Resistance to immune checkpoint inhibitors in colorectal cancer with deficient mismatch repair/microsatellite instability: misdiagnosis, pseudoprogression and/or tumor heterogeneity?

Colorectal carcinoma (CRC) with deficiency of the deficient mismatch repair (dMMR) pathway/microsatellite instability (MSI) is characterized by a high mutation load and infiltration of immune cells in the tumor microenvironment. In agreement with these findings, clinical trials have demonstrated a significant activity of immune checkpoint inhibitors (ICIs) in dMMR/MSI metastatic CRC (mCRC) patients and, more recently, in CRC patients with early disease undergoing neoadjuvant therapy. However, despite high response rates and durable clinical benefits, a fraction of mCRC patients, up to 30%, showed progressive disease when treated with single agent anti-programmed cell death 1 (PD-1) antibody. This article discusses the three main causes that have been associated with early progression of dMMR/MSI mCRC patients while on treatment with ICIs, i.e., misdiagnosis, pseudoprogression and tumor heterogeneity. While pseudoprogression probably does not play a relevant role, data from clinical studies demonstrate that some dMMR/MSI CRC cases with rapid progression on ICIs may be misdiagnosed, underlining the importance of correct diagnostics. More importantly, evidence suggests that dMMR/MSI mCRC is a heterogeneous group of tumors with different sensitivity to ICIs. Therefore, we propose novel diagnostic and therapeutic strategies to improve the outcome of dMMR/MSI CRC patients.

The development of an archive of patient-reported outcome measures (PROMs) in oncology: The Italian PRO4All project.

BACKGROUND: Choosing the most adequate measure of patient-reported outcomes (PROs) for a specific medical condition is not straightforward. This study aimed to develop a comprehensive archive of patient-reported outcome measures (PROMs), observer-reported outcome measures (ObsROMs) and caregiver-reported outcome measures (CROMs) in oncology and identify their main characteristics and target outcome domains. MATERIALS AND METHODS: As part of the Italian PRO4All Project, we retrieved questionnaires through an extensive search of online databases. We developed a data extraction form to collect information on cancer type, questionnaire variant(s), recall period, and scoring system. We performed a content analysis of the questionnaires to assign each item a specific outcome domain according to a predefined 38-item taxonomy. RESULTS: A total of 386 PROMs (n = 356), ObsROMs (n = 13) and CROMs (n = 17) were identified and described; of these, 358 were also analyzed in their content. 47.3 % of the instruments were cancer type-specific, 45.1 % were generic for cancer and 7.9 % were developed for the general population but also recommended in oncology. The great majority (92.2 %) were patient-reported. In 50.3 % the recall period was "last week". The mean number of items per questionnaire was 22.0 (range: 1-130). 7794 items were assigned an outcome domain, the most frequent being emotional functioning/wellbeing (22 %), physical functioning (15.7 %), general outcomes (10.1 %) and delivery of care (8.9 %). CONCLUSIONS: There are a variety of patient and caregiver-reported measures in oncology. This archive can guide researchers and practitioners in selecting the most suitable measures and fostering a patient-centered approach in clinical trials, clinical practice, and regulatory activities.

Rare Driver Mutations in Advanced, Oncogene-Addicted Non-Small Cell Lung Cancer: A North Italian, Real-World, Registry Experience.

The real-world, retrospective, NEROnE registry investigated the impact of next-generation sequencing (NGS) in advanced non-small-cell lung cancer (NSCLC) patients (pts) at three oncology units in the north of Italy between January 2020 and December 2022. We focused on the clinical characterization and outcomes of NSCLC with rare molecular alterations: EGFR exon 20 insertion, non-activating EGFR mutations, BRAF V600E and non-V600, ROS1 and RET rearrangements, MET, ErbB2, and FGFR mutations. Overall, these represented 6.4% (62/970) of the pts analysed with NGS in the daily practice. The most heavily represented rare alterations were ROS1 rearrangement (15 pts-24%) and MET exon 14 skipping mutation (11 pts-18%). No associations were found with the demographic and clinical features. Forty-nine pts received targeted therapies, of which 38.8% were first- and 9.8% were second-line. The remaining pts received chemotherapy and/or immunotherapy. In terms of the clinical outcomes, although not statistically significant, a tendency toward shorter OS was seen when therapies other than specific targeted therapies were used (HR: 1.84, 95% CI: 0.79-4.33, p = 0.158). The pts with co-mutations (19.4%) seemed to receive an advantage from the front-line chemotherapy-based regimen. Finally, an NLR score (a well-known inflammatory index) ≥ 4 seemed to be related to shorter OS among the pts treated with immunotherapy alone or in combination with chemotherapy (HR: 2.83, 95% CI: 1.08-7.40, p = 0.033). Prospective evaluations need to be performed to clarify whether these indexes may help to identify patients with oncogene-addicted NSCLC who could benefit from immunotherapy.

Corrigendum to "Comparison of baseline patient characteristics in Italian oncology drug monitoring registries and clinical trials: a real-world cross-sectional study" [The Lancet Regional Health - Europe 41 (2024) 100912].

[This corrects the article DOI: 10.1016/j.lanepe.2024.100912.].

Comparison of baseline patient characteristics in Italian oncology drug monitoring registries and clinical trials: a real-world cross-sectional study.

Background: Generalizability of registrative clinical trials to real-world clinical practice is influenced by comparability of patients in the two settings. We compared characteristics of cancer patients in registrative trials with real-world clinical practice in Italy. Methods: Data on age, sex and performance status (PS) were derived from web-based monitoring registries developed by Italian Medicines Agency (AIFA) and corresponding registrative trials reported in the European Public Assessment Reports (EPAR) of European Medicines Agency (EMA). Weighted means were calculated in registries and trials and differences were described. Multivariate analysis was performed using Principal Component Analysis and Cluster Analysis. Findings: From January, 2013 to April, 2023, 419,461 unique pairs of patients and therapeutic indications were recorded in 129 AIFA registries. Within 140 related trials, 87,452 patients had been enrolled. Median age and rate of elderly (≥65 years old) patients were higher in monitoring registries than in clinical trials [mean difference of median age 5.3 years, p < 0.001; mean difference of elderly rate 17.17% (95% CI 1.06, 1.48)]. Overall, rate of female patients was not different between registries and trials [mean difference -0.55% (95% CI -1.06, -0.05)]. Mean rate of patients with deteriorated PS was low both in trials (3.1%) and in registries (4.3%) with a mean difference of 1.27% (95% CI 1.06, 1.48). Two clusters were identified with multivariate analysis: one including more registries (higher median age and elderly rate, lower female rate, higher rate of deteriorated patients), the other more trials (lower median age and elderly rate, higher female rate, lower rate of deteriorated patients). Interpretation: This study supports that cancer patients enrolled in trials do only partially represent those who have been treated in Italy in clinical practice. Inclusiveness of registrative trials should be increased to ensure generalizability of results to real-world population. Funding: Partially supported by Italian Ministry of Health.

Atherosclerosis and the Bidirectional Relationship between Cancer and Cardiovascular Disease: From Bench to Bedside-Part 1.

Atherosclerosis, a complex metabolic-immune disease characterized by chronic inflammation driven by the buildup of lipid-rich plaques within arterial walls, has emerged as a pivotal factor in the intricate interplay between cancer and cardiovascular disease. This bidirectional relationship, marked by shared risk factors and pathophysiological mechanisms, underscores the need for a comprehensive understanding of how these two formidable health challenges intersect and influence each other. Cancer and its treatments can contribute to the progression of atherosclerosis, while atherosclerosis, with its inflammatory microenvironment, can exert profound effects on cancer development and outcomes. Both cancer and cardiovascular disease involve intricate interactions between general and personal exposomes. In this review, we aim to summarize the state of the art of translational data and try to show how oncologic studies on cardiotoxicity can broaden our knowledge of crucial pathways in cardiovascular biology and exert a positive impact on precision cardiology and cardio-oncology.

Corrigendum: Aromatase inhibitors: the journey from the state of the art to clinical open questions.

[This corrects the article DOI: 10.3389/fonc.2023.1249160.].

Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Versus Cetuximab as Maintenance Therapy in First-Line Therapy for RAS and BRAF Wild-Type Metastatic Colorectal Cancer: Phase III ERMES Study.

PURPOSE: The intensity of anti-EGFR-based first-line therapy for RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC), once disease control is achieved, is controversial. A de-escalation strategy with anti-EGFR monotherapy represents a potential option to maintain efficacy while reducing cytotoxicity. METHODS: In this multicenter, open-label, phase III trial, patients with untreated RAS/BRAF wt mCRC were randomly assigned to receive either fluorouracil, leucovorin, and irinotecan/cetuximab (FOLFIRI/Cet) until disease progression (arm A) or FOLFIRI/Cet for eight cycles followed by Cet alone (arm B). The coprimary end points were a noninferior progression-free survival (PFS) in the modified per-protocol (mPP) population (>eight cycles) and a lower incidence of grade (G) 3-4 adverse events (AEs) for arm B compared with arm A. RESULTS: Overall, 606 patients were randomly assigned, with 300 assigned to arm A and 306 to arm B. The median follow-up was 22.3 months. In the mPP population, 291 events occurred with a PFS of 10 versus 12.2 months for arms B and A, respectively (P of noninferiority = .43). In the intention-to-treatment (ITT, ≥one cycle) population, 503 events occurred with a PFS of 9 versus 10.7 months (P = .39). The overall survival was 35.7 versus 30.7 months (P = .119) and 31.0 versus 25.2 months (P = .32) in the mPP and ITT population, respectively. Arm B had lower G3-4 AEs during the maintenance period than arm A (20.2% v 35.1%). CONCLUSION: The ERMES study did not demonstrate noninferiority of maintenance with Cet alone. Despite a more favorable safety profile, maintenance with single-agent Cet after induction with FOLFIRI/Cet cannot be recommended for all patients but could represent an option in selected cases.

Standardized and simplified reporting of next-generation sequencing results in advanced non-small-cell lung cancer: Practical indications from an Italian multidisciplinary group.

Molecular biomarker testing is increasingly becoming standard of care for advanced non-small cell lung cancer (NSCLC). Tissue and liquid biopsy-based next-generation sequencing (NGS) is now highly recommended and has become an integral part of the routine management of advanced NSCLC patients. This highly sensitive approach can simultaneously and efficiently detect multiple biomarkers even in scant samples. However full optimization of NGS in clinical practice requires accurate reporting and interpretation of NGS findings. Indeed, as the number of NSCLC biomarkers continues to grow, clinical reporting of NGS data is becoming increasingly complex. In this scenario, achieving standardization, simplification, and improved readability of NGS reports is key to ensuring timely and appropriate treatment decisions. In an effort to address the complexity and lengthy reporting of NGS mutation results, an Italian group of 14 healthcare professionals involved in NSCLC management convened in 2023 to address the content, structure, and ease-of-use of NGS reporting practices and proposed a standard report template for clinical use This article presents the key discussion points addressed by the Italian working group and describes the essential elements of the report template.

Cetuximab every 2 weeks versus standard weekly dosing administration schedule.

Cetuximab every 2 weeks (Q2W) dosing schedule is approved by the US FDA and by the Japanese Pharmaceuticals and Medical Devices Agency in patients with metastatic colorectal cancer and squamous cell carcinoma of the head and neck. Phase II trials have found comparable efficacy and safety for the weekly (Q1W) and Q2W schedules, and real-world studies have shown noninferiority of the Q2W compared with the Q1W schedule. Several guidelines recommend cetuximab Q2W administration as an alternative to the Q1W dosing schedule. Cetuximab Q2W can be administered with a Q2W dose of chemotherapy, making it a more convenient option to the Q1W schedule, potentially resulting in reduced costs for administration, increased flexibility for clinical staff and improved patient adherence.

Cetuximab is a drug for patients with colorectal cancer or cancer of the head and neck. It is usually administered once a week. However, studies have shown that cetuximab given once every 2 weeks instead has similar clinical benefits and side effects. Based on this evidence, the every 2 weeks dosing schedule has been approved for use in USA and Japan. The every 2 weeks dosing schedule is a convenient alternative to the weekly schedule. It may result in fewer hospital visits, improved patient quality of life, reduced healthcare costs and more flexibility for medical staff. This review summarizes the current evidence and benefits for the every 2 weeks dosing schedule.

Incidence and Survival of Testicular Cancers in a Province in Northern Italy and Their Association with Second Tumors.

This study investigated the incidence, mortality, and 5-year survival rates of testicular cancers diagnosed in a northern Italian province, which were eventually associated with previous or subsequent extratesticular neoplasms. Cases from 1996 to 2020 were examined by age and histotype (seminoma vs. non-seminoma). The standardized incidence rate was calculated using the European population, and the annual percent change (APC) was reported. The five-year relative survival was estimated using the Pohar Perme method. The association with the second neoplasm was also evaluated. In our study, 385 patients with testicular cancer were included, most of whom were aged between 30 and 40 years. The non-seminoma and seminoma groups accounted for 44% and 18% of younger adults, respectively. The incidence rate increased during the study period (APC 1.6*); however, it increased in seminomas (APC 2.3*) but not in non-seminomas (APC -0.1). Conversely, the mortality rate remained constantly low either overall or in each of the two groups. The overall 5-year survival rate of testicular cancer patients was 95% (99% and 88% for seminomas and non-seminomas, respectively). Primary extratesticular tumors were documented in 37 cases, 18 after and 19 before the testicular cancer diagnosis. Our study confirms that the increased incidence and excellent survival rate are the prerogative of seminomas.

Implementation of Precision Oncology in the National Healthcare System: A Statement Proposal Endorsed by Italian Scientific Societies.

PURPOSE: Precision oncology (PO) promises positive results for patients. To date, in Italy, the effort to implement PO has been made autonomously by regional health institutions in a top-down fashion. This approach is not very efficient and jeopardizes patients' equal access to PO. Similar outcomes have been recorded in other Western countries. We tested a method of collaboration among professionals, scientific societies, and government institutions to facilitate the delivery of PO innovation to patients' bedsides. METHOD: We designed an organizational research project on the basis of a bottom-up approach. We started by observing PO-related activities in five health care authorities (HCAs) in one Italian region. We then compared the issues that emerged with those of three additional HCAs in other Italian regions. Using the results of the initial observation and adopting validated multiple-step consensus methods, we finally derived 14 statements that were approved by the four main scientific societies of oncology and pathology at the national level. RESULTS: The 14 statements addressed the main issues linked to the implementation of PO in clinical practice. The strong professional consensus advocated for prompt adoption within the national healthcare system. CONCLUSIONS: The consensus on the statements that were obtained shows the importance of a synergistic effort among professionals, scientific societies, and health care institutions in defining homogeneous solutions for innovation implementation within the health care system.

Using peripheral immune-inflammatory blood markers in tumors treated with immune checkpoint inhibitors: An INVIDIa-2 study sub-analysis.

The neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammatory index (SII) have been reported as prognosticators in non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and melanoma. This analysis of the INVIDIa-2 study on influenza vaccination in patients with cancer treated with immune checkpoint inhibitors (ICIs) assessed NLR and SII on overall survival (OS) by literature-reported (LR), receiver operating characteristic curve (ROC)-derived (ROC) cutoffs or as continuous variable (CV). NLR and SII with ROC cutoffs of <3.4 (p < 0.001) and <831 (p < 0.001) were independent factors for OS in multivariate analysis. SII with LR, ROC, or CV significantly predicted OS in NSCLC (p = 0.002, p = 0.003, p = 0.003), RCC (p = 0.034, p = 0.014, p = 0.014), and melanoma (p = 0.038, p = 0.022, p = 0.019). NLR with LR and ROC cutoffs predicted OS in first line (p < 0.001 for both) and second line or beyond (p = 0.006 for both); likewise SII (p < 0.001; p = 0.002 and p < 0.001). NLR and SII are prognosticators in NSCLC, RCC, and melanoma treated with ICIs.

[Hormone therapy, cardio-metabolic profile, and cardiotoxicity. Still a dark side of cardio-oncology - Part 2: Prostate cancer]. / Terapia ormonale, assetto cardio-metabolico e cardiotossicità. Il lato ancora oscuro della cardioncologia ­ Parte 2: Tumore della prostata.

Hormone therapies (HTs) with anti-androgenic properties are a cornerstone for the treatment of prostate cancer (PC) and have significantly improved the survival of patients, though exposing them to a higher risk of cardiovascular diseases (CVDs), which represent a major cause of morbidity and mortality. This occurs due to the high average age of patients undergoing HT for PC, an age group in which CVDs have a high prevalence and incidence, and due to the type and duration of HTs that are increasingly effective but at the same time more aggressive towards cardiovascular health. Recent evidence from the real world suggests, however, that the cardiometabolic risk is widely underestimated and undertreated with significant impact also on the oncological prognosis. In the light of the results of the PRONOUNCE study, in this review it is emphasized the need for a multidisciplinary management of patients with PC who are candidate for or treated with HT by implementing a personalized treatment program in accordance with the current European guidelines on CVD prevention.

Implementation of precision medicine in healthcare-A European perspective.

The technical development of high-throughput sequencing technologies and the parallel development of targeted therapies in the last decade have enabled a transition from traditional medicine to personalized treatment and care. In this way, by using comprehensive genomic testing, more effective treatments with fewer side effects are provided to each patient-that is, precision or personalized medicine (PM). In several European countries-such as in England, France, Denmark, and Spain-the governments have adopted national strategies and taken "top-down" decisions to invest in national infrastructure for PM. In other countries-such as Sweden, Germany, and Italy with regionally organized healthcare systems-the profession has instead taken "bottom-up" initiatives to build competence networks and infrastructure to enable equal access to PM. In this review, we summarize key learnings at the European level on the implementation process to establish sustainable governance and organization for PM at the regional, national, and EU/international levels. We also discuss critical ethical and legal aspects of implementing PM, and the importance of access to real-world data and performing clinical trials for evidence generation, as well as the need for improved reimbursement models, increased cross-disciplinary education and patient involvement. In summary, PM represents a paradigm shift, and modernization of healthcare and all relevant stakeholders-that is, healthcare, academia, policymakers, industry, and patients-must be involved in this system transformation to create a sustainable, non-siloed ecosystem for precision healthcare that benefits our patients and society at large.

The role of nanoliposomal irinotecan plus fluorouracil/leucovorin in the continuum of care of patients with metastatic pancreatic ductal adenocarcinoma.

BACKGROUND: The NAPOLI-I trial showed better outcome of nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) compared to 5-FU/LV in patients with advanced pancreatic ductal adenocarcinoma cancer (advPDAC) progressed to gemcitabine-based therapy. This study aims to explore the real-world efficacy and safety of 5-FU/LV-nal-IRI. METHODS: This is a retrospective multicenter analysis including advPDAC patients receiving 5-FU/LV-nal-IRI after failure of gemcitabine-based therapy. Survival analyses were performed using Kaplan-Meier method, univariate and multivariate analyses by Cox regression. RESULTS: A total of 296 patients (median age 64.4 years, ECOG PS ≥1 in 56% of cases) were treated at 11 Italian institutions between 2016 and 2018. 34% of them underwent primary tumor resection, and 79% received gemcitabine-nabpaclitaxel as first line. 5-FU/LV-nal-IRI was administered as second-line in 73% of cases. Objective response and disease control rate were 12% and 41%, respectively. Treatment was well tolerated with dose reductions in 50% of patients but no one permanent discontinuation; the commonest grade ≥3 toxicities were neutropenia (14%) and diarrhea (12%). Median PFS and OS from 5-FU/LV-nal-IRI initiation was 3.2 and 7.1 months, respectively. CONCLUSIONS: These real-world data confirm the 5-FU/LV-nal-IRI efficacy and safety in advPDAC patients progressed to gemcitabine-based therapy, with outcomes comparable to NAPOLI-1, even in a less-selected population and with more modern therapeutic algorithm.

Changes in the Histology of Lung Cancer in Northern Italy: Impact on Incidence and Mortality.

This study assessed the incidence, mortality, and survival of lung cancer subtypes of NSCSLC (non-small-cell lung cancer), SCLC (small-cell lung cancer), and other morphologies. It is an observational epidemiological study using 7197 cases from the Reggio Emilia Cancer Registry recorded between 2001 and 2020 in males and females. The incidence of NSCLC in 5104 males indicates a significant 3% annual increase until 2013 and then a decline of -3.2% that is not statistically significant; until 2014, mortality increased significantly (3.2%), but it then decreased non-significantly (-12.1%), especially squamous cell cancer. In 2093 females, the incidence and mortality trends continued to rise significantly through 2012, and then they began to slightly decline (not statistically significant). The two-year relative survival of NSCLC increased from 32% to 38% in males and from 42% to 56% in females. SCLC in males decreased significantly both in incidence and mortality, while in women, it showed a slight increase (significantly for incidence but not for mortality). This study is important because it analyzes the decrease in lung cancer in males and the increase in females in relation to the different histotypes. Our study's findings confirmed a decline in male incidence and death beginning in 2013. We were unable to determine if the drop in cigarette smoking and the introduction of new drugs such as EGFR in first-line therapy were responsible for the lower incidence.

Current practice of genomic profiling of patients with advanced solid tumours in Italy: the Italian Register of Actionable Mutations (RATIONAL) study.

BACKGROUND: The Italian Register of Actionable Mutations (RATIONAL) is a multicentric, observational study collecting next-generation sequencing (NGS)-based tumour profiling data of patients with advanced solid tumours. METHODS: The study enrols patients who had available an NGS-based tumour profiling (Pathway-A) or undergo comprehensive genomic profiling (CGP) with FoundationOne CDx assays within the trial (Pathway-B). The primary endpoint was the rate of actionable mutations identified. RESULTS: Sequencing data were available for 738 patients in Pathway-A (218) and -B (520). In Pathway-A, 154/218 (70.6%) tests were performed using NGS panels ≤52 genes, and genomic alterations (GAs) were found in 164/218 (75.2%) patients. In Pathway-B, CGP revealed GAs in 512/520 (98.5%) patients. Levels I/II/III actionable GAs according to the European Society of Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) were identified in 254/554 (45.8%) patients with non-small-cell lung cancer, cholangiocarcinoma, colorectal, gastric, pancreatic and breast cancer. The rate of patients with level I GAs was similar in Pathways A and B (69 versus 102). CGP in Pathway-B revealed a higher number of patients with level II/III GAs (99 versus 20) and potentially germline pathogenic/likely pathogenic variants (58 versus 15) as compared with standard testing in Pathway-A. In patients with cancer of unknown primary, CGP detected OncoKB levels 3B/4 GAs in 31/58 (53.4%) cases. Overall, 67/573 (11.7%) of patients received targeted therapy based on genomic testing. CONCLUSION: The Italian Register of Actionable Mutations represents the first overview of genomic profiling in Italian current clinical practice and highlights the utility of CGP for identifying therapeutic targets in selected cancer patients.

The Impact of COVID-19 on New Kidney Cancer Diagnosis: Stage and Treatment in Northern Italy.

This study aims to evaluate the impact of COVID-19 on new renal carcinoma (RC) diagnoses using data from the Reggio Emilia Cancer Registry in 2018-2020. A total of 293 RCs were registered, with roughly 100 cases yearly. The distribution by age shows a significant decrease in the 30-59 age group (33.7% in 2018, 24.8% in 2019, and 19.8% in 2020). The incidence of Stage I was 59.4%, 46.5%, and 58.2% in 2018, 2019, and 2020, respectively, whereas the Stage II rate had values of 6.9%, 7.9%, and 2.2% in the years 2018, 2019, and 2020, respectively. Slight non-significant variations were observed in Stages III and IV. Surgery was performed in 83.2% of cases in 2018, 78.2% in 2019, and 82.4% in 2020; the surgery distribution by stage showed no significant differences. Chemotherapy showed an increase in 2020, which was statistically significant only for Stage IV. The gender incidence trends over the last 25 years showed an increase in the male sex in the first period; then, a decline was documented, likely due to a decrease in cigarette consumption. In females, the trend was constant. The RC mortality trend significantly dropped in both genders over the entire study period.