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Introduction: Early phase therapeutic trials in oncology are being offered to an increasing number of patients. The objective of this study is to retrospectively evaluate the treatment efficacy and survival of patients included in early phase trials at the "Institut de Cancérologie de l'Ouest" (ICO), as well as the interest of the Royal Marsden Hospital (RMH) and PRONOPALL scores in this population., Patients and Methods: All patients with cancer screened or included for an early phase trial at ICO between January 2012 and December 2015 have been identified., Results: Out of 1312-screened patients, 710 were included in 115 trials (34 phase 1 trials). The absence of molecular anomaly was the main cause of inclusion failure (49.5%). The disease control rate was 90.9%, the median overall survival was 14.7 months (95% CI 12.7 to 16.4) and the median progression-free survival was 5.7 months (95% CI 5.5 to 6.6). The median overall survival was better for patients with good prognosis based on Royal Marsden Hospital score (16.6 months versus 6 months, P=0.0011) and PRONOPALL score (15.6 months versus 4.6 months, P<0.001)., Discussion: Our results are better than in the literature, mainly because of the high proportion of first-line treatments and the consideration of phase II trials. Patients with lung cancer particularly benefited from these treatments, in part because of the role of immunotherapy. The Royal Marsden Hospital score can guide the decision to include in early phase trials, whereas the PRONOPALL score is not enough efficient., (Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Five-year overall survival (OS) of localized RMS exceeds 70% in children (<18) but is very poor in adult patients. We analyzed the outcome and prognostic factors (PF) of a national series of adult patients with RMS in a large study. The study population consisted of two different cohorts: a retrospective cohort (157 adult patients treated in 13 reference centers between 05/1981 and 02/2010) and the prospective cohort (292 patients with RMS diagnosed and treated between 01/2010 and 12/2014 in France) included in the NetSarc database. A descriptive analysis of patients' characteristics and prognostic factors was conducted on both series which were compared. In the retrospective series, histological subtypes were embryonal (E-RMS) for 21% of patients, alveolar (A-RMS) for 35% of patients, and "adult-type" P-RMS (pleomorphic, spindle cell RMS, not otherwise specified) (P) for 44% patients. This distribution significantly differed in the prospective cohort: A-RMS: 18%; E-RMS: 17%; and P-RMS 65%. With a median follow-up of 8.5 years, 5-year OS for localized RMS and advanced RMS (with nodes and/or metastases) was 43% and 5%, respectively, (P < 0.0001), and median OS was 51, 33, and 16 months for E-RMS, A-RMS, and P-RMS, respectively, in the retrospective cohort. The median OS was less than 40 months for the prospective nationwide cohort for the entire population. In a multivariate analysis of the retrospective study, independent prognostic factors for OS were A-RMS, R0 resection, and adjuvant radiotherapy (RT). For localized RMS, age and use of pediatric chemotherapy (CT) regimen are independent prognostic factors. Adult patients with RMS have a poorer overall survival than pediatric patients, and survival varies considerably across histological subtypes., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Hypoxia is a major factor in prostate cancer aggressiveness and radioresistance. Predicting which patients might be bad candidates for radiotherapy may help better personalize treatment decisions in intermediate-risk prostate cancer patients. We assessed spatial distribution of 18 F-Misonidazole (FMISO) PET/CT uptake in the prostate prior to radiotherapy treatment., Materials and Methods: Intermediate-risk prostate cancer patients about to receive high-dose (>74 Gy) radiotherapy to the prostate without hormonal treatment were prospectively recruited between 9/2012 and 10/2014. Prior to radiotherapy, all patients underwent a FMISO PET/CT as well as a MRI and 18 F-choline-PET. 18 F-choline and FMISO-positive volumes were semi-automatically determined using the fuzzy locally adaptive Bayesian (FLAB) method. In FMISO-positive patients, a dynamic analysis of early tumor uptake was performed. Group differences were assessed using the Wilcoxon signed rank test. Parameters were correlated using Spearman rank correlation., Results: Of 27 patients (median age 76) recruited to the study, 7 and 9 patients were considered positive at 2.5h and 3.5h FMISO PET/CT respectively. Median SUV max and SUV max tumor to muscle (T/M) ratio were respectively 3.4 and 3.6 at 2.5h, and 3.2 and 4.4 at 3.5h. The median FMISO-positive volume was 1.1 ml., Conclusions: This is the first study regarding hypoxia imaging using FMISO in prostate cancer showing that a small FMISO-positive volume was detected in one third of intermediate-risk prostate cancer patients., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Introduction: The identification of RAS status (KRAS and NRAS) has changed the management of metastatic colorectal cancer (mCRC). The impact of the RAS mutation on cytotoxic chemotherapy efficacy has not yet been determined. Nevertheless, several retrospective studies suggest a greater efficacy of oxaliplatin in mCRC with KRAS mutation., Methods: We analyzed retrospectively the progression free survival (PFS) and overall survival (OS) in 216 patients with mCRC receiving first line treatment between 2008 and 2010 according to KRAS status and chemotherapy regimen used (oxaliplatin- or irinotecan-based, in association with fluoropyrimidine and bevacizumab)., Results: In KRAS mutated tumors, median OS was 23.4 months with oxaliplatin-based regimen, and 23.6 months with irinotecan-based regimen, with no significant difference (HR 1.30; 95 % CI 0.81-2.09; P=0.27). In KRAS wild-type tumors, median OS was 30.3 months with oxaliplatin-based regimen, and 25.4 months with irinotecan-based regimen, with no significant difference (HR 0.81; 95 % CI 0.52-1.24; P=0.33). Similarly, KRAS mutational status had no significant effect on efficacy of oxaliplatin or irinotecan regarding PFS., Discussion: In this retrospective study, KRAS mutational status does not influence the efficacy of first line cytotoxic chemotherapy in association with bevacizumab., (Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Objective: Burkitt lymphoma (BL) is a rare and aggressive form of B-cell lymphoma that is curable using intensive chemotherapy. Obtaining a complete response (CR) at the end of induction chemotherapy is a major prognostic factor. This study retrospectively evaluates the potential impact of (18)FDG-PET in the management of children with BL after induction chemotherapy, and the prognostic performance of the Deauville criteria., Methods: Nineteen children with BL treated according to the French LMB2001 protocol between 2005 and 2012 were included. (18)FDG-PET and conventional imaging (CI) were performed after induction chemotherapy to confirm CR. (18)FDG-PET was interpreted according to Deauville criteria with follow-up and/or histology as the gold standard., Results: (18)FDG-PET was negative in 15 cases, in agreement with CI in 9/15 cases. The six discordant cases confirmed to be negative by histology, were considered as true negative for (18)FDG-PET. Negative predictive value (NPV) of CI and (18)FDG-PET were 73 and 93%, respectively. The 5-year progression-free survival (PFS) was significantly higher in patients with negative (18)FDG-PET than those with positive (18)FDG-PET (p = 0.011)., Conclusion: (18)FDG-PET interpreted using Deauville criteria can help confirm CR at the end of induction chemotherapy, with a prognostic impact on 5-year PFS. Its high NPV could limit the use of residual mass biopsy. Given the small size of our population, these results need to be confirmed by future prospective studies on a larger population.

Purpose: PET is a powerful tool for assessing targeted therapy. Since (18)F-FDG shows a potential prognostic value in medullary thyroid carcinoma (MTC), this study evaluated (18)F-FDG PET alone and combined with morphological and biomarker evaluations as a surrogate marker of overall survival (OS) in patients with progressive metastatic MTC treated with pretargeted anti-CEA radioimmunotherapy (pRAIT) in a phase II clinical trial., Methods: Patients underwent PET associated with morphological imaging (CT and MRI) and biomarker evaluations, before and 3 and 6 months, and then every 6 months, after pRAIT for 36 months. A combined evaluation was performed using anatomic, metabolic and biomarker methods. The prognostic value of the PET response was compared with demographic parameters at inclusion including age, sex, RET mutation, time from initial diagnosis, calcitonin and CEA concentrations and doubling times (DT), SUVmax, location of disease and bone marrow involvement, and with response using RECIST, biomarker concentration variation, impact on DT, and combined methods., Results: Enrolled in the study were 25 men and 17 women with disease progression. The median OS from pRAIT was 3.7 years (0.2 to 6.5 years) and from MTC diagnosis 10.9 years (1.7 to 31.5 years). After pRAIT, PET/CT showed 1 patient with a complete response, 4 with a partial response and 24 with disease stabilization. The combined evaluation showed 20 responses. For OS from pRAIT, univariate analysis showed the prognostic value of biomarker DT (P = 0.011) and SUVmax (P = 0.038) calculated before pRAIT and impact on DT (P = 0.034), RECIST (P = 0.009), PET (P = 0.009), and combined response (P = 0.004) measured after pRAIT. PET had the highest predictive value with the lowest Akaike information criterion (AIC 74.26) as compared to RECIST (AIC 78.06), biomarker variation (AIC 81.94) and impact on DT (AIC 79.22). No benefit was obtained by combining the methods (AIC 78.75). This result was confirmed by the analysis of OS from MTC diagnosis., Conclusion: (18)F-FDG PET appeared as the most potent and simplest prognostic method to predict survival in patients with progressive MTC treated with pRAIT. Biomarker DT before pRAIT also appeared as an independent prognostic factor, but no benefit was found by adding morphological and biomarker evaluation to PET assessment.

Aim: To develop novel biomarkers of rectal radiotherapy, we measured gene expression profiles on biopsies taken before and during preoperative radiotherapy., Methods: Six patients presenting with a locally advanced rectal cancer (T>T2, N0/Nx, M0) eligible for preoperative radiotherapy (45 Gy in 25 fractions) were selected in a pilot study. Six tumor and 3 normal tissues biopsies were taken before and during radiotherapy, after a dose of 7.2 Gy at a median time of 1 h following irradiation (0:27-2:12). Tumor or normal tissue purity was assessed by a pathologist prior to RNA extraction. Mean RNA content was 23 μg/biopsy (14-37) before radiotherapy and 22.7 μg/biopsy (12-35) during radiotherapy. After RNA amplification, biopsies were analysed with 54K HG-U133A Plus 2.0 Affymetrix expression micro-arrays. Data were normalized according to MAS5 algorithm. A gene expression ratio was calculated as: (gene expression during radiotherapy - gene expression before radiotherapy)/gene expression before radiotherapy. Were selected genes that showed a ratio higher than ± 0.5 in all 6 patients., Results: Microarray analysis showed that preoperative radiotherapy significantly up-regulated 31 genes and down-regulated 6 genes. According to the Gene Ontology project classification, these genes are involved in protein metabolism (ADAMDEC1; AKAP7; CAPN5; CLIC5; CPE; CREB3L1; NEDD4L; RAB27A), ion transport (AKAP7; ATP2A3; CCL28; CLIC5; F2RL2; NEDD4L; SLC6A8), transcription (AKAP7; CREB3L1; ISX; PABPC1L; TXNIP), signal transduction (CAPN5; F2RL2; RAB27A; TNFRSF11A), cell adhesion (ADAMDEC1; PXDN; SPON1; S100A2), immune response (CCL28; PXDN; TNFRSF11A) and apoptosis (ITM2C; PDCD4; PVT1). Up-regulation of 3 genes (CCL28; CLIC5; PDCD4) was detected by 2 different probes and up-regulation of 2 genes (RAB27A; TXNIP) by 3 probes., Conclusion: Micro-arrays can efficiently assess early transcriptomic changes during preoperative radiotherapy for rectal cancer, and may help better understand tumor radioresistance.

We recently developed a user-friendly web-based application called bc-GenExMiner (http://bcgenex.centregauducheau.fr), which offered the possibility to evaluate prognostic informativity of genes in breast cancer by means of a 'prognostic module'. In this study, we develop a new module called 'correlation module', which includes three kinds of gene expression correlation analyses. The first one computes correlation coefficient between 2 or more (up to 10) chosen genes. The second one produces two lists of genes that are most correlated (positively and negatively) to a 'tested' gene. A gene ontology (GO) mining function is also proposed to explore GO 'biological process', 'molecular function' and 'cellular component' terms enrichment for the output lists of most correlated genes. The third one explores gene expression correlation between the 15 telomeric and 15 centromeric genes surrounding a 'tested' gene. These correlation analyses can be performed in different groups of patients: all patients (without any subtyping), in molecular subtypes (basal-like, HER2+, luminal A and luminal B) and according to oestrogen receptor status. Validation tests based on published data showed that these automatized analyses lead to results consistent with studies' conclusions. In brief, this new module has been developed to help basic researchers explore molecular mechanisms of breast cancer. DATABASE URL: http://bcgenex.centregauducheau.fr

We used a 2D-electrophoresis (2-DE) proteomic approach to identify novel biomarkers in node-negative breast cancers. This retrospective study focused on a population of patients with ductal pN0M0 tumours. A subset of patients who developed metastases and in whose tumours were found high levels of uPA and PAI-1 (metastatic relapse, MR: n=20) were compared to another subset in whom no metastatic relapse occurred and whose tumours were found to have low levels of uPA and PAI-1 (no relapse, NR: n=21). We used a 2-DE coupled with MS approach to screen cytosol fractions using two pH-gradient scales, a broad scale (3.0-11.0) and a narrower scale focussing in on a protein rich region (5.0-8.0). This study was conducted on 41 cytosol specimens analyzed in duplicate on two platforms. The differential analysis of more than 2,000 spots in 2-DE gels, obtained on the two platforms, allowed the identification of 13 proteins which were confirmed by western blotting. Two proteins, GPDA and FABP4 were down-regulated in the MR subset whereas all the others were up-regulated. An in silico analysis revealed that GMPS (GUAA), GAPDH (G3P), CFL1 (COF1) and FTL (FRIL), the most informative genes, displayed a proliferation profile (high expression in basal-like, HER2+ and luminal B molecular subtypes). Inversely, similar to FABP4, GPD1 [GPDA] displayed a high expression in luminal A subtype, a profile characteristic of tumour suppressor genes. Despite the small size of our cohort, the 2-DE analysis gave interesting results which were confirmed by the in silico analysis showing that some of the corresponding genes had a strong prognostic impact in breast cancer, mostly because of their link with proliferation: GMPS, GAPDH, FTL and GPD1. A validation phase on a larger cohort is now needed before these biomarkers could be considered for use in clinical practice.

Purpose: To evaluate the efficacy and toxicity of high-dose-rate (HDR) brachytherapy in patients with inoperable endobronchial carcinoma., Methods and Materials: We retrospectively reviewed the records (April 1991-May 2004) of patients with non-small-cell carcinoma, with no extrabronchial spread on computed tomography scans, who underwent HDR brachytherapy because of contraindications to surgery and external beam radiation therapy. Kaplan-Meier survival curves were compared by the log-rank test. Prognostic factors were analyzed by multivariate analysis., Results: 226 patients (223 men, 3 women, mean age: 62.2 years (range, 40-84)) were included. Of those, 217 (97%) had squamous cell carcinoma (Tis/T1/T2/Tx: 60/153/9/4). Dose was prescribed at 1 cm from the radius (24-35 Gy in 4-6 fractions). Mean follow-up was 30.4 months (range, 9-116). Complete endoscopic response rate was 93.6% at 3 months. One hundred twenty-eight patients (56%) died of intercurrent disease (n = 45), local failure (n = 36), metastasis (n = 10), local failure and metastasis (n = 11), complications (n = 13), and other causes (n = 12). The 2-year and 5-year survival rates were, respectively, 57% and 29% (overall) (median, 28.6 months), 81% and 56% (cancer-specific), and 68% and 50% (local disease-free). Acute toxicity included pneumothorax (1.5%) and mucosal inflammation (10%). Late complications were hemoptysis (6.6% with 5% of fatalities), bronchitis (19.5%), and necrosis (3.5%). In multivariate analysis, a distal tumor location and the use of two catheters were associated with improved local disease-free survival (p = 0.003 and p = 0.007, respectively) and a distal tumor location with improved overall survival (p = 0.0001)., Conclusions: This large retrospective study confirms that HDR brachytherapy is an efficient and safe treatment in patients with inoperable endobronchial carcinoma., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Deletion of the 17p13 chromosomal region [del(17p)] is associated with a poor outcome in multiple myeloma. Most of the studies have targeted the TP53 gene for deletion analyses, although no study showed that this gene is the deletion target. In order to address this issue, we sequenced the TP53 gene in 92 patients with multiple myeloma at diagnosis, 54 with a del(17p) and 38 lacking del(17p). At least one mutation was found in 20 patients, all of them presenting a del(17p). The analysis of the mutation location showed that virtually all of them occurred in highly conserved domains involved in the DNA-protein interactions. In conclusion, we showed that 37% of the myeloma patients with del(17p) present a TP53 mutation versus 0% in patients lacking the del(17p). The prognostic significance of these mutations remains to be evaluated.

Purpose: To determine prospectively intermediate-term toxicity and quality of life (QoL) of prostate cancer patients after intensity-modulated radiotherapy (IMRT)., Patients and Methods: Fifty-five patients with localized prostate adenocarcinoma were treated by IMRT (76 Gy). Physicians scored acute and late toxicity using the Common Terminology Criteria for Adverse Events version 3.0. Patients assessed general and prostate-specific QoL before IMRT (baseline) and at 2, 6, and 18 months using European Organization for Research and Treatment of Cancer questionnaires QLQ-C30(+3) and QLQ-PR25., Results: Median age was 73 years (range, 54-80 years). Risk categories were 18% low risk, 60% intermediate risk, and 22% high risk; 45% of patients received hormonal therapy (median duration, 6 months). The incidence of urinary and bowel toxicity immediately after IMRT was, respectively, 38% and 13% (Grade 2) and 2% and none (Grade 3); at 18 months it was 15% and 11% (Grade 2) and none (Grade 3). Significant worsening of QoL was reported at 2 months with regard to fatigue (+11.31, p = 1.10(-7)), urinary symptoms (+9.07, p = 3.10(-11)), dyspnea (+7.27, p = 0.008), and emotional (-7.02, p = 0.002), social (-6.36, p = 0.003), cognitive (-4.85, p = 0.004), and physical (-3.39, p = 0.007) functioning. Only fatigue (+5.86, p = 0.003) and urinary symptoms (+5.86, p = 0.0004) had not improved by 6 months. By 18 months all QoL scores except those for dyspnea (+8.02, p = 0.01) and treatment-related symptoms (+4.24, p = 0.01) had returned to baseline. These adverse effects were exacerbated by hormonal therapy., Conclusion: High-dose IMRT with accurate positioning induces only a temporary worsening of QoL., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: The aim of this retrospective study was to evaluate the contribution of (18)F-FDG PET to the clinical management and survival outcome of patients suspected of recurrent cervical carcinoma and in line with the hypothesis that early diagnosis of recurrent cervical cancer may improve overall survival., Methods: A total of 40 patients underwent conventional imaging (CI) and FDG PET/CT for suspected cervical cancer. Clinical management decisions were recorded with CI and additional PET/CT. Discordances and concordances between CI and PET/CT results were compared to the final diagnosis as based on histopathology analysis or follow-up considered as the gold standard., Results: The final diagnosis was established pathologically (n = 25) or by median clinical follow-up for 48 months after the PET (n = 15). The PET/CT was positive in 76% (20/26) of patients compared to 19% (6/26) with CI. Globally PET/CT modified the treatment plan in 55% (22/40) of patients and in 75% (18/24) when the CI was negative prior to PET/CT. These changes led to the use of previously unplanned therapeutic procedures in 37.5% (15/40). When FDG PET was positive for recurrence (> 3 foci), the median overall survival was 12 months (2-70) compared to patients with PET findings with < or = 1 focus for which the median survival was not attained (p = 0.007). A multivariate analysis of prognostic factors demonstrated that abnormal FDG uptake (> 3 foci) was the most significant factor (p < 0.03) for death from cervical cancer., Conclusion: FDG PET is a valuable tool in the case of suspected recurrence of cervical cancer on account of its impact on treatment planning and especially in predicting patient outcome.

This multicenter study assesses the value of O(6)-methylguanine-DNA methyltransferase (MGMT) status for predicting overall survival in glioblastoma patients. Five methods are used, to identify the approach with the best prognostic value. Eighty-one tumors were obtained from patients with glioblastomas treated by surgery and radiotherapy with concomitant temozolomide (TMZ) followed by adjuvant TMZ. MGMT promoter methylation was assessed by qualitative methyl-specific polymerase chain reaction (MSP), semiquantitative methyl-specific polymerase chain reaction (SQ-MSP), and pyrosequencing, while MGMT expression was measured at the RNA level by quantitative real-time PCR (Q-RT-PCR) and at the protein level by immunohistochemistry (IHC). MGMT promoter methylation as evaluated by MSP, SQ-MSP, and pyrosequencing was significantly correlated with overall survival. The best predictive value was obtained by pyrosequencing of one specific CpG position. Overall survival was 14 and 25 months for patients with percentages of methylation below and above the median, respectively. In contrast, MGMT status determined by Q-RT-PCR and IHC showed little or no correlation with overall survival, respectively. These results confirm the prognostic value of MGMT promoter methylation in glioblastoma patients initially treated with TMZ. SQ-MSP allowed better discrimination than classical MSP, and pyrosequencing represented a good option.

The combination of bortezomib and dexamethasone is becoming the reference induction treatment for multiple myeloma patients younger than 65 years. Despite its advantage over vincristin adryamicin dexamethasone induction treatment, bortezomib does not benefit all patients. We hypothesize that heterogeneity of the response experienced by myeloma patients is, at least in part, due to genomic variations in the malignant plasma cells. To test this hypothesis we used gene expression profiling to identify early responsive genes induced by bortezomib in resistant myeloma cells. Our study revealed: (i) a dramatic induction of REDD1, a negative regulator of mammalian target of rapamycin kinase complex 1 (mTORC1) activity, in these cells; (ii) a transient cell size decrease associated with REDD1 overexpression; and (iii) partial restoration of bortezomib sensitivity in REDD1 knockdown bortezomib-resistant myeloma cells. Together, these results identify a possible novel mechanism of bortezomib resistance in myeloma patients mediated by REDD1 overexpression involving inhibition of mTORC1 activity and suggest that the use of mammalian target of rapamycin inhibitors in myeloma patients could be deleterious.

Purpose: (18)F-FDG PET has been successfully evaluated in the management of Hodgkin's lymphoma (HL) and the most recent international guidelines recommended (18)F-FDG PET for initial staging and final therapeutic assessment. However, (18)F-FDG PET diffuse bone marrow uptake (BMU) and splenic uptake (SU) are frequently observed at the initial imaging and remain difficult to analyse. The aim of this retrospective study was to evaluate the significance of (18)F-FDG diffuse BMU and SU in initial staging of HL., Methods: A total of 106 patients (median age: 31 years, range: 9-81, 51 female, 55 male) underwent (18)F-FDG PET/CT for initial staging of HL. BMU level was assessed visually according to liver uptake (1 = below liver uptake, 2 = corresponding to liver uptake, 3 = above liver uptake) and semi-quantitatively using the maximum standardized uptake value (SUV(max)) measured in the sacral area. SU was assessed visually according to liver uptake (1 = below liver uptake, 2 = corresponding to liver uptake, 3 = above liver uptake). These data were compared with the patient's characteristics including sex, age, Ann Arbor staging, bulky disease (tumour burden > 10 cm), presence of B symptoms, bone foci on PET (n = 106), bone marrow involvement (BMI) on biopsy (n = 75), leukocyte count (n = 74), lactic dehydrogenase (LDH) (n = 87), C-reactive protein (CRP) (n = 83) and fibrinogen (n = 60). Univariate and multivariate analyses were performed., Results: Multivariate analysis found an independent correlation between BMU visual grading and CRP level (p = 0.007). For semi-quantitative BMU evaluation, multivariate analysis found an independent correlation between sacral SUVs and CRP level (p = 0.032) and Ann Arbor stage (p = 0.005). No BMI was found in patients who presented with SUV(max) below 3.4. For splenic evaluation, multivariate analysis found an independent correlation between SU and splenic foci (p = 0.034). No statistical link was found between SU and inflammatory markers., Conclusion: Our study demonstrates that diffuse BMU at initial staging of HL could be due to bone marrow involvement but more likely to bone marrow inflammatory change and that diffuse SU in contrast is probably more associated with disease involvement than with inflammatory change.

Interleukin-6 (IL-6) is a cytokine involved in different physiologic and pathophysiologic processes including carcinogenesis. In 2003, a single nucleotide polymorphism (-174G/C) of the IL-6 gene promoter has been linked to breast cancer prognosis in node-positive (N+) breast cancer patients. Since, different studies have led to conflicting conclusions about its role as a prognostic and/or diagnostic marker. The primary aim of our study was to investigate the link between -174G/C polymorphism and breast cancer risk on the one hand, and -174G/C polymorphism and prognosis in different groups of patients: sporadic N+breast cancers (n=138), sporadic N- breast cancers (n=95) and familial breast cancer (n=60) on the other hand. The variables of interest were disease-free survival and overall survival. The secondary aim of the study was to screen IL-6 gene promoter using direct sequencing to identify new polymorphisms in our French Caucasian breast cancer population. No association or trend of association between -174G/C polymorphism of IL-6 gene promoter gene and breast cancer diagnosis or prognosis was shown, even in meta-analyses. Furthermore, we have identified four novel polymorphic sites in the IL-6 gene promoter region: -764G-->A, -757C-->T, -233T-->A, 15C-->A.

Currently, no prognostic gene-expression signature (GES) established from node-positive breast cancer cohorts, able to predict evolution after systemic adjuvant chemotherapy, exists. Gene-expression profiles of 252 node-positive breast cancer patients (median follow-up: 7.7 years), mostly included in a randomized clinical trial (PACS01), receiving systemic adjuvant regimen, were determined by means of cDNA custom array. In the training cohort, we established a GES composed of 38 genes (38-GES) for the purpose of predicting metastasis-free survival. The 38-GES yielded unadjusted hazard ratio (HR) of 4.86 (95% confidence interval = 2.76-8.56). Even when adjusted with the best two clinicopathological prognostic indexes: Nottingham prognostic index (NPI) and Adjuvant!, 38-GES HRs were 3.30 (1.81-5.99) and 3.40 (1.85-6.24), respectively. Furthermore, 38-GES improved NPI and Adjuvant! classification. In particular, NPI intermediate-risk patients were divided into 2/3 close to low-risk group and 1/3 close to high-risk group (HR = 6.97 [2.51-19.36]). Similarly, Adjuvant! intermediate-risk patients were divided into 2/3 close to low-risk group and 1/3 close to high-risk group (HR = 4.34 [1.64-11.48]). The 38-GES was validated on gene-expression datasets from three external node-positive breast cancer subcohorts (n = 224) generated from different microarray platforms, with HR = 2.95 (1.74-5.01). Moreover, 38-GES showed prognostic performance in supplementary cohorts with different lymph-node status and endpoints (1,040 new patients). The 38-GES represents a robust tool able to type systemic adjuvant treated node-positive patients at high risk of metastatic relapse, and is especially powerful to refine NPI and Adjuvant! classification for those patients.

Breast cancer is a very heterogeneous disease, and markers for disease subtypes and therapy response remain poorly defined. For that reason, we employed a retrospective study in node-positive breast cancer to identify molecular signatures of gene expression correlating with metastatic free survival. Patients were primarily included in FEC100 (5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2) and cyclophosphamide 500 mg/m(2)) arms of two multicentric prospective adjuvant clinical trials (PACS01 and PEGASE01-FNCLCC cooperative group). Data from nylon microarrays containing 8,032 cDNA unique sequences, representing 5,776 distinct genes, have been used to develop a predictive model for treatment outcome. We obtained the gene expression profiles for 150 of these patients, and used stringent univariate selection techniques based on Cox regression combined with principal component analysis to identify a genomic signature of metastatic relapse after adjuvant FEC100 regimen. Most of the 14 selected genes have a clear role in breast cancer, carcinogenesis or chemotherapy resistance. Six genes have been previously described in other genomic studies (UBE2C, CENPF, C16orf61 [DC13], STMN1, CCT5 and BCL2A1). Furthermore, we showed the interest of combining transcriptomic data with clinical data into a clinicogenomic model for patients subtyping. The described model adds predictive accuracy to that provided by the well-established Nottingham prognostic index or by our genomic signature alone.

Background: The study aimed to evaluate FDG-PET imaging for early prediction of response to radioimmunotherapy in patients with non-Hodgkin's lymphoma., Design and Methods: Twenty-seven patients from a large ongoing, multicenter, phase I/II trial of fractionated radioimmunotherapy using anti-CD22 (90)Y-epratuzumab underwent FDG-PET imaging. They also underwent assessment by conventional diagnostic methods that included chemotherapy at baseline and six weeks post-radioimmunotherapy, and every three months until progression. Responses evaluated from conventional methods were classified using International Workshop Response Criteria as complete response, unconfirmed CR, partial response, stable disease, or progression of disease. FDG-PET images were evaluated visually and were classified as complete response, partial response or progression of disease. The gold standard was histology and follow-up., Results: A total of 81 paired imaging studies were obtained post-radioimmunotherapy (including 3 patients after retreatment) and evaluated as complete response (n=34), partial response (n=24) or progression of disease (n=23) by FDG-PET, and complete response (n=12), unconfirmed complete response (n=31), partial response (n=15), stable disease (n=8) or progression of disease (n=15) by conventional methods. Of the 31 responses evaluated as unconfirmed complete response by conventional methods, 20 (65%) were classified as negative for disease (complete response) by PET while the other 11 (35%) were positive for disease (7 partial response and 4 progression of disease). Among 22 assessable PET images acquired at six weeks post-radioimmunotherapy, the mean time-to-progression was 15.6 months when PET was negative for disease (complete response), compared with 5.4 months when PET was positive (partial response or progression of disease) (p=0.008). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET six weeks after radioimmunotherapy were 86%, 63%, 80%, 71% and 77% respectively, compared with 36%, 87%, 83%, 44% and 55% respectively using conventional methods., Conclusions: A positive assessment of disease by PET acquired six weeks after radioimmunotherapy corresponded with a shorter time to progression.

Background: In breast cancer treatment, FEC100 (fluorouracil, epirubicin and cyclophosphamide) chemotherapy delivered in a neoadjuvant setting is still applied empirically to all patients. The aim of this study was to establish a multigene classifier of sensitivity to neoadjuvant FEC100., Materials and Methods: cDNA nylon microarrays, containing 15,000 genes, were used to analyze the gene expression profiles of tumour biopsies collected before chemotherapy: 8 were typed as pathological complete responders and 8 as non-responders according to their histological and clinical responses., Results: A classifier was generated by means of Linear Discriminant Analysis and was evaluated by leave-one-out cross-validation. The difference of expression of the NDUFB5 gene (NADH dehydrogenase 1 beta subcomplex, 5), the best discriminating gene, was verified using RT-PCR., Conclusion: This preliminary work requires further investigations, especially in terms of larger cohorts, before the results can be transferred to clinical practice., (Copyright© 2006 International Institute of Anticaner Research (Dr. John G. Delinassios), All rights reserved.)

Unlabelled: Safety, targeting, and antitumor efficacy of pretargeted radioimmunotherapy using anti-carcinoembryonic antigen (CEA) hMN-14 x m734 bispecific antibody (BsmAb) and 131I-di-diethylenetriamine pentaacetic acid (DTPA)-indium hapten were evaluated in a phase I study performed on patients with CEA-expressing tumors., Methods: Twenty-two patients with nonmedullary thyroid carcinoma (non-MTC) (group I, 13 patients) or medullary thyroid carcinoma (MTC) (group II, 9 patients) were enrolled. These patients received a 75 mg/m2 (11 patients) or 40 mg/m2 (11 patients) dose of BsmAb and escalating activities of (131)I-di-DTPA-indium 5 d later. Toxicity and tumor response were assessed in 20 patients who received a therapeutic (>2.2 GBq) hapten dose of radioactivity., Results: The percentage of lesions detected by immunoscintigraphy after injection of the therapeutic dose of hapten was 70% on an anatomic-site basis. High bone uptake was relatively frequent. A transient grade I or II hepatic toxicity was observed in 5 patients (45%) injected with 75 mg/m2 of BsmAb and in 1 patient (11%) injected with 40 mg/m2. No other nonhematologic toxicity was observed. With 75 mg/m2 of BsmAb, hematologic toxicity was high: 5 cases of grade III or IV leukopenia (45%) and 5 cases of grade III or IV thrombopenia (45%). With a 40 mg/m2 dose of BsmAb, hematologic toxicity was reduced significantly: 3 cases of grade III or IV leukopenia (33%) and 1 case of grade III or IV thrombopenia (11%) (P = 0.02). Toxicity was significantly higher in MTC patients than in non-MTC patients (P = 0.019). Nine cases of tumor stabilization of 3 mo to more than 12 mo were observed (45%), 6 in the MTC group and 3 in the non-MTC group. The rate of disease stabilization was significantly higher with 75 mg/m2 of BsmAb (64%) than with 40 mg/m2 (22%) (P = 0.04). Human antimouse antibody elevation was observed in 1 patient (8%) and human antihuman antibody in 4 (33%)., Conclusion: A BsmAb dose of 40 mg/m2 and a 5-d interval appeared to be a better dose/schedule regimen, with acceptable toxicity. Under these conditions, the maximal tolerated activity was 3 GBq of 131I-di-DTPA-indium in MTC patients. In non-MTC patients, dose escalation should continue.

A significant antitumor effect associated with moderate toxicity was obtained previously with anticarcinoembryonic antigen x antidiethylene-triaminepentaacetic acid (DTPA)-indium F6-734 bispecific antibody and iodine-131-labeled DTPA-indium bivalent hapten in an animal model of medullary thyroid cancer (MTC). The purpose of this study was to determine whether the cytotoxic agents doxorubicin and paclitaxel, also known as radiosensitizers, improve efficacy of pretargeted radioimmunotherapy (RIT) in experimental MTC. Nude mice bearing TT MTC xenograft were treated with F6-734 and iodine-131-labeled DTPA-indium bivalent hapten injected 48 h apart with or without doxorubicin or paclitaxel. The maximum tolerated dose (MTD) of RIT was 92.5 MBq (as determined previously) and that of doxorubicin and paclitaxel 200 and 1000 micrograms, respectively. A control group received no treatment. Animal weight, hematotoxicity, tumor volume, and serum calcitonin were monitored for 5 months. Tumor growth inhibition induced by drugs alone, RIT alone, or combined therapy was characterized by measuring relative tumor volume 20, 40, and 60 days after treatment to detect additivity or synergism. Mean tumor volume doubling time (MTVDT) was 13 +/- 4 days in the control group, 15 +/- 8 days in the group treated with the MTD of doxorubicin, and 32 +/- 13 days in the group treated with the MTD of paclitaxel. After RIT alone at 92.5 MBq, MTVDT was 86 +/- 22 days. After RIT at 74 MBq (80% of MTD), MTVDT was 56 +/- 10 days. MTVDT was not significantly different from this value after RIT plus doxorubicin, 60 +/- 16 days (65 and 100% of the respective single-agent MTDs). Combination of RIT with paclitaxel (65 and 100% of the respective single-agent MTDs) prolonged the suppression of tumor growth. One complete response was observed, and MTVDT was 114 +/- 44 days. This value was significantly longer than the value obtained with RIT alone at 74 MBq (P < 0.05) or with RIT combined with doxorubicin (P < 0.02). The change in serum calcitonin levels paralleled those in tumor volume. Analysis of dose-response curves at days 20 and 40 showed additivity between RIT and paclitaxel, and analysis at day 60 suggested a synergistic effect. In conclusion, addition of doxorubicin did not improve RIT efficacy, whereas paclitaxel improved RIT efficacy significantly without increasing toxicity.