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Treatment options for malignant pleural mesothelioma are scarce. Tazemetostat, a selective oral enhancer of zeste homolog 2 (EZH2) inhibitor, has shown antitumour activity in several haematological cancers and solid tumours. We aimed to evaluate the anti-tumour activity and safety of tazemetostat in patients with measurable relapsed or refractory malignant pleural mesothelioma. We conducted an open-label, single-arm phase 2 study at 16 hospitals in France, the UK, and the USA. Eligible patients were aged 18 years or older with malignant pleural mesothelioma of any histology that was relapsed or refractory after treatment with at least one pemetrexed-containing regimen, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a life expectancy of greater than 3 months. In part 1 of the study, participants received oral tazemetostat 800 mg once on day 1 and then twice daily from day 2 onwards. In part 2, participants received oral tazemetostat 800 mg twice daily starting on day 1 of cycle 1, using a two-stage Green-Dahlberg design. Tazemetostat was administered in 21-day cycles for approximately 17 cycles. The primary endpoint of part 1 was the pharmacokinetics of tazemetostat and its metabolite at day 15 after administration of 800 mg tazemetostat, as measured by maximum serum concentration (Cmax), time to Cmax (Tmax), area under the concentration-time curve (AUC) to day 15 (AUC0–t), area under the curve from time 0 extrapolated to infinity (AUC0–∞), and the half-life (t1/2) of tazemetostat, assessed in all patients enrolled in part 1. The primary endpoint of part 2 was the disease control rate (the proportion of patients with a complete response, partial response, or stable disease) at week 12 in patients with malignant pleural mesothelioma per protocol with BAP1 inactivation determined by immunohistochemistry. The safety population included all the patients who had at least one post-dose safety assessment. This trial is now complete and is registered with ClinicalTrials.gov, NCT02860286. Between July 29, 2016, and June 2, 2017, 74 patients were enrolled (13 in part 1 and 61 in part 2) and received tazemetostat, 73 (99%) of whom had BAP1-inactivated tumours. In part 1, following repeat dosing of tazemetostat at steady state, on day 15 of cycle 1, the mean Cmax was 829 ng/mL (coefficient of variation 56·3%), median Tmax was 2 h (range 1–4), mean AUC0–twas 3310 h·ng/mL (coefficient of variation 50·4%), mean AUC0–∞ was 3180 h·ng/mL (46·6%), and the geometric mean t1/2 was 3·1 h (13·9%). After a median follow-up of 35·9 weeks (IQR 20·6–85·9), the disease control rate in part 2 in patients with BAP1-inactivated malignant pleural mesothelioma was 54% (95% CI 42–67; 33 of 61 patients) at week 12. No patients had a confirmed complete response. Two patients had a confirmed partial response: one had an ongoing partial response with a duration of 18 weeks and the other had a duration of 42 weeks. The most common grade 3–4 treatment-emergent adverse events were hyperglycaemia (five [7%] patients), hyponatraemia (five [7%]), and anaemia (four [5%]); serious adverse events were reported in 25 (34%) of 74 patients. Five (7%) of 74 patients died while on study; no treatment-related deaths occurred. Further refinement of biomarkers for tazemetostat activity in malignant pleural mesothelioma beyond BAP1 inactivation could help identify a subset of tumours that are most likely to derive prolonged benefit or shrinkage from this therapy. Epizyme.

Only a minority of patients derive long-term clinical benefit from anti-PD1/PD-L1 monoclonal antibodies. The presence of tertiary lymphoid structures (TLS) has been associated with improved survival in several tumor types. Here, using a large-scale retrospective analysis of three independent cohorts of cancer patients treated with anti-PD1/PD-L1 antibodies, we showed that the presence of mature TLS was associated with improved objective response rate, progression-free survival, and overall survival independently of PD-L1 expression status and CD8+ T-cell density. These results pave the way for using TLS detection to select patients who are more likely to benefit from immune checkpoint blockade.

•First estimates of mCRPC incidence and prevalence.•Based on a validated algorithm and the French nationwide healthcare database.•Estimates standardized on the European Standard Population.•Annual incidence of mCRPC: 21 per 100 000 men.•Prevalence of mCRPC: 62 per 100 000 men. There is a lack of information about the burden of metastatic castration-resistant prostate cancer (mCRPC). The present work aims to estimate the incidence and prevalence of mCRPC in 2014 using the French nationwide healthcare database (SNDS). Prevalence and incidence were estimated based on an SNDS extraction of men covered by the general healthcare insurance (86 % of the French population), and aged ≥40. Patients with mCRPC were identified amongst prostate cancer cases using an algorithm estimating a date of first metastasis management and a date of castration resistance. This algorithm was validated by clinical experts through a blind review of 200 anonymized medical charts from SNDS data. Prevalence and incidence were standardized on the European Standard Population (2013 edition). Prevalence and incidence of mCRPC were estimated as, respectively, 62 and 21 cases per 100 000 men in 2014. Less than one mCRPC case per 100 000 was observed in men aged 40–49. Maximum mCRPC incidence was in men aged 80–89 (175 per 100 000). The algorithm used for mCRPC identification had 97 % positive and 99 % negative predictive values. The good performances of the algorithm for mCRPC identification and the consistency of the generated results with the existing data highlight the robustness of these first estimates of mCRPC prevalence and incidence. Future updates will call for algorithm adjustment as practices evolve over time. These first real-life data will serve for future follow-up of the impact of changes in the management of prostate cancer.

Preclinical data have shown that ERBB2 activating mutations are responsive to HER2 tyrosine kinase inhibitors. The aim of this study is to characterize the landscape of ERBB2 mutations in solid tumors and the potential efficacy of ERBB2 targeting. We analyzed the next-generation sequencing results from 17,878 patients with solid tumors and reported the outcome of 4 patients with advanced ERBB2-mutated tumors treated with a combination of trastuzumab and lapatinib. ERBB2 mutations occurred in 510 patients (2.85%). The tumor types with the highest incidence of ERBB2 mutations were the following: bladder (16.6%), small bowel (8.6%), ampullar (6.5%), skin non-melanoma (6.1%), and cervical cancer (5.5%). 49.4% ( n  = 282) were known as activating mutations. ERBB2 mutation was not mutually exclusive of ERBB2 amplification which occurred in up to 10% of cases. PI3KCA activating mutations were associated with ERBB2 mutations in 12.4% of cases mainly in breast and lung cancer. Four patients (endometrial, colorectal, cholangiocarcinoma, and adenosarcoma of the uterus) were treated with a combination of trastuzumab and lapatinib. All of them experienced tumor shrinkage resulting in stable disease in three cases and partial response in one case. One patient developed secondary resistance. Sequencing of the progressing metastasis allowed the identification of the ERBB2 L869R mutation previously associated with resistance to lapatinib in vitro. These results support further clinical investigation aiming to demonstrate that ERBB2 -mutational driven therapy can improve patient care irrespective of histology.

Background Diagnosis performances of case-identifying algorithms developed in healthcare database are usually assessed by comparing identified cases with an external data source. When this is not feasible, intra-database validation can present an appropriate alternative. Objectives To illustrate through two practical examples how to perform intra-database validations of case-identifying algorithms using reconstituted Electronic Health Records (rEHRs). Methods Patients with 1) multiple sclerosis (MS) relapses and 2) metastatic castration-resistant prostate cancer (mCRPC) were identified in the French nationwide healthcare database (SNDS) using two case-identifying algorithms. A validation study was then conducted to estimate diagnostic performances of these algorithms through the calculation of their positive predictive value (PPV) and negative predictive value (NPV). To that end, anonymized rEHRs were generated based on the overall information captured in the SNDS over time (e.g. procedure, hospital stays, drug dispensing, medical visits) for a random selection of patients identified as cases or non-cases according to the predefined algorithms. For each disease, an independent validation committee reviewed the rEHRs of 100 cases and 100 non-cases in order to adjudicate on the status of the selected patients (true case/ true non-case), blinded with respect to the result of the corresponding algorithm. Results Algorithm for relapses identification in MS showed a 95% PPV and 100% NPV. Algorithm for mCRPC identification showed a 97% PPV and 99% NPV. Conclusion The use of rEHRs to conduct an intra-database validation appears to be a valuable tool to estimate the performances of a case-identifying algorithm and assess its validity, in the absence of alternative.

Previous precision medicine studies have investigated conventional molecular techniques and/or limited sets of gene alterations. The aim of this study was to describe the impact of the next-generation sequencing of the largest panel of genes used to date in tumour tissue and blood in the context of institutional molecular screening programmes. DNA analysis was performed by next-generation sequencing using a panel of 426 cancer-related genes and by comparative genomic hybridization from formalin-fixed and paraffin-embedded archived tumour samples when available or from fresh tumour samples. Five hundred sixty-eight patients were enrolled. The median number of prior lines of treatment was 2 (range 0–9). The most common primary tumour types were lung (16.9%), colorectal (14.4%), breast (10.6%), ovarian (10.2%) and sarcoma (10.2%). The median patient age was 63 years (range 19–88). A total of 292 patients (51.4%) presented with at least one actionable genetic alteration. The 20 genes most frequently altered were TP53 , CDKN2A , KRAS , PTEN , PI3KCA , RB1 , APC , ERBB2 , MYC , EGFR , CDKN2B , ARID1A , SMAD4 , FGFR1 , MDM2 , BRAF , ATM , CCNE1 , FGFR3 and FRS2 . One hundred fifty-nine patients (28%) were included in early phase trials. The treatment was matched with a tumour profile in 86 cases (15%). The two main reasons for non-inclusion were non-progressive disease (31.5%) and general status deterioration (25%). Twenty-eight percent of patients presented with a growth modulation index (time to progression under the early phase trial treatment/time to progression of the previous line of treatment) >1.3. Extensive molecular profiling using high-throughput techniques allows for the identification of actionable mutations in the majority of cases and is associated with substantial clinical benefit in up to one in four patients.

Brain metastases are a frequent complication in patients with advanced breast cancer. Whole-brain radiation therapy (WBRT) is the standard treatment for these patients, but it can cause neurocognitive damage, and results are suboptimal. Therapies that reduce toxic effects, improve local control, and prevent recurrences are needed. The authors of this Review outline the current strategies and novel developments in WBRT, and discuss new irradiation modalities that are improving outcomes in breast cancer patients with brain metastases. Over the past 10 years, improving the outcome of breast cancer patients with brain metastases has become an important challenge. The suboptimal results of whole-brain radiation therapy (WBRT) in these patients have led to the development of irradiation modalities with new technical and biological approaches. By ensuring better sparing of critical organs such as the hippocampus, highly conformal irradiation therapy may partially preserve long-term neurocognitive functions. An additional radiation boost to the tumor bed improves local control. Radiosensitizing agents and radioprotectors that modify response to radiation have also been designed to improve the efficacy of treatment or prevent neurological toxicity. This Review outlines the current strategies and novel developments in WBRT, with a particular focus on new irradiation modalities and experiences of radiosensitization. Key Points Whole-brain radiation therapy remains the standard treatment for breast cancer patients with four or more brain metastases Age, number of brain metastases, controlled primary tumor, and performance status are important prognostic factors; molecular features should also be considered for predicting prognosis in patients with breast cancer Delivering a radiation boost to the tumor bed could improve local control in selected patients, but improvements in overall survival have not been established Intensity-modulated radiation therapy allows sparing of critical organs, such as the hippocampus, but its benefits have not yet been validated Undifferentiated chemoradiation approaches have shown no conclusive benefit, but innovative strategies that target specific molecular subsets are encouraged Radioprotectors designed to prevent neurological toxicity, such as amifostine, have not yet demonstrated clinical benefit

We performed a prospective study in the French Armed Forces regarding testicular cancer. Our primary objective was to assess whether willingness to have a testicular examination by medical doctor could be improved by a self-administered questionnaire through invitation to self-reflection. A total of 415 soldiers were enrolled. The study used a test-posttest design in that soldiers estimated their willingness to have a testicular palpation before and after responding to a self-administered questionnaire. The willingness to have testicular palpation significantly increased after responding to the questionnaire (p < 0.000001). Acceptance of testicular palpation after responding the questionnaire did not change in 82.25%, increased in 15%, and decreased in 2.75%. Analysis of responses to the questionnaire showed that 26.75% of soldiers (n = 107) had previously received general information on testicular cancer and 85.8% (n = 343) declared that they would be delighted if they were proposed a short educational course on testicular cancer. As a conclusion, this study demonstrates that the willingness to have a testicular examination by medical doctor could be easily improved, since there is a strong demand on medical education regarding testicular cancer.

Tumor-associated macrophages (TAMs) having immunosuppressive properties are one of the most abundant immune cells in the tumor microenvironment (TME). Preclinical studies have highlighted the potential role of TAMs in resistance to immune checkpoint blockers (ICBs). Here, we investigated the predictive value of TAM infiltration in patients with non-small cell lung cancer (NSCLC) treated with ICBs and characterized their transcriptomic profiles. Tumor samples were collected from 152 patients with NSCLC before ICB treatment onset. After immunohistochemical staining and image analysis, the correlation between CD163+ cell infiltration and survival was analyzed. Spatial transcriptomic analyses were performed using the NanoString GeoMx Immune Pathways assay to compare the gene expression profile of tumors with high or low levels of CD163+ cell infiltration and to identify determinants of response to ICBs in tumors with high CD163+ infiltration. Low intratumoral CD163+ cell infiltration was associated with longer progression-free survival (PFS; HR 0.61, 95% CI 0.40 to 0.94, p=0.023) and overall survival (OS; HR 0.48, 95% CI 0.28 to 0.80, p=0.004) under ICB treatment. Spatial transcriptomic profiles of 16 tumors revealed the upregulation of , CD27, and in tumors with high CD163+ cell infiltration. Moreover, in tumors with high macrophage infiltration, the upregulation of genes associated with the interferon-γ signaling pathway and the M1 phenotype was associated with better responses under immunotherapy. Surprisingly, we found also a significantly higher expression of in the tumors of responders. Analysis of three independent data sets confirmed that high expression was associated with an increased durable clinical benefit rate (47% vs 6%, p=0.004), PFS (median 10.89 months vs 1.67 months, p=0.001), and OS (median 23.11 months vs 2.66 months, p<0.001) under ICB treatment. Enrichment of TAMs in the TME of NSCLC is associated with resistance to immunotherapy regardless of the programmed death ligand 1 status and is driven by upregulation of , and gene expression within the tumor compartment. Our transcriptomic analyses identify new potential targets to alter TAM recruitment/polarization and highlight the complexity of the CSF1R pathway, which may not be a suitable target to improve ICB efficacy.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common, potentially severe and dose-limiting adverse effect; however, it is poorly investigated at an early stage due to the lack of a simple assessment tool. As sweat glands are innervated by small autonomic C-fibers, sudomotor function testing has been suggested for early screening of peripheral neuropathy. This study aimed to evaluate Sudoscan, a non-invasive and quantitative method to assess sudomotor function, in the detection and follow-up of CIPN. Eighty-eight patients receiving at least two infusions of Oxaliplatin only (45.4 %), Paclitaxel only (14.8 %), another drug only (28.4 %) or two drugs (11.4 %) were enrolled in the study. At each chemotherapy infusion the accumulated dose of chemotherapy was calculated and the Total Neuropathy Score clinical version (TNSc) was carried out. Small fiber neuropathy was assessed using Sudoscan (a 3-min test). The device measures the Electrochemical Skin Conductance (ESC) of the hands and feet expressed in microSiemens (µS). For patients receiving Oxaliplatin mean hands ESC changed from 73 ± 2 to 63 ± 2 and feet ESC from 77 ± 2 to 66 ± 3 µS (p < 0.001) while TNSc changed from 2.9 ± 0.5 to 4.3 ± 0.4. Similar results were observed in patients receiving Paclitaxel or another neurotoxic chemotherapy. During the follow-up, ESC values of both hands and feet with a corresponding TNSc < 2 were 70 ± 2 and 73 ± 2 µS respectively while they were 59 ± 1.4 and 64 ± 1.5 µS with a corresponding TNSc ≥ 6 (p < 0.0001 and p = 0.0003 respectively). This preliminary study suggests that small fiber neuropathy could be screened and followed using Sudoscan in patients receiving chemotherapy.