Bridging the gap between tumor-on-chip and clinics: a systematic review of 15 years of studies.

Over the past 15 years, the field of oncology research has witnessed significant progress in the development of new cell culture models, such as tumor-on-chip (ToC) systems. In this comprehensive overview, we present a multidisciplinary perspective by bringing together physicists, biologists, clinicians, and experts from pharmaceutical companies to highlight the current state of ToC research, its unique features, and the challenges it faces. To offer readers a clear and quantitative understanding of the ToC field, we conducted an extensive systematic analysis of more than 300 publications related to ToC from 2005 to 2022. ToC offer key advantages over other in vitro models by enabling precise control over various parameters. These parameters include the properties of the extracellular matrix, mechanical forces exerted on cells, the physico-chemical environment, cell composition, and the architecture of the tumor microenvironment. Such fine control allows ToC to closely replicate the complex microenvironment and interactions within tumors, facilitating the study of cancer progression and therapeutic responses in a highly representative manner. Importantly, by incorporating patient-derived cells or tumor xenografts, ToC models have demonstrated promising results in terms of clinical validation. We also examined the potential of ToC for pharmaceutical industries in which ToC adoption is expected to occur gradually. Looking ahead, given the high failure rate of clinical trials and the increasing emphasis on the 3Rs principles (replacement, reduction, refinement of animal experimentation), ToC models hold immense potential for cancer research. In the next decade, data generated from ToC models could potentially be employed for discovering new therapeutic targets, contributing to regulatory purposes, refining preclinical drug testing and reducing reliance on animal models.

Association of Endocrine Therapy for HR+/ERBB2+ Metastatic Breast Cancer With Survival Outcomes.

Importance: Evidence suggests that patients with human epidermal growth factor receptor 2-positive (ERBB2+ [formerly HER2+]) metastatic breast cancer (MBC) have different clinical characteristics and outcomes according to their hormone receptor (HR) status. The place of endocrine therapy (ET) for patients with HR+/ERBB2+ is still not clearly defined in this setting. Objective: To evaluate the association of HR status and first-line inclusion of ET with outcomes among patients with ERBB2+ MBC. Design, Setting, and Participants: This cohort study was an analysis of clinical data from the French clinical Epidemiological Strategy and Medical Economics (ESME) cohort, including patients with MBC who started treatment between 2008 and 2017. The last date of follow-up was June 18, 2020. Data were analyzed from May 2021 to May 2022. Exposures: Patients were treated with first-line ERBB2-targeted therapy and either chemotherapy (CT) with or without ET or ET alone. For the study of the association of maintenance ET with outcomes, we included patients treated with first-line ERBB2-targeted therapy with CT and with or without maintenance ET. Main Outcomes and Measures: Median overall survival (OS) and median first-line progression-free survival (PFS) were reported using the Kaplan-Meier method. Cox proportional hazards models and a propensity score were constructed to report and adjust for prognostic factors. Multivariable analysis included age at MBC, time to MBC, number of metastatic sites, type of metastases, and Eastern Cooperative Oncology Group performance status. Results: Among 4145 women with ERBB2+ MBC, 2696 patients had HR+ (median [IQR] age, 58.0 [47.0-67.0] years) and 1449 patients had HR- (56.0 [47.0-64.0] years) tumors. The median OS for patients with HR+ vs HR- tumors was 55.9 months (95% CI, 53.7-59.4 months) vs 42.0 months (95% CI, 38.8-45.2 months), confirmed in multivariable analysis (hazard ratio, 1.40; 95% CI, 1.26-1.56; P < .001). The median PFS for patients with HR+ vs HR- tumors was 12.2 months (95% CI, 11.5-12.9 months) vs 9.8 months (95% CI, 9.2-11.0 months; P = .01), and the HR was 1.15 (95% CI, 1.06-1.26; P < .001). In multivariable analysis, no significant difference was found in OS or PFS for 1520 patients treated with ERBB2-targeted therapy with CT and with or without ET vs 203 patients receiving ERBB2-targeted therapy with ET, regardless of type of ERBB2-targeted therapy (trastuzumab or trastuzumab with pertuzumab). This result was confirmed by matching patients using a propensity score. Using the time-dependent ET variable among patients with ERBB2-targeted therapy with CT, those with maintenance ET had significantly better PFS (hazard ratio, 0.70; 95% CI, 0.60-0.82; P < .001) and OS (hazard ratio, 0.47; 95% CI, 0.39-0.57; P < .001). Conclusions and Relevance: These results suggest that ET-containing first-line regimens may be associated with benefits among a subgroup of patients with HR+/ERBB2+ MBC.

Clinicopathological characteristics and prognosis of breast cancer patients with isolated central nervous system metastases in the multicentre ESME database.

BACKGROUND: As a result of progress in diagnosis and treatment, there is a growing prevalence of metastatic breast cancer (MBC) with isolated CNS metastases. This study describes the largest-to-date real-life cohort of this clinical setting and compares it to other clinical presentations. METHODS: We retrospectively analysed the French Epidemiological Strategy and Medical Economics (ESME) MBC database including patients who initiated treatment for MBC between 2008 and 2016. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Descriptive statistics and multivariate Cox model were used. RESULTS: Of 22,266 patients, 647 (2.9%) and 929 (4.2%) patients had isolated first-site CNS metastases or combined with extra-CNS metastases, with longer OS for the group with isolated CNS metastases (16.9 versus 13.9 months, adjusted HR = 1.69 (95% CI: 1.50-1.91), p < 0.001). Among the 541 (2.4%) patients with isolated CNS metastases and no intrathecal therapy (excluding leptomeningeal metastases), HER2+ cases were preponderant over TN or HR+ /HER2- cases (41.6% versus 26.1% versus 28.5%, respectively, p < 0.01). The treatment strategy consisted of a combination of local treatment and systemic therapy (49.2%), local treatment only (35.5%) or systemic therapy only (11.4%), or symptomatic therapy only (3.9%). Median PFS was 6.1 months (95% CI: 5.7-6.8). Median OS was 20.7 months (95% CI: 17.3-24.3), reaching 37.9 months (95% CI: 25.9-47.6) in the HR+ /HER2+ subgroup. Older age, TN subtype, MBC-free interval of 6-12 months, lower performance status, and WBRT were associated with poorer survival. Patients who received systemic therapy within 3 months from MBC diagnosis had longer OS (24.1 versus 16.1 months, p = 0.031), but this was not significant on multivariate analysis [HR = 1.0 (95% CI: 0.7-1.3), p = 0.806]. CONCLUSIONS: Patients with isolated CNS metastases at MBC diagnosis represent a distinct population for which the role of systemic therapy needs to be further investigated in prospective studies.

Tumour growth rate improves tumour assessment and first-line systemic treatment decision-making for immunotherapy in patients with liver metastatic uveal melanoma.

BACKGROUND: The RECIST-based response variably matches the clinical benefit of systemic therapies for liver metastatic uveal melanoma (LMUM). The aims were to determine whether the tumour growth rate (TGR) can help predict the survival in patients with LMUM and to provide information for the management of first-line systemic treatment. METHODS: This retrospective study included 147 (training: n = 110, validation: n = 37) patients with LMUM treated with first-line systemic treatment between 2010 and 2021. Two TGR-derived parameters were calculated, TGR0 and TGR3m. Multivariate Cox analyses identified independent predictors of progression-free survival (PFS) and overall survival (OS). RESULTS: TGR3m was a strong independent prognostic factor of PFS and OS (p < 0.001). The RECIST-based response was no longer significant in the OS analyses. Only immunotherapy regimens correlated with higher OS (HR = 0.2; 95% CI, 0.1-0.5; p < 0.001) in the low-TGR3m (≤50%/m) subgroup. These findings were confirmed in the validation cohort. TGR0, disease-free interval (DFI), and the sum of target lesions at baseline were predictive factors of low TGR3m. DISCUSSION: The use of TGR3m would improve tumour assessment by identifying patients who would benefit from first-line immunotherapy regimens despite PD. TGR0, DFI and the sum of target lesions were correlated with TGR3m, which can support first-line treatment decision-making for immunotherapy.

Oral etoposide in heavily pre-treated metastatic breast cancer: results from the ESME cohort and comparison with other chemotherapy regimens.

INTRODUCTION: HER2-negative metastatic breast cancer (MBC) is a common setting in which chemotherapy could be effective even in later lines of treatment. Oral etoposide has demonstrated clinical activity in this setting in small-scale studies, but its efficacy has not been compared to that of other chemotherapy regimens. METHODS: We used the ESME database (Epidemiological Strategy and Medical Economics), a real-life national French multicentre cohort of MBC patients initiating therapy between 1 January 2008 to 31 December 2014. HER2-negative MBC patients who received oral etoposide as > 3rd chemotherapy line and for more than 14 days were included. Primary objective was progression-free survival (PFS); secondary objectives were overall survival (OS), and propensity-score matched Cox models including comparison with other therapies in the same setting. RESULTS: Three hundred forty-five out of 16,702 patients received oral etoposide and 222 were eligible. Median PFS was 3.2 months [95% CI 2.8-4] and median OS 7.3 months [95% CI 5.7-10.3]. Median PFS did not significantly differ according to the therapeutic line. The only prognostic factor for both PFS and OS was the MBC phenotype (hormone receptor-positive versus triple-negative, HR = 0.71 [95% CI 0.52-0.97], p = 0.028 for PFS and HR = 0.65 [0.46-0.92], p = 0.014 for OS). After matching for the propensity score, no differential effect on PFS or OS was observed between oral etoposide and other chemotherapy regimens administered in the same setting (HR = 0.94 [95% CI 0.77-1.15], p = 0.55 for PFS and HR = 1.10 [95% CI 0.88-1.37], p = 0.40 for OS). CONCLUSION: Oral etoposide retains some efficacy in selected heavily pre-treated patients with HER2-negative MBC, with the advantages of oral administration.