Erin Leigh Symonds

With rising global incidence and improved survival, colorectal cancer (CRC) survivors face an increasing risk of developing multiple primary cancers (MPCs). Despite the growing clinical significance, the epidemiology, molecular basis and optimal clinical management of MPCs remain incompletely understood. This narrative review summarises historical perspectives on the definition of MPCs and synthesises current epidemiological, clinical and molecular evidence on MPCs among CRC survivors, focusing on incidence, risk factors, biological mechanisms, mortality and clinical implications of MPCs in CRC survivors. Available evidence indicate that up to 20% of CRC survivors develop one or more subsequent MPCs, with risk influenced by age at diagnosis of the index CRC, sex, tumour characteristics, comorbidities and variation in tumour coding practices. Survivors diagnosed before the age of 50 years have the highest risk of MPCs. The most commonly reported MPCs include gastrointestinal, prostate, breast, lung, urinary tract, haematological and gynaecological cancers. The presence of MPCs is associated with substantially poorer outcomes and increased mortality, with deaths frequently attributable to lung, gastrointestinal, prostate, urinary tract and haematological cancers. The molecular mechanisms underlying MPC development are poorly understood. Although germline pathogenic variants account for a subset of cases, evidence suggest that somatic mutations, tumour mutational burden and field cancerisation may contribute to the development of multiple malignancies. However, no consistent molecular drivers of MPCs have been identified. Clinical management is further complicated by the absence of evidence‐based guidelines, under‐representation of cancer survivors in clinical trials, biological heterogeneity of tumours and the complexity of synchronous and metachronous disease presentations. In conclusion, MPCs represent an increasingly important challenge in CRC survivorship and contribute substantially to long‐term morbidity and mortality. Future advances will require integration of large‐scale clinical and molecular datasets, improved understanding of underlying biological mechanisms and development of risk‐stratified surveillance and treatment strategies. Progress in preclinical disease models and targeted therapies may ultimately improve outcomes for the growing survivor population.

Most population colorectal cancer (CRC) screening programs use the faecal immunochemical test (FIT), which quantifies occult haemoglobin in faeces and has proven to be effective in detecting and reducing CRC incidence and mortality. Sessile serrated lesions (SSLs) account for up to 30% of sporadic CRC, yet FIT has low sensitivity to detect them. Faecal microbial biomarkers may improve their detection, but FIT samples have not previously been used to study the SSL microbiome. We asked whether FIT samples preserve the faecal microbiome as accurately as fresh collection, and whether they can reveal a microbial signature of SSL. We first reanalysed a published dataset of paired FIT and fresh faecal samples from the same participants. Donor identity explained 63.5% of compositional variance compared with 16.7% for collection method, indicating that FIT preserves the donor-specific signature on which biomarker discovery depends. We then generated shotgun metagenomes from FIT samples of 24 adults scheduled for diagnostic colonoscopy, twelve with at least one clinically significant SSL and twelve with no neoplasia (NN) and compared each group with a published fresh faeces cohort matched on colonoscopy outcome. Collection method explained 6.3% to 7.6% of variance, and no individual species was significantly differentially abundant between methods. Between SSL and NN FIT samples, community structure did not significantly differ, and conservative differential abundance analysis returned no results. More permissive count-based models suggested a depletion of fermentative commensals in SSL. Functionally, SSL samples encoded significantly fewer KEGG orthologs and less polyamine biosynthesis capacity, while orthologs carried by several Bifidobacterium species were more abundant. Many depleted functions reflected Enterobacteriaceae gene content concentrated in a few control samples. No single feature was diagnostic on its own. A multi-feature signature, confirmed in larger cohorts and applied to samples that screening programs already collect, may increase the detection rate of SSLs.

Background: Measurement of faecal haemoglobin (f‐Hb) using the faecal immunochemical test (FIT) in population screening for colorectal cancer (CRC) has reduced cancer‐related incidence and mortality. However, temperature‐induced f‐Hb degradation can decrease FIT accuracy. This study assessed the f‐Hb preservation capacity of a new FIT Hb‐stabilising buffer at different temperatures and durations. Methods: Fresh whole faecal samples from individuals with active colorectal bleeding were used for collection of samples using the OC‐Sensor FIT (EIKEN CHEMICAL CO. LTD, Japan) containing either the standard (SOC3) or new formulation (SOC4) buffer. Pooled faeces‐buffer mixtures ( n = 29) were divided into aliquots for incubation at 4°C, 23°C, 35°C, 45°C, and 50°C and analysed for f‐Hb concentration at days 0, 3, 7, 10, 14, 21, and 28. Relative f‐Hb (percentage change of day 0) in both buffer types was compared between temperatures at each timepoint. Generalised linear modelling identified variables influencing f‐Hb degradation. Results: SOC3 exhibited significant f‐Hb decline from day 10 at 23°C and from day 3 at all higher temperatures assessed ( p < 0.05). In contrast, f‐Hb concentrations remained stable within SOC4 for up to 28 days at 23°C, with reductions observed after 7, 7, and 14 days at 50°C, 45°C, and 35°C, respectively ( p < 0.05). Higher temperatures and longer storage duration significantly decreased f‐Hb concentration, while SOC4 demonstrated superior f‐Hb preservation relative to SOC3 (generalised linear model estimate = 15.4, p < 0.001). Conclusion: The SOC4 FIT buffer improves f‐Hb stability compared with the current formulation and may improve CRC screening accuracy, particularly in high‐temperature environments.

Background: Modifiable lifestyle factors may contribute additively to colorectal cancer (CRC) risk in individuals who already have non-modifiable risk factors, such as prior colorectal neoplasia or significant family history of CRC. However, the impact of multicomponent lifestyle interventions (such as dietary modification, physical activity, and counselling) on behavioural modification, risk of colorectal neoplasia, and quality of life (QoL) in this population has not yet been systematically reviewed. Aims: The primary aim was behavioural change (change in body weight, diet, physical activity, sedentary lifestyle, smoking, and alcohol consumption). The secondary aim was colorectal neoplasia outcomes, including the incidence of precancerous lesions and/or cancer and CRC mortality/survival, and QoL, including specific domains. Methods: This review was conducted following the Cochrane guidelines for Systematic Reviews of Interventions. Both randomised and non-randomised studies assessing the effect of multicomponent lifestyle interventions on behavioural modification, risk of colorectal neoplasia, mortality, and quality of life in people at above-average risk of CRC were included. Medline/Ovid, Cochrane Library, Web of Science, and Scopus were searched. Screening, data extraction, and risk of bias assessment were independently performed by two reviewers using the revised Cochrane Risk of Bias (RoB) tools. Results: Of the 4174 studies screened, 10 interventional studies were eligible for inclusion, which had outcomes for behavioural change or quality of life. No interventions assessed neoplasia risk or mortality outcomes. Multicomponent lifestyle interventions mainly targeting diet and physical activity, delivered via a telephone-based or health coaching approach, showed positive effects on healthy behaviours and quality of life compared with usual care, although some studies reported inconsistent results. Conclusions: There is emerging evidence that multicomponent lifestyle interventions may offer beneficial effects on practicing healthy behaviours and improving QoL for individuals at above-average risk for CRC and undergoing colonoscopy surveillance.

Purpose: Clinical guidelines recommend regular colonoscopy surveillance for individuals at elevated risk for colorectal cancer (CRC). While colonoscopy surveillance is proven to reduce the incidence of CRC, colonoscopy is an invasive procedure that can impact patient-reported outcomes (PROs). Assessment of PROs is recommended as a key indicator of the quality of health service delivery. However, there is no standard set of PROs and PRO measures (PROMs) to be applied in individuals undergoing regular surveillance colonoscopy. The aim of this scoping review was to identify PROs and PROMs applied for this population. Methods: The review followed the Joanna Briggs Institute guidelines. Five databases were searched: Medline (OVID), Scopus, Web of Science, CINAHL, and PsycINFO (OVID). Data extracted included the PROs assessed, PROMs used, indications for surveillance colonoscopy, and assessment timepoints. Results: 8684 studies were screened, and 91 were included. Eighteen PROs and 12 PROMs were identified. Abdominal discomfort (60%), abdominal pain (60%) and nausea (56%) were the most frequently collected PROs. PROs were predominantly assessed after bowel preparation/before colonoscopy (55%) and 1–2 days after colonoscopy (48%). Hospital Anxiety and Depression Scale (33.3%), Short Form-36 (33%), the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-item (27%), and EQ-5D-5L (20%) were the most frequently used PROMs. Conclusion: There is variability in PROs and PROMs applied. This highlights the need for consensus on a standardised set of PROs to be assessed and PROMs to facilitate consistent and reliable data collection to better inform implementation and improve healthcare quality.

Purpose: Colorectal cancer (CRC) treatment failure results in high mortality. The current CRC treatment response monitoring blood biomarker carcinoembryonic antigen (CEA) lacks specificity. Methylated BCAT1/IKZF1 circulating tumour DNA (ctDNA) indicates CRC, but its utility during therapy is uncertain. This study examined whether during-treatment measurement of BCAT1/IKZF1 ctDNA reflects CRC treatment efficacy. Methods: Plasma was collected from CRC patients before and during chemotherapy, targeted therapy and/or radiotherapy. Cell-free DNA was extracted, bisulphite-converted and assayed via multiplex qPCR for BCAT1/IKZF1 methylation (%pg/ ACTB ). Patients with detectable ctDNA pre-treatment were included. CEA was measured via chemiluminescent immunoassay. Radiological treatment response assessments were performed ± 3 months of blood collection or < 8 months post-treatment. Biomarker levels were compared using Mann–Whitney U and Kruskal–Wallis tests. Results: 56 samples from 29 patients (64.3% male, median age 55 years) were analysed. Patients with residual cancer had higher ctDNA levels (median 0.036%, IQR 0–1.17%) than cancer-free patients (0%, IQR 0–0.005%; p < 0.05). There were no significant differences for CEA. When normalised to pre-treatment measurements, treatment-responders demonstrated a median 100% ctDNA reduction from baseline (IQR − 100% to − 7.53%), which was greater than non-responders (0.13% reduction, IQR − 38.1% to + 0.03%; p < 0.001). Responders also demonstrated greater CEA reduction (median − 1.50 ng/mL, IQR − 6.28 to 0.18 ng/mL) compared to non-responders (median 2.3 ng/mL, IQR − 0.50 to 17.7 ng/mL; p = 0.001). Conclusions: Methylated BCAT1 / IKZF1 ctDNA reflects treatment response, offering a tool for personalised treatment.

Summary: Esophagogastric adenocarcinomas have poor survival, and accurate prognosis assessment is required to guide appropriate treatment. Pre-treatment planning can be challenging and would benefit from non-invasive prognostic tools. Methylated circulating tumor DNA (ctDNA) has prognostic value in colorectal cancer. The aim of the study was to evaluate the prognostic value of methylated ctDNA biomarkers in esophageal and gastric cancers. Circulating cell free DNA, isolated from plasma collected prior to treatment from 122 patients diagnosed with esophagogastric cancer was assayed for methylated BCAT1 and IKZF1. Test positivity was assessed against clinicopathological features, and prognostic factors associated with recurrence-free survival (RFS) and overall survival (OS) were investigated with Cox regression analysis. Methylated BCAT1/IKZF1 DNA was detected in 54.9% (67/122) of patients following a diagnosis of esophagogastric cancer. Advanced disease had higher detection rates, with a significant association between test positivity and pathological node-positive disease (odds ratio [OR] for pN2: 5.63, 95% CI 1.27–24.86, P = 0.02), and metastatic disease (OR 4.92, 95% CI 1.94–12.47, P < 0.01). A positive ctDNA result at diagnosis was associated with worse RFS for individuals considered in remission (hazard ratio [HR] 4.49, 95% CI 1.48–13.67, P < 0.01), and a worse OS in all patients (HR 3.64, 95% CI 1.73–7.68, P < 0.01), independent of stage and other clinical variables, compared to a negative ctDNA result. Detection of circulating methylated BCAT1/IKZF1 DNA is a promising prognostic biomarker in esophagogastric cancers. Prospective studies are warranted to investigate the utility of methylated BCAT1/IKZF1 for monitoring treatment response and for risk stratification to guide adjuvant therapeutic decisions.

Bisulfite conversion remains the gold standard method for DNA methylation analysis but has known limitations. Enzymatic conversion has recently been developed and overcomes some of these pitfalls. This study compared both methods by measuring known colorectal cancer (CRC) methylated biomarkers in colorectal tissues. Colorectal tumors and matched adjacent normal tissues were collected before treatment at surgery from 24 patients with stage I–IV CRC (n = 6 per stage), aged 46–81 years (50% male). Tissue DNA was extracted and converted using bisulfite and enzymatic conversion. Methylation levels of BCAT1, IKZF1, and SEPTIN9 were quantified by methylation specific quantitative PCR (MS–qPCR) as a percentage of the reference gene (ACTB). Biomarker positivity in tissues was tested using a series of percentage methylation thresholds between ≥1% and ≥20%, and percentile-based cutoffs ranging from 50th to 95th percentiles. The Kruskal–Wallis test compared the methylation levels between the conversion methods. There were no significant differences in methylation levels between the bisulfite and enzymatic conversion methods for normal tissue DNA (P > 0.05). In tumor tissues, IKZF1 and SEPTIN9 had significantly higher DNA methylation levels with bisulfite conversion compared to enzymatic conversion (P < 0.05), while BCAT1 showed no significant difference (P > 0.05). Across all thresholds, there were no significant differences in colorectal tissue positivity between conversion techniques (P > 0.05), except IKZF1 at the 50th percentile in normal tissues was significantly hypermethylated in enzymatically converted DNA (P < 0.05). Bisulfite conversion has higher DNA methylation levels for certain CRC biomarkers in tumor tissues, suggesting over-estimation of methylation that could affect biomarker specificity.