Publications by authors named "Pierre Fumoleau"

112 Publications

6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial.

Lancet 2019 06 6;393(10191):2591-2598. Epub 2019 Jun 6.

Department of Statistics, University of Rouen, Rouen, France.

Background: In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. Here, we report the planned final analysis based on the prespecified number of occurring events.

Methods: PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901.

Findings: 3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3-8·8), 704 events relevant to disease-free survival were observed (345 [20·4%] in the 12-month group and 359 [21·2%] in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93-1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group.

Interpretation: The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months.

Funding: The French National Cancer Institute.
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http://dx.doi.org/10.1016/S0140-6736(19)30653-1DOI Listing
June 2019

Clinical and genetic landscape of treatment naive cervical cancer: Alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome.

EBioMedicine 2019 May 2;43:253-260. Epub 2019 Apr 2.

Institut de cancérologie de l'Ouest - site Paul Papin (ICO) 15, Rue André Boquel, 49055 Angers, France.

Background: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome.

Methods: Between 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome.

Findings: At a median follow up (FU) of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65•4% [CI95%: 60•2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters.

Interpretation: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. FUND: European Union's Seventh Program grant agreement No 304810.
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http://dx.doi.org/10.1016/j.ebiom.2019.03.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562019PMC
May 2019

Nuclear Imaging Study of the Pharmacodynamic Effects of Debio 1143, an Antagonist of Multiple Inhibitor of Apoptosis Proteins (IAPs), in a Triple-Negative Breast Cancer Model.

Contrast Media Mol Imaging 2018 2;2018:8494031. Epub 2018 Dec 2.

Centre Georges-François Leclerc, Dijon, France.

Background: Debio 1143, a potent orally available SMAC mimetic, targets inhibitors of apoptosis proteins (IAPs) members and is currently in clinical trials. In this study, nuclear imaging evaluated the effects of Debio 1143 on tumor cell death and metabolism in a triple-negative breast cancer (TNBC) cell line (MDA-MB-231)-based animal model.

Methods: Apoptosis induced by Debio 1143 was assessed by FACS (caspase-3, annexin 5 (A5)), binding of Tc-HYNIC-Annexin V, and a cell proliferation assay. Tc-HYNIC-Annexin V SPECT and [F]-FDG PET were also performed in mice xenografted with MDA-MB-231 cells.

Results: Debio 1143 induced early apoptosis both and 6 h after treatment. Debio 1143 inhibited tumor growth, which was associated with a decreased tumor [F]-FDG uptake when measured during treatment.

Conclusions: This imaging study combining SPECT and PET showed the early proapoptotic effects of Debio 1143 resulting in a robust antitumor activity in a preclinical TNBC model. These imaging biomarkers represent valuable noninvasive tools for translational and clinical research in TNBC.
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http://dx.doi.org/10.1155/2018/8494031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305031PMC
May 2019

Long-Term Gynecological Cancer Survivors in Côte d'Or: Health-Related Quality of Life and Living Conditions.

Oncologist 2019 07 21;24(7):e490-e500. Epub 2018 Dec 21.

Breast and Gynecologic Cancer Registry of Côte d'Or, Georges-François Leclerc Cancer Centre-UNICANCER, Dijon, France

Background: The likelihood that health-related quality of life (HRQoL) could depend on factors other than clinical data increases with the duration of follow-up since diagnosis. The aim of this study was to identify determinants of long-term HRQoL in women with cervical, endometrial, and ovarian cancer. Secondary objectives were to describe their living conditions (sexual function, psychological distress, social and professional reinsertion).

Materials And Methods: In a cross-sectional survey, women diagnosed with cervical, endometrial, and ovarian cancers from 2006 to 2013 were selected through the French gynecological cancers registry of Côte d'Or. Validated questionnaires exploring HRQoL (short-form health survey; SF-12), anxiety and depression (Hospital Anxiety and Depression Scale), social support (Sarason's Social Support Questionnaire), sexual function (Female Sexual Function Index), and living conditions (EPICES questionnaire) were used to assess HRQoL and its determinants. Social and professional reinsertion were also investigated using study-specific questionnaires. Determinants of HRQoL were identified using a multivariable mixed-regression model for each composite score of the SF-12.

Results: In total, 195 gynecological cancer survivors participated in the survey. HRQoL was deteriorated for almost all the SF-12 dimensions. The main determinants of poor HRQoL were comorbidities, deprivation, lack of availability and satisfaction with social support, and psychological outcomes. Thirty-four percent of survivors of gynecological cancer reported a negative impact of cancer on their work, and 73% reported an impaired ability to work after treatment.

Conclusions: Long-term HRQoL of survivors of gynecological cancer is not impacted by stage of disease. Specific interventions should focus on issues that promote social and professional reintegration and improve HRQoL.

Implications For Practice: This study shows that women with gynecological cancer have problems related to work and sexual dysfunction, even 5 years after diagnosis. The results of this study will help improve clinicians' awareness of the factors affecting the lives of gynecological cancer survivors, even long after diagnosis and treatment. They will also highlight for clinicians the areas that are of importance to gynecological cancer survivors, making it possible to guide management of these patients with a view to preventing deteriorated health-related quality of life after treatment. For the health authorities, the results of this study underline that more than 5 years after gynecological cancer, the initial stage of disease no longer affects quality of life, but there is a clear need for actions targeting socio-professional reintegration of survivors.
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http://dx.doi.org/10.1634/theoncologist.2018-0347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656453PMC
July 2019

FDG PET/CT for prognostic stratification of patients with metastatic breast cancer treated with first line systemic therapy: Comparison of EORTC criteria and PERCIST.

PLoS One 2018 16;13(7):e0199529. Epub 2018 Jul 16.

Department of Nuclear Medicine, Centre Georges-François Leclerc, Dijon, France.

Aim: Evaluate response and predict prognosis of patients with newly diagnosed metastatic breast cancer treated with first line systemic therapy using European Organization for Research and Treatment of Cancer (EORTC) criteria and PET Response Criteria in solid Tumours (PERCIST).

Methods: From December 2006 to August 2013, 57 women with newly diagnosed metastatic breast cancer were retrospectively evaluated. FDG-PET/CT was performed within one month before treatment and repeated after at least 3 cycles of treatment. Metabolic response evaluation was evaluated by two readers according to both EORTC criteria and PERCIST, classifying the patients into 4 response groups: complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD).

Results: With EORTC criteria, 22 patients had CMR, 17 PMR, 6 SMD and 12 PMD. With PERCIST, 20 patients had CMR, 15 PMR, 10 SMD and 12 PMD. There was agreement between EORTC and PERCIST in 84% of the patients. By log-rank analysis, metabolic response evaluated with both EORTC criteria and PERCIST was able to predict overall survival (p = 0.028 and 0.002 respectively). CMR patient group had longer median OS than patients in the combined PMR+SMD+PMD group (60 vs 26 months both with EORTC and PERCIST; p = 0.009 and 0.006 respectively). By multivariate analysis, CMR either with EORTC or PERCIST remained an independent predictor of survival.

Conclusion: Metabolic response evaluation with EORTC criteria and PERCIST gave similar prognostic stratification for metastatic breast cancer treated with a first line of systemic therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199529PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047783PMC
January 2019

Fluctuation of the left ventricular ejection fraction in patients with HER2-positive early breast cancer treated by 12 months of adjuvant trastuzumab.

Breast 2018 Oct 15;41:1-7. Epub 2018 Jun 15.

Centre Paul Strauss, Strasbourg, France. Electronic address:

Background: Cardiac toxicity with a decrease of the left ventricular ejection fraction (LVEF) is the main side effect induced by trastuzumab. This study reports the fluctuation of LVEF over the 12 months of adjuvant trastuzumab in PHARE trial (NCT00381901).

Methods: LVEF assessment was performed every 3 months while patients received trastuzumab and after completion of treatment over the first 2 years and then every 6 months afterwards. The fluctuations of LVEF over time were described and a logistic regression model was performed investigating associated factors to LVEF perfect recovery at baseline value.

Results: A total of 1631 patients who received 12 months of trastuzumab from PHARE trial, were considered in the analysis. A total of 13 881 LVEF measurements were assessed. Baseline mean LVEF was 66.08% (standard error (SE): 0.15) and the mean relative LVEF decrease observed at 12-month was 3.61% (SE: 0.31). No clinical characteristic was significantly associated to LVEF fluctuation. After completion of trastuzumab, the relative difference progressively disappeared with beyond 30 months a relative difference value of 0.08% (SE: 0.42). Nevertheless, at 30 months, 48.53% of patients with available measures (379/781) did not fully recover their baseline LVEF value.

Conclusion: The LVEF decreased during treatment with trastuzumab and rose up after the completion of treatment without coming back to the initial values for a substantial subset. These results would suggest investigating some strategies aimed to improve the ability to achieve a full recovery.
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http://dx.doi.org/10.1016/j.breast.2018.06.001DOI Listing
October 2018

The 21-gene Recurrence Score® assay predicts distant recurrence in lymph node-positive, hormone receptor-positive, breast cancer patients treated with adjuvant sequential epirubicin- and docetaxel-based or epirubicin-based chemotherapy (PACS-01 trial).

BMC Cancer 2018 May 4;18(1):526. Epub 2018 May 4.

Department of Medical Oncology, Institut Claudius Régaud, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France.

Background: The 21-gene Recurrence Score (RS) result predicts outcome and chemotherapy benefit in node-negative and node-positive (N+), estrogen receptor-positive (ER+) patients treated with endocrine therapy. The purpose of this study was to evaluate the prognostic impact of RS results in N+, hormone receptor-positive (HR+) patients treated with adjuvant chemotherapy (6 cycles of FEC100 vs. 3 cycles of FEC100 followed by 3 cycles of docetaxel 100 mg/m) plus endocrine therapy (ET) in the PACS-01 trial (J Clin Oncol 2006;24:5664-5671).

Methods: The current study included 530 HR+/N+ patients from the PACS-01 parent trial for whom specimens were available. The primary objective was to evaluate the relationship between the RS result and distant recurrence (DR).

Results: There were 209 (39.4%) patients with low RS (< 18), 159 (30%) with intermediate RS (18-30) and 162 (30.6%) with high RS (≥ 31). The continuous RS result was associated with DR (hazard ratio = 4.14; 95% confidence interval: 2.67-6.43; p <  0.001), adjusting for treatment. In multivariable analysis, the RS result remained a significant predictor of DR (p <  0.001) after adjustment for number of positive nodes, tumor size, tumor grade, Ki-67 (immunohistochemical status), and chemotherapy regimen. There was no statistically significant interaction between RS result and treatment in predicting DR (p = 0.79).

Conclusions: After adjustment for clinical covariates, the 21-gene RS result is a significant prognostic factor in N+/HR+ patients receiving adjuvant chemoendocrine therapy.

Trial Registration: Not applicable.
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http://dx.doi.org/10.1186/s12885-018-4331-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5936023PMC
May 2018

Breast Cancer Blood Flow and Metabolism on Dual-Acquisition F-FDG PET: Correlation with Tumor Phenotype and Neoadjuvant Chemotherapy Response.

J Nucl Med 2018 07 9;59(7):1035-1041. Epub 2018 Feb 9.

Department of Nuclear Medicine, Centre G.F. Leclerc, Dijon, France.

Early changes in tumor glucose metabolism (SUV) and in tumor blood flow (BF) have been evaluated separately for monitoring breast cancer response to neoadjuvant chemotherapy (NAC). This study used a single F-FDG dual-acquisition PET examination to simultaneously assess these two imaging features and to determine whether they correlate with the same pretherapy tumor phenotypic features and whether they are comparable or complementary in predicting pathologic complete response (pCR). This prospective study included 150 women with breast cancer and an indication for NAC. A 2-min chest-centered dynamic PET acquisition was performed at the time of F-FDG injection, followed by a delayed static PET acquisition 90 min later. Tumor BF was calculated from the dynamic acquisition using a validated first-pass model, and tumor SUV was calculated from the delayed acquisition. This dual acquisition was repeated after the first cycle of NAC to measure early changes in tumor BF and SUV A weak correlation was found between SUV and BF at baseline ( = 0.22; = 0.006). A high baseline SUV was associated with all biologic markers of tumor aggressiveness, including the triple-negative breast cancer subtype ( < 0.0001). In contrast, a high baseline BF was associated only with obesity ( = 0.002). The change in SUV (mean, -44.6% ± 27.4%) varied depending on the Scarff-Bloom-Richardson grade, overexpression of human epidermal growth factor receptor 2 (HER2-positive), and lack of hormone receptor expression ( = 0.04, < 0.001, and = 0.01, respectively). BF (mean change, -26.9% ± 54.3%) showed a drastic reduction only in HER2-positive subtypes (-58.7% ± 30.0%), supporting the antiangiogenic effect of trastuzumab. Changes in SUV outperformed changes in BF for predicting pCR in all tumor subtypes: the areas under the curve for change in SUV were 0.82, 0.65, and 0.90 in the triple-negative, HER2-positive, and luminal subtypes, respectively. Of the two biologic hallmarks of cancer evaluated in this study, a reduction in tumor glucose metabolism was more accurate than a reduction in tumor BF for predicting pCR in the different subtypes of breast cancer.
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http://dx.doi.org/10.2967/jnumed.117.203075DOI Listing
July 2018

Assessment of the prognostic role of a 94-single nucleotide polymorphisms risk score in early breast cancer in the SIGNAL/PHARE prospective cohort: no correlation with clinico-pathological characteristics and outcomes.

Breast Cancer Res 2017 Aug 22;19(1):98. Epub 2017 Aug 22.

Centre d'Etudes du Polymorphisme Humain, 27 rue Juliette Dodu, 75010, Paris, France.

Background: Genome-wide association studies (GWAS) have to date identified 94 genetic variants (single nucleotide polymorphisms (SNPs)) associated with risk of developing breast cancer. A score based on the combined effect of the 94 risk alleles can be calculated to measure the global risk of breast cancer. We aimed to test the hypothesis that the 94-SNP-based risk score is associated with clinico-pathological characteristics, breast cancer subtypes and outcomes in early breast cancer.

Methods: A 94-SNP risk score was calculated in 8703 patients in the PHARE and SIGNAL prospective case cohorts. This score is the total number of inherited risk alleles based on 94 selected SNPs. Clinical data and outcomes were prospectively registered. Genotyping was obtained from a GWAS.

Results: The median 94-SNP risk score in 8703 patients with early breast cancer was 77.5 (range: 58.1-97.6). The risk score was not associated with usual prognostic and predictive factors (age; tumor, node, metastasis (TNM) status; Scarff-Bloom-Richardson grade; inflammatory features; estrogen receptor status; progesterone receptor status; human epidermal growth factor receptor 2 (HER2) status) and did not correlate with breast cancer subtypes. The 94-SNP risk score did not predict outcomes represented by overall survival or disease-free survival.

Conclusions: In a prospective case cohort of 8703 patients, a risk score based on 94 SNPs was not associated with breast cancer characteristics, cancer subtypes, or patients' outcomes. If we hypothesize that prognosis and subtypes of breast cancer are determined by constitutional genetic factors, our results suggest that a score based on breast cancer risk-associated SNPs is not associated with prognosis.

Trial Registration: PHARE cohort: NCT00381901 , Sept. 26, 2006 - SIGNAL cohort: INCa RECF1098, Jan. 28, 2009.
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http://dx.doi.org/10.1186/s13058-017-0888-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568360PMC
August 2017

Clinical value of CA 15-3 for detection of distant metastases in newly diagnosed breast cancer.

Ann Biol Clin (Paris) 2017 Aug;75(4):421-429

Département de biologie et pathologie des tumeurs, Centre Georges François Leclerc, Dijon, France.

The aim of the study is to investigate the clinical value of CA 15-3 for detection of distant metastases (DM) in newly diagnosed breast cancer. This retrospective study focuses on a population of 1,007 patients with locally advanced breast cancer (n=561) or metastatic breast cancer (n=446) diagnosed at the CGFL (Centre Georges Francois Leclerc) from March 1998 to October 2013. These patients underwent a measurement of CA 15-3 and an assessment of extension before any treatment. The cut-off value of CA 15-3 was determined and verified on two independents subpopulations determined in drawing lots. The ROC curve shows an AUC of 0.85 (p<0.0001). At the threshold of 50 kU/L, CA 15-3 before treatment has a predictive value on the existence of DM independently of the other prognostics factors. This predictive value has been found in every molecular subtype (AUC≥ 0.70; p≤ 0,085). The rate of false negative is of 38% and depends on the number and the type of the metastatic localization. Among the 28 patients without DM and a CA 15-3> 50 kU/L, 13 have developed DM and 11 died of cancer. In conclusion, these facts confirm the independently predictive value of CA 15-3 before treatment on the existence of DM and the complementarity of the marker with the assessment of extension by imagery.
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http://dx.doi.org/10.1684/abc.2017.1257DOI Listing
August 2017

Constitutional variants are not associated with HER2-positive breast cancer: results from the SIGNAL/PHARE clinical cohort.

NPJ Breast Cancer 2017 23;3. Epub 2017 Feb 23.

Centre National du Génotypage, 2 rue Gaston Crémieux, CP 5721, Evry, CEDEX 91057 France.

Human epidermal growth factor receptor 2-positive breast cancer is a subtype of interest regarding its outcome and the impressive impact of human epidermal growth factor receptor 2 targeted therapy. Constitutional variants may be involved in the aetiology of human epidermal growth factor receptor 2-positive breast cancer, and we propose a case-case study to test the hypothesis that single nucleotide polymorphisms may be associated with human epidermal growth factor receptor 2 status. A Genome-Wide Association Study was used in a cohort of 9836 patients from the SIGNAL/PHARE study (NCT00381901-RECF1098). The main goal was to identify variants specifically related to human epidermal growth factor receptor 2-positive breast cancer. A two-staged genotyping strategy was carried out to cover as large a proportion of the genome as possible. All subjects were genotyped using the Illumina HumanCore Exome chip set. Principal Components Analysis and -means were then used to characterize the ancestry of the participants. A random sample of subjects from the main "European" cluster was genotyped with the Omni5 chip set. These data were then used to impute missing genotypes from the remaining subjects genotyped only using the HumanCore Exome array. From the 9836 patients, a total of 8703 cases including 3230 patients with human epidermal growth factor receptor 2-positive breast cancer were analyzed. Despite having 80% power to detect an odds ratio of 1.23 in this population, no variant achieved genome-wide significance for association with the occurrence of human epidermal growth factor receptor 2-positive breast cancer vs. any other subtype of breast tumour. Our study was unable to identify constitutional polymorphisms that are strongly associated with human epidermal growth factor receptor 2-positive status among breast cancer patients.
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http://dx.doi.org/10.1038/s41523-017-0005-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445615PMC
February 2017

Superimposable outcomes for sequential and concomitant administration of adjuvant trastuzumab in HER2-positive breast cancer: Results from the SIGNAL/PHARE prospective cohort.

Eur J Cancer 2017 08 16;81:151-160. Epub 2017 Jun 16.

Oncologie Sénologie, ICM Institut Régional du Cancer, 34298 Montpellier Cedex, France.

Aim: Adjuvant clinical trials in early human epidermal growth factor receptor 2 (HER2)-positive breast cancer have assessed either sequential or concomitant incorporation of trastuzumab with chemotherapy; only the North Central Cancer Treatment Group (NCCTG)-N9831 trial prospectively compared both modalities. In routine trastuzumab has been incorporated into a concurrent regimen with taxane chemotherapy instead of sequential modality on the basis of a positive risk-benefit ratio. This present study assessed sequential versus concomitant administration of adjuvant trastuzumab.

Methods: A population combining patients from Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) a randomised phase III clinical trial (NCT00381901) and SIGNAL (RECF1098) a prospective study specifically designed for Genome-wide Association Studies (GWAS) analyses was studied. In this cohort with 58 months of median follow-up, the comparison in the HER2-positive group of adjuvant trastuzumab and chemotherapy modalities was based on a propensity score methodology. Treatment modalities were based on physician's choice and comparisons adjustment were made by a propensity score methodology. Overall Survival (OS) and Disease-Free Survival (DFS) were estimated using the Kaplan-Meier method, and comparisons between groups were based on the log rank test.

Results: The SIGNAL/PHARE cohort included 11,728 breast cancer cases treated in adjuvant setting; some 5502 of them with HER2-positive tumour: 34.5% (1897/5502) were treated by sequential and 65.5% (3605/5502) by concomitant modality of administration for taxane-chemotherapy and trastuzumab. The adjusted comparison found similar OS (HR = 1.01; 95% CI: 0.86-1.19) and similar DFS (HR = 1.08; 95% CI: 0.96-1.21).

Conclusion: These results suggest that the sequential administration of trastuzumab given after the completion of adjuvant chemotherapy might be as valid as the concomitant administration of trastuzumab and taxane chemotherapy in the adjuvant setting.
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http://dx.doi.org/10.1016/j.ejca.2017.05.020DOI Listing
August 2017

Exosomes in cancer theranostic: Diamonds in the rough.

Cell Adh Migr 2017 03 6;11(2):151-163. Epub 2017 Feb 6.

a INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France.

During the last 10 years, exosomes, which are small vesicles of 50-200 nm diameter of endosomal origin, have aroused a great interest in the scientific and clinical community for their roles in intercellular communication in almost all physiological and pathological processes. Most cells can potentially release these nanovesicles that share with the parent cell a similar lipid bilayer with transmembrane proteins and a panel of enclosed soluble proteins such as heat shock proteins and genetic material, thus acting as potential nanoshuttles of biomarkers. Exosomes surface proteins allow their targeting and capture by recipient cells, while the exosomes' content can modify the physiological state of recipient cells. Tumor derived exosomes by interacting with other cells of the tumor microenvironment modulate tumor progression, angiogenic switch, metastasis, and immune escape. Targeting tumor-derived exosomes might be an interesting approach in cancer therapy. Furthermore, because a key issue to improve cancer patients' outcome relies on earlier cancer diagnosis (metastases, as opposed to the primary tumor, are responsible for most cancer deaths) exosomes have been put forward as promising biomarker candidates for cancer diagnosis and prognosis. This review summarizes the roles of exosomes in cancer and clinical interest, focusing on the importance of exosomal heat shock proteins (HSP). The challenges of clinical translation of HSP-exosomes as therapeutic targets and biomarkers for early cancer detection are also discussed.
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http://dx.doi.org/10.1080/19336918.2016.1250999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351734PMC
March 2017

[The anti-tumor immune response in breast cancer: Update and therapeutic perspectives].

Ann Pathol 2017 Feb 31;37(1):133-141. Epub 2017 Jan 31.

Département d'oncologie médicale, centre Georges-François-Leclerc, 21000 Dijon, France; Plateforme de transfert en biologie cancérologique, centre Georges-François-Leclerc, 21000 Dijon, France; UMR Inserm U866, faculté de médecine de Dijon, 21000 Dijon, France; UFR des sciences de santé, 21000 Dijon, France; Université de Bourgogne, 21000 Dijon, France.

The role of the immune response in breast cancer is now well recognized and increasingly taken in account. The goal of this article is, in the first part, to underline its prognostic impact and to precise the immunosurvelliance, immunoselection and the immunosubversion concepts involved in the control and evasion of breast carcinoma. In the second part, therapeutic strategies for the restauration of anti-tumor immunity are developed. Vaccination strategies and checkpoints inhibitors blockade strategies are discussed as well as the immunogenic death linked to the conventional treatments of breast cancer.
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http://dx.doi.org/10.1016/j.annpat.2016.12.012DOI Listing
February 2017

18F-FDG PET-Derived Tumor Blood Flow Changes After 1 Cycle of Neoadjuvant Chemotherapy Predicts Outcome in Triple-Negative Breast Cancer.

J Nucl Med 2016 Nov 21;57(11):1707-1712. Epub 2016 Apr 21.

Department of Nuclear Medicine, Centre GF Leclerc, Dijon, France.

Previous studies have suggested that early changes in blood flow (BF) in response to neoadjuvant chemotherapy and evaluated with O-water are a surrogate biomarker of outcome in women with breast cancer. This study investigates, in the triple-negative breast cancer subtype, the prognostic relevance of tumor BF changes (ΔBF) in response to chemotherapy, assessed using a short dynamic F-FDG PET acquisition.

Methods: Forty-six consecutive women with triple-negative breast cancer and an indication for neoadjuvant chemotherapy were prospectively included. Women benefited from a baseline F-FDG PET examination with a 2-min chest-centered dynamic acquisition, started at the time of F-FDG injection. Breast tumor perfusion was calculated from this short dynamic image using a first-pass model. This dynamic PET acquisition was repeated after the first cycle of chemotherapy to measure early ΔBF. Delayed static PET acquisitions were also performed (90 min after F-FDG injection) to measure changes in tumor glucose metabolism (ΔSUV). The association between tumor BF, clinicopathologic characteristics, and patients' overall survival (OS) was evaluated.

Results: Median baseline tumor BF was 21 mL/min/100 g (range, 6-46 mL/min/100 g) and did not significantly differ according to tumor size, Scarf-Bloom-Richardson grade, or Ki-67 expression. Median tumor ∆BF was -30%, with highly scattered values (range, -93% to +118%). A weak correlation was observed between ΔBF and ∆SUV (r = +0.40, P = 0.01). The median follow-up was 30 mo (range, 6-73 mo). Eight women developed recurrent disease, 7 of whom died. Low OS was associated with menopausal history (P = 0.03), persistent or increased tumor vascularization on the interim PET (ΔBF cutoff = -30%; P = 0.03), non-breast-conserving surgery (P = 0.04), and the absence of a pathologic complete response (pCR) (P = 0.01). ΔBF and pCR provided incremental prognostic stratification: 3-y OS was 100% in pCR women, 87% in no-pCR women but achieving an early tumor BF response, and only 48% in no-pCR/no-BF-response women (ΔBF cutoff = -30%, P < 0.001).

Conclusion: This study suggests the clinical usefulness of an early user- and patient-friendly 2-min dynamic acquisition to monitor breast tumor ΔBF to neoadjuvant chemotherapy using F-FDG PET/CT. Monitoring tumor perfusion and angiogenesis response to treatment seems to be a promising target for PET tracers.
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http://dx.doi.org/10.2967/jnumed.116.172759DOI Listing
November 2016

The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families?

Oncotarget 2017 Jan;8(2):1957-1971

Centre of Genetic, Children Hospital, CHU, Dijon, France.

Until recently, the molecular diagnosis of hereditary breast and ovarian cancer (HBOC) was mostly based on BRCA1/2 testing. Next generation sequencing and the recent discovery of new genes involved in HBOC now permit the transfer of genomic capture targeting multiple candidate genes from research to clinical use. However, the implications for the management of patients and their families have not been extensively studied, in particular since some of these genes are not well-established cancer predisposing genes. We studied 583 consecutive patients from Burgundy (France) fulfilling the criteria for BRCA testing using a next generation sequencing 25-genes panel including 20 well-established high-risk cancer genes as well as more recently identified predisposing HBOC cancer. A pathogenic BRCA1/2 mutation was found in 51 patients (9%). Besides, we found 37 pathogenic or likely pathogenic mutations in 10 different high to low-risk genes in 34 patients (6%). The most frequently mutated genes were CHEK2 (n = 12; 2%), ATM (n = 9; 1.5%), and PALB2 (n = 4; 0.6%). Three patients had a mutation in two different predisposing genes. The analysis of clinical actionability conducted in mutation-positive individuals revealed that additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone had been recommended in 69% of cases. In conclusion, multigene panel testing is a powerful tool to identifying high to low-risk HBOC susceptibility genes. The penetrance and spectrum of cancers with these other genes are sometimes undefined, and further collaborative work is crucial to address this question.
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http://dx.doi.org/10.18632/oncotarget.12699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356770PMC
January 2017

GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients.

Oncotarget 2016 Nov;7(47):77358-77364

Centre National du Génotypage, Institut de Génomique, CEA, CP 5721, 91057 Evry Cedex, France.

Genetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46×10-12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16×10-11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors.
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http://dx.doi.org/10.18632/oncotarget.12669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363591PMC
November 2016

A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers.

Nat Commun 2016 07 13;7:12222. Epub 2016 Jul 13.

Centre Antoine Lacassagne, Département d'Oncologie Médicale, 33 Avenue de Valombrose, 06189 Nice, France.

HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal-basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage-fusion-bridge mechanism.
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http://dx.doi.org/10.1038/ncomms12222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947184PMC
July 2016

[CEA and early detection of relapse in breast cancer subtypes: Comparison with CA 15-3].

Bull Cancer 2016 May 8;103(5):434-43. Epub 2016 Mar 8.

Centre Georges-François-Leclerc, département d'oncologie médicale, 1, rue de Pr.-Marion, 21079 Dijon cedex, France.

This retrospective study evaluates the interest of CEA measurement for early detection of breast cancer recurrences. Among 804 patients with invasive breast cancer, we selected 97 patients without recurrence (WR) for 5 years or more, 32 with a local recurrence (LR) and 131 with at least one distant metastasis (DM). Elevated CEA and CA 15-3 levels (>3.1 μg/L and >26 kU/L respectively) were found in 6 % and 22 % of patients with RL respectively and in 49 % and 69 % of patients with DM. Both CEA and CA 15-3 retained a significant value in predicting DM by univariate and multivariate analysis. Higher sensitivity of CEA and CA 15-3 were found in tumors with positive hormonal receptor status. CEA and CA 15-3 levels at DM were raised respectively in 23 and 65 % of the triple negative group, 58 and 75 % of the luminal, 56 and 78 % of the luminal-HER2 and 50 and 30 % of HER2-enriched group (P=0.0094 and 0.0252 respectively). The combination of CEA and CA 15-3 increased CA 15-3 sensitivity in especially luminal and HER2-enriched groups. In conclusion, elevated CA 15-3 and CEA levels at initial diagnosis of recurrence were found to be associated with hormonal receptor status and breast cancer subtypes. The combination of CEA and CA 15-3 appeared useful especially luminal and HER2-enriched groups.
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http://dx.doi.org/10.1016/j.bulcan.2016.02.003DOI Listing
May 2016

Identification of early breast cancer patient cohorts who may benefit from lapatinib therapy.

Eur J Cancer 2016 Mar 30;56:85-92. Epub 2016 Jan 30.

Massachusetts General Hospital, Boston, MA, USA. Electronic address:

In resource-constrained environments many patients with human epidermal growth factor receptor 2 (HER2)+ early breast cancer are currently not offered adjuvant anti-HER2 therapy. For patients who might be able to receive the tyrosine kinase inhibitor (TKI) lapatinib (e.g. after patent expiration), it is important to identify subgroups of patients for whom anti-HER2 TKI therapy could be beneficial. To do this, we used data from 2489 patients with centrally confirmed HER2+ disease enrolled in the adjuvant Tykerb Evaluation After Chemotherapy (TEACH) trial, investigating the effect of lapatinib in patients with HER2+ early breast cancer not treated with trastuzumab. We performed subgroup analyses and number-needed-to-treat (NNT) calculations using patient and tumour associated predictors. Hormone receptor negative (HR-) patients on lapatinib had a significantly prolonged disease-free survival (DFS) compared to HR- patients on placebo (hazard ratio 0.64, P=0.003). For patients with HR- disease, starting treatment with lapatinib ≤1 year from diagnosis improved DFS by 12.1% [2.1-22.1] at 2 years and 15.7% [4.1-27.2] at 5 years. Depending on lymph node status and time since diagnosis the NNT for recurrence (at 5 years) was between 5.9 (node positive patients <1 year from diagnosis) and 15.9. These numbers are in range with numbers reported for up-front adjuvant trastuzumab for HR unselected patients (e.g. 15.6 for DFS at 4 years in HERA). In a subgroup analysis of the adjuvant TEACH trial, we show that anti-HER2 monotherapy with a TKI is beneficial as adjuvant therapy in a subgroup of patients. NNT in HER2+ HR- patients are in range with those reported from up-front adjuvant trastuzumab trials.
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http://dx.doi.org/10.1016/j.ejca.2015.12.024DOI Listing
March 2016

A Phase I, Dose-Escalation Trial of Pazopanib in Combination with Cisplatin in Patients with Advanced Solid Tumors: A UNICANCER Study.

Oncol Ther 2016 18;4(2):211-223. Epub 2016 Aug 18.

Institut Claudius Regaud, Inserm, UMR1037 CRCT, Université Toulouse III-Paul Sabatier, Toulouse, France.

Introduction: To determine the feasibility, maximum-tolerated dose (MTD), and dose-limiting toxicities (DLT) of pazopanib in combination with cisplatin.

Methods: Patients with advanced malignancies were included in a 3 + 3 dose-escalation phase I study. Pazopanib administration started 8 days before the first infusion of cisplatin; some patients were treated according to a reverse sequence (cisplatin first). Five dose levels (DLs) were planned. MTD was based on DLT observed during cycles 1 and 2.

Results: Thirty-five patients were enrolled. The MTD was reached at the first DL, (pazopanib 400 mg daily + cisplatin 75 mg/m every 21 days). Main DLTs were pulmonary embolism, neutropenia, thrombocytopenia, and elevation of liver enzymes. Overall, most common adverse events were anemia (83%), fatigue (80%), thrombocytopenia (80%), neutropenia (73%), hypertension (59%), neurotoxicity (56%), and anorexia (53%). Sixteen patients (46%) discontinued the study due to toxicity. One patient (sarcoma) had a complete response, and three patients (one with breast cancer and two with ovarian cancers) had a partial response. Pharmacokinetic (PK) analyses showed interactions with aprepitant, resulting in increased exposure to pazopanib, which might explain partly the poor tolerance of the combination.

Conclusion: Cisplatin and pazopanib could not be administered at their single agent full doses, partly due to a PK interaction between pazopanib and aprepitant.

Funding: This work was funded by GlaxoSmithKline and by the charity Ligue Nationale de Lutte Contre le Cancer.

Trial Registered: ClinicalTrials.gov identifier, NCT01165385.
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http://dx.doi.org/10.1007/s40487-016-0027-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315079PMC
August 2016

Restoring Anticancer Immune Response by Targeting Tumor-Derived Exosomes With a HSP70 Peptide Aptamer.

J Natl Cancer Inst 2016 Mar 22;108(3). Epub 2015 Nov 22.

Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).

Background: Exosomes, via heat shock protein 70 (HSP70) expressed in their membrane, are able to interact with the toll-like receptor 2 (TLR2) on myeloid-derived suppressive cells (MDSCs), thereby activating them.

Methods: We analyzed exosomes from mouse (C57Bl/6) and breast, lung, and ovarian cancer patient samples and cultured cancer cells with different approaches, including nanoparticle tracking analysis, biolayer interferometry, FACS, and electron microscopy. Data were analyzed with the Student's t and Mann-Whitney tests. All statistical tests were two-sided.

Results: We showed that the A8 peptide aptamer binds to the extracellular domain of membrane HSP70 and used the aptamer to capture HSP70 exosomes from cancer patient samples. The number of HSP70 exosomes was higher in cancer patients than in healthy donors (mean, ng/mL ± SD = 3.5 ± 1.7 vs 0.17 ± 0.11, respectively, P = .004). Accordingly, all cancer cell lines examined abundantly released HSP70 exosomes, whereas "normal" cells did not. HSP70 had higher affinity for A8 than for TLR2; thus, A8 blocked HSP70/TLR2 association and the ability of tumor-derived exosomes to activate MDSCs. Treatment of tumor-bearing C57Bl/6 mice with A8 induced a decrease in the number of MDSCs in the spleen and inhibited tumor progression (n = 6 mice per group). Chemotherapeutic agents such as cisplatin or 5FU increase the amount of HSP70 exosomes, favoring the activation of MDSCs and hampering the development of an antitumor immune response. In contrast, this MDSC activation was not observed if cisplatin or 5FU was combined with A8. As a result, the antitumor effect of the drugs was strongly potentiated.

Conclusions: A8 might be useful for quantifying tumor-derived exosomes and for cancer therapy through MDSC inhibition.
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http://dx.doi.org/10.1093/jnci/djv330DOI Listing
March 2016

Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer.

Autophagy 2015 ;11(10):1878-90

f Metabolomics and Cell Biology Platforms; Gustave Roussy Cancer Campus ; Villejuif , France.

In spite of adjuvant chemotherapy, a significant fraction of patients with localized breast cancer (BC) relapse after optimal treatment. We determined the occurrence of cytoplasmic MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3B)-positive puncta, as well as the presence of nuclear HMGB1 (high mobility group box 1) in cancer cells within surgical BC specimens by immunohistochemistry, first in a test cohort (152 patients) and then in a validation cohort of localized BC patients who all received adjuvant anthracycline-based chemotherapy (1646 patients). Cytoplasmic LC3B(+) puncta inversely correlated with the intensity of SQSTM1 staining, suggesting that a high percentage cells of LC3B(+) puncta reflects increased autophagic flux. After setting optimal thresholds in the test cohort, cytoplasmic LC3B(+) puncta and nuclear HMGB1 were scored as positive in 27.2% and 28.6% of the tumors, respectively, in the validation cohort, while 8.7% were considered as double positive. LC3B(+) puncta or HMGB1 expression alone did not constitute independent prognostic factors for metastasis-free survival (MFS) in multivariate analyses. However, the combined positivity for LC3B(+) puncta and nuclear HMGB1 constituted an independent prognostic factor significantly associated with prolonged MFS (hazard ratio: 0.49 95% confidence interval [0.26-0.89]; P = 0.02), and improved breast cancer specific survival (hazard ratio: 0.21 95% confidence interval [0.05-0.85]; P = 0.029). Subgroup analyses revealed that within patients with poor-prognosis BC, HMGB1(+) LC3B(+) double-positive tumors had a better prognosis than BC that lacked one or both of these markers. Altogether, these results suggest that the combined positivity for LC3B(+) puncta and nuclear HMGB1 is a positive predictor for longer BC survival.
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http://dx.doi.org/10.1080/15548627.2015.1082022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824597PMC
September 2016

[Clinical value of CA 15-3 for early detection of relapse in locally advanced breast cancer].

Bull Cancer 2015 Oct 28;102(10):834-44. Epub 2015 Sep 28.

Centre Georges-François-Leclerc, département de biologie et pathologie des tumeurs, 1, rue de Pr.-Marion, 21079 Dijon cedex, France. Electronic address:

This retrospective study evaluates the interest of CA 15-3 measurement for early detection of breast cancer recurrences. Among 804 patients with invasive breast cancer we selected 117 patients without recurrence (WR) for 5 years or more, 33 with a local recurrence (LR) and 149 with at least one distant metastasis (DM). The sensitivity of CA 15-3 depends on the type of recurrence ([LR] or [DM]), the localization of unique DM, the presence and the number of metastatic sites, on hormonal receptor status and tumor subtypes. The number of metastatic sites and hormonal receptor status are independent predictive criteria of an elevation of CA 15-3. The analysis of ROC curve in order to separate patients with DM and patients WR shows an AUC of 0.87 (p<0.0001). The optimal discriminative threshold is 26 kU/L. In conclusion, these data confirm that CA 15-3 increase depends on the kind of evolution and on initial tumor's hormonal status.
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http://dx.doi.org/10.1016/j.bulcan.2015.07.011DOI Listing
October 2015

Challenges in the implementation of trastuzumab biosimilars: an expert panel's recommendations.

Anticancer Drugs 2015 Nov;26(10):1009-16

aDepartment of Medical Oncology, University Hospital Jean Minjoz, Besançon bFaculty of Pharmacy of Lyon cLéon Bérard Cancer Center, Lyon dGeorge François Leclerc Cancer Center, Dijon eDeparment of Radiotherapy, University Hospital Tenon, Paris fFSNB Health & Care, Paris gDepartment of Pharmacy, University Hospital Jean Minjoz, Besançon, France.

Trastuzumab has transformed the treatment of HER2-positive breast cancer. Because of impending European patent expiry in 2017, numerous trastuzumab biosimilars are currently undergoing comparability exercises for marketing authorization. Although biosimilar products have been approved in Europe since 2006, many obstacles are expected for trastuzumab, resulting from its nature as a monoclonal antibody, its impact on overall survival, and its extensive biochemical complexities. Unsolved questions need to be addressed for the evaluation of biosimilars' activity in terms of appropriate clinical endpoint definitions for such anticancer drugs, specific assessment pathways and comparative testing of biosimilars, untested ensuing de facto combination of trastuzumab biosimilars with cytotoxics, and immunogenicity monitoring among immunocompromised patients. In such a context of uncertainties, the recent approval by the French parliament of biosimilar substitution, which would allow dispensing trastuzumab biosimilars in place of the originator, should interrogate the oncological community. A think tank of experts was created to delineate specificities and challenges stemming from trastuzumab biosimilars.
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http://dx.doi.org/10.1097/CAD.0000000000000287DOI Listing
November 2015

Coexpression of androgen receptor and FOXA1 in nonmetastatic triple-negative breast cancer: ancillary study from PACS08 trial.

Future Oncol 2015 ;11(16):2283-97

Department of Pathology, Institut Claudius Régaud, 20/24 rue du Pont Saint Pierre, 31300 Toulouse, France.

Aim: Microarray studies identified a subgroup of molecular apocrine tumors (estrogen receptor [ER] negative/androgen receptor [AR] positive) that express luminal genes including FOXA1. FOXA1 may direct AR to sites normally occupied by ER in luminal tumors, inducing an estrogen-like gene program that stimulated proliferation.

Materials & Methods: Expression of AR and FOXA1 was evaluated by immunohistochemistry in 592 patients with nonmetastatic triple-negative breast cancer (TNBC).

Results: Coexpression of AR and FOXA1 was found in 15.2% of patients. These tumors were more frequently lobular, found in older patients and exhibited a lower nuclear grade and a greater degree of node involvement. They less often exhibited lymphocytic infiltrate, pushing margins, syncytial architecture, central fibrosis or necrosis.

Conclusion: TNBC with coexpression of AR and FOXA1 seems to behave like luminal tumors with a morphological profile distinct from other TNBC. These biomarkers could be useful to identify a subgroup of TNBC and could have future therapeutic implications.
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http://dx.doi.org/10.2217/fon.15.102DOI Listing
May 2016

Cardiac toxicity events in the PHARE trial, an adjuvant trastuzumab randomised phase III study.

Eur J Cancer 2015 Sep 7;51(13):1660-6. Epub 2015 Jul 7.

Centre Georges François Leclerc, Dijon, France.

Background: This article reports, the cardiac toxicity according to 6- versus 12-month durations of adjuvant trastuzumab in PHARE randomised trial (NCT00381901).

Patients And Methods: Cardiac follow-up and Left Ventricular Ejection Fraction (LVEF) assessment by echocardiography or multigated acquisition scan were performed every 3 months while patients received trastuzumab and after completion of treatment over the first 2 years and every 6 months afterwards. The primary cardiac end-point was Cardiac Heart Failure (CHF) defined as New York Heart Association (NYHA) class III or IV. The secondary cardiac end-points were: cardiac events, cardiac dysfunctions defined by NYHA class I and II; LVEF decreases, cardiac recoveries. The cardiac subcommittee reviewed cardiac events and assessed if patients had favourable outcomes or not on the basis of trends from LVEF measurements.

Results: Among 3380 patients the cardiac dysfunction assessment included 14,055 and 13,218 LVEF measurements in the 12- and 6-month arms. The overall incidences of CHF were 0.65% (11/1690) and 0.53% (9/1690) in the 12 and 6 month arms, respectively (p>0.05). Cardiac dysfunction occurred in 5.9% (100/1690) and 3.4% (58/1690) of patients in the 12 and 6 month arms, respectively (p=0.001). Recoveries were observed for the majority patients and 0.79% (27/3380) of patients experienced an unfavourable cardiac outcome.

Conclusion: PHARE confirm that the incidence of cardiac end-points remains low and mostly reversible after trastuzumab. Identification at baseline of cardiac risk categories of patients should be of interest to provide an optimal adaptation of adjuvant modalities and a shorter duration might be an option.
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http://dx.doi.org/10.1016/j.ejca.2015.05.028DOI Listing
September 2015

Identification of Biomarkers Including 18FDG-PET/CT for Early Prediction of Response to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer.

Clin Cancer Res 2015 Dec 30;21(24):5460-8. Epub 2015 Jun 30.

Department of Nuclear Medicine, Centre GF Leclerc, Dijon, France. Université de Bourgogne, UMR CNRS 6306, Dijon, France. Imaging Department, CHU Le Bocage, Dijon, France.

Purpose: To investigate the value of the metabolic tumor response assessed with (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET), compared with clinicobiologic markers to predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in women with triple-negative breast cancer (TNBC).

Experimental Design: Fifty consecutive women with TNBC and an indication for NAC were prospectively included. Different pretreatment clinical, biologic, and pathologic biomarkers, including SBR grade, the Ki-67 proliferation index, androgen receptor expression, EGF receptor (EGFR), and cytokeratin 5/6 staining, were assessed. Tumor glucose metabolism at baseline and its change after the first cycle of NAC (ΔSUVmax) were assessed using FDG-PET.

Results: The pCR rate was 42%. High Ki-67 proliferation index (P = 0.016), negative EGFR status (P = 0.042), and high ΔSUVmax (P = 0.002) were significantly associated with pCR. In multivariate logistic regression, both negative EGFR status (OR, 6.4; P = 0.043) and high ΔSUVmax (OR, 7.1; P = 0.014) were independent predictors of pCR. Using a threshold at -50%, tumor ΔSUVmax predicted pCR with a negative, a positive predictive value, and an accuracy of 79%, 70%, and 75%, respectively. Combining a low ΔSUVmax and positive EGFR status could predict non-pCR with an accuracy of 92%.

Conclusions: It is important to define the chemosensitivity of TNBC to NAC early. Combining EGFR status and the metabolic response assessed with FDG-PET can help the physician to early predict the probability of achieving pCR or not. Given these results, the interest of response-guided tailoring of the chemotherapy might be tested in multicenter trials. Clin Cancer Res; 21(24); 5460-8. ©2015 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-0384DOI Listing
December 2015

Long-term hazard of recurrence in HER2+ breast cancer patients untreated with anti-HER2 therapy.

Breast Cancer Res 2015 Apr 16;17:56. Epub 2015 Apr 16.

Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA, 02114, USA.

Introduction: Worldwide, many patients with HER2+ (human epidermal growth factor receptor 2-positive) early breast cancer (BC) do not receive adjuvant trastuzumab. Hazards of recurrence of these patients with respect to hormone receptor status of the primary tumor have not been described.

Methods: Using data from 1,260 patients randomized to placebo in the adjuvant TEACH trial, we report 10-year annual hazards of recurrence in HER2+ patients not treated with anti-HER2 therapy.

Results: Disease-free survival (DFS) was 75% after 5 and 61% after 10 years, respectively. Patients with HER2+ hormone receptor-positive (HR+ (hormone receptor-positive); ER+ (estrogen receptor-positive) or PR+ (progesterone receptor-positive)) disease had a significantly better DFS than patients with HER2+ HR- (ER-/PR-) disease (hazard ratio 0.72, P=0.02). This difference was explainable by a significantly higher hazard of recurrence in years 1 to 5 in HER2+ HR- compared to HER2+ HR+ patients, with a mean risk of recurrence of 9%/year for HR- versus 5%/year in HR+ patients (hazard ratio 0.59, P=0.002 for years 1 to 5). The high early risk of recurrence of HER2+ HR- patients declined sharply over time, so that it was similar to that seen in HER2+ HR+ patients in years 6 to 10 (hazard ratio 0.97, P=0.92 for years 6 to 10).

Conclusions: Our results show that outcomes in HER2+ patients with early BC not receiving anti-HER2 therapy strongly depend on HR expression. The very high early risk of relapse seen in HER2+ HR- patients is particularly relevant in health care settings with limited access to adjuvant anti-HER2 treatment. The event rates shown for subpopulations of HER2+ BC patients suggest that in resource-constrained environments patients with HER2+ HR- early BC should be prioritized for consideration of adjuvant anti-HER2 therapy.
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http://dx.doi.org/10.1186/s13058-015-0568-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423419PMC
April 2015
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