BACKGROUND:Over the past decade, there has been a significant shift from paper-based to digital medical record management, driven largely by advances in digital technology. This transition has led to widespread adoption of Electronic Medical Records (EMRs), with the expectation that paper documentation will soon be fully replaced. In response, the European Medicines Agency's "Guideline on Computerised Systems in Clinical Trials" outlines essential criteria for validated EMR systems to ensure data integrity and security, and sets standards for electronic source documents in clinical trials. METHODS:From December 2023 to March 2024, the Italian Group of Data Managers and Clinical Research Coordinators (GIDMcrc) conducted an online survey across clinical research sites in Italy, France and Belgium to assess the characteristics of medical records and source documents. RESULTS:The survey was completed by 37 centres: 70.3% from Italy, 16.2% from France and 13.5% from Belgium. Most sites use a mixed paper/electronic Source Document (SD) system (72.3%), with fewer centres having fully electronic SD systems (13.5%) or fully paper-based systems (16.2%). EMR systems are used in 70.3% of sites, but only 23.8% comply with EMA guidelines for computerised systems. A country-specific analysis was also conducted to further explore the situations in Italy and France/Belgium. CONCLUSION:Despite the widespread use of Electronic Medical Records (EMRs) in Italy, France and Belgium, Italy lags behind the other two countries in terms of digitization. Despite the presence of an EMR, many centres still use a mixed system of paper and electronic source documents. There is also a lack of awareness regarding EMA and GCP standards, particularly concerning training and system testing. The higher response rate from Italian centres highlights the need for a larger sample in France and Belgium, and a follow-up survey would be beneficial for assessing progress and refining corrective actions.

Abstract Purpose: Little is known regarding the prognostic and predictive role of tumor immunological features in HR+/HER2- MBC treated with CT or CDK4/6i+ET. Methods: The Italian KENDO phase 2 trial randomized CT-naïve patients with HR+/HER2-neg. MBC with aggressive characteristics to receive CDK4/6i+ET (arm A) or CT+/-ET (arm B). Primary endpoint was progression-free survival (PFS). A tumor sample from the primary or metastatic tumor (archived or newly-obtained) was mandatory for inclusion. In this correlative biomarker analysis, tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLS) were detected on baseline tumor samples by hematoxylin&eosin staining, while immune genomic signatures were assessed with the nCounter BC360 panel. Immune pattern at immunohistochemistry was defined as inflamed (IF), excluded (IE) or desert (ID). TILs and signatures were dichotomized (high vs. low) with the maximally-selected rank statistics (MSRS) method. Survival analyses were conducted with the Kaplan-Meier (KM) method and differences were tested with log-rank test. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated with Cox regression. Significance was set at p≤0.05. Since the trial was stopped earlier due to slow accrual all analyses were exploratory. Results: Forty-nine patients were randomized, 17 (34.7%) in arm A and 32 (65.3%) in arm B. No significant clinicopathological differences were observed at baseline between the two arms, except for tumors in arm B showing more TLS (50.0% vs. 12.5%, p=0.013). Median PFS (mPFS) with CT+/-ET was numerically shorter than mPFS with CDK4/6i+ET (11.2 vs. 19.9 months, HR: 1.41, 95%CI: 0.75-2.64, p=0.289). The median OS (mOS) for arm A was not estimable (NE) vs. 30.6 months in arm B (p=0.283). In arm A, median TILs levels were 3% (interquartile range [IQR]: 1-5%) and TLS, with/without germinal centers, were present in 2 cases (12.5%). These were also the only IF tumors in the arm, whereas the rest (87.5%) were ID. In arm B, 7 (25.0%) tumors were IF, 19 (87.5%) ID and 2 (7.1%) IE. Median TILs were 4.5% (IQR: 2-12.8%) and TLS were present in 50% cases. In arm A, ID tumors showed lower mPFS than IF (15.8 vs. 27.5 months), with concordant trend at the OS KM curve. In arm B there was no clear difference in PFS, but IF tumors did not reach mOS, differently from ID (28.7 months) and IE (28.1 months). High vs. low TILs levels were significantly associated with better PFS (p=0.003) and OS (p=0.005) in arm A. High levels of a TGFβ gene expression signature were significantly associated with better PFS (p=0.020) and OS (p=0.005) in arm A and PFS (p=0.03) in arm B; higher levels of a cytokine/chemokine signature were associatedwith better PFS (p=0.02) in arm A, and higher levels of a mastcells signature was associated with worse OS in both arms (p=0.02 and p=0.03). In arm B, higher levels of a macrophage (p < 0.001) and antigen presentation signatures (p=0.04) were associated with worse and better OS, respectively, whereas higher levels of an immune infiltration and a cytotoxic cells signature were associated with better PFS (p=0.03 both). TLS presence was numerically associated to longer mPFS (23.5 vs. 15.8 months) in arm A, with consistent OS KM curve’s trend, and longer mOS (44.5 vs. 28.1 months) in arm B. Conclusions: The KENDO trial further supports CDK4/6i+ET use in aggressive CT-naïve HR+/HER2- MBC. Biomarkers of immune activation such as IF tumors, higher TILs and presence of TLS pointed towards better survival outcomes. Genomic immunological features also showed prognostic effect, with differences according to treatment arm and/or the immune process or cell line tracked. Further research on larger cohorts is needed to confirm these preliminary findings. Citation Format: Francesco Schettini, Michela Palleschi, Francesca Mannozzi, Fara Brasó-Maristany, Lorenzo Cecconetto, Patricia Galván, Marita Mariotti, Alessia Ferrari, Emanuela Scarpi, Anna Miserocchi, Oriana Nanni, Esther Sanfeliu, Aleix Prat, Andrea Rocca, Ugo De Giorgi. Immunologic features and association with prognosis in hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC) treated with chemotherapy (CT) or CDK4/6-inhibitors (CDK4/6i) + endocrine therapy (ET) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-14-06.

BACKGROUND:The optimal treatment approach for hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2-negative MBC) with aggressive characteristics remains controversial, with lack of randomized trials comparing cyclin-dependent kinase (CDK)4/6-inhibitors (CDK4/6i) + endocrine therapy (ET) with chemotherapy + ET. MATERIALS AND METHODS:We conducted an open-label randomized phase II trial (NCT03227328) to investigate whether chemotherapy + ET is superior to CDK4/6i + ET for HR+/HER2-negative MBC with aggressive features. PAM50 intrinsic subtypes (IS), immunological features, and gene expression were assessed on baseline samples. RESULTS:Among 49 randomized patients (median follow-up: 35.2 months), median progression-free survival (mPFS) with chemotherapy + ET (11.2 months, 95% confidence interval [CI]: 7.7-15.4) was numerically shorter than mPFS (19.9 months, 95% CI: 9.0-30.6) with CDK4/6i + ET (hazard ratio: 1.41, 95% CI: 0.75-2.64). Basal-like tumors under CDK4/6i + ET exhibited worse PFS (mPFS: 11.4 months, 95% CI: 3.00-not reached [NR]) and overall survival (OS; mOS: 18.8 months, 95% CI: 18.8-NR) compared to other subtypes (mPFS: 20.7 months, 95% CI: 9.00-33.4; mOS: NR, 95% CI: 24.4-NR). In the chemotherapy arm, luminal A tumors showed poorer PFS (mPFS: 5.1 months, 95% CI: 2.7-NR) than other IS (mPFS: 13.2 months, 95% CI: 10.6-28.1). Genes/pathways involved in BC cell survival and proliferation were associated with worse outcomes, as opposite to most immune-related genes/signatures, especially in the CDK4/6i arm. CD24 was the only gene significantly associated with worse PFS in both arms. Tertiary lymphoid structures and higher tumor-infiltrating lymphocytes also showed favorable survival trends in the CDK4/6i arm. CONCLUSIONS:The KENDO trial, although closed prematurely, adds further evidence supporting CDK4/6i + ET use in aggressive HR+/HER2-negative MBC instead of chemotherapy. PAM50 IS, genomic, and immunological features are promising biomarkers to personalize therapeutic choices.

Background: Post-COVID-19, rapid technological progress enabled remote healthcare interactions, fostering DCT activities. Sponsors and sites adapted by digitizing traditional model, utilizing wearables and home nursing. However, challenges like staff oversight and logistics demand careful evaluation for regulatory compliance. Methods: Italian association of medical oncology's study coordinators working group, in collaboration with Italian group of data managers, conducted an anonymous online survey among Italian oncology professionals. Survey aimed to explore their perceptions of remote patient monitoring, trial activities, and home nursing in oncology clinical trials. Results: Out of 111 professionals (42.3% coordinators, 27.0% physicians, 18.8% nurses), 29.7% lacked prior experience in remote patient data capture, while 61.3% had low or medium experience. On a 0-10 VAS scale, 58.6% found remote modalities very useful, with high scores (8-10) for various remote activities like quality of life data capture (71.2%), vital signs transmission (66.7%), and home nursing tasks (65.8%). Regarding home nursing in oncology clinical trials 73.0% of participants (n=81) have declared no previous experience. However this remote activity is considered highly useful for tasks such as biological samples collection (76.6%), vital signs collection (73.9%), quality of life evaluation (71.2%), and adverse events monitoring (65.8%). Conclusions: Electronic devices for remote data capture are prevalent in oncology trials, positively perceived by a significant portion of staff. Remote data collection correlates with improved workload perception. Although home nursing is less common in Italy, healthcare professionals show a positive perception, indicating potential benefits for clinical trial efficiency and workload improvement.

Background: Serum biomarkers have been investigated as predictive risk factors for cancer-related cardiovascular (CV) risk, but their analysis is limited to their baseline level rather than their overtime change. Besides historically validated causal factors, inflammatory and oxidative stress (OS) related markers seem to be correlated to CV events but this association needs to be further explored. We conducted an observational study to determine the predictive role of the longitudinal changes of commonly used and OS-related biomarkers during the cancer treatment period. Methods: Patients undergoing anticancer therapies, either aged 75+ years old or younger with an increased CV risk according to European Society of Cardiology guidelines, were enrolled. We assessed the predictive value of biomarkers for the onset of CV events at baseline and during therapy using Cox model, Subpopulation Treatment-Effect Pattern Plot (STEPP) method and repeated measures analysis of longitudinal data. Results: From April 2018 to August 2021, 182 subjects were enrolled, of whom 168 were evaluable. Twenty-eight CV events were recorded after a median follow up of 9.2 months (Interquartile range, IQR: 5.1–14.7). Fibrinogen and troponin levels were independent risk factors for CV events. Specifically, patients with higher than the median levels of fibrinogen and troponin at baseline had higher risk compared with patients with values below the medians, hazard ratio (HR) = 3.95, 95% CI, 1.25–12.45 and HR = 2.48, 0.67–9.25, respectively. STEPP analysis applied to Cox model showed that cumulative event-free survival at 18 and 24 months worsened almost linearly as median values of fibrinogen increased. Repeated measure analysis showed an increase over time of D-Dimer (p-interaction event*time = 0.08), systolic (p = 0.07) and diastolic (p = 0.05) blood pressure and a decrease of left ventricular ejection fraction (p = 0.15) for subjects who experienced a CV event. Conclusions: Higher levels of fibrinogen and troponin at baseline and an increase over time of D-Dimer and blood pressure are associated to a higher risk of CV events in patients undergoing anticancer therapies. The role of OS in fibrinogen increase and the longitudinal monitoring of D-dimer and blood pressure levels should be further assessed.

Background: Routine imaging can be inaccurate, especially in metastatic breast cancer (MBC) with bone-only disease or mainly bone disease. This analysis investigates how the use of whole-body magnetic resonance imaging (WB-MRI), in addition to routine computed tomography (CT) and bone scintigraphy (BS), can influence treatment decisions in patients with known MBC. Methods: In a prospective observational study, in our Institute, we performed WB-MRI as baseline and follow-up examination in addition to routine imaging (CT, BS) in luminal/HER2-negative BC patients with prevalence of bone disease potentially candidate to CDK 4/6 inhibitors. All examinations were interpreted by two experienced radiology specialists. Using the results of the examination, a multidisciplinary oncology committee (MOC) reported on the treatment strategy. A positive impact on clinical management was considered if the examination determined a modification in the treatment strategy compared to the MOC decision before WB-MRI. Results: Thirty consecutive luminal breast cancer patients in a metastatic setting at standard imaging were recruited. All these patients underwent CT and BS followed by WB-MRI study. At standard imaging, fourteen patients (46.7%) presented with bone-only disease, while eight patients (26.6%) did not show bone lesions. In 18 of 30 cases (60%) WB-MRI led to a modification of the therapeutic approach. Due to the detection of new metastatic lesions or progression of known metastatic sites, reported on WB-MRI alone, the therapeutic decision changed in 6 (20%) and 3 (10%) patients, respectively. In one patient (3%) the therapeutic decision changed because of both findings. Nine patients (30%) started a new therapeutic line due to evidence of progressive disease on WB-MRI, while 4 patients (13.3%) underwent radiotherapy and 1 patient received orthopaedic counselling for high risk WB-MRI-assessed bone lesions. In 8 patients (26.6%) the disease was re-classified as early breast cancer based on WB-MRI assessment. Conclusions: WB-MRI could play a role in the clinical assessment of luminal MBC. Further studies are needed to better address the potential use of WB-MRI in the assessment and monitoring of bone only/bone predominant luminal MBC and/or in equivocal cases. Citation Format: Filippo Merloni, Michela Palleschi, Alice Rossi, Andrea Prochowski Iamurri, Caterina Gianni, Samanta Sarti, Francesca Mannozzi, Federica Fiori, Giandomenico Di Menna, Lorenzo Cecconetto, Marianna Sirico, Chiara Casadei, Sara Bleve, Lorenzo Gasperoni, Roberto Casadei, Luca Tontini, Antonino Romeo, Domenico Barone, Ugo De Giorgi. Clinical impact of whole-body magnetic resonance imaging on subsequent management in luminal/HER2-negative breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-13.

We are currently witnessing an increase in procedural and managerial complexities within the field of clinical research, which require greater human and infrastructural resources as well as imply the need for a greater skill set and expertise on the part of professionals. Within this frame of reference clinical trial units and clinical research coordinators play a vital role in the design and conduct of clinical trials in Italy. There is a current recruitment and retention crisis for this specialist role due to a complex set of factors, most likely to have come to a head due to the lack of recognition at the Italian institutional level, that lead to precarious work contracts, lack of identity, and excessive turnover at experimental sites. This article, led by the Italian Group of Clinical Research Coordinator (GIDMcrc), presents some of the issues and ways in which national stakeholders may be able to address this.

Background: In an era where clinical trials have become more and more complex and regulatory authorities impose very high quality standards, the education of clinical research professionals becomes crucial. As one of ICH-GCP guiding principles, adequate training should be ensured and included in educational programs. Methods: In 2021, the Italian Group of Data Managers and Clinical Research Coordinators shared among professionals involved in clinical research an online survey aimed at investigating quality and characteristics of clinical research training provided during undergraduate and postgraduate Italian programs. Results: The survey was completed by 280 professionals: 178 study coordinators, 29 clinical research associates, 20 project managers, 7 study nurses, and 44 others. The majority were 25-45 years old (n = 242, 86.4%), worked at experimental sites (n = 211, 75.4%), and almost all (n = 252, 90.0%) had at least a master’s degree, mainly in biology/biotechnology (n = 162, 57.9%) and pharmacy (n = 64, 22.9%). Clinical research education during the degree courses was considered poor by 73.6% (n = 206). The knowledge on clinical research professional world at the time of graduation was considered poor by 71.1% of participants (n = 199), like the knowledge of related career opportunities (71.1%, n = 199, poor). According to 85.0% of professionals (n = 238) additional postgraduate trainings were needed, mainly university master courses (47.50%, n = 133) and private institution courses (47.86%, n = 134). Postgraduate trainings were considered very useful by 71.4% (n = 200) of responders. Conclusion: Our data suggest undergraduate programs on clinical research education failing at providing even the basic information on clinical research. Therefore, most professionals resort to specific additional postgraduate courses.

Body composition parameters (BCp) have been associated with outcome in different tumor types. However, their prognostic value in patients with HER2-positive metastatic breast cancer (BC) receiving first line treatment with dual anti-HER2 antibody blockade is unknown. Preclinical evidences suggest that adipocytes adjacent to BC cells can influence response to anti-HER2 treatments. We retrospectively analyzed Computed Tomography (CT)-based BCp from 43 patients with HER2-positive metastatic BC who received first line pertuzumab/trastuzumab-based treatment between May 2009 and March 2020. The impact of baseline CT-based BCp on progression-free survival (PFS) was tested using Kaplan–Meier estimates and univariate and multivariate Cox regression models. We found a significantly worse PFS for patients with high baseline subcutaneous fat index (median 7.9 vs 16.1 months, p = 0.047, HR = 2.04, 95%CI 1–4.17) and for those with high total abdominal fat index (8.1 vs 18.8 months, p = 0.030, HR = 2.17, 95%CI 1.06–4.46). Patients with baseline sarcopenia did not show shorter PFS compared to those without sarcopenia (10.4 vs 9.2 months, p = 0.960, HR = 0.98, 95%CI 0.47–2.03). Total abdominal fat index remained a significant predictor of PFS at multivariate analysis. Our findings suggest that a high quantity of total abdominal fat tissue is a poor prognostic factor in patients receiving trastuzumab/pertuzumab-based first-line treatment for HER2-positive metastatic BC.

: CDK4/6 inhibitors (CDK4/6i) are recommended in patients with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer (ABC). Up to now, no prognostic biomarkers have been identified in this setting. We retrospectively analyzed the expression of progesterone receptor (PR) and Ki67, assessed by immunohistochemistry, in 71 ABC patients treated with CDK4/6i and analyzed the impact of these markers on progression-free survival (PFS). The majority of patients 63/71 (88.7%) received palbociclib, 4 (5.6%) received ribociclib, and 4 (5.6%) received abemaciclib. A higher median value of Ki67 was observed in cases undergoing second-line treatment (p = 0.047), whereas the luminal B subtype was more prevalent (p = 0.005). In the univariate analysis of the first-line setting, luminal A subtype showed a trend towards a correlation with a longer PFS (p = 0.053). A higher continuous Ki67 value led to a significantly shorter PFS. When the interaction between pathological characteristics and line of treatment was considered, luminal B subtype showed a significantly (p = 0.043) worse outcome (Hazard Ratio (HR) 2.84; 1.03–7.82 95% Confidence Interval (CI)). PFS in patients undergoing endocrine therapy plus CDK4/6i was inversely correlated with Ki67 expression but not with PR, suggesting that tumor proliferation has a greater impact on cell cycle inhibitors combined with endocrine therapy than PR expression.