Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00).

BACKGROUND: The aim of this study was to evaluate the efficacy and tolerability of fulvestrant, an estrogen receptor antagonist, in postmenopausal women with hormone-responsive tumors progressing after aromatase inhibitor (AI) treatment. PATIENTS AND METHODS: This is a phase II, open, multicenter, noncomparative study. Two patient groups were prospectively considered: group A (n=70) with AI-responsive disease and group B (n=20) with AI-resistant disease. Fulvestrant 250 mg was administered as intramuscular injection every 28 (+/-3) days. RESULTS: All patients were pretreated with AI and 84% also with tamoxifen or toremifene; 67% had bone metastases and 45% liver metastases. Fulvestrant administration was well tolerated and yielded a clinical benefit (CB; defined as objective response or stable disease [SD] for >or=24 weeks) in 28% (90% confidence interval [CI] 19% to 39%) of patients in group A and 37% (90% CI 19% to 58%) of patients in group B. Median time to progression (TTP) was 3.6 (95% CI 3.0 to 4.8) months in group A and 3.4 (95% CI 2.5 to 6.7) months in group B. CONCLUSIONS: Overall, 30% of patients who had progressed following prior AI treatment gained CB with fulvestrant, thereby delaying indication to start chemotherapy. Prior response to an AI did not appear to be predictive for benefit with fulvestrant.

Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07.

BACKGROUND: We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). RESULTS: Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). CONCLUSIONS: The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicity.

Evaluation of a stage II screening protocol for prostate cancer

In 2003, prostate cancer (PCa) is estimated to be the most commonly diagnosed cancer and third leading cause of cancer death in Canada. During PCa population screening, approximately 25% of patients with a normal digital rectal examination (DRE) and intermediate serum prostate specific antigen (PSA) level have PCa. Since all patients typically undergo biopsy, it is expected that approximately 75% of these procedures are unnecessary. The purpose of this study was to compare the degree of efficacy of clinical tests and algorithms in stage II screening for PCa while preventing unnecessary biopsies from occurring. The sample consisted of 201 consecutive men who were suspected of PCa based on the results of a DRE and serum PSA. These men were referred for venipuncture and transrectal ultrasound (TRUS). Clinical tests included TRUS, agespecific reference range PSA (Age-PSA), prostate specific antigen density (PSAD), and free-to-total prostate specific antigen ratio (%fPSA). Clinical results were evaluated individually and within algorithms. Cutoffs of 0.12 and 0.15 ng/ml/cc were employed for PSAD. Cutoffs that would provide a minimum sensitivity of 0.90 and 0.95, respectively were utilized for %fPSA. Statistical analysis included ROC curve analysis, calculated sensitivity (Sens), specificity (Spec), and positive likelihood ratio (LR), with corresponding confidence intervals (Cl). The %fPSA, at a 23% cutoff ({ Sens=0.92; CI, 0.06}, {Spec=0.4l; CI, 0.09}, {LR=1.56; CI, O.ll}), proved to be the most efficacious independent clinical test. The combination of PSAD (cutoff 0.15 ng/ml/cc) and %fPSA (cutoff 23%) ({Sens=0.93; CI, 0.06}, {Spec=0.38; CI, 0.08}, {LR=1.50; CI, 0.10}) was the most efficacious clinical algorithm. This study advocates the use of %fPSA at a cutoff of 23% when screening patients with an intermediate serum PSA and benign DRE.

Prostate Cancer and the Search for Novel Biomarkers

The primary objective of this research project was to identify prostate cancer (PCa) -specific biomarkers from urine. This was done using a multi-faceted approach that targeted (1) the genome (DNA); (2) the transcriptome (mRNA and miRNA); and (3) the proteome. Toward this end, urine samples were collected from ten healthy individuals, eight men with PCa and twelve men with enlarged, non-cancerous prostates or with Benign Prostatic Hyperplasia (BPH). Urine samples were also collected from the same patients (PCa and BPH) as part of a two-year follow-up. Initially urinary nucleic acids and proteins were assessed both qualitatively and quantitatively for characteristics either unique or common among the groups. Subsequently macromolecules were pooled within each group and assessed for either protein composition via LC-MS/MS or microRNA (miRNA) expression by microarray. A number of potential candidates including miRNAs were identified as being deregulated in either pooled PCa or BPH with respect to the healthy control group. Candidate biomarkers were then assessed among individual samples to validate their utility in diagnosing PCa and/or differentiating PCa from BPH. A number of potential targets including deregulation of miRNAs 1825 and 484, and mRNAs for Fibronectin and Tumor Protein 53 Inducible Nuclear Protein 2 (TP53INP2) appeared to be indicative of PCa. Furthermore, deregulation of miR-498 appeared to be indicative of BPH. The sensitivities and specificities associated with using deregulation in many of these targets to subsequently predict PCa or BPH were also determined. This research project has identified a number of potential targets, detectable in urine, which merit further investigation towards the accurate identification of PCa and its discrimination from BPH. The significance of this work is amplified by the non-invasive nature of the sample source from which these candidates were derived, urine. Many cancer biomarker discovery studies have tended to focus primarily on blood (plasma or serum) and/or tissue samples. This is one of the first PCa biomarker studies to focus exclusively on urine as a sample source.

Potential Urinary Protein Biomarker Candidates for the Accurate Detection of Prostate Cancer among Benign Prostatic Hyperplasia Patients

Globally, Prostate cancer (PCa) is the most frequently occurring non-cutaneous cancer, and is the second highest cause of cancer mortality in men. Serum prostate specific antigen (PSA) has been the standard in PCa screening since its approval by the American Food & Drug Administration (FDA) in 1994. Currently, PSA is used as an indicator for PCa - patients with a serum PSA level above 4ng/mL will often undergo prostate biopsy to confirm cancer. Unfortunately fewer than similar to 30% of these men will biopsy positive for cancer, meaning that the majority of men undergo invasive biopsy with little benefit. Despite PSA's notoriously poor specificity (33%), there is still a significant lack of credible alternatives. Therefore an ideal biomarker that can specifically detect PCa at an early stage is urgently required. The aim of this study was to investigate the potential of using deregulation of urinary proteins in order to detect Prostate Cancer (PCa) among Benign Prostatic Hyperplasia (BPH). To identify the protein signatures specific for PCa, protein expression profiling of 8 PCa patients, 12 BPH patients and 10 healthy males was carried out using LC-MS/MS. This was followed by validating relative expression levels of proteins present in urine among all the patients using quantitative real time-PCR. This was followed by validating relative expression levels of proteins present in urine among all the patients using quantitative real time-PCR. This approach revealed that significant the down-regulation of Fibronectin and TP53INP2 was a characteristic event among PCa patients. Fibronectin mRNA down-regulation, was identified as offering improved specificity (50%) over PSA, albeit with a slightly lower although still acceptable sensitivity (75%) for detecting PCa. As for TP53INP2 on the other hand, its down-regulation was moderately sensitive (75%), identifying many patients with PCa, but was entirely non-specific (7%), designating many of the benign samples as malignant and being unable to accurately identify more than one negative.

Potential Urinary miRNA Biomarker Candidates for the Accurate Detection of Prostate Cancer among Benign Prostatic Hyperplasia Patients

MicroRNAs (miRNAs) are a class of short (similar to 22nt), single stranded RNA molecules that function as post-transcriptional regulators of gene expression. MiRNAs can regulate a variety of important biological pathways, including: cellular proliferation, differentiation and apoptosis. Profiling of miRNA expression patterns was shown to be more useful than the equivalent mRNA profiles for characterizing poorly differentiated tumours. As such, miRNA expression "signatures" are expected to offer serious potential for diagnosing and prognosing cancers of any provenance. The aim of this study was to investigate the potential of using deregulation of urinary miRNAs in order to detect Prostate Cancer (PCa) among Benign Prostatic Hyperplasia (BPH). To identify the miRNA signatures specific for PCa, miRNA expression profiling of 8 PCa patients, 12 BPH patients and 10 healthy males was carried out using whole genome expression profiling. Differential expression of two individual miRNAs between healthy males and BPH patients was detected and found to possibly target genes related to PCa development and progression. The sensitivity and specificity of miR-1825 for detecting PCa among BPH individuals was found to be 60% and 69%, respectively. Whereas, the sensitivity and specificity of miR-484 were 80% and 19%, respectively. Additionally, the sensitivity and specificity for miR-1825/484 in tandem were 45% and 75%, respectively. The proposed PCa miRNA signatures may therefore be of great value for the accurate diagnosis of PCa and BPH. This exploratory study has identified several possible targets that merit further investigation towards the development and validation of diagnostically useful, non-invasive, urine-based tests that might not only help diagnose PCa but also possibly help differentiate it from BPH.

Modulators and effectors of inositol hexakisphosphate activity in prostate cancer cells : from clinical prognosis to enhanced therapeutics

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal.

Sunlight exposure and prostate cancer risk : a case-control study in Montreal, Canada

Objectifs: Évaluer l’association entre l’exposition récréative, professionnelle et globale au soleil et le risque de cancer de la prostate (CaP). Méthodes: Dans le contexte d’une étude cas-témoins sur le CaP menée à Montréal, Canada, des entrevues ont été complétées auprès de 1371 cas incidents de CaP diagnostiqués en 2005-2009, et 1479 témoins de la population générale. Des questionnaires détaillés ont permis d’obtenir de l’information sur la fréquence et la durée de participation à toute activité extérieure lors des loisirs durant l’âge adulte, ainsi qu’une description de chaque emploi tenu au cours de la vie. Une matrice emploi-exposition canadienne a été appliquée à chaque emploi afin d’assigner un niveau d’exposition professionnelle au soleil. Des indices cumulatifs de l’exposition au soleil basés sur le nombre d’événements récréatifs, la durée d’exposition professionnelle, ainsi qu’un indice d’exposition global ont été développés. La régression logistique a été utilisée pour estimer l’association entre chaque indice d’exposition et le CaP, en ajustant pour des variables de confusion potentielles. Résultats: Globalement, il n’y avait pas d’association entre chacun des indices d’exposition et le risque de CaP. Certaines tendances en accord avec un risque légèrement plus faible chez les hommes exposés au soleil ont été observées mais les résultats n’étaient pas statistiquement significatifs et il n’y avait pas de relation dose-réponse. Conclusion: Notre étude apporte peu de soutien à l’hypothèse d’une association entre l’exposition au soleil et le risque de développer un cancer de la prostate.

A systematic analysis of the detrimental effect of hormonotherapy on skeletal and non-skeletal morbidities in male with prostate cancer

Plusieurs patients atteints d’un cancer de la prostate (CaP) se verront prescrire l'hormonothérapie (HT) en raison du stade avancé ou en cas d’une récidive de la maladie, pour freiner la progression de la maladie et améliorer leur survie. Cependant, l’HT présente des effets pouvant nuire significativement à la santé du patient.

Evaluating DNA damage response (DDR) activation in human prostate cancer

Introduction: Au Canada, le cancer de la prostate est le cancer le plus fréquemment diagnostiqué chez les hommes et le plus mortel après les cancers du poumon et du côlon. Il y a place à optimiser le traitement du cancer de la prostate de manière à mettre en œuvre une médecine personnalisée qui s’adapte aux caractéristiques de la maladie de chaque patient de façon individuelle. Dans ce mémoire, nous avons évalué la réponse aux dommages de l’ADN (RDA) comme biomarqueur potentiel du cancer de la prostate. Les lésions potentiellement oncogènes de l'ADN déclenche une cascade de signalisation favorisant la réparation de l'ADN et l’activation des points de contrôle du cycle cellulaire pour préserver l’intégrité du génome. La RDA est un mécanisme central de suppression tumorale chez l’homme. La RDA joue un rôle important dans l’arrêt de la prolifération des cellules dont les génomes sont compromis, et donc, prévient la progression du cancer en agissant comme une barrière. Cette réponse cellulaire détermine également comment les cellules normales et cancéreuses réagissent aux agents utilisés pour endommager l'ADN lors du traitement du cancer comme la radiothérapie ou la chimiothérapie, en plus la présence d,un certain niveau de RDA dans les cellules du cancer de la prostate peuvent également influer sur l'issue de ces traitements. L’activation des signaux de la RDA peut agir comme un frein au cancer dans plusieurs lésions pré-néoplasiques de l'homme, y compris le cancer de la prostate. Il a été démontré que la RDA est augmentée dans les cellules de néoplasie intra- épithéliale (PIN) comparativement aux cellules prostatiques normales. Toutefois, le devient de la RDA entre le PIN et l’adénocarcinome est encore mal documenté et aucune corrélation n'a été réalisée avec les données cliniques des patients. Notre hypothèse est que les niveaux d’activation de la RDA seront variables selon les différents grades et agressivité du cancer de la prostate. Ces niveaux pourront être corrélés et possiblement prédire les réponses cliniques aux traitements des patients et aider à définir une stratégie plus efficace et de nouveaux biomarqueurs pour prédire les résultats du traitement et personnaliser les traitements en conséquence. Nos objectifs sont de caractériser l'activation de la RDA dans le carcinome de la prostate et corréler ses données avec les résultats cliniques. Méthodes : Nous avons utilisé des micro-étalages de tissus (tissue microarrays- TMAs) de 300 patients ayant subi une prostatectomie radicale pour un cancer de la prostate et déterminé le niveau d’expression de protéines de RDA dans le compartiment stromal et épithélial des tissus normaux et cancéreux. Les niveaux d’expression de 53BP1, p-H2AX, p65 et p-CHK2 ont été quantifiés par immunofluorescence (IF) et par un logiciel automatisé. Ces marqueurs de RDA ont d’abord été validés sur des TMAs-cellule constitués de cellules de fibroblastes normales ou irradiées (pour induire une activation du RDA). Les données ont été quantifiées à l'aide de couches binaires couramment utilisées pour classer les pixels d'une image pour que l’analyse se fasse de manière indépendante permettant la détection de plusieurs régions morphologiques tels que le noyau, l'épithélium et le stroma. Des opérations arithmétiques ont ensuite été réalisées pour obtenir des valeurs correspondant à l'activation de la RDA qui ont ensuite été corrélées à la récidive biochimique et l'apparition de métastases osseuses. Résultats : De faibles niveaux d'expression de la protéine p65 dans le compartiment nucléaire épithélial du tissu normal de la prostate sont associés à un faible risque de récidive biochimique. Par ailleurs, nous avons aussi observé que de faibles niveaux d'expression de la protéine 53BP1 dans le compartiment nucléaire épithéliale du tissu prostatique normal et cancéreux ont été associés à une plus faible incidence de métastases osseuses. Conclusion: Ces résultats confirment que p65 a une valeur pronostique chez les patients présentant un adénocarcinome de la prostate. Ces résultats suggèrent également que le marqueur 53BP1 peut aussi avoir une valeur pronostique chez les patients avec le cancer de la prostate. La validation d'autres marqueurs de RDA pourront également être corrélés aux résultats cliniques. De plus, avec un suivi des patients plus long, il se peut que ces résultats se traduisent par une corrélation avec la survie. Les niveaux d'activité de la RDA pourront éventuellement être utilisés en clinique dans le cadre du profil du patient comme le sont actuellement l’antigène prostatique spécifique (APS) ou le Gleason afin de personnaliser le traitement.

Glycan alterations of serum proteins as tumour markers. Prostate-specific antigen in prostate cancer and acute-phase proteins in pancreatic cancer

Els pacients amb càncer presenten una taxa de supervivència superior si es diagnostiquen a estadis inicials, per la qual cosa és indispensable disposar de marcadors tumorals adequats. Glicoformes de proteïnes específiques es podrian utilizar com marcadors tumorals. S’han investigat les subformes i glicosilació de l’Antígen Prostàtic Específic (PSA) per millorar la seva capacitat de diagnosis de pacients amb càncer de pròstata vs aquells amb hiperplàsia benigna prostàtica. També s’han avaluat glicoproteïnes sèriques amb alteracions glucídiques en pacients de càncer de pàncrees, comparat amb pacients amb pancreatitis crònica i controls. S’ha observat una disminució de la fucosilació core i sialilació del PSA en càncer de pròstata i un augment de la fucosilació core i Sialyl-Lewis X en algunes Proteïnes de fase Aguda en càncer de pàncrees. Aquest canvis s’haurien d’avaluar en un cohort de pacients més gran per determinar el seu paper en el cribratge, diagnòstic o monitorització dels cancers estudiats.

Relationship between milk consumption and prostate cancer: a short review

Epidemiological evidence based on both case–control and prospective cohort studies points to an overall positive relationship between consumption of milk/dairy products and the risk of developing prostate cancer. There are inconsistencies in the data, but taken together, the increased relative risk does not seem to be high. A number of mechanisms have been proposed to account for the relationship, with most attention being focused on the involvement of calcium/vitamin D, insulin-like growth factor-1 and oestrogens, although it is unlikely that a single factor in milk is implicated. In any event, any added risk of prostate cancer from increased milk consumption has to be set alongside other evidence, which shows that increased milk consumption can provide substantially reduced risk of coronary heart disease, stroke and colorectal cancer, particularly because cardiovascular disease accounts for vastly more deaths than prostate cancer (although the latter is of course restricted to men).