The TRIPLEX study: use of patient-derived tumor organoids as an innovative tool for precision medicine in triple-negative breast cancer.

BACKGROUND: Triple negative breast cancers (TNBC) account for approximately 15% of all breast cancers and are associated with a shorter median survival mainly due to locally advanced tumor and high risk of metastasis. The current neoadjuvant treatment for TNBC consists of a regimen of immune checkpoint blocker and chemotherapy (chemo-ICB). Despite the frequent use of this combination for TNBC treatment, moderate results are observed and its clinical benefit in TNBC remains difficult to predict. Patient-derived tumor organoids (PDTO) are 3D in vitro cellular structures obtained from patient's tumor samples. More and more evidence suggest that these models could predict the response of the tumor from which they are derived. PDTO may thus be used as a tool to predict chemo-ICB efficacy in TNBC patients. METHOD: The TRIPLEX study is a single-center observational study conducted to investigate the feasibility of generating PDTO from TNBC and to evaluate their ability to predict clinical response. PDTO will be obtained after the dissociation of biopsies and embedding into extra cellular matrix. PDTO will be cultured in a medium supplemented with growth factors and signal pathway inhibitors. Molecular and histological analyses will be performed on established PDTO lines to validate their phenotypic proximity with the original tumor. Response of PDTO to chemo-ICB will be assessed using co-cultures with autologous immune cells collected from patient blood samples. PDTO response will finally be compared with the response of the patient to evaluate the predictive potential of the model. DISCUSSION: This study will allow to assess the feasibility of using PDTO as predictive tools for the evaluation of the response of TNBC patients to treatments. In the event that PDTO could faithfully predict patient response in clinically relevant time frames, a prospective clinical trial could be designed to use PDTO to guide clinical decision. This study will also permit the establishment of a living biobank of TNBC PDTO usable for future innovative strategies evaluation. TRIAL REGISTRATION: The clinical trial (version 1.2) has been validated by local research ethic committee on December 30th 2021 and registered at ClinicalTrials.gov with the identifier NCT05404321 on June 3rd 2022, version 1.2.

ORGAVADS: establishment of tumor organoids from head and neck squamous cell carcinoma to assess their response to innovative therapies.

BACKGROUND: Radiotherapy is one of the cornerstones of the treatment of Head and Neck Squamous Cell Carcinomas (HNSCC). However, radioresistance is associated with a high risk of recurrence. To propose strategies (such as combinations with drugs) that could over intrinsic radioresistance, it is crucial to predict the response to treatment. Patient-Derived Tumor Organoids (PDTO) are in vitro tridimensional microtumors obtained from patient' own cancer samples. They have been shown to serve as reliable surrogates of the tumor response in patients. METHODS: The ORGAVADS study is a multicenter observational trial conducted to investigate the feasibility of generating and testing PDTO derived from HNSCC for the evaluation of sensitivity to treatments. PDTO are obtained after dissociation of resected tumors remaining from tissues necessary for the diagnosis. Embedding of tumor cells is then performed in extracellular matrix and culture in medium supplemented with growth factors and inhibitors. Histological and immunohistochemical characterizations are performed to validate the resemblance between PDTO and their original tumor. Response of PDTO to chemotherapy, radiotherapy and innovating combinations are assessed, as well as response to immunotherapy using co-cultures of PDTO with autologous immune cells collected from patient blood samples. Transcriptomic and genetic analyses of PDTO allow validation of the models compared to patients' own tumor and identification of potential predictive biomarkers. DISCUSSION: This study is designed to develop PDTO models from HNSCC. It will allow comparing the response of PDTO to treatment and the clinical response of the patients from whom they are derived. Our aim is to study the PDTO ability to predict the clinical response to treatment for each patient in view of a personalized medicine as well as to establish a collection of HNSCC models that will be useful for future innovative strategies evaluation. TRIAL REGISTRATION: NCT04261192, registered February 7, 2020, last amendment v4 accepted on June, 2021.

Parenthood in survivors of Hodgkin lymphoma: an EORTC-GELA general population case-control study.

PURPOSE: We investigated the impact of Hodgkin lymphoma (HL) on parenthood, including factors influencing parenthood probability, by comparing long-term HL survivors with matched general population controls. PATIENTS AND METHODS: A Life Situation Questionnaire was sent to 3,604 survivors treated from 1964 to 2004 in successive clinical trials. Responders were matched with controls (1:3 or 4) for sex, country, education, and year of birth (10-year groups). Controls were given an artificial date of start of treatment equal to that of their matched case. The main end point was presence of biologic children after treatment, which was evaluated by using conditional logistic regression analysis. Logistic regression analysis was used to analyze factors influencing spontaneous post-treatment parenthood. RESULTS: In all, 1,654 French and Dutch survivors were matched with 6,414 controls. Median follow-up was 14 years (range, 5 to 44 years). After treatment, the odds ratio (OR) for having children was 0.77 (95% CI, 0.68 to 0.87; P < .001) for survivors compared with controls. Of 898 survivors who were childless before treatment, 46.7% achieved post-treatment parenthood compared with 49.3% of 3,196 childless controls (OR, 0.87; P = .08). Among 756 survivors with children before treatment, 12.4% became parents after HL treatment compared with 22.2% of 3,218 controls with children before treatment (OR, 0.49; P < .001). Treatment with alkylating agents, second-line therapy, and age older than 35 years at treatment appeared to reduce the chances of spontaneous post-treatment parenthood. CONCLUSION: Survivors of HL had slightly but significantly fewer children after treatment than matched general population controls. The difference concerned only survivors who had children before treatment and appears to have more personal than biologic reasons. The chance of successful post-treatment parenthood was 76%.

Evaluation of current practice: management of chemotherapy-related toxicities.

Adverse effects induced by cytotoxic chemotherapy (CT) have been mostly evaluated in clinical trials. The aim of this study was to assess in a nonselected patients group the incidence of CT-related toxicities and to identify risk factors in daily practice. Patients treated with CT (except cisplatin-based or carboplatin-based CT), for a solid tumour, were included in a prospective multicentre observational study. Clinical parameters, renal function and albumin level were assessed at baseline. Multivariate logistic regression was used to identify risk factors of CT-related toxicities. A total of 502 patients were recruited in different types of oncology departments. During CT, 62% of patients experienced grade 2-4 toxicities. Haematological toxicities affected 34% of patients and 20% of patients developed an infection requiring antibiotics. For 55% of patients, toxicities induced dose reduction (59% of cases), CT delay (25%) or discontinuation (16%) according to the management habits in the investigating centre. Performance status≥1, breast cancer, lymphopenia, hypoalbuminaemia and clearance creatinine<60 ml/min were risk factors for haematological toxicity. Performance status≥1, hypoalbuminaemia, proteinuria and clearance creatinine<90 ml/min were risk factors for change of CT schedule. A majority of patients receiving CT experienced significant toxicity leading to change of standard CT protocol. Albumin, creatinine clearance and lymphocyte should be routinely monitored at baseline to manage CT and to prevent their toxicities.

Cancer incidence within a cohort occupationally exposed to asbestos: a study of dose--response relationships.

OBJECTIVES: The aim of our study was to analyse the dose-response relationship between occupational asbestos exposure and risk of cancer. METHODS: Our study was a retrospective morbidity study based on 2024 subjects occupationally exposed to asbestos, conducted over the period 1 January 1978 to 31 December 2004. Analysis of the dose-response relationship between occupational asbestos exposure, as a time-dependant variable, and risk of cancer was performed using a Cox model. In order to account for the effect of latency, we conducted the analysis with a lag of 10 years. RESULTS: 285 cases of cancers were observed in our cohort. The relative risk of pleuro-peritoneal mesothelioma, lung cancer and colorectal cancer associated with asbestos exposure, adjusted for age as a time-dependant variable and for sex, was correlated with exposure intensity (or average exposure level, AEL). The risk of cancer, whatever the anatomical site, did not increase with the duration of exposure to asbestos. CONCLUSION: While confirming the established relationship between asbestos exposure and pleuropulmonary and peritoneal cancers, this study also suggests a causal relationship between asbestos exposure and colorectal cancer.