Sequential RAS mutations evaluation in cell-free DNA of patients with tissue RAS wild-type metastatic colorectal cancer: the PERSEIDA (Cohort 2) study.

PURPOSE: RAS (KRAS/NRAS) mutational status on a tumor biopsy is mandatory to guide the best treatment in metastatic colorectal cancer (mCRC). Determining the RAS mutational status by tumor-tissue biopsy is essential in guiding the optimal treatment decision for mCRC. RAS mutations are negative predictive factors for the use of EGFR monoclonal antibodies. Cell-free DNA (cfDNA) analysis enables minimally invasive monitoring of tumor evolution. METHODS/PATIENTS: PERSEIDA was an observational, prospective study assessing cfDNA RAS, BRAF and EGFR mutations (using Idylla™) in first-line mCRC, RAS wild-type (baseline tumor-tissue biopsy) patients (cohort 2). Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. RESULTS: 117 patients were included (103 received panitumumab + chemotherapy as first-line treatment). At baseline, 7 (6.8%) patients had RAS mutations, 4 (3.9%) BRAF mutations and no EGFR mutations were detected (cfDNA, panitumumab + chemotherapy subpopulation [panitumumab + Ch]). The baseline RAS mutational status concordance between tissue and liquid biopsies was 94.0% (93.2%, panitumumab + Ch). At 20 weeks, only one patient in the study (included in the panitumumab + Ch) had an emerging cfDNA RAS mutation. No emerging BRAF or EGFR mutations were reported. At disease progression, 6 patients had emergent mutations not present at baseline (RAS conversion rate: 13.3% [6/45]; 15.0% [6/40], panitumumab + Ch). CONCLUSIONS: The concordance rate between liquid and solid biopsies at baseline was very high, as previously reported, while our results suggest a considerable emergence of RAS mutations during disease progression. Thus, the dynamics of the genomic landscape in ctDNA may provide relevant information for the management of mCRC patients.

Real-world study on microsatellite instability and mismatch repair deficiency testing patterns among patients with metastatic colorectal cancer in Spain / Estudio en el mundo real sobre patrones de prueba de inestabilidad de microsatélites y deficiencia de reparación de desajustes en pacientes con cáncer colorrectal metastásico en España

Purpose: Clinical practice guidelines recommend that all patients with metastatic colorectal cancer (mCRC) should be tested for mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). We aimed to describe the dMMR/MSI-H testing practice in patients with mCRC in Spanish centers.Methods: Multicenter, observational retrospective study that included patients newly diagnosed with mCRC or who progressed to a metastatic stage from early/localized stages. Results: Three hundred patients were included in the study from May 2020 through May 2021, with a median age of 68 years, and two hundred twenty-five (75%) had stage IV disease at initial diagnosis; two hundred eighty-four patients received first-line treatment, and dMMR/MSI-H testing was performed in two hundred fifty-one (84%) patients. The results of the dMMR/MSI-H tests were available in 61 (24%) of 251 patients before the diagnosis of metastatic disease and in 191 (81%) of 236 evaluable patients for this outcome before the initiation of first-line treatment. Among the 244 patients who were tested for dMMR/MSI-H with IHC or PCR, 14 (6%) were MMR deficient. The most frequent type of first-line treatment was the combination of chemotherapy and biological agent, that was received by 71% and 50% of patients with MMR proficient and deficient tumors, respectively, followed by chemotherapy alone, received in over 20% of patients in each subgroup. Only 29% of dMMR/MSI-H tumors received first-line immunotherapy. Conclusion: Our study suggests that a high proportion of patients with mCRC are currently tested for dMMR/MSI-H in tertiary hospitals across Spain. However, there is still room for improvement until universal testing is achieved.(AU)

Is there a preferred platinum and fluoropyrimidine regimen for advanced HER2-negative esophagogastric adenocarcinoma? Insights from 1293 patients in AGAMENON-SEOM registry.

BACKGROUND: The optimal chemotherapy backbone for HER2-negative advanced esophagogastric cancer, either in combination with targeted therapies or as a comparator in clinical trials, is uncertain. The subtle yet crucial differences in platinum-based regimens' safety and synergy with combination treatments need consideration. METHODS: We analyzed cases from the AGAMENON-SEOM Spanish registry of HER2-negative advanced esophagogastric adenocarcinoma treated with platinum and fluoropyrimidine from 2008 to 2021. This study focused exclusively on patients receiving one of the four regimens: FOLFOX (5-FU and oxaliplatin), CAPOX (capecitabine and oxaliplatin), CP (capecitabine and cisplatin) and FP (5-FU and cisplatin). The aim was to determine the most effective and tolerable platinum and fluoropyrimidine-based chemotherapy regimen and to identify any prognostic factors. RESULTS: Among 1293 patients, 36% received either FOLFOX (n = 468) or CAPOX (n = 466), 20% CP (n = 252), and 8% FP (n = 107). FOLFOX significantly increased PFS (progression free survival) compared to CP, with a hazard ratio of 0.73 (95% CI 0.58-0.92, p = 0.009). The duration of treatment was similar across all groups. Survival outcomes among regimens were similar, but analysis revealed worse ECOG-PS (Eastern Cooperative Oncology Group-Performance Status), > 2 metastatic sites, bone metastases, hypoalbuminemia, higher NLR (neutrophil-to-lymphocyte ratio), and CP regimen as predictors of poor PFS. Fatigue was common in all treatments, with the highest incidence in FOLFOX (77%), followed by FP (72%), CAPOX (68%), and CP (60%). Other notable toxicities included neuropathy (FOLFOX 69%, CAPOX 62%), neutropenia (FOLFOX 52%, FP 55%), hand-foot syndrome in CP (46%), and thromboembolic events (FP 12%, CP 11%). CONCLUSIONS: FOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin.

Efficacy and safety of chemotherapy in young patients with advanced gastroesophageal adenocarcinoma: data from the Spanish AGAMENON-SEOM registry.

BACKGROUND: Gastroesophageal adenocarcinoma in young adults (GCYA) counts for 10-15% of diagnoses. Previous studies have mainly focused on surgical outcomes in patients with resectable tumors; however, systemic therapy for advanced GCYA remains under-evaluated. This study aims to assess the efficacy-related outcomes and safety of first-line chemotherapy (CT) in younger versus older patients with advanced gastroesophageal adenocarcinoma. METHODS: Patients with advanced gastroesophageal adenocarcinoma from the AGAMENON-SEOM registry treated with first-line polychemotherapy between January 2008 and October 2022 were included. We compared clinicopathological features, therapies received, efficacy-related outcomes, and toxicity between individuals aged < and ≥ 45 years. RESULTS: Out of 3386 patients, 263 (7.8%) were < 45 years. Young patients exhibited a higher proportion of females affected, lower ECOG-PS ≥ 2, fewer comorbidities, and more aggressive disease-related features, such as higher proportion of diffuse subtype, signet-ring cells, plastic linitis, grade 3, peritoneal metastases and metastatic disease at diagnosis. They received more triple-agent combinations and underwent more surgeries in metastatic setting. No significant differences were observed between groups in overall response rate (53.1% vs. 52.3% in < and ≥ 45 years, respectively, p = 0.579), progression-free survival (6.1 vs. 6.83 months, p = 0.158) and overall survival (11.07 vs. 10.81 months, p = 0.82), even after adjusting for potential confounding factors. Grade 3-4 adverse events were comparable in both groups, although toxicity leading to treatment discontinuation was more frequent in older patients. CONCLUSIONS: In the AGAMENON-SEOM registry, younger patients with GCYA exhibited more aggressive clinicopathological features, and despite receiving more aggressive treatments, similar efficacy outcomes and toxicity profiles were achieved compared to their older counterparts. In the AGAMENON-SEOM registry, GEAC in < 45 years showed more aggressive clinicopathological features and, although treated with more intense first-line CT regimens, similar efficacy outcomes and toxicity were achieved compared to older patients.

Use of multi-gene panels in patients at high risk of hereditary digestive cancer: position statement of AEG, SEOM, AEGH and IMPaCT-GENÓMICA consortium. / Uso de paneles de genes en pacientes con alto riesgo de cáncer digestivo hereditario: documento de posicionamiento de la AEG, SEOM, AEGH y consorcio IMPaCT-GENÓMICA.

This position statement, sponsored by the Asociación Española de Gastroenterología, the Sociedad Española de Oncología Médica, the Asociación Española de Genética Humana and the IMPaCT-Genómica Consortium aims to establish recommendations for use of multi-gene panel testing in patients at high risk of hereditary gastrointestinal and pancreatic cancer. To rate the quality of the evidence and the levels of recommendation, we used the methodology based on the GRADE system (Grading of Recommendations Assessment, Development and Evaluation). We reached a consensus among experts using a Delphi method. The document includes recommendations on clinical scenarios where multi-gene panel testing is recommended in colorectal cancer, polyposis syndromes, gastric and pancreatic cancer, as well as the genes to be considered in each clinical scenario. Recommendations on the evaluation of mosaicisms, counseling strategies in the absence of an index subject and, finally, constitutional analysis after identification of pathogenic tumor variants are also made.

Real-world study on microsatellite instability and mismatch repair deficiency testing patterns among patients with metastatic colorectal cancer in Spain.

PURPOSE: Clinical practice guidelines recommend that all patients with metastatic colorectal cancer (mCRC) should be tested for mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). We aimed to describe the dMMR/MSI-H testing practice in patients with mCRC in Spanish centers. METHODS: Multicenter, observational retrospective study that included patients newly diagnosed with mCRC or who progressed to a metastatic stage from early/localized stages. RESULTS: Three hundred patients were included in the study from May 2020 through May 2021, with a median age of 68 years, and two hundred twenty-five (75%) had stage IV disease at initial diagnosis; two hundred eighty-four patients received first-line treatment, and dMMR/MSI-H testing was performed in two hundred fifty-one (84%) patients. The results of the dMMR/MSI-H tests were available in 61 (24%) of 251 patients before the diagnosis of metastatic disease and in 191 (81%) of 236 evaluable patients for this outcome before the initiation of first-line treatment. Among the 244 patients who were tested for dMMR/MSI-H with IHC or PCR, 14 (6%) were MMR deficient. The most frequent type of first-line treatment was the combination of chemotherapy and biological agent, that was received by 71% and 50% of patients with MMR proficient and deficient tumors, respectively, followed by chemotherapy alone, received in over 20% of patients in each subgroup. Only 29% of dMMR/MSI-H tumors received first-line immunotherapy. CONCLUSION: Our study suggests that a high proportion of patients with mCRC are currently tested for dMMR/MSI-H in tertiary hospitals across Spain. However, there is still room for improvement until universal testing is achieved. TRIAL REGISTRATION: Not applicable.

Analysis of Circulating Tumor DNA in Synchronous Metastatic Colorectal Cancer at Diagnosis Predicts Overall Patient Survival.

Sporadic colorectal cancer (sCRC) initially presents as metastatic tumors in 25-30% of patients. The 5-year overall survival (OS) in patients with metastatic sCRC is 50%, falling to 10% in patients presenting with synchronous metastatic disease (stage IV). In this study, we systematically analyzed the mutations of RAS, PIK3CA and BRAF genes in circulating tumor DNA (ctDNA) and tumoral tissue DNA (ttDNA) from 51 synchronous metastatic colorectal carcinoma (SMCC) patients by real-time PCR, and their relationship with the clinical, biological and histological features of disease at diagnosis. The highest frequency of mutations detected was in the KRAS gene, in tumor biopsies and plasma samples, followed by mutations of the PIK3CA, NRAS and BRAF genes. Overall, plasma systematically contained those genetic abnormalities observed in the tumor biopsy sample from the same subject, the largest discrepancies detected between the tumor biopsy and plasma from the same patient being for mutations in the KRAS and PIK3CA genes, with concordances of genotyping results between ttDNA and ctDNA at diagnosis of 75% and 84%, respectively. Of the 51 SMCC patients in the study, 25 (49%) showed mutations in at least 1 of the 4 genes analyzed in patient plasma. From the prognostic point of view, the presence and number of the most common mutations in the RAS, PIK3CA and BRAF genes in plasma from SMCC patients are independent prognostic factors for OS. Determination of the mutational status of ctDNA in SMCC could be a key tool for the clinical management of patients.

The AGAMENON-SEOM model for prediction of survival in patients with advanced HER2-positive oesophagogastric adenocarcinoma receiving first-line trastuzumab-based therapy.

Background: Trastuzumab and chemotherapy is the standard first-line treatment in human epidermal growth factor receptor 2 (HER2)-positive advanced gastro-oesophageal cancer. The objective was to develop a predictive model for overall survival (OS) and progression-free survival (PFS) in patients treated with trastuzumab. Methods: Patients with HER2-positive advanced gastro-oesophageal adenocarcinoma (AGA) from the Spanish Society of Medical Oncology (SEOM)-AGAMENON registry and treated first line with trastuzumab and chemotherapy between 2008 and 2021 were included. The model was externally validated in an independent series (The Christie NHS Foundation Trust, Manchester, UK). Results: In all, 737 patients were recruited (AGAMENON-SEOM, n = 654; Manchester, n = 83). Median PFS and OS in the training cohort were 7.76 [95% confidence interval (CI), 7.13-8.25] and 14.0 months (95% CI, 13.0-14.9), respectively. Six covariates were significantly associated with OS: neutrophil-to-lymphocyte ratio, Eastern Cooperative Oncology Group performance status, Lauren subtype, HER2 expression, histological grade and tumour burden. The AGAMENON-HER2 model demonstrated adequate calibration and fair discriminatory ability with a c-index for corrected PFS/OS of 0.606 (95% CI, 0.578-0.636) and 0.623 (95% CI, 0.594-0.655), respectively. In the validation cohort, the model is well calibrated, with a c-index of 0.650 and 0.683 for PFS and OS, respectively. Conclusion: The AGAMENON-HER2 prognostic tool stratifies HER2-positive AGA patients receiving trastuzumab and chemotherapy according to their estimated survival endpoints.

Telomere Length as a New Risk Marker of Early-Onset Colorectal Cancer.

Early-onset colorectal cancer (EOCRC; age younger than 50 years) incidence has been steadily increasing in recent decades worldwide. The need for new biomarkers for EOCRC prevention strategies is undeniable. In this study, we aimed to explore whether an aging factor, such as telomere length (TL), could be a useful tool in EOCRC screening. The absolute leukocyte TL from 87 microsatellite stable EOCRC patients and 109 healthy controls (HC) with the same range of age, was quantified by Real Time Quantitative PCR (RT-qPCR). Then, leukocyte whole-exome sequencing (WES) was performed to study the status of the genes involved in TL maintenance (hTERT, TERC, DKC1, TERF1, TERF2, TERF2IP, TINF2, ACD, and POT1) in 70 sporadic EOCRC cases from the original cohort. We observed that TL was significantly shorter in EOCRC patients than in healthy individuals (EOCRC mean: 122 kb vs. HC mean: 296 kb; p < 0.001), suggesting that telomeric shortening could be associated with EOCRC susceptibility. In addition, we found a significant association between several SNPs of hTERT (rs79662648), POT1 (rs76436625, rs10263573, rs3815221, rs7794637, rs7784168, rs4383910, and rs7782354), TERF2 (rs251796 and rs344152214), and TERF2IP (rs7205764) genes and the risk of developing EOCRC. We consider that the measurement of germline TL and the status analysis of telomere maintenance related genes polymorphisms at early ages could be non-invasive methods that could facilitate the early identification of individuals at risk of developing EOCRC.

Evolution of RAS Mutations in Cell-Free DNA of Patients with Tissue RAS Wild-Type Metastatic Colorectal Cancer Receiving First-Line Treatment: The PERSEIDA Study.

The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA RAS (KRAS/NRAS) mutational status evolution in first-line, metastatic CRC, RAS wild-type (according to baseline tumor tissue biopsy) patients. Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. One hundred and nineteen patients were included (102 received panitumumab and chemotherapy as first-line treatment-panitumumab subpopulation). Fifteen (12.6%) patients presented baseline cfDNA RAS mutations (n = 14 [13.7%], panitumumab subpopulation) (mutant allele fraction ≥0.02 for all results). No patients presented emergent mutations (cfDNA RAS mutations not present at baseline) at 20 weeks. At disease progression, 11 patients (n = 9; panitumumab subpopulation) presented emergent mutations (RAS conversion rate: 19.0% [11/58]; 17.7% [9/51], panitumumab subpopulation). In contrast, three (5.2%) patients presenting baseline cfDNA RAS mutations were RAS wild-type at disease progression. No significant associations were observed between overall response rate or progression-free survival and cfDNA RAS mutational status in the total panitumumab subpopulation. Although, in patients with left-sided tumors, a significantly longer progression-free survival was observed in cfDNA RAS wild-type patients compared to those presenting cfDNA RAS mutations at any time. Continuous evaluation of RAS mutations may provide valuable insights on tumor molecular dynamics that can help clinical practice.

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.

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.

Autoimmune Haemolytic Anaemia Due to Cold Antibodies in a Renal Cancer Patient.

Autoimmune haemolytic anaemia (AIHA) is an acquired disorder in which antibodies are produced against self-erythrocyte antigens. We distinguish those produced by cold antibodies (IgM), which may be associated with lymphoproliferative syndromes, infectious diseases, other autoimmune phenomena, as well as drugs or solid tumours. We report a case of AIHA due to cold antibodies as a paraneoplastic syndrome (PNS) in a patient with metastatic renal carcinoma. A 67-year-old man with newly diagnosed stage IV renal carcinoma with hepatic, bone, and lymph node involvement was consulted for abdominal pain. Laboratory tests showed grade 4 anaemia (4.5 g/dL), with positive direct Coombs' test C3bC3d and agglutinated red blood cells in the blood smear. AIHA by cold antibodies was labelled as PNS in the context of the patient; therefore, blood transfusion as well as treatment of the underlying disease with tyrosine kinase inhibitors (sunitinib) were initiated, with subsequent clinical and analytical improvement. AIHA due to cold antibodies is a well-known PNS in lymphoproliferative disorders, although association with solid tumours, such as Kaposi's sarcoma and non-small-cell lung cancer have also been described in a small percentage. However, there are few reported cases of AIHA due to cold antibodies associated with renal carcinoma. Management with corticosteroids and immunosuppressors is effective in the majority of cases, but treatment of the underlying disease is critical.

Fulminant myocarditis in a patient with a lung adenocarcinoma after the third dose of modern COVID-19 vaccine. A case report and literature review.

Introduction COVID-19 disease has caused a global health and economic crisis. The introduction of the different COVID-19 vaccines has resulted in a significant decrease in the morbidity and mortality associated with this disease. Adverse effects have been reported, including cardiological ones such as myocarditis or pericarditis after administration. Likewise, tyrosine kinase inhibitor drugs such as osimertinib used in lung cancer patients with epidermal growth factor receptor (EGFR) mutation are associated with heart failure or prolongation of the QT interval. Case report 62-year-old woman diagnosed in September 2019 of lung adenocarcinoma stage IV with bilateral lung and lymph node involvement, carrier of an EGFR mutation (Ex19Del) on treatment with osimertinib. She attended emergency department for fever and hypotension 24 h after administration of the third dose of Moderna® COVID-19 vaccine in the context of acute myocarditis with evidence of severe left ventricular (LV) dysfunction in cardiogenic shock. She required vasoactive support, non-invasive mechanical ventilation, corticotherapy, immunoglobulins and subsequent ventricular support with Impella, with improvement of the clinical picture after 3 days. Cardiac magnetic resonance imaging (MRI) showed evidence of global myocardial oedema compatible with acute myocarditis. Coronary CT showed a lesion in the anterior descending coronary artery requiring revascularization. A few days later, she presented febrile symptoms with isolation of Staphylococcus aureus in the central line catheter and antibiotherapy with cloxacillin was started, with subsequent resolution of the infectious symptoms. Conclusion This is an exceptional and controversial case of fulminant myocarditis probably related to the Modern COVID-19 vaccine in a patient diagnosed with metastatic lung adenocarcinoma on treatment with osimertinib. An increasing number of cases of myocarditis and pericarditis have been reported following vaccination with COVID-19 mRNA vaccines. In addition, retrospective data have shown an increased risk of QT prolongation and heart failure in patients treated with tyrosine kinase inhibitors. Hence, the need for close monitoring of cardiac function during treatment of these patients. Future studies will be necessary to evaluate unknown adverse reactions of these vaccines and their possible interaction with other antineoplastic drugs.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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 <5% (Group A), and in 32 biopsies (43.8%), the expression was ≥5% (Group B). In the general analysis, no differences were observed in overall survival (OS) (A: 12 months vs B: 20 months; p = 0.070) or progression-free survival (PFS) (A: 4 m vs B: 7 m; p = 0.064). Significant differences were observed in adenocarcinomas for both OS (A: 8 m vs B: median not reached; p = 0.002) and PFS (A: 3 m vs 8 m; p = 0.013). No differences in PFS and OS were observed in squamous cell carcinoma. Significant differences were observed in OS in the PD-L1 negative group (0% expression) (A: 13 m vs B: 39 m; p = 0.024), but not in PFS (A: 3 m vs B: 7 m; p = 0.70). No differences were observed in the PD-L1 positive group. CONCLUSIONS: 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.

Severe Hyponatremia Masking Central Diabetes Insipidus in a Patient with a Lung Adenocarcinoma.

Altered natremia is a common electrolyte disorder in clinical practice and a paraneoplastic manifestation. The syndrome of inappropriate antidiuretic hormone secretion is the first diagnostic suspicion in a patient with cancer and hyponatremia, although entities such as adrenal insufficiency primary or secondary to metastatic involvement must be taken into account. Likewise, immunorelated endrocrinopathies such as hypophysitis have been reported after the introduction of checkpoint inhibitors. A 46-year-old man diagnosed with metastatic adenocarcinoma of the lung with severe hyponatremia (111 mmol/L) consulted due to altered level of consciousness. The initial cranial CT scan did not reveal pituitary brain metastatic involvement; however, an MRI could not be performed due to the patient's clinical situation and subsequent exitus. The water restriction test confirmed the diagnostic suspicion of central diabetes insipidus. Medical treatment with desmopressin was started to avoid fluid depletion with improvement of natremia figures. It represents an exceptional case of central diabetes insipidus masked by severe hyponatremia in a patient with metastatic lung adenocarcinoma without initial evidence of pituitary metastatic involvement by CT imaging in treatment with nivolumab (anti-PD-1 agent). Secondary adrenal insufficiency due to pituitary metastatic involvement and endocrinologic toxicity immunorelated to the new checkpoint inhibitors should be considered as possible etiologic agents of central diabetes insipidus, even with hyponatremia.

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 > 3 and LDH > 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 < 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 < 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.

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.

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.