Publications by authors named "Mathilde Guerin"

12 Publications

  • Page 1 of 1

Metastatic hormone sensitive prostate cancer: local treatment strategies.

World J Urol 2021 Feb 25;39(2):327-337. Epub 2020 Jun 25.

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

Purpose: The landscape of the management of metastatic prostate cancer is changing rapidly and there is growing interest in the local treatment of the primary in these patients. The effect of local treatment on the outcome of metastatic prostate cancer patients was addressed based on retrospective analysis but now also based on prospective randomized trials. This article provides an overview of the currently available literature in this field.

Methods: A literature review was done searching the Medline database for English language articles using the keywords "metastatic prostate cancer", and "local treatment", "radiotherapy", "prostatectomy". The data of prospective randomized studies and the data of case-control studies or retrospective analysis were summarized in a narrative fashion.

Results: Data from two prospective randomized trials exploring the effect of local treatment of the prostate in hormone-sensitive metastatic prostate cancer showed no improvement of overall survival in the individual overall cohorts as well as in the pooled analysis (HR 0.92, 95% CI 0.81-1.04). There was an improvement of failure-free survival (pooled analysis HR 0.76, 95% CI 0.69-0.0.84). There was also an improved overall survival associated with radiotherapy in patients with < 5 metastases and with low volume disease. Data from prospective non-randomized or retrospective studies are inconclusive and underlies major selection biases.

Conclusion: Based on prospective randomized trials, local treatment by radiotherapy does not improve the overall survival in unselected metastatic prostate cancer patients. An effect can be seen in low volume patients or patients with < 5 metastases.
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http://dx.doi.org/10.1007/s00345-020-03296-8DOI Listing
February 2021

New Therapeutics in HER2-Positive Advanced Breast Cancer: Towards a Change in Clinical Practices?pi.

Cancers (Basel) 2020 Jun 14;12(6). Epub 2020 Jun 14.

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

Over the last few decades, improved knowledge of oncogenic activation mechanisms of HER2 protein has led to the development of HER2 targeted therapies that are currently commonly used in HER2-positive advanced breast cancer, such as trastuzumab, lapatinib, pertuzumab, and ado-trastuzumab emtansine. The management of this breast cancer subgroup has thus been revolutionized and its prognosis has changed dramatically. Nevertheless, HER2-positive advanced breast cancer remains an incurable disease and resistance to conventional anti-HER2 drugs is almost unavoidable. Nowadays, biochemical and pharmaceutical advances are meeting the challenge of developing increasingly sophisticated therapies directed against HER2, including novel anti HER2 antibodies with increased affinity. New antibody-drug conjugates (ADC) with more advanced pharmacological properties, and dual targeting of epitopes via bispecific monoclonal antibodies are also emerging. In addition, more potent and more specific HER2 tyrosine kinase inhibitors have shown interesting outcomes and are under development. Finally, researchers' interest in tumor microenvironment, particularly tumor-infiltrating lymphocytes, and the major role that signaling pathways, such as the PI3K/AKT/mTOR pathway, play in the development of resistance to anti-HER2 therapies have spurred the development of clinical trials evaluating innovative combinations of anti-HER2 with PD-1/PDL-1, CDK4/6 and PI3K inhibitors. However, several questions remain unresolved, like the optimal management of HER2-positive/HR-positive advanced breast cancer and the identification of predictive biomarkers to better define populations that can benefit most from these new therapies and approaches.
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http://dx.doi.org/10.3390/cancers12061573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352740PMC
June 2020

Neuroendocrine Carcinoma of the Urinary Bladder: A Large, Retrospective Study From the French Genito-Urinary Tumor Group.

Clin Genitourin Cancer 2020 08 5;18(4):295-303.e3. Epub 2019 Dec 5.

Department of Medical Oncology, Hôpital Européen Georges Pompidou, Paris, France; Association pour la Recherche et les Thérapeutiques Innovantes en Cancérologie, Paris, France; University René Descartes, Paris, France.

Background: Neuroendocrine carcinoma of the urinary bladder (NCUB) is rare, accounting for < 1% of bladder cancer cases, with scarce reported data available.

Materials And Methods: We retrospectively reviewed the data from patients with NCUB treated at French institutions. The objectives were to describe the patient characteristics, treatments received, and outcomes (ie, disease-free survival [DFS], progression-free survival, overall survival [OS]) and investigate the prognostic factors.

Results: From 1997 to 2017, we included 236 patients, 173 with early-stage NCUB and 63 with advanced-stage NCUB. For those with early-stage disease, the median DFS was better for the patients who had received cisplatin-based chemotherapy compared with carboplatin (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.1-3.46), with no difference found between the neoadjuvant and adjuvant settings (HR, 1.1; 95% CI, 0.61-1.97). The median OS was 36 months (95% CI, 29-43 months) for stage I and II, 26 months (95% CI, 18 months to not reached) for stage IIIA, 16 months (95% CI, 12-21 months) for stage IIIB. The HR for stage IIIB compared with stage I/II was 2.6 (95% CI, 1.5-4.4). The DFS at 6 months was associated with OS (HR, 7.8; 95% CI, 4.1-15.0). For patients with metastases at diagnosis who had received chemotherapy, the median progression-free survival was 9 months (95% CI, 8-11) for first-line cisplatin and 6 months (95% CI, 4-13 months) for carboplatin; the median OS was 13 months (95% CI, 9-15 months). A high-risk Bajorin score (HR, 11.5; 95% CI, 1.2-112.6) and the use of carboplatin (HR, 2.26; 95% CI, 1.03-4.96) were associated with worse outcomes.

Conclusions: In early-stage disease, a shorter DFS was associated with worse OS, and the use of cisplatin was associated with better OS. For the patients with metastases at diagnosis, a high-risk Bajorin score and the use of carboplatin were associated with worse outcomes.
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http://dx.doi.org/10.1016/j.clgc.2019.11.014DOI Listing
August 2020

Vitiligo Adverse Event Observed in a Patient With Durable Complete Response After Nivolumab for Metastatic Renal Cell Carcinoma.

Front Oncol 2019 9;9:1033. Epub 2019 Oct 9.

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

Renal cell carcinoma is the third most prevalent urological cancer worldwide and about 30% of patients present with metastatic disease at the time of diagnosis. Systemic treatments for metastatic renal cell carcinoma have improved recently. Vascular endothelial growth factor targeting therapies were the previous standard of care. However, immune checkpoint inhibitors used in second line therapy have now been shown to improve patient survival. We report a case of metastatic renal cell carcinoma with nivolumab as a second-line therapy after progression with tyrosine kinase inhibitor therapy. Unusual adverse events in metastatic renal cell carcinoma, such as vitiligo, were observed in this patient who developed a remarkable documented pathological complete response to his renal tumor. A 60-year-old caucasian male was diagnosed with a pulmonary metastatic clear cell renal cell carcinoma. Sunitinib was used as first line treatment without success. He received nivolumab in second-line treatment. He developed several immune-related adverse events, most notably vitiligo. The patient had a radiological complete response on metastatic sites, with a significant decrease of renal tumor volume and underwent cytoreductive nephrectomy after 2 years of treatment, confirming the pathological complete response. The patient remains disease-free for 10 months without further systemic therapy after nivolumab discontinuation. Pathological complete response with nivolumab in metastatic renal cell carcinoma is rare. This case further highlights the potentially predictive role of immune-related adverse events during nivolumab therapy for metastatic renal cell carcinoma and raises questions concerning the role of nephrectomy after immune checkpoint inhibitor therapy. Further studies are needed to better identify predictive factors for treatment response to immunotherapy in metastatic renal cell carcinoma, and to better understand the role of nephrectomy after nivolumab treatment.
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http://dx.doi.org/10.3389/fonc.2019.01033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795279PMC
October 2019

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

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

How may targeted proteomics complement genomic data in breast cancer?

Expert Rev Proteomics 2017 01 15;14(1):43-54. Epub 2016 Nov 15.

a Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille Protéomique , Marseille , France.

Introduction: Breast cancer (BC) is the most common female cancer in the world and was recently deconstructed in different molecular entities. Although most of the recent assays to characterize tumors at the molecular level are genomic-based, proteins are the actual executors of cellular functions and represent the vast majority of targets for anticancer drugs. Accumulated data has demonstrated an important level of quantitative and qualitative discrepancies between genomic/transcriptomic alterations and their protein counterparts, mostly related to the large number of post-translational modifications. Areas covered: This review will present novel proteomics technologies such as Reverse Phase Protein Array (RPPA) or mass-spectrometry (MS) based approaches that have emerged and that could progressively replace old-fashioned methods (e.g. immunohistochemistry, ELISA, etc.) to validate proteins as diagnostic, prognostic or predictive biomarkers, and eventually monitor them in the routine practice. Expert commentary: These different targeted proteomic approaches, able to complement genomic data in BC and characterize tumors more precisely, will permit to go through a more personalized treatment for each patient and tumor.
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http://dx.doi.org/10.1080/14789450.2017.1256776DOI Listing
January 2017

Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity.

Cancer Res 2016 04 5;76(8):2153-65. Epub 2016 Apr 5.

Centre de Recherche en Cancérologie de Marseille, INSERM U1068/CNRS U7258, Marseille, France. Institut Paoli-Calmettes, Marseille, France. Aix Marseille Université, Marseille, France.

The field of immunotherapy for solid tumors, such as prostate cancer, has been recently focusing on therapies that can counter tumor-mediated immunosuppression. Precise quantification and characterization of the immune infiltrates in tumors is crucial to improve treatment efficacy. Natural killer (NK) cells, major components of the antitumor immune system, have never been isolated from prostate tumors, despite their suspected role in disease progression. Here, we examined the frequency, phenotype, and functions of NK cells infiltrating control and tumor prostate tissues. NK cell infiltrates in prostate tissues were mainly CD56 (NCAM1)-positive and displayed an unexpected immature, but activated, phenotype with low or no cytotoxic potential. Furthermore, we show that TGFβ1 (TGFB1) is highly secreted into the prostate environment and partly mediates the immunosuppressive effects on NK cells. In addition to this basal level of immunotolerance to NK cells, the prostate environment became further resistant to NK cell-mediated immunity upon cancer cell infiltration. Coculture experiments revealed that prostate cancer cells induced the expression of inhibitory receptor (ILT2/LILRB1) and downregulated the expression of activating receptors NKp46 (NCR1), NKG2D (KLRK1), and CD16 (FCGR3) by NK cells, thus preventing their recognition of tumor cells. Notably, blood levels of NKp46 were also decreased in prostate cancer patients and were inversely correlated with levels of prostate-specific antigen, the main prognostic factor in prostate cancer. Our study shows that a strong immunosuppressive environment impairs NK cell function at multiple levels in prostate cancer and provides a rationale for the design of therapies that restore NK cell efficiency in the prostate tumor microenvironment. Cancer Res; 76(8); 2153-65. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-1965DOI Listing
April 2016

Highly effective NK cells are associated with good prognosis in patients with metastatic prostate cancer.

Oncotarget 2015 Jun;6(16):14360-73

Centre de Recherche en Cancérologie de Marseille, Inserm, Marseille, France.

Clinical outcome of patients with metastatic prostate cancer (mPC) at diagnosis is heterogeneous and unpredictable; thus alternative treatments such as immunotherapy are investigated. We retrospectively analyzed natural killer (NK) cells by flow cytometry in peripheral blood from 39 mPC patients, with 5 year-follow-up, and their correlation with time to castration resistance (TCR) and overall survival (OS). In parallel, NK functionality was carried out against prostate tumor cell lines, analyzed for the expression of NK cell ligands, to identify the receptors involved in PC recognition. NK cells from patients with longer TCR and OS displayed high expression of activating receptors and high cytotoxicity. The activating receptors NKp30 and NKp46 were the most obvious predictive markers of OS and TCR in a larger cohort of mPC patients (OS: p= 0.0018 and 0.0009; TCR: p= 0.007 and < 0.0001 respectively, log-rank test). Importantly, blocking experiments revealed that NKp46, along with NKG2D and DNAM-1 and, to a lesser extent NKp30, were involved in prostate tumor recognition by NK cells. These results identify NK cells as potential predictive biomarkers to stratify patients who are likely to have longer castration response, and pave the way to explore therapies aimed at enhancing NK cells in mPC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546472PMC
http://dx.doi.org/10.18632/oncotarget.3965DOI Listing
June 2015

[Trastuzumab emtansine (Kadcyla(®)) approval in HER2-positive metastatic breast cancers].

Bull Cancer 2015 Apr 16;102(4):390-7. Epub 2015 Mar 16.

Institut Paoli-Calmettes, oncologie médicale, 232, boulevard Ste-Marguerite, 13009 Marseille, France; Inserm U1068-CNRS U7258, Aix-Marseille université, centre de recherche en cancérologie de Marseille, 13009 Marseille, France; Aix-Marseille université, 13284 Marseille cedex 07, France. Electronic address:

HER2 (human epidermal growth factor receptor 2) is overexpressed in 15 to 20% of breast cancer. Anti-HER2 targeted therapies, notably trastuzumab, have transformed the natural history of this disease. Trastuzumab emtansine, consisting of trastuzumab coupled to a cytotoxic agent, emtansine (DM1), by a stable linker, has been approved in November 2013 by the European Medicine Agency. Trastuzumab emtansine targets and inhibits HER2 signaling, but also allows emtansine to be directly delivered inside HER2-positive cancer cells. It is indicated as single-agent in taxane and trastuzumab-pretreated HER2-positive breast cancer patients with metastatic and locally recurrent unresecable disease or relapsing within 6 months of the end of adjuvant therapy. This indication is based on the results of the EMILIA study, an open label phase III randomized trial comparing trastuzumab emtansine to lapatinib-capecitabine. The two primary endpoints were reached. The progression-free survival was 6.4 months in the lapatinib-capecitabine arm versus 9.6 months for the trastuzumab emtansine arm (HR=0.65; 95% CI=0.55-0.77, P<0.001). Overall survival at the second interim analysis was 25.1 months in the lapatinib-capecitabine arm versus 30.9 months in the trastuzumab emtansine arm (HR=0.68; 95% CI=0.55-0.85, P<0.001). Moreover, adverse events were more frequent in the lapatinib-capecitabine arm.
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http://dx.doi.org/10.1016/j.bulcan.2015.02.007DOI Listing
April 2015

Major response with sorafenib in advanced renal cell carcinoma after 14 years of follow-up.

World J Surg Oncol 2013 Sep 27;11:243. Epub 2013 Sep 27.

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

Tyrosine kinase inhibitors have dramatically improved the prognosis of metastatic renal cell carcinoma (RCC). However, it remains unknown whether treatment should be continued until progression or discontinued in patients with good response. We present the history of a woman diagnosed with RCC in 1997, who started sorafenib in 2004, two years after the occurrence of lung and mediastinal metastases. Over the following 8 years, the sorafenib dose was reduced at least 3 times due to toxicity and the treatment was discontinued twice upon the patient's decision, from May 2005 to March 2009, then from January 2011 to August 2011. The last evaluation in January 2013 showed stable disease. This case illustrates the feasibility of treatment discontinuation without negative impact on survival, as previously shown by some authors.
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http://dx.doi.org/10.1186/1477-7819-11-243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3851250PMC
September 2013