colon cancer.

Specific activity of cyclin dependent kinase 1 as a novel predictor of recurrence risk in stage II colon cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 402-402
Author(s):  
M. Maak ◽  
E. Zeestraten ◽  
M. Shibayama ◽  
T. Schuster ◽  
H. Friess ◽  
...  
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Cancer Patients ◽  
Specific Activity ◽  
Risk Group ◽  
Tumor Resection ◽  
Recurrence Risk ◽  
High Risk Group ◽  
Stage Ii ◽  
Stage Ii Colon Cancer

402 Background: Altered cell cycle dynamics and check points are typical features of solid tumors, and cyclin dependent kinases (CDKs) play pivotal roles in these processes. Previously we have demonstrated that CDK-based analysis, composed of CDK1 and CDK2, is useful in the prediction of outcomes in early breast cancer patients (Ann Oncol. 19(1):68-72, 2008, Br J Cancer. 100(3):494-500, 2009). Clinically, there is a need for risk stratification in patients with stage II colon cancer who have a recurrence risk of 20 to 30%. Therefore we investigated the use of CDK-based analysis for recurrence prediction of stage II colon cancer patients. Methods: Fresh frozen tissue samples of 254 patients with histologically confirmed adenocarcinoma of the colon, UICC stage II, who received primary tumor resection in Munich (217 cases), and Leiden (37 cases) were used. Protein expression and activity of CDK1 and CDK2 were determined by in vitro assays as previously described. Specific activity (SA) of CDKs was calculated as kinase activity in relation to its corresponding mass concentration. Results: Development of distant metastasis was observed in 27 patients (10.6%) after a median follow up of 86 months. We found that predictive performance of CDK1SA, but not CDK2SA, for the metastasis was substantial and almost constant for long-term event prediction (average area under the curve (AUC) = 0.69). Tumor recurrence risk analysis in association with CDK1SA identified a low- (41% of population) and high- risk group (59%). Cox proportional hazard model analysis retained the CDK-based patient classification as an independent prognostic factor for distant metastases-free survival (low vs. high-risk group: Hazard ratio = 6.2, 95% CI: 1.45 to 26.9, p=0.0049). Clinical parameters such as grading, T-categories, age, and sex were excluded as confounding factors for CDK1SA-risk. Conclusions: CDK1SA allows stratification of different risk subgroups of stage II colon cancer patients. CDK1SA-based analysis is useful for predicting patients with high risk of distant recurrence, who should be treated with chemotherapy. No significant financial relationships to disclose.

scholarly journals Validation of the 12-Gene Colon Cancer Recurrence Score in NSABP C-07 As a Predictor of Recurrence in Patients With Stage II and III Colon Cancer Treated With Fluorouracil and Leucovorin (FU/LV) and FU/LV Plus Oxaliplatin

2013 ◽  
Vol 31 (36) ◽  
pp. 4512-4519 ◽  
Author(s):  
Greg Yothers ◽  
Michael J. O'Connell ◽  
Mark Lee ◽  
Margarita Lopatin ◽  
Kim M. Clark-Langone ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Adjuvant Therapy ◽  
Cox Regression ◽  
Cancer Recurrence ◽  
Recurrence Score ◽  
Recurrence Risk ◽  
Stage Ii ◽  
Stage Iii ◽  
Treatment Benefit ◽  
Stage Ii Colon Cancer

Purpose Accurate assessments of recurrence risk and absolute treatment benefit are needed to inform colon cancer adjuvant therapy. The 12-gene Recurrence Score assay has been validated in patients with stage II colon cancer from the Cancer and Leukemia Group B 9581 and Quick and Simple and Reliable (QUASAR) trials. We conducted an independent, prospectively designed clinical validation study of Recurrence Score, with prespecified end points and analysis plan, in archival specimens from patients with stage II and III colon cancer randomly assigned to fluorouracil (FU) or FU plus oxaliplatin in National Surgical Adjuvant Breast and Bowel Project C-07. Methods Recurrence Score was assessed in 892 fixed, paraffin-embedded tumor specimens (randomly selected 50% of patients with tissue). Data were analyzed by Cox regression adjusting for stage and treatment. Results Continuous Recurrence Score predicted recurrence (hazard ratio for a 25-unit increase in score, 1.96; 95% CI, 1.50 to 2.55; P < .001), as well as disease-free and overall survival (both P < .001). Recurrence Score predicted recurrence risk (P = .001) after adjustment for stage, mismatch repair, nodes examined, grade, and treatment. Recurrence Score did not have significant interaction with stage (P = .90) or age (P = .76). Relative benefit of oxaliplatin was similar across the range of Recurrence Score (interaction P = .48); accordingly, absolute benefit of oxaliplatin increased with higher scores, most notably in patients with stage II and IIIA/B disease. Conclusion The 12-gene Recurrence Score predicts recurrence risk in stage II and stage III colon cancer and provides additional information beyond conventional clinical and pathologic factors. Incorporating Recurrence Score into the clinical context may better inform adjuvant therapy decisions in stage III as well as stage II colon cancer.

Stage II high-risk colon cancer: A retrospective analysis of the benefit of chemotherapy in patient subgroups based on the risk factor.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16068-e16068
Author(s):  
Linu Abraham Jacob
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Risk Group ◽  
Disease Free Survival ◽  
High Risk Group ◽  
Stage Ii ◽  
Resected Stage ◽  
Stage Ii Colon Cancer ◽  
Patient Subgroups

e16068 Background: Adjuvant chemotherapy is routinely recommended for patients with high risk stage II colon cancer. However the risk conferred by each high risk feature (HRF) may be different. This study was done to analyze the magnitude of benefit of chemotherapy in individual HRF patient subgroups. Methods: Resected stage II colon cancer patients during the period January 2012 to March 2018 were retrospectively analyzed for risk features, chemotherapy treatment and survival. Statistical analysis was done with SPSS 16.0. Results: A total of 41 patients were identified as having pathological stage II colon cancer during the study period - 63.4% were males and 36.6%, females. 68.3% had left sided tumor while 31.7% had right sided tumor. 29.3% had none of the high risk features and received no adjuvant chemotherapy. 70.7% patients had at least one of the high risk features and received adjuvant chemotherapy with fluoropyrimidine ± oxaliplatin. 90.2%, 7.3% and 2.5% had stage IIA, IIB and IIC disease respectively. 36.6%, 43.9% and 19.5% had grade I, II and III tumors respectively. Lymphovascular invasion (LVI) and perineural invasion (PNI) were present in 14.6% and 19.5% patients respectively. 29.3% had inadequate lymph node dissection. 22.0% patients had elevated CEA prior to surgery and 4.9% patients had presented with intestinal obstruction. After a minimum follow up period of 20 months the median disease free survival (DFS) was 26 months for the entire cohort. Left sided tumors had significantly prolonged median DFS compared to the right sided tumors (31 vs 26 months; p = 0.05). Median DFS was 24 months for the high risk group compared to 33 months for the low risk group (p = 0.002). On subset analysis T4 HRF subgroup had superior DFS, while LVI HRF subgroup had inferior DFS both of which were statistically significant. Conclusions: Magnitude of chemotherapy benefit was highest in the T4 subgroup, while it was lowest in the LVI subgroup in resected stage II high risk colon cancer [Table: see text]

scholarly journals Adjuvant systemic chemotherapy for stages II and III colon cancer after complete resection: a clinical practice guideline

2016 ◽  
Vol 23 (6) ◽  
pp. 418 ◽  
Author(s):  
B.M. Meyers ◽  
R. Cosby ◽  
F. Quereshy ◽  
D. Jonker
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Practice Guideline ◽  
Stage Ii ◽  
Stage Iii ◽  
Cochrane Library ◽  
Stage Iii Colon Cancer ◽  
Resected Stage ◽  
Stage Ii Colon Cancer

Background Updated practice guidelines on adjuvant chemotherapy for completely resected colon cancer are lacking. In 2008, Cancer Care Ontario’s Program in Evidence-Based Care developed a guideline on adjuvant therapy for stages ii and iii colon cancer. With newer regimens being assessed in this patient population and older agents being either abandoned because of non-effectiveness or replaced by agents that are more efficacious, a full update of the original guideline was undertaken.Methods Literature searches (January 1987 to August 2015) of medline, embase, and the Cochrane Library were conducted; in addition, abstracts from the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Cancer Congress were reviewed (the latter for January 2007 to August 2015). A practice guideline was drafted that was then scrutinized by internal and external reviewers whose comments were incorporated into the final guideline.Results Twenty-six unique reports of eighteen randomized controlled trials and thirteen unique reports of twelve meta-analyses or pooled analyses were included in the evidence base. The 5 recommendations developed included 3 for stage ii colon cancer and 2 for stage iii colon cancer.Conclusions Patients with completely resected stage iii colon cancer should be offered adjuvant 5-fluorouracil (5fu)–based chemotherapy with or without oxaliplatin (based on definitive data for improvements in survival and disease-free survival). Patients with resected stage ii colon cancer without “high-risk” features should not receive adjuvant chemotherapy. For patients with “high-risk” features, 5fu-based chemotherapy with or without oxaliplatin should be offered, although no clinical trials have been conducted to conclusively demonstrate the same benefits seen in stage iii colon cancer.

Validation of the 12-gene colon cancer recurrence score (RS) in NSABP C07 as a predictor of recurrence in stage II and III colon cancer patients treated with 5FU/LV (FU) and 5FU/LV+oxaliplatin (FU+Ox).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3512-3512 ◽  
Author(s):  
Michael O'Connell ◽  
Mark Lee ◽  
Margarita Lopatin ◽  
Greg Yothers ◽  
Kim Clark-Langone ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cox Regression ◽  
Cox Model ◽  
Disease Free Survival ◽  
Recurrence Score ◽  
Recurrence Risk ◽  
Stage Ii ◽  
Rt Pcr ◽  
Relative Benefit ◽  
Stage Ii Colon Cancer

3512 Background: Standardized clinical tools which accurately quantify recurrence risk are needed for optimal adjuvant treatment of colon cancer. The 12-gene RS has been validated in stage II colon cancer pts from QUASAR and CALGB 9581. We conducted a large prospectively-designed clinical validation study of RS, w/ pre-specified endpoints, methods, and analysis plan, in stage II and III colon cancer pts randomized to FU or FU+Ox in NSABP C-07. Methods: 50% of C-07 pts w/ tissue were randomly selected, stratified on stage (AJCC 6th) and recurrence. Gene expression was quantitated by RT-PCR on 25 µm manually microdissected fixed colon tumor tissue. Data were analyzed by Cox regression controlling for stage and treatment (TRT). Results: RT-PCR was successful in 892/921 pts (97%): 449 FU, 443 FU + Ox; 264 st II, 409 st IIIA/B, 219 st IIIC. The primary endpoint was met: RS predicted recurrence (HR/25 units=1.96, 95% CI 1.50-2.55 p<.001). RS also predicted disease-free survival (p<.001) and overall survival (p<.001). RS predicted recurrence (p=.001) independent of T and N stage, MMR, nodes examined, grade, and TRT. Predefined high RS group (26% of pts) had higher recurrence risk than low RS group (39% of pts): HR=2.11, p<.001. Cox model 5 yr recurrence risk (95%CI) in FU treated pts by RS group (low, int, high): st II 9% (6-13%), 13% (8-17%), 18% (12-25%); st IIIA/B 21% (16-26%), 29% (24-34%), 38% (30-46%); st IIIC 40% (32-48%), 51% (43-59%), 64% (55-74%). RS did not have significant interaction w/ stage (p=0.90) or age (p=0.76). Relative benefit of Ox was similar across range of RS (interaction p=0.48); accordingly, in Cox model and Kaplan-Meier analyses, absolute benefit of Ox increased w/ higher RS. Conclusions: RS predicts recurrence risk in stage II and III colon cancer, capturing underlying biology and providing risk information beyond conventional factors. RS is not predictive of relative benefit of Ox added to adjuvant FU but enables better discrimination of absolute Ox benefit as a function of risk. Incorporating RS into the clinical context may better inform adjuvant therapy decisions for pts w/ stage III as well as stage II colon cancer.

Impact of adjuvant chemotherapy on recurrence risk in stage II colon cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 533-533
Author(s):  
Taiwo Adesoye ◽  
Chung-Yuan Hu ◽  
Amanda Cuddy ◽  
Amanda B. Francescatti ◽  
Jessica R. Schumacher ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Recurrence Rate ◽  
Recurrence Risk ◽  
Stage Ii ◽  
Stage Iii ◽  
Stage Ii Colon Cancer ◽  
The Impact

533 Background: Although clinical guidelines recommend consideration of adjuvant chemotherapy in high-risk stage II colon cancer, the impact on recurrence risk and cancer related survival is unclear. Furthermore, among Medicare patients, adjuvant chemotherapy was not associated with improved survival. We examine the effect of adjuvant chemotherapy on recurrence risk and overall survival in a diverse cohort. Methods: 6,095 patients who underwent surgery for stage II-III colon cancer (2006-2007) were randomly selected from facilities reporting to the National Cancer Data Base for additional abstraction of tumor information, 5 year recurrence and survival. Death or second cancer within 6 months were excluded. Patients were classified as high or low risk using standard pathologic factors. Multivariate Cox regression with propensity score weighting was performed to compare recurrence risk and overall survival. Results: Of 3,423 patients with stage II colon cancer, 26.9% (n = 883) received chemotherapy compared to 76.2% (n = 1,839) of stage III patients. Among stage II patients, 47.8% (n = 1,636) had at least one high risk feature and 30.8% (n = 481) of these received chemotherapy. Five year recurrence rate in stage II patients was 13% (n = 392), greater in high risk compared to non-high risk patients (13.3% vs 9.3% p < 0.0001) and 24.4% (n = 874) in stage III patients. Chemotherapy did not improve recurrence risk in stage II patients regardless of risk status (High risk: hazard ratio [HR] 1.37; 95% CI 0.96 - 1.97; Non-high risk: HR 1.39; 95% CI 0.91 - 2.11). Chemotherapy was associated with a significant improvement in recurrence risk in stage III patients (HR 0.79; 95% CI 0.63 - 0.96). However, chemotherapy was associated with improved overall survival in both high (HR 0.69; 95% CI 0.51 - 0.92) and non-high risk stage II patients (HR 0.76; 95% CI 0.55 - 1.04), and also in stage III patients (HR 0.47; 95% CI 0.41 - 0.54). Conclusions: Adjuvant chemotherapy was not associated with a lower recurrence rate among stage II colon cancer patients. The observed survival benefit associated with chemotherapy is likely attributable to non-oncologic factors such as patient selection. Decision-making regarding chemotherapy use in this cohort should be carefully approached.

Validation Study of a Quantitative Multigene Reverse Transcriptase–Polymerase Chain Reaction Assay for Assessment of Recurrence Risk in Patients With Stage II Colon Cancer

2011 ◽  
Vol 29 (35) ◽  
pp. 4611-4619 ◽  
Author(s):  
Richard G. Gray ◽  
Philip Quirke ◽  
Kelly Handley ◽  
Margarita Lopatin ◽  
Laura Magill ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Recurrence Score ◽  
Recurrence Risk ◽  
Cox Proportional Hazards ◽  
Stage Ii ◽  
Treatment Benefit ◽  
Risk Of Recurrence ◽  
T Stage ◽  
Stage Ii Colon Cancer

Purpose We developed quantitative gene expression assays to assess recurrence risk and benefits from chemotherapy in patients with stage II colon cancer. Patients and Methods We sought validation by using RNA extracted from fixed paraffin-embedded primary colon tumor blocks from 1,436 patients with stage II colon cancer in the QUASAR (Quick and Simple and Reliable) study of adjuvant fluoropyrimidine chemotherapy versus surgery alone. A recurrence score (RS) and a treatment score (TS) were calculated from gene expression levels of 13 cancer-related genes (n = 7 recurrence genes and n = 6 treatment benefit genes) and from five reference genes with prespecified algorithms. Cox proportional hazards regression models and log-rank methods were used to analyze the relationship between the RS and risk of recurrence in patients treated with surgery alone and between TS and benefits of chemotherapy. Results Risk of recurrence was significantly associated with RS (hazard ratio [HR] per interquartile range, 1.38; 95% CI, 1.11 to 1.74; P = .004). Recurrence risks at 3 years were 12%, 18%, and 22% for predefined low, intermediate, and high recurrence risk groups, respectively. T stage (HR, 1.94; P < .001) and mismatch repair (MMR) status (HR, 0.31; P < .001) were the strongest histopathologic prognostic factors. The continuous RS was associated with risk of recurrence (P = .006) beyond these and other covariates. There was no trend for increased benefit from chemotherapy at higher TS (P = .95). Conclusion The continuous 12-gene RS has been validated in a prospective study for assessment of recurrence risk in patients with stage II colon cancer after surgery and provides prognostic value that complements T stage and MMR. The TS was not predictive of chemotherapy benefit.

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