CTNND1 is involved in germline predisposition to early-onset gastric cancer by affecting cell-to-cell interactions.

BACKGROUND: CDH1 and CTNNA1 remain as the main genes for hereditary gastric cancer. However, they only explain a small fraction of gastric cancer cases with suspected inherited basis. In this study, we aimed to identify new hereditary genes for early-onset gastric cancer patients (EOGC; < 50 years old). METHODS: After germline exome sequencing in 20 EOGC patients and replication of relevant findings by gene-panel sequencing in an independent cohort of 152 patients, CTNND1 stood out as an interesting candidate gene, since its protein product (p120ctn) directly interacts with E-cadherin. We proceeded with functional characterization by generating two knockout CTNND1 cellular models by gene editing and introducing the detected genetic variants using a lentiviral delivery system. We assessed ß-catenin and E-cadherin levels, cell detachment, as well as E-cadherin localization and cell-to-cell interaction by spheroid modeling. RESULTS: Three CTNND1 germline variants [c.28_29delinsCT, p.(Ala10Leu); c.1105C > T, p.(Pro369Ser); c.1537A > G, p.(Asn513Asp)] were identified in our EOGC cohorts. Cells encoding CTNND1 variants displayed altered E-cadherin levels and intercellular interactions. In addition, the p.(Pro369Ser) variant, located in a key region in the E-cadherin/p120ctn binding domain, showed E-cadherin mislocalization. CONCLUSIONS: Defects in CTNND1 could be involved in germline predisposition to gastric cancer by altering E-cadherin and, consequently, cell-to-cell interactions. In the present study, CTNND1 germline variants explained 2% (3/172) of the cases, although further studies in larger external cohorts are needed.

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.

Impact of systemic cancer treatment on quality of life and mental well-being: a comparative analysis of patients with localized and advanced cancer.

INTRODUCTION: This study investigated the impact of systemic cancer therapy on the quality of life, mental well-being, and life satisfaction of cancer patients. METHODS: This prospective study was promoted by the Spanish Society of Medical Oncology (SEOM) and enrolled patients with localized, resected, or unresectable advanced cancer from 15 Spanish medical oncology departments. Patients completed surveys on quality of life (EORTC-QoL-QLQ-C30), psychological distress (BSI-18) and life satisfaction (SWLS) before and after systemic cancer treatment. RESULTS: The study involved 1807 patients, 944 (52%) having resected, localized cancer, and 863 with unresectable advanced cancer. The mean age was 60 years, and 53% were female. The most common types of localized cancer were colorectal (43%) and breast (38%), while bronchopulmonary (32%), non-colorectal digestive (23%), and colorectal (15%) were the most frequent among those with advanced cancer. Before systemic treatment, patients with advanced cancer had poorer scores than those with localized cancer on physical, role, emotional, cognitive, social limitations, symptoms, psychological distress, and life satisfaction (all p < 0.001), but there were no differences in financial hardship. Patients with localized cancer had greater life satisfaction and better mental well-being than those with advanced cancer before systemic treatment (p < 0.001). After treatment, patients with localized cancer experienced worsening of all scales, symptoms, and mental well-being (p < 0.001), while patients with advanced disease had a minor decline in quality of life. The impact on quality of life was greater on all dimensions except economic hardship and was independent of age, cancer location, and performance status in participants with resected disease after adjuvant chemotherapy. CONCLUSION: In conclusion, our study highlights that systemic cancer treatment can improve quality of life in patients with advanced cancer, while adjuvant treatments for localized disease may have a negative impact on quality of life and psychological well-being. Therefore, treatment decisions should be carefully evaluated on an individual basis.

Can Oncologists Prompt Patient Prognostic Awareness to Enhance Decision-Making? Data From the NEOetic Study.

INTRODUCTION: Anti-neoplastic therapy improves the prognosis for advanced cancer, albeit it is not curative. An ethical dilemma that often arises during patients' first appointment with the oncologist is to give them only the prognostic information they can tolerate, even at the cost of compromising preference-based decision-making, versus giving them full information to force prompt prognostic awareness, at the risk of causing psychological harm. METHODS: We recruited 550 participants with advanced cancer. After the appointment, patients and clinicians completed several questionnaires about preferences, expectations, prognostic awareness, hope, psychological symptoms, and other treatment-related aspects. The aim was to characterize the prevalence, explanatory factors, and consequences of inaccurate prognostic awareness and interest in therapy. RESULTS: Inaccurate prognostic awareness affected 74%, conditioned by the administration of vague information without alluding to death (odds ratio [OR] 2.54; 95% CI, 1.47-4.37, adjusted P = .006). A full 68% agreed to low-efficacy therapies. Ethical and psychological factors oriented first-line decision-making, in a trade-off in which some lose quality of life and mood, for others to gain autonomy. Imprecise prognostic awareness was associated with greater interest in low-efficacy treatments (OR 2.27; 95% CI, 1.31-3.84; adjusted P = .017), whereas realistic understanding increased anxiety (OR 1.63; 95% CI, 1.01-2.65; adjusted P = 0.038), depression (OR 1.96; 95% CI, 1.23-3.11; adjusted P = .020), and diminished quality of life (OR 0.47; 95% CI, 0.29-0.75; adjusted P = .011). CONCLUSION: In the age of immunotherapy and targeted therapies, many appear not to understand that antineoplastic therapy is not curative. Within the mix of inputs that comprise inaccurate prognostic awareness, many psychosocial factors are as relevant as the physicians' disclosure of information. Thus, the desire for better decision-making can actually harm the patient.

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.

Role of sex on psychological distress, quality of life, and coping of patients with advanced colorectal and non-colorectal cancer.

BACKGROUND: Patients with advanced gastrointestinal cancer must cope with the negative effects of cancer and complications. AIM: To evaluate psychological distress, quality of life, and coping strategies in patients with advanced colorectal cancer compared to non-colorectal cancer based on sex. METHODS: A prospective, transversal, multicenter study was conducted in 203 patients; 101 (50%) had a colorectal and 102 (50%) had digestive, non-colorectal advanced cancer. Participants completed questionnaires evaluating psychological distress (Brief Symptom Inventory-18), quality of life (EORTC QLQ-C30), and coping strategies (Mini-Mental Adjustment to Cancer) before starting systemic cancer treatment. RESULTS: The study included 42.4% women. Women exhibited more depressive symptoms, anxiety, functional limitations, and anxious preoccupation than men. Patients with non-colorectal digestive cancer and women showed more somatization and physical symptoms than subjects with colorectal cancer and men. Men with colorectal cancer reported the best health status. CONCLUSION: The degree of disease acceptance in gastrointestinal malignancies may depend on sex and location of the primary digestive neoplasm. Future interventions should specifically address sex and tumor site differences in individuals with advanced digestive cancer.

5-fluorouracil toxicity in the treatment of colon cancer associated with the genetic polymorphism 2846 A>G (rs67376798).

Colorectal cancer is the second most common cancer in Europe. Most antineoplastic regimens in first-line treatment involve 5-fluorouracil or oral prodrug capecitabine, combined with other antineoplastic agents such as oxaliplatin or irinotecan. It is well known that 5-fluorouracil and capecitabine are agents that can be toxic in cases of decreased dihydropyrimidine dehydrogenase activity because this enzyme is the main limiting factor in the metabolism of both agents. In this paper, we describe the case of a patient who developed severe toxicity to 5-fluouracil and who had a mutation in the gene encoding the enzyme dihydropyrimidine dehydrogenase.