Publications by authors named "Patrice Viens"

175 Publications

Comparative transcriptional analyses of preclinical models and patient samples reveal MYC and RELA driven expression patterns that define the molecular landscape of IBC.

NPJ Breast Cancer 2022 Jan 18;8(1):12. Epub 2022 Jan 18.

Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp, Belgium.

Inflammatory breast cancer (IBC) is an aggressive disease for which the spectrum of preclinical models was rather limited in the past. More recently, novel cell lines and xenografts have been developed. This study evaluates the transcriptome of an extended series of IBC preclinical models and performed a comparative analysis with patient samples to determine the extent to which the current models recapitulate the molecular characteristics of IBC observed clinically. We demonstrate that the IBC preclinical models are exclusively estrogen receptor (ER)-negative and of the basal-like subtype, which reflects to some extent the predominance of these subtypes in patient samples. The IBC-specific 79-signature we previously reported was retrained and discriminated between IBC and non-IBC preclinical models, but with a relatively high rate of false positive predictions. Further analyses of gene expression profiles revealed important roles for cell proliferation, MYC transcriptional activity, and TNFɑ/NFκB in the biology of IBC. Patterns of MYC expression and transcriptional activity were further explored in patient samples, which revealed interactions with ESR1 expression that are contrasting in IBC and nIBC and notable given the comparatively poor outcomes of ER+ IBC. Our analyses also suggest important roles for NMYC, MXD3, MAX, and MLX in shaping MYC signaling in IBC. Overall, we demonstrate that the IBC preclinical models can be used to unravel cancer cell intrinsic molecular features, and thus constitute valuable research tools. Nevertheless, the current lack of ER-positive IBC models remains a major hurdle, particularly since interactions with the ER pathway appear to be relevant for IBC.
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http://dx.doi.org/10.1038/s41523-021-00379-6DOI Listing
January 2022

The Management of a Comprehensive Cancer Center during the First Six Months of the COVID-19 Pandemic in the South of France: Lessons from the Paoli-Calmettes Institute's Experience.

Clin Hematol Int 2021 Dec 27;3(4):119-129. Epub 2021 Sep 27.

Aix-Marseille University (AMU), Marseille, France.

During the COVID-19 pandemic, it was rapidly established that cancer patients have an increased risk of developing severe forms of the 2019 coronavirus disease (COVID-19) due to a backlog of cancer diagnostics and immunosuppressive treatments. Cancer centers had to quickly adapt to continue cancer therapies despite the high infection risks and major disruptions in the French healthcare system. We described and analyzed the impact of the pandemic in our institution: management adjustments, COVID-19 infection rates in patients and staff, and impacts on clinical activities and finances during the first wave of the pandemic from March to September 2020. We also compared the results to the clinical activity data from preceding periods. A crisis unit was rapidly created that met 27 times over 66 days, generating numerous changes in hospital protocol. While our area was devastated by the pandemic, the infection rate of our staff and patients remained low (less than 1.5% of all employees). However, the lockdown period was accompanied with a reduction of most clinical activities, leading to decreases of 43%, 36%, 36%, 1%, and 10% in surgery, endoscopy, radiotherapy, and in- and out-patient chemotherapy sessions, respectively, with substantial financial loss. Our report highlights the need for the rapid creation, implementation, and adaptation of new protocols during a pandemic's evolution to prevent disease transmission. Lessons from this situation should provide motivation to better prepare for/limit the dismantling of cancer therapies that can dramatically impact patient care and have deleterious consequences on an institution's financial situation.
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http://dx.doi.org/10.2991/chi.k.210919.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8690701PMC
December 2021

A study of elite sport-inspired coaching for patients after allogeneic hematopoietic stem cell transplantation.

Bone Marrow Transplant 2021 Nov 14;56(11):2755-2762. Epub 2021 Jul 14.

Management Sport Cancer Laboratory (UR 20122035V), Faculty of Sport Sciences, Aix-Marseille University, Marseille, France.

A need for social support is often expressed after hospitalization post HSCT. Emotional support and positive psychological constructs play an important role in post-HSCT recovery. Interventions generating positive affect can influence the health and well-being of transplant patients. It has been established that coaching in elite sport area leads to performance by playing a decisive role in maintaining the athlete's feelings of hope and autonomy in order to enable him or her to achieve their goals. In this single-center, prospective, one-arm study, we evaluated, in 32 post-HSCT patients, the acceptability of a coaching program inspired by elite sport coaching. Benefits were evaluated by questionnaires and semi-structured interviews. The coaching program was accepted by 97% of the patients. Analysis of the scores on the "Means" sub-dimension of Hope showed a significant increase over time (p = 0.0249 < 0.05) for every patient. Qualitative analysis of patient's satisfaction pointed out that this support facilitated the transition to a life without illness in particular in the non-hospital context of coaching sessions. Our results show that a "sport-inspired coaching" may offer an innovative approach supporting psychological and social recovery after HSCT and helping to start and/or maintain the processes leading to psychological well-being.
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http://dx.doi.org/10.1038/s41409-021-01401-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277989PMC
November 2021

Immune landscape of inflammatory breast cancer suggests vulnerability to immune checkpoint inhibitors.

Oncoimmunology 2021 05 23;10(1):1929724. Epub 2021 May 23.

Predictive Oncology Laboratory, "Equipe Labellisée Ligue Contre Le Cancer", Centre De Recherche En Cancérologie De Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille Université, Marseille, France.

. Anti-PD1/PDL1 immune checkpoint inhibitors (ICIs) showed promising results in breast cancer, and exploration of additional actionable immune checkpoints is ongoing. Inflammatory breast cancer (IBC) is an aggressive form of disease, the immune tumor microenvironment (TME) of which is poorly known. We aimed at providing the first comprehensive immune portrait of IBCs. . From the gene expression profiles of 137 IBC and 252 non-IBC clinical samples, we measured the fractions of 22 immune cell types, expression of signatures associated with tertiary lymphoid structures (TLS) and with the response to ICIs (T cell-inflamed signature: TIS) and of 18 genes coding for major actionable immune checkpoints. The IBC/non-IBC comparison was adjusted upon the clinicopathological variables. . The immune profiles of IBCs were heterogeneous. CIBERSORT analysis showed profiles rich in macrophages, CD8+ and CD4 + T-cells, with remarkable similarity with melanoma TME. The comparison with non-IBCs showed significant enrichment in M1 macrophages, γδ T-cells, and memory B-cells. IBCs showed higher expression of TLS and TIS signatures. The TIS signature displayed values in IBCs close to those observed in other cancers sensitive to ICIs. Two-thirds of actionable immune genes (, and ) were overexpressed in IBCs as compared to normal breast and two-thirds were overexpressed in IBCs non-IBCs, with very frequent co-overexpression. For most of them, the overexpression was associated with better pathological response to chemotherapy. . Our results suggest the potential higher vulnerability of IBC to ICIs. Clinical trials.
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http://dx.doi.org/10.1080/2162402X.2021.1929724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158040PMC
May 2021

Prospective high-throughput genome profiling of advanced cancers: results of the PERMED-01 clinical trial.

Genome Med 2021 05 18;13(1):87. Epub 2021 May 18.

Department of Medical Oncology, Gustave Roussy Cancer Campus, UMR981 Inserm, Villejuif, France.

Background: The benefit of precision medicine based on relatively limited gene sets and often-archived samples remains unproven. PERMED-01 (NCT02342158) was a prospective monocentric clinical trial assessing, in adults with advanced solid cancer, the feasibility and impact of extensive molecular profiling applied to newly biopsied tumor sample and based on targeted NGS (t-NGS) of the largest gene panel to date and whole-genome array-comparative genomic hybridization (aCGH) with assessment of single-gene alterations and clinically relevant genomic scores.

Methods: Eligible patients with refractory cancer had one tumor lesion accessible to biopsy. Extracted tumor DNA was profiled by t-NGS and aCGH. We assessed alterations of 802 "candidate cancer" genes and global genomic scores, such as homologous recombination deficiency (HRD) score and tumor mutational burden. The primary endpoint was the number of patients with actionable genetic alterations (AGAs). Secondary endpoints herein reported included a description of patients with AGA who received a "matched therapy" and their clinical outcome, and a comparison of AGA identification with t-NGS and aCGH versus whole-exome sequencing (WES).

Results: Between November 2014 and September 2019, we enrolled 550 patients heavily pretreated. An exploitable complete molecular profile was obtained in 441/550 patients (80%). At least one AGA, defined in real time by our molecular tumor board, was found in 393/550 patients (71%, two-sided 90%CI 68-75%). Only 94/550 patients (17%, 95%CI 14-21) received an "AGA-matched therapy" on progression. The most frequent AGAs leading to "matched therapy" included PIK3CA mutations, KRAS mutations/amplifications, PTEN deletions/mutations, ERBB2 amplifications/mutations, and BRCA1/2 mutations. Such "matched therapy" improved by at least 1.3-fold the progression-free survival on matched therapy (PFS2) compared to PFS on prior therapy (PFS1) in 36% of cases, representing 6% of the enrolled patients. Within patients with AGA treated on progression, the use of "matched therapy" was the sole variable associated with an improved PFS2/PFS1 ratio. Objective responses were observed in 19% of patients treated with "matched therapy," and 6-month overall survival (OS) was 62% (95%CI 52-73). In a subset of 112 metastatic breast cancers, WES did not provide benefit in term of AGA identification when compared with t-NGS/aCGH.

Conclusions: Extensive molecular profiling of a newly biopsied tumor sample identified AGA in most of cases, leading to delivery of a "matched therapy" in 17% of screened patients, of which 36% derived clinical benefit. WES did not seem to improve these results.

Trial Registration: ID-RCB identifier: 2014-A00966-41; ClinicalTrials.gov identifier: NCT02342158 .
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http://dx.doi.org/10.1186/s13073-021-00897-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132379PMC
May 2021

Corrigendum to "The use of 'added benefit' to determine the price of new anti-cancer drugs in France, 2004-2017" [Eur J Canc 145 (2021) 11-18].

Eur J Cancer 2021 Jul 11;152:259-261. Epub 2021 May 11.

Institut Paoli Calmettes, SESSTIM UMR1252, Aix Marseille Univ, INSERM, IRD, Marseille, France. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2021.04.018DOI Listing
July 2021

The use of 'added benefit' to determine the price of new anti-cancer drugs in France, 2004-2017.

Eur J Cancer 2021 03 4;145:11-18. Epub 2021 Jan 4.

Institut Paoli Calmettes, SESSTIM UMR1252, Aix Marseille Univ, INSERM, IRD, Marseille, France. Electronic address:

Background: Increasing drug prices strains budgets. Assessing the relation between added benefit and prices can help clinical decision-making and resource allocation.

Methods: We assessed, over a period of 13 years, the relation between added therapeutic benefit and prices for drugs to treat solid tumours in France using the French High Authority of Health Scale (ASMR) and the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (MCBS).

Results: In total, 36 medications were approved for 68 indications. There was a weak correlation between ASMR and MCBS scales (Spearman's |ρ| = 0.28). Drugs had low added benefit on both ASMR (71%) and MCBS (49%). Mean monthly price for new drugs was €4616 (S.D., €3096), ranging from €1795 to €19,675 and increased by 47% comparing 2004-2012 with 2013-2017. The mean monthly price difference of new drugs over their comparator was €3700 (S.D., €3934) ranging between a €13,853 decrease and a €19,675 increase. There was a weak but statistically significant correlation between ASMR and price (|ρ| = 0.35, p = 0.004) and between MCBS and price (|ρ| = 0.33, p = 0.005). Correlations between added benefit and prices were similar or higher for first indications (ASMR, |ρ| = 0.37, p = 0.030; MCBS, |ρ| = 0.48, p = 0.004). In first indications, mean monthly prices increased €3954 for drugs without ASMR added benefit. The mean annual price and price increase for first indications offering no ASMR benefit was €57,312 and €47,448, respectively.

Conclusion: Prices and benefit are weakly correlated. However, prices increased substantially even for drugs with no added benefit.
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http://dx.doi.org/10.1016/j.ejca.2020.11.031DOI Listing
March 2021

REBOUND "Trained to live again": The practice of great Olympic coaches improves and enhances the quality of life of cancer patients in remission after hematopoietic stem cell allogeneic transplantation.

Bone Marrow Transplant 2020 06 2;55(6):997-999. Epub 2020 Mar 2.

Department of Medical Oncology, Management Sport Cancer Laboratory EA4670, Aix-Marseille University and Institut Paoli-Calmettes, Marseille, France.

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http://dx.doi.org/10.1038/s41409-020-0845-1DOI Listing
June 2020

NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non-inflammatory breast cancers.

Mol Oncol 2020 03 5;14(3):504-519. Epub 2020 Feb 5.

Translational Cancer Research Unit and Center for Oncological Research (CORE), Faculty of Medicine and Health Sciences, GZA Hospitals Sint-Augustinus and University of Antwerp Wilrijk, Antwerp, Belgium.

Inflammatory breast cancer (IBC) is the most pro-metastatic form of breast cancer. Better understanding of its pathophysiology and identification of actionable genetic alterations (AGAs) are crucial to improve systemic treatment. We aimed to define the DNA profiles of IBC vs noninflammatory breast cancer (non-IBC) clinical samples in terms of copy number alterations (CNAs), mutations, and AGAs. We applied targeted next-generation sequencing (tNGS) and array-comparative genomic hybridization (aCGH) to 57 IBC and 50 non-IBC samples and pooled these data with four public datasets profiled using NGS and aCGH, leading to a total of 101 IBC and 2351 non-IBC untreated primary tumors. The respective percentages of each molecular subtype [hormone receptor-positive (HR+)/HER2-, HER2+, and triple-negative] were 68%, 15%, and 17% in non-IBC vs 25%, 35%, and 40% in IBC. The comparisons were adjusted for both the molecular subtypes and the American Joint Committee on Cancer (AJCC) stage. The 10 most frequently altered genes in IBCs were TP53 (63%), HER2/ERBB2 (30%), MYC (27%), PIK3CA (21%), BRCA2 (14%), CCND1 (13%), GATA3 (13%), NOTCH1 (12%), FGFR1 (11%), and ARID1A (10%). The tumor mutational burden was higher in IBC than in non-IBC. We identified 96 genes with an alteration frequency (p < 5% and q < 20%) different between IBC and non-IBC, independently from the molecular subtypes and AJCC stage; 95 were more frequently altered in IBC, including TP53, genes involved in the DNA repair (BRCA2) and NOTCH pathways, and one (PIK3CA) was more frequently altered in non-IBC. Ninety-seven percent of IBCs displayed at least one AGA. This percentage was higher than in non-IBC (87%), notably for drugs targeting DNA repair, NOTCH signaling, and CDK4/6, whose pathways were more frequently altered (DNA repair) or activated (NOTCH and CDK4/6) in IBC than in non-IBC. The genomic landscape of IBC is different from that of non-IBC. Enriched AGAs in IBC may explain its aggressiveness and provide clinically relevant targets.
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http://dx.doi.org/10.1002/1878-0261.12621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053236PMC
March 2020

[E-health and "Cancer outside the hospital walls", Big Data and artificial intelligence].

Bull Cancer 2020 Jan 19;107(1):102-112. Epub 2019 Sep 19.

Institut Paoli-Calmettes, département d'oncologie médicale, 13009 Marseille, France; Aix-Marseille université, Centre de recherche en cancérologie de Marseille, Inserm U1068-CNRS U7258, 13009 Marseille, France.

To heal otherwise in oncology has become an imperative of Public Health and an economic imperative in France. Patients can therefore receive live most of their care outside of hospital with more ambulatory care. This ambulatory shift will benefit from the digital revolution and the development of digital health or e-health. Cancer research will also benefit with Big Data and artificial intelligence, which gather and analyze a huge amount of data. In this synthesis, we describe the different e-health tools and their potential impacts in oncology, at the levels of education and information of patients and caregivers, prevention, screening and diagnosis, treatment, follow-up, and research. A few randomized studies have already demonstrated clinical benefits. Large Big Data projects such as ConSoRe and Health Data Hub have been launched in France. We also discuss the issues and limitations of "cancer outside the hospital walls and e-health" from the point of view of patients, health care professionals, health facilities and government. This new organization will have to provide remote support "outside the walls" with care and follow-up of quality, continuous and prolonged in total safety and equity. Ongoing and future randomized clinical trials will need to definitively demonstrate areas of interest, advantages and drawbacks not only for patients, but also for caregivers, health facilities and governments.
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http://dx.doi.org/10.1016/j.bulcan.2019.07.006DOI Listing
January 2020

A Tyrosine Kinase Expression Signature Predicts the Post-Operative Clinical Outcome in Triple Negative Breast Cancers.

Cancers (Basel) 2019 Aug 13;11(8). Epub 2019 Aug 13.

Department of Medical Oncology, Institut Paoli-Calmettes, Aix-Marseille Univ, CRCM, CNRS, INSERM, 13000 Marseille, France.

Triple negative breast cancer (TNBC) represent 15% of breast cancers. Histoclinical features and marketed prognostic gene expression signatures (GES) failed to identify good- and poor-prognosis patients. Tyrosine kinases (TK) represent potential prognostic and/or therapeutic targets for TNBC. We sought to define a prognostic TK GES in a large series of TNBC. mRNA expression and histoclinical data of 6379 early BCs were collected from 16 datasets. We searched for a TK-based GES associated with disease-free survival (DFS) and tested its robustness in an independent validation set. A total of 1226 samples were TNBC. In the learning set of samples (N = 825), we identified a 13-TK GES associated with DFS. This GES was associated with cell proliferation and immune response. In multivariate analysis, it outperformed the previously published GESs and classical prognostic factors in the validation set (N = 401), in which the patients classified as "low-risk" had a 73% 5-year DFS versus 53% for "high-risk" patients = 1.85 × 10). The generation of 100,000 random 13-gene signatures by a resampling scheme showed the non-random nature of our classifier, which was also prognostic for overall survival in multivariate analysis. We identified a robust and non-random 13-TK GES that separated TNBC into subgroups of different prognosis. Clinical and functional validations are warranted.
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http://dx.doi.org/10.3390/cancers11081158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721506PMC
August 2019

PD-1/PD-L1 Targeting in Breast Cancer: The First Clinical Evidences Are Emerging. A Literature Review.

Cancers (Basel) 2019 Jul 22;11(7). Epub 2019 Jul 22.

Department of Medical Oncology, Aix-Marseille University, Inserm U1068, CNRS UMR7258, Institute Paoli-Calmettes, 13009 Marseille, France.

Recently, the development of immunotherapy through the immune checkpoint blockade led to long-lasting responses in several types of cancers that are refractory to conventional treatments, such as melanoma or non-small cell lung cancer. Immunotherapy has also demonstrated significant improvements in various other types of cancers. However, breast cancer remains one of the tumors that have not experienced the explosion of immunotherapy yet. Indeed, breast cancer was traditionally considered as being weakly immunogenic with a lower mutational load compared to other tumor types. In the last few years, anti-PD1/PD-L1 (Programmed death-ligand 1) agents have been evaluated in breast cancer, particularly in the triple negative subtype, with promising results observed when delivered as monotherapy or in combination with conventional treatments. In this review, we will report the results of the most recent studies evaluating immune checkpoint inhibitors in breast cancer. In addition, we will discuss the concomitant development of possible biomarkers, which is required for improving the selection of patients with the highest probability of benefiting from these agents.
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http://dx.doi.org/10.3390/cancers11071033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679223PMC
July 2019

A Comparison of DNA Mutation and Copy Number Profiles of Primary Breast Cancers and Paired Brain Metastases for Identifying Clinically Relevant Genetic Alterations in Brain Metastases.

Cancers (Basel) 2019 May 13;11(5). Epub 2019 May 13.

Laboratoire d'Oncologie Prédictive, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068, CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, F-13009 Marseille, France.

Improving the systemic treatment of brain metastases (BM) in primary breast cancer (PBC) is impaired by the lack of genomic characterization of BM. To estimate the concordance of DNA copy-number-alterations (CNAs), mutations, and actionable genetic alterations (AGAs) between paired samples, we performed whole-genome array-comparative-genomic-hybridization, and targeted-next-generation-sequencing on 14 clinical PBC-BM pairs. We found more CNAs, more mutations, and higher tumor mutational burden, and more AGAs in BM than in PBC; 92% of the pairs harbored at least one AGA in the BM not observed in the paired PBC. This concerned various therapeutic classes, including tyrosine-kinase-receptor-inhibitors, phosphatidylinositol 3-kinase/AKT/ mammalian Target of Rapamycin (PI3K/AKT/MTOR)-inhibitors, poly ADP ribose polymerase (PARP)-inhibitors, or cyclin-dependent kinase (CDK)-inhibitors. With regards to the PARP-inhibitors, the homologous recombination defect score was positive in 79% of BM, compared to 43% of PBC, discordant in 7 out of 14 pairs, and positive in the BM in 5 out of 14 cases. CDK-inhibitors were associated with the largest percentage of discordant AGA appearing in the BM. When considering the AGA with the highest clinical-evidence level, for each sample, 50% of the pairs harbored an AGA in the BM not detected or not retained from the analysis of the paired PBC. Thus, the profiling of BM provided a more reliable opportunity, than that of PBC, for diagnostic decision-making based on genomic analysis. Patients with BM deserve an investigation of several targeted therapies.
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http://dx.doi.org/10.3390/cancers11050665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562582PMC
May 2019

Stem Cells Inhibition by Bevacizumab in Combination with Neoadjuvant Chemotherapy for Breast Cancer.

J Clin Med 2019 May 6;8(5). Epub 2019 May 6.

Department of Medical Oncology, Institut Paoli-Calmettes, 13009 Marseille, France.

Preclinical works have suggested cytotoxic chemotherapies may increase the number of cancer stem cells (CSC) whereas angiogenesis inhibition may decrease CSC proliferation. We developed a proof of concept clinical trial to explore bevacizumab activity on breast CSC. Breast cancer patients requiring preoperative chemotherapy were included in this open-label, randomized, prospective, multicenter phase II trial. All received FEC-docetaxel combination, and patients randomized in the experimental arm received concomitant bevacizumab. The primary endpoint was to describe ALDH1 (Aldehyde dehydrogenase 1) positive tumor cells rate before treatment and after the fourth cycle. Secondary objectives included safety, pathological complete response (pCR) rate, disease-free survival (DFS), relapse-free survival (RFS), and overall survival (OS). Seventy-five patients were included. ALDH1+ cells rate increase was below the predefined 5% threshold in both arms for the 32 patients with two time points available. Grade 3 or 4 adverse events rates were similar in both arms. A non-significant increase in pCR was observed in the bevacizumab arm (42.6% vs. 18.2%, = 0.06), but survival was not improved (OS: = 0.89; DFS: = 0.45; and RFS: = 0.68). The increase of ALDH1+ tumor cells rate after bevacizumab-based chemotherapy was less than 5%. However, as similar results were observed with chemotherapy alone, bevacizumab impact on breast CSC cells cannot be confirmed.
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http://dx.doi.org/10.3390/jcm8050612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572380PMC
May 2019

The immunologic constant of rejection classification refines the prognostic value of conventional prognostic signatures in breast cancer.

Br J Cancer 2018 11 24;119(11):1383-1391. Epub 2018 Oct 24.

Department of Science, University of Sannio, Benevento, Italy.

Background: The immunologic constant of rejection (ICR) is a broad phenomenon of Th-1 immunity-mediated, tissue-specific destruction.

Methods: We tested the prognostic value of a 20-gene ICR expression signature in 8766 early breast cancers.

Results: Thirty-three percent of tumours were ICR1, 29% ICR2, 23% ICR3, and 15% ICR4. In univariate analysis, ICR4 was associated with a 36% reduction in risk of metastatic relapse when compared with ICR1-3 (p = 2.30E-03). In multivariate analysis including notably the three major prognostic signatures (Recurrence score, 70-gene signature, ROR-P), ICR was the strongest predictive variable (p = 9.80E-04). ICR showed no prognostic value in the HR+/HER2- subtype, but prognostic value in the HER2+ and TN subtypes. Furthermore, in each molecular subtype and among the tumours defined as high risk by the three prognostic signatures, ICR4 patients had a 41-75% reduction in risk of relapse as compared with ICR1-3 patients. ICR added significant prognostic information to that provided by the clinico-genomic models in the overall population and in each molecular subtype. ICR4 was independently associated with achievement of pathological complete response to neoadjuvant chemotherapy (p = 2.97E-04).

Conclusion: ICR signature adds prognostic information to that of current proliferation-based signatures, with which it could be integrated to improve patients' stratification and guide adjuvant treatment.
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http://dx.doi.org/10.1038/s41416-018-0309-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265245PMC
November 2018

Development of parallel reaction monitoring (PRM)-based quantitative proteomics applied to HER2-Positive breast cancer.

Oncotarget 2018 Sep 18;9(73):33762-33777. Epub 2018 Sep 18.

Aix-Marseille University, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Marseille Proteomics, Marseille, France.

Introduction: treatments targeting the Human Epidermal Growth Factor Receptor 2 (HER2/ERBB2) have improved the natural history of HER2-positive breast cancer. However, except HER2 protein expression and gene amplification, there is no predictive biomarker to guide the HER2-targeted therapies. We developed Parallel reaction monitoring (PRM) a powerful approach, to quantify and evaluate key proteins involved in the HER2 pathway and/or anti-HER2 treatment sensitivity.

Results: in BCLs, PRM measurements correlated with western blot immunocytochemistry and transcriptomic data. At baseline, higher expression of HER2, EGFR, PTEN and HER3 but lower expression of phospho-HER2 correlated with trastuzumab sensitivity. Under trastuzumab, PRM demonstrated a decrease in HER2 and an increase in phospho-HER2, which correlated with drug sensitivity. The opposite was observed under lapatinib. HER2 quantification was also correlated with immunohistochemistry in PDXs and clinical breast cancer samples.

Discussion: in conclusion, PRM-based assay, developed to quantify proteins of the HER2 pathway in breast cancer samples revealed a large magnitude of expression, which may have relevance in terms of treatment sensitivity.

Materials And Methods: we first evaluated PRM in term of sensitivity, linearity and reproducibility. PRM was then applied to breast cancer cell lines (BCLs) including BCLs exposed to anti-HER2 agents, patient-derived xenografts (PDXs) and frozen breast cancer samples.
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http://dx.doi.org/10.18632/oncotarget.26031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173470PMC
September 2018

Circulating Tumor Cells in Breast Cancer Patients Treated by Neoadjuvant Chemotherapy: A Meta-analysis.

J Natl Cancer Inst 2018 06;110(6):560-567

Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.

Background: We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) detection as a prognostic marker.

Methods: We collected individual patient data from 21 studies in which CTC detection by CellSearch was performed in early breast cancer patients treated with NCT. The primary end point was overall survival, analyzed according to CTC detection, using Cox regression models stratified by study. Secondary end points included distant disease-free survival, locoregional relapse-free interval, and pathological complete response. All statistical tests were two-sided.

Results: Data from patients were collected before NCT (n = 1574) and before surgery (n = 1200). CTC detection revealed one or more CTCs in 25.2% of patients before NCT; this was associated with tumor size (P < .001). The number of CTCs detected had a detrimental and decremental impact on overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P < .001), but not on pathological complete response. Patients with one, two, three to four, and five or more CTCs before NCT displayed hazard ratios of death of 1.09 (95% confidence interval [CI] = 0.65 to 1.69), 2.63 (95% CI = 1.42 to 4.54), 3.83 (95% CI = 2.08 to 6.66), and 6.25 (95% CI = 4.34 to 9.09), respectively. In 861 patients with full data available, adding CTC detection before NCT increased the prognostic ability of multivariable prognostic models for overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P = .008).

Conclusions: CTC count is an independent and quantitative prognostic factor in early breast cancer patients treated by NCT. It complements current prognostic models based on tumor characteristics and response to therapy.
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http://dx.doi.org/10.1093/jnci/djy018DOI Listing
June 2018

Safety Results and Analysis of Eribulin Efficacy according to Previous Microtubules-Inhibitors Sensitivity in the French Prospective Expanded Access Program for Heavily Pre-treated Metastatic Breast Cancer.

Cancer Res Treat 2018 Oct 28;50(4):1226-1237. Epub 2017 Dec 28.

Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France.

Purpose: Eribulin is approved for advanced breast cancers refractory to anthracyclines and taxanes. Efficacy according to sensitivity to previous therapies has been poorly explored.

Materials And Methods: Safety data were collected prospectively and we retrospectively collected efficacy data from the five French centres that participated in the Eribulin E7389-G000-398 expanded access program. Our main objectiveswere exploration of safety and analysis of eribulin efficacy (progression-free survival [PFS] and overall survival [OS]) according to sensitivity to the last microtubule-inhibiting agent administered.

Results: Median eribulin treatment duration was 3.3 months for the 250 patients included in this prospective single-arm study. Two hundreds and thirty-nine patients (95.6%) experienced an adverse event (AE) related to treatment including 129 (51.6%) with grade ≥ 3 AEs. The most frequently observed toxicities were cytopenias (59.6% of included patients), gastrointestinal disorders (59.2%), and asthenia (56.4%). The most frequent grade 3-4 AE was neutropenia (37.2% with 4.8% febrile neutropenia). Median PFS and OS were 4.6 and 11.8 months, respectively. Patients classified as responders to the last microtubule-inhibiting therapy had a longer OS (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.51 to 0.94; p=0.017), and tended to display a better PFS (HR, 0.78; 95% CI, 0.58 to 1.04; p=0.086). OS improvement was still significant in multivariate analysis (adjusted HR, 0.53; 95% CI, 0.35 to 0.79; p=0.002).

Conclusion: This work based on a prospective study suggests that identification of patients likely to be more sensitive to eribulin could be based on their previous response to microtubules inhibitors.
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http://dx.doi.org/10.4143/crt.2017.446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192912PMC
October 2018

[Sport coaching for psychological and social recovery after hematological cancer: An innovative perspective].

Bull Cancer 2017 Oct 12;104(10):823-830. Epub 2017 Oct 12.

Centre de recherche en cancérologie (CRCM), Marseille, France; Aix-Marseille université (AMU), Marseille, France; Institut Paoli-Calmette, département d'oncologie, 232, boulevard Sainte-Marguerite, BP 156, 13273 Marseille cedex 9, France. Electronic address:

This study is a first step towards the transfer of knowledge and practices between psychological support and performance in elite sport and a patient's "social recovery" in oncology. This proposal brings together people engaged in a variety of healthcare and relationship support roles, and aims to set up a support system beyond the hospital context. It questions the ability of elite sport management and its main actors, the "Great Coaches", to contribute to the support of patients in cancer remission through an onco-coaching approach. This innovative proposal is initiated by a life coaching pilot study designed for hematologic cancer patients in remission after a hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1016/j.bulcan.2017.08.006DOI Listing
October 2017

Similar response profile to neoadjuvant chemotherapy, but different survival, in inflammatory locally advanced breast cancers.

Oncotarget 2017 Sep 31;8(39):66019-66032. Epub 2017 Jul 31.

Département d'Oncologie Médicale, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Marseille, France.

Inflammatory breast cancer (IBC) is a very aggressive form of breast cancer, as compared to locally advanced breast cancer (LABC). Neoadjuvant chemotherapy followed by surgery is the standard treatment in both cases. Whether IBC is less chemosensitive than LABC remains unclear. We retrospectively compared the rate of pathological complete response (pCR) to neoadjuvant chemotherapy in IBC and LABC.

Methods: Patients with IBC or LABC treated with neoadjuvant anthracycline-based chemotherapy followed by surgery were selected from our institutional database. The primary endpoint was the pCR rate, defined as absence of invasive tumor in breast and axillary lymph nodes.

Results: A total of 450 patients were included, 144 with IBC and 306 with LABC. The pCR rate was similar between the two groups, in the whole population (31%) and in each molecular subtype separately. Univariate analyses for pCR in IBC and LABC separately identified the same predictive variables, except the pathological type that was associated with pCR in LABC only, but not in IBC. IBC patients displayed shorter 5-year metastasis-free survival and overall survival than LABC patients in the whole population (57% and 69% and 88% respectively), and in each molecular subtype separately. The IBC phenotype was an independent prognostic feature. Similarly, IBC patients displayed shorter 5-year loco-regional relapse-free survival than LABC patients (86% 95%).

Conclusions: Similar pCR rates to chemotherapy were found in IBC and LABC, suggesting that IBC is not less chemosensitive than LABC. Survival was shorter in IBC, suggesting that the corresponding poorer prognosis is more due to a higher metastatic risk and/or other feature(s) than to a lesser chemosensitivity.
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http://dx.doi.org/10.18632/oncotarget.19732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630389PMC
September 2017

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

Eur J Cancer 2017 11 23;86:28-36. Epub 2017 Sep 23.

Aix-Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France. Electronic address:

Background: Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms.

Patients And Methods: PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments.

Results: A total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug-drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57-92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12-51%]).

Conclusion: Combining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population.

Trial Registration Id: NCT01589861.
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http://dx.doi.org/10.1016/j.ejca.2017.08.025DOI Listing
November 2017

The use of systemic therapies to prevent progression of inflammatory breast cancer: which targeted therapies to add on cytotoxic combinations?

Expert Rev Anticancer Ther 2017 07 25;17(7):593-606. Epub 2017 May 25.

a Department of Medical Oncology, Institut Paoli-Calmettes, Aix Marseille Univ , CNRS U7258, INSERM U1068, CRCM , Marseille , France.

Introduction: Inflammatory breast cancer is a rare but frequently fatal disease, essentially because of its high ability to develop distant metastases. Even though the prognosis of IBC was significantly improved by multimodal management, including the systematic use of cytotoxic-based induction, the prognosis remains largely dismal. Areas covered: This review presents the main achievements in the systemic treatment of IBC during the past 30 years. It focuses more specifically on recent results obtained with targeted therapies, including anti-HER2 and anti-angiogenic agents. Novel approaches under investigation are presented. Expert commentary: Current management of IBC is subtype-specific and the largest benefit has been achieved in HER2-positive disease. The identification of breakthrough therapeutic advances is eagerly awaited and will require the development of IBC-specific clinical trials. Future clinical investigations should not only aim to increase the pathological response rate but also to eradicate distant metastases, which ultimately lead to patient death.
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http://dx.doi.org/10.1080/14737140.2017.1330655DOI Listing
July 2017

Optimal duration of adjuvant chemotherapy for high-risk node-negative (N-) breast cancer patients: 6-year results of the prospective randomised multicentre phase III UNICANCER-PACS 05 trial (UCBG-0106).

Eur J Cancer 2017 07 11;79:166-175. Epub 2017 May 11.

Institut Claudius Regaud, Institut Universitaire Cancer Toulouse-Oncopole, 1 avenue Irèle joliot-Curie, 31059 Toulouse Cedex 9, France. Electronic address:

Purpose: Optimal duration of adjuvant chemotherapy in the treatment of early-stage breast cancer remained to be investigated rigorously for the standard regimens in widespread use in North America (doxorubicin/cyclophosphamide, AC) and Europe (5-fluorouracil/epirubicin/cyclophosphamide, FEC). Whether six cycles of FEC 100 present an advantage, or not, compared with only four cycles was tested directly in a phase III prospective multicentre trial.

Patients And Methods: Between 2002 and 2006, 1515 women between 18 and 65°years of age, with node negative N(-) high-risk early-stage breast cancer, were included in the study following breast surgery and axillary lymph node dissection or procedure by sentinel node technique. Inclusion in the study required tumour size T ≥ 1 cm and at least one of the high-risk factors: T > 2 cm, negative oestrogen receptor/progesterone receptor (ER- and PR-), Scarff-Bloom-Richardson (SBR) grade II or III and age ≤ 35°years. Patients were randomly assigned to either six FEC 100 (Arm A) or four FEC 100 (Arm B). The trial was powered to detect an absolute difference ≥6% in disease-free survival (DFS) at 5°years.

Results: At 6.1°years median follow-up, with 91 (12%) events recorded in Arm A versus 106 (14%) in Arm B, no statistically significant risk increase was associated with four versus six FEC 100: DFS (hazard ratio (HR) = 1.18; CI 95% [0.89-1.56], P = .24) and overall survival (OS) (HR = 1.39; CI 95% [0.91-2.13], P = .12).

Conclusion: Differences in chemotherapy duration did not induce notably different outcomes in our cohort of high-risk patients.

Clinical Trial Registry Number: NCT00055679, Agence National de Sécurité du Médicament (ANSM) - France.
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http://dx.doi.org/10.1016/j.ejca.2017.03.004DOI Listing
July 2017

A scoring system to guide the decision for a new systemic treatment after at least two lines of palliative chemotherapy for metastatic cancers: a prospective study.

Support Care Cancer 2017 09 28;25(9):2715-2722. Epub 2017 Mar 28.

Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France.

Purpose: A four-parameter score has been identified as associated with overall survival (OS) in patients with advanced cancer with an estimated survival inferior to 6 months. Here, we tested its prognostic value for OS in patients who had received more than two lines of systemic therapy.

Methods: We prospectively enrolled patients with advanced cancer who were going to receive a third or more therapeutic line outside classical clinical guidelines. The four parameters (Eastern Cooperative Oncology Group performance status, number of metastatic sites, serum LDH, and serum albumin) were collected at baseline, allowing to calculate the score, which sorted the patients in three groups, A, B, and C (low, intermediate, and high score, respectively). We then searched for correlations between this grouping and clinicopathological features particularly OS.

Results: From August 2013 to March 2014, 65 patients were enrolled and corresponded after determining their score to 26 patients in group A, 30 in B, and 9 in C. The median OS of the cohort was 4.4 months, and the 6-month OS was 42%. Overall survival was different between the three groups, with respective 6-month OS equal to 80% in group A, 17% in group B, and 0% in group C and respective median OS of 9, 2.3, and 1.6 months. Such prognostic value persisted in multivariate analysis. Similar OS differences were observed in patients with PS ≤2.

Conclusion: This simple scoring should help oncologists identify which patients, after at least two lines of systemic therapy, might benefit from best supportive care alone.
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http://dx.doi.org/10.1007/s00520-017-3680-1DOI Listing
September 2017

[Impact of Her2 and BRCA1/2 status in high-dose chemotherapy and autologous stem cells transplantation in the treatment of breast cancer: The Institut Paoli Calmettes' experience].

Bull Cancer 2017 Apr 16;104(4):332-343. Epub 2017 Feb 16.

Institut Paoli-Calmettes (IPC), département d'oncologie médicale, 232, boulevard de Sainte-Marguerite, 13009 Marseille cedex 9, France; Centre de recherches en cancérologie de Marseille (CRCM), UMR Inserm 1068/CNRS 7258/AMU 105/IPC, 232, boulevard de Sainte-Marguerite, 13009 Marseille, France; Aix-Marseille université, Jardin du Pharo, 58, boulevard Charles-Livon, 13284 Marseille, France. Electronic address:

Introduction: Studies evaluating chemotherapy high dose chemotherapy with autologous haematopoietic stem cell transplantation (HDC-ACSH) in the treatment of metastatic (MBC), locally advanced (LABC) and inflammatory (IBC) breast cancer have in common lack of biomarker information, in particular the HER2 status.

Patients And Methods: All consecutive female patients treated for breast cancer with HDC and AHSCT at Institut Paoli Calmettes between 2003 and 2012 were included. Patients were categorized in three subtypes based on hormonal receptor (HR) and HER2 status of the primary tumor: luminal, (HR+/HER2-), HER2 (HER2+, any HR) and triple negative (TN) (HER2- and HR-). The main objective was the analysis of overall survival (OS) according to the IHC subtypes.

Results: Three hundred and seventy-seven patients were included. For MBC, the TN subtype appeared to have the worst prognosis with a median OS of 19.68 months (95 % CI 11.76-44.4) compared to 44.64 months (95 % CI 40.32-67.56) for the luminal subtype and a median OS not reached for the HER2 subtype (P<0.01). For IBC, HER2 subgroup appeared to have the best prognosis with a 5-year OS of 89 % (95 % CI 64-97) compared to 57 % (95 % CI 33-76) for the TN subgroup (HR 5.38, 95 % CI 1.14-25.44; P=0.034). For CSLA, luminal subgroup appeared to have the best prognosis with a 5-year OS of 92 % (95 % CI 71-98) against 75 % (95 % CI 46-90) for HER 2 subtype and 70 % (95 %CI 97-88) for TN subtype (P=0.301).

Conclusion: The HDC-ACSH does not change the prognosis value of IHC subtype in breast cancer patients.
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http://dx.doi.org/10.1016/j.bulcan.2016.12.007DOI Listing
April 2017

Marketing Authorization Procedures for Advanced Cancer Drugs: Exploring the Views of Patients, Oncologists, Healthcare Decision Makers, and Citizens in France.

Med Decis Making 2017 07 15;37(5):555-566. Epub 2017 Feb 15.

Institut Paoli Calmettes, Department of Molecular Oncology, and CRCM, Inserm, U1068; Aix-Marseille Université, UM 105; CNRS, UMR7258, F-13009, Marseille, France (AG, PV).

Background: The past decades have seen advances in cancer treatments in terms of toxicity and side effects but progress in the treatment of advanced cancer has been modest. New drugs have emerged improving progression free survival but with little impact on overall survival, raising questions about the criteria on which to base decisions to grant marketing authorizations and about the authorization procedure itself. For decisions to be fair, transparent and accountable, it is necessary to consider the views of those with relevant expertise and experience.

Methods: We conducted a Q-study to explore the views of a range of stakeholders in France, involving: 54 patients (18 months after diagnosis); 50 members of the general population; 27 oncologists; 19 healthcare decision makers; and 2 individuals from the pharmaceutical industry.

Results: Three viewpoints emerged, focussing on different dimensions entitled: 1) 'Quality of life (QoL), opportunity cost and participative democracy'; 2)'QoL and patient-centeredness'; and 3) 'Length of life'. Respondents from all groups were associated with each viewpoint, except for healthcare decision makers, who were only associated with the first one.

Conclusion: Our results highlight plurality in the views of stakeholders, emphasize the need for transparency in decision making processes, and illustrate the importance of a re-evaluation of treatments for all 3 viewpoints. In the context of advanced cancer, our results suggest that QoL should be more prominent amongst authorization criteria, as it is a concern for 2 of the 3 viewpoints.
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http://dx.doi.org/10.1177/0272989X17691953DOI Listing
July 2017

Bevacizumab in HER2-negative inflammatory breast cancer.

Oncoscience 2016 15;3(11-12):297-298. Epub 2016 Nov 15.

Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France.

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http://dx.doi.org/10.18632/oncoscience.324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5235910PMC
November 2016

MARCKS protein overexpression in inflammatory breast cancer.

Oncotarget 2017 Jan;8(4):6246-6257

Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille, Aix Marseille Université, Marseille, France.

Background: Inflammatory breast cancer (IBC) is the most aggressive form of locally-advanced breast cancer. Identification of new therapeutic targets is crucial. We previously reported MARCKS mRNA overexpression in IBC in the largest transcriptomics study reported to date. Here, we compared MARCKS protein expression in IBC and non-IBC samples, and searched for correlations between protein expression and clinicopathological features.

Results: Tumor samples showed heterogeneity with respect to MARCKS staining: 18% were scored as MARCKS-positive (stained cells ≥ 1%) and 82% as MARCKS-negative. MARCKS expression was more frequent in IBC (36%) than in non-IBC (11%; p = 1.4E-09), independently from molecular subtypes and other clinicopathological variables. We found a positive correlation between protein and mRNA expression in the 148/502 samples previously analyzed for MARCKS mRNA expression. MARCKS protein expression was associated with other poor-prognosis features in the whole series of samples such as clinical axillary lymph node or metastatic extension, high pathological grade, ER-negativity, PR-negativity, HER2-positivity, and triple-negative and HER2+ statutes. In IBC, MARCKS expression was the sole tested variable associated with poor MFS.

Materials And Methods: We retrospectively analyzed MARCKS protein expression by immunohistochemistry in 502 tumors, including 133 IBC and 369 non-IBC, from Tunisian and French patients. All samples were pre-therapeutic clinical samples. We searched for correlations between MARCKS expression and clinicopathological features including the IBC versus non-IBC phenotype and metastasis-free survival (MFS).

Conclusions: MARCKS overexpression might in part explain the poor prognosis of IBC. As an oncogene associated with poor MFS, MARCKS might represent a new potential therapeutic target in IBC.
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http://dx.doi.org/10.18632/oncotarget.14057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351628PMC
January 2017
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