European Institute Of Oncology Research Articles

CDH1 Genotype Exploration in Women With Hereditary Lobular Breast Cancer Phenotype

Pathogenic or likely pathogenic (P/LP) germline CDH1 variants are associated with risk for diffuse gastric cancer and lobular breast cancer (LBC) in the so-called hereditary diffuse gastric cancer (HDGC) syndrome. However, in some circumstances, LBC can be the first manifestation of this syndrome in the absence of diffuse gastric cancer manifestation. To evaluate the frequency of germline CDH1 variants in women with the hereditary LBC (HLBC) phenotype, somatic CDH1 gene inactivation in germline CDH1 variant carriers' tumor samples, and the association of genetic profiles with clinical-pathological data and survival. This single-center, longitudinal, prospective cohort study was conducted from January 1, 1997, to December 31, 2021, with follow-up until January 31, 2023. Women with LBC seen at the European Institute of Oncology were included. Testing for germline CDH1, BRCA1, and BRCA2 genes was performed. Somatic profiling was assessed for germline CDH1 carriers. Accurate estimates of prevalence of germline CDH1 variants among patients with HLBC and the association of somatic sequence alteration with HLBC syndrome. The Kaplan-Meier method and a multivariable Cox proportional hazards regression model were applied for overall and disease-free survival analysis. Of 5429 cases of primary LBC, familial LBC phenotype accounted for 1867 (34.4%). A total of 394 women with LBC were tested, among whom 15 germline CDH1 variants in 15 unrelated families were identified. Among these variants, 6 (40.0%) were P/LP, with an overall frequency of 1.5% (6 of 394). Of the 6 probands with P/LP CDH1 LBC, 5 (83.3%) had a positive family history of BC and only 1 (16.7%) had sporadic juvenile early-onset LBC. No germline BRCA1 and BRCA2 variants were identified in CDH1 carriers. An inactivating CDH1 mechanism (second hit) was identified in 4 of 6 explored matched tumor samples (66.7%) in P/LP germline carriers. The P/LP CDH1 LBC variant carriers had a significantly lower age at diagnosis compared with the group carrying CDH1 variants of unknown significance or likely benign (42.5 [IQR, 38.3-43.0] vs 51.0 [IQR, 45.0-53.0] years; P = .03). In this cohort study, P/LP germline CDH1 variants were identified in individuals not fulfilling the classic clinical criteria for HDGC screening, suggesting that identification of these variants may provide a novel method to test women with LBC with early age at diagnosis and/or positive family history of BC.

Resection to restoration: Assessing the synergy of polypropylene mesh (Marlex®) combined with methyl-methacrylate and latissimus dorsi flap for primary chest wall sarcomas

BackgroundChest-wall sarcomas are treated with extensive resections and complex defect reconstruction to restore chest-wall integrity. It is a difficult surgical procedure that incorporates a multidisciplinary approach for the best outcome, preventing paradoxical chest movement issues and reducing complications. ObjectiveWe aimed to describe our experience of chest-wall reconstruction using polypropylene mesh (Marlex® Mesh) combined with methyl-methacrylate and soft-tissue coverage with a latissimus dorsi flap following sarcoma resection. Patients and methodsAmong the 53 patients treated for primary chest-wall sarcomas at the European Institute of Oncology (IEO) in Milan, Italy, from 1998 to 2020, 14 cases underwent chest-wall resection and reconstruction using polypropylene mesh, methyl-methacrylate and the latissimus dorsi flap.Patients with locally advanced breast cancers, locally advanced lung cancers, squamous cell carcinomas, and other secondary chest-wall malignancies were excluded from the study, as were the patients with different types of chest-wall reconstruction. ResultsIn this study, 14 patients (6 men and 8 women) with various primary chest-wall sarcomas were enrolled. On an average, 2 ribs (range: 1–5) were removed during the surgeries, and the chest-wall defects ranged from 20 to 150 cm2 with an average size of 73 cm2. The mean follow-up period for these patients was approximately 63.80 months ConclusionThe combination of Marlex® mesh filled with methyl-methacrylate and covered using latissimus dorsi myocutaneous flap provides safe, low-cost and effective single-stage chest-wall reconstruction after surgery for primary sarcomas.

Cancers of Unknown Primary Origin: Real-World Clinical Outcomes and Genomic Analysis at the European Institute of Oncology.

Cancer of unknown primary origin (CUP) poses a significant challenge due to poor clinical outcomes and limited treatment options. As such, further definition of clinicopathological factors and genomic profile to better adapt treatment strategies is required. Medical records were interrogated to retrospectively include CUP with available clinical and genomics data at the European Institute of Oncology. Next-generation sequencing (NGS) included targeted panels. Statistical analyses were conducted with R Software 4.2.2. A total of 44 patients were included. With a median follow-up of 39.46 months (interquartile range [IQR] 35.98-47.41 months), median PFS (mPFS) to first-line regimen was 3.98 months (95% CI 3.22-5.98), with a clinical benefit rate of 26% (95% CI 14%-49%), and disease control rate (DCR) limited to 48.28%. Most patients (26 of 31, 83.87%) received platinum-doublet chemotherapy, with no statistically significant difference between first-line treatment regimens. Median OS (mOS) was 18.8 months (95% CI 12.3-39.9), with a 12-month OS rate of 66% (95% CI 50%-85%). All patients received comprehensive genomic profiling (CGP). For 11 patients, NGS was unsuccessful due to low sample quantity and/or quality. For the remaining, TP53 (n = 16, 48%) and KRAS (n = 10, 30%) represented the most altered (alt) genes. No microsatellite instability was observed (0 of 28), while 6 of 28 (21.43%) tumors carried high TMB (≥10 mutation per megabase). Eight of 33 tumors (24.2%) displayed at least one actionable alteration with potential clinical benefit according to ESCAT. Only 2 of them received targeted therapy matched to genomic alterations, with a combined mPFS of 2.63 months (95% CI 1.84-not evaluable) as third-line regimens. Six patients received anti-PD1/PD-L1 therapy, showing a meaningful mPFS of 13 months (95% CI 2.04-not evaluable). CUP exhibits poor prognosis with limited benefits from standard treatment regimens. A significant proportion of CUPs carry actionable alterations, underscoring the importance of genomic profiling to gather additional treatment opportunities. In addition, immunotherapy might represent a valuable treatment option for a subset of CUP. Finally, accurate definition of sequencing methods and platforms is crucial to overcome NGS failures.

A multicenter high-quality data registry for advanced proton therapy approaches: the POWER registry

BackgroundPaucity and low evidence-level data on proton therapy (PT) represent one of the main issues for the establishment of solid indications in the PT setting. Aim of the present registry, the POWER registry, is to provide a tool for systematic, prospective, harmonized, and multidimensional high-quality data collection to promote knowledge in the field of PT with a particular focus on the use of hypofractionation.MethodsAll patients with any type of oncologic disease (benign and malignant disease) eligible for PT at the European Institute of Oncology (IEO), Milan, Italy, will be included in the present registry. Three levels of data collection will be implemented: Level (1) clinical research (patients outcome and toxicity, quality of life, and cost/effectiveness analysis); Level (2) radiological and radiobiological research (radiomic and dosiomic analysis, as well as biological modeling); Level (3) biological and translational research (biological biomarkers and genomic data analysis). Endpoints and outcome measures of hypofractionation schedules will be evaluated in terms of either Treatment Efficacy (tumor response rate, time to progression/percentages of survivors/median survival, clinical, biological, and radiological biomarkers changes, identified as surrogate endpoints of cancer survival/response to treatment) and Toxicity. The study protocol has been approved by the IEO Ethical Committee (IEO 1885). Other than patients treated at IEO, additional PT facilities (equipped with Proteus®ONE or Proteus®PLUS technologies by IBA, Ion Beam Applications, Louvain-la-Neuve, Belgium) are planned to join the registry data collection. Moreover, the registry will be also fully integrated into international PT data collection networks.

Unlocking tracheoesophageal speech from pharyngoesophageal spasm: preliminary results of a videofluoroscopic-guided botulinum toxin A injection technique.

The tracheoesophageal puncture for the voice prosthesis (VP) placement is the recognized gold standard in post-laryngectomy voice rehabilitation. Despite the development of specific intraoperative techniques, a subset of patients will suffer from poor functional outcomes due to pharyngoesophageal spasms (PES). This paper evaluates the functional outcomes after transcutaneous botulinum toxin type A (BTX-A) infiltration for PES with a videofluoroscopy-guided technique. Since 2022, eight consecutive patients with VP and affected by PES were treated with BTX-A injection by a standard videofluoroscopic guided technique at the European Institute of Oncology, IRCCS (IEO) in Milan. A lidocaine test was performed pre-operatively to evaluate the potential effect of chemical neurectomy. All patients with positive lidocaine tests were injected with 50IU of BTX-A (Allergan, Irvine, CA) according to the sites marked during the videofluoroscopy. Reported symptoms (VHI, SECEL), perceptual (INFVo), aerodynamic (MPT) and manometric parameters were collected before and after treatment. In all cases, BTX-A was performed as an outpatient procedure without complications. For seven patients, only one BTX-A injection was needed, while one patient required a re-injection. Subjective and perceptive improvement after BTX-A was significant for VHI, SECEL and INFVo. MPT showed significant improvement after a chemical neurectomy. After a mean follow-up of 6months, all patients maintained a good TES quality. The videofluoroscopic guided BTX-A injection of the pharyngoesophageal tract showed to be a feasible and reproducible technique in all cases. The pharyngoesophageal videofluoroscopy allows defining of patients' anatomical landmarks that help the surgeon to perform a homogeneous injection, empowered by post-injection massage.

Clinicopathological characteristics of multiple-classifier endometrial cancers: a cohort study and systematic review.

Endometrial cancers with more than one molecular feature-POLE mutations (POLEmut), mismatch repair protein deficiency (MMRd), p53 abnormality (p53abn)-are called 'multiple classifiers'. To describe our cohort of multiple classifiers and to report the results of a review on their incidence and the techniques used to identify them. Multiple classifiers identified at the European Institute of Oncology, Milan, between April 2019 and Decmber 2022, were included. Clinicopathological, molecular characteristics, and oncologic outcomes were summarized and compared between single and multiple classifiers sharing common features. Studies on molecular classification of endometrial cancer were searched in the PubMed Database to collect data on the incidence of multiple classifiers and the techniques used for classification. Among 422 patients, 48 (11.4%) were multiple classifiers: 15 (3.6%) POLEmut-p53abn, 2 (0.5%) POLEmut-MMRd, 28 (6.6%) MMRd-p53abn, and 3 (0.7%) POLEmut-MMRd-p53abn. MMRd-p53abn and MMRd differed in histotype (non-endometrioid: 14.8% vs 2.0%, p=0.006), grade (high-grade: 55.6% vs 22.2%, p=0.001), and MMR proteins expression, whereas they differed from p53abn in histotype (non-endometrioid: 14.8% vs 50.0%, p=0.006). POLEmut-p53abn and POLEmut differed only in grade (high-grade: 66.7% vs 22.7%, p=0.008), while they differed from p53abn in age (56.1 vs 66.7 years, p=0.003), stage (advanced: 6.7% vs 53.4%, p=0.001), and histotype (non-endometrioid: 6.7% vs 50.0%, p=0.002). Two (7.1%) patients with MMRd-p53abn, 4 (4.0%) with MMRd, and 25 (34.3%) with p53abn had a recurrence. No recurrences were observed in POLEmut-p53abn and POLEmut. TP53 sequencing allowed the detection of additional 7 (18.9%) multiple classifiers with normal p53 immunostaining. The incidence of multiple classifiers ranged from 1.8% to 9.8% in 10 published studies including >100 patients. When only p53 immunohistochemistry was performed, the highest incidence was 3.9%. The characteristics of POLEmut-p53abn resembled those of POLEmut, whereas MMRd-p53abn appeared to be intermediate between MMRd and p53abn. The high proportion of multiple classifiers may be related to the methods used for molecular classification, which included both p53 immunohistochemistry and TP53 sequencing.

Interview with Sara Sigismund – President of the Italian Association of Cell Biology and Differentiation

ABSTRACT Sara Sigismund is an Associate Professor at the Department of Oncology and Hemato-Oncology at the University of Milan, and a Researcher in the Department of Experimental Oncology at the European Institute of Oncology (IEO) in Milan, Italy. Her research aims to understand the role of endocytosis in the regulation of EGFR signalling, focusing on non-clathrin endocytosis and its role in health and disease. In addition to running a research group, Sara is the current President of the Italian Association of Cell Biology and Differentiation (Associazione di Biologia Cellulare e del Differenziamento; ABCD). We spoke to Sara about her career path, her advice for early career researchers and her role as President of the ABCD.

A Machine Learning Model to Predict Patients' Adherence Behavior and a Decision Support System for Patients With Metastatic Breast Cancer: Protocol for a Randomized Controlled Trial.

Adherence to oral anticancer treatments is critical in the disease trajectory of patients with breast cancer. Given the impact of nonadherence on clinical outcomes and the associated economic burden for the health care system, finding ways to increase treatment adherence is particularly relevant. The primary end point is to evaluate the effectiveness of a decision support system (DSS) and a machine learning web application in promoting adherence to oral anticancer treatments among patients with metastatic breast cancer. The secondary end point is to collect a set of new physical, psychological, social, behavioral, and quality of life predictive variables that could be used to refine the preliminary version of the machine learning model to predict patients' adherence behavior. This prospective, randomized controlled study is nested in a large-scale international project named "Enhancing therapy adherence among metastatic breast cancer patients" (Pfizer 65080791), aimed to develop a predictive model of nonadherence and associated DSS and guidelines to foster patients' engagement and therapy adherence. A web-based DSS named TREAT (treatment adherence support) was developed using a patient-driven approach, with 4 sections, that is, Section A: Metastatic Breast Cancer; Section B: Adherence to Cancer Therapies; Section C: Promoting Adherence; and Section D: My Adherence Diary. Moreover, a machine learning-based web application was developed to predict patients' risk factors of adherence to anticancer treatment, specifically pertaining to physical status and comorbid conditions, as well as short and long-term side effects. Overall, 100 patients consecutively admitted at the European Institute of Oncology (IEO) at the Division of Medical Senology will be enrolled; 50 patients with metastatic breast cancer will be exposed to the DSS and machine learning web application for 3 months (experimental group), and 50 patients will not be exposed to the intervention (control group). Each participant will fill a weekly medication diary and a set of standardized self-reports evaluating psychological and quality of life variables (Adherence Attitude Inventory, Beck Depression Inventory-II, Brief Pain Inventory, 13-item Sense of Coherence scale, Brief Italian version of Cancer Behavior Inventory, European Organization for Research and Treatment of Cancer Quality of Life 23-item Breast Cancer-specific Questionnaire, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, 8-item Morisky Medication Adherence Scale, State-Trait Anxiety Inventory forms I and II, Big Five Inventory, and visual analogue scales evaluating risk perception). The 3 assessment time points are T0 (baseline), T1 (1 month), T2 (2 months), and T3 (3 months). This study was approved by the IEO ethics committee (R1786/22-IEO 1907). The recruitment process started in May 2023 and is expected to conclude on December 2023. The contribution of machine learning techniques through risk-predictive models integrated into DSS will enable medication adherence by patients with cancer. ClinicalTrials.gov NCT06161181; https://clinicaltrials.gov/study/NCT06161181. DERR1-10.2196/48852.

Circulating Tumor DNA and Risk of Venous Thromboembolism in Locally Advanced Rectal Cancer

Venous thromboembolism (VTE) is a common complication in cancer patients, which negatively affects treatment delivery and, consequently, prognosis. The pathophysiology of cancer-associated thrombosis (CAT) is extremely complex, relying on cytokine release in response to interactions between tumor cells and macrophages, thus leading to endothelial damage and activation of coagulation. Several risk factors may contribute to VTE risk, including tumor types, advanced stage, and anti-cancer treatments. Anti-angiogenic agents or combination of systemic chemotherapy and concomitant radiotherapy (CT-RT), for instance, are well-established risk factors across different malignancies. Colorectal cancer (CRC) is not listed as a high-risk VTE tumor according to pivotal risk assessment models, although retrospective studies showed a VTE rate of around 20%. Consequently, considering the high prevalence of the disease, VTE in CRC represents a main burden in terms of morbidity, increased healthcare costs, and mortality. Rectal cancer (RC) comprises approximately 30% of all CRC. The treatment of locally advanced disease (LARC) consists of a multimodal approach which includes chemotherapy, radiotherapy, and surgery. In the context of CRC management, circulating tumor DNA (ctDNA) is a fast-growing tool able to detect minimal residual disease, useful for improving patients' stratification and prognosis. Moreover, its determination at the time of diagnosis may represent a surrogate of tumor burden, potentially increasing the risk of VTE compared to ctDNA negative patients. Due to the paucity of prospective data of VTE in LARC, the aim of this analysis is to describe the rate of VTE and the potential association between ctDNA levels at baseline and VTE occurrence. We conducted a prospective observational study enrolling patients with LARC managed with neoadjuvant CT-RT (capecitabine 1650 mg/m2 concomitant with 50,4 Gy pelvic long course radiotherapy), surgery, plus/minus adjuvant chemotherapy at European Institute of Oncology (IEO) between November 2014 and November 2019. Blood samples for ctDNA were obtained at pre-planned timepoints: baseline (T0), end of CT-RT (T1), after surgery (T2), end of adjuvant chemotherapy (T3). ctDNA was extracted from plasma and mutations detected on tumor biopsy (KRAS, NRAS, BRAF, PIK3CA) were evaluated on ctDNA. Among other clinical information, VTE events were collected, including pulmonary embolism (PE), deep vein thrombosis (DVT) and visceral venous thrombosis (VVT). VTE was counted when occurred after or whitin 30 days before LARC diagnosis. The ctDNA value, defined as variant allele frequency (VAF) in a targeted mutation, was analyzed for correlation with clinical outcomes and VTE events. Median baseline ctDNA value was set as threshold to subdivide patients in VAF high and VAF low. We enrolled 111 patients. Sixty-one (55%) patients harboring tumoral tissue mutations underwent liquid biopsy. KRAS mutation was the most frequent one (42%), followed by NRAS (7%) and PIK3CA (5%). Fifty-one patients (83%) had a clinical node positive disease. Baseline Khorana Score (KS) was 0 in 54 patients (88%) and 1 in 7. Median ctDNA value at T0 was 0.11 ng/2ml (range: 0.00 - 17.40). After a median follow up of 82 months, 9 VTE events (15%) were diagnosed, 4 PE, 3 DVT and 2 VVT. The median time from diagnosis to VTE event was 14 months (IQR 6 - 51). VTE occurrence was associated with VAF high at baseline, even though not statistically significant (Hazard Ratio [HR]: 2.85; 95% CI: 0.71-11.4, p value = 0.14). Looking specifically at KRAS mutant patients, 6 VTE events were observed, all experienced by VAF high patients (HR not estimable, p value = 0.001). Considering the overall population, VTE rate was 14% and no statistical differences were observed for VTE development according to mutational profile. In our prospective study on LARC patients, VTE was associated with high levels of ctDNA at diagnosis, although not statistically significant. However, the association was significant in KRAS mutant tumors, which may represent a subset of patients with higher risk of thromboembolic complications. Prospective translational studies using deeper molecular techniques and wider populations are required to define the role of ctDNA as additional predictive tool to stratify VTE risk in cancer patients.

Dose-dense neoadjuvant chemotherapy before radical surgery in cervical cancer: a retrospective cohort study and systematic literature review

ObjectiveTo evaluate the role of dose-dense neoadjuvant chemotherapy followed by radical hysterectomy in reducing adjuvant radiotherapy in International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IB1-IB2/IIA1 cervical cancer with...

Human Papillomavirus Genotype Richness and the Biodiversity of Squamous and Glandular Cervical Dysplasias: A Cross-Sectional Study.

The impact of multiple infections on the risk of cervical lesions is a subject of ongoing debate. This study aims to explore whether the richness of HPV genotype infections and the biodiversity of squamous and glandular cervical dysplasias could influence the progression of precancerous lesions. We conducted a cross-sectional analysis involving 469 women who attended the Colposcopy Unit at the European Institute of Oncology in Milan, Italy, from December 2006 to December 2014. HPV type richness was measured as the number of different genotypes per patient. We calculated the associations between richness and age, as well as histologic grade, along with Simpson's biodiversity index for cervical dysplasias. We observed significant inverse relationships between the richness of high-risk (HR) genotypes and both age (p = 0.007) and histologic grade (p < 0.001). Furthermore, as the histologic grade increased, the mean biodiversity index of cervical dysplasias decreased, with exceptions noted in cases of normal histology and adenocarcinoma in situ. Different histologic grades formed five clusters with distinct mean ages and mean biodiversity indices. These findings suggest that HPV genotype richness and the biodiversity of cervical dysplasias may play a crucial role in predicting the risk of high-grade cervical lesions, enabling personalized management of precancers.

Multimodal treatment for resectable neuroendocrine carcinoma of the cervix.

Non-metastatic neuroendocrine carcinoma of the cervix (NECC) is a rare and aggressive disease. Lacking prospective studies, the optimal multimodal treatment approach has not yet been clearly defined. This study aims to assess the clinical outcomes of patients with non-metastatic NECC treated with surgery and (neo)adjuvant chemotherapy, according to pathologic prognostic factors and multimodal treatments received. We retrospectively examined data from patients with non-metastatic NECC candidate to receive surgery and (neo)adjuvant chemotherapy and discussed at the European Institute of Oncology's Multidisciplinary Neuroendocrine Tumor Board, between January 2003 and December 2021. Primary endpoints were event-free survival and overall survival. A total of 27 consecutive patients were evaluated, 15 with early stage NECC and 12 with a locally advanced NECC. Eight patients received neoadjuvant and 19 adjuvant platinum-based chemotherapy; 14 received adjuvant pelvic radiotherapy, half with external-beam radiation therapy alone, and half combined with brachytherapy. No patients progressed or relapsed during (neo)adjuvant chemotherapy. The median event-free survival was 21.1 months and the median overall survival was 33.0 months. Pathological FIGO stage ≥ IIB, adjuvant external-beam radiation therapy with or without brachytherapy emerged as significant and independent prognostic factors for event-free survival. Brachytherapy was also prognostic for overall survival. Non-metastatic NECC requires a multimodal approach, mainly weighted on the FIGO stage. The addition of brachytherapy should be considered, especially in patients with locally advanced disease. Because of the scarcity of robust clinical data, treatment strategy should be discussed in multidisciplinary board, taking into account patient.

Clinical and radiological criteria for candidate patients with small bowel neuroendocrine neoplasms (SB-NEN) for minimally invasive surgery: A single-centre experience.

e16246 Background: Although open resection represents the standard of care of localized small bowel neuroendocrine neoplasms (SB-NEN), minimally invasive surgery (MIS) has proven to be a viable alternative in patients with low disease burden. This study aims to assess the reliability of preoperative clinical and radiological criteria used at European Institute of Oncology (IEO) to candidate patients with SI-NEN to MIS. Methods: Patients diagnosed with SB-NEN and eligible for MIS at IEO were retrospectively evaluated between 2013 and 2022. Preoperative physical examination, CT enterography (CTE) and Ga68-DOTATOC-PET-CT were used for clinical staging. At IEO NEN multidisciplinary tumor board, the following eligibility criteria were adopted to candidate patients to MIS (curative or palliative): number and localization of primary tumor, grade of superior mesentery artery and vein encasement by lymph-node metastases of 0-2 according IEO criteria (based on Lardiere-Degalte classification). Information on morphology and carcinoid syndrome were collected. The primary endpoint was laparotomy conversion rate. Results: Twelve patients were selected. Patients’ characteristics are available. Median age at surgery was 55 years (range: 33–73). Among these patients, based on pathological findings, 8 (67%) had confirmed nodal involvement, 3 (25%) metastatic disease and 4 (33%) multifocal primary tumor. Vascular involvement (based on IEO criteria) was found in 9 patients (75%). Of note, only 3 (25%) patients had a functioning tumor as a preoperative finding and all tumors resulted well-differentiated. Among 12 patients which underwent laparoscopic surgery, none has been converted to laparotomy surgery. After a median follow-up of 25.3 months (range: 2.5-71.3), the 1-year disease free survival for non-metastatic patients was of 100%. Conclusions: the assessment of tumor burden with 68Ga-PET-CT and CTE according to IEO criteria could be a reliable method to candidate patients affected by SB-NEN to MIS, according to a multidisciplinary approach.[Table: see text]

Usability Testing of a New Digital Integrated Health Ecosystem (PainRELife) for the Clinical Management of Chronic Pain in Patients With Early Breast Cancer: Protocol for a Pilot Study

Chronic pain (CP) and its management are critical issues in the care pathway of patients with breast cancer. Considering the complexity of CP experience in cancer, the international scientific community has advocated identifying cutting-edge approaches for CP management. Recent advances in the field of health technology enable the adoption of a novel approach to care management by developing integrated ecosystems and mobile health apps. The primary end point of this pilot study is to evaluate patients' usability experience at 3 months of a new digital and integrated technological ecosystem, PainRELife, for CP in a sample of patients with breast cancer. The PainRELife ecosystem is composed of 3 main technological assets integrated into a single digital ecosystem: Fast Healthcare Interoperability Resources-based cloud platform (Nu platform) that enables care pathway definition and data collection; a big data infrastructure connected to the Fast Healthcare Interoperability Resources server that analyzes data and implements dynamic dashboards for aggregate data visualization; and an ecosystem of personalized applications for patient-reported outcomes collection, digital delivery of interventions and tailored information, and decision support of patients and caregivers (PainRELife app). This is an observational, prospective pilot study. Twenty patients with early breast cancer and chronic pain will be enrolled at the European Institute of Oncology at the Division of Medical Senology and the Division of Pain Therapy and Palliative Care. Each patient will use the PainRELife mobile app for 3 months, during which data extracted from the questionnaires will be sent to the Nu Platform that health care professionals will manage. This pilot study is nested in a large-scale project named "PainRELife," which aims to develop a cloud technology platform to interoperate with institutional systems and patients' devices to collect integrated health care data. The study received approval from the Ethical Committee of the European Cancer Institute in December 2021 (number R1597/21-IEO 1701). The recruitment process started in May 2022 and ended in October 2022. The new integrated technological ecosystems might be considered an encouraging affordance to enhance a patient-centered approach to managing patients with cancer. This pilot study will inform about which features the health technological ecosystems should have to be used by cancer patients to manage CP. DERR1-10.2196/41216.

Lynch syndrome: toward an increasingly complex picture. The case of PMS2.

Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, IRCCS, Milan, Italy Received 28 February 2023 Accepted 28 February 2023. Correspondence to Mariarosaria Calvello, Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, IRCCS, Milan, Italy, E-mail: [email protected]

Abstract P4-01-25: Safety analysis after 11 years of follow-up of the randomized phase III trial SAKK22/99: upfront chemotherapy in advanced HER2 positive breast cancer

Abstract Background: The SAKK 22/99 is a phase III randomized clinical trial launched by the Swiss Group for Clinical Cancer Research and the European Institute of Oncology in Milan in 99 for women with HER2-positive advanced breast cancer (ABC). 175 patients were randomized 1:1 from Sept 99 to Jan 2013 to receive first-line trastuzumab (T) alone followed at disease progression by the combination with chemo (Arm A) vs the upfront combination of T and chemo (Arm B). The results were published in 2017 (O. Pagani et al Ann Onc 28: 305–312, 2017). The outcome was similar for sequential T-chemo or upfront combination The patients’ treatment and FU continued until March 2022 and we now report the safety data after 135.2 months of median FU. Patients and methods: at the time of study termination 1 patient with SD was still receiving T alone in the study and T was continued after trial closure. The safety analyses include 86 pts allocated to arm A and 88 to arm B. 1 pt did not receive any trial treatment and was excluded from this analyses. 19 of the 86 patients in arm A stopped trial treatment after T alone, 67 continued with T+ chemo. Baseline characteristics were well balanced and are summarized in Table 1. Treatment The T loading dose of 4 mg/kg/iv was followed by 2 mg/kg/iv weekly. In the 1st-line population (84) chemo was weekly paclitaxel (90 mg/m2/iv-3/4 weeks). After amendment 1 chemo was at investigator’s choice (taxanes, vinorelbine, platin) according to label indications and could be stopped after 24 weeks (6–8 cycles) in responding patients or after unacceptable toxicity. Results: 7 patients in arm A (8%) and 11 in arm B (13%) stopped trial treatment due to toxicities (Fisher’s exact test, p=0.46). 3 of the 7 patients in arm A stopped under T alone and 4 under T+chemo (all paclitaxel weekly) Treatment durations of these 7 and 11 patients were 7.7 months (range 0.5 – 49) in arm A and 5.5 months (range 0.6 – 31 months) in arm B, respectively. Cardiovascular toxicities: The most common toxicities were thromboembolic events, blood pressure disorders and arrhythmia. 6 patients (7%) in arm A and 10 (11%) in arm B had cardiac events (Fisher’s exact test, p=0.43). G1-3 toxicities occurred in 2 (2%), 2 (2%) and 2 (2%) patients of arm A and in 5 (7%), 2 (2%) and 3 (3%) of arm B. We observed no grade 4 events. Split by treatment phase in arm A, G1-3 toxicities were seen in in 1 (1%), 2 (2%) and 1 (1%) patient under T alone (N=86) and in 1 (1%), 0 (0%) and 2 (3%) under T+chemo (N=67). LVEF-decline: 78 patients in arm A and 74 in arm B had sequential LVEF measurements. A decline ≥ 10% was found in 35 patients (45%) in arm A and in 20 (27%) in arm B (Fisher’s exact test, p=0.028). Among the 35 patients in arm A, 12 had the decline under T alone, 14 under T+chemo, and 9 under both T alone and T+chemo. A decline ≥ 20% was found in 10 patients (13%) in arm A and in 3 (4%) in arm B (Fisher’s exact test, p=0.08). Among the 10 patients in arm A, 7 had the decline under T alone, 3 under T+chemo. Sensory neuropathy 43 patients (50%) in arm A and 48 (54%) in arm B had neuropathy (Fisher’s exact test, p=0.65). G1-3 toxicity in arm A was developed by 26 (30%), 11 (13%) and 6 (7%) patients, respectively; in arm B 30 (34%), 12 (14%) and 6 (7%). No grades 4 events occurred. Conclusion: After more than 11 years of follow-up, no relevant toxicities were found in these patients receiving T for ABC. In particular, the incidence and grade of cardiac toxicity was low. The decline in LVEF was numerically higher in the arm A and in particular in the T alone group, but was not clinically relevant. Our data potentially suggest that T+chemo followed by T maintenance could have less cardiotoxicity than T followed by T+chemo. The possible causes for the difference in LVEF decline between the two arms are unclear, but could be related to treatment duration. The women in Arm A shows a trend to longer therapy: Median treatment duration (months) in Arm A was 7.92 (0.46 - 135.98) vs 6.62 (0.56 - 71.28) in Arm B. This long-term analysis confirms the favorable safety and good tolerability of the reported regimes. Table 2: Treatment duration Citation Format: Manuela Rabaglio, Daniel Dietrich, Bernhard Scheibe, Thomas Ruhstaller, Franco Nole, Serenella Eppenberger, Christian Oehlschlegel, Dagmar Hess, Christoph Mamot, Elisabetta Munzone, Bernhard Pestalozzi, Stefan Aebi, Marcus Vetter, Beat Thuerlimann, Roger von Moos, Khalil Zaman, Olivia Pagani. Safety analysis after 11 years of follow-up of the randomized phase III trial SAKK22/99: upfront chemotherapy in advanced HER2 positive breast cancer [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 P4-01-25.

71P Molecular Tumor Board at the European Institute of Oncology: An early Italian precision oncology experience

71P Molecular Tumor Board at the European Institute of Oncology: An early Italian precision oncology experience

Abstract P6-02-11: Implementation of multigene panel testing in triple-negative breast cancer. The PERSONA-breast trial

Abstract Kahler Ribeiro Fontana S1, Bonetti E2, Bernard L3, Calvello M4, Bonanni B4, Bonizzi G 5, Veronesi P1,6, Mazzarella L 2, Galimberti V1 Introduction Triple-negative breast cancer (TNBC) is frequently associated with germline genetic variants associated with cancer predisposition. Approximately 20% of TNBC carry a germline BRCA1 or BRCA2 mutation. Germline mutations in other genes involved in DNA repair, specifically Homologous Recombination (HRR), including ATM, BARD1, BRIP1, CHEK2, PALB2, RAD50, RAD51C, RAD51D may be associated with TNBC however remain imprecise in several populations as in Italy. In recent years, there has been an increase in multigenic panel testing thanks to better technology and the fact that genetic testing is no longer done just for prevention but they have become relevant in the clinical setting and this is especially true for triple negative disease. At the European Institute of Oncology, we conducted a prospective clinical trial, the PERSONA Breast trial, aimed at providing a more comprehensive picture of the mutational landscape and cancer risk in patients with TNBC by multigene germline genetic testing. Methods PERSONA is a prospective observational trial conducted between June 2018 and January 2022 on 313 patients with a diagnosis of TNBC ≤ 60 years and able to undergo surgery (primary or post-neoadjuvant). Peripheral blood DNA was sequenced with the Illumina TruSight Cancer panel (94 cancer predisposition genes). Genes were classified as germline actionable (n. 15) or non-actionable (n. 79) according to their associated relative risk of cancer. Genetic variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines and the databases of genetic variants (ClinVar, LOVD, BRCA-Exchange,). All enrolled patients were followed up six-monthly for 10 years from informed consent or to death or withdrawal of consent. Results We present preliminary germline results from a 94-gene panel testing performed on a cohort of 313 TNBC patients. The clinical data of these patients was considered for a descriptive analysis of the cohort. Data on outcome such as overall survival and disease-free survival were not yet available. Germline multigene testing detected 62 unique (i.e., n. 49 in actionable, n. 13 in non-actionable genes) pathogenic (C5) and likely pathogenic (C4) variants in 25.2% of TNBC patients (79/313). As expected, 53.2% (42/79) of TNBC patients were carriers of a C5/C4 in BRCA1. C4/C5 were identified also in other actionable genes: 13.9% (11/79) in BRCA2, 8.9% (7/79) in MUTYH, 3.8% (3/79) in PALB2, 2.5% (2/79) in MSH2, 1.3% (1/79) in PMS2, and 1.3% (1/79) in TP53. In addition, 12 TNBC patients had C4/C5 variants in non-actionable genes, and 4 were carriers of both C4/C5 variants in actionable and non-actionable genes. Multigene testing resulted in the identification of 655 (i.e., n.82 in actionable, n. 573 in non-actionable genes) variants of uncertain significance (C3 or VUS) in 89.8% (281/313) of patients. Of the 281 C3 carriers, 60 had other variants (C4 and/or C5), of an uncertain result (in whom C3 was the highest class of variant) only in 70.6% (221/313) of TNBC patients. In 13 patients (13/313; 4.1%) only benign (C1) or likely benign (C2) variants were identified. Regarding family history, 67% of BRCA1 carriers versus 30% of BRCA2 carriers were familial. Conclusion Germline multigene testing in TNBC can identify C4/C5 in actionable genes providing information for a more tailored management of TNBC. Our study showed that the rate of VUS remains high using multigene testing. Of note, VUS were mainly identified in non-actionable genes supporting the rationale of the use in the clinical setting of phenotype-specific multigene panels, including a minor, but more appropriate, number of genes. Citation Format: sabrina K. kahler ribeiro fontana, emanuele bonetti, loris bernard, mariarosaria calvello, Bernardo Bonanni, ppina Bonizzi, Paolo Veronesi, Luca Mazzarella, Viviana Galimberti, claudia sangalli. Implementation of multigene panel testing in triple-negative breast cancer. The PERSONA-breast trial [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 P6-02-11.

Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience.

Cervico-vaginal (CV) localization of extra-mammary Paget's disease (EMPD) of the vulva is extremely rare. In order to investigate the incidence risk and the pathognomonic clinical and pathological features of this condition, a retrospective analysis was conducted including 94 women treated for vulvar EMPD at the European Institute of Oncology, Milan, Italy, from October 1997 to May 2020. Overall nine patients developed CV involvement from EMPD, with a cumulative incidence of 2.5% (95% CI: 0.5-8.0%) at 5 years, 6.5% (95% CI: 1.9-15.1%) at 10 years and 14.0% (95% CI: 4.8-27.8%) at 15 years, respectively. All cases except one were firstly detected by abnormal glandular cytology. None reported vaginal bleeding or other suspicious symptoms. The colposcopic findings were heterogeneous and could sometimes be misdiagnosed. Cervical and/or vaginal biopsies were always performed for histopathological diagnosis by identification of Paget cells in the epithelium or stroma. Most patients developed invasive EMPD (5/9) of the cervix and/or vagina and underwent hysterectomy with partial or total colpectomy. CV involvement from EMPD should not be underestimated in women with a long-standing history of vulvar Paget's disease. Liquid-based cytology with immunocytochemistry represents a valuable tool for early diagnosis and should be routinely performed during the required lifelong follow-up.

Which Risk Factors and Colposcopic Patterns Are Predictive for High-Grade VAIN? A Retrospective Analysis.

Colposcopic patterns of Vaginal Intraepithelial Neoplasia (VAIN) are not definitively related to histological grade. The aim of the present study was to investigate any correlation between clinical and colposcopic features and the development of high-grade VAIN. Two hundred and fifty-five women diagnosed with VAIN (52 VAIN1, 55 VAIN2 and 148 VAIN3) at the European Institute of Oncology, Milan, Italy, from January 2000 to June 2022, were selected for a retrospective analysis. Multivariate logistic regression was performed to estimate the association of risk factors and colposcopic patterns with VAIN grade. Smoking was associated with the development of VAIN (34.1%, p = 0.01). Most women diagnosed with VAIN3 (45.3%, p = 0.02) had a previous history of hysterectomy for CIN2+. At multivariate analysis, colposcopic grade G2 (OR = 20.4, 95%CI: 6.67−61.4, p < 0.001), papillary lesion (OR = 4.33, 95%CI: 1.79−10.5, p = 0.001) and vascularity (OR = 14.4, 95%CI: 1.86−112, p = 0.01) were significantly associated with a greater risk of VAIN3. The risk of high-grade VAIN should not be underestimated in women with a history of smoking and previous hysterectomy for CIN2+, especially when colposcopic findings reveal vaginal lesions characterized by grade 2, papillary and vascular patterns. Accurate diagnosis is crucial for an optimal personalized management, based on risk factors, colposcopic patterns and histologic grade of VAIN.