A Comprehensive Biomarker Analysis of Microsatellite Unstable/Mismatch Repair Deficient Colorectal Cancer Cohort Treated with Immunotherapy.

The search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were included. According to whether the progression-free survival with PD-1/PD-L1 inhibitors was longer than 6 months or shorter, patients were clustered into the IT-responder group (n: 9 patients) or IT-resistant group (n: 7 patients), respectively. In order to evaluate determinants of benefit with PD-1/PD-L1 inhibitors, we performed multimodal analysis including genomics (through NGS panel tumour-only with 431 genes) and the immune microenvironment (using CD3, CD8, FOXP3 and PD-L1 antibodies). The following mutations were more frequent in IT-resistant compared with IT-responder groups: B2M (4/7 versus 2/9), CTNNB1 (2/7 versus 0/9), and biallelic PTEN (3/7 versus 1/9). Biallelic ARID1A mutations were found exclusively in the IT-responder group (4/9 patients). Tumour mutational burden did not correlate with immunotherapy benefit, neither the rate of indels in homopolymeric regions. Of note, biallelic ARID1A mutated tumours had the highest immune infiltration and PD-L1 scores, contrary to tumours with CTNNB1 mutation. Immune microenvironment analysis showed higher densities of different T cell subpopulations and PD-L1 expression in IT-responders. Misdiagnosis of MSI-H/dMMR inferred by discordances between immunohistochemistry and polymerase chain reaction was only found in the IT-resistant population (3/7 patients). Biallelic ARID1A mutations and Wnt signalling activation through CTNNB1 mutation were associated with high and low T cell immune infiltrates, respectively, and deserve special attention as determinants of response to PD-1/PD-L1 inhibitors. The non-MSI-H phenotype in dMMR is associated with poor benefit to immunotherapy. Our results suggest that mechanisms of resistance to immunotherapy are multi-factorial.

Challenges in assessing the real incidence of chronic lymphocytic leukemia: 16 years of epidemiological data from the province of Girona, Spain.

Determining chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) incidence is challenging for two reasons: cancer registries tend to underreport CLL cases and its diagnostic criteria changed markedly in 2008. No studies have reported incidence rates dealing with both difficulties, and thus CLL/SLL burden in Europe is currently uncertain. Herein, we present accurate CLL/SLL incidence in a Spanish region during 1998-2013, using the population-based Girona Cancer Registry (GCR). We detected an 18.2% under-reporting of CLL/SLL cases when combining records from the GCR and additional information sources (i.e., records of flow cytometry laboratories, hospital registries and hematologists' databases). In addition, age-adjusted rates (using the 2013 European population) changed from 7.57 (95% CI 6.87; 8.30) in 1998-2008 to 6.35 (95% CI 5.51; 7.30) in 2009-2013. Overall, completeness of CLL/SLL data requires accurate diagnosis and reporting of cases. Revision of cancer registry operations to include CLL/SLL-specific surveillance is likely to ensure that the monitoring of this malignancy is entirely accurate.

Impact of the COVID-19 pandemic in the early-onset colorectal cancer.

The COVID19 pandemic has affected the spectrum of cancer care worldwide. Early onset colorectal cancer (EOCRC) is defined as diagnosis below the age of 50. Patients with EOCRC faced multiple challenges during the COVID19 pandemic and in some institutions it jeopardized cancer diagnosis and care delivery. Our study aims to identify the clinicopathological features and outcomes of patients with EOCRC in our Centre during the first wave of the pandemic in comparison with the same period in 2019 and 2021. Patients with EOCRC visited for the first time at Vall d'Hebron University Hospital in Spain from the 1st March to 31st August of 2019, 2020 and 2021 were included in the analysis. 177 patients with EOCRC were visited for the first time between 2019 and 2021, of which 90 patients met the inclusion criteria (2019: 30 patients, 2020: 29 patients, 2021: 31 patients). Neither differences in frequency nor in stage at diagnosis or at first visit during the given periods were observed. Of note, indication of systemic therapy in the adjuvant or metastatic setting was not altered. Days to treatment initiation and enrollment in clinical trials in this subpopulation was not affected due to the COVID-19 outbreak.

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer.

Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12-0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10-0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.

Incidence and survival of Hodgkin lymphoma patients in Girona (Spain) over three decades: a population-based study.

Hodgkin lymphoma (HL) is characterized by heterogeneous histologic findings, clinical presentation and outcomes. Using the Girona population-based cancer registry data we sought to explore the incidence of HL over three decades in Girona Province (Spain) and examine the relationship between clinical features at diagnosis and survival. From 1985 to 2013, 459 cases were recorded. Patients were stratified by sex, age group, stage at diagnosis, histological subtypes and the presence of B-symptoms. The crude incidence rate (CR) was 2.7 and the corresponding European age-adjusted rate was 2.6, being higher in men than in women (sex ratio=1.6). Incidence remained constant throughout the period of study. Nodular sclerosis was the most frequent histology and showed an increasing incidence over time [estimated annual percentage change=+2.4, 95% confidence interval (CI): 0.8-4.0]. The 5-year observed survival and relative survival of patients diagnosed with HL were 73.1% (95% CI: 69.0-77.5) and 74.6% (95% CI: 70.0-79.4), respectively. No statistical differences in observed survival were observed across the three decades of study (P=0.455). Clinical parameters negatively influencing 5-year relative survival in the multivariate analysis were as follows: age at diagnosis at least 65 years; clinical stage IV; and presence of B-symptoms. These current patterns of presentation and outcomes of HL help delineate key populations in order to explore risk factors for HL and strategies to improve treatment outcomes.

Descriptive epidemiology of primary malignant and non-malignant central nervous tumors in Spain: Results from the Girona Cancer Registry (1994-2013).

BACKGROUND: Systematic registration of non-malignant central nervous system (CNS) tumors is a rare practice among European cancer registries. Thus, the real burden of all CNS tumors across Europe is underestimated. The Girona Cancer Registry provides here the first data on CNS tumor incidence and survival trends in Spain for all histological types, including malignant and non-malignant tumors. METHODS: Data on all incident cases of primary CNS tumors notified to the Girona population-based cancer registry from 1994 to 2013 (n=2,131) were reviewed. Incidences rates (IRs) were standardized to the 2013 European population and annual percentage changes (EAPC) were estimated using a piecewise log linear model. 1- and 5-year observed (OS) and relative survival (RS) were also calculated. Results were expressed by sex, age-group, histological subtype and behavior. RESULTS: The overall IR was 16.85 and increased across the period of study (EAPC=+2.2%). The proportion and IRs of malignant (50.2%; IR=9.35) and non-malignant cases (49.8%; IR=9.14) were similar; however, non-malignant tumors were more frequent in women (sex ratio=0.63). The most frequently reported histologies were meningioma (27.6%; IR=5.11) and glioblastoma (22.2%; IR=4.15), which also accounted for the highest and lowest 5-year RS (80.2%; 3.7%, respectively). Globally, 5-year RS was lower in men (42.6% vs. 58.3%, respectively) and in the elderly (64.9% for 0-14years vs. 23.0% for >74years). CONCLUSION: This study presents a comprehensive overview of the epidemiology of malignant and non-malignant CNS primary tumors from the well-established region-wide Girona Cancer Registry (1994-2013). Incidence rates were recovered for all histologies. Survival is still dramatically associated to both age and histological subtype.