Publications by authors named "Joseph Gligorov"

128 Publications

Development and clinical validation of a simple and fast UPLC-ESI-MS/MS method for simultaneous quantification of nine kinase inhibitors and two antiandrogen drugs in human plasma: Interest for their therapeutic drug monitoring.

J Pharm Biomed Anal 2021 Feb 14;197:113968. Epub 2021 Feb 14.

AP-HP.Sorbonne Université, Department of Pharmacology and Clinical Investigation Center (CIC-1901), Pitié-Salpêtrière Hospital, INSERM, CIC-1901 and UMR-S 1166, Sorbonne Université, Faculty of Medicine Sorbonne Université, Faculty of Medicine, Paris, France. Electronic address:

Kinase inhibitors (KIs) and antiandrogen drugs (AAs) are oral anticancer drugs with narrow therapeutic index that exhibit high inter- and intra-individual variability. We describe here a UPLC-MS/MS method for the simultaneous quantification of nine KIs: cobimetinib, dasatinib, ibrutinib, imatinib, nilotinib, palbociclib, ruxolitinib, sorafenib and vemurafenib; two active metabolites of them: N-desmethyl imatinib, N-oxide sorafenib; and two AAs: abiraterone and enzalutamide; with short pre-treatment and run time in order to be easily used in clinical practice for their therapeutic drug monitoring (TDM) and facilitating pharmacokinetics and pharmacokinetics/pharmacodynamics studies. Plasma samples were prepared by a single-step protein precipitation. Analytes were separated on a Waters Acquity UPLC® T3 HSS C18 column by non-linear gradient elution; with subsequent detection by Xevo® TQD triple quadrupole tandem mass spectrometer in a positive ionization mode. Analysis time was 2.8 min per run, and all analytes eluted within 1.46-1.97 minutes. The analytical performance of the method in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, dilution integrity and stability of analytes under different conditions met all criteria for a bioanalytical method for the quantification of drugs. The calibration curves were linear over the range of 1-500 ng/mL for abiraterone, dasatinib and ibrutinib; 5-500 ng/mL for cobimetinib and palbociclib; 10-5,000 ng/mL for imatinib, N-desmethyl imatinib, nilotinib, sorafenib, N-oxide sorafenib and ruxolitinib; 100-50,000 ng/mL for enzalutamide and 100-100,000 ng/mL for vemurafenib with coefficient of correlation above 0.995 for all analytes. This novel method was successfully applied to TDM in clinical practice.
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http://dx.doi.org/10.1016/j.jpba.2021.113968DOI Listing
February 2021

Clinical practice guidelines for BRCA1 and BRCA2 genetic testing.

Eur J Cancer 2021 Feb 10;146:30-47. Epub 2021 Feb 10.

Medical Oncology Department, Hospital Nuestra Señora de Sonsoles, Ávila, Ávila, Spain. Electronic address:

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices.
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http://dx.doi.org/10.1016/j.ejca.2020.12.023DOI Listing
February 2021

Addressing disparities and challenges in underserved patient populations with metastatic breast cancer in Europe.

Breast 2021 Feb 13;55:79-90. Epub 2020 Dec 13.

ABC Global Alliance, C/o Champalimaud Foundation, Av. Brasília, Lisbon, 1400-038, Portugal; Breast Unit, Champalimaud Clinical Center/Champalimaud Foundation, Lisbon, Portugal. Electronic address:

People with metastatic breast cancer face many challenges and disparities in obtaining optimal cancer care. These challenges are accentuated in underserved patient populations across Europe, who are less likely to receive quality healthcare for reasons including socioeconomic inequalities, educational or cultural status, or geographic location. While there are many local and national initiatives targeted to address these challenges, there remains a need to reduce disparities and improve access to healthcare to improve outcomes, with a focus on multidisciplinary stakeholder engagement. In October 2019, a range of experts in metastatic breast cancer, including healthcare professionals, patient representatives, policymakers and politicians, met to discuss and prioritize the critical needs of underserved patient populations with metastatic breast cancer in Europe. Six key challenges faced by these communities were identified: the need for amplification of the metastatic breast cancer patient voice, better and wider implementation of high-quality guidelines for metastatic breast cancer, more collaboration between stakeholders, tailored support for patients from different cultural and ethnic backgrounds, improved data sharing, and work-related issues. The Expert Panel then conceived and discussed potential actionable goals to address each key challenge. Their conclusions present a set of interrelated approaches to address the different challenges and could serve as the basis for concerted improvement of the lives of patients with metastatic breast cancer in Europe.
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http://dx.doi.org/10.1016/j.breast.2020.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772562PMC
February 2021

The management of patients with cancer of unknown primary in middle-income countries: an ESO-AROME survey.

Future Oncol 2021 Jan 11;17(2):151-157. Epub 2020 Dec 11.

Institut Universitaire de Cancerologie APHP-Sorbonne Université, 75006, Paris, France.

To report on the management strategies in patients with cancer of unknown primary (CUP) in middle-income countries. We conceived a survey of 20 items concerning the management of patients with CUP in daily clinical practice. Only participants from lower- and higher-middle-income countries, as per the World Bank Classification, were eligible for this study. The indications for the first-line treatment did not differ between the two economic regions, whereas those for second-line treatment were more prevalent in higher-middle-income countries. The use of targeted therapy based on immunohistochemistry alone was higher in lower-middle-income countries, although the access to CUP classifiers was similar between the two regions. Proper recommendations must ensure that the economic burden is minimized and that other benefits outweigh the limited survival benefit achieved in patients with CUP.
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http://dx.doi.org/10.2217/fon-2020-0677DOI Listing
January 2021

Prognosis of HER2-positive pregnancy-associated breast cancer: Analysis from the French CALG (Cancer Associé à La Grossesse) network.

Breast 2020 Dec 26;54:311-318. Epub 2020 Nov 26.

Department of Gynaecology and Obstetrics, Tenon University Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Sorbonne University, Institut Universitaire de Cancérologie (IUC), France; Centre CALG (Cancer Associé à La Grossesse), France; UMRS-938 4, Faculté de Médecine Sorbonne Université, France.

Introduction: The prevalence of pregnancy-associated breast cancer is increasing. HER2-positive breast cancers typically have a poor prognosis. The objective of our study was to compare the prognosis of patients with HER2-positive breast cancer diagnosed during pregnancy (HER2-positive BCP) to young women diagnosed with HER2-positive breast cancer outside of pregnancy (HER2 non-BCP).

Methods: Data of patients managed for invasive breast carcinoma between January 2005 and 2020 were retrospectively collected from the database of Tenon University Hospital (Paris, France), part of the "Cancer lié à la Grossesse" network.

Results: Fifty-one patients with HER2-positive BCP were matched on age at diagnosis with 51 HER2-positive non-BCP patients. Locally advanced disease with axillary lymph node involvement were frequent. Tumors were frequently aggressive with high grade (p = 0.57) and high Ki67 (p = 0.15). Among the HER2-positive BCP patients, the mean term at diagnosis was 19.3 week of gestation (WG). Eighty-four percent of the patients continued their pregnancy with a mean term at delivery of 34.2WG. Chemotherapy modalities differed between the two groups: neoadjuvant chemotherapy was more frequent in the HER2-positive BCP group (p = 0.03) and adjuvant chemotherapy more frequent in the HER2 non-BCP group (p = 0.009). The recurrence rate was 10% (n = 5) and 18% (n = 9) in the HER2-positive BCP and HER2 non-BCP groups, respectively, p = 0.25. Breast cancer-free survival was poorer in the HER2-positive BCP group with earlier recurrence, p = 0.008. No difference in type of recurrence was found between the groups (p = 0.58).

Conclusion: This matched case-control study implies that patients with HER2-positive BCP still have a poorer prognosis than non-pregnant HER-positive patients.
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http://dx.doi.org/10.1016/j.breast.2020.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711283PMC
December 2020

Trastuzumab Emtansine Plus Non-Pegylated Liposomal Doxorubicin in HER2-Positive Metastatic Breast Cancer (Thelma): A Single-Arm, Multicenter, Phase Ib Trial.

Cancers (Basel) 2020 Nov 25;12(12). Epub 2020 Nov 25.

Medical Department, Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ 07450, USA.

The paper assesses the dose-limiting toxicities and the maximum tolerated dose (MTD) of trastuzumab emtansine (T-DM1) combined with non-pegylated liposomal doxorubicin (NPLD) in HER2-positive (HER2+) metastatic breast cancer (MBC). This single-arm, open-label, phase Ib trial (NCT02562378) enrolled anthracycline-naïve HER2+ MBC patients who had progressed on trastuzumab and taxanes. Patients received a maximum of 6 cycles of NPLD intravenously (IV) at various dose levels (45, 50, and 60 mg/m) in the "3 plus 3" dose-escalation part. During expansion, they received 60 mg/m of NPLD every 3 weeks (Q3W) plus standard doses of T-DM1. The MTD was T-DM1 3.6 mg/kg plus NPLD 60 mg/m administered IV Q3W. No clinically relevant worsening of cardiac function was observed. Among all evaluable patients, the overall response rate was 40.0% (95%CI, 16.3-67.7) with a median duration of response of 6.9 months (95%CI, 4.8-9.1). Clinical benefit rate was 66.7% (95%CI, 38.4-88.2) and median progression-free survival was 7.2 months (95%CI, 4.5-9.6). No significant influence of NPLD on T-DM1 pharmacokinetics was observed. The addition of NPLD to T-DM1 is feasible but does not seem to improve the antitumor efficacy of T-DM1 in HER2+ MBC patients.
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http://dx.doi.org/10.3390/cancers12123509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760511PMC
November 2020

Creating Synthetic Patients to Address Interoperability Issues: A Case Study with the Management of Breast Cancer Patients.

Stud Health Technol Inform 2020 Nov;275:177-181

Sorbonne Université, Université Sorbonne Paris Nord, INSERM, UMR S_1142, LIMICS, Paris, France.

Interoperability issues are common in biomedical informatics. Reusing data generated from a system in another system, or integrating an existing clinical decision support system (CDSS) in a new organization is a complex task due to recurrent problems of concept mapping and alignment. The GL-DSS of the DESIREE project is a guideline-based CDSS to support the management of breast cancer patients. The knowledge base is formalized as an ontology and decision rules. OncoDoc is another CDSS applied to breast cancer management. The knowledge base is structured as a decision tree. OncoDoc has been routinely used by the multidisciplinary tumor board physicians of the Tenon Hospital (Paris, France) for three years leading to the resolution of 1,861 exploitable decisions. Because we were lacking patient data to assess the DESIREE GL-DSS, we investigated the option of reusing OncoDoc patient data. Taking into account that we have two CDSSs with two formalisms to represent clinical practice guidelines and two knowledge representation models, we had to face semantic and structural interoperability issues. This paper reports how we created 10,681 synthetic patients to solve these issues and make OncoDoc data re-usable by the GL-DSS of DESIREE.
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http://dx.doi.org/10.3233/SHTI200718DOI Listing
November 2020

Utility of a mainstreamed genetic testing pathway in breast and ovarian cancer patients during the COVID-19 pandemic.

Eur J Med Genet 2020 Dec 10;63(12):104098. Epub 2020 Nov 10.

UF d'Oncogénétique, Département de Génétique et Institut Universitaire de Cancérologie, Groupe Hospitalier Pitié-Salpêtrière, AP-HP.Sorbonne Université, 47-83 Boulevard de l'Hôpital, F-75013 Paris, France; Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 et SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, 184 rue du Faubourg Saint-Antoine, F-75012 Paris, France.

Introduction: Mainstreamed genetic testing (MGT) obviates the need for a cancer genetics consultation, since trained oncologists (O) and gynaecologists (G) provide counseling, prescribe testing and deliver results. We report results from our MGT program and emphasize its utility during the COVID-19 lockdown, when cancer genetics clinics had suspended their activity.

Methods: An MGT pathway for breast and ovarian cancer (BC/OC) patients was established in Jan-2018 between the Assistance Publique - Hôpitaux de Paris.Sorbonne Université Cancer Genetics team and the Oncology/Gynecology departments at one teaching and two regional hospitals. Trained O + G evaluated patients with the Manchester Scoring System. A 12-point threshold was recommended for testing. Next-generation sequencing of BRCA1, BRCA2, PALB2, RAD51C and RAD51D was performed. Results were delivered to the patient by O/G. Pathogenic variants (PV) carriers were referred to the genetics clinic. Results are reported for the 2nd-Jan-2018 to 1st-June-2020 period. That includes the eight-week COVID-19 lockdown and three-week de-confinement phase 1.

Results: Results were available for 231/234 patients. Twenty-eight (12.1%) carried a PV. Of the 27 patients tested during the COVID-19 period, three carried a PV, two in BRCA1 and one in RAD51C. The clinical impact was immediate for the two BRCA1 BC cases undergoing neo-adjuvant chemotherapy, since double mastectomy and salpingo-oophorectomy will now be performed using two-step strategies.

Conclusions: MGT guaranteed care continuity in BC/OC patients during the critical phases of the COVID-19 pandemic, with immediate implications for PV carriers. More broadly, we report for the first time the successful implementation of MGT in France.
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http://dx.doi.org/10.1016/j.ejmg.2020.104098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654320PMC
December 2020

Efficacy of Circulating Tumor Cell Count-Driven vs Clinician-Driven First-line Therapy Choice in Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer: The STIC CTC Randomized Clinical Trial.

JAMA Oncol 2021 Jan;7(1):34-41

Department of Medical Oncology, Institut Curie, Université de Paris, Paris, France.

Importance: The choice between chemotherapy and endocrine therapy as first-line treatment for hormone receptor-positive, ERBB2 (also known as HER2)-negative metastatic breast cancer is usually based on the presence of clinical features associated with a poor prognosis. In this setting, a high circulating tumor cell (CTC) count (≥5 CTCs/7.5 mL) is a strong adverse prognostic factor for overall survival and progression-free survival (PFS).

Objective: To compare the efficacy of a clinician-driven treatment choice vs a CTC-driven choice for first-line treatment.

Interventions: In the CTC arm, patients received chemotherapy or endocrine therapy according to the CTC count (chemotherapy if ≥5 CTCs/7.5 mL; endocrine therapy if <5 CTCs/7.5 mL), whereas in the control arm, the choice was left to the investigator.

Design, Setting, And Participants: In the STIC CTC randomized, open-label, noninferiority phase 3 trial, participants were randomized to a clinician-driven choice of first-line treatment or a CTC count-driven first-line treatment choice. Eligible participants were premenopausal and postmenopausal women 18 years or older diagnosed with hormone receptor-positive, ERBB2-negative metastatic breast cancer. Data were collected at 17 French cancer centers from February 1, 2012, to July 28, 2016, and analyzed June 2019 to October 2019.

Main Outcome And Measures: The primary end point was the investigator-assessed PFS in the per-protocol population, with a noninferiority margin of 1.25 for the 90% CI of the hazard ratio.

Results: Among the 755 women in the per-protocol population, the median (range) age was 63 (30-88) years [64 (30-88) years for the 377 patients allocated to the CTC arm and 63 (31-87) years for the 378 patients allocated to the standard arm]; 138 (37%) and 103 (27%) received chemotherapy, respectively. Median PFS was 15.5 months (95% CI, 12.7-17.3) in the CTC arm and 13.9 months (95% CI, 12.2-16.3) in the standard arm. The primary end point was met, with a hazard ratio of 0.94 (90% CI, 0.81-1.09).

Conclusions And Relevance: This randomized clinical trial found that the CTC count may be a reliable biomarker method for guiding the choice between chemotherapy and endocrine therapy as the first-line treatment in hormone receptor-positive, ERBB2-negative metastatic breast cancer.

Trial Registration: ClinicalTrials.gov Identifier: NCT01710605.
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http://dx.doi.org/10.1001/jamaoncol.2020.5660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645742PMC
January 2021

[First results of a breast cancer risk assessment and management consultation].

Bull Cancer 2020 Oct 23;107(10):972-981. Epub 2020 Sep 23.

AP-HP, institut universitaire de cancérologie, Sorbonne Université (IUC AP-HP.SU), Paris, France.

Introduction: In France, participation in the organized breast cancer screening program remains insufficient. A personalized approach adapted to the risk factors for breast cancer (RBC) should make screening more efficient. A RBC evaluation consultation would therefore make it possible to personalize this screening. Here we report our initial experience.

Material And Method: This is a prospective study on women who were seen at the RBC evaluation consultation and analyzing: their profile, their risk assessed according to Tyrer Cuzick model (TC)±Mammorisk© (MMR), the existence of an indication of oncogenetic consultation (Eisinger and Manchester score), their satisfaction and the recommended monitoring.

Results: Among the women who had had a TCS and/or MMR evaluation of SCR (n=153), 76 (50%) had a high risk (n=67) or a very high risk (n=9). Almost half (47%) had a possible (15%) or certain (32%) indication to an oncogenetic consultation. Regarding this consultation, 98% of women were satisfied or very satisfied. In total, 60% of women had a change in screening methods.

Conclusion: This RBC evaluation consultation satisfies women and for a majority of them, modifies their methods of breast cancer screening.
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http://dx.doi.org/10.1016/j.bulcan.2020.08.003DOI Listing
October 2020

Breast Cancer Management during the COVID 19 Pandemic: French Guidelines.

Eur J Breast Health 2020 Jul 21;16(3):160-161. Epub 2020 Apr 21.

Executive Director of Institut Universitaire de Cancérologie AP-HP, Sorbonne Université, Paris, France.

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http://dx.doi.org/10.5152/ejbh.2020.200420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337915PMC
July 2020

Anticancer drugs and COVID-19 antiviral treatments in patients with cancer: What can we safely use?

Eur J Cancer 2020 09 10;136:1-3. Epub 2020 Jun 10.

Sorbonne Université, Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Oncology, F-75013 Paris, France; Institut Universitaire de Cancérologie. AP-HP Sorbonne Université, Paris, France; INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, équipe Theravir, France.

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http://dx.doi.org/10.1016/j.ejca.2020.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284279PMC
September 2020

A review of the international early recommendations for departments organization and cancer management priorities during the global COVID-19 pandemic: applicability in low- and middle-income countries.

Eur J Cancer 2020 08 8;135:130-146. Epub 2020 Jun 8.

Department of Medical Oncology, Tenon Hospital, Institut Universitaire de Cancérologie AP-HP. Sorbonne University, Paris, France.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a new virus that has never been identified in humans before. COVID-19 caused at the time of writing of this article, 2.5 million cases of infections in 193 countries with 165,000 deaths, including two-third in Europe. In this context, Oncology Departments of the affected countries had to adapt quickly their health system care and establish new organizations and priorities. Thus, numerous recommendations and therapeutic options have been reported to optimize therapy delivery to patients with chronic disease and cancer. Obviously, while these cancer care recommendations are immediately applicable in Europe, they may not be applicable in certain emerging and low- and middle-income countries (LMICs). In this review, we aimed to summarize these international guidelines in accordance with cancer types, making a synthesis for daily practice to protect patients, staff and tailor anti-cancer therapy delivery taking into account patients/tumour criteria and tools availability. Thus, we will discuss their applicability in the LMICs with different organizations, limited means and different constraints.
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http://dx.doi.org/10.1016/j.ejca.2020.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834380PMC
August 2020

Severe acute respiratory syndrome Coronavirus 2 infection in cancer population: Are patient-related symptoms helpful to track a harmful invisible?

Int J Cancer 2020 12 14;147(12):3576-3578. Epub 2020 Jul 14.

Medicine Faculty, University Hospital Tenon, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne University, Institut Universitaire de Cancérologie, Paris, France.

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http://dx.doi.org/10.1002/ijc.33167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361566PMC
December 2020

[Analytical review of doctoral theses in medicine and pharmacy carried out in oncology at the universities of Ouagadougou from 1982 to 2016].

Bull Cancer 2020 Jul - Aug;107(7-8):726-729. Epub 2020 May 26.

Université de Sorbonne Paris-VI, Paris, France; Hôpital Tenon, service d'oncologie et thérapie ciblée, Paris, France.

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http://dx.doi.org/10.1016/j.bulcan.2020.04.012DOI Listing
September 2020

Predicting the likelihood of recurrence of pregnancy-associated breast cancer: Nomogram based on analysis of the French cancer network: Cancer Associé à La Grossesse.

J Gynecol Obstet Hum Reprod 2021 Mar 20;50(3):101766. Epub 2020 Apr 20.

Department of Gynaecology and Obstetrics, Tenon University Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Faculté de Médecine Sorbonne Université, Institut Universitaire de Cancérologie (IUC), France; Centre CALG (Cancer Associé à La Grossesse), France; UMRS-938 Sorbonne University, Paris, France.

Objective: Pregnancy associated breast cancer (PABC) are defined as breast cancer diagnosed during pregnancy and during the year following delivery. The prediction of poor prognosis events (PPE) such as recurrence is a major medical challenge of management for women with PABC. The aim of this study was to build a nomogram based on selected clinical and histological variables to predict recurrence.

Study Design: This retrospective study included 96 patients with PABC from January 2002 to January 2018. A multivariate Cox analysis of selected risk factors was performed and a nomogram to predict recurrence was built. The nomogram was internally validated.

Results: The overall recurrence rate was 22% (21/95) and the 3-years recurrence rate was 13% (12/95). Age at diagnosis, histological type, immuno-histological class, tumor stage (TNM), node stage (TNM) were associated with PPE in univariate analysis, and were included in the final Cox model to develop the nomogram. The predictive model had a concordance index of 0.83 (95% Confidence Interval (CI), 0.81-0.85) and 0.78 (95% CI, 0.76-0.80) before and after the 200 repetitions of bootstrap sample corrections, respectively, and showed a good calibration.

Conclusion: Our results support the use of the present nomogram based on 5 clinical and pathological characteristics to predict PPE in PABC with a high concordance. External validation is required to recommend this nomogram in routine practice.
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http://dx.doi.org/10.1016/j.jogoh.2020.101766DOI Listing
March 2021

An updated evaluation of serum sHER2, CA15.3, and CEA levels as biomarkers for the response of patients with metastatic breast cancer to trastuzumab-based therapies.

PLoS One 2020 7;15(1):e0227356. Epub 2020 Jan 7.

Laboratoire de Biochimie et Hormonologie, Hôpital Tenon, Groupe Hospitalier Est Parisien, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: The transmembrane receptor tyrosine kinase HER2 is overexpressed in approximately 15% of breast tumors and correlates with poor clinical prognosis. Several treatments that target HER2 are approved for treatment of HER2-positive metastatic breast cancer. The serum biomarkers most widely used to monitor anti-HER2 therapies in patients with HER2-positive metastatic breast cancer currently are CA15.3 and CEA. Nevertheless, their clinical utility in patients with breast cancer remains a subject of discussion and controversy; thus, additional markers may prove useful in monitoring the therapeutic responses of these patients. The extracellular domain of HER2 can be shed by proteolytic cleavage into the circulation and this shed form, sHER2, is reported to be augmented during metastasis of HER2-positive breast tumors. Here, we studied the clinical usefulness of sHER2, CA15.3, and CEA for monitoring treatment for breast cancer.

Methods: We measured prospectively pretreatment and post-treatment serum levels (day 1, 30, 60 and 90) of these three biomarkers in 47 HER2-positive, metastatic breast cancer patients treated with trastuzumab in combination with paclitaxel. Evaluation of the disease was performed according to the Response Evaluation Criteria in Solid Tumor (RECIST) at day 90.

Results: Patients with progressive disease at day 90 had smaller relative changes between day 1 and day 30 than those with complete, partial or stable responses at day 90: -9% versus -38% for sHER2 (P = 0.02), +23% versus -17% for CA15.3 (P = 0.005) and +29% versus -26% for CEA (P = 0.02). Patients with progressive disease at day 90 were less likely than the other patients to have a relative decrease of > 20% in their biomarker levels at day 30: 6% vs 33% for sHER2 (P = 0.03), 0% vs 27% for CA15.3 (P = 0.03), 4% vs 29% for CEA (P = 0.04). No patient with progressive disease at day 90 had > 20% reduction of the average combined biomarker levels at day 30 whereas 63% of the other patients had (P = 0.003). Moreover, when we analyzed a > 10% reduction of the average biomarker levels no patient with progressive disease at day 90 had a decrease > 10% at day 30 whereas 78% of other patients had (P<0.001, Se = 100%, Sp = 78%).

Conclusion: We show that regular measurement of sHER2, CA15.3, and CEA levels is useful for predicting the therapeutic response and for monitoring HER2-targeted therapy in patients with HER2-positive metastatic breast cancer. The average decrease of the three biomarkers with a threshold of > 10% appears to be the best parameter to distinguish patients who go on to have progressive disease from those who will have a complete, partial or stable response.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227356PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946590PMC
April 2020

CDK4/6 inhibition in low burden and extensive metastatic breast cancer: summary of an pro and con discussion.

ESMO Open 2019 13;4(6):e000565. Epub 2019 Nov 13.

Vienna Cancer Center, Medical University of Vienna and Vienna Hospital Association, Vienna, Austria.

In December 2017, convened a round-table discussion on the background and latest data regarding cyclin-dependent kinase (CDK)4/6 inhibitors with endocrine therapy (ET) in the treatment of endocrine-sensitive breast cancer (BC). A review on this discussion was published in summer 2018 (https://esmoopen.bmj.com/content/3/5/e000368).Endocrine-sensitive BC with non-visceral disease and limited spread of the metastases.Endocrine-sensitive BC with non-life-threatening visceral involvement. Several open questions were identified, which led to a second discussion on CDK4/6 inhibitors, taking place in December 2018 and covered in this article. The panel discussed two important clinical scenarios and the pro and cons of a treatment approach with CDK4/6 inhibitors for each scenario:Endocrine-sensitive BC with non-visceral disease and limited spread of the metastases.Endocrine-sensitive BC with non-life-threatening visceral involvement. Regarding scenario 1, the panel agreed that CDK4/6 inhibitors should be recommended in first-line therapy for most patients if cost and practicality allow. However, the use of single-agent ET with an aromatase inhibitor in the first-line treatment of these patients is still a possibility for a small group of patients with very limited disease, such as one or two bone lesions or limited lymph node involvement. Regarding scenario 2, chemotherapy is the first approach for patients with endocrine-sensitive metastatic BC with life-threatening visceral involvement because of the need for a faster response. The therapeutic approaches for patients with non-life-threatening visceral involvement are still under debate. Nevertheless, CDK4/6 inhibitors are currently the treatment of choice for most patients with a close follow-up of tumour response. A treatment algorithm has been suggested at the round table.
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http://dx.doi.org/10.1136/esmoopen-2019-000565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863664PMC
June 2020

AROME-ESO Oncology Consensus Conference: access to cancer care innovations in countries with limited resources. Association of Radiotherapy and Oncology of the Mediterranean Area (AROME-Paris) and European School of Oncology (ESO - Milan).

J BUON 2019 Sep-Oct;24(5):2180-2197

Clinical Center of Montenegro, University of Montenegro, Podgorica, Montenegro.

Purpose: Cancer is a leading cause of mortality worldwide. Its incidence is still increasing, particularly in developing countries. Recent progresses further strengthen the differences between low/middle and high-income countries. This situation calls for joint action to reduce inequities in cancer outcomes among the patients. The Association of Radiotherapy and Oncology of the Mediterranean Area (AROME) and the European School of Oncology (ESO), have initiated joint conferences devoted to access to innovations in oncology in the Mediterranean area. The heterogeneity of the economic, political and cultural situations of the different participating countries, offers the opportunity to develop consensus conference.

Methods: Cancer prevention and treatment strategies were discussed according to existing international guidelines. The Scientific committee prepared 111 questions with an objective to prioritize the access to treatments and innovations in low/middle-income Mediterranean countries. The results from the votes of 65 oncology experts, coming from 16 countries and 33 institutions have been analysed and access priorities classified accordingly.

Results: Ninety six percent of the proposed general recommendations concerning national health care strategies, oncology education, and treatment organization were considered to be high priorities. Regarding access to systemic treatments, 41% of the drugs without validated predictive markers and 53% of those with validated predictive markers were considered to be 1st level priority. Only 4 biological tests were considered to be 1st level priority to access to innovation.

Conclusions: AROME-ESO consensus offers to cancer specialists from developing countries a basis for discussion with health authorities and payers on the prioritization of access to innovations in cancer care.
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April 2020

Percutaneous Image-Guided Electrochemotherapy of Spine Metastases: Initial Experience.

Cardiovasc Intervent Radiol 2019 Dec 22;42(12):1806-1809. Epub 2019 Aug 22.

Vectorology and Anticancer Therapies, UMR8203, CNRS, University of Paris-Sud, Gustave Roussy, Université Paris-Saclay, 94805, Villejuif, France.

Two patients underwent percutaneous image-guided electrochemotherapy on blastic spine metastases involving posterior walls of the lumbar vertebral bodies with epidural extension. These treatments were performed safely under cone beam computed tomography. Local tumor control was obtained on the subsequent follow-up as well as pain relief and disability improvement. Electrochemotherapy might be considered for patients with thus far no other alternative in order to obtain tumor control and improvement in patients' quality of life.
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http://dx.doi.org/10.1007/s00270-019-02316-4DOI Listing
December 2019

Iniparib administered weekly or twice-weekly in combination with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: a phase II randomized open-label study with pharmacokinetics.

Breast Cancer Res Treat 2019 Sep 6;177(2):383-393. Epub 2019 Jun 6.

Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

Purpose: Metastatic triple-negative breast cancer (TNBC) is a phenotypic breast cancer subgroup with a very poor prognosis, despite standard treatments. Combined twice-weekly iniparib and gemcitabine/carboplatin (GC+tw-iniparib) showed benefit over gemcitabine/carboplatin in a randomized phase II trial, and a phase III was initiated comparing these regimens. The present phase II study was initiated to compare GC+tw-iniparib with a more practical once-weekly schedule (GC+w-iniparib) in TNBC.

Methods: Metastatic TNBC patients were randomized to receive iniparib weekly (11.2 mg/kg on days 1 and 8) or twice-weekly (5.6 mg/kg on days 1, 4, 8, and 11) with gemcitabine (1000 mg/m) and carboplatin (area under the curve 2 on days 1 and 8), every 3 weeks. The primary endpoint was the overall response rate (ORR). Pharmacokinetics of iniparib and its two metabolites were analyzed.

Results: A total of 163 patients were randomized, 82 GC+w-iniparib and 81 GC+tw-iniparib. Demographic and baseline characteristics were well balanced. ORR was 34.1% (95% CI 23.9-44.4%) vs. 29.6% (95% CI 19.7-39.6%) and median progression-free survival was 5.5 months (95% CI 4.2-5.7) vs. 4.3 months (95% CI 3.0-5.8) for GC+w-iniparib and GC+tw-iniparib, respectively. Safety was similar across treatment arms in terms of event severity and type. Iniparib plasma concentrations and exposure were two-fold higher with w-iniparib compared to tw-iniparib. Iniparib and its metabolites were cleared rapidly with a terminal half-life of < 1 h, without accumulation.

Conclusions: Despite a doubled maximum concentration with weekly iniparib, no detectable differences in safety or efficacy were observed between the weekly and twice-weekly administration schedules in this population.

Trial Registration: ClinicalTrial.gov Identifier NCT01045304.
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http://dx.doi.org/10.1007/s10549-019-05305-wDOI Listing
September 2019

Citrate targets FBPase and constitutes an emerging novel approach for cancer therapy.

Cancer Cell Int 2018 8;18:175. Epub 2018 Nov 8.

5Faculty of Pharmacy of Lyon, CRCL Lyon, Unité Inserm 1052, CNRS 5286, Lyon, France.

Gao-Min Liu and Yao-Ming Zhang recently published a review entitled «Targeting FBPase is an emerging novel approach for cancer therapy» (Liu and Zhang in Cancer Cell Int 18:36, 2018). In this paper, the authors highlighted how the down regulation or inactivation of FBPase, a rate limiting enzyme of gluconeogenesis, can promote the Warburg effect and cancer growth. In contrast, activation of this enzyme demonstrates anti-cancer effects and may appear as emerging novel approach for cancer therapy. Among the potential activators of FBP listed by Liu and Zhang, citrate was surprisingly not mentioned although it is an activator of FBPase, also demonstrating various anti-cancer effects in pre-clinical studies. Thus, citrate should be tested as a new therapeutic strategy, in particular in clinical studies.
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http://dx.doi.org/10.1186/s12935-018-0676-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225682PMC
November 2018

[Metastatic stomach cancer: Clinical trials in Asia and in Occident].

Bull Cancer 2018 Oct 20;105(10):932-943. Epub 2018 Sep 20.

Public Assistance-Paris Hospitals, AP-HP, Alliance pour la recherche en cancérologie (APREC), department of medical oncology, hospital Tenon, 4 rue de la Chine, 75020 Paris, France. Electronic address:

Although cytotoxic chemotherapy is the main therapeutic option to treat gastric cancer in the metastatic setting, molecular targeted agents have recently been introduced in an effort to improve survival outcomes which in average do not exceed 1 year. Trastuzumab and ramucirumab, antibodies directed against HER2 and VEGFR2, respectively, may provide clinical benefit for some patients. Results of clinical studies show that Asian patients have increased survival compared to Caucasian patients. Differences between populations, and in particular the presence of polymorphisms capable of influencing the availability of fluorouracil, have been suggested as possible explanations. Other factors including histology, surgical procedures, administration of neoadjuvant chemotherapy in Western countries and screening programs in Asia have also been suggested. However, none of these elements can fully explain this phenomenon. The aim of this article is to present the main protocols used in clinical practice, the perspectives of metastatic gastric cancer treatment and the particularities observed in Asian and Caucasian patients.
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http://dx.doi.org/10.1016/j.bulcan.2018.07.012DOI Listing
October 2018

Guidelines for reporting secondary findings of genome sequencing in cancer genes: the SFMPP recommendations.

Eur J Hum Genet 2018 12 8;26(12):1732-1742. Epub 2018 Aug 8.

Université de Montpellier, Montpellier, France.

In oncology, the expanding use of multi-gene panels to explore familial cancer predisposition and tumor genome analysis has led to increased secondary findings discoveries (SFs) and has given rise to important medical, ethical, and legal issues. The American College of Medical Genetics and Genomics published a policy statement for managing SFs for a list of genes, including 25 cancer-related genes. Currently, there are few recommendations in Europe. From June 2016 to May 2017, the French Society of Predictive and Personalized Medicine (SFMPP) established a working group of 47 experts to elaborate guidelines for managing information given on the SFs for genes related to cancers. A subgroup of ethicists, lawyers, patients' representatives, and psychologists provided ethical reflection, information guidelines, and materials (written consent form and video). A subgroup with medical expertise, including oncologists and clinical and molecular geneticists, provided independent evaluation and classification of 60 genes. The main criteria were the "actionability" of the genes (available screening or prevention strategies), the risk evaluation (severity, penetrance, and age of disease onset), and the level of evidence from published data. Genes were divided into three classes: for class 1 genes (n = 36), delivering the information on SFs was recommended; for class 2 genes (n = 5), delivering the information remained questionable because of insufficient data from the literature and/or level of evidence; and for class 3 genes (n = 19), delivering the information on SFs was not recommended. These guidelines for managing SFs for cancer-predisposing genes provide new insights for clinicians and laboratories to standardize clinical practices.
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http://dx.doi.org/10.1038/s41431-018-0224-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244405PMC
December 2018

Adjuvant Subcutaneous Trastuzumab for HER2-Positive Early Breast Cancer: Subgroup Analyses of Safety and Active Medical Conditions by Body Weight in the SafeHer Phase III Study.

Oncologist 2018 10 17;23(10):1137-1143. Epub 2018 Jul 17.

Oncology Department, School of Medicine, Cairo University, Cairo, Egypt.

Background: This SafeHer subgroup analysis assessed the safety of fixed-dose subcutaneous trastuzumab (H SC) as an adjuvant therapy in HER2-positive early breast cancer (EBC) by body weight.

Patients And Methods: Patients with HER2-positive EBC not previously treated with anti-HER2 therapy received H SC 600 mg (every 3 weeks for 18 cycles), with neoadjuvant or adjuvant chemotherapy or without adjuvant chemotherapy. Adverse events (AEs) were assessed throughout treatment and at final follow-up (28 ±5 days after last treatment). Subgroups were categorized by body weight, Asian origin, and chemotherapy administration. All analyses were descriptive.

Results: Of 2,577 patients enrolled, 2,573 received ≥1 dose of study medication and were included in this safety analysis. Median body weight at baseline was 67.0 kg (range 33.6-150.0 kg). Any-grade AEs occurred in 88.7% (2,282/2,573) of the overall population, versus 87.1% (590/677) of the lowest bodyweight quartile (≤59 kg), 90.0% (561/623) of the highest quartile (>77 kg), and 86.5% (327/378) of the Asian population. Grade ≥3 AEs occurred in 23.2% (596/2,573) of the overall population, 17.9% (121/677) of the lowest bodyweight quartile, 26.8% (167/623) of the highest quartile, and 15.3% (58/378) of the Asian population. The highest bodyweight quartile had the highest incidence of medical conditions at baseline (highest quartile, 75.6%; lowest quartile, 56.1%).

Conclusion: These data support the use of fixed-dose H SC as an adjuvant therapy in HER2-positive EBC and confirm the comparable safety profile of H SC in patients with low body weight or of Asian origin versus the overall population in SafeHer. ClinicalTrials.gov: NCT01566721.

Implications For Practice: The safety profile of fixed-dose subcutaneous trastuzumab (H SC) was comparable between patients in the lowest bodyweight subgroup and the overall patient population, and also between patients of Asian origin (of whom a higher proportion often fall within the lower bodyweight quartiles) and the overall population. The safety data from this SafeHer subgroup analysis therefore support the use of fixed-dose H SC 600 mg administered every 3 weeks as an adjuvant therapy for patients with HER2-positive early breast cancer across different bodyweight subgroups and in the Asian patient population.
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http://dx.doi.org/10.1634/theoncologist.2018-0065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263135PMC
October 2018

Local and Regional Breast Cancer Recurrences: Salvage Therapy Options in the New Era of Molecular Subtypes.

Front Oncol 2018 17;8:112. Epub 2018 Apr 17.

Sorbonne University, INSERM U938, APHP Tenon, Breast Cancer Expert Center, Paris, France.

Isolated local or regional recurrence of breast cancer (BC) leads to an increased risk of metastases and decreased survival. Ipsilateral breast recurrence can occur at the initial tumor bed or in another quadrant of the breast. Depending on tumor patterns and molecular subtypes, the risk and time to onset of metastatic recurrence differs. HER2-positive and triple-negative (TNG) BC have a risk of locoregional relapse between six and eight times than luminal A. Thus, the management of local and locoregional relapses must take into account the prognostic factors for metastatic disease development. It is important to personalize the overall management, including or not systemic treatment according to the metastatic risk. All isolated recurrence cases should be treated with curative intent. Complete surgical resection is recommended whenever possible. Patients who did not receive postoperative irradiation during their initial management should receive full-dose radiotherapy to the chest wall and to the regional lymph nodes if appropriate. Overall, total mastectomy is the "gold standard" among patients who were previously treated by conservative surgery followed by radiation therapy. In terms of systemic therapy, the benefits of additional treatments are not conclusively proven in cases of isolated recurrence. The beneficial role of chemotherapy has been reported in at least one randomized trial, while endocrine therapy and anti-HER2 are common practice. This review will discuss salvage treatment options of local and locoregional recurrences in the new era of BC molecular subtypes.
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http://dx.doi.org/10.3389/fonc.2018.00112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913327PMC
April 2018

[Including recovery in the care pathway after cancer].

Soins 2018 Apr;63(824):66-68

Département de psychiatrie, Université de Montréal, pavillon Roger-Gaudry 2900, boul. Édouard-Montpetit, bureau S-750, Montréal H3T 1J4, Québec.

The period after cancer treatments have finished requires personalised services and support, based on the theoretical and clinical concept of recovery. The recovery phase comprises several dimensions: it is not because a patient is in remission or declared medically cured that he or she has recovered.
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http://dx.doi.org/10.1016/j.soin.2018.02.016DOI Listing
April 2018

Propensity score to evaluate prognosis in pregnancy-associated breast cancer: Analysis from a French cancer network.

Breast 2018 Aug 14;40:10-15. Epub 2018 Apr 14.

Department of Gynaecology and Obstetrics, Tenon University Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Faculté de Médecine Sorbonne Université, Institut Universitaire de Cancérologie (IUC), France; Centre CALG (Cancer Associé à La Grossesse), France; UMRS-938 4. Faculté de Médecine Sorbonne Université, France.

Purpose: To compare the prognosis of pregnancy associated breast cancer occurring during pregnancy (BCP) to non-pregnancy associated breast cancers (non-BCP) in young women managed at a national expert center.

Methods: Retrospective cohort study of a prospective database using propensity score matching (PSM) analysis with known prognostic factors.

Results: We analyzed data of 49 patients with BCP and 104 with non-BCP diagnosed between 2002 and 2017 at Tenon University Hospital (Paris, France). The BCP tumors were often locally advanced (lymph node metastases in 59%), of high grade (55%) and highly proliferative (67% with Ki67 ≥ 20%). After PSM, breast cancer-free survival (p = 0.45) and breast cancer specific survival (p = 0.81) were similar in the two groups. The recurrence rate was 12% vs 18% (p = 0.45) and the death rate was 6% vs 8% (p = 0.74) for the BCP and non-BCP groups, respectively. No difference in recurrence type was observed between the groups (p = 0.60).

Conclusions: After PSM for known prognostic factors, the prognosis of BCP patients did not differ from that of young patients with non-BCP.
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http://dx.doi.org/10.1016/j.breast.2018.03.014DOI Listing
August 2018