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PURPOSE: High densities of tumor infiltrating CD3 and CD8 T-cells are associated with superior prognosis in colorectal cancer (CRC). Their value as predictors of benefit from adjuvant chemotherapy is uncertain. PATIENTS AND METHODS: Tumor tissue from 868 patients in the QUASAR trial (adjuvant fluorouracil/folinic acid v observation in stage II/III CRC) was analyzed by CD3 and CD8 immunohistochemistry. Pathologists, assisted by artificial intelligence, calculated CD3 and CD8 cell densities (cells/mm2) in the core tumor (CT) and invasive margin (IM). Participants were randomly partitioned into training and validation sets. The primary outcome was recurrence-free interval (RFI), 2-year RFI for assessment of biomarker-treatment interactions. Maximum-likelihood methods identified optimal high-risk/low-risk group cutpoints in the training set. Prognostic analyses were repeated in the validation set. RESULTS: In the training set, the recurrence rate in the high-risk group was twice that in the low-risk group for all measures (CD3-CT: rate ratio [RR], 2.00, P = .0008; CD3-IM: 2.38, P < .00001; CD8-CT: 2.17, P = .0001; CD8-IM: 2.13, P = .0001). This was closely replicated in the validation set (RR, 1.96, 1.79, 1.72, 1.72, respectively). In multivariate analyses, prognostic effects were similar in colon and rectal cancers, and in stage II and III disease. Proportional reductions in recurrence with adjuvant chemotherapy were of similar magnitude in the high- and low-recurrence risk groups. Combining information from CD3-IM and CD3-CT (CD3 Score) generated high-, intermediate-, and low-risk groups with numbers needed to treat (NNTs) to prevent one disease recurrence being 11, 21, and 36, respectively. CONCLUSION: Recurrence rates in the high-risk CD3/CD8 groups are twice those in the low-risk groups. Proportional reductions with chemotherapy are similar, allowing NNTs derived in QUASAR to be updated using contemporary, nonrandomized data sets.

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PURPOSE: High tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in a retrospective analysis of clinical trial data. Here, AREG/EREG IHC was analyzed in a cohort of patients who received anti-EGFR therapy as part of routine care, including key clinical contexts not investigated in the previous analysis. EXPERIMENTAL DESIGN: Patients who received panitumumab or cetuximab ± chemotherapy for treatment of RAS wild-type mCRC at eight UK cancer centers were eligible. Archival formalin-fixed paraffin-embedded tumor tissue was analyzed for AREG and EREG IHC in six regional laboratories using previously developed artificial intelligence technologies. Primary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 494 of 541 patients (91.3%) had adequate tissue for analysis. A total of 45 were excluded after central extended RAS testing, leaving 449 patients in the primary analysis population. After adjustment for additional prognostic factors, high AREG/EREG expression (n = 360; 80.2%) was associated with significantly prolonged PFS [median: 8.5 vs. 4.4 months; HR, 0.73; 95% confidence interval (CI), 0.56-0.95; P = 0.02] and OS [median: 16.4 vs. 8.9 months; HR, 0.66 95% CI, 0.50-0.86; P = 0.002]. The significant OS benefit was maintained among patients with right primary tumor location (PTL), those receiving cetuximab or panitumumab, those with an oxaliplatin- or irinotecan-based chemotherapy backbone, and those with tumor tissue obtained by biopsy or surgical resection. CONCLUSIONS: High tumor AREG/EREG expression was associated with superior survival outcomes from anti-EGFR therapy in mCRC, including in right PTL disease. AREG/EREG IHC assessment could aid therapeutic decisions in routine practice. See related commentary by Randon and Pietrantonio, p. 4021.

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AIM: FOxTROT1 established a new standard of care for managing locally advanced colon cancer (CC) with neoadjuvant chemotherapy (NAC). Six weeks of neoadjuvant oxaliplatin and fluoropyrimidine (OxFp) chemotherapy was associated with greater 2-year disease-free survival (DFS) when compared with proceeding straight to surgery (STS). There is now a need to refine the use of NAC and identify those most likely to benefit. FOxTROT2 will aim to investigate NAC in older adults and those with frailty. FOxTROT3 will aim to assess whether intensified triplet NAC provides additional benefits over OxFp. METHOD: FOxTROT2 and FOxTROT3 are international, open-label, phase III randomized controlled trials. Eligible patients will be identified by the multidisciplinary team. Patient age, frailty and comorbidities will be considered to guide trial entry. Participants will be randomized 2:1 to the intervention or control arm: 6 weeks of dose-adapted neoadjuvant OxFp versus STS in FOxTROT2 and 6 weeks of neoadjuvant modified oxaliplatin, 5-fluorouracil and irinotecan versus OxFp in FOxTROT3. The primary endpoint in FOxTROT2 is 3-year DFS. In FOxTROT3, tumour regression grade and 3-year DFS are co-primary endpoints. DISCUSSION: FOxTROT2 and FOxTROT3 will establish the FOxTROT platform, a key part of our long-term strategy to develop neoadjuvant treatments for CC. FOxTROT2 will investigate NAC in a population under-represented in FOxTROT1 and wider research. FOxTROT3 will assess whether it is possible to induce greater early tumour responses and whether this translates to superior long-term outcomes. Looking ahead, the FOxTROT platform will facilitate further trial comparisons and extensive translational research to optimize the use of NAC in CC.

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PURPOSE: High tumor mRNA levels of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are associated with anti-EGFR agent response in metastatic colorectal cancer (mCRC). However, ligand RNA assays have not been adopted into routine practice due to issues with analytic precision and practicality. We investigated whether AREG/EREG IHC could predict benefit from the anti-EGFR agent panitumumab. EXPERIMENTAL DESIGN: Artificial intelligence algorithms were developed to assess AREG/EREG IHC in 274 patients from the PICCOLO trial of irinotecan with or without panitumumab (Ir vs. IrPan) in RAS wild-type mCRC. The primary endpoint was progression-free survival (PFS). Secondary endpoints were RECIST response rate (RR) and overall survival (OS). Models were repeated adjusting separately for BRAF mutation status and primary tumor location (PTL). RESULTS: High ligand expression was associated with significant PFS benefit from IrPan compared with Ir [8.0 vs. 3.2 months; HR, 0.54; 95% confidence interval (CI), 0.37-0.79; P = 0.001]; whereas low ligand expression was not (3.4 vs. 4.4 months; HR, 1.05; 95% CI, 0.74-1.49; P = 0.78). The ligand-treatment interaction was significant (P interaction = 0.02) and remained significant after adjustment for BRAF-mutation status and PTL. Likewise, RECIST RR was significantly improved in patients with high ligand expression (IrPan vs. Ir: 48% vs. 6%; P < 0.0001) but not those with low ligand expression (25% vs. 14%; P = 0.10; P interaction = 0.01). The effect on OS was similar but not statistically significant. CONCLUSIONS: AREG/EREG IHC identified patients who benefitted from the addition of panitumumab to irinotecan chemotherapy. IHC is a practicable assay that may be of use in routine practice.

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OBJECTIVES: Patient-reported symptoms correlate poorly with mucosal inflammation. Clinical decision-making may, therefore, not be based on objective evidence of disease activity. We conducted a study to determine factors associated with clinical decision-making in a secondary care inflammatory bowel disease (IBD) population, using a cross-sectional design. METHODS: Decisions to request investigations or escalate medical therapy were recorded from outpatient clinic encounters in a cohort of 276 patients with ulcerative colitis (UC) or Crohn's disease (CD). Disease activity was assessed using clinical indices, self-reported flare or faecal calprotectin ≥ 250 µg/g. Demographic, disease-related and psychological factors were assessed using validated questionnaires. Logistic regression was performed to determine the association between clinical decision-making and symptoms, mucosal inflammation and psychological comorbidity. RESULTS: Self-reported flare was associated with requesting investigations in CD [odds ratio (OR) 5.57; 95% confidence interval (CI) 1.84-17.0] and UC (OR 10.8; 95% CI 1.8-64.3), but mucosal inflammation was not (OR 1.62; 95% CI 0.49-5.39; and OR 0.21; 95% CI 0.21-1.05, respectively). Self-reported flare (OR 7.96; 95% CI 1.84-34.4), but not mucosal inflammation (OR 1.67; 95% CI 0.46-6.13) in CD, and clinical disease activity (OR 10.36; 95% CI 2.47-43.5) and mucosal inflammation (OR 4.26; 95% CI 1.28-14.2) in UC were associated with escalation of medical therapy. Almost 60% of patients referred for investigation had no evidence of mucosal inflammation. CONCLUSIONS: Apart from escalation of medical therapy in UC, clinical decision-making was not associated with mucosal inflammation in IBD. The use of point-of-care calprotectin testing may aid clinical decision-making, improve resource allocation and reduce costs in IBD.

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BACKGROUND & AIMS: Symptoms compatible with irritable bowel syndrome (IBS) are common in patients with inflammatory bowel disease (IBD), but it is unclear whether this relates to occult IBD activity. We attempted to resolve this issue in a secondary care population by using a cross-sectional study design. METHODS: We analyzed Rome III IBS symptoms, disease activity indices, and psychological, somatization, and quality of life data from 378 consecutive, unselected adult patients with IBD seen in clinics at St James's University Hospital in Leeds, United Kingdom from November 2012 through June 2015. Participants provided a stool sample for fecal calprotectin (FC) analysis; levels ≥250 µg/g were used to define mucosal inflammation. By using symptom data and FC levels we identified 4 distinct groups of patients: those with true IBS-type symptoms (IBS-type symptoms with FC levels <250 µg/g, regardless of disease activity indices), quiescent IBD (no IBS-type symptoms with FC levels <250 µg/g, regardless of disease activity indices), occult inflammation (normal disease activity indices and FC levels ≥250 µg/g, regardless of IBS symptom status), or active IBD (abnormal disease activity indices with FC levels ≥250 µg/g, regardless of IBS symptom status). We compared characteristics between these groups. RESULTS: Fifty-seven of 206 patients with Crohn's disease (27.7%) and 34 of 172 patients with ulcerative colitis (19.8%) had true IBS-type symptoms. Levels of psychological comorbidity and somatization were significantly higher among patients with true IBS-type symptoms than patients with quiescent IBD or occult inflammation. Quality of life levels were also significantly reduced compared with patients with quiescent disease or occult inflammation and were similar to those of patients with active IBD. By using FC levels ≥100 µg/g to define mucosal inflammation, we found a similar effect of IBS-type symptoms on psychological health and quality of life. CONCLUSIONS: In a cross-sectional study, we identified a distinct group of patients with IBD and genuine IBS-type symptoms in the absence of mucosal inflammation. These symptoms had negative effects on psychological well-being and quality of life to the same degree as active IBD. New management strategies are required for this patient group.

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OBJECTIVES: There is a move toward patient-reported outcome measures as end points in clinical trials of novel therapies for inflammatory bowel disease (IBD). However, the association between patient-reported symptoms and mucosal inflammation, and the influence of psychological factors, remains unclear. We examined this in a secondary care population. METHODS: Validated patient-reported disease activity indices were used to define clinically active disease in a cohort of 356 patients with ulcerative colitis (UC) or Crohn's disease (CD). A fecal calprotectin ≥250 µg/g was used to define active mucosal inflammation. The hospital anxiety and depression scale (HADS) and patient health questionnaire (PHQ)-15 were used to assess for anxiety, depression, or somatization, respectively. Logistic regression analysis was performed to determine the association between symptoms, mucosal inflammation, and psychological comorbidity. RESULTS: Clinical disease activity was associated with mucosal inflammation in UC (odds ratio (OR) 3.36; 95% confidence interval (CI) 1.34-8.47) but not in CD (OR 1.69; 95% CI 0.74-3.83). Depression in UC (OR 1.21 per 1-point increase in HADS; 95% CI 1.02-1.44) and somatization in UC (OR 1.17 per 1-point increase in PHQ-15; 95% CI 1.03-1.33) and CD (OR 1.31 per 1-point increase in PHQ-15; 95% CI 1.13-1.52) were associated with clinical disease activity. Overall, patient-reported symptoms yielded poor positive predictive values for mucosal inflammation in both CD and UC. CONCLUSIONS: Patient-reported symptoms and the Harvey-Bradshaw index were poor predictors of mucosal inflammation in CD. Psychological comorbidity was associated with gastrointestinal symptom-reporting. A shift in the focus of IBD management toward one addressing both psychological and physical well-being is required.

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