Effects of the intestinal microbiota on prostate cancer treatment by androgen deprivation therapy

Prostate cancer (PC) can be kept in check by androgen deprivation therapy (ADT, usually with the androgen synthesis inhibitor abiraterone acetate or the androgen receptor antagonist such as enzalutamide) until the tumor evolves to castration-resistant prostate cancer (CRPC). The transition of hormone-sensitive PC (HSPC) to CPRC has been explained by cancer cell-intrinsic resistance mechanisms. Recent data indicate that this transition is also marked by cancer cell-extrinsic mechanisms such as the failure of ADT-induced PC immunosurveillance, which depends on the presence of immunostimulatory bacteria in the gut. Moreover, intestinal bacteria that degrade drugs used for ADT, as well as bacteria that produce androgens, can interfere with the efficacy of ADT. Thus, specific bacteria in the gut serve as a source of testosterone, which accelerates prostate cancer progression, and men with CRPC exhibit an increased abundance of such bacteria with androgenic functions. In conclusion, the response of PC to ADT is profoundly influenced by the composition of the microbiota with its immunostimulatory, immunosuppressive and directly ADT-subversive elements

Influence of microbiota-associated metabolic reprogramming on clinical outcome in patients with melanoma from the randomized adjuvant dendritic cell-based MIND-DC trial

Tumor immunosurveillance plays a major role in melanoma, prompting the development of immunotherapy strategies. The gut microbiota composition, influencing peripheral and tumoral immune tonus, earned its credentials among predictors of survival in melanoma. The MIND-DC phase III trial (NCT02993315) randomized (2:1 ratio) 148 patients with stage IIIB/C melanoma to adjuvant treatment with autologous natural dendritic cell (nDC) or placebo (PL). Overall, 144 patients collected serum and stool samples before and after 2 bimonthly injections to perform metabolomics (MB) and metagenomics (MG) as prespecified exploratory analysis. Clinical outcomes are reported separately. Here we show that different microbes were associated with prognosis, with the health-related Faecalibacterium prausnitzii standing out as the main beneficial taxon for no recurrence at 2 years (p = 0.008 at baseline, nDC arm). Therapy coincided with major MB perturbations (acylcarnitines, carboxylic and fatty acids). Despite randomization, nDC arm exhibited MG and MB bias at baseline: relative under-representation of F. prausnitzii, and perturbations of primary biliary acids (BA). F. prausnitzii anticorrelated with BA, medium- and long-chain acylcarnitines. Combined, these MG and MB biomarkers markedly determined prognosis. Altogether, the host-microbial interaction may play a role in localized melanoma. We value systematic MG and MB profiling in randomized trials to avoid baseline differences attributed to host-microbe interactions

Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment.

The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation

Impact of the Microbiome-Thymus Axis in the Efficacy of Androgen Deprivation and Immune-Surveillance in Prostate Cancer

La déprivation androgénique est la pierre angulaire du traitement du cancer de la prostate (CaP), mais la plupart des patients deviendront réfractaires à la castration (CRPC). En outre, les immunothérapies par inhibiteurs de points de contrôle immunitaire ne sont pour l’instant pas un standard dans la prise en charge de ce cancer en raison de son environnement immunosuppresseur. Notre hypothèse est que pour accroître la sensibilité des patients aux traitements immuno-modulateurs (déprivation androgénique, inhibiteurs des points de contrôle immunitaire et autres), il faudrait restaurer l’environnement immunitaire systémique de l’hôte, et rétablir ainsi un microenvironnement intra-tumoral immuno-reactif de manière plus précoce dans la prise en charge de la maladie.Étant donné que les patients atteints d'un cancer avancé peuvent présenter une dysbiose intestinale, qu’on sait que la composition du microbiote intestinal joue un rôle essentiel dans le succès de tout traitement immuno-modulateur, nous avons donc analysé l'impact du système immunitaire, de la composition du microbiote intestinal et la relation entre les deux composants sur la durée de l’hormono-sensibilité chez les patients atteints de CaP et dans un modèle murin de cancer de la prostate (Lignées Myc-CaP).Tout d'abord, en utilisant des anticorps depletant les lymphocytes CD4 ou CD8 et des souris nudes- athymiques, nous avons démontré le rôle clé des lymphocytes T dans le temps jusqu’à résistance à la castration. Ensuite, à l'aide d'expériences d'antibiotiques à large spectre, de « cohousing », de transplantation microbienne fécale (FMT) et d’utilisation de probiotiques immunogènes nous avons dévoilé le rôle fondamental du microbiote intestinal de l’hôte dans le contrôle de la croissance des tumeurs pendant la suppression androgénique. Troisièmement, la métagénomique des fèces couplées aux analyses métabolomiques sanguines ont mis en évidence des changements significatifs associés à la castration et aux manipulations du microbiote. Enfin, l’intégrité du thymus semble être compromise par la présence du cancer de la prostate, que la castration ne restaure pas. Néanmoins, un microbiote sain restaurerait la thymopoïèse et l'émigration des lymphocytes matures associés à une immunosurveillance anticancéreuse efficace. Dans l'ensemble, nous démontrons que la déprivation androgénique permet d'obtenir une efficacité anti-cancéreuse optimale et de longue durée, de manière dépendante des lymphocytes T lorsque la dysbiose intestinale est compensée par la FMT d’individus sains ou par des probiotiques immunogènes. Par ailleurs ce renforcement du tonus immunitaire de l’hôte permettrait de sensibiliser le cancer de la prostate aux traitements ultérieurs par immunothérapie.Androgen deprivation therapy (ADT) is the backbone treatment for Prostate cancer (PCa), but most patients will become refractory to castration (CRPC). In addition, immune checkpoint blockade may not be an option for CRPC. Given that advanced cancer patients may exhibit a gut dysbiosis and the pivotal role of the intestinal microbiota composition in dictating the success of chemo-and immuno-therapy, we analyzed the role of the immune system, the impact of the gut microbiota and the inter-relationship between both components in the time to CRPC in PCa patients and in a mouse model of prostate cancer (MyC-CaP cell line). First, using CD4 or CD8 depleting antibodies and athymic nude mice, we demonstrated the key role of T lymphocytes in the time to progression during ADT. Secondly, using cohousing experiments, fecal microbial transplantation and broad spectrum antibiotics, we unveiled the seminal role of the host microbiota in governing tumor growth control during ADT. Third, metagenomics coupled with metabolomics analyses highlighted significant changes associated with ADT, their physiological relevance being currently investigated. Finally, while the development of PCa compromises the thymus integrity despite ADT; healthy microbiota restores thymopoiesis and the emigration of mature lymphocytes associated with effective anticancer immunosurveillance. Altogether, ADT mediates a full blown T cell-dependent anti-PCa cancer efficacy when intestinal dysbiosis is compensated by FMT or immunogenic probiotics

Primary adenocarcinoma of the seminal vesicle

Primary adenocarcinoma of the seminal vesicle is a rare condition with only about 60 cases described in the literature. The unusual characteristics of this disease makes diagnosis difficult and treatment strategies differ as there are no specific guidelines available. This report presents a case of adenocarcinoma of the seminal vesicle with lung metastases in which surgical and chemotherapeutic treatments have been carried out. The MVAC dose dense regimen following local resection seems effective in this scenario and may be used in the treatment of this disease

Survival of Patients with Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small Cell Lung Cancer Treated beyond the Second Line in the Tyrosine Kinase Inhibitor Era

International audienceBackground: The identification of activating mutations in specific genes led to the development of targeted therapies for NSCLC. TKI directed against EGFR-mutations were the first to prove their major efficacy. Medical associations recommend their use as first and second-line metastatic treatments in EGFR-mutated patients. Our objective was to analyze the survival of EGFR-mutated patients treated beyond the second line of treatment.Methods: We performed a longitudinal, retrospective and analytical study at APHP (Assistance Publique Hopitaux de Paris) Saint Louis, Paris, France, from 1 January 2010 to 31 December 2020 (11 years), on EGFR-mutated patients with metastatic NSCLC which received TKI or chemotherapy (CT) in third-line.Results: Out of about 107 EGFR-mutated patients, 31 patients who benefited from TKI or CT in the third line of treatment were retained for this study. The mean age was 60.03 ± 11.93 years and the sex ratio male/female was 0.24. Mutations of exon 19, 21 and 20 were found in 21 (67.7%), 7 (22.6%) and 7 (22.6%) patients, respectively. Third-line treatment was CT for 16 patients (51.6%) and TKI for the 15 remaining patients (48.4%). Osimertinib was the most used TKI in third-line (n = 10/15; 66.67%). The median duration of third-line treatment was 5.37 months (range 0.53–37.6) and the median follow-up duration was 40.83 months (range 11.33–88.57). There was a significant difference in PFS between patients treated with TKI and CT in third-line (p = 0.028). For patients treated with CT in second-line, there was a significant difference of PFS (p < 0.001) and OS (p = 0.014) in favor of the use of TKI in third-line.Conclusions: For patients receiving CT in second-line, TKI appears to be a better alternative in third-line compared to CT. Osimertinib may be used in third line treatment if not used before

Survival of Patients with Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small Cell Lung Cancer Treated beyond the Second Line in the Tyrosine Kinase Inhibitor Era

Background: The identification of activating mutations in specific genes led to the development of targeted therapies for NSCLC. TKI directed against EGFR-mutations were the first to prove their major efficacy. Medical associations recommend their use as first and second-line metastatic treatments in EGFR-mutated patients. Our objective was to analyze the survival of EGFR-mutated patients treated beyond the second line of treatment. Methods: We performed a longitudinal, retrospective and analytical study at APHP (Assistance Publique Hopitaux de Paris) Saint Louis, Paris, France, from 1 January 2010 to 31 December 2020 (11 years), on EGFR-mutated patients with metastatic NSCLC which received TKI or chemotherapy (CT) in third-line. Results: Out of about 107 EGFR-mutated patients, 31 patients who benefited from TKI or CT in the third line of treatment were retained for this study. The mean age was 60.03 ± 11.93 years and the sex ratio male/female was 0.24. Mutations of exon 19, 21 and 20 were found in 21 (67.7%), 7 (22.6%) and 7 (22.6%) patients, respectively. Third-line treatment was CT for 16 patients (51.6%) and TKI for the 15 remaining patients (48.4%). Osimertinib was the most used TKI in third-line (n = 10/15; 66.67%). The median duration of third-line treatment was 5.37 months (range 0.53–37.6) and the median follow-up duration was 40.83 months (range 11.33–88.57). There was a significant difference in PFS between patients treated with TKI and CT in third-line (p = 0.028). For patients treated with CT in second-line, there was a significant difference of PFS (p &lt; 0.001) and OS (p = 0.014) in favor of the use of TKI in third-line. Conclusions: For patients receiving CT in second-line, TKI appears to be a better alternative in third-line compared to CT. Osimertinib may be used in third line treatment if not used before

Standard or accelerated methotrexate, vinblastine, doxorubicin and cisplatin as neoadjuvant chemotherapy for locally advanced urothelial bladder cancer: Does dose intensity matter?

International audienceBackground There is continuing controversy regarding the optimal regimen for neoadjuvant chemotherapy (NAC) in bladder cancer. Patients and methods We performed a retrospective analysis of 241 consecutive bladder cancer patients who received a combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) using a standard (52 patients) or an accelerated schedule (189 patients) as NAC before radical cystectomy in 17 centres of the French GEnito-urinary TUmour Group from March 2004–May 2013. Results The median age was 62 years. As expected, the median number of cycles, the median total dose of cisplatin and the median cisplatin dose intensity were higher in patients treated with the accelerated regimen. Conversely, the median duration of chemotherapy was shorter. Regarding toxicity, grade III/IV neutropenia, grade III thrombocytopenia and grade III anaemia as well were more frequently observed in patients treated with the standard regimen. Among 211 (88%) patients who proceeded to cystectomy, 75 (35%) patients achieved an ypT0 pN0 status (no pathologic residual tumour cells) with no significant difference according to the MVAC schedule. Three-year overall survival rates were 66.5% (95% confidence interval [CI], 56–79) and 72% (95% CI, 59.5–88) in the standard and accelerated cohorts, respectively. In the multivariate analysis, two independent prognostic parameters were retained: the ypT0 stage and the ypN0 stage. Heterogeneity test did not show any interaction with NAC regimens. Conclusion Similar pathological response and survival rates were observed whatever the chemotherapy regimen used. Haematological toxicity was greater in patients who received standard MVA

Overall Survival in Men With Bone Metastases From Castration-Resistant Prostate Cancer Treated With Bone-Targeting Radioisotopes: A Meta-analysis of Individual Patient Data From Randomized Clinical Trials.

Importance Both α-emitting and β-emitting bone-targeted radioisotopes (RIs) have been developed to treat men with metastatic castration-resistant prostate cancer (CRPC). Only 1 phase 3 randomized clinical trial has demonstrated an overall survival (OS) benefit from an α-emitting RI, radium 223 (223Ra), vs standard of care. Yet no head-to-head comparison has been done between α-emitting and β-emitting RIs. Objective To assess OS in men with bone metastases from CRPC treated with bone-targeted RIs and to compare the effects of α-emitting RIs with β-emitting RIs. Data Sources PubMed, Cochrane Library, ClinicalTrials.gov, and meeting proceedings between January 1993 and June 2013 were reviewed. Key terms included randomized trials, radioisotopes, radiopharmaceuticals, and prostate cancer. Data were collected, checked, and analyzed from February 2017 to October 2018. Study Selection Selected trials included patients with prostate cancer, recruited more than 50 patients from January 1993 to June 2013, compared RI use with no RI use (placebo, external radiotherapy, or chemotherapy), and were randomized. Patients were diagnosed with histologically proven prostate cancer and disease progression after both surgical or chemical castration and have evidence of bone metastasis. Nine randomized clinical trials were identified as eligible, but 3 were excluded for insufficient data. Data Extraction and Synthesis Individual patient data were requested for each eligible trial, and all data were checked with a standard procedure. The log-rank test stratified by trial was used to estimate hazard ratios (HRs), and a similar fixed-effects (FE) model was used to estimate odds ratios (ORs). The between-trial heterogeneity of treatment effects was evaluated by Cochran test and I2 and was accounted by a random-effects (RE) model. Main Outcomes and Measures Overall survival; secondary outcomes were symptomatic skeletal event (SSE)-free survival and adverse events. Results Based on 6 randomized clinical trials including 2081 patients, RI use was significantly associated with OS compared with no RI use (HR, 0.86; 95% CI, 0.77-0.95; P = .004) with high heterogeneity (χ25 = 24.46; P < .001; I2 = 80%), but this association disappeared when using an RE model (HR, 0.80; 95% CI, 0.61-1.06; P = .12; τ2 = 0.08). The heterogeneity is explained both by the type of RI and by the inclusion of 2 outlier trials that included 275 patients; the OS benefit was significantly higher with the α-emitting RI 223Ra (HR, 0.70; 95% CI, 0.58-0.83) but not significant with the β-emitting RI strontium-89 (HR, 0.96; 95% CI, 0.84-1.10) (P for interaction = .004). Excluding the outlier trials led to an overall HR of 0.82 (95% CI, 0.73-0.92; P < .001) (between-trial heterogeneity: χ23 = 6.51; P = .09; I2 = 54%) using an FE model and an HR of 0.80 (95% CI, 0.65-0.99; P = .04; τ2 = 0.02) using an RE model. The HR for SSE-free survival was 0.81 (95% CI, 0.69-0.93; P = .004) (between-trial heterogeneity: χ23 = 6.71; P = .08; I2 = 55%) when using an FE model and was 0.76 (95% CI, 0.58-1.01; P = .06; τ2 = 0.04) when using an RE model. There were more hematological toxic effects with RI use compared with no RI use (OR, 1.48; 95% CI, 1.17-1.88; P = .001). Conclusions and Relevance In metastatic CRPC, a significant improvement of OS and SSE-free survival was obtained with bone-targeted α-emitting but not β-emitting RIs. Caution is necessary for generalizability of these results, given the between-trial heterogeneity