Loss of expression of ATM is associated with worse prognosis in colorectal cancer and loss of Ku70 expression is associated with CIN

Repair of double strand DNA breaks (DSBs) is pivotal in maintaining normal cell division and disruption of this system has been shown to be a key factor in carcinogenesis. Loss of expression of the DSB repair proteins have previously been shown to be associated with poorer survival in colorectal cancer. We wished to ascertain the relationship of altered expression of the DSB repair proteins γ-H2AX (gamma-H2AX), ATM and Ku70 with biological and clinico-pathological features of colorectal cancer. 908 tumours from the VICTOR clinical trial of stage II/III colorectal cancer were analysed for expression of γ-H2AX, ATM and Ku70 using immunohistochemistry. Expression levels were correlated with CIN and with diseasefree survival, correcting for microsatellite instability, BRAF/KRAS mutation status, Dukes stage, chemo/radiotherapy, age, gender and tumour location. Down-regulated Ku70 expression was associated with chromosomal instability (p=0.029) in colorectal cancer. Reduced ATM expression was an independent marker of poor disease-free survival (HR=1.67, 95% CI 1.11-2.50, p=0.015). For Ku70, further studies are required to investigate the potential relationship of non-homologous end joining with chromosomal instability. Loss of ATM expression might serve as a biomarker of poor prognosis in colorectal cancer

Whole-genome methylation analysis of benign and malignant colorectal tumours

Changes in DNA methylation, whether hypo- or hypermethylation, have been shown to be associated with the progression of colorectal cancer. Methylation changes substantially in the progression from normal mucosa to adenoma and to carcinoma. This phenomenon has not been studied extensively and studies have been restricted to individual CpG islands, rather than taking a whole-genome approach. We aimed to study genome-wide methylation changes in colorectal cancer. We obtained 10 fresh-frozen normal tissue-cancer sample pairs, and five fresh-frozen adenoma samples. These were run on the lllumina HumanMethylation27 whole-genome methylation analysis system. Differential methylation between normal tissue, adenoma and carcinoma was analysed using Bayesian regression modelling, gene set enrichment analysis (GSEA) and hierarchical clustering (HC). The highest-rated individual gene for differential methylation in carcinomas versus normal tissue and adenomas versus normal tissue was GRASP (padjusted  = 1.59 × 10(-5) , BF = 12.62, padjusted  = 1.68 × 10(-6) , BF = 14.53). The highest-rated gene when comparing carcinomas versus adenomas was ATM (padjusted  = 2.0 × 10(-4) , BF = 10.17). Hierarchical clustering demonstrated poor clustering by the CIMP criteria for methylation. GSEA demonstrated methylation changes in the Netrin-DCC and SLIT-ROBO pathways. Widespread changes in DNA methylation are seen in the transition from adenoma to carcinoma. The finding that GRASP, which encodes the general receptor for phosphoinositide 1-associated scaffold protein, was differentially methylated in colorectal cancer is interesting. This may be a potential biomarker for colorectal cancer

Assessment of a staging system for sigmoid colon cancer based on tumor deposits and extramural venous invasion on computed tomography

Importance: Pre-operative TNM stratification of colon cancer on computed tomography (CT) at present does not identify patients at high risk of recurrence that could be selected for pre-operative treatment. Objective: To evaluate the prognostic importance of CT imaging features of sigmoid colon cancer. Design: Retrospective database analysis performed April 2019. Setting Tertiary centre receiving international and national referrals for colorectal cancer. Participants: Patients undergoing bowel resection for sigmoid colon cancer between 2006 and 2015. Main Outcome and Measures: Cox regression analysis was performed to investigate CT risk factors associated with recurrence. Kaplan Meier survival plots were calculated for disease free survival (DFS) using CT staging systems. Results: Among the 414 patients included with sigmoid cancer with a median follow up of 61 months, 122 patients developed recurrence (29.5%). On multivariate analysis, nodal disease was not prognostic and only TDs (HR 1.90) and EMVI (HR 1.97) on CT were associated with recurrence. Significant differences in DFS were found by CT-T3 substage classification (HR 1.88, 95% CI(1.32-2.68)) but not CT-TNM (HR 1.55, 95% CI(0.94-255)). The presence of EMVI or TDs on CT (HR 2.45, 95% CI(1.68-3.56)) best identified poor outcome. Conclusions and Relevance: T3 substaging and detection of TDs or EMVI on CT were prognostic factors for DFS, whereas TNM and nodal staging on CT held no prognostic value. TDV staging of sigmoid colon cancer is superior to TNM on CT and could be used to pre-operatively identify patients at high risk of recurrence

Interobserver agreement of radiologists assessing the response of rectal cancers to preoperative chemoradiation using the MRI tumour regression grading (mrTRG)

AIM: To investigate whether the magnetic resonance imaging (MRI) tumour regression grading (mrTRG) scale can be taught effectively resulting in a clinically reasonable interobserver agreement (>0.4; moderate to near perfect agreement). MATERIALS AND METHODS: This study examines the interobserver agreement of mrTRG, between 35 radiologists and a central reviewer. Two workshops were organised for radiologists to assess regression of rectal cancers on MRI staging scans. A range of mrTRGs on 12 patient scans were used for assessment. RESULTS: Kappa agreement ranged from 0.14–0.82 with a median value of 0.57 (95% CI: 0.37–0.77) indicating good overall agreement. Eight (26%) radiologists had very good/near perfect agreement (κ>0.8). Six (19%) radiologists had good agreement (0.8≥κ>0.6) and a further 12 (39%) had moderate agreement (0.6≥κ>0.4). Five (16%) radiologists had a fair agreement (0.4≥κ>0.2) and two had poor agreement (0.2>κ). There was a tendency towards good agreement (skewness: 0.92). In 65.9% and 90% of cases the radiologists were able to correctly highlight good and poor responders, respectively. CONCLUSIONS: The assessment of the response of rectal cancers to chemoradiation therapy may be performed effectively using mrTRG. Radiologists can be taught the mrTRG scale. Even with minimal training, good agreement with the central reviewer along with effective differentiation between good and intermediate/poor responders can be achieved. Focus should be on facilitating the identification of good responders. It is predicted that with more intensive interactive case-based learning a κ>0.8 is likely to be achieved. Testing and retesting is recommended

Defining response to radiotherapy in rectal cancer using magnetic resonance imaging and histopathological scales

Aim: To define good and poor regression using pathology and MRI regression scales after neo-adjuvant chemotherapy for rectal cancer. Methods: A systematic review of all studies up to December 2015, without language restriction that were identified from MEDLINE, Cochrane Controlled Trials Register (1960–2015), and EMBASE (1991–2015). Searches were performed of article bibliographies and conference abstracts. MeSH and text words, included “tumour regression”, “mrTRG”, “poor response” and “colorectal cancers”. Clinical studies using either MRI or histopathological TRG scales to define good and poor responders were included in relation to outcomes (local (LR), distant recurrence (DR), disease free (DFS), overall survival (OS)). There was no age restriction to included patients nor stage of cancer.Data was extracted by two authors independently using pre-defined outcome measures. Results: Quantitative data (prevalence) were extracted and analysed according to meta-analytical techniques using comprehensive meta-analysis. Qualitative data (LR, DR, DFS &OS) were presented as ranges. The overall proportion of poor responders after neo-adjuvant CRT was 37.7% (CI: 30.1 to 45.8). There were 19 different reported histopathological scales and one MRI regression scale (mrTRG). Clinical studies used nine and six histopathological scales for poor and good responders respectively. All studies using MRI to define good and poor response used one scale. The most common histopathological definition for good response was the Mandard grades 1&2 or Dworak grades 3&4; Mandard 3,4&5 and Dworak 0,1&2 were used for poor response. For histopathological grades, the 5-year outcomes for poor responders were LR 3.4-4.3%, DR 14.3-20.3%, DFS 61.7-68.1% and OS 60.7-69.1. Good pathological response 5-year outcomes were LR, 0-1.8%; DR, 0-11.6%; DFS, 78.4-86.7%; and, OS, 77.4-88.2%. A poor response on MRI (mrTRG 4,5) resulted in 5-year LR 4-29%, DR 9%, DFS 31-59% and OS 27-68%. The 5-year outcomes with a good response on MRI (mrTRG 1,2 & 3) was LR 1-14%, DR 3%, DFS 64-83% and OS 72-90%. Conclusions: For histopathology regression assessment Mandard1,2/Dworak3,4 should be used for good and Mandard3,4,5/Dworak0,1,2 for poor response. MRI indicates good and poor response by mrTRG1-3 and mrTRG4-5 respectively

From diagnosis of colorectal cancer to diagnosis of Lynch syndrome: The RM Partners quality improvement project.

AIM: The UK National Institute for Health and Care Excellence guideline DG27 recommends universal testing for Lynch syndrome (LS) in all newly diagnosed colorectal cancer (CRC) patients. However, DG27 guideline implementation varies significantly by geography. This quality improvement project (QIP) was developed to measure variation and deliver an effective diagnostic pathway from diagnosis of CRC to diagnosis of LS within the RM Partners (RMP) West London cancer alliance. METHOD: RM Partners includes a population of 4 million people and incorporates nine CRC multidisciplinary teams (MDTs), overseen by a Pathway Group, and three regional genetic services, managing approximately 1500 new CRC cases annually. A responsible LS champion was nominated within each MDT. A regional project manager and nurse practitioner were appointed to support the LS champions, to develop online training packages and patient consultation workshops. MDTs were supported to develop an 'in-house' mainstreaming service to offer genetic testing in their routine oncology clinics. Baseline data were collected through completion of the LS pathway audit of the testing pathway in 30 consecutive CRC patients from each CRC MDT, with measurement of each step of the testing pathway. Areas for improvement in each MDT were identified, delivered by the local champion and supported by the project team. RESULTS: Overall, QIP measurables improved following the intervention. The Wilcoxon signed rank test revealed significant differences with strong effect sizes on the percentile of CRC cases undergoing mismatch repair (MMR) testing in endoscopic biopsies (p = 0.008), further testing with either methylation or BRAF V600E (p = 0/03) and in effective referral for genetic testing (from 10% to 74%; p = 0.02). During the QIP new mainstreaming services were developed, alongside the implementation of systematic and robust testing pathways. These pathways were tailored to the needs of each CRC team to ensure that patients with a diagnosis of CRC had access to testing for LS. Online training packages were produced which remain freely accessible for CRC teams across the UK. CONCLUSION: The LS project was completed by April 2022. We have implemented a systematic approach with workforce transformation to facilitate identification and 'mainstreamed' genetic diagnosis of LS. This work has contributed to the development of a National LS Transformation Project in England which recommends local leadership within cancer teams to ensure delivery of diagnosis of LS and integration of genomics into clinical practice

MRI-Diagnosed Tumour Deposits and EMVI Status Have Superior Prognostic Accuracy to Current Clinical TNM Staging in Rectal Cancer.

BACKGROUND DATA: MRI assessment of rectal cancer not only assesses tumour depth and surgical resectability but also extramural disease which affects prognosis. We have observed that non-nodal tumour nodules (tumour deposits; mrTDs) have a distinct MRI appearance compared to lymph node metastases (mrLNMs). OBJECTIVE: We aimed to assess whether mrTDs and mrLNMs have different prognostic implications and compare these to other known prognostic markers. METHODS: This was a retrospective cohort study of 233 patients undergoing resection for rectal cancer from January 2007-October 2015. Data were obtained from electronic records and MRIs blindly re-reported. Survival was determined using Kaplan-Meier method. Prognostic markers were evaluated using Cox regression and competing risks analysis. Inter-observer agreement for mrTD was measured using Cohen's Kappa. RESULTS: On multivariable analysis, baseline mrTD/mrEMVI (extramural venous invasion) status was the only significant MRI factor for adverse survival (HR 2.36 (1.54-3.61) for OS, 2.37 (1.47-3.80) for DFS (both p < 0.001), superseding T and N categories. mrLNMs were associated with good prognosis (HR 0.50 (0.31-0.80)p= 0.004 for OS, 0.60 (0.40-0.90)p = 0.014 for DFS). On multivariable analysis, mrTDs/mrEMVI were strongly associated with distant recurrence (HR 6.53 (2.52-16.91) p = < 0.001) whereas T and N category were not. In a subgroup analysis of post-treatment MRIs in post-chemoradiotherapy (CRT) patients, mrTD/mrEMVI status was again the only significant prognostic factor; furthermore those who showed a good treatment response had a prognosis similar to patients who were negative at baseline. Inter-observer agreement for detection of mrTDs was κ0.77 and κ0.83. CONCLUSION: Current MRI staging predicting T and N status does not adequately predict prognosis. Positive mrTD/mrEMVI status has greater prognostic accuracy and would be superior in determining treatment and follow-up protocols. CRT may be a highly effective treatment strategy in mrTD/mrEMVI positive patients

Prioritisation by FIT to mitigate the impact of delays in the 2-week wait colorectal cancer referral pathway during the COVID-19 pandemic: a UK modelling study

OBJECTIVE: To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic. DESIGN: We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval. RESULTS: Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%. CONCLUSIONS: Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the appreciable false-negative rate of FIT in symptomatic patients means most colonoscopies will still be required

Prioritisation by FIT to mitigate the impact of delays in the 2-week wait colorectal cancer referral pathway during the COVID-19 pandemic: a UK modelling study

OBJECTIVE: To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic. DESIGN: We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval. RESULTS: Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%. CONCLUSIONS: Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the appreciable false-negative rate of FIT in symptomatic patients means most colonoscopies will still be required

Faecal immunochemical testing (FIT) in patients with signs or symptoms of suspected colorectal cancer (CRC): a joint guideline from the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and the British Society of Gastroenterology (BSG)

Faecal immunochemical testing (FIT) has a high sensitivity for the detection of colorectal cancer (CRC). In a symptomatic population FIT may identify those patients who require colorectal investigation with the highest priority. FIT offers considerable advantages over the use of symptoms alone, as an objective measure of risk with a vastly superior positive predictive value for CRC, while conversely identifying a truly low risk cohort of patients. The aim of this guideline was to provide a clear strategy for the use of FIT in the diagnostic pathway of people with signs or symptoms of a suspected diagnosis of CRC. The guideline was jointly developed by the Association of Coloproctology of Great Britain and Ireland/British Society of Gastroenterology, specifically by a 21-member multidisciplinary guideline development group (GDG). A systematic review of 13 535 publications was undertaken to develop 23 evidence and expert opinion-based recommendations for the triage of people with symptoms of a suspected CRC diagnosis in primary care. In order to achieve consensus among a broad group of key stakeholders, we completed an extended Delphi of the GDG, and also 61 other individuals across the UK and Ireland, including by members of the public, charities and primary and secondary care. Seventeen research recommendations were also prioritised to inform clinical management