Jean-Marie Boher

Androgen Deprivation Therapy (ADT) Plus Docetaxel Versus ADT Alone in Metastatic Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the Randomized Phase 3 GETUG-AFU15 Trial

BACKGROUNDnThe role of chemotherapy in metastatic non castrate prostate cancer (mNCPC) is debated. Survival benefits of docetaxel (D) added to androgen-deprivation therapy (ADT) were shown in the CHAARTED trial in patients with metastatic high-volume disease (HVD).nnnOBJECTIVEnTo assess the impact of metastatic burden and to update overall survival (OS) data of the GETUG-AFU15 study.nnnDESIGN, SETTING, AND PARTICIPANTSnRandomized phase 3 trial of ADT plus D versus ADT alone in 385 mNCPC patients; median follow-up of 7 yr.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnPrimary end point was OS. Secondary end points were biochemical progression-free survival (bPFS) and radiographic progression-free survival (rPFS). Retrospective analysis was by tumor volume.nnnRESULTS AND LIMITATIONSnAfter a median follow-up of 83.9 mo, median OS in the overall population was 62.1 mo (95% confidence interval [CI], 49.5-73.7) and 48.6 mo (95% CI, 40.9-60.6) for ADT plus D and ADT arms, respectively (hazard ratio [HR]: 0.88 [95% CI, 0.68-1.14]; p=0.3). Median OS in ADT plus D and ADT arms, respectively, was for HVD patients: 39.8 mo (95% CI, 28.0-53.4) versus 35.1 mo (95% CI, 29.9-43.6) (HR: 0.78 [95% CI, 0.56-1.09]; p=0.14), for low-volume disease (LVD) patients; median was not reached (NR; 95% CI, 69.5-NR) and 83.4 mo (95% CI, 61.8-NR) (HR: 1.02 [95% CI, 0.67-1.55]; p=0.9). For upfront metastatic patients, OS was 52.6 mo (95% CI, 43.3-66.8) and 41.5 mo (95% CI, 36.3-54.5), respectively (HR: 0.93 [95% CI, 0.69-1.25]; p=0.6). The bPFS (HR: 0.73 [95% CI, 0.56-0.94]; p=0.014) and rPFS (HR: 0.75 [95% CI, 0.58-0.97]; p=0.030) were significantly longer in the ADT plus D arm. Limitations included the retrospective analysis of metastatic extent and the lack of statistical power to detect a significant difference in subgroups.nnnCONCLUSIONSnThe post hoc analyses of the GETUG-AFU15 study demonstrated a nonsignificant 20% reduction in the risk of death in the HVD subgroup. Patients with LVD had no survival improvement with early D.nnnPATIENT SUMMARYnIn this study, docetaxel added to castration did not improve survival in patients with metastatic hormone-sensitive prostate cancer, partly due to methodological issues. However, early chemotherapy should be discussed with all patients, given the data of three randomized trials including GETUG-AFU15.

Prognostic Factors for Survival in Noncastrate Metastatic Prostate Cancer: Validation of the Glass Model and Development of a Novel Simplified Prognostic Model

BACKGROUNDnThe Glass model developed in 2003 uses prognostic factors for noncastrate metastatic prostate cancer (NCMPC) to define subgroups with good, intermediate, and poor prognosis.nnnOBJECTIVEnTo validate NCMPC risk groups in a more recently diagnosed population and to develop a more sensitive prognostic model.nnnDESIGN, SETTING, AND PARTICIPANTSnNCMPC patients were randomized to receive continuous androgen deprivation therapy (ADT) with or without docetaxel in the GETUG-15 phase 3 trial. Potential prognostic factors were recorded: age, performance status, Gleason score, hemoglobin (Hb), prostate-specific antigen, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), metastatic localization, body mass index, and pain.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnThese factors were used to develop a new prognostic model using a recursive partitioning method. Before analysis, the data were split into learning and validation sets. The outcome was overall survival (OS).nnnRESULTS AND LIMITATIONSnFor the 385 patients included, those with good (49%), intermediate (29%), and poor (22%) prognosis had median OS of 69.0, 46.5 and 36.6 mo (p=0.001), and 5-yr survival estimates of 60.7%, 39.4%, and 32.1%, respectively (p=0.001). The most discriminatory variables in univariate analysis were ALP, pain intensity, Hb, LDH, and bone metastases. ALP was the strongest prognostic factor in discriminating patients with good or poor prognosis. In the learning set, median OS in patients with normal and abnormal ALP was 69.1 and 33.6 mo, and 5-yr survival estimates were 62.1% and 23.2%, respectively. The hazard ratio for ALP was 3.11 and 3.13 in the learning and validation sets, respectively. The discriminatory ability of ALP (concordance [C] index 0.64, 95% confidence interval [CI] 0.58-0.71) was superior to that of the Glass risk model (C-index 0.59, 95% CI 0.52-0.66). The study limitations include the limited number of patients and low values for the C-index.nnnCONCLUSIONnA new and simple prognostic model was developed for patients with NCMPC, underlying the role of normal or abnormal ALP.nnnPATIENT SUMMARYnWe analyzed clinical and biological factors that could affect overall survival in noncastrate metastatic prostate cancer. We showed that normal or abnormal alkaline phosphatase at baseline might be useful in predicting survival.

Two-stage design of clinical trials involving recurrent events

Mixed Poisson models are often used for the design of clinical trials involving recurrent events since they provide measures of treatment effect based on rate and mean functions and accommodate between individual heterogeneity in event rates. Planning studies based on these models can be challenging when there is a little information available on the population event rates, or the extent of heterogeneity characterized by the variance of individual-specific random effects. We consider methods for adaptive two-stage clinical trial design, which enable investigators to revise sample size estimates using data collected during the first phase of the study. We describe blinded procedures in which the group membership and treatment received by each individual are not revealed at the interim analysis stage, and a partially blinded procedure in which group membership is revealed but not the treatment received by the groups. An EM algorithm is proposed for the interim analyses in both cases, and the performance is investigated through simulation. The work is motivated by the design of a study involving patients with immune thrombocytopenic purpura where the aim is to reduce bleeding episodes and an illustrative application is given using data from a cardiovascular trial.

The Short- and Long-term Outcomes of Pancreaticoduodenectomy for Cancer in Child a Patients Are Acceptable: a Patient-control Study from the Surgical French Association Report for Pancreatic Surgery

On the basis of now dated studies, cirrhosis is usually considered to be a contraindication in pancreatoduodenectomy (PD) for adenocarcinoma of the pancreatic head (APH).

Overexpression of the Promigratory and Prometastatic PTK7 Receptor Is Associated with an Adverse Clinical Outcome in Colorectal Cancer

Biomarkers and novel therapeutic targets are urgently needed in colorectal cancer (CRC). The pseudo tyrosine kinase receptor 7 (PTK7) is involved in planar cell polarity and it is deregulated in various malignancies, including CRC. Yet, little is known about its protein expression in human CRC, or about a possible correlation of its expression with clinical endpoints. Using a clinically annotated Tissue MicroArray (TMA) produced from from 192 consecutive CRC patients treated by initial surgery, we examined PTK7 expression by immunohistochemistry in tumoral tissue and matched normal mucosae, and correlated its expression with clinico-pathological features and patient outcome. PTK7 depletion by specific shRNA in HCT116 and HCT15 CRC cell lines was found to affect cell proliferation, resistance to drugs and cell migration. Tumor growth and metastatic phenotype were investigated in vivo using a xenograft mouse model of CRC cells with modulated expression of PTK7 levels. PTK7 was significantly up-regulated in CRC tissue as compared to matched healthy mucosae, and significant overexpression was found in 34% of patients. PTK7 overexpression was significantly associated with a reduced metastasis-free survival in non-metastatic patients. In HCT116 and HCT15 cells, shRNA PTK7 reduced migration but did not affect cell proliferation and resistance to drugs. In a xenograft mouse of HCT15 cells, downregulation of PTK7 led to reduced tumor growth, whereas its overexpression in PTK7-negative cancer cells led to increased metastatic events. PTK7 expression thus represents a potential prognostic biomarker and a novel therapeutic target in CRC.

Ganglion sentinelle envahi : faut-il faire le curage ou pas ? Essai randomisé SERC

Contribution of axillary lymph node dissection (ALND) is questioned for positive sentinel node (SN), micro-metastasis and isolated tumor cells but also for macro-metastasis. The aim of this work is to precise why a prospective randomized trial is necessary and the design of this trial. Why? For positive SN, the scientific level evidence appears insufficient for validation of ALND omission as a new standard. Rational is presented with non-sentinel node involved rate and number of NSL involved at complementary ALND, axillary recurrence rate, disease free survival rate and adjuvant treatment decision impact. How? The proposed Sentinelle Envahi et Randomisation du Curage (SERC) trial will randomly assign to observation only or complementary ALND with positive SN. The aim is to demonstrate the non-inferiority of ALND omission versus ALND.

Anticancer Activity and Tolerance of Treatments Received Beyond Progression in Men Treated Upfront with Androgen Deprivation Therapy With or Without Docetaxel for Metastatic Castration-naïve Prostate Cancer in the GETUG-AFU 15 Phase 3 Trial

BACKGROUNDnAndrogen deprivation therapy (ADT) plus docetaxel is the standard of care in fit men with metastatic castration-naive prostate cancer (mCNPC) following results from GETUG-AFU 15, CHAARTED, and STAMPEDE. No data are available on the efficacy of treatments used for metastatic castration-resistant prostate cancer (mCRPC) in men treated upfront with ADT plus docetaxel for mCNPC.nnnOBJECTIVEnTo investigate the efficacy and tolerance of subsequent treatments in patients treated upfront with chemo-hormonal therapy for mCNPC.nnnDESIGN, SETTING, AND PARTICIPANTSnRetrospective data from the GETUG-AFU 15 phase 3 trial were collected for treatments received for mCRPC.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnFor the first three lines of salvage treatment for mCRPC we investigated the biochemical progression-free survival, maximum prostate-specific antigen (PSA) decline, overall survival, and tolerance.nnnRESULTS AND LIMITATIONSnOverall, 245 patients received at least one treatment for mCRPC. For docetaxel used in first-line, a PSA decline ≥50% was observed in 25/66 (38%) and in 4/20 patients (20%) who had received upfront ADT alone and ADT plus docetaxel (p=0.14). The median biochemical progression-free survival was 6.0 mo (95% confidence interval: 3.6-7.7) and 4.1 mo (95% confidence interval: 1.3-4.9), respectively. For docetaxel used in first- or second-line, a PSA decline ≥50% was observed in 36/80 (45%) and in 4/29 patients (14%) who had received upfront ADT alone and ADT plus docetaxel (p=0.07). PSA declines ≥50% were observed with bicalutamide in 12/28 (43%) and 4/23 patients (17%) who had received upfront ADT alone and ADT plus docetaxel. Among men treated upfront with ADT plus docetaxel who received abiraterone or enzalutamide for mCRPC, 10/19 patients (53%) achieved a PSA decline ≥50%. Few grade 3-4 events occurred. Study limitations include the observational design and retrospective characteristics of this analysis, without standardized therapeutic salvage protocols, and the limited number of patients in some of the treatment subgroups.nnnCONCLUSIONSnDocetaxel rechallenge following progression to mCRPC after upfront ADT plus docetaxel for mCNPC was active only in a limited number of patients. Available data on abiraterone and enzalutamide support maintained efficacy in this setting. The lack of standardized therapeutic protocols for men developing mCRPC limits the comparability between patients.nnnPATIENT SUMMARYnRechallenging docetaxel at castration-resistance was active only in a limited number of patients treated upfront with chemo-hormonal therapy for metastatic castration-naive prostate cancer. Anticancer activity was suggested with abiraterone or enzalutamide in this setting.

Prediction of Early Breast Cancer Metastasis from DNA Microarray Data Using High-Dimensional Cox Regression Models

Background DNA microarray studies identified gene expression signatures predictive of metastatic relapse in early breast cancer. Standard feature selection procedures applied to reduce the set of predictive genes did not take into account the correlation between genes. In this paper, we studied the performances of three high-dimensional regression methods – CoxBoost, LASSO (Least Absolute Shrinkage and Selection Operator), and Elastic net – to identify prognostic signatures in patients with early breast cancer. Methods We analyzed three public retrospective datasets, including a total of 384 patients with axillary lymph node-negative breast cancer. The Amsterdam vant Veers training set of 78 patients was used to determine the optimal gene sets and classifiers using sensitivity thresholds resulting in misclassification of no more than 10% of the poor-prognosis group. To ensure the comparability between different methods, an automatic selection procedure was used to determine the number of genes included in each model. The van de Vijvers and Desmedts datasets were used as validation sets to evaluate separately the prognostic performances of our classifiers. The results were compared to the original Amsterdam 70-gene classifier. Results The automatic selection procedure reduced the number of predictive genes up to a minimum of six genes. In the two validation sets, the three models (Elastic net, LASSO, and CoxBoost) led to the definition of genomic classifiers predicting the 5-year metastatic status with similar performances, with respective 59, 56, and 54% accuracy, 83, 75, and 83% sensitivity, and 53, 52, and 48% specificity in the Desmedts dataset. In comparison, the Amsterdam 70-gene signature showed 45% accuracy, 97% sensitivity, and 34% specificity. The gene overlap and the classification concordance between the three classifiers were high. All the classifiers added significant prognostic information to that provided by the traditional prognostic factors and showed a very high overlap with respect to gene ontologies (GOs) associated with genes overexpressed in the predicted poor-prognosis vs. good-prognosis classes and centred on cell proliferation. Interestingly, all classifiers reported high sensitivity to predict the 4-year status of metastatic disease. Conclusions High-dimensional regression methods are attractive in prognostic studies because finding a small subset of genes may facilitate the transfer to the clinic, and also because they strengthen the robustness of the model by limiting the selection of false-positive predictive genes. With only six genes, the CoxBoost classifier predicted the 4-year status of metastatic disease with 93% sensitivity. Selecting a few genes related to ontologies other than cell proliferation might further improve the overall sensitivity performance.

Impact of preoperative magnetic resonance imaging in breast cancer patients candidates for an intraoperative partial breast irradiation

Objective: Partial breast irradiation (PBI) could be a reasonable option in patients with early breast cancer (BC) provided that an adequate patient selection, based on robustly established criteria is performed. A preoperative magnetic resonance imaging (MRI) in patient selection for PBI is not consensual. The aim of this retrospective study was to assess the impact of preoperative MRI on patient eligibility for PBI. n Methods: Since March 2012, patients with early BC, meeting the Inca’s criteria for PBI were offered the possibility of shortened treatment through intra-operative radiation therapy, either in a prospective trial or off protocol. Eligibility criteria based on physical examination, mammography and ultrasound, and a pathological exam of biopsy, were as follows: menopaused woman 55 years or older with a T1, N0, hormonal-receptor-positive and HER2-negative, invasive, non-lobular epithelioma, without extensive intraductal component (defined as more than 25% of ductal component on biopsy), non-fast-growing tumor, without lymphovascular invasion (LVI), without criteria for adjuvant chemotherapy. A contrast-enhanced MRI was not routinely performed, but at the discretion of the physician as was the rule in TARGIT-A trial. We assessed the rate of additional cancer revealed by the preoperative MRI, remote in the same breast not detected by mammography and/or ultrasound. n Results: Between March 2012 and February 2014, 179 early BC patients meeting the required criteria were planned for an intraoperative radiotherapy (IORT)-PBI. Seventy nine percent of them (141/179) underwent a breast MRI as part of preoperative assessment. ACR3-ACR4 abnormalities not detected by mammograms or ultrasound were found in 44 patients (31%), which prompted a focused mammary ultra-sound, and a biopsy was realized in 29/141 patients (21%). A second breast carcinoma was found in 10 patients (7% of patients with a preoperative MRI, 4 ipsilateral lesions, 5 contralateral lesions, and one both ipsi- and contralateral lesion, precluding IORT-PBI in 5/141 patients (4%). n Conclusions: The use of preoperative MRI in patient staging leads to diagnosis of an ipsilateral second BC in 4% of cases, which appears substantial in a highly selected population. We therefore support the routine use of this exam for the staging of patient candidate for a PBI.

PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer.

BACKGROUNDnPhosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms.nnnPATIENTS AND METHODSnPIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80xa0mg) and lapatinib (750, 1000 or 1250xa0mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokineticxa0(PK) assessments.nnnRESULTSnA total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80xa0mg/dxa0+xa0lapatinib 1250xa0mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80xa0mgxa0+xa0lapatinib 1000xa0mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug-drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57-92%], one patient obtained a complete remission, and six additional patients experienced stable disease forxa0≥xa024 weeks (clinical benefit rate of 29% [95% CI 12-51%]).nnnCONCLUSIONnCombining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidencexa0of antitumour activity was observed in this heavily pre-treated population.nnnTRIAL REGISTRATION IDnNCT01589861.