Jean-Emmanuel Kurtz

Screening for Vulnerability in Older Cancer Patients: The ONCODAGE Prospective Multicenter Cohort Study

Background Geriatric Assessment is an appropriate method for identifying older cancer patients at risk of life-threatening events during therapy. Yet, it is underused in practice, mainly because it is time- and resource-consuming. This study aims to identify the best screening tool to identify older cancer patients requiring geriatric assessment by comparing the performance of two short assessment tools the G8 and the Vulnerable Elders Survey (VES-13). Patients and Methods The diagnostic accuracy of the G8 and the (VES-13) were evaluated in a prospective cohort study of 1674 cancer patients accrued before treatment in 23 health care facilities. 1435 were eligible and evaluable. Outcome measures were multidimensional geriatric assessment (MGA), sensitivity (primary), specificity, negative and positive predictive values and likelihood ratios of the G8 and VES-13, and predictive factors of 1-year survival rate. Results Patient median age was 78.2 years (70-98) with a majority of females (69.8%), various types of cancer including 53.9% breast, and 75.8% Performance Status 0-1. Impaired MGA, G8, and VES-13 were 80.2%, 68.4%, and 60.2%, respectively. Mean time to complete G8 or VES-13 was about five minutes. Reproducibility of the two questionnaires was good. G8 appeared more sensitive (76.5% versus 68.7%, P =  0.0046) whereas VES-13 was more specific (74.3% versus 64.4%, P<0.0001). Abnormal G8 score (HR = 2.72), advanced stage (HR = 3.30), male sex (HR = 2.69) and poor Performance Status (HR = 3.28) were independent prognostic factors of 1-year survival. Conclusion With good sensitivity and independent prognostic value on 1-year survival, the G8 questionnaire is currently one of the best screening tools available to identify older cancer patients requiring geriatric assessment, and we believe it should be implemented broadly in daily practice. Continuous research efforts should be pursued to refine the selection process of older cancer patients before potentially life-threatening therapy.

Constitutive activation of the androgen receptor by a point mutation in the hinge region: A new mechanism for androgen‐independent growth in prostate cancer

Androgen receptor (AR) mutations that modify both the ligand binding and the transactivation capacities of the AR represent one of the mechanisms involved in the transition of prostate cancer (PCa) from androgen‐dependent to androgen‐independent growth. We use a yeast‐based functional assay to detect and analyze mutant ARs in PCa. We report the detection of 2 different mutant ARs within the same metastatic tumour sample harvested in a patient with advanced PCa who had escaped androgen deprivation. Concomitantly to the widely described T877A mutant AR, we identified an additional double mutant AR harboring the nonsense mutation Q640Stop just downstream the DNA binding domain together with the T877A point mutation. This type of mutation, which leads to a c‐terminal truncated AR, has not been described yet in PCa. Using luciferase reporter assays we demonstrated that this truncated AR exhibited constitutive transactivation properties. In conclusion, our data suggest that mutation‐induced constitutive activation of the AR could be a mechanism used by PCa cells to escape androgen deprivation.

Identification of novel truncated androgen receptor (AR) mutants including unreported pre-mRNA splicing variants in the 22Rv1 hormone-refractory prostate cancer (PCa) cell line†

Advanced prostate cancer (PCa) has emerged as a public health concern due to population aging. Although androgen deprivation has proven efficacy in this condition, most advanced PCa patients will have to face failure of androgen deprivation as a treatment. Mutations in the androgen receptor (AR) from tumor cells have been shown to induce androgen independency both in PCa cell lines and in the clinic. We have investigated the molecular events leading to androgen independency in the 22Rv1 cell line, a commonly used preclinical model of PCa. Besides AR mutants that have been described so far, including nonsense mutations, recent data have focused on AR pre‐mRNA aberrant splicing as a new mechanism leading to constitutively active truncated AR variants. In this article, we describe two novel variants arising from aberrant splicing of AR pre‐mRNA, characterized by long mRNA transcripts that encode truncated, constitutively active proteins. We also describe several new nonsense mutants that share ligand independency and transcriptional activity. Finally, we show that alongside these mutants, 22Rv1 cells also express a mutant AR lacking exon 3 tandem duplication, a major feature of this cell line. By describing unreported AR mutants in the 22Rv1 cell line, our data emphasize the complexity and heterogeneity of molecular events that occur in preclinical models, and supposedly in the clinic. Future work on the 22Rv1 cell line should take into account the concomitant expression of various AR mutants. Hum Mutat 31:74–80, 2010.

Advanced chondrosarcomas: role of chemotherapy and survival

BACKGROUND There are limited data about the role of chemotherapy in patients with advanced chondrosarcomas. METHODS The medical charts of 180 patients with advanced chondrosarcomas having received chemotherapy in 15 participating institutions between 1988 and 2011 were reviewed. RESULTS Median age was 52 years. Sixty-three percent of patients had conventional chondrosarcoma and 88% had metastatic disease. Combination chemotherapy was delivered in 98 cases (54.5%). One hundred and thirty-one patients (73%) received an anthracycline-containing regimen. Using RECIST, the objective response rate was significantly different according to histological subtype, being 31% for mesenchymal chondrosarcoma, 20.5% for dedifferentiated chondrosarcoma, 11.5% for conventional chondrosarcoma and 0% for clear-cell chondrosarcoma (P = 0.04). Median progression-free survival (PFS) was 4.7 months [95% confidence interval (CI) 3-6.5]. Performance status (PS) ≥2, number of metastatic sites ≥1 and single-agent regimen were independently associated with poor PFS. Median overall survival (OS) was 18 months (95% CI 14.5-21.6). PS, number of metastatic sites and palliative surgery were independently associated with OS. CONCLUSIONS Conventional chemotherapy have very limited efficacy in patients with advanced chondrosarcoma, the highest benefit being observed in mesenchymal and dedifferentiated chondrosarcoma. These data should be used as a reference for response and outcome in the assessment of investigational drugs in advanced chondrosarcoma.

The syndrome of food-cobalamin malabsorption revisited in a department of internal medicine. A monocentric cohort study of 80 patients.

BACKGROUND: To date, only case reports or small studies have documented the syndrome of food-cobalamin malabsorption in specific populations of patients or situations. In this paper, we present the data from 80 unselected patients with cobalamin deficiency related to food-cobalamin malabsorption. METHODS: We studied 80 patients with well-established food-cobalamin malabsorption who were extracted from an observational cohort study (1995-2000) of 127 consecutive patients with cobalamin deficiency and who were followed in a department of internal medicine. RESULTS: The median age of patients was 66 years and the female to male ratio was 1.2. The mean hemoglobin level was 113+/-27 g/l (range 32-159 g/l) and the mean erythrocyte cell volume was 95.4+/-12.3 fl (range 55-140 fl). Mean serum vitamin B12 and homocysteine levels were 153+/-74 pg/ml (range 35-200 pg/ml) and 20.6+/-15.7 μmol/l (range 8-97 μmol/l), respectively. The main clinical findings noted were peripheral neuropathy (46.2%), stroke (12.5%), confusion or dementia (10%), asthenia (18.7%), leg edema (11.2%), and digestive disorders (7.5%). The commonest associated conditions were atrophic gastritis (39%) with evidence of Helicobacter pylori infection (12.2%) and alcohol abuse (13.7%). Three patients had Sjögrens syndrome and one had systemic sclerosis. Ten percent of all patients were on long-term metformin (10%) and 7.5% on acid-suppressive drugs. Correction of the serum vitamin B12 levels and hematological abnormalities was achieved equally well in all patients treated with either intramuscular or oral crystalline cyanocobalamin. CONCLUSION: This study suggests that food-cobalamin malabsorption may be the leading cause of vitamin B12 deficiency in adults. As other studies have also reported, the condition is often associated with neuro-psychiatric findings and with several other conditions. Oral and parenteral cobalamin appear to be equally effective in correcting serum B12 levels and hematological abnormalities and, in many cases, they also relieve symptoms.

Insulin-like growth factor type 1 receptor (IGF-1R) exclusive nuclear staining: a predictive biomarker for IGF-1R monoclonal antibody (Ab) therapy in sarcomas.

AIMS A minority of patients with advanced sarcoma achieve prolonged progression free survival (PFS) with insulin growth factor type 1 receptor (IGF-1R) monoclonal antibody (Ab) therapy. A biomarker identifying those patients beforehand would be useful to select patients for the development of these agents. METHODS This single centre series includes patients with unresectable or metastatic soft tissue sarcomas (STS), Ewing sarcoma (ES) and osteosarcoma treated with IGF-1R Ab (R1507, IMC-A12, SCH 717454 and CP-751.871) in the Centre Léon Bérard. Tumour samples were analysed by immunohistochemistry for expression of IGF-1R, insulin-like growth factor binding protein type 3 (IGFBP-3), Ki67, epidermal growth factor receptor (HER1) and human epidermal growth factor receptor 2 (HER2). Predictive factors for PFS and overall survival (OS) were investigated. RESULTS All tumour samples had a positive IGF-1R immunostaining on 60% to 100% of tumour cells. IGFBP-3 immunostaining was observed in 12 (75%) samples with 5% to 100% of positive cells. IGF-1R immunostaining was nuclear (n=9, 56%), cytoplasmic (n=4, 25%), or nuclear +cytoplasmic (n=3, 19%). Neither IGFBP-3 expression, nor Ki67 was correlated to PFS. HER2 and HER1 staining were positive in 0 and 2 samples respectively (both primary resistant to IGF-1R Ab therapy). Exclusive intra-nuclear immunoreactivity for IGF-1R was significantly associated with a better PFS (p=0.01) and OS (p=0.007). CONCLUSION Exclusive nuclear localisation of IGF-1R is an easily testable biomarker associated with a better PFS and OS for patients treated with IGF-1R Ab therapy. Nuclear localisation of IGF-1R in tumour cells might be a hallmark of pathway activation.

Primary cardiac sarcomas: a retrospective study of the French Sarcoma Group.

INTRODUCTION Primary cardiac sarcomas (PCS) are rare tumours of dismal prognosis. METHODS Data of 124 patients with PCS referred to institutions of the French Sarcoma Group (FSG) from 1977 and 2010 were reviewed. RESULTS Median age was 48.8years. PCS were poorly-differentiated sarcomas (N=45, 36.3%), angiosarcomas (N=40, 32.3%), leiomyosarcomas (N=16, 12.9%) and others (N=23, 18.6%). At diagnosis, 100 patients (80.6%) were localised and 24 (19.4%) metastatic. Tumours were located in the right (N=47, 38.8%), left atrial cavities (N=45, 37.2%) or encompassed several locations in nine cases (7.4%). Surgery was performed in 81 cases (65.3%). Heart transplant was performed in five patients. Radiotherapy adjuvant (N=18, 14.5%) or alone (N=6, 4.8%) was performed in non-metastatic patients only (N=24, 19.4%). With a median follow-up of 51.2months, median overall survival (OS) was 17.2months for the entire cohort, 38.8months after complete resection versus 18.2 after incomplete resection and 11.2months in non-resected patients. Radiotherapy was associated with improved progression-free survival (PFS) on multivariate analysis. Chemotherapy was significantly associated with better OS only in non-operated patients but not in operated patients. In non-metastatic patients, surgery (hazard ratio [HR]=0.42, p<0.001), male gender (HR=0.56, p=.032) was associated with better OS and surgery (HR=0.61; p=.076), radiotherapy (HR=0.43; p=.004) and chemotherapy (HR=0.30, p=.003) improved PFS. CONCLUSION Only surgical resection is associated with a perspective of prolonged survival. Chemotherapy is associated with a better outcome in non-resected patients.

Bevacizumab plus capecitabine in patients with progressive advanced well-differentiated neuroendocrine tumors of the gastro-intestinal (GI-NETs) tract (BETTER trial) – A phase II non-randomised trial

AIM OF THE STUDY Gastro-intestinal neuroendocrine tumours (GI-NETs) are chemotherapy-resistant tumours. Bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), has shown promising results in several phase II trials of gastro-entero-pancreatic-NETs. We assessed bevacizumab combined with capecitabine, specifically in GI-NET patients. PATIENTS AND METHODS BEvacizumab in The Treament of neuroEndocrine tumoRs (BETTER) was a multicentre, open-label, non-randomised, two-group phase II trial. Here we present the group of patients with progressive, metastatic, well-differentiated GI-NETs. Patients Eastern Cooperative Oncology Group-performance status (ECOG-PS)⩽2, Ki-67 proliferation rate <15% and no prior systemic chemotherapy were treated with bevacizumab (7.5 mg/kg/q3w) and capecitabine (1000 mg/m2 twice daily, orally d1-14, resumed on d22) for 6-24 months. The primary end-point was progression-free survival (PFS); secondary end-points included overall survival (OS), response rate, safety and quality of life. RESULTS Of the 49 patients included, 53% were men, median age was 60 years (41-82), primary tumour site was ileal in 82% patients and Ki-67 was <15% in 48 patients and not available for one patient. After a maximum of 24 month follow-up per patient, the median PFS by investigator assessment was 23.4 months [95% confidence interval (CI): 13.2; not reached] and the overall disease control rate was 88% (18% partial response, 70% stable disease). The 2-year survival rate was 85%. Median OS was not reached. The most frequent grade 3-4 adverse events were hypertension (31%), diarrhoea (14%) and hand-foot syndrome (10%). CONCLUSION The combination of bevacizumab and capecitabine showed clinical activity and a manageable safety profile in the treatment of GI-NETs that warrant confirmation in a randomised phase III trial.

18F-Fluorodihydroxyphenylalanine PET/CT in Patients with Neuroendocrine Tumors of Unknown Origin: Relation to Tumor Origin and Differentiation

This work was performed to evaluate the performance of 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT in detecting primary neuroendocrine tumors (NETs) occult on morphologic and functional imaging, in relation to tumor origin and differentiation. Methods: A retrospective study of NET patients who were investigated with 18F-FDOPA PET/CT imaging in 2 academic endocrine tumor centers was conducted. Only patients with negative conventional and somatostatin receptor scintigraphy (SRS) results were studied. Results: Twenty-seven patients were evaluated with 18F-FDOPA PET/CT, 23 at their initial staging and 4 during their follow-up. The primary occult NET was localized by 18F-FDOPA PET/CT in 12 patients (overall sensitivity, 44%; 52% in patients evaluated at initial diagnosis), leading to tumor resection in all cases. The primary tumors were distributed and graded as follows: 1 duodenum G2 lesion, 7 ileum G2 lesions, 2 terminal ileum G1 lesions, 1 pancreas G2 lesion, and 1 gallbladder G3 lesion. Patients with positive 18F-FDOPA PET/CT results had higher values of serum chromogranin A (100% vs. 20%, P = 0.0003), serotonin, or urinary 5-hydroxyindolacetic acid (83% vs. 20%, P = 0.003). Two false-negative results were related to poorly differentiated duodenal and prostatic NETs (G3). 18F-FDOPA PET/CT showed more metastatic anatomic regions than SRS in 17 patients. Conclusion: 18F-FDOPA PET appears to be a sensitive functional imaging tool for the detection of primary NETs occult on SRS, especially tumors with a well-differentiated pattern and serotonin secretion.

Constitutively Active Androgen Receptor Variants Upregulate Expression of Mesenchymal Markers in Prostate Cancer Cells

Androgen receptor (AR) signaling pathway remains the foremost target of novel therapeutics for castration-resistant prostate cancer (CRPC). However, the expression of constitutively active AR variants lacking the carboxy-terminal region in CRPC may lead to therapy inefficacy. These AR variants are supposed to support PCa cell growth in an androgen-depleted environment, but their mode of action still remains unresolved. Moreover, recent studies indicate that constitutively active AR variants are expressed in primary prostate tumors and may contribute to tumor progression. The aim of this study was to investigate the impact of constitutively active AR variants on the expression of tumor progression markers. N-cadherin expression was analyzed in LNCaP cells overexpressing the wild type AR or a constitutively active AR variant by qRT-PCR, Western blot and immunofluorescence. We showed here for the first time that N-cadherin expression was increased in the presence of constitutively active AR variants. These results were confirmed in C4-2B cells overexpressing these AR variants. Although N-cadherin expression is often associated with a downregulation of E-cadherin, this phenomenon was not observed in our model. Nevertheless, in addition to the increased expression of N-cadherin, an upregulation of other mesenchymal markers expression such as VIMENTIN, SNAIL and ZEB1 was observed in the presence of constitutively active variants. In conclusion, our findings highlight novel consequences of constitutively active AR variants on the regulation of mesenchymal markers in prostate cancer.