[Prognostic value of testosterone during androgene deprivation therapy]. / Valeur pronostique de la testostéronémie lors de l'hormonothérapie intermittente du cancer de la prostate.

INTRODUCTION: The concept of intermittent androgen deprivation therapy (IADT) for prostate cancer (PCa) was introduced in order to improve treatment tolerance with the same carcinological efficiency as continuous androgen deprivation therapy (CADT). Furthermore, studies have shown that PCa prognosis during CADT was correlated to the extent of testosterone collapse. The aim of this study was to assess the link between testosterone levels at the end of the first off-treatment phase and time to occurrence of castrate-resistant prostate cancer. METHODS: We retrospectively analyzed the files of 69 patients having undergone IADT. Intermittence was offered to the patients showing PSA<4ng/mL after at least six months of androgen deprivation therapy (ADT) using a LHRH analog. CRPC was defined according to the AFU oncological guidelines. Patients were sorted into three groups according to their testosterone levels at the end of the first off-treatment phase T<0.5ng/mL, 0.53.4ng/mL. CRPC free-survival, metastasis-free survival and overall survival as well as adverse events frequency were compared between the groups. The impact of initial ADT duration on CRPC occurrence, mean off-treatment phase duration and IADT duration was also studied. RESULTS: Testosterone levels at the end of the first and second off-treatment phases were not linked to time to CRPC occurence (p=0.5), mestastasis occurence (p=0.4) or death (p=0.3). It was associated neither with adverse effects frequency (p=0.2) nor with cancer-related complications (p=0.6). Initial ADT duration was not linked to CRPC occurrence (p=0.6), mean off-treatment phase duration (p=0.5) or mean IADT duration (p=0.6). CONCLUSION: This study did not show any link between testosterone levels at the end of the first off-treatment phase (before reintroducing ADT) and overall survival, metastasis-free survival and CRPC-free survival. Likewise, it was not associated with the frequency of adverse events or cancer-related complications. Initial ADT duration was not linked to CRPC occurrence or IADT chronological parameters.

[Qualitative and quantitative hormonal regulation in castration-resistant prostate cancer]. / Régulation hormonale qualitative et quantitative dans le cancer de la prostate résistant à la castration.

INTRODUCTION: Despite initial sensitivity to androgen deprivation, most metastatic prostate cancer patients will experience recurrence or progression. This evolution, which occurs while seric testosterone level is low, is called castration resistant prostate cancer (CRPC). MATERIAL AND METHODS: MEDLINE database was requested for French or English articles published until September 2012 responding to the following keywords: "castration resistant", "prostatic neoplasms", "androgens", "testosterone", "regulat*". Here is a summary of relevant data concerning both qualitative and quantitative hormonal regulation. RESULTS: androgen blood testing is not related to tissue concentrations, as prostate cancer cells exhibit higher hormones levels. Despite its higher biological efficiency, dihydrotestosterone is not the only mediator of androgen-dependent transcription. Androgen synthesis implies many pathways including lot of alternative ones. Steroïdogenesis can occur out of the testicles and the adrenals, and maybe in tumor cell or tissue. Major and minor androgens levels, as those of co-repressors and activators inside the tumor cell leads to a smooth androgen activity modulation. Many drugs have the ability to block those different steps. CONCLUSION: Castration resistance reflects an androgen activity in tumor cells while major androgen pathway activators are lowered. Alternate pathway include steroids pumps, de novo synthesis by tumor cells or their environment, minor androgens activation by co-factors regulation. Many drugs are known to inhibit those escaping ways. Nowadays they are not efficient enough, because of other minor pathways becoming dominant. Investigations are required but would need new detection techniques of low androgen concentrations in blood as in tissues.

[Corticotherapy in castration-resistant prostate cancer]. / Corticothérapie dans le cancer de la prostate résistant à la castration.

INTRODUCTION: Corticosteroids are commonly used in the treatment of prostate cancer resistant to castration (PCRC), partly due to the inhibitory effects on adrenal androgen production acting as a pituitary suppressant. METHODS: A literature search was conducted in PubMed/MEDLINE database using the following key words: prostate cancer; castration resistance; metastasis; corticotherapy. RESULTS: Corticosteroids exert direct anti-tumoral activities mediated by the glucocorticoids receptor and involving cellular/tissue functions as growth, apoptosis, inflammation, metastasis, differentiation and angiogenesis. As a pain relieving agents, corticosteroids significantly relieve PCRC clinical symptoms, especially those due to bone metastasis. In the comparative arm of phase II-III trials, corticosteroids administered daily produce a PSA decline. Among the adverse effects due to corticosteroids, bone loss and cardiovascular risk should be carefully monitored. In association with abiraterone acetate, corticosteroids increase overall survival in PCRC patients, and reduce the mineralocorticoid side effects of abiraterone. CONCLUSION: Corticosteroids in monotherapy for PCRC have a limited efficacy. In association with abiraterone acetate it reduces the mineralocorticoid toxicity and enhances the androgenic suppression.

[Choice of new drugs in castration-resistant prostate cancer: predictive factors and effectiveness assessment]. / Choix des nouveaux traitements médicaux dans le cancer de la prostate résistant à la castration: marqueurs prédictifs et évaluation de l'efficacité.

INTRODUCTION: Docetaxel has been the cornerstone in the treatment of castration- resistant prostate cancer (CRPC) since 2004. The recent and almost simultaneous arrival of new and effective molecules - several of which are already available on the market - has added to the CRPC treatment arsenal. Several studies have explored the optimal order in which these new treatments should be administered. The aim of this review was to present their respective predictive and evaluative factors and suggest potential administration sequences. METHODS: The PubMed medical literature citations database was searched using the following key words: prostate cancer, castration resistant, metastatic, targeted therapy, treatment sequence, immunotherapy and clinical trials. The reports of the most recent European and North American congresses were also included. RESULTS: While no predictive factors have been clearly identified for these new therapies to date, a Gleason score of not less than 8 and one or more chemotherapy sessions seemed to be predictive of lower efficacy for abiraterone. Promising elements for further investigation include the circulating tumour cell count and variation in this count per treatment, ERG mutation status or the intratumoural androgen status. Substitution criteria have not yet been reported but, as is the case with all hormone therapies, changes in PSA levels emerge as a valuable indicator of the efficacy of abiraterone. The best treatment sequence for patients who develop castration-resistance remains to be defined. CONCLUSION: Although new molecules have recently become available, the experience with their use is limited. Thus, no predictive markers of response rates and treatment outcomes or data concerning the best treatment sequence to use in patients with CRPC are as yet available.

[Molecular signatures in castration-resistant prostate cancers: An update]. / Signatures moléculaires dans les cancers de la prostate résistants à la castration : état des lieux.

Castration resistant prostate cancers are highly heterogenous at the molecular level. With the use of new generation sequencing technologies, a series of alterations were identified, opening the way for potential alternative treatments that could be more efficient for specific molecular subtypes. In this brief update, we summarize the new targetable pathways that are currently investigated. In this era of liquid biopsy and of precision medicine, it seems pertinent to be able to screen for these alterations on a more systematic basis before initiating any treatment.

[Molecular biology of castration-resistant prostate cancer]. / Bases de biologie moléculaire du cancer de la prostate résistant à la castration.

Castration-resistant prostate cancer was subjected to a paradigm switch from hormone resistance to androgen deprivation therapy resistance during the last decade. Indeed, new therapeutics targeting the androgen receptor showed clinical efficacy in patients with progressive disease under castration. Thus, it is a proof that the AR remains a dominant driver of oncogenesis in earlier-called hormone resistant prostate cancer. This review summarizes the molecular mechanisms involved in castration-resistant prostate cancer.