Mismatch repair deficiency: how reliable is the two-antibody approach? A national real-life study.

AIMS: Traditionally, mismatch repair (MMR) status is determined by a panel of four antibodies (MLH1, PMS2, MSH2, MSH6). If all proteins are retained, cases are MMR proficient (pMMR), while loss of one or more proteins is indicative of MMR deficiency (dMMR). This approach has been challenged in favour of a two-antibody approach, using PMS2 and MSH6 as a first screening. Their retainment is deemed sufficient to declare cases pMMR. In this study we aim to verify the validity of the two-antibody approach. METHODS AND RESULTS: We performed a nationwide study in colorectal cancer (CRC) and endometrial cancer (EC) diagnosed between 2016 and 2023, including 47,657 patients to evaluate the two-antibody approach. In 0.17% and 0.4% of cases of CRC and EC, respectively, dMMR cases would be missed with the two-antibody approach. Subgroup analyses pointed towards slightly increased miss rates in younger patients (under the age of 50 years) in both groups and identified special subtypes (signet ring cell carcinoma, medullary carcinoma, and mucinous carcinoma in CRC and clear cell carcinoma in EC) with increased miss rates. For these specific subgroups, a low threshold should be used for further testing. In case of ambiguous or heterogeneous staining patterns, four antibodies should be used. CONCLUSION: In general, the application of a two-antibody MMR testing strategy does not lead to considerable failure of dMMR identification and saves costs.

Deficient mismatch repair screening of advanced adenomas in the population screening program for colorectal cancer is not effective.

AIM: Currently, screening of colorectal cancers (CRC) by assessing mismatch repair deficiency (dMMR) or microsatellite instability (MSI) is used to identify Lynch syndrome (LS) patients. Advanced adenomas are considered immediate precursor lesions of CRC. In this study we investigate the relevance of screening of advanced adenomas for LS in population screening. METHODS AND RESULTS: Advanced adenomas (n = 1572) were selected from the Dutch colorectal cancer population screening programme, based on one or more of the criteria: tubulovillous (n = 848, 54%) or villous adenoma (n = 118, 7.5%), diameter ≥ 1 cm (n = 1286, 82%) and/or high-grade dysplasia (n = 176, 11%). In 86 cases (5%), all three criteria were fulfilled at the same time. MMR-IHC and/or MSI analyses were performed on all cases. Only five advanced adenomas (0.3%) showed dMMR and MSI, including two cases with hypermethylation. In at least two patients a germline event was suspected based on allelic frequencies. No pathogenic explanation was found in the last case. CONCLUSION: Timely testing of precursor lesions would be preferable to detect new LS patients before CRC development. However, standard assessment of dMMR of advanced adenomas from the population screening is not effective.

Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer.

Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4−82.6), 88.1% (95%-CI, 85.7−90.4), 93.4% (95%-CI, 91.1−95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18−0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17−0.50); p < 0.0001) of the patient's gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01−0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.

Incidental findings in the bowel cancer population screening program: other polyps and malignancies - A nationwide study.

The introduction of bowel cancer population screening programs has had a profound impact on gastrointestinal pathology. While the focus is mainly on quality assurance of diagnoses relevant for the outcome of these programs (colorectal cancer and its precursors), incidental findings are increasingly diagnosed. The incidence of such findings is largely unknown. Therefore, we investigated the incidence of incidental findings within the national screening program of the Netherlands. From the Dutch nationwide pathology databank (PALGA), we retrieved all histological diagnoses of patients participating in the national bowel cancer screening program from the start in 2014 until 1/1/2021. Descriptive statistics were used. During these 7 years, in total 9407 other polyps and malignancies (262 per 10,000 colonoscopies) were diagnosed. The majority (65%) were classified as inflammatory polyps. The most common malignancies were neuroendocrine tumours (n = 198, 6 per 10,000 colonoscopies); less common were lymphomas (n = 64) and metastases (n = 33). Mesenchymal polyps, such as leiomyomas and lipomas, were relatively common (27 and 16 per 10,000 colonoscopies, respectively), in comparison with neural polyps such as perineuriomas, ganglioneuromas, and neurofibromas (respectively 3, 2, and 1 per 10,000 colonoscopies). This is the largest study into the incidence of nonconventional colorectal polyps and malignancies in a homogeneous cohort of asymptomatic patients. Several of these diagnoses may have consequences for treatment and follow-up, in particular the malignancies and detection of patients with hereditary cancer syndromes.

Prognosis of mucinous colon cancer is determined by histological biomarkers rather than microsatellite instability.

The prognostic value of microsatellite instability (MSI), as well as other histological characteristics such as lymphovascular invasion (LI), perineural invasion (PNI) and extramural vascular invasion (EMVI), is unclear in colorectal mucinous carcinoma (MC). This study aims to determine the relevance of these factors in MC patients and analyses the role of MSI in stage III MC patients treated with adjuvant chemotherapy. A cohort of 650 patients diagnosed with stages I-IV colonic MC from 2000 to 2010 was selected from PALGA, the nationwide Dutch pathology databank. Histopathology was revised and mismatch repair (MMR) status determined. Univariate and multivariate survival analyses were performed. Deficient MMR (dMMR) was found in 33% of MCs and correlated with female gender and right-sidedness, but also with lower tumour stage (stages I/II: 73.2 versus 47%; P < 0.0001) and the absence of EMVI (9.7 versus 23.7%; P < 0.0001) and PNI (5.6 versus 12.7%; P = 0.005). On univariate analysis OS was better for dMMR MC than for proficient MMR (pMMR) MC (median OS of 9.7 versus 5.0 years; P = 0.009), but MMR status was no longer a relevant prognostic factor on multivariate analysis [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.70-1.18]. Stage III MC patients benefited from adjuvant chemotherapy, and dMMR status was associated with better OS in this group (HR = 0.35, 95% CI = 0.13-0.94). EMVI, LI and PNI, but not MMR, status are independent prognostic factors for survival in MC patients. Stage III MC patients benefit from adjuvant chemotherapy and dMMR status is associated with improved survival when adjuvant chemotherapy is given.

Clinical Performance of the Consensus Immunoscore in Colon Cancer in the Asian Population from the Multicenter International SITC Study.

BACKGROUND: In this study, we evaluated the prognostic value of Immunoscore in patients with stage I−III colon cancer (CC) in the Asian population. These patients were originally included in an international study led by the Society for Immunotherapy of Cancer (SITC) on 2681 patients with AJCC/UICC-TNM stages I−III CC. METHODS: CD3+ and cytotoxic CD8+ T-lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The association of Immunoscore with prognosis was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). RESULTS: Immunoscore stratified Asian patients (n = 423) into different risk categories and was not impacted by age. Recurrence-free rates at 3 years were 78.5%, 85.2%, and 98.3% for a Low, Intermediate, and High Immunoscore, respectively (HR[Low-vs-High] = 7.26 (95% CI 1.75−30.19); p = 0.0064). A High Immunoscore showed a significant association with prolonged TTR, OS, and DFS (p < 0.05). In Cox multivariable analysis stratified by center, Immunoscore association with TTR was independent (HR[Low-vs-Int+High] = 2.22 (95% CI 1.10−4.55) p = 0.0269) of the patient's gender, T-stage, N-stage, sidedness, and MSI status. A significant association of a High Immunoscore with prolonged TTR was also found among MSS (HR[Low-vs-Int+High] = 4.58 (95% CI 2.27−9.23); p ≤ 0.0001), stage II (HR[Low-vs-Int+High] = 2.72 (95% CI 1.35−5.51); p = 0.0052), low-risk stage-II (HR[Low-vs-Int+High] = 2.62 (95% CI 1.21−5.68); p = 0.0146), and high-risk stage II patients (HR[Low-vs-Int+High] = 3.11 (95% CI 1.39−6.91); p = 0.0055). CONCLUSION: A High Immunoscore is significantly associated with the prolonged survival of CC patients within the Asian population.

Diagnostic variability in the histopathological assessment of advanced colorectal adenomas and early colorectal cancer in a screening population.

AIM: The aim of this study was to evaluate interobserver variability between individual pathologists and a panel of pathologists in the histopathological assessment of advanced colorectal neoplasms in the Dutch bowel cancer screening population. METHODS AND RESULTS: Histological slides of adenomas with high-grade dysplasia and early colorectal carcinomas (CRC) from 20 different laboratories were reviewed by the pathology panel of the Dutch bowel screening programme. Interobserver variability was reported by descriptive statistics. In addition, potential clinical consequences of discrepancies were evaluated. A total of 104 cases of adenomas with high-grade dysplasia and 83 early CRCs were reviewed. Discrepancies were observed in 41 of 104 (39.4%) adenoma cases, which potentially had clinical consequences in 16 (15.4%) cases. For CRC, discrepancies were shown in 44 of 83 cases (53.0%) and would have potentially led to alternative treatment strategies in 25 (30.1%) cases. Most frequently, discrepancies were observed in the assessment of lymphovascular invasion (23 of 73 cases, 31.5%). CONCLUSION: This study showed that considerable interobserver variability is present in the histopathological assessment of advanced colorectal neoplasia, which may impact upon treatment choices. Additional stains and education, as well as intercollegial consultation, might decrease this variability.

Quality Assessment of Gallbladder Cancer Pathology Reports: A Dutch Nationwide Study.

Adequate reporting of pathological findings is essential for optimal patient management and to perform high-quality research. The aim of this study was to assess the completeness of pathology reports of gallbladder cancer (GBC) at the nationwide level to assess guideline adherence and make recommendations for improvement. A retrospective population-based cohort of GBC patients diagnosed in the Netherlands from 2000 to 2019 was collected using data from the Dutch Cancer Registry and the nationwide network and registry of histology. Pathology reports were scored on the presence and content of essential and optional items according to the Dutch consensus-based guideline on biliary tract cancer. By histopathological review of cases, we compared findings with the conclusion of the corresponding pathology report. All pathology reports (n = 849) had a narrative, nonstructured format. Overall completeness was low. Information on key prognostic factors, such as tumor side (hepatic vs. serosal), status of cystic duct and liver surgical margins and venous and perineural invasion, was frequently lacking (80%, 23%, 59%, 74% and 74% missing, respectively). Whereas certain items were often missing from the report, they could be retrospectively detected in a substantial proportion of cases during pathology review (n = 738). In conclusion, significant improvements could be made in the reporting of GBC in the Netherlands. Synoptic reporting could greatly enhance the completeness of reports, as already demonstrated for tumor types.

Unraveling Neuroendocrine Gallbladder Cancer: Comprehensive Clinicopathologic and Molecular Characterization.

PURPOSE: Neuroendocrine carcinomas and mixed neuroendocrine non-neuroendocrine neoplasms of the gallbladder (NE GBC) are rare and highly aggressive entities. The cell of origin of NE GBC has been a matter of controversy. Here, we performed a comparative histopathologic and molecular analysis of NE GBC cases and, if present, associated precancerous lesions. PATIENTS AND METHODS: We selected cases diagnosed between 2000 and 2019 in the Netherlands. Precursors and carcinomas were immunohistochemically compared and analyzed for mutations, gene amplifications, microsatellite instability, and tumor mutational burden using an next-generation sequencing panel containing 523 cancer-related genes. In addition, presence of fusion genes was analyzed using a panel of 55 genes. RESULTS: Sixty percent of neuroendocrine cases (6/10) presented with a precursor lesion, either intracholecystic papillary neoplasm (n = 3) or biliary intraepithelial neoplasia (n = 3). Immunohistochemically, neuroendocrine components were different from the epithelial precursor lesions. Molecular profiling, however, revealed TP53 mutations shared between different components in five of six cases, indicating a clonal relation. Furthermore, 40% of cases (4/10) harbored at least one potentially actionable alteration. This included (likely) pathogenic mutations in RAD54L, ATM, and BRCA2; amplifications of ERBB2 and MDM2; and a gene fusion involving FGFR3-TACC3. All cases were microsatellite-stable and had a tumor mutational burden of < 10 mutations/Mb. CONCLUSION: Our data provide insight into the development of NE GBC and suggest a common origin of precancerous epithelial lesions and invasive neuroendocrine components, favoring the hypothesis of lineage transformation. Moreover, nearly half of the NE GBCs carried at least one potentially actionable molecular alteration, highlighting the importance of molecular testing in this highly lethal cancer.

Clinical, Pathology, Genetic, and Molecular Features of Colorectal Tumors in Adolescents and Adults 25 Years or Younger.

BACKGROUND & AIMS: Colorectal cancers (CRCs) are rare in adolescents and adults ages 25 years or younger. We analyzed clinical, pathology, and molecular features of colorectal tumors from adolescents and young adults in an effort to improve genetic counseling, surveillance, and, ultimately, treatment and outcomes. METHODS: We analyzed clinical data and molecular and genetic features of colorectal tumor tissues from 139 adolescents or young adults (age, ≤25 y; median age, 23 y; 58% male), collected from 2000 through 2017; tumor tissues and clinical data were obtained from the nationwide network and registry of histopathology and cytopathology and The Netherlands Cancer Registry, respectively. DNA samples from tumors were analyzed for microsatellite instability, mutations in 56 genes, and genome-wide somatic copy number aberrations. RESULTS: Mucinous and/or signet ring cell components were observed in 33% of tumor samples. A genetic tumor risk syndrome was confirmed for 39% of cases. Factors associated with shorter survival time included younger age at diagnosis, signet ring cell carcinoma, the absence of a genetic tumor risk syndrome, and diagnosis at an advanced stage of disease. Compared with colorectal tumors from patients ages 60 years or older in the Cancer Genome Atlas, higher proportions of tumors from adolescents or young adults were microsatellite stable with nearly diploid genomes, or contained somatic mutations in TP53 and POLE, whereas lower proportions contained mutations in APC. CONCLUSIONS: We found clinical, molecular, and genetic features of CRCs in adolescents or young adults to differ from those of patients older than age 60 years. In 39% of patients a genetic tumor risk syndrome was identified. These findings provide insight into the pathogenesis of CRC in young patients and suggest new strategies for clinical management. Performing genetic and molecular analyses for every individual diagnosed with CRC at age 25 years or younger would aid in this optimization.

RNF43 mutation analysis in serrated polyposis, sporadic serrated polyps and Lynch syndrome polyps.

AIMS: RNF43 is suggested to be involved in the serrated pathway towards colorectal cancer and encodes a transmembrane Ring-type E3 ubiquitin ligase that negatively regulates the Wnt pathway. This study aimed to elucidate the role of RNF43 gene variants in serrated polyposis syndrome (SPS) and serrated polyps. METHODS AND RESULTS: Three cohorts were tested. The first cohort included germline DNA of 26 SPS patients tested for pathogenic variants in RNF43 by Sanger sequencing all exons. In the second cohort we tested somatic DNA for RNF43 mutations from sporadic serrated lesions: 25 hyperplastic polyps, 35 sessile serrated lesions and 38 traditional serrated adenomas (TSA). In the third cohort we investigated RNF43 mutations in 49 serrated polyps and 60 conventional adenomas from 40 patients with Lynch syndrome. No germline RNF43 pathogenic variants were detected in our SPS cohort. In sporadic colorectal lesions we detected RNF43 deleterious frameshift mutations in three TSA and one SSL. The RNF43 mutations in previously described homopolymeric hot-spots were detected in microsatellite-instable (MSI) polyps and the other RNF43 mutations in microsatellite-stable (MSS) serrated polyps. RNF43 hot-spot mutations were discovered in seven serrated polyps and 12 conventional adenomas from Lynch patients. CONCLUSION: Truncating germline RNF43 mutations are uncommon in SPS patients. Somatic mutations in RNF43 were found in sporadic TSA and SSL and both serrated polyps and adenomas from Lynch syndrome patients, suggesting that they do not develop early in the pathway to CRC and are not specific for serrated polyp subtypes.

Multicenter International Society for Immunotherapy of Cancer Study of the Consensus Immunoscore for the Prediction of Survival and Response to Chemotherapy in Stage III Colon Cancer.

PURPOSE: The purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR). METHODS: An international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy. RESULTS: Patients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high v low], 0.48; 95% CI, 0.32 to 0.71; P = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all P < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high v low], 0.41; 95% CI, 0.25 to 0.67; P = .0003) of patient's sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR [high v low], 0.36; 95% CI, 0.21 to 0.62; P = .0003). Immunoscore had the strongest contribution χ2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy v no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; P = .0011) and high-risk (HR [chemotherapy v no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; P = .0015) patients, in contrast to the low-Immunoscore group (P > .12). CONCLUSION: This study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.

Reasons why the diagnosis of serrated polyposis syndrome is missed.

OBJECTIVES: Serrated polyposis syndrome (SPS) is a relatively new and under-recognized colorectal cancer (CRC) predisposition syndrome. Previous studies have reported miss-rates of SPS diagnosis varying from 40 to 82%. As SPS patients and their first-degree relatives have an increased risk of CRC, early recognition is important. We aimed to determine the miss-rate of SPS and to determine the reasons for missed diagnosis. PATIENTS AND METHODS: We retrospectively identified all patients diagnosed with at least one colorectal polyp or carcinoma detected at our tertiary referral center between January 1986 and July 2013 using the nationwide pathology registry. On the basis of cumulative polyp count with size and location, SPS patients were identified. We checked whether the SPS diagnosis was made in the medical files and, if not, what might have been the reason for missing the diagnosis. RESULTS: We randomly assessed 5000 patients, of whom 25 patients fulfilled the WHO criteria for SPS. In six patients, no previous SPS diagnosis had been made, leading to a miss-rate of 24.0% (95% confidence interval: 7.3-40.7). The reasons for missed diagnosis were polyps removed before establishment of the WHO criteria, unavailable pathology reports, and failure to apply the criteria by the clinician. CONCLUSION: The miss-rate for the diagnosis of SPS is considerable, even during longer follow-up with repeated colonoscopies. A preventable reason for missing SPS cases is failure to apply the WHO criteria. Awareness of this CRC predisposition syndrome needs to be raised to decrease the miss-rate of SPS.

International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study.

BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance. FINDINGS: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0·20, 95% CI 0·10-0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21-0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system. INTERPRETATION: The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer. FUNDING: French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer.

MicroRNA-143 is a putative predictive factor for the response to fluoropyrimidine-based chemotherapy in patients with metastatic colorectal cancer.

Approximately half of the colorectal cancer (CRC) patients develop metastatic disease. Fluoropyrimidine-based chemotherapy forms the backbone of treatment in these patients. However, the response to this therapy varies between individuals. Therefore, an important challenge in CRC research is to identify biomarkers that are predictive of this response. In this study, we explored the potential of miRNAs, and the miRNA producing protein Dicer, as biomarkers that can predict chemo-sensitivity to fluoropyrimidine chemotherapy in patients with metastatic colorectal cancer (mCRC). We analyzed the levels of 22 miRNAs and the Dicer protein in primary tumors from patients with mCRC who were treated with first-line capecitabine monotherapy within the CAIRO trial of the Dutch Colorectal Cancer Group. Correlation between the expression status of miRNAs or Dicer in primary tumors and the progression free survival (PFS) were investigated. Patients with low expression of miR-143 in their primary tumor had increased median PFS compared to those with high expression of miR-143. Furthermore, FXYD3, an ion transport regulator and a putative target of miR-143, also showed an association with PFS. These findings warrant further studies to investigate the relationship between miR-143, FXYD3 and fluoropyrimidines, and the clinical utility of miR-143 as biomarker.