Caroline Bascoul-Mollevi

Impact of FOLFIRINOX Compared With Gemcitabine on Quality of Life in Patients With Metastatic Pancreatic Cancer: Results From the PRODIGE 4/ACCORD 11 Randomized Trial

PURPOSE To compare the quality of life (QoL) of patients receiving oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) or gemcitabine as first-line chemotherapy and to assess whether pretreatment QoL predicts survival in patients with metastatic pancreatic cancer. PATIENTS AND METHODS Three hundred forty-two patients with performance status 0 or 1 were randomly assigned to receive FOLFIRINOX (oxaliplatin, 85 mg/m(2); irinotecan, 180 mg/m(2); leucovorin, 400 mg/m(2); and fluorouracil, 400 mg/m(2) bolus followed by 2,400 mg/m(2) 46-hour continuous infusion, once every 2 weeks) or gemcitabine 1,000 mg/m(2) weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. QoL was assessed using European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30 every 2 weeks. RESULTS Improvement in global health status (GHS; P < .001) was observed in the FOLFIRINOX arm and improvement in emotional functioning (P < .001) was observed in both arms, along with a decrease in pain, insomnia, anorexia, and constipation in both arms. A significant increase in diarrhea was observed in the FOLFIRINOX arm during the first 2 months of chemotherapy. Time until definitive deterioration ≥ 20 points was significantly longer for FOLFIRINOX compared with gemcitabine for GHS, physical, role, cognitive, and social functioning, and six symptom domains (fatigue, nausea/vomiting, pain, dyspnea, anorexia, and constipation). Physical functioning, constipation, and dyspnea were independent significant prognostic factors for survival with treatment arm, age older than 65 years, and low serum albumin. CONCLUSION FOLFIRINOX significantly reduces QoL impairment compared with gemcitabine in patients with metastatic pancreatic cancer. Furthermore, baseline QoL scores improved estimation of survival probability when added to baseline clinical and demographic variables.

Prognostic Factors in Patients With Metastatic Germ Cell Tumors Who Experienced Treatment Failure With Cisplatin-Based First-Line Chemotherapy

PURPOSE To develop a prognostic model in patients with germ cell tumors (GCT) who experience treatment failure with cisplatin-based first-line chemotherapy. PATIENTS AND METHODS Data from 1,984 patients with GCT who progressed after at least three cisplatin-based cycles and were treated with cisplatin-based conventional-dose or carboplatin-based high-dose salvage chemotherapy was retrospectively collected from 38 centers/groups worldwide. One thousand five hundred ninety-four (80%) of 1,984 eligible patients were randomly divided into a training set of 1,067 patients (67%) and a validation set of 527 patients (33%). Seminomas were set aside for posthoc analyses. Primary end point was the 2-year progression-free survival after salvage treatment. RESULTS Overall, 990 patients (62%) relapsed and 604 patients (38%) remained relapse free. Histology, primary tumor location, response, and progression-free interval after first-line treatment, as well as levels of alpha fetoprotein, human chorionic gonadotrophin, and the presence of liver, bone, or brain metastases at salvage were identified as independent prognostic variables and used to build a prognostic model in the training set. Survival rates in the training and validation set were very similar. The estimated 2-year progression-free survival rates in patients not included in the training set was 75% in very low risk, 51% in low risk, 40% in intermediate risk, 26% in high risk, and only 6% in very high-risk patients. Due to missing values in individual variables, 69 patients could not reliably be classified into one of these categories. CONCLUSION Prognostic variables are important in patients with GCT who experienced treatment failure with cisplatin-based first-line chemotherapy and can be used to construct a prognostic model to guide salvage strategies.

Conventional-Dose Versus High-Dose Chemotherapy As First Salvage Treatment in Male Patients With Metastatic Germ Cell Tumors: Evidence From a Large International Database

PURPOSE Conventional-dose chemotherapy (CDCT) and high-dose chemotherapy (HDCT) may both be successfully used as salvage treatment for patients with metastatic germ cell tumors (GCTs) who experience progression with first-line treatment. PATIENTS AND METHODS Data on 1,984 patients with GCTs who experienced progression after at least three cisplatin-based cycles and were treated with either cisplatin-based CDCT or carboplatin-based HDCT chemotherapy were collected from 38 centers or groups worldwide. Of 1,984 patients, 1,594 (80%) were eligible, and among the eligible patients, 1,435 (90%) could reliably be classified into one of the following five prognostic categories based on prior prognostic classification: very low (n = 76), low (n = 257), intermediate (n = 646), high (n = 351), and very high risk (n = 105). Within each of the five categories, the progression-free survival (PFS) and overall survival (OS) after CDCT and HDCT were compared using the Cox model adjusted for significant distributional differences between important variables. RESULTS Overall, 773 patients received CDCT, and 821 patients received HDCT. Both treatment modalities were used with similar frequencies within each prognostic category. The hazard ratio for PFS was 0.44 (95% CI, 0.39 to 0.51) stratified on prognostic category, and the hazard ratio for OS was 0.65 (95% CI, 0.56 to 0.75), favoring HDCT. These results were consistent within each prognostic category except among low-risk patients, for whom similar OS was observed between the two treatment groups. CONCLUSION This retrospective analysis suggests a benefit from HDCT given as intensification of first salvage treatment in male patients with GCTs and emphasizes the need for another prospective randomized trial comparing CDCT to HDCT in this patient population.

Gene Expression Signature in Advanced Colorectal Cancer Patients Select Drugs and Response for the Use of Leucovorin, Fluorouracil, and Irinotecan

PURPOSE In patients with advanced colorectal cancer, leucovorin, fluorouracil, and irinotecan (FOLFIRI) is considered as one of the reference first-line treatments. However, only about half of treated patients respond to this regimen, and there is no clinically useful marker that predicts response. A major clinical challenge is to identify the subset of patients who could benefit from this chemotherapy. We aimed to identify a gene expression profile in primary colon cancer tissue that could predict chemotherapy response. PATIENTS AND METHODS Tumor colon samples from 21 patients with advanced colorectal cancer were analyzed for gene expression profiling using Human Genome GeneChip arrays U133. At the end of the first-line treatment, the best observed response, according to WHO criteria, was used to define the responders and nonresponders. Discriminatory genes were first selected by the significance analysis of microarrays algorithm and the area under the receiver operating characteristic curve. A predictor classifier was then constructed using support vector machines. Finally, leave-one-out cross validation was used to estimate the performance and the accuracy of the output class prediction rule. RESULTS We determined a set of 14 predictor genes of response to FOLFIRI. Nine of nine responders (100% specificity) and 11 of 12 nonresponders (92% sensitivity) were classified correctly, for an overall accuracy of 95%. CONCLUSION After validation in an independent cohort of patients, our gene signature could be used as a decision tool to assist oncologists in selecting colorectal cancer patients who could benefit from FOLFIRI chemotherapy, both in the adjuvant and the first-line metastatic setting.

Overexpression of phosphoserine aminotransferase PSAT1 stimulates cell growth and increases chemoresistance of colon cancer cells

BackgroundColorectal cancer (CRC) is one of the most common causes of cancer death throughout the world. In this work our aim was to study the role of the phosphoserine aminotransferase PSAT1 in colorectal cancer development.ResultsWe first observed that PSAT1 is overexpressed in colon tumors. In addition, we showed that after drug treatment, PSAT1 expression level in hepatic metastases increased in non responder and decreased in responder patients.In experiments using human cell lines, we showed that ectopic PSAT1 overexpression in colon carcinoma SW480 cell line resulted in an increase in its growth rate and survival. In addition, SW480-PSAT1 cells presented a higher tumorigenic potential than SW480 control cells in xenografted mice. Moreover, the SW480-PSAT1 cell line was more resistant to oxaliplatin treatment than the non-transfected SW480 cell line. This resistance resulted from a decrease in the apoptotic response and in the mitotic catastrophes induced by the drug treatment.ConclusionThese results show that an enzyme playing a role in the L-serine biosynthesis could be implicated in colon cancer progression and chemoresistance and indicate that PSAT1 represents a new interesting target for CRC therapy.

Identification of a new panel of serum autoantibodies associated with the presence of in situ carcinoma of the breast in younger women.

Purpose: We examined the feasibility of using a panel of autoantibodies to multiple tumor-associated proteins as a method for early detection of breast cancer and, more particularly, carcinoma in situ (CIS). Experimental Design: PPIA, PRDX2, and FKBP52 were identified as early-stage breast cancer autoantigens by proteomic approaches. The seroreactivity of a panel of antibodies consisting of these three antigens and two previously described autoantigens, HSP60 and MUC1, was tested on 235 samples (60 from primary breast cancer patients, 82 from CIS patients, and 93 from healthy controls) with the use of specific ELISAs. FKBP52, PPIA, and PRDX2 mRNA and protein expression levels were evaluated by reverse transcription-PCR and immunohistochemistry in early-stage breast tumors. Results: Three of five autoantibodies, FKBP52, PPIA, and PRDX2, showed significantly increased reactivity in primary breast cancer and CIS compared with healthy controls. When combined, the five markers significantly discriminated primary breast cancer [receiver operating characteristic area under the curve, 0.73; 95% confidence interval (95% CI), 0.60-0.79] and CIS (receiver operating characteristic area under the curve, 0.80; 95% CI, 0.71-0.85) from healthy individuals. Importantly, the receiver operating characteristic–area under the curve value of the autoantibody panel was able to distinguish CIS, including high grades, from healthy controls in women under the age of 50 years (receiver operating characteristic area under the curve, 0.85; 95% CI, 0.61-0.92). Finally, only FKBP52 mRNA and protein levels were found to be increased in CIS and primary breast cancer compared with healthy breast tissue. Conclusions: This autoantibody assay against a panel of five antigens allows for an accurate discrimination between early-stage breast cancer, especially CIS, and healthy individuals. These results could be of interest in detecting early breast cancer as an aid to mammography, especially in women under the age of 50 years with aggressive cancers.

Cell membrane is a more sensitive target than cytoplasm to dense ionization produced by auger electrons.

Abstract Pouget, J-P., Santoro, L., Raymond, L., Chouin, N., Bardiès, M., Bascoul-Mollevi, C., Huguet, H., Azria, D., Kotzki, P-O., Pè legrin, M., Vivès, E. and Pèlegrin, A. Cell Membrane is a More Sensitive Target than Cytoplasm to Dense Ionization Produced by Auger Electrons. Radiat. Res. 170, 192–200 (2008). To improve radioimmunotherapy with Auger electron emitters, we assessed whether the biological efficiency of 125I varied according to its localization. A-431 and SK-OV-3 carcinoma cells were incubated with increasing activities (0–4 MBq/ml) of 125I-labeled vectors targeting the cell membrane, the cytoplasm or the nucleus. We then measured cell survival by clonogenic assay and the mean radiation dose to the nucleus by assessing the cellular medical internal radiation dose (MIRD). The relationship between survival and the radiation dose delivered was investigated with a linear mixed regression model. For each cell line, we obtained dose–response curves for the three targets and the reference values (i.e., the dose leading to 75, 50 or 37% survival). When cell survival was expressed as a function of the total cumulative decays, nuclear 125I disintegrations were more harmful than disintegrations in the cytoplasm or at the cell membrane. However, when survival was expressed as a function of the mean radiation dose to the nucleus, toxicity was significantly higher when 125I was targeted to the cell membrane than to the cytoplasm. These findings indicate that the membrane is a more sensitive target than the cytoplasm for the dense ionization produced by Auger electrons. Moreover, cell membrane targeting is as cytotoxic as nuclear targeting in SK-OV-3 cells. We suggest that targeting the membrane rather than the cytoplasm may contribute to the development of more efficient radioimmunotherapies based on Auger electron radiation, also because most of the available vectors are directed against cell surface antigens.

Quality of life assessment after concurrent chemoradiation for invasive bladder cancer: results of a multicenter prospective study (GETUG 97-015).

PURPOSE To evaluate bladder preservation and functional quality after concurrent chemoradiotherapy for muscle-invasive cancer in 53 patients included in a Phase II trial. PATIENT AND METHODS Pelvic irradiation delivered 45 Gy, followed by an 18-Gy boost. Concurrent chemotherapy with cisplatin and 5-fluorouracil by continuous infusion was performed at Weeks 1, 4, and 7 during radiotherapy. Patients initially suitable for surgery were evaluated with macroscopically complete transurethral resection after 45 Gy, followed by radical cystectomy in case of incomplete response. The European Organization for Research and Treatment of Cancer quality of life questionnaire QLQ-C30, specific items on bladder function, and the Late Effects in Normal Tissues-Subjective, Objective, Management, and Analytic (LENT-SOMA) symptoms scale were used to evaluate quality of life before treatment and 6, 12, 24, and 36 months after treatment. RESULTS Median age was 68 years for 51 evaluable patients. Thirty-two percent of patients had T2a tumors, 46% T2b, 16% T3, and 6% T4. A visibly complete transurethral resection was possible in 66%. Median follow-up was 8 years. Bladder was preserved in 67% (95% confidence interval, 52-79%) of patients. Overall survival was 36% (95% confidence interval, 23-49%) at 8 years for all patients, and 45% (28-61%) for the 36 patients suitable for surgery. Satisfactory bladder function, according to LENT-SOMA, was reported for 100% of patients with preserved bladder and locally controlled disease 6-36 months after the beginning of treatment. Satisfactory bladder function was reported for 35% of patients before treatment and for 43%, 57%, and 29%, respectively, at 6, 18, and 36 months. CONCLUSIONS Concurrent chemoradiation therapy allowed bladder preservation with tumor control for 67% patients at 8 years. Quality of life and quality of bladder function were satisfactory for 67% of patients.

Prognostic Significance of TRIM24/TIF-1α Gene Expression in Breast Cancer

In this study, we have analyzed the expression of TRIM24/TIF-1α, a negative regulator of various transcription factors (including nuclear receptors and p53) at the genomic, mRNA, and protein levels in human breast tumors. In breast cancer biopsy specimens, TRIM24/TIF-1α mRNA levels (assessed by Real-Time Quantitative PCR or microarray expression profiling) were increased as compared to normal breast tissues. At the genomic level, array comparative genomic hybridization analysis showed that the TRIM24/TIF-1α locus (7q34) exhibited both gains and losses that correlated with mRNA levels. By re-analyzing a series of 238 tumors, high levels of TRIM24/TIF-1α mRNA significantly correlated with various markers of poor prognosis (such as the molecular subtype) and were associated with worse overall survival. By using a rabbit polyclonal antibody for immunochemistry, the TRIM24/TIF-1α protein was detected in nuclei of normal luminal epithelial breast cells, but not in myoepithelial cells. Tissue microarray analysis confirmed that its expression was increased in epithelial cells from normal to breast infiltrating duct carcinoma and correlated with worse overall survival. Altogether, this work is the first study that shows that overexpression of the TRIM24/TIF-1α gene in breast cancer is associated with poor prognosis and worse survival, and it suggests that this transcription coregulator may play a role in mammary carcinogenesis and represent a novel prognostic marker.

Time-resolved Fluorescence Resonance Energy Transfer (TR-FRET) to Analyze the Disruption of EGFR/HER2 Dimers A NEW METHOD TO EVALUATE THE EFFICIENCY OF TARGETED THERAPY USING MONOCLONAL ANTIBODIES

In oncology, simultaneous inhibition of epidermal growth factor receptor (EGFR) and HER2 by monoclonal antibodies (mAbs) is an efficient therapeutic strategy but the underlying mechanisms are not fully understood. Here, we describe a time-resolved fluorescence resonance energy transfer (TR-FRET) method to quantify EGFR/HER2 heterodimers on cell surface to shed some light on the mechanism of such therapies. First, we tested this antibody-based TR-FRET assay in NIH/3T3 cell lines that express EGFR and/or HER2 and in various tumor cell lines. Then, we used the antibody-based TR-FRET assay to evaluate in vitro the effect of different targeted therapies on EGFR/HER2 heterodimers in the ovarian carcinoma cell line SKOV-3. A simultaneous incubation with Cetuximab (anti-EGFR) and Trastuzumab (anti-HER2) disturbed EGFR/HER2 heterodimers resulting in a 72% reduction. Cetuximab, Trastuzumab or Pertuzumab (anti-HER2) alone induced a 48, 44, or 24% reduction, respectively. In contrast, the tyrosine kinase inhibitors Erlotinib and Lapatinib had very little effect on EGFR/HER2 dimers concentration. In vivo, the combination of Cetuximab and Trastuzumab showed a better therapeutic effect (median survival and percentage of tumor-free mice) than the single mAbs. These results suggest a correlation between the extent of the mAb-induced EGFR/HER2 heterodimer reduction and the efficacy of such mAbs in targeted therapies. In conclusion, quantifying EGFR/HER2 heterodimers using our antibody-based TR-FRET assay may represent a useful method to predict the efficacy and explain the mechanisms of action of therapeutic mAbs, in addition to other commonly used techniques that focus on antibody-dependent cellular cytotoxicity, phosphorylation, and cell proliferation.