Temporal trends and regional variability in BRAF and KRAS genetic testing in Denmark (2010-2022): Implications for precision medicine.

OBJECTIVE: This study aims to evaluate the developments in the testing of Kirsten Rat Sarcoma viral oncogene homolog (KRAS) and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations across different cancer types and regions in Denmark from 2010 to 2022. STUDY DESIGN AND SETTING: Using comprehensive data from the Danish health registries, we linked molecular test results from the Danish Pathology Registry with cancer diagnoses from the Danish National Patient Registry between 2010 and 2022. We assessed the frequency and distribution of KRAS and BRAF mutations across all cancer types, years of testing, and the five Danish regions. RESULTS: The study included records of KRAS testing for 30 671 patients and BRAF testing for 30 860 patients. Most KRAS testing was performed in colorectal (78%) and lung cancer (18%), and BRAF testing in malignant melanoma (13%), colorectal cancer (67%), and lung cancer (12%). Testing rates and documentation mutational subtypes increased over time. Reporting of wildtype results varied between lung and colorectal cancer, with underreporting in lung cancer. Regional variations in testing and reporting were observed. CONCLUSION: Our study highlights substantial progress in KRAS and BRAF testing in Denmark from 2010 to 2022, evidenced by increased and more specific reporting of mutational test results, thereby improving the precision of cancer diagnosis and treatment. However, persistent regional variations and limited testing for cancer types beyond melanoma, colorectal, and lung cancer highlight the necessity for a nationwide assessment of the optimal testing approach.

Colorectal serrated lesions and polyps in the Danish population: A large nationwide register-based cohort study.

Background and study aims Colorectal serrated lesions and polyps (SPs) include hyperplastic polyps (HP), sessile serrated lesions-/+dysplasia (SSL/SSL-D), and traditional serrated adenomas (TSA). From 20% to 30% of colorectal cancers (CRC) develop from SP. We present incidence and baseline characteristics of SP in a Danish cohort. Patients and methods We used The Danish Pathology Registry to include all SPs in the Danish population from January 1, 2000 to December 31, 2021. Based on the unique Danish personal identification number and SNOMED-codes, combined with the age and sex of patients, and date of procedure, we determined the incidence of the SP subtypes, anatomical location, and changes over time. Results During the period from 2000 to 2021, a total of 292,761 SPs were removed from 163,840 patients: 51,649 SSLs, 5959 SSL-Ds, 224,860 HDs, and 10,293 TSAs. The median age of patients was 64.1 years (range 55.2-71.6) and 53.3% were male. We found a general increase in SPs from 3525 in 2000 to 25,853 in 2021 and a rise in the SSL proportion from 1.7% in 2006 to 38% in 2021. Half of all patients had more than one lesion at endoscopy with conventional adenomas being the most common. CRC was found along with SPs in 3.3% of procedures, while 1% to 2.5% of the patients developed metachronous CRC. Conclusions We found an increasing number of SPs, especially SSLs. From 2019 to 2021 the number of SPs seem to stabilize, while the proportion of SSLs keeps rising. Synchronous lesions were common along all subtypes of SP.

Prediction of disease recurrence or residual disease after primary endoscopic resection of pT1 colorectal cancer-results from a large nationwide Danish study.

PURPOSE: Risk assessment of disease recurrence in pT1 colorectal cancer is crucial in order to select the appropriate treatment strategy. The study aimed to develop a prediction model, based on histopathological data, for the probability of disease recurrence and residual disease in patients with pT1 colorectal cancer. METHODS: The model dataset consisted of 558 patients with pT1 CRC who had undergone endoscopic resection only (n = 339) or endoscopic resection followed by subsequent bowel resection (n = 219). Tissue blocks and slides were retrieved from Pathology Departments from all regions in Denmark. All original slides were evaluated by one experienced gastrointestinal pathologist (TPK). New sections were cut and stained for haematoxylin and eosin (HE) and immunohistochemical markers. Missing values were multiple imputed. A logistic regression model with backward elimination was used to construct the prediction model. RESULTS: The final prediction model for disease recurrence demonstrated good performance with AUC of 0.75 [95% CI 0.72-0.78], HL chi-squared test of 0.59 and scaled Brier score of 10%. The final prediction model for residual disease demonstrated medium performance with an AUC of 0.68 [0.63-0.72]. CONCLUSION: We developed a prediction model for the probability of disease recurrence in pT1 CRC with good performance and calibration based on histopathological data. Together with lymphatic and venous invasion, an involved resection margin (0 mm) as opposed to a margin of ≤ 1 mm was an independent risk factor for both disease recurrence and residual disease.

Cancer risk and mortality in patients with solitary juvenile polyps-A nationwide cohort study with matched controls.

INTRODUCTION: The risk of cancer in patients with solitary colorectal juvenile polyps (JPs) is poorly investigated and several studies have reported polyps with dysplastic and adenomatous alterations. We aimed to investigate the long-term risk of cancer and mortality in these patients by merging data from national registers and comparing them to a matched control cohort. MATERIALS AND METHODS: Patients with a solitary JP were identified in The Danish National Pathology Register and Data Bank (DNPR). The included patients were matched on sex, age, and place of birth with 50 controls. The groups were then analyzed for risk of cancer using the Danish Cancer Registry and mortality using the Danish Cause of Death Registry. RESULTS: We identified 1781 patients with solitary JPs and matched them with 83,713 controls. The mean follow-up time was 7.65 years for cases and 7.36 years for controls. The risk of cancer, including colorectal cancer, did not differ for the two groups and when adjusting for sex and year of birth, the hazard ratio (HR) was 1.15 (confidence interval [CI] 95% 0.94-1.41, p = 0.162). There was no increased risk of death (HR: 1.07, CI 95% 0.88-1.30, p = 0.486). The risk did not differ for different age groups or sex. CONCLUSION: There is no increased risk of cancer or mortality for patients with solitary colorectal JPs. Thus, endoscopic follow-up may be safely omitted in these patients.

Completion total mesorectal excision following transanal endoscopic microsurgery does not compromise outcomes in patients with rectal cancer.

BACKGROUND: Transanal endoscopic microsurgery (TEM) represents a choice of treatment in patients with neoplastic lesions in the rectum. When TEM fails, completion total mesorectal excision (cTME) is often required. However, a concern is whether cTME increases the rate of abdominoperineal resections (APR) and is associated with higher risk of incomplete mesorectal fascia (MRF) resection. The aim of this study was to compare outcomes of cTME with primary TME (pTME) in patients with rectal cancer. METHODS: This was a nationwide study on all patients with cTME from the Danish Colorectal Cancer Group database between 2005 and 2015. Patients with cTME were compared to patients with pTME after propensity score matching (matching ratio 1:2). Matching variables were age, gender, tumor distance from anal verge, American Society of Anesthesiologists (ASA) score and American Joint Committee on Cancer (AJCC) stage. RESULTS: A total of 60 patients with cTME were compared with 120 patients with pTME. Patients with cTME experienced more intraoperative complications as compared to pTME patients (18.3% vs. 6.7%, p = 0.021). However, there was no difference in the rate of perforations at or near the tumor/previous TEM site (6.7% vs. 2.5%, p = 0.224), conversion to open surgery (p = 0.733) or 30-day morbidity (p = 0.86). On multivariate analysis, cTME was not a risk factor for APR (OR 2.49; 95% CI 0.95-6.56; p = 0.064) or incomplete MRF (OR 1.32; 95% CI 0.48-3.63; p = 0.596). There was no difference in the rate of local recurrence between cTME and pTME (5.2% vs. 4.3%, p = 0.1), distant metastases (6.8% vs. 6.8%, p = 1), or survival (p = 0.081). The mean follow-up time was 6 years. CONCLUSION: In our study, the largest so far on the subject, we find no difference in postoperative short- or long-term outcomes between cTME and pTME.

Novel Genetic Causes of Gastrointestinal Polyposis Syndromes.

Hereditary polyposis syndromes are characterized by a large number and/or histopathologically specific polyps in the gastrointestinal tract and a high risk of both colorectal cancer and extracolonic cancer at an early age. While the genes responsible for some of the syndromes, eg, APC in familial adenomatous polyposis and STK11 in Peutz-Jeghers syndrome, have been known for decades, novel genetic causes have recently been detected that have shed light on the broader clinical spectrum of syndromes. Genetic diagnoses are important because they can facilitate a personalized surveillance program. Furthermore, at-risk members of the patient's family can be tested and enrolled in surveillance as needed. In some cases, prenatal diagnostics should be offered. In this paper, we describe the development in germline genetics of the hereditary polyposis syndromes over the last 10-12 years, their clinical characteristics, as well as how to implement genetic analyses in the diagnostic pipeline.

Improving tumor budding reporting in colorectal cancer: a Delphi consensus study.

Tumor budding is a long-established independent adverse prognostic marker in colorectal cancer, yet methods for its assessment have varied widely. In an effort to standardize its reporting, a group of experts met in Bern, Switzerland, in 2016 to reach consensus on a single, international, evidence-based method for tumor budding assessment and reporting (International Tumor Budding Consensus Conference [ITBCC]). Tumor budding assessment using the ITBCC criteria has been validated in large cohorts of cancer patients and incorporated into several international colorectal cancer pathology and clinical guidelines. With the wider reporting of tumor budding, new issues have emerged that require further clarification. To better inform researchers and health-care professionals on these issues, an international group of experts in gastrointestinal pathology participated in a modified Delphi process to generate consensus and highlight areas requiring further research. This effort serves to re-affirm the importance of tumor budding in colorectal cancer and support its continued use in routine clinical practice.

Incidents in Molecular Pathology: Frequency and Causes During Routine Testing.

CONTEXT.­: Errors in laboratory medicine could compromise patient safety. Good laboratory practice includes identifying and managing nonconformities in the total test process. Varying error percentages have been described in other fields but are lacking for molecular oncology. OBJECTIVES.­: To gain insight into incident causes and frequency in the total test process from 8 European institutes routinely performing biomarker tests in non-small cell lung cancer and colorectal cancer. DESIGN.­: All incidents documented in 2018 were collected from all hospital services for pre-preanalytical entries before the biomarker test, as well as specific incidents for biomarker tests. RESULTS.­: There were 5185 incidents collected, of which 4363 (84.1%) occurred in the pre-preanalytical phase (all hospital services), 2796 of 4363 (64.1%) related to missing or incorrect request form information. From the other 822 specific incidents, 166 (20.2%) were recorded in the preanalytical phase, 275 (33.5%) in the analytical phase, and 194 (23.6%) in the postanalytical phase, mainly due to incorrect report content. Only 47 of 822 (5.7%) incidents were recorded in the post-postanalytical phase, and 123 (15.0%) in the complete total test process. For 17 of 822 (2.1%) incidents the time point was unknown. Pre-preanalytical incidents were resolved sooner than incidents on the complete process (mean 6 versus 60 days). For 1215 of 5168 (23.5%) incidents with known causes a specific action was undertaken besides documenting them, not limited to accredited institutes. CONCLUSIONS.­: There was a large variety in the number and extent of documented incidents. Correct and complete information on the request forms and final reports are highly error prone and require additional focus.