12-gene Recurrence Score Research Articles

SY19-4 Precision oncology for adjuvant treatment of colon cancer

Accurate prediction of recurrence risk is extremely important for tailoring adjuvant chemotherapy for individual colon cancer patients. To date, some multi-gene assay systems have been developed to evaluate recurrence risk in patients with colon cancer. The 12-gene Recurrence Score assay (Oncotype DX) for colon cancer has been validated in stage II and III colon cancer as well as breast cancer. Another micro array based assay system, 55-gene classifier (55GC) for colon cancer has also been validated in resected stage II and stage III treated with adjuvant chemotherapy in Japan.

Impact of the 12-gene recurrence score assay on deciding adjuvant chemotherapy for stage II and IIIA/B colon cancer: the SUNRISE-DI study

BackgroundRecent advances in adjuvant chemotherapy for early colon cancer have widened physicians' recommendations on the regimen and duration (3 or 6 months) of the treatment. We conducted this prospective study to evaluate whether the 12-gene recurrence score (12-RS) assay affected physicians' recommendations on adjuvant treatment selection.Patients and methodsPatients with stage IIIA/IIIB or stage II colon cancer were enrolled. After the patients discussed adjuvant treatment with their treating physicians, the physicians filled in the questionnaire before assay indicating the treatment recommendation. When the 12-RS assay results were available, the physicians again filled in the questionnaire after assay. The primary endpoint was the rate of change in treatment recommendations from before to after the assay, with a threshold rate of change being 20%. Patients with stage IIIA/B to II were enrolled in a ratio of 2 : 1.ResultsOverall, the treatment recommendations changed in 40% of cases after obtaining 12-RS assay results. Recommendations were changed in 45% (80/178; 95% confidence interval, 37% to 53%; P < 0.001) and 30% (29/97; 95% confidence interval, 21% to 40%; P < 0.001) of patients with stage IIIA/B and II colon cancer, respectively. Patients with stage IIIA/B cancer had significantly more change than those with stage II cancer (P = 0.0148). From before to after the 12-RS assay, the percentage of patients whose physicians reported being confident in their treatment recommendations significantly increased from 54% to 81% in stage IIIA/B (P < 0.001) and from 65% to 83% in stage II (P < 0.001).ConclusionOur study confirmed the usefulness of the 12-RS assay in aiding the physician–patient decision-making process for tailoring adjuvant chemotherapy for stage IIIA/B colon cancer.

O-017 - SUNRISE-DI study: decision impact of the 12-gene recurrence score (12-RS) assay on adjuvant chemotherapy recommendation for stage II and IIIA/B colon cancer

O-017 - SUNRISE-DI study: decision impact of the 12-gene recurrence score (12-RS) assay on adjuvant chemotherapy recommendation for stage II and IIIA/B colon cancer

Cost-effectiveness analysis of multigene expression profiling assays to guide adjuvant therapy decisions in women with invasive early-stage breast cancer.

Gene expression profiling (GEP) testing using 12-gene recurrence score (RS) assay (EndoPredict®), 58-gene RS assay (Prosigna®), and 21-gene RS assay (Oncotype DX®) is available to aid in chemotherapy decision-making when traditional clinicopathological predictors are insufficient to accurately determine recurrence risk in women with axillary lymph node-negative, hormone receptor-positive, and human epidermal growth factor-receptor 2-negative early-stage breast cancer. We examined the cost-effectiveness of incorporating these assays into standard practice. A decision model was built to project lifetime clinical and economic consequences of different adjuvant treatment-guiding strategies. The model was parameterized using follow-up data from a secondary analysis of the Anastrozole or Tamoxifen Alone or Combined randomized trial, cost data (2017 Canadian dollars) from the London Regional Cancer Program (Canada) and secondary Canadian sources. The 12-gene, 58-gene, and 21-gene RS assays were associated with cost-effectiveness ratios of $36,274, $48,525, and $74,911/quality-adjusted life year (QALY) gained and resulted in total gains of 379, 284.3, and 189.5 QALYs/year and total budgets of $12.9, $14.2, and $16.6 million/year, respectively. The total expected-value of perfect information about GEP assays' utility was $10.4 million/year. GEP testing using any of these assays is likely clinically and economically attractive. The 12-gene and 58-gene RS assays may improve the cost-effectiveness of GEP testing and offer higher value for money, although prospective evidence is still needed. Comparative field evaluations of GEP assays in real-world practice are associated with a large societal benefit and warranted to determine the optimal and most cost-effective assay for routine use.

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

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. 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. 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%). 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.

PD-012 Validation study of the 12-gene Recurrence Score (RS) in patients (pts) with stage II and III colon cancer (CC) without adjuvant chemotherapy; SUNRISE Study

PD-012 Validation study of the 12-gene Recurrence Score (RS) in patients (pts) with stage II and III colon cancer (CC) without adjuvant chemotherapy; SUNRISE Study

Validation of the 12-Gene Colon Cancer Recurrence Score as a Predictor of Recurrence Risk in Stage II and III Rectal Cancer Patients

The 12-gene Recurrence Score assay is a validated predictor of recurrence risk in stage II and III colon cancer patients. We conducted a prospectively designed study to validate this assay for prediction of recurrence risk in stage II and III rectal cancer patients from the Dutch Total Mesorectal Excision (TME) trial. RNA was extracted from fixed paraffin-embedded primary rectal tumor tissue from stage II and III patients randomized to TME surgery alone, without (neo)adjuvant treatment. Recurrence Score was assessed by quantitative real time-polymerase chain reaction using previously validated colon cancer genes and algorithm. Data were analysed by Cox proportional hazards regression, adjusting for stage and resection margin status. All statistical tests were two-sided. Recurrence Score predicted risk of recurrence (hazard ratio [HR] = 1.57, 95% confidence interval [CI] = 1.11 to 2.21, P = .01), risk of distant recurrence (HR = 1.50, 95% CI = 1.04 to 2.17, P = .03), and rectal cancer-specific survival (HR = 1.64, 95% CI = 1.15 to 2.34, P = .007). The effect of Recurrence Score was most prominent in stage II patients and attenuated with more advanced stage (P(interaction) ≤ .007 for each endpoint). In stage II, five-year cumulative incidence of recurrence ranged from 11.1% in the predefined low Recurrence Score group (48.5% of patients) to 43.3% in the high Recurrence Score group (23.1% of patients). The 12-gene Recurrence Score is a predictor of recurrence risk and cancer-specific survival in rectal cancer patients treated with surgery alone, suggesting a similar underlying biology in colon and rectal cancers.

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.

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. 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. 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. 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.

Is adjuvant oxaliplatin (Ox) overutilized in colon cancer (CC): 408 cases from the practices of 102 oncologists.

e14564 Background: Recent long-term clinical trial follow-up suggests that adding Ox to a fluoropyrimidine (FP) may provide less benefit in adjuvant CC than originally believed (Tournigand JCO 2012). In addition, emerging data on tissue biomarkers such as microsatellite mismatch repair (MMR) and the 12-gene Recurrence Score (RS) suggest these assays may be helpful in better defining treatment benefit, and a new report provides evidence that RS may specifically predict the value of Ox (O'Connell ASCO 2012). In view of these developments we sought to document current use of adjuvant chemotherapy and physician perceptions about these decisions. Methods: U.S.-based oncologists were recruited to complete a survey and contribute treatment data for their last three patients (pts) with stage II disease and last pt with a stage III tumor. Results: 25 gastrointestinal cancer clinical investigators and 77 practicing oncologists participated, providing data from a total of 408 cases (92% treated since 2011). Findings from the two groups are similar and are presented in aggregate. A median of 9 and 15 pts annually were evaluated with Stage II and III tumors, respectively. Clinicians stated that they require a median of a 5% absolute reduction in relapse rate to use a FP alone and an additional 5% reduction to add Ox. Ox/FP was administered to 95 of 102 pts with stage III tumors (93%) and 85 of 306 pts with stage II disease (28%), particularly to those under age 70 or with T4 tumors (Table). MMR was evaluated in 127 pts (42%) with stage II and 20 pts (20%) with stage III disease. RS was obtained for 46 pts (15%) with stage II tumors, but only 2 pts (2%) with stage III. Conclusions: Adjuvant Ox is employed widely in spite of the fact that it may provide less benefit than many oncologists report requiring to initiate its use. However, several recent research developments may be laying the groundwork for a change in this treatment practice. [Table: see text]

Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581.

A greater understanding of the biology of tumor recurrence should improve adjuvant treatment decision making. We conducted a validation study of the 12-gene recurrence score (RS), a quantitative assay integrating stromal response and cell cycle gene expression, in tumor specimens from patients enrolled onto Cancer and Leukemia Group B (CALGB) 9581. CALGB 9581 randomly assigned 1,713 patients with stage II colon cancer to treatment with edrecolomab or observation and found no survival difference. The analysis reported here included all patients with available tissue and recurrence (n = 162) and a random (approximately 1:3) selection of nonrecurring patients. RS was assessed in 690 formalin-fixed paraffin-embedded tumor samples with quantitative reverse transcriptase polymerase chain reaction by using prespecified genes and a previously validated algorithm. Association of RS and recurrence was analyzed by weighted Cox proportional hazards regression. Continuous RS was significantly associated with risk of recurrence (P = .013) as was mismatch repair (MMR) gene deficiency (P = .044). In multivariate analyses, RS was the strongest predictor of recurrence (P = .004), independent of T stage, MMR, number of nodes examined, grade, and lymphovascular invasion. In T3 MMR-intact (MMR-I) patients, prespecified low and high RS groups had average 5-year recurrence risks of 13% (95% CI, 10% to 16%) and 21% (95% CI, 16% to 26%), respectively. The 12-gene RS predicts recurrence in stage II colon cancer in CALGB 9581. This is consistent with the importance of stromal response and cell cycle gene expression in colon tumor recurrence. RS appears to be most discerning for patients with T3 MMR-I tumors, although markers such as grade and lymphovascular invasion did not add value in this subset of patients.

Is adjuvant oxaliplatin (Ox) overutilized in colon cancer (CC)? 408 cases from the practices of 102 oncologists.

479 Background: Recent long-term clinical trial follow-up suggests that adding Ox to a fluoropyrimidine (FP) may provide less benefit in adjuvant CC than originally believed (Tournigand JCO 2012). In addition, emerging data on tissue biomarkers such as microsatellite mismatch repair (MMR) and the 12-gene Recurrence Score (RS) suggest these assays may be helpful in better defining treatment benefit, and a new report provides evidence that RS may specifically predict the value of Ox. (O’Connell ASCO 2012) In view of these developments we sought to document current use of adjuvant chemotherapy and physician perceptions about these decisions. Methods: US-based oncologists were recruited to complete a survey and contribute treatment data for their last 3 patients (pts) with stage II disease and last pt with a stage III tumor. Results: 25 gastrointestinal cancer clinical investigators and 77 practicing oncologists participated, providing data from a total of 408 cases (92% treated since 2011). Findings from the 2 groups are similar and are presented in aggregate. A median of 9 and 15 pts annually were evaluated with stage II and III tumors, respectively. Clinicians stated that they require a median of a 5% absolute reduction in relapse rate to use a FP alone and an additional 5% reduction to add Ox. Ox/FP was administered to 95 of 102 pts with stage III tumors (93%) and 85 of 306 pts with stage II disease (28%), particularly to those under age 70 or with T4 tumors (Table). MMR was evaluated in 127 pts (42%) with stage II and 20 pts (20%) with stage III disease. RS was obtained for 46 pts (15%) with stage II tumors, but only 2 pts (2%) with stage III. Conclusions: Adjuvant Ox is employed extensively in spite of the fact that it may provide less benefit than many oncologists report requiring to initiate its use. However, several recent research developments may be laying the groundwork for a change in this treatment practice. [Table: see text]

523PD - The 12-Gene Colon Cancer Recurrence Score (RS) Predicts Recurrence in Stage II and III Colon Cancer Patients Treated with 5FU/LV (FU) and 5FU/LV + Oxaliplatin (FU + OX): Validation in NSABP C07

ABSTRACT Background Standardized 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 C-07. Methods 50% of C-07 pts w/ tissue were randomly selected, stratified on stage and recurrence. Gene expression was quantitated by RT-PCR on 25 µm manually microdissected fixed 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 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 Ox benefit 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. Disclosure M. Lee: I am an employee and stockholder of Genomic Health, Inc. M. Lopatin: I am an employee and stockholder of Genomic Health, Inc. K.M. Clark-Langone: I am an employee and stockholder of Genomic Health, Inc. C. Millward: I am an employee and stockholder of Genomic Health, Inc. S. Shak: I am Chief Medical Officer and a stockholder of Genomic Health, Inc. All other authors have declared no conflicts of interest.

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).

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&lt;.001). RS also predicted disease-free survival (p&lt;.001) and overall survival (p&lt;.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&lt;.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.

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

We developed quantitative gene expression assays to assess recurrence risk and benefits from chemotherapy in patients with stage II colon cancer. 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. 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). 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.

Validation of a 12-gene colon cancer recurrence score (RS) in patients (pts) with stage II colon cancer (CC) from CALGB 9581.

3518 Background: The 12-gene RS (Genomic Health, Inc.) has been shown to predict risk of recurrence in stage II colon cancer (CC) pts in QUASAR. We conducted a validation study in tumor specimens from pts enrolled in CALGB 9581, which found no difference for edrecolomab (MoAb 17-1A) v. observation in 1672 pts with, on average, low risk stage II CC (14% 5-yr recurrence.) Methods: Cohort sampling included all pts with available tissue and recurrence and random pts w/o recurrence (3:1 ratio). Gene expression was analyzed by RT-PCR using FFPE from primary tumor. Mismatch repair (MMR) protein status (D= Deficient; I= Intact) was assessed by IHC for MLH1 and MSH2. Primary aim: prognostic value of continuous RS alone and in presence of MMR and traditional clinical/pathologic prognostic variables. A weighted Cox proportional hazards model was used to test the association between RS and recurrence-free interval (RFI) based on a Wald-type test statistic constructed using a weighted partial likelihood estimate and robust variance estimate. Results: Tumor was available for 1361/1672 (81%) pts. RT-PCR was successful in 690 (162 recurrences) of 736 pts (21% MMR-D, 35% > 70 yrs old, 47% < 12 nodes.) The continuous RS was significantly associated with RFI in univariate analysis (hazard ratio (HR)/ 25 units, 1.52; 95% CI, 1.09-2.12; p=0.01). MMR-D was also associated with RFI (HR, 0.62; 95%CI, 0.39-0.99; p=0.04); # nodes examined and lymphovascular invasion (LVI) were borderline significant (both p=0.06). In a pre-specified multivariate analysis w/ MMR, T-stage, nodes examined, grade, and LVI, RS was the only significant predictor of recurrence (HR/25 units=1.68, 95%CI 1.18-2.38; p=0.004). Recurrence risk at 5 yrs increased as RS increased and among subgroups defined by T-stage and MMR. In pts with T3, MMR-I tumors (n=488) pre-specified low (44% of pts RS < 29), intermediate (33%), and high (22% w/ RS > 39) RS groups had average 5-yr recurrence risks of 13%, 16%, and 21%, respectively. Conclusions: In 9581, RS improves the ability to discriminate higher from lower recurrence risk stage II CC pts beyond known prognostic factors, particularly in T3, MMR-I pts where traditional factors like grade and LVI were not prognostic.

Reproducibility of colon tumor grade and relationship to recurrence in the context of clinical, pathologic, and genomic tumor features in 504 patients with stage II colon cancer treated with surgery alone at the Cleveland Clinic.

526 Background: High tumor grade is included in practice guidelines as a marker of higher recurrence risk in stage II colon cancer. Multiple systems for tumor grading exist, without a standardized approach. We characterize agreement of 2 methods for tumor grading and association with recurrence in the context of clinical, pathologic, and genomic tumor features including mismatch repair (MMR) and the 12-gene recurrence score (RS). Methods: Colon tumors were graded independently by 2 academic GI pathologists (P1, P2). Grade was defined by % tumor with gland-like structures: well (&gt; 95%), moderately (50-95%) and poorly (&lt; 50%) differentiated. P1 used this 3-tier system while P2 used 2-tier scheme with well and moderately differentiated tumors defined as low grade and poorly differentiated as high grade. All mucinous tumors were high-grade by P2 but not P1. Relationship to recurrence-free interval (RFI) was assessed by Cox regression. Results: Primary tumors from 504 stage II colon cancer treated with surgery alone were included. 18% (P1) and 31% (P2) were high grade. High grade tumors were more likely right-sided (≥ 60%) and MMR deficient (≥ 35%) for P1 and P2 (all p &lt; 0.001). Proportion of mucinous tumors was similar for high and low grade by P1 (25% vs. 21%, p = 0.39). P2 high grade trended to lower recurrence (HR = 0.63, p = 0.10) while P1 grade was not associated w/ RFI (p = 0.46). In multivariate analyses including grade and RS, P2 high grade was associated with lower recurrence (p = 0.007) but P1 grade was not associated w/ RFI (p = 0.30). Neither grade was associated w/ RFI (p &gt; 0.30) after controlling for RS, MMR, tumor location and mucinous histology. Using the two-tier scheme, agreement b/w the 2 pathologists was low (kappa = 0.30, 95% CI 0.21-0.39) in all pts and moderate if mucinous tumors were excluded (kappa = 0.52, 95% CI 0.40-0.64). Conclusions: High tumor grade was not found to be a marker of higher recurrence risk in stage II colon cancer. Other markers validated in stage II colon cancer, such as MMR and RS, should be considered. Interpathologist agreement on colon tumor grade is modest, even with central expert review. [Table: see text]