Caracterización clínico-biológica de pacientes con cáncer colorrectal. Cribado poblacional de síndrome de Lynch

[ES] El cáncer colorrectal (CCR) es un tumor con una elevada incidencia y prevalencia en nuestro medio, siendo la edad y la interacción ambiente-gen los principales factores de riesgo. El conocimiento de las características moleculares y genéticas que conducen a la aparición de tumores con una predisposición hereditaria y su extrapolación a tumores esporádicos con características biológicas similares, ha permitido avanzar en el diagnóstico, el tratamiento y el pronóstico del CCR. La investigación actual en el cáncer colorrectal va encaminada a buscar agrupaciones, clasificaciones, marcadores moleculares que, pongan de manifiesto las semejanzas y diferencias entre los distintos tumores que padecen nuestros pacientes con el fin último de poder seleccionar aquellos sensibles a unos tratamientos y resistentes a otros y, así, hacer una medicina personalizada que redunde en una mejora de la supervivencia y de la calidad de vida, evitando toxicidades de fármacos no eficaces. Este trabajo pretende caracterizar clínica y biológicamente a los pacientes diagnosticados de CCR en el Complejo Asistencial Universitario de Salamanca mediante el empleo de la historia clínica personal, la historia de agregación familiar de cáncer y el empleo de herramientas de biología molecular, con el fin de contribuir en la búsqueda del conocimiento científico en cáncer colorrectal. Por ello, como objetivo general nos planteamos analizar las características clínico-biológicas de los pacientes diagnosticados de CCR y realizar un estudio experimental prospectivo en una población seleccionada para determinar características moleculares. Finalmente, estudiar el papel de la IHQ de las proteínas implicadas en la ruta de reparación de bases desapareadas del DNA, como cribado poblacional de Síndrome de Lynch. Nuestro estudio contribuye a profundizar en el conocimiento de las bases clínicas y moleculares del cáncer colorrectal. La determinación de tumores con inestabilidad de microsatélites está siendo fundamental a la hora de clasificar el CCR; es, en nuestros días, el único subtipo molecular de consenso que es posible definir con los medios que tenemos a nuestro alcance. En resumen, a pesar de ser una muestra relativamente pequeña y de un solo centro, el estudio de los pacientes y sus tumores en base a la expresión IHQ de los genes del sistema MMR en estos, muestra datos muy interesantes a la hora de clasificar el CCR y a la hora de establecer una estrategia universal de cribado de SL. Nuestros datos parecen suficientemente robustos para poder extraer conclusiones ya que el análisis de la literatura muestra resultados en la misma dirección

Cohort profile: the Spanish Early-onset Colorectal Cancer (SECOC) cohort: a multicentre cohort study on the molecular basis of colorectal cancer among young individuals in Spain

Càncer colorectal; Base molecularCáncer colorrectal; Base molecularColorectal cancer; Molecular basisPurpose The Spanish Early-onset Colorectal Cancer (SECOC) study is a multicentre prospective cohort established in Spain to investigate the molecular basis of early-onset colorectal cancer (EOCRC), including metabolic alterations. Participants 220 patients with EOCRC have been enrolled since January 2019 through 18 centres across Spain. Individual-level data were collected by questionnaire, including lifestyle and other colorectal cancer-related factors. Medical record review was performed to capture clinical, histopathological and familial cancer history data. Biospecimen collection (blood, stool, tissue) at diagnosis and at various time points across treatment, as applicable, is also completed. Findings to date Participants had a median age of 44 years (range 14–49), and the majority are men (60%), with individuals age 40–49 years at EOCRC diagnosis being over-represented. Forty-three per cent of participants were diagnosed with a tumour in the rectosigmoid junction/rectum. Nearly two-thirds of EOCRC cases (64%) were diagnosed with advanced stage (III–IV) disease, and 28% of cases had no reported familial history of cancer. Future plans We are actively recruiting and observing participants; we plan to administer follow-up questionnaires and perform additional biospecimen collection. This prospective cohort offers a unique, rich resource for research on EOCRC aetiologies and will contribute to larger international efforts to disentangle the rising disease burden.This work was funded by Projects PI16/01650 and PI20/00974 to JP, from the Spanish Ministry of Health and Consumer Affairs and FEDER. ANH was supported by the National Institutes of Health (NIH) K12 HD043483 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. This work was also supported by the American Cancer Society (#IRG-19-139-59) to ANH

Recurrent NOMO1 gene deletion is a potential clinical marker in early-onset colorectal cancer and is involved in the regulation of cell migration

The incidence of early-onset colorectal cancer (EOCRC; age younger than 50 years) has been progressively increasing over the last decades globally, with causes unexplained. A distinct molecular feature of EOCRC is that compared with cases of late-onset colorectal cancer, in EOCRC cases, there is a higher incidence of Nodal Modulator 1 (NOMO1) somatic deletions. However, the mechanisms of NOMO1 in early-onset colorectal carcinogenesis are currently unknown. In this study, we show that in 30% of EOCRCs with heterozygous deletion of NOMO1, there were pathogenic mutations in this gene, suggesting that NOMO1 can be inactivated by deletion or mutation in EOCRC. To study the role of NOMO1 in EOCRC, CRISPR/cas9 technology was employed to generate NOMO1 knockout HCT-116 (EOCRC) and HS-5 (bone marrow) cell lines. NOMO1 loss in these cell lines did not perturb Nodal pathway signaling nor cell proliferation. Expression microarrays, RNA sequencing, and protein expression analysis by LC–IMS/MS showed that NOMO1 inactivation deregulates other signaling pathways independent of the Nodal pathway, such as epithelial–mesenchymal transition and cell migration. Significantly, NOMO1 loss increased the migration capacity of CRC cells. Additionally, a gut-specific conditional NOMO1 KO mouse model revealed no subsequent tumor development in mice. Overall, these findings suggest that NOMO1 could play a secondary role in early-onset colorectal carcinogenesis because its loss increases the migration capacity of CRC cells. Therefore, further study is warranted to explore other signalling pathways deregulated by NOMO1 loss that may play a significant role in the pathogenesis of the disease.This study was supported by the health research program of the Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness, PI20/01569 and PI20/0974), co-funded by FEDER funds, and Mutua Madrileña Foundation (FMM20/001). A.M.-M was supported by a predoctoral research grant from the Dr. Moraza Fundation (FMoraza18/001). P.G.V and N.G.-U were supported by a predoctoral research grant from the Consejería de Educación—Junta de Castilla y León. A.N.H. was supported by the National Institutes of Health K12 HD043483 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development

External validity of clinical trials with diverse trastuzumab-based chemotherapy regimens in advanced gastroesophageal adenocarcinoma: data from the AGAMENON-SEOM registry

Background: Trastuzumab combined with cisplatin and fluoropyrimidines, either capecitabine or 5-fluorouracile (XP/FP), is the standard first-line treatment for advanced, HER2-positive, gastric cancer patients based on the ToGA trial. Despite the lack of phase III trials, many clinicians administer trastuzumab with alternative regimens. One meta-analysis suggests that substituting cisplatin for oxaliplatin might lead to greater efficacy and less toxicity. Methods: 594 patients with HER2-positive gastroesophageal adenocarcinoma were recruited from the AGAMENON-SEOM registry. The objective was to evaluate the external validity of clinical trials with chemotherapy and trastuzumab. Results: The regimens used in at least 5% of the patients were XP (27%), oxaliplatin and capecitabine (CAPOX) (26%), oxaliplatin and 5-fluorouracil (FOLFOX) (14%), FP (14%), triplet with anthracycline/docetaxel (7%), and carboplatin-FU (5%). Median exposure to trastuzumab was longer with FOLFOX (11.4 months, 95% CI, 9.1-21.0) versus ToGA regimens (7.5, 6.4-8.5), p < 0.001. Patients with HER2-IHC 3+ cancers had higher response rates than those with IHC 2+/FISH+, odds-ratio 1.97 (95% CI, 1.25-3.09). The results achieved with CAPOX-trastuzumab were comparable to those attained with ToGA regimens. FOLFOX-trastuzumab was superior to ToGA schemes in terms of overall survival (OS), with a greater magnitude of effect in IHC 2+/FISH+ tumors (HR 0.47, 0.24-0.92) compared with IHC 3+ (HR 0.69, 0.49-0.96), and in diffuse (HR 0.37, 0.20-0.69) versus intestinal-type tumors (HR 0.76, 0.54-1.06). Conclusion: We have updated the external validity of clinical trials with trastuzumab in first-line treatment of gastric cancer. Our data confirm the comparable outcomes of ToGA regimens and CAPOX-trastuzumab in clinical practice and point toward a possible benefit of FOLFOX-trastuzumab, contingent on the subtypes typically less sensitive to trastuzumab, to be confirmed in clinical trials

Dysregulated Expression of Three Genes in Colorectal Cancer Stratifies Patients into Three Risk Groups

Despite advances in recent years in the study of the molecular profile of sporadic colorectal cancer (sCRC), the specific genetic events that lead to increased aggressiveness or the development of the metastatic process of tumours are not yet clear. In previous studies of the gene expression profile (GEP) using a high-density array (50,000 genes and 6000 miRNAs in a single assay) in sCRC tumours, we identified a 28-gene signature that was found to be associated with an adverse prognostic value for predicting patient survival. Here, we analyse the differential expression of these 28 genes for their possible association with tumour local aggressiveness and metastatic processes in 66 consecutive sCRC patients, followed for >5 years, using the NanoString nCounter platform. The global transcription profile (expression levels of the 28 genes studied simultaneously) allowed us to discriminate between sCRC tumours and nontumoral colonic tissues. Analysis of the biological and functional significance of the dysregulated GEPs observed in our sCRC tumours revealed 31 significantly altered canonical pathways. Among the most commonly altered pathways, we observed the increased expression of genes involved in signalling pathways and cellular processes, such as the PI3K-Akt pathway, the interaction with the extracellular matrix (ECM), and other functions related to cell signalling processes (SRPX2). From a prognostic viewpoint, the altered expression of BST2 and SRPX2 genes were the only independent variables predicting for disease-free survival (DFS). In addition to the pT stage at diagnosis, dysregulated transcripts of ADH1B, BST2, and FER1L4 genes showed a prognostic impact on OS in the multivariate analysis. Based on the altered expression of these three genes, a scoring system was built to stratify patients into low-, intermediate-, and high-risk groups with significantly different 5-year OS rates: 91%, 83%, and 52%, respectively. The prognostic impact was validated in two independent series of sCRC patients from the public GEO database (n = 562 patients). In summary, we show a strong association between the altered expression of three genes and the clinical outcome of sCRC patients, making them potential markers of suitability for adjuvant therapy after complete tumour resection. Additional prospective studies in larger series of patients are required to confirm the clinical utility of the newly identified biomarkers because the number of patients analysed remains small

High-Risk Clinicopathological and Genetic Features and Outcomes in Patients Receiving Neoadjuvant Radiochemotherapy for Locally Advanced Rectal Cancer

Administering preoperative radiochemotherapy (RCT) in stage II-III tumors to locally advanced rectal carcinoma patients has proved to be effective in a high percentage of cases. Despite this, 20–30% of patients show no response or even disease progression. At present, preoperative response is assessed by a combination of imaging and tumor regression on histopathology, but recent studies suggest that various genetic abnormalities may be associated with the sensitivity or resistance of rectal cancer tumor cells to neoadjuvant therapy. In the present study we investigated the relationship between genetic lesions detected by high-density single-nucleotide polymorphisms (SNP) arrays 6.0 and response to neoadjuvant RCT, evaluated according to Dworak criteria in 39 rectal cancer tumors before treatment. The highest frequency of copy-number (CN) losses detected corresponded to chromosomes 18q (n = 27; 69%), 1p (n = 22; 56%), 15q (n = 19; 49%), 8p (n = 18; 48%), 4q (n = 17; 46%), and 22q (n = 17; 46%); in turn, CN gains more frequently involved chromosomes 20p (n = 22; 56%), 8p (n = 20; 51%), and 15q (n = 16; 41%). There was a significant association between alterations in the 1p, 3q, 7q, 12p, 17q, 20p, and 22q chromosomal regions and the degree of response to therapy prior to surgery. However, 4q, 15q11.1, and 15q14 chromosomal region alterations were identified as important by five prediction algorithms, i.e., those with the greatest influence on predicting the tumor response to treatment with preoperative RCT. Multivariate analysis of prognostic factors showed that gains on 15q11.1 and carcinoembryonic antigen (CEA) levels serum at diagnosis were the only independent variables predicting disease-free survival (DFS). Lymph node involvement also showed a prognostic impact on overall survival (OS) in the multivariate analysis. A deep-learning-based algorithm showed a 100% success rate in predicting both DFS and OS at 60 months after diagnosis of the disease. In summary, our results indicate the existence of an association between tumor genetic abnormalities at diagnosis, response to neoadjuvant therapy, and survival of patients with locally advanced rectal cancer. In addition to the clinical and biological characteristics of locally advanced rectal cancer patients, these could be used in the future as therapeutic and prognostic biomarkers, to identify patients sensitive or resistant to preoperative treatment, helping guide therapeutic decision-making. Additional prospective studies in larger series of patients are required to confirm the clinical utility of the newly identified biomarkers

Response to Treatment with an Anti-Interleukin-6 Receptor Antibody (Tocilizumab) in a Patient with Hemophagocytic Syndrome Secondary to Immune Checkpoint Inhibitors

Background. Immunotherapy represents one of the fundamental treatments in the management of some types of cancer, especially malignant melanoma. Toxicity derived from increased immune system activity can manifest in multiple organs and systems. We present a case of hematological toxicity, manifested as hemophagocytic syndrome (HPS), which was successfully treated with an anti-interleukin-6 antibody (tocilizumab). Case Report. This case presents a 75-year-old woman diagnosed with metastatic choroidal melanoma, refractory to several lines of treatment. After the failure of the previous lines, ipilimumab was started. After the third dose, she developed grade 2 thrombocytopenia and anemia accompanied by elevated levels of ferritin, triglycerides, and decreased fibrinogen. Hemophagocytosis was observed in the bone marrow biopsy, and a PET-CT showed splenomegaly with increased metabolism. Treatment was based on high doses of corticosteroids and tocilizumab. Four days after the start of treatment, progressive clinical and analytical improvement was observed, achieving total remission of the condition. Discussion. HPS induced by immunotherapy is due to an immunorelated cytokine storm syndrome (CSS). The administration of the anti-interleukin-6 receptor antibody drug acted on this cytokine cascade, leading to stabilization and subsequent remission. For this reason, the use of tocilizumab should be part of the immunotherapy-induced HPS treatment algorithm

Recurrent NOMO1 Gene Deletion Is a Potential Clinical Marker in Early-Onset Colorectal Cancer and Is Involved in the Regulation of Cell Migration

The incidence of early-onset colorectal cancer (EOCRC; age younger than 50 years) has been progressively increasing over the last decades globally, with causes unexplained. A distinct molecular feature of EOCRC is that compared with cases of late-onset colorectal cancer, in EOCRC cases, there is a higher incidence of Nodal Modulator 1 (NOMO1) somatic deletions. However, the mechanisms of NOMO1 in early-onset colorectal carcinogenesis are currently unknown. In this study, we show that in 30% of EOCRCs with heterozygous deletion of NOMO1, there were pathogenic mutations in this gene, suggesting that NOMO1 can be inactivated by deletion or mutation in EOCRC. To study the role of NOMO1 in EOCRC, CRISPR/cas9 technology was employed to generate NOMO1 knockout HCT-116 (EOCRC) and HS-5 (bone marrow) cell lines. NOMO1 loss in these cell lines did not perturb Nodal pathway signaling nor cell proliferation. Expression microarrays, RNA sequencing, and protein expression analysis by LC&ndash;IMS/MS showed that NOMO1 inactivation deregulates other signaling pathways independent of the Nodal pathway, such as epithelial&ndash;mesenchymal transition and cell migration. Significantly, NOMO1 loss increased the migration capacity of CRC cells. Additionally, a gut-specific conditional NOMO1 KO mouse model revealed no subsequent tumor development in mice. Overall, these findings suggest that NOMO1 could play a secondary role in early-onset colorectal carcinogenesis because its loss increases the migration capacity of CRC cells. Therefore, further study is warranted to explore other signalling pathways deregulated by NOMO1 loss that may play a significant role in the pathogenesis of the disease

Association of the Lung Immune Prognostic Index with Immunotherapy Outcomes in Mismatch Repair Deficient Tumors

Background: MSI-H/dMMR is considered the first predictive marker of efficacy for immune checkpoint inhibitors (ICIs). However, around 39% of cases are refractory and additional biomarkers are needed. We explored the prognostic value of pretreatment LIPI in MSI-H/dMMR patients treated with ICIs, including identification of fast-progressors. Methods: A multicenter retrospective study of patients with metastatic MSI-H/dMMR tumors treated with ICIs between April 2014 and May 2019 was performed. LIPI was calculated based on dNLR &gt; 3 and LDH &gt; upper limit of normal. LIPI groups were good (zero factors), intermediate (one factor) and poor (two factors). The primary endpoint was overall survival (OS), including the fast-progressor rate (OS &lt; 3 months). Results: A total of 151 patients were analyzed, mainly female (59%), with median age 64 years, performance status (PS) 0 (42%), and sporadic dMMR status (68%). ICIs were administered as first or second-line for 59%. The most frequent tumor types were gastrointestinal (66%) and gynecologic (22%). LIPI groups were good (47%), intermediate (43%), and poor (10%). The median follow-up was 32 months. One-year OS rates were 81.0%, 67.1%, and 21.4% for good, intermediate, and poor-risk groups (p &lt; 0.0001). After adjustment for tumor site, metastatic sites and PS, LIPI remained independently associated with OS (HR, poor-LIPI: 3.50, 95%CI: 1.46–8.40, p = 0.02. Overall, the fast-progressor rate was 16.0%, and 35.7% with poor-LIPI vs. 7.5% in the good-LIPI group (p = 0.02). Conclusions: LIPI identifies dMMR patients who do not benefit from ICI treatment, particularly fast-progressors. LIPI should be included as a stratification factor for future trials

Immunohistochemical Assessment of the P53 Protein as a Predictor of Non-Small Cell Lung Cancer Response to Immunotherapy.

Determining predictive biomarkers for immune checkpoint inhibitors (ICIs) is a current challenge in oncology. Previous studies on non-small cell lung cancer (NSCLC) have shown how TP53 gene mutations are correlated with different responses to ICIs. Strong and diffuse immuno-expression of p53 by immunohistochemistry (IHC) is interpreted as a likely indicator of a TP53 gene mutation. We aimed to assess the p53 protein expression via IHC in NSCLC as a predictive biomarker of the response to ICIs. This was a retrospective hospital-based study of patients with NSCLC treated with Nivolumab in the University Hospital of Salamanca. All diagnostic biopsies were studied via IHC (measuring p53 protein expression, peroxidase anti-peroxidase immunohistochemistry technique using Leica BOND Polymer development kits). Survival analysis was performed by subgroups of expression of p53 and other factors using the Kaplan-Meier estimator and Cox proportional-hazards model. Seventy-three patients were included (59 men and 14 women). The median age was 68 (44-84) years. Thirty-six biopsies were adenocarcinoma, 34 were squamous, and three were undifferentiated. In 41 biopsies (56.2%), the cellular expression of p53 was A trend toward a greater response to ICIs was observed in the PFS and OS of patients with high expression of p53 by IHC (TP53 mutation), especially in the PD-L1 negative adenocarcinoma subgroup. These results will make it possible to make future modifications to the clinical guidelines of NSCLC according to the expression of p53