European Journal of Cancer最新文献

Mismatch repair deficiency (MMR-d) and microsatellite instability (MSI) are prognostic and predictive biomarkers in oncology. Current testing for MMR/MSI relies on immunohistochemistry (IHC) for MMR proteins and molecular assays for MSI detection. This combined diagnostic strategy, however, lacks tumor specificity and does not account for gene variants. This study provides an in-depth analysis of MMR mutations frequency, spectrum, and distribution in solid tumors. Data from 23,893 patients across 11 tumor types, using 66 publicly available studies, were analyzed. MMR-mutated (MMR-m) status was defined by alterations in MLH1, PMS2, MSH2, and/or MSH6; MSI was assessed by MSIsensor. Cases with indeterminate labelling were excluded. Survival was analyzed using the Kaplan-Meier method. Among 19,353 tumors, 949 MMR variants were identified, comprising 432 pathogenic and 517 variants of unknown significance (VUS), as defined by OncoKB. MSH6 mutations were the most frequent (n = 279, 29.4 %), followed by MSH2 (n = 198, 20.9 %), MLH1 (n = 187, 19.7 %), and PMS2 (n = 161, 16.9 %). MMR-m cases were more frequent in endometrial (EC, 20.5 %), colorectal (CRC, 8.2 %), bladder (BLCA, 8.7 %), and gastroesophageal cancers (GEC, 5.4 %). Pathogenic mutations were more common than non-pathogenic in EC, CRC, and GEC (p < 0.001, p = 0.01, p = 0.32, respectively). MMR-m status was not associated with MSI in 247 (48.9 %) cases, including 67 (13.2 %) with pathogenic mutations. The highest concordance between MMR-m and MSI was observed in CRC (65.7 %), EC (91.2 %), and GEC (69.6 %), while the lowest in pancreatic (0.2 %) and lung cancers (0.1 %). MMR-m GECs showed improved overall survival compared to MMR-wt (p = 0.009), a relationship not observed in other tumor types. This study demonstrates that the MMR spectrum is extremely hetoerogeneous in solid tumors, highliting the need for comprehensive and tumor-specific testing strategies.

Purpose: Moderate hypofractionation was adopted to reduce hospital visits during the COVID-19 pandemic aiming to maintain treatment efficacy for soft tissue sarcoma (STS) patients, shifting preoperative schedules from 25 fractions of 2 Gy to 14-15 fractions of 3 Gy. This study evaluates the clinical implications and outcomes of this schedule, focusing on wound complications, radiation toxicity, local tumour control, and distant metastases.

Patients and methods: Data was collected from patients treated between 01 and 01-2020 and 31-12-2023. Outcomes included wound complications within 120 days post-surgery, local-recurrence, distant metastases and radiation toxicity. Logistic regression was performed to identify factors associated with wound complications. The cumulative incidence of local recurrence and distant metastases were estimated with a competing risk model.

Results: Sixty-six patients were analysed, with a mean age of 74 years (standard deviation (SD)± 11). Tumours were mainly localized in the lower extremities (64 %), mean size 103 mm (SD±58). Median follow-up was 29 months (range 2-50). A R0 resection margin was achieved in 77 % of the operated patients. The wound complication rate was 33 %, with moderate complications in 13 patients and severe in 6. The cumulative incidences of local recurrence and distant metastases at 2 years were 7.6 % (standard error (SE) 3.7 %) and 29 % (SE 6 %, Fig. 1) respectively. Acute grade 3 dermatitis occurred in one patient (1.5 %)and two patients experienced late grade 3 toxicity (fractures, 3.0 %). Twenty patients developed distant metastases, two diagnosed before start of the treatment. Eighteen patients died, with six deaths from distant metastases and one from the primary tumour.

Conclusion: Preoperative moderate hypofractionation for STS during COVID-19 showed promising results, with no increase in postoperative wound complications and favourable local failure rates.

Background: Epidemiological data for sarcoma in adolescents and young adults (AYAs) and across age groups are limited. We aim to: 1) update sarcoma incidence, survival, and changes over time in European AYAs; 2) provide an updated comparison of sarcoma survival in AYAs versus children and mature adults.

Methods: We calculated crude incidence rates (IR) per 100,000 European population per year from 2006 to 2013. Using the period approach, we calculated 5-year relative survival (RS) for the follow-up period 2010-2014. We estimated changes in incidence and survival for bone sarcoma (BS) and soft tissue sarcoma (STS) subtypes in AYAs in the years 2000-2013.

Findings: In European AYAs, the IR was 0.81/100,000 for BS and 1.45/100,000 for STS. Five-year RS was 69 % and 65 % for BS and STS, respectively. Compared to children, AYAs had poorer survival for Ewing sarcoma of bone, synovial sarcoma, Ewing sarcoma of soft tissue and rhabdomyosarcoma. Compared to mature adults, AYAs had higher 5-year RS for all BS and for most of the STS subtypes. In AYAs, incidence increased for a few bone and soft tissue subtypes. Survival increased mainly for BS.

Interpretation: The reason for the better survival observed in AYAs compared to mature adults is probably multifactorial. The limited improvement of STS survival in AYAs may reflect the relative absence of new drugs for STS during the study period. The increase in RS for BS might relate to general improvements in radiological and surgical approaches and radiotherapy techniques.

Fewer than 10 % of children with diffuse midline glioma (DMG) survive 2 years from diagnosis. Radiation therapy remains the cornerstone of treatment and there are no medicinal products with regulatory approval. Although the biology of DMG is better characterized, this has not yet translated into effective treatments. H3K27-alterations initiate the disease but additional drivers are required for malignant growth. Hence, there is an urgent unmet need to develop new multi-modality therapeutic strategies, including alternative methods of drug delivery. ONC201 (DRD2 antagonist and mitochondrial ClpP agonist) is the most widely evaluated investigational drug. Encouraging early data is emerging for CAR T-cells and oncolytic viruses. GD2, B7-H3 and PI3K signalling are ubiquitous targets across all subtypes and therapeutics directed to these targets would potentially benefit the largest number of children. PI3K, ACVR1, MAPK and PDGFRA pathways should be targeted in rational biological combinations. Drug discovery is a very high priority. New specific and potent epigenetic modifiers (PROTACS e.g. SMARCA4 degraders), with blood-brain penetrance are needed. Cancer neuroscience therapeutics are in early development. Overall survival is the preferred regulatory endpoint. However, the evaluation of this can be influenced by the use of re-irradiation at the time of progression. An efficient clinical trial design fit for regulatory purposes for the evaluation of new therapeutics would aid industry and facilitate more efficient therapy development. Challenges in conducting clinical trials such as the need for comparator data and defining endpoints, could be addressed through an international, first-in-child, randomised, complex innovative design trial. To achieve progress: i) drug discovery; ii) new multi-modality, efficient, collaborative, pre-clinical approaches, possibly including artificial intelligence and, iii) efficient clinical trial designs fit for regulatory purposes are required.

Background: CONCORD-3 highlighted wide disparities in population-based 5-year net survival for cutaneous melanoma during 2000-2014. Studies showed a survival advantage in women, but the reasons are not completely understood. We aim to estimate trends in age-standardised 5-year net survival by sex and to examine the role of age, anatomic location and stage on the survival advantage for women worldwide.

Methods: Patients were grouped into five anatomic locations (head and neck, trunk, limbs, genital organs and not otherwise specified locations), into five age groups (15-29, 30-44, 45-59, 60-74 and 75-99 years) and into binary stage (non-metastatic vs. metastatic). We estimated net survival with the non-parametric Pohar Perme estimator, correcting for background mortality by single-year of age, sex, race/ethnicity where possible and calendar year in each country. All-ages estimates were standardised with the International Cancer Survival Standard weights.

Results: Men were generally older and with higher proportion of metastatic melanomas than women. Overall, the trunk was the most common location in men (range 31 %-58 %) and the lower limbs and hips in women (26 %-40 %). Age-standardised 5-year net survival was lower in men (43 %-92 %) than in women (54 %-95 %) in all countries during 2010-2014 and it was lower at older ages for both sexes. A survival advantage for women was observed for all anatomic sites and for localised disease.

Conclusions: Women had a more favourable distribution of main prognostic factors, and showed highest survival for any prognostic factor. Public health efforts should focus on raising awareness of early signs of melanoma, especially among elderly in South-East Europe and to increase awareness in East-Asia, where survival was poorest.

The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Utility - Core 10 Dimensions (QLU-C10D) adds a preference-based scoring algorithm to the EORTC measurement portfolio. It is built on the most widely used health-related quality of life (HRQoL) measure in oncology, the EORTC Quality of Life Questionnaire - Core 30 (QLQ-C30), allowing for the calculation of both HRQoL profiles and health utilities. This is an important advancement for integrating cancer-specific values into health economic evaluations and decision making, offering greater content validity and statistical power than some generic measures. This article presents an outline of the EORTC QLU-C10D User Manual to inform health-technology bodies, academic researchers, and industry, on the why and how of using this instrument for utility measurement. It covers basic concepts, proper use of the tool, including administration and scoring. Further, we summarise the presently published valuation studies, country-specific value sets, and body of evidence about psychometric properties. Current methodological questions are discussed, including mapping between utility measures and adaptions of generic measures for use in cancer populations. Taking into account empirical studies on psychometric properties, like content and construct validity, and comparisons with generic measures, we argue that the QLU-C10D is a reliable and valid instrument for cancer populations. Without imposing additional patient and administrative burden it has the potential to support health economic decisions in cancer by providing high-quality cancer-specific utility scores, to complement the more detailed HRQoL information from the QLQ-C30.

Background: Sublobar resection is increasingly recognized as an effective treatment for early-stage NSCLC. However, no studies to date have investigated the potential role of preoperative ctDNA detection in guiding surgical decisions, such as opting for sublobar resection, in stage I NSCLC.

Methods: Patients with solid-dominant (CTR>0.5), clinical stage I NSCLC were prospectively recruited between March 2014 and December 2020. Pre-surgical plasma samples were analyzed using a tumor-naïve, methylation-based cell-free DNA assay. The impact of sublobar resection versus lobectomy on recurrence-free survival (RFS) was assessed according to pre-surgical ctDNA status. Associations between pre-surgical ctDNA detection and clinicopathologic factors were also investigated.

Results: The analysis included 544 patients (178 women [33 %]; median age 66 [IQR, 60-71] years). Pre-surgical ctDNA was detected in 188 (35 %) patients. In patients without presurgical ctDNA, sublobar resection did not significantly increase the risk of relapse (adjusted HR, 1.01, p = 0.98). However, among ctDNA-positive patients, sublobar resection was associated with an increased risk of relapse (adjusted HR, 2.25; 95 % CI, 1.12-4.54; p = 0.024). Patients with presurgical ctDNA had higher rates of nodal upstaging (OR, 3.58; p < 0.001) and exhibited higher pathologic grade (p = 0.021), perineural invasion (p < 0.001), and lymphovascular invasion (p < 0.001).

Conclusions: Pre-surgical tumor-naïve ctDNA analysis holds promise in identifying patients with aggressive tumors that may not be sufficiently managed with sublobar resection. This approach can help personalize treatment strategies, potentially improving outcomes for patients with early-stage NSCLC.

Background: Targeting modifiable factors offers significant potential for primary cancer prevention. For public health strategies, it is essential to quantify the contribution from each factor on a national level. We estimated the contribution of 12 modifiable factors on cancer incidence in the Norwegian population.

Methods: Nationally representative data (1990-2015) on the prevalence of tobacco smoking, over-exposure to ultraviolet radiation (UVR), alcohol consumption, physical inactivity, overweight and obesity, intake of processed and red meat, fibre and calcium, menopausal hormone therapy (MHT), human papilloma virus (HPV) infection and insufficient breastfeeding were collected from health surveys. Using these prevalences, cancer risk estimates for for the exposures, and average annual cancer incidence rates for 2016-2020, we estimated annual population-attributable fractions (PAFs) and numbers of preventable cases.

Results: Of the average 24,608 annual cases of cancers related to our included modifiable factors, 12,12,250 (6240 in women and 6009 in men) (41 %) were attributed to these factors. Tobacco smoking caused the highest proportion of cancers cases, 20 % in men and 13 % in women. Sunburn and indoor tanning caused 13 % and 10 % of cancers in men and women, respectively, and overweight and obesity caused 4.5 % of the cases. Cancers of skin, lung, colon and female breast had the highest number of preventable cases.

Conclusion: Over a third of the annual cancer cases in Norway were attributed to 12 modifiable factors. Based on this study, efforts to reduce tobacco smoking, UVR over-exposure, and overweight and obesity could be the most effective in primary prevention of cancer.