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Background Studies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer. Patients and Methods This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes’ B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes’ B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes’ B2 colon cancer with no additional chemotherapy. Results From August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03–20.3 years). Among patients with Dukes’ B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes’ B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity.

Pharmacodynamic studies of everolimus and sapanisertib treated PDX-PNETs using Western blot analysis of mTOR pathway targets.

Patients with pancreatic neuroendocrine tumors (PNET) commonly develop advanced disease and require systemic therapy. However, treatment options remain limited, in part, because experimental models that reliably emulate PNET disease are lacking. We therefore developed a patient-derived xenograft model of PNET (PDX-PNET), which we then used to evaluate two mTOR inhibitor drugs: FDA-approved everolimus and the investigational new drug sapanisertib. PDX-PNETs maintained a PNET morphology and PNET-specific gene expression signature with serial passage. PDX-PNETs also harbored mutations in genes previously associated with PNETs (such as MEN1 and PTEN), displayed activation of the mTOR pathway, and could be detected by Gallium-68 DOTATATE PET-CT. Treatment of PDX-PNETs with either everolimus or sapanisertib strongly inhibited growth. As seen in patients, some PDX-PNETs developed resistance to everolimus. However, sapanisertib, a more potent inhibitor of the mTOR pathway, caused tumor shrinkage in most everolimus-resistant tumors. Our PDX-PNET model is the first available, validated PDX model for PNET, and preclinical data from the use of this model suggest that sapanisertib may be an effective new treatment option for patients with PNET or everolimus-resistant PNET.

BACKGROUND: Little is known about the interaction of comorbidities and age on survival outcomes in colorectal ancer (mCRC), nor how comorbidities impact treatment tolerance. METHODS: We utilized a cohort of 1,345 mCRC patients enrolled in CALGB/SWOG 80405, a multicenter phase III trial of fluorouracil/leucovorin + oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) plus bevacizumab, cetuximab or both. Endpoints were overall survival (OS), progression-free survival (PFS), and grade ≥3 toxicities assessed using NCI CTCAE v.3.0. Participants completed a questionnaire, including a modified Charlson Comorbidity Index. Adjusted Cox and logistic regression models tested associations of comorbidities and age on the endpoints. RESULTS: In CALGB/SWOG 80405, 1,095 (81%) subjects were

Supplemental figure 3. Mutation frequencies in pre-and on-treatment plasma samples as determined by next-generation sequencing of cfDNA using the Guardant360 assay.

Purpose: Bevacizumab is a VEGF-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of multiple cancers. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood.Experimental Design: To identify genomic regions associated with bevacizumab-induced hypertension risk, sequencing of candidate genes and flanking regulatory regions was performed on 61 patients treated with bevacizumab (19 cases developed early-onset grade 3 hypertension and 42 controls had no reported hypertension in the first six cycles of treatment). SNP-based tests for common variant associations and gene-based tests for rare variant associations were performed in 174 candidate genes.Results: Four common variants in independent linkage disequilibrium blocks between SLC29A1 and HSP90AB1 were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3+ hypertension (P = 0.01; OR, 2.4) and systolic blood pressure >180 mm Hg (P = 0.02; OR, 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 (P = 0.03; OR, 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. In vitro overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure.Conclusions: The genomic region between SLC29A1 and HSP90AB1 and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension. Clin Cancer Res; 24(19); 4734–44. ©2018 AACR.

Supplementary Tables 1-2, Figures 1-4. Supplementary Table 1: List of assay primer sets used in this study. Supplementary Table 2. Table of co-regulation among the 14 genes using a Kendall tau analysis. Supplementary Figure 1: Forest plots showing associations of gene expression levels with OS in KRAS WT (A) and KRAS Mut (B) pts. All assayed genes are shown. Supplementary Figure 2: Forest plots showing associations of gene expression levels with PFS in KRAS WT (A) and KRAS Mut (B) pts. Supplementary Figure 3: Forest plots showing associations of gene expression levels and treatment group with OS in KRAS WT (A) and KRAS Mut (B) pts. Supplementary Figure 4: Forest plots showing associations of gene expression levels and treatment group with PFS in KRAS WT (A) and KRAS Mut (B) pts. All assayed genes are shown.

Purpose:Previous studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival. However, the influence of vitamin D status on disease progression and patient survival remains largely unknown for patients with advanced or metastatic colorectal cancer.Experimental Design:We prospectively collected blood samples in 1,041 patients with previously untreated advanced or metastatic colorectal cancer participating in a randomized phase III clinical trial of first-line chemotherapy plus biologic therapy. We examined the association of baseline plasma 25(OH)D levels with overall survival (OS) and progression-free survival (PFS). Cox proportional hazards models were used to calculate hazard ratios (HRs) and confidence intervals (CIs), adjusted for prognostic factors and confounders.Results:At study entry, 63% of patients were vitamin D deficient (Ptrend = 0.0009 and 0.03, respectively). Compared with patients in the bottom quintile of 25(OH)D (≤10.8 ng/mL), those in the top quintile (≥24.1 ng/mL) had a multivariable-adjusted HR of 0.66 (95% CI, 0.53–0.83) for OS and 0.81 (95% CI, 0.66–1.00) for PFS. The improved survival associated with higher 25(OH)D levels was consistent across patient subgroups of prognostic patient and tumor characteristics.Conclusions:In this large cohort of patients with advanced or metastatic colorectal cancer, higher plasma 25(OH)D levels were associated with improved OS and PFS. Clinical trials assessing the benefit of vitamin D supplementation in patients with colorectal cancer are warranted.

Demographics of the cases used in the EC/GEJC RWE testing set.

Supplemental Methods, Tables and Figures Table S1. Analyzed candidate genes Table S2. Gene sets and pathways used for candidate gene selection Table S3. Quality of sequencing reads per sample Table S4. Post-QC quality per sample Table S5. Replication cohorts Table S6. Gene-based analysis of rare and low frequency variants (MAF < 0.03) in candidate genes Table S7. Characteristics of replication patient subgroups Figure S1. Candidate gene analysis workflow. Figure S2. Associations with bevacizumab-induced hypertension in the SLC29A1-HSP90AB1 region. Figure S3. Top SLC29A1-HSP90AB1 SNPs are in predicted transcriptionally active regions in human umbilical vein endothelial cells. Figure S4. Proportion of high-grade hypertension in replication cohorts stratified by variant allele carrier status. Figure S5. Dose-dependent effects of adenosine on cyclic AMP and nitric oxide levels. Figure S6. Effects of adenosine receptor blockade on cyclic AMP and nitric oxide levels in HUVEC. Figure S7. Effect of ENT1 inhibition on cyclic AMP levels. Figure S8. Effect of SLC29A1-overexpression on cyclic AMP levels in HUVEC. Figure S9. Linkage disequilibrium plot of SLC29A1-HSP90AB1 intergenic region.

Supplementary Table from Plasma Protein Biomarkers in Advanced or Metastatic Colorectal Cancer Patients Receiving Chemotherapy With Bevacizumab or Cetuximab: Results from CALGB 80405 (Alliance)

Supplementary Data from Tumor Immunogenomic Features Determine Outcomes in Patients with Metastatic Colorectal Cancer Treated with Standard-of-Care Combinations of Bevacizumab and Cetuximab

Purpose:FOLFOX, FOLFIRI, or FOLFOXIRI chemotherapy with bevacizumab is considered standard first-line treatment option for patients with metastatic colorectal cancer (mCRC). We developed and validated a molecular signature predictive of efficacy of oxaliplatin-based chemotherapy combined with bevacizumab in patients with mCRC.Experimental Design:A machine-learning approach was applied and tested on clinical and next-generation sequencing data from a real-world evidence (RWE) dataset and samples from the prospective TRIBE2 study resulting in identification of a molecular signature, FOLFOXai. Algorithm training considered time-to-next treatment (TTNT). Validation studies used TTNT, progression-free survival, and overall survival (OS) as the primary endpoints.Results:A 67-gene signature was cross-validated in a training cohort (N = 105) which demonstrated the ability of FOLFOXai to distinguish FOLFOX-treated patients with mCRC with increased benefit from those with decreased benefit. The signature was predictive of TTNT and OS in an independent RWE dataset of 412 patients who had received FOLFOX/bevacizumab in first line and inversely predictive of survival in RWE data from 55 patients who had received first-line FOLFIRI. Blinded analysis of TRIBE2 samples confirmed that FOLFOXai was predictive of OS in both oxaliplatin-containing arms (FOLFOX HR, 0.629; P = 0.04 and FOLFOXIRI HR, 0.483; P = 0.02). FOLFOXai was also predictive of treatment benefit from oxaliplatin-containing regimens in advanced esophageal/gastro-esophageal junction cancers, as well as pancreatic ductal adenocarcinoma.Conclusions:Application of FOLFOXai could lead to improvements of treatment outcomes for patients with mCRC and other cancers because patients predicted to have less benefit from oxaliplatin-containing regimens might benefit from alternative regimens.

Supplementary Figures 1-5 and Supplementary Tables 1-5

A) Correlation of TTNT and PFS of cases in the TRIBE2 trial. B) Distribution of mCRC RWE TNTs compared with PFS from the FOLFOX and FOLFOXIRI arms of the TRIBE2 trial.

Purpose:Irinotecan/5-fluorouracil (5-FU; FOLFIRI) or oxaliplatin/5-FU (FOLFOX), combined with bevacizumab or cetuximab, are approved, first-line treatments for metastatic colorectal cancer (mCRC). We aimed at identifying germline variants associated with survival in patients with mCRC treated with these regimens in Cancer and Leukemia Group B/SWOG 80405.Experimental Design:Patients with mCRC receiving either FOLFOX or FOLFIRI were randomized to either cetuximab or bevacizumab. DNA from peripheral blood was genotyped for approximately 700,000 SNPs. The association between SNPs and overall survival (OS) was tested in 613 patients of genetically estimated European ancestry using Cox proportional hazards models.Results:The four most significant SNPs associated with OS were three haplotypic SNPs between microsomal glutathione S-transferase 1 (MGST1) and LIM domain only 3 (LMO3, representative HR, 1.56; P = 1.30 × 10−6), and rs11644916 in AXIN1 (HR, 1.39, P = 4.26 × 10−6). AXIN1 is a well-established tumor suppressor gene in colorectal cancer, and rs11644916 (G>A) conferred shorter OS. Median OS for patients with the AA, AG, or GG genotypes was 18.4, 25.6, or 36.4 months, respectively. In 90 patients with stage IV colorectal cancer from The Cancer Genome Atlas (TCGA), rs11649255 in AXIN1 [in almost complete linkage disequilibrium (LD) with rs11644916], was associated with shorter OS (HR, 2.24, P = 0.0096). Using rs11648673 in AXIN1 (in very high LD with rs11644916 and with functional evidence), luciferase activity in three colorectal cancer cell lines was reduced.Conclusions:This is the first large genome-wide association study ever conducted in patients with mCRC treated with first-line standard treatment in a randomized phase III trial. A common SNP in AXIN1 conferred worse OS and the effect was replicated in TCGA. Further studies in colorectal cancer experimental models are required.

Supplemental figure 1. Abdominal CT scans from a patient who achieved minor response following 2 cycles of treatment. Representative sections from baseline (left) and on-treatment (right) scans are shown.

Supplementary Figure and Table

Purpose: On the basis of preclinical evidence of synergistic activity between MEK and EGFR inhibitors in pancreatic ductal adenocarcinoma (PDAC), we evaluated the safety and efficacy of selumetinib, a MEK1/2 inhibitor, plus erlotinib in patients with previously treated advanced PDAC.Experimental Design: In this single-arm phase II trial, eligible patients received the combination of erlotinib 100 mg plus selumetinib 100 mg daily in 3-week cycles. Study assessments included measurement of clinical outcomes, with a primary endpoint of overall survival, and exploration of potential molecular predictors of treatment benefit.Results: Forty-six patients were enrolled and received a median of two cycles (range, 1–7). Although no objective responses were observed, 19 patients (41%) showed evidence of stable disease for ≥6 weeks, and 13 of 34 patients (38%) had a CA19-9 decline ≥50%. Median progression-free survival was 1.9 months [95% confidence interval (CI), 1.4–3.3 months], with a median overall survival of 7.3 months (95% CI, 5.2–8.0 months). Common adverse events included rash, diarrhea, and nausea/vomiting. Patients with tumors exhibiting an epithelial phenotype (demonstrated by a high level of E-cadherin expression) were more likely to be sensitive to study treatment. Tumor-derived DNA was detectable in plasma from the majority of patients using next-generation digital DNA sequencing, and its relative abundance correlated with tumor burden.Conclusions: A therapeutic strategy of dual targeted inhibition of the MEK and EGFR pathways shows modest antitumor activity in pancreatic cancer. Specific molecular subtypes may derive greatest benefit from this combination. Further exploration, both with more potent MEK inhibitors and in molecularly enriched patient subsets, is warranted. Clin Cancer Res; 22(1); 61–68. ©2015 AACR.

Purpose: Formalin-fixed, paraffin-embedded tumor samples from CALGB 80203 were analyzed for expression of EGFR axis–related genes to identify prognostic or predictive biomarkers for cetuximab treatment.Patients and Methods: Patients (238 total) with first-line metastatic colorectal cancer (mCRC) were randomized to FOLFOX or FOLFIRI chemotherapy ± cetuximab. qRT-PCR analyses were conducted on tissues from 103 patients at baseline to measure gene expression levels of HER-related genes, including amphiregulin (AREG), betacellulin (BTC), NT5E (CD73), DUSP4, EGF, EGFR, epigen (EPGN), epiregulin (EREG), HBEGF, ERBB2 (HER2), ERBB3 (HER3), ERBB4 (HER4), PHLDA1, and TGFA. The interactions between expression levels and treatment with respect to progression-free survival (PFS) and overall survival (OS) were modeled using multiplicative Cox proportional hazards models.Results: High tumor mRNA levels of HER2 [hazard ratio (HR), 0.64; P = 0.002] and EREG (HR, 0.89; P = 0.016) were prognostic markers associated with longer PFS across all patients. HER3 and CD73 expression levels were identified as potential predictive markers of benefit from cetuximab. In KRAS wild-type (WT) tumors, low HER3 expression was associated with longer OS from cetuximab treatment, whereas high HER3 expression was associated with shorter OS from cetuximab treatment (chemo + cetuximab: HR, 1.15; chemo-only: HR, 0.48; Pinteraction = 0.029). High CD73 expression was associated with longer PFS from cetuximab treatment in patients with KRAS-WT (chemo + cetuximab: HR, 0.91; chemo-only: HR, 1.57; Pinteraction = 0.026) and KRAS-mutant (Mut) tumors (chemo + cetuximab: HR, 0.80; chemo-only: HR, 1.29; P = 0.025).Conclusions: Gene expression of HER3 and CD73 was identified as a potential predictive marker for cetuximab. These data implicate HER axis signaling and immune modulation as potential mechanisms of cetuximab action and sensitivity. Clin Cancer Res; 21(5); 1078–86. ©2014 AACR.

Purpose:CALGB 80405 compared the combination of first-line chemotherapy with cetuximab or bevacizumab in the treatment of advanced or metastatic colorectal cancer (mCRC). Although similar clinical outcomes were observed in the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group, biomarkers could identify patients deriving more benefit from either biologic agent.Patients and Methods:In this exploratory analysis, the Angiome, a panel of 24 soluble protein biomarkers were measured in baseline plasma samples in CALGB 80405. Prognostic biomarkers were determined using univariate Cox proportional hazards models. Predictive biomarkers were identified using multivariable Cox regression models including interaction between biomarker level and treatment.Results:In the total population, high plasma levels of Ang-2, CD73, HGF, ICAM-1, IL6, OPN, TIMP-1, TSP-2, VCAM-1, and VEGF-R3 were identified as prognostic of worse progression-free survival (PFS) and overall survival (OS). PlGF was identified as predictive of lack of PFS benefit from bevacizumab [bevacizumab HR, 1.51; 95% confidence interval (CI), 1.10–2.06; cetuximab HR, 0.94; 95% CI, 0.71–1.25; Pinteraction = 0.0298] in the combined FOLFIRI/FOLFOX regimens. High levels of VEGF-D were predictive of lack of PFS benefit from bevacizumab in patients receiving FOLFOX regimen only (FOLFOX/bevacizumab HR, 1.70; 95% CI, 1.19–2.42; FOLFOX/cetuximab HR, 0.92; 95% CI, 0.68–1.24; Pinteraction = 0.0097).Conclusions:In this exploratory, hypothesis-generating analysis, the Angiome identified multiple prognostic biomarkers and two potential predictive biomarkers for patients with mCRC enrolled in CALGB 80405. PlGF and VEGF-D predicted lack of benefit from bevacizumab in a chemo-dependent manner.See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725

Supplemental figure 2. Distribution of proportion of E-cadherin expressing tumor cells across all cases.

Supplementary Figure from Tumor Immunogenomic Features Determine Outcomes in Patients with Metastatic Colorectal Cancer Treated with Standard-of-Care Combinations of Bevacizumab and Cetuximab

Supplementary Figure from Plasma Protein Biomarkers in Advanced or Metastatic Colorectal Cancer Patients Receiving Chemotherapy With Bevacizumab or Cetuximab: Results from CALGB 80405 (Alliance)

Purpose:CALGB/SWOG 80405 was a randomized phase III trial in first-line patients with metastatic colorectal cancer treated with bevacizumab, cetuximab, or both, plus chemotherapy. We tested the effect of tumor immune features on overall survival (OS).Experimental Design:Primary tumors (N = 554) were profiled by RNA sequencing. Immune signatures of macrophages, lymphocytes, TGFβ, IFNγ, wound healing, and cytotoxicity were measured. CIBERSORTx scores of naive and memory B cells, plasma cells, CD8+ T cells, resting and activated memory CD4+ T cells, M0 and M2 macrophages, and activated mast cells were measured.Results:Increased M2 macrophage score [HR, 6.30; 95% confidence interval (CI), 3.0–12.15] and TGFβ signature expression (HR, 1.35; 95% CI, 1.05–1.77) were associated with shorter OS. Increased scores of plasma cells (HR, 0.55; 95% CI, 0.38–0.87) and activated memory CD4+ T cells (HR, 0.34; 95% CI, 0.16–0.65) were associated with longer OS. Using optimal cutoffs from these four features, patients were categorized as having either 4, 3, 2, or 0–1 beneficial features associated with longer OS, and the median (95% CI) OS decreased from 42.5 (35.8–47.8) to 31.0 (28.8–34.4), 25.2 (20.6–27.9), and 17.7 (13.5–20.4) months respectively (P = 3.48e–11).Conclusions:New immune features can be further evaluated to improve patient response. They provide the rationale for more effective immunotherapy strategies.

Purpose We aimed to estimate the effect of a 12-week web-based dietary intervention with text messages on quality of life (QoL) among colorectal cancer (CRC) survivors. Methods Between 2017 and 2018, 50 CRC survivors were randomized (1:1) to receive a 12-week web-based dietary intervention with daily text messages or wait-list control. Health-related QoL was assessed using the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 (QLQ-C30) and colorectal quality of life module (QLQ-CR29) at baseline, 12, and 24 weeks. Within- and between-group mean changes in health-related QoL with 95% confidence intervals (CI) were calculated for both arms. Results Compared to the controls, participants receiving the intervention had an improvement in emotional functioning (mean change: 14.3; 95% CI: 3.0, 25.6) at 12 weeks and social functioning (mean change: 13.8; 95% CI: 2.1, 25.5) at 24 weeks. A decrease of fatigue from baseline was also observed in the intervention arm (mean change: − 9.1; 95% CI: − 17.1, − 1.1) at 24 weeks. No other changes in QoL scores were associated with the intervention. Conclusion CRC survivors randomized to receive a web-based dietary intervention with text messages experienced higher emotional and social functioning. Further study with a larger population may be warranted. Trial registration clinicaltrials.gov, NCT02965521. Registered 16 November 2016, https://clinicaltrials.gov/ct2/keydates/NCT02965521

Colorectal cancer (CRC) affects many older adults. We investigated the efficacy and safety of adding anti-epidermal growth factor receptor (EGFR) agents to doublet chemotherapy (DC) in older patients.Patients with RAS wild-type (WT) metastatic CRC (mCRC) receiving first-line DC + anti-EGFR (n = 1191) or DC alone (n = 729) from seven trials in the Aide de Recherche en Cancerologie Digestive database were included. The prognostic and predictive effects of age were investigated. Progression-free and overall survival (OS) were evaluated between age groups (≥70 vs 70) for DC + anti-EGFR. In addition, outcomes were compared between DC+/-anti-EGFR within age groups in three trials with a DC alone arm. Subsequently, the same analysis was conducted for left-sided tumours. Adverse events grade ≥3 (G3+) were compared between age groups.Older (vs younger) patients receiving DC + anti-EGFR had similar progression-free survival (PFS) (8.7 vs 10.3 months; hazard ratio (HR) = 1.20 [0.96-1.49];p = 0.107) but inferior OS (21.3 vs 26.3; HR = 1.36 [1.08-1.72];p = 0.011). DC + anti-EGFR (vs DC alone) improved OS (23.9 vs 20.3; HR = 0.82 [0.70-0.95];p = 0.008) and PFS (11.2 vs 8.9; HR = 0.70 [0.60-0.82];p 0.001) in younger but not older patients: OS (24.7 vs 17.6; HR [95% confidence interval {CI}] = 0.77 [0.58-1.04];p = 0.092) and PFS (9.1 vs 8.7; HR [95% CI] = 0.85[0.63-1.15];p = 0.287). In left-sided 'only' tumours, the following outcomes for older (vs younger) patients were observed. For DC + anti-EGFR, PFS 9 versus 11.2 months; HR1.10 (95% CI 0.83-1.46); p = 0.52, OS 25.6 vs 30.3 HR 1.32 (95% CI 0.97-1.79), p = 0.086. For DC + anti-EGFR (vs DC alone), PFS and OS for younger patients were 11.9 vs 9.2 months HR 0.60 (95% CI 0.47-0.78) p 0.001 and 24.1 versus 23.3 months HR 0.84 (95% CI 0.67-1.04), respectively. For older patients, PFS and OS were 13.1 versus 8.5 months, HR 0.51 (95% CI, 0.28-0.93), P = 0.027 and 26.3 versus 16.5 months HR 0.49 (95% CI, 0.28-0.85), respectively. There was no significant difference in toxicity among different age groups.Older (vs younger) patients with mCRC RAS WT patients had comparable toxicity and efficacy with the addition of anti-EGFR agents to chemotherapy.

Purpose: CALGB/SWOG 80405 was a randomized phase III trial in first-line patients with metastatic colorectal cancer treated with bevacizumab, cetuximab, or both, plus chemotherapy. We tested the effect of tumor immune features on overall survival (OS). Experimental Design: Primary tumors (N = 554) were profiled by RNA sequencing. Immune signatures of macrophages, lymphocytes, TGFβ, IFNγ, wound healing, and cytotoxicity were measured. CIBERSORTx scores of naive and memory B cells, plasma cells, CD8+ T cells, resting and activated memory CD4+ T cells, M0 and M2 macrophages, and activated mast cells were measured. Results: Increased M2 macrophage score [HR, 6.30; 95% confidence interval (CI), 3.0–12.15] and TGFβ signature expression (HR, 1.35; 95% CI, 1.05–1.77) were associated with shorter OS. Increased scores of plasma cells (HR, 0.55; 95% CI, 0.38–0.87) and activated memory CD4+ T cells (HR, 0.34; 95% CI, 0.16–0.65) were associated with longer OS. Using optimal cutoffs from these four features, patients were categorized as having either 4, 3, 2, or 0–1 beneficial features associated with longer OS, and the median (95% CI) OS decreased from 42.5 (35.8–47.8) to 31.0 (28.8–34.4), 25.2 (20.6–27.9), and 17.7 (13.5–20.4) months respectively (P = 3.48e–11). Conclusions: New immune features can be further evaluated to improve patient response. They provide the rationale for more effective immunotherapy strategies.

Purpose: CALGB 80405 compared the combination of first-line chemotherapy with cetuximab or bevacizumab in the treatment of advanced or metastatic colorectal cancer (mCRC). Although similar clinical outcomes were observed in the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group, biomarkers could identify patients deriving more benefit from either biologic agent. Patients and Methods: In this exploratory analysis, the Angiome, a panel of 24 soluble protein biomarkers were measured in baseline plasma samples in CALGB 80405. Prognostic biomarkers were determined using univariate Cox proportional hazards models. Predictive biomarkers were identified using multivariable Cox regression models including interaction between biomarker level and treatment. Results: In the total population, high plasma levels of Ang-2, CD73, HGF, ICAM-1, IL6, OPN, TIMP-1, TSP-2, VCAM-1, and VEGF-R3 were identified as prognostic of worse progression-free survival (PFS) and overall survival (OS). PlGF was identified as predictive of lack of PFS benefit from bevacizumab [bevacizumab HR, 1.51; 95% confidence interval (CI), 1.10–2.06; cetuximab HR, 0.94; 95% CI, 0.71–1.25; Pinteraction = 0.0298] in the combined FOLFIRI/FOLFOX regimens. High levels of VEGF-D were predictive of lack of PFS benefit from bevacizumab in patients receiving FOLFOX regimen only (FOLFOX/bevacizumab HR, 1.70; 95% CI, 1.19–2.42; FOLFOX/cetuximab HR, 0.92; 95% CI, 0.68–1.24; Pinteraction = 0.0097). Conclusions: In this exploratory, hypothesis-generating analysis, the Angiome identified multiple prognostic biomarkers and two potential predictive biomarkers for patients with mCRC enrolled in CALGB 80405. PlGF and VEGF-D predicted lack of benefit from bevacizumab in a chemo-dependent manner. See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725

BackgroundThe incidence of young-onset colorectal cancer (yoCRC) is increasing. It is unknown if there are survival differences between young and older patients with metastatic colorectal cancer (mCRC).MethodsWe studied the association of age with survival in 2326 mCRC patients enrolled in the Cancer and Leukemia Group B and SWOG 80405 trial, a multicenter, randomized trial of first-line chemotherapy plus biologics. The primary and secondary outcomes of this study were overall survival (OS) and progression-free survival (PFS), respectively, which were assessed by Kaplan-Meier method and compared among younger vs older patients with the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated based on Cox proportional hazards modeling, adjusting for known prognostic variables. All statistical tests were 2-sided.ResultsOf 2326 eligible subjects, 514 (22.1%) were younger than age 50 years at study entry (yoCRC cohort). The median age of yoCRC patients was 44.3 vs 62.5 years in patients aged 50 years and older. There was no statistically significant difference in OS between yoCRC vs older-onset patients (median = 27.07 vs 26.12 months; adjusted HR = 0.98, 95% CI = 0.88 to 1.10; P = .78). The median PFS was also similar in yoCRC vs older patients (10.87 vs 10.55 months) with an adjusted hazard ratio of 1.02 (95% CI = 0.92 to 1.13; P = .67). Patients younger than age 35 years had the shortest OS with median OS of 21.95 vs 26.12 months in older-onset patients with an adjusted hazard ratio of 1.08 (95% CI = 0.81 to 1.44; Ptrend = .93).ConclusionIn this large study of mCRC patients, there were no statistically significant differences in survival between patients with yoCRC and CRC patients aged 50 years and older.

Germline variants might predict cancer progression. Bevacizumab improves overall survival (OS) in patients with advanced cancers. No biomarkers are available to identify patients that benefit from bevacizumab. A meta-analysis of genome-wide association studies (GWAS) was conducted in 1,520 patients from Phase III trials (CALGB 80303, 40503, 80405 and ICON7), where bevacizumab was randomized to treatment without bevacizumab. We aimed to identify genes and single nucleotide polymorphisms (SNPs) associated with survival independently of bevacizumab treatment or through interaction with bevacizumab. A cause-specific Cox model was used to test the SNP-OS association in both arms combined (prognostic), and the effect of SNPs-bevacizumab interaction on OS (predictive) in each study. The SNP effects across studies were combined using inverse variance. Findings were tested for replication in advanced colorectal and ovarian cancer patients from The Cancer Genome Atlas (TGCA). In the GWAS meta-analysis, patients with rs680949 in PRUNE2 experienced shorter OS compared to patients without it (P = 1.02 × 10-7 , hazard ratio [HR] = 1.57, 95% confidence interval [CI] 1.33-1.86), as well as in TCGA (P = .0219, HR = 1.58, 95% CI 1.07-2.35). In the GWAS meta-analysis, patients with rs16852804 in BARD1 experienced shorter OS compared to patients without it (P = 1.40 × 10-5 , HR = 1.51, 95% CI 1.25-1.82) as well as in TCGA (P = 1.39 × 10-4 , HR = 3.09, 95% CI 1.73-5.51). Patients with rs3795897 in AGAP1 experienced shorter OS in the bevacizumab arm compared to the nonbevacizumab arm (P = 1.43 × 10-5 ). The largest GWAS meta-analysis of bevacizumab treated patients identified PRUNE2 and BARD1 (tumor suppressor genes) as prognostic genes of colorectal and ovarian cancer, respectively, and AGAP1 as a potentially predictive gene that interacts with bevacizumab with respect to patient survival.

This selection from the NCCN Guidelines for Rectal Cancer focuses on management of malignant polyps and resectable nonmetastatic rectal cancer because important updates have been made to these guidelines. These recent updates include redrawing the algorithms for stage II and III disease to reflect new data supporting the increasingly prominent role of total neoadjuvant therapy, expanded recommendations for short-course radiation therapy techniques, and new recommendations for a “watch-and-wait” nonoperative management technique for patients with cancer that shows a complete response to neoadjuvant therapy. The complete version of the NCCN Guidelines for Rectal Cancer, available online at NCCN.org, covers additional topics including risk assessment, pathology and staging, management of metastatic disease, posttreatment surveillance, treatment of recurrent disease, and survivorship.

PURPOSE To evaluate the use of early assessment of chemotherapy responsiveness by positron emission tomography (PET) imaging to tailor therapy in patients with esophageal and esophagogastric junction adenocarcinoma. METHODS After baseline PET, patients were randomly assigned to an induction chemotherapy regimen: modified oxaliplatin, leucovorin, and fluorouracil (FOLFOX) or carboplatin-paclitaxel (CP). Repeat PET was performed after induction; change in maximum standardized uptake value (SUV) from baseline was assessed. PET nonresponders (< 35% decrease in SUV) crossed over to the alternative chemotherapy during chemoradiation (50.4 Gy/28 fractions). PET responders (≥ 35% decrease in SUV) continued on the same chemotherapy during chemoradiation. Patients underwent surgery at 6 weeks postchemoradiation. Primary end point was pathologic complete response (pCR) rate in nonresponders after switching chemotherapy. RESULTS Two hundred forty-one eligible patients received Protocol treatment, of whom 225 had an evaluable repeat PET. The pCR rates for PET nonresponders after induction FOLFOX who crossed over to CP (n = 39) or after induction CP who changed to FOLFOX (n = 50) was 18.0% (95% CI, 7.5 to 33.5) and 20% (95% CI, 10 to 33.7), respectively. The pCR rate in responders who received induction FOLFOX was 40.3% (95% CI, 28.9 to 52.5) and 14.1% (95% CI, 6.6 to 25.0) in responders to CP. With a median follow-up of 5.2 years, median overall survival was 48.8 months (95% CI, 33.2 months to not estimable) for PET responders and 27.4 months (95% CI, 19.4 months to not estimable) for nonresponders. For induction FOLFOX patients who were PET responders, median survival was not reached. CONCLUSION Early response assessment using PET imaging as a biomarker to individualize therapy for patients with esophageal and esophagogastric junction adenocarcinoma was effective, improving pCR rates in PET nonresponders. PET responders to induction FOLFOX who continued on FOLFOX during chemoradiation achieved a promising 5-year overall survival of 53%.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co‐primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Acquired genomic alterations (Acq-GAs), specifically RAS, BRAF, and EGFR-ectodomain mutations and ERBB2 and MET amplifications, are recognized as major mechanisms of resistance to later-line anti–EGFR-antibody therapy in metastatic colorectal cancer (mCRC). However, data regarding emergence of these Acq-GAs under the selective pressure of first-line anti–EGFR-chemotherapy are lacking. We performed next-generation sequencing (Guardant360) on circulating tumor DNA obtained from paired plasma samples (pretreatment and postprogression) from the CALGB/SWOG-80405 trial, which randomly assigned patients with mCRC between first-line chemotherapy with cetuximab (anti–EGFR-chemotherapy) or bevacizumab (anti–VEGF-chemotherapy). The primary objective was to determine the prevalence of Acq-GAs on anti–EGFR-chemotherapy and compare this to the prevalence with anti–VEGF-chemotherapy on trial and pooled estimates (N = 292) seen with later-line anti–EGFR-antibody therapy as reported in the literature. Among the 61 patients on anti–EGFR-chemotherapy, only four (6.6%) developed ≥ 1 Acq-GAs of interest compared with 10.1% (7) on anti–VEGF-chemotherapy (odds ratio, 0.62; 95% CI, 0.20 to 2.11) and 62.0% on anti–EGFR-antibody therapy in later lines (odds ratio, 0.09; 95% CI, 0.03 to 0.23). Acq-GAs, classically associated with anti–EGFR-antibody resistance in later lines ( RAS, BRAF, and EGFR-ectodomain mutations; ERBB2 and MET amplifications), were rare with up-front use of anti–EGFR-chemotherapy indicating divergent resistance mechanisms. These findings have critical translational relevance to timing and value of circulating tumor DNA–guided anti-EGFR rechallenge in patients with mCRC, especially those treated with anti-EGFR therapy upfront.

The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.

Few treatment advances have been observed in recent years for the treatment of advanced colorectal cancer (CRC). The goal remains to find approaches beyond FOLFOX and bevacizumab that will prolong remission. Immunotherapy for patients with microsatellite instability–high tumors represents progress, but this is a very small subset and approximately 30% of patients will not experience response. In locally advanced CRC, good long-term outcomes and manageable toxicity are being achieved with contemporary treatment strategies. Total neoadjuvant therapy, which incorporates induction or consolidation chemotherapy, has improved the treatment of patients with rectal cancer and is now a standard of care, although optimal sequencing is still being debated. Nonoperative management is an emerging option for sphincter preservation, and ongoing studies are evaluating the omission of radiation in select patients.

Abstract Purpose We sought to determine whether adherence to the American Cancer Society (ACS) Nutrition and Physical Activity Guidelines was associated with better bowel function among colon cancer survivors. Methods This prospective cohort study included patients surgically treated for stage I–IV colon cancer enrolled in the Lifestyle and Outcomes after Gastrointestinal Cancer (LOGIC) study between February 2017 and May 2021. Participants were assigned an ACS score (0–6 points) at enrollment. Stool frequency (SF) was assessed every 6 months using the EORTC QLQ-CR29. Higher SF is an indication of bowel function impairment. ACS score at enrollment was examined in relation to SF at enrollment and over a 3-year period. Secondarily, we examined associations between the ACS score components (body mass index, dietary factors, and physical activity) and SF. Multivariable models were adjusted for demographic and surgical characteristics. Results A total of 112 people with colon cancer (59% women, mean age 59.5 years) were included. Cross-sectionally, for every point increase in ACS score at enrollment, the odds of having frequent stools at enrollment decreased by 43% (CI 0.42–0.79; p Conclusions Colon cancer survivors who more closely followed the ACS nutrition and physical activity guidelines had lower SF, an indication of better bowel function. Implications for Cancer Survivors Our findings highlight the value of interventions that support health behavior modification as part of survivorship care for long-term colon cancer survivors.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation–positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org. Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.

Purpose: FOLFOX, FOLFIRI, or FOLFOXIRI chemotherapy with bevacizumab is considered standard first-line treatment option for patients with metastatic colorectal cancer (mCRC). We developed and validated a molecular signature predictive of efficacy of oxaliplatin-based chemotherapy combined with bevacizumab in patients with mCRC. Experimental Design: A machine-learning approach was applied and tested on clinical and next-generation sequencing data from a real-world evidence (RWE) dataset and samples from the prospective TRIBE2 study resulting in identification of a molecular signature, FOLFOXai. Algorithm training considered time-to-next treatment (TTNT). Validation studies used TTNT, progression-free survival, and overall survival (OS) as the primary endpoints. Results: A 67-gene signature was cross-validated in a training cohort (N = 105) which demonstrated the ability of FOLFOXai to distinguish FOLFOX-treated patients with mCRC with increased benefit from those with decreased benefit. The signature was predictive of TTNT and OS in an independent RWE dataset of 412 patients who had received FOLFOX/bevacizumab in first line and inversely predictive of survival in RWE data from 55 patients who had received first-line FOLFIRI. Blinded analysis of TRIBE2 samples confirmed that FOLFOXai was predictive of OS in both oxaliplatin-containing arms (FOLFOX HR, 0.629; P = 0.04 and FOLFOXIRI HR, 0.483; P = 0.02). FOLFOXai was also predictive of treatment benefit from oxaliplatin-containing regimens in advanced esophageal/gastro-esophageal junction cancers, as well as pancreatic ductal adenocarcinoma. Conclusions: Application of FOLFOXai could lead to improvements of treatment outcomes for patients with mCRC and other cancers because patients predicted to have less benefit from oxaliplatin-containing regimens might benefit from alternative regimens.

TPS817 Background: Metastatic disease remains a consistent challenge for patients with gastrointestinal (GI) malignancies. Multiple immune checkpoint inhibitors (ICI) have been FDA approved for several GI indications. Still, patients will progress on these therapies, either immediately or after initial response. Palliative radiation therapy (RT) is an effective treatment that can be delivered to symptomatic metastases. It also has been reported to lead to an abscopal effect, which is an induction of response in a distant tumor. This is thought to result from increased tumor immunogenicity, tumor microenvironment modulation, and immune cell recruitment. Thus, palliative RT could not only relieve symptoms, but also potentially reinvigorate the immune response, prolong ICI efficacy, and delay next-line systemic therapy that carries risks of unknown efficacy and tolerability. Ongoing studies seek to elucidate prognostic and predictive biomarkers of the abscopal effect. However, cohorts of patients with GI malignancies are limited, so there remains a need for research in combining RT and immunotherapy in the context of metastatic GI cancer. ARM-GI aims to study the radiation-augmented immune response in patients with metastatic GI cancers progressing on immunotherapy. Methods: ARM-GI is a phase 2, single arm study. Key eligibility criteria include confirmed metastatic GI malignancy, progressive disease per RECIST v1.1 on any ICI, and at least 2 metastases, one of which can be safely left unirradiated. The target prescription dose is 30 Gy in 5 fractions to symptomatic sites through intensity modulated RT or stereotactic body RT. Patients will continue the same immunotherapy after RT and be evaluated per RECIST v1.1 longitudinally. The primary endpoint is overall response rate (ORR) per RECIST v1.1. Secondary endpoints include ORR per iRECIST, progression free survival, overall survival, local control in radiated lesion(s), effect of distant radiation on unirradiated target lesions, incidence of new metastatic lesions, safety by CTCAE v5.0, and time to new systemic therapy. The study will enroll 28 patients, with recruitment ongoing. Serial peripheral blood samples are collected for exploratory studies that will analyze for association with disease response and quantification of changes in circulating immune cell subsets after RT compared to baseline. Clinical trial information: NCT04221893 .

TPS630 Background: Hepatocellular Carcinoma (HCC) is among the most common types and leading causes of cancer death globally, and the incidence is on the rise. For patients with advanced hepatocellular carcinoma (HCC), immune checkpoint inhibitors (ICI) in combination with anti-angiogenic agents or other ICI improve survival compared with tyrosine kinase inhibition. Though ICI-based regimens can achieve prolonged responses in some patients and prolong overall survival, only a subset of patients achieve durable responses. There is an urgent need for strategies to overcome primary and acquired resistance. Many of these patients have symptomatic sites of disease which could benefit from local palliative radiotherapy. Radiotherapy also has the potential to elicit an abscopal immune response when combined with ICI. We hypothesize that combining Radiation Treatment (RT) with Durvalumab or the combination of Durvalumab + Tremelimumab (combination D+T in STRIDE regimen showed OS improvement in HIMALAYA trial in 1st line HCC) will achieve a meaningful response rate in advanced HCC patients after progression on other ICI-based therapies. Methods: This is an open label, single center, two-arm, non-comparative phase II trial. Key eligibility criteria are; histologically-diagnosed HCC with progression during or after prior PD-(L)1 checkpoint inhibitor immunotherapy and at least 1 RECIST 1.1-measurable tumor present which has not received RT or other local therapy prior to enrollment, ECOG 0-1, and Child Pugh score of A, B7, or B8. Patients are assigned sequentially to either single-agent durvalumab initiated starting 3 to 10 days after completing RT (25 Gy in 5 fractions to 1-5 sites of disease), at fixed dose of 1500 mg IV every 28 days, or a single fixed dose of tremelimumab of 300 mg IV administered on Day 1, initiated within 3-10 days of completing RT, in combination with durvalumab at fixed dose of 1500 mg IV every 28 days; for up to 24 months or until confirmed radiographic progression. The primary end point is overall response rate (ORR) and secondary endpoints include proportion of participants with adverse events, overall survival, progression free survival and duration of response. Exploratory endpoints include profiling of peripheral blood mononuclear cell immune cells and plasma biomarkers. We plan to accrue 30 patients to this study, 15 to each Arm, to evaluate ORR which would allow us to detect at least a 20% ORR, which would be a clinically meaningful improvement in efficacy in this population with otherwise poor treatment options assuming a statistical power of 87% and a directional 5% statistical significance level based upon an exact binomial test. The trial is open and enrolling. Clinical trial information: NCT04430452 .

The American Cancer Society and American Institute for Cancer Research recommend that cancer survivors limit intake of red and processed meats. This recommendation is based on consistent associations between red and processed meat intake and cancer risk, particularly risk of colorectal cancer, but fewer data are available on red and processed meat intake after cancer diagnosis.To examine whether intake of unprocessed red meat or processed meat is associated with risk of cancer recurrence or mortality in patients with colon cancer.This prospective cohort study used data from participants with stage III colon cancer enrolled in the Cancer and Leukemia Group B (CALGB 89803/Alliance) trial between 1999 and 2001. The clinical database for this analysis was frozen on November 9, 2009; the current data analyses were finalized in December 2021.Quartiles of unprocessed red meat and processed meat intake assessed using a validated food frequency questionnaire during and 6 months after chemotherapy.Hazard ratios (HRs) and 95% CIs for risk of cancer recurrence or death and all-cause mortality.This study was conducted among 1011 patients with stage III colon cancer. The median (IQR) age at enrollment was 60 (51-69) years, 442 patients (44%) were women, and 899 patients (89%) were White. Over a median (IQR) follow-up period of 6.6 (1.9-7.5) years, we observed 305 deaths and 81 recurrences without death during follow-up (386 events combined). Intake of unprocessed red meat or processed meat after colon cancer diagnosis was not associated with risk of recurrence or mortality. The multivariable HRs comparing the highest vs lowest quartiles for cancer recurrence or death were 0.84 (95% CI, 0.58-1.23) for unprocessed red meat and 1.05 (95% CI, 0.75-1.47) for processed meat. For all-cause mortality, the corresponding HRs were 0.71 (95% CI, 0.47-1.07) for unprocessed red meat and 1.04 (95% CI, 0.72-1.51) for processed meat.In this cohort study, postdiagnosis intake of unprocessed red meat or processed meat was not associated with risk of recurrence or death among patients with stage III colon cancer.

BACKGROUND: Individualized estimates of the risk of recurrence in colon cancer patients are needed that reflect current medical practice and available treatment options. METHODS: Three validation studies of the 12-gene colon recurrence score assay were used with pre-specified patient-specific meta-analysis (PSMA) methods to integrate the 12-gene Oncotype DX Colon Recurrence Score result (RS) with the clinical and pathology risk factors stage, T-stage, mis-match repair (MMR) status, and number of nodes examined to calculate individualized recurrence risk estimates. Baseline risk estimation used the most recent studies, so the risk estimates reflect current medical practice. The effect of fluorouracil (5FU) was estimated with a meta-analysis of two studies. The effect of oxaliplatin was estimated using one of the RS assay validation studies, in which patients were randomized to 5FU with or without oxaliplatin. RESULTS: The RS result and each of the clinical-pathologic factors provided independent prognostic information for recurrence. Among stage II, T3, MMR-proficient patients with ≥12 nodes examined (the most common scenario), patients with RS ≤30 (approximately 48%) have estimated 5-year recurrence risk ≤10% with surgery alone. Among stage IIIA/B, T3, MMR-deficient patients with ≥12 nodes examined, patients with RS ≤19 (approximately 14%) have an estimated 5-year recurrence risk ≤10% with surgery alone. Among stage IIIA/B, T3, MMR-proficient patients with ≥12 nodes examined, those with RS ≤14 (approximately 6%) have estimated 5-year recurrence risk ≤10% with 5FU alone. DISCUSSION: The PSMA integrates the 12-gene colon RS result with clinical and pathology factors to provide individualized recurrence risk estimates that reflect current medical practice. The risk estimates are in a range that may help inform treatment decisions for a substantial number of stage II and stage III patients.