Publications by authors named "Renaud Sabatier"

53 Publications

The impact of modern preoperative high-dose-rate brachytherapy in early-stage cervical cancer.

Gynecol Oncol 2021 Feb 6. Epub 2021 Feb 6.

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

Purpose: To analyze the clinical outcomes and the safety of preoperative high-dose-rate (HDR) image-guided adaptive brachytherapy (IGABT) followed by minimally invasive surgery (MIS) in the multidisciplinary management of early-stage cervical cancer.

Methods And Materials: Medical records of all consecutive patients with early-stage cervical cancer treated at our institution between 2012 and 2018 with preoperative IGABT in a multidisciplinary approach were reviewed. Treatment schedule was pelvic node dissection, preoperative IGABT followed 6-8 week later by MIS hysterectomy.

Results: Seventy patients with cervical cancer FIGO stages (IB1 18.6%, IB2 75.7% and IIA1 5.7%) were treated by preoperative HDR brachytherapy. With a median follow-up of 37.4 months [95% confidence interval, 32.1-39.7 months] isolated vaginal vault recurrence was not observed, 3 pelvic relapses were reported (4.3%). None of patients received postoperative radiotherapy (EBRT) or radiochemotherapy. The estimated 3-year local and pelvis relapse free survival for the entire population were respectively 98% [95% confidence interval, 89%-100%] and 90% [80%-96%]. The estimated 3-year disease-free survival (DFS) for the entire population was 88% [77-94%]. The 3-year overall survival (OS) rate was 97% [88%-99%]. Microscopic vaginal resection margin (R1) was observed in one patient ([1].4%). Lymph-vascular space invasion (LVSI) was found found in 6 (8.6%) patients. Forty-eight late complications in 36 patients (51.4%) were observed. Five (7.1%) grade 3 vaginal wound dehiscence toxicities were observed. Urinary and gastrointestinal toxicities were grade 1-2. No grade 4-5 complications were observed.

Conclusions: Preoperative image-guided adaptive brachytherapy followed by minimally invasive surgery allows high local control, reduces positive surgical margins and rates of lymph-vascular space invasion avoiding adjuvants treatments. Surgical approaches must be discussed with patients including preoperative brachytherapy as a down-staging treatment.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.034DOI Listing
February 2021

Circulating Tumor Cells and Bevacizumab Pharmacokinetics during Neoadjuvant Treatment Combining Chemotherapy and Bevacizumab for Early Breast Cancer: Ancillary Analysis of the AVASTEM Trial.

Cancers (Basel) 2021 Jan 5;13(1). Epub 2021 Jan 5.

CNRS U7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Aix Marseille University, 13009 Marseille, France.

The phase II AVASTEM trial explored the impact of chemotherapy-bevacizumab combination on breast cancer stem cells in the neoadjuvant setting. We aimed to identify biological features associated with preoperative chemotherapy efficacy and prognosis by analyses of circulating tumor cells (CTCs) and bevacizumab pharmacokinetics (PK). The main objective was to assess the prognostic (relapse-free survival and overall survival) and predictive (pathological complete response, pCR) values of CTCs (CellSearch technology) and bevacizumab PK (ELISA). Seventy-five patients were included. Out of them 50 received bevacizumab-chemotherapy and 25 received chemotherapy alone. CTC results were available for 60 patients and PK data for 29 patients in the experimental arm. The absence of CTC at inclusion was correlated to better outcome. Five-years overall survival (OS) was 91% for CTC-negative patients vs. 54% for CTC-positive cases (HR = 6.21; 95%CI (1.75-22.06), = 0.001, log-rank test). Similar results were observed for RFS with 5 y-RFS of 78% vs. 44% (HR = 3.51; 95%CI (1.17-10.52), = 0.017, log-rank test). However, CTC status at baseline was not predictive of pCR ( = 0.74). CTC status after one cycle was not a significant prognostic factor (HR = 1.56; 95%CI (0.19-12.67); = 0.68 for OS and HR = 2.76; 95%CI (0.60-12.61); = 0.17 for RFS, log-rank test). Bevacizumab serum levels could not predict pCR and survival. PK values were not associated with treatment-related toxicities. In conclusion, CTCs detection at baseline is a prognostic marker for breast cancer receiving a neoadjuvant chemotherapy-bevacizumab combination independently of tumor response.
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http://dx.doi.org/10.3390/cancers13010140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796232PMC
January 2021

[PARP inhibitors in breast cancer: Current clinical development and perspectives].

Bull Cancer 2020 Oct 28;107(10):1024-1041. Epub 2020 Sep 28.

Aix-Marseille Université, Institut Paoli-Calmettes, CNRS, département d'Oncologie Médicale, CRCM, Inserm, 232, boulevard Sainte-Marguerite, BP 156, 13273 Marseille cedex 9, France. Electronic address:

The association of a germline mutation in the BRCA1/2 genes in breast cancer leads to a higher genomic instability and, thus, a potential higher sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. In this review, we will summarize the different DNA-repair pathways including PARP-dependent mechanisms that support the use of PARP inhibitors. We will present clinical trials evaluating PARP inhibitors alone or in combination in early or advanced stage breast cancer. We will then discuss the different mechanisms involved in the resistance to PARP inhibitors. We will also introduce the concept of BRCAness by which the use of PARP inhibitors could be extended to BRCA1/2-wild type patients. Finally, we will describe the new channels implemented for the theranostic genetic screening.
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http://dx.doi.org/10.1016/j.bulcan.2020.07.011DOI Listing
October 2020

Clinical Activity and Safety of the Anti-Programmed Death 1 Monoclonal Antibody Dostarlimab for Patients With Recurrent or Advanced Mismatch Repair-Deficient Endometrial Cancer: A Nonrandomized Phase 1 Clinical Trial.

JAMA Oncol 2020 Oct 1. Epub 2020 Oct 1.

Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille-Predictive Oncology Laboratory, Centre de Recherche en Cancérologie de Marseille, Department of Medical Oncology, Aix-Marseille University, Inserm, Centre National de la Recherche Scientifique, Marseille, France.

Importance: Deficient mismatch mutation repair mechanisms may sensitize endometrial cancers to anti-programmed death 1 (PD-1) therapies. Dostarlimab (TSR-042) is an investigational anti-PD-1 antibody that binds with high affinity to the PD-1 receptor.

Objective: To assess the antitumor activity and safety of dostarlimab for patients with deficient mismatch repair endometrial cancer.

Design, Setting, And Participants: This ongoing, open-label, single-group, multicenter study began part 1 on March 7, 2016, and began enrolling patients with deficient mismatch mutation repair endometrial cancer on May 8, 2017. Median follow-up was 11.2 months (range, 0.03 [ongoing] to 22.11 [ongoing] months; based on radiological assessments). Statistical analysis was performed July 8 to August 9, 2019.

Interventions: Patients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, treatment discontinuation, or withdrawal.

Main Outcomes And Measures: The primary end point was objective response rate and duration of response by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1.

Results: As of the data cutoff, 104 women (median age, 64.0 years [range, 38-80 years]) with deficient mismatch mutation repair endometrial cancers were enrolled and treated with dostarlimab. Of these, 71 had measurable disease at baseline and at 6 months or more of follow-up and were included in the analysis. There was a confirmed response in 30 patients (objective response rate, 42.3%; 95% CI, 30.6%-54.6%); 9 patients (12.7%) had a confirmed complete response, and 21 patients (29.6%) had a confirmed partial response. Responses were durable; the median duration of response was not reached (median follow-up was 11.2 months). The estimated likelihood of maintaining a response was 96.4% at 6 months and 76.8% at 12 months. Anemia (3 of 104 [2.9%]), colitis (2 of 104 [1.9%]), and diarrhea (2 of 104 [1.9%]) were the most common grade 3 or higher treatment-related adverse events.

Conclusions And Relevance: In this nonrandomized trial, dostarlimab was associated with clinically meaningful and durable antitumor activity with an acceptable safety profile for patients with deficient mismatch mutation repair endometrial cancers after prior platinum-based chemotherapy.

Trial Registration: ClinicalTrials.gov identifier: NCT02715284.
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http://dx.doi.org/10.1001/jamaoncol.2020.4515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530821PMC
October 2020

[New European approvals: Alpelisib for HRpos/HER2neg metastatic breast cancer with PIK3CA mutation].

Bull Cancer 2020 Oct 22;107(10):959-960. Epub 2020 Sep 22.

Institut Paoli-Calmettes, Centre de recherche en cancérologie de Marseille, laboratoire d'oncologie prédictive, département d'oncologie médicale, Inserm UMR1068, CNRS UMR7258, Aix-Marseille Université, 13009 Marseille, France.

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http://dx.doi.org/10.1016/j.bulcan.2020.07.007DOI Listing
October 2020

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

Fertility and prognosis of borderline ovarian tumor after conservative management: Results of the multicentric OPTIBOT study by the GINECO & TMRG group.

Gynecol Oncol 2020 04;157(1):29-35

Institut Curie, St Cloud, France; Inserm U900, Institut Curie, St Cloud, France. Electronic address:

Objectives: Description of fertility and prognosis of patients with borderline ovarian tumor (BOT) treated by fertility-sparing surgery through a longitudinal study from the French national cancer network.

Methods: All consecutive patients diagnosed with BOT from the French National Network dedicated to Ovarian Malignant Rare Tumors from 2010 and 2017 were selected. In 2018, an update was made by sending a questionnaire regarding recurrence and fertility to patients aged under 43 years at diagnosis and treated conservatively. We compared the characteristics of the patients with/without recurrence and with/without live birth.

Results: Fifty-two patients aged 18 to 42 years presented a desire of pregnancy. Thirty patients (58%) presented a FIGO IA tumor, and 20 patients were treated by bilateral cystectomies (38%). We observed at least one live birth for 33 patients (63%) and local recurrences in 20 patients (38%). Both recurrence and live birth in 17 patients (33%) were reported, with recurrence occurring before pregnancy, after a second fertility-sparing treatment, in half of the cases. No factors associated with recurrence or live birth in this study were identified. Moreover, in this population, both recurrence and live birth were independent of age, with a linear risk along time. Disease-free survival was worse for patients treated with bilateral cystectomy (n = 20, 38%), with no difference in terms of fertility.

Conclusion: Two third of the patients experienced life birth after conservation surgery. We did not highlight an age/time from surgery for which the risk of recurrence outweighs the chance of pregnancy and to radicalize surgery. Moreover, almost a quarter of the live birth occurred after recurrence, with no more further event to date in these patients. The results encourage to consider a second fertility-sparing surgery after local borderline recurrence in the case of pregnancy desire. All these decisions must be discussed in specialized multidisciplinary boards.
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http://dx.doi.org/10.1016/j.ygyno.2019.12.046DOI Listing
April 2020

[2019 international oncology news: A compendium].

Bull Cancer 2020 Feb 10;107(2):148-156. Epub 2020 Feb 10.

Centre hospitalier universitaire Giscard d'Estaing, service thérapie cellulaire et hématologie clinique, 58, rue Montalembert, 63000 Clermont Ferrand, France.

Over the past years, planet oncology has kept changing and moving forward. Recent results of important clinical trials are challenging our daily practices. With modesty, the Editorial Board of BulletinduCancer has selected some clinical trials they consider as "must-know about" even if they go beyond our medical fields.
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http://dx.doi.org/10.1016/j.bulcan.2020.01.010DOI Listing
February 2020

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

Prediction of early discharge after gynaecological oncology surgery within ERAS.

Surg Endosc 2020 May 15;34(5):1985-1993. Epub 2019 Jul 15.

Department of Surgery, Paoli Calmettes Institute, Marseille, France.

Objectives: Enhanced recovery after surgery programs (ERAS) have been proven to decrease the length of hospital stay without increasing readmission rates or complications. However, the patient and operative characteristics that improve the chance of a successful early hospital discharge are not well established. The aim of this study was to design a nomogram which could be used before surgery, using the characteristics of patients, to establish who could benefit from early discharge (POD ≤ 2 days).

Methods: This observational study has been prospectively conducted. All the included patients were referred for surgical treatment of gynecologic cancer. We defined two sub-groups of patients on surgical procedure characteristics: isolated procedures (hysterectomy or lymphadenectomy) and combined procedures (at least the association of two procedures).

Results: 230 patients were enrolled during the study protocol. 83.9% of patients were treated with a minimally invasive surgery (MIS). 159 patients (69.1%) were discharged on or before POD 2. On multivariate analysis, the surgical approach (open surgery vs. laparoscopy, OR  0.02 (95% CI [0-0.07]), p < 0.001) and the type of surgery (combined procedure versus isolated procedure, OR  0.41 (95% CI [0.18-0.91]), p = 0.028) were found to be significant predictors of increased hospital stay. A nomogram has been built for the purpose of predicting eligible patients for early post-operative discharge based on the multivariate analysis results (AUC = 0.86, 95% CI [0.81-0.92]).

Conclusion: The use of MIS for isolated procedures in oncologic indications constitutes an independent factor of early discharge in a setting of ERAS. These promising preliminary results still require to be validated on a prospective cohort.
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http://dx.doi.org/10.1007/s00464-019-06974-wDOI Listing
May 2020

Liquid Biopsies for Ovarian Carcinoma: How Blood Tests May Improve the Clinical Management of a Deadly Disease.

Cancers (Basel) 2019 Jun 4;11(6). Epub 2019 Jun 4.

CRCM-Predictive Oncology laboratory, Institut Paoli-Calmettes, Inserm, CNRS, Aix-Marseille Univ, 232 Boulevard Sainte Marguerite, 13009 Marseille, France.

Ovarian cancers (OvC) are frequent, with more than 22,000 new cases each year for 14,000 deaths in the United States. Except for patients with or mutations, diagnostic methods, prognostic tools, and therapeutic strategies have not much improved in the last two decades. High throughput tumor molecular analyses have identified important alterations involved in ovarian carcinoma growth and spreading. However, these data have not modified the clinical management of most of patients. Moreover, tumor sample collection requires invasive procedures not adapted to objectives, such as the screening, prediction, or assessment of treatment efficacy, monitoring of residual disease, and early diagnosis of relapse. In recent years, circulating tumor biomarkers (also known as "liquid biopsies") such as circulating tumor cells, circulating nucleotides (DNA or miRNA), or extracellular vesicles, have been massively explored through various indications, platforms, and goals, but their use has not yet been validated in routine practice. This review describes the methods of analysis and results related to liquid biopsies for ovarian epithelial cancer. The different settings that a patient can go through during her journey with OvC are explored: screening and early diagnosis, prognosis, prediction of response to systemic therapies for advanced stages, and monitoring of residual subclinical disease.
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http://dx.doi.org/10.3390/cancers11060774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627130PMC
June 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

[Circulating tumor DNA assessment for gynaecological cancers management].

Bull Cancer 2019 Mar 11;106(3):237-252. Epub 2019 Feb 11.

Aix-Marseille university, CNRS U7258, Inserm U1068, institut Paoli-Calmettes, département d'oncologie médicale, CRCM, Marseille cedex 9, France; Aix-Marseille university, CNRS U7258, Inserm U1068, institut Paoli-Calmettes, CRCM, laboratoire d'oncologie prédictive, Marseille cedex 9, France. Electronic address:

Gynaecological cancers are frequent, with more than 16,000 cases per year in France for 6500 deaths. Few improvements in diagnostic methods, prognostic tools, and therapeutic strategies have occurred in the last two decades. Tumour genomic analyses from, at least in part, the Cancer Genome Atlas have identified some of the molecular alterations involved in gynaecological tumours growth and spreading. However, these data remain incomplete and have not led to dramatic changes in the clinical management of our patients. Moreover, they require invasive samples that are not suitable to objectives like screening/early diagnosis, assessment of treatment efficacy, monitoring of residual disease or early diagnosis of relapse. In the last years, the analysis of circulating tumour biomarkers (also called "liquid biopsies") based on tumour cells (circulating tumour cells) or tumour nucleotides (circulating DNA or RNA) has been massively explored through various indications, platforms, objectives; data related to circulating tumour DNA being the most important in terms of number of publications and interest for clinical practice. This review aims to describe the methods of analysis as well as the observations from the analysis of circulating tumour DNA in gynaecological tumours, from screening/early diagnosis to the adaptation of treatment for advanced stages, through choice of treatments and monitoring of subclinical disease.
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http://dx.doi.org/10.1016/j.bulcan.2018.11.018DOI Listing
March 2019

Targeting Deficiency in Breast Cancer: What are the Clinical Evidences and the Next Perspectives?

Cancers (Basel) 2018 Dec 11;10(12). Epub 2018 Dec 11.

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

Breast cancers (BC) associated with germline mutations of represent 3⁻5% of cases. -associated BC have biological features leading to genomic instability and potential sensitivity to DNA damaging agents, including poly(ADP-ribose) polymerase (PARP) and platinum agents. In this review, we will summarize clinical trials of chemotherapy and PARP inhibitors (PARPi), alone or in combination, at the early or late stage of -associated BC. We will also present the mechanisms of resistance to PARPi as well as the new therapeutic strategies of association with PARPi. Finally, we will discuss under which conditions the use of DNA damaging agents can be extended to the -wild type population, the ness concept.
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http://dx.doi.org/10.3390/cancers10120506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316565PMC
December 2018

Thrombotic microangiopathy associated with gemcitabine use: Presentation and outcome in a national French retrospective cohort.

Br J Clin Pharmacol 2019 02 18;85(2):403-412. Epub 2018 Dec 18.

Department of Nephrology, Aix-Marseille University, AP-HM Hôpital de la Conception, Marseille, France.

Aims: Gemcitabine has been associated with thrombotic microangiopathy (TMA). We conducted a national retrospective study of gemcitabine-associated TMA (G-TMA).

Methods: From 1998 to 2015, all cases of G-TMA reported to the French Pharmacovigilance Network and the French TMA Reference Center, and cases explored for complement alternative pathway abnormalities, were analysed.

Results: G-TMA was diagnosed in 120 patients (median age 61.5 years), after a median of 210 days of treatment, and a cumulative dose of 12 941 mg m . Gemcitabine indications were: pancreatic (52.9%), pulmonary (12.6%) and breast (7.6%) cancers, metastatic in 34.2% of cases. Main symptoms were oedema (56.7%) and new-onset or exacerbated hypertension (62.2%). Most patients presented with haemolytic anaemia (95.6%) and thrombocytopenia (74.6%). Acute kidney injury was reported in 97.4% and dialysis was required in 27.8% of patients. Treatment consisted of: plasma exchange (PE; 39.8%), fresh frozen plasma (21.4%), corticosteroids (15.3%) and eculizumab (5.1%). A complete remission of TMA was obtained in 42.1% of patients and haematological remission in 23.1%, while 34.7% did not improve. The survival status was known for 52 patients, with 29 deaths (54.7%). Patients treated with PE, despite a more severe acute kidney injury, requiring dialysis more frequently, displayed comparable rates of remission, but with more adverse events. No abnormality in complement alternative pathway was documented in patients explored.

Conclusion: This large cohort confirms the severity of G-TMA, associated with severe renal failure and death. Oedema and hypertension could be monitored in patients treated with gemcitabine to detect early TMA. The benefit of PE or eculizumab deserves further investigation.
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http://dx.doi.org/10.1111/bcp.13808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339967PMC
February 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

Nivolumab in routine practice for older patients with advanced or metastatic non-small cell lung cancer.

J Geriatr Oncol 2018 09 9;9(5):494-500. Epub 2018 Mar 9.

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

Background: Nivolumab is approved worldwide as second-line treatment for metastatic non-small cell lung cancer (NSCLC). Despite the fact that most of these cancers are being diagnosed in the older patients, few of the patients were included in pivotal trials. We aimed to describe efficacy and safety in a "real-world" older population.

Patients And Methods: We retrospectively collected data from older patients (≥70 years old) with advanced or metastatic NSCLC treated with Nivolumab in our institution. We analyzed safety (CTCAE v4.0 criteria), efficacy (clinical benefit rate, progression-free survival, and overall survival), and correlated these features to geriatric parameters and PD-L1 expression. Along with this cohort, we assessed safety at a national level by retrieving all cases of Nivolumab (prescribed for NSCLC) induced adverse events analyzed by the French pharmacovigilance network during the inclusion period.

Results: From July 2015 to September 2016, 30 patients were enrolled with a median age of 75.2. Clinical benefit rate was 30.6%. Median progression-free survival and overall survival were 3.3 and 7.1 months, respectively. Fifteen patients (50%) presented an immune-related adverse event (IrAE) of any grade, including four high grade IrAEs. Two hundred and eighty IrAEs had been notified to the French pharmacovigilance network including 91 (35.2%) concerning older patients. Frequency and pattern of IrAEs were similar for older patients and younger subjects.

Conclusions: Even though frequency and patterns of IrAEs are different from pivotal studies, these results don't seem specific to older patients. Further prospective investigations are needed to better characterize and predict the impact of Nivolumab on older patients with NSCLC.
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http://dx.doi.org/10.1016/j.jgo.2018.02.011DOI Listing
September 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

Safety and efficacy of eribulin for "real-world" older patients with metastatic breast cancer.

J Geriatr Oncol 2018 05 22;9(3):281-283. Epub 2017 Nov 22.

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

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http://dx.doi.org/10.1016/j.jgo.2017.11.003DOI Listing
May 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

Immune checkpoints inhibitors for solid tumours after allogeneic haematopoietic stem-cell transplantation: About four clinical cases.

Eur J Cancer 2017 08;81:138-141

Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France; Aix Marseille Univ, CNRS U7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Marseille, France. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2017.05.023DOI Listing
August 2017

Value of Dynamic Contrast-enhanced and Diffusion-weighted MR Imaging in the Detection of Pathologic Complete Response in Cervical Cancer after Neoadjuvant Therapy: A Retrospective Observational Study.

Radiology 2017 08 16;284(2):432-442. Epub 2017 Mar 16.

From the Departments of Radiology (A.J.C., B.D., R.V.M., B.D., A.D.), Gynecology (E.L., G.H.), Radiotherapy (M.M., A.T.), and Oncology (R.S.), Institut Paoli-Calmettes, 232 Boulevard Sainte-Marguerite, 13009 Marseille, France; CRCM and Université Aix-Marseille, Marseille, France (G.H.); Department of Radiology, Hôpital Tenon, APHP, Paris, France (I.T.N.); and Department of Radiology, UPMC, Université Paris 06, IUC, Sorbonne Universités, Paris, France (I.T.N.).

Purpose To evaluate the association between dynamic contrast material-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance (MR) imaging with pathologic complete response after preoperative combined chemotherapy and radiation therapy for cervical carcinoma and evaluate the risk of local recurrence. Materials and Methods The institutional ethics committee approved the study and waived the requirement to obtain informed consent. The study comprised 52 patients with locally advanced carcinoma, treated first with combined chemotherapy and radiation therapy, who underwent MR imaging before final surgery between June 2011 and July 2015. Three radiologists evaluated conventional, DW, and DCE MR images to identify a complete response. The standard of reference was surgical-pathologic findings. Results An initial increase in signal intensity on DCE MR images that was greater in the cervical lesion than in the myometrium was defined as time-signal intensity curve type B and showed a significant association with incomplete response (P = .0004). DCE MR imaging parameters (ie, maximum slope enhancement, area under the gadolinium concentration-time curve during the first 90 seconds after gadolinium injection [AUGC90], and volume transfer constant [K]) and a low signal intensity on apparent diffusion coefficient (ADC) maps were significantly associated with an incomplete response (P = .027, P = .041, P = .037, and P = .032, respectively). A mean ADC of 0.0014 m/sec or less (hazard ratio [HR] = 8.3), low ADC signal intensity (HR = 7.3), high signal intensity at DW imaging (HR = 7.1), and time-signal intensity curve type B (HR = 4.3) were associated with earlier recurrence (P < .05). Excellent agreement between readers was found for time-signal intensity curve analysis (κ > 0.9) and the following parameters: AUGC90, K, and maximum slope enhancement (intraclass correlation coefficient, >0.9). Conclusion DCE MR imaging parameters, especially the time-signal intensity curve, and DW imaging are associated with complete response and incomplete response and could potentially help oncologists with management decisions. Moreover, DCE and DW MR imaging could help oncologists accentuate the follow-up for patients with a high risk of local recurrence to assess for recurrence. RSNA, 2017 Online supplemental material is available for this article.
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http://dx.doi.org/10.1148/radiol.2017161299DOI Listing
August 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

Benefit of adjuvant chemotherapy with or without trastuzumab in pT1ab node-negative human epidermal growth factor receptor 2-positive breast carcinomas: results of a national multi-institutional study.

Breast Cancer Res Treat 2017 04 2;162(2):307-316. Epub 2017 Feb 2.

Aix-Marseille University, Marseille, France.

Purpose: Benefit of adjuvant trastuzumab-based chemotherapy for node-positive and/or >1 cm human epidermal growth factor receptor 2-positive (HER2+) breast carcinomas has been clearly demonstrated in randomized clinical trials. Yet, evidence that adjuvant chemotherapy with or without trastuzumab is effective in pT1abN0 HER2+ tumors is still limited. The primary objective of this study was to investigate the impact of adjuvant chemotherapy ± trastuzumab on outcome in this subpopulation.

Patients And Methods: A total of 356 cases of pT1abN0M0 HER2 + breast cancers were retrospectively identified from a large cohort of 22,334 patients, including 1248 HER2+ patients who underwent primary surgery at 17 French centers, between December 1994 and January 2014. The primary end point was disease-free survival (DFS). A multivariate Cox model was built, including adjuvant chemotherapy, tumor size, hormone receptor status, and Scarff Bloom Richardson (SBR) grade.

Results: A total of 138 cases (39%) were treated with trastuzumab-based chemotherapy, 29 (8%) with chemotherapy alone, and 189 (53%) received neither trastuzumab nor chemotherapy. Adjuvant chemotherapy ± trastuzumab was associated with a significant DFS benefit (3-year 99 vs. 90%, and 5-year 96 vs. 84%, Hazard ratio, HR 0.26 [0.10-0.67]; p = 0.003, logrank test) which was maintained in multivariate analysis (HR 0.19 [0.07-0.52]; p = 0.001). Metastasis-free survival was also increased (HR 0.25 [0.07-0.86]; p = 0.018, logrank test) at 3-year (99 vs. 95%) and 5-year (98 vs. 89%) censoring. Exploratory subgroup analysis found DFS benefit to be significant in hormone receptor-negative, hormone receptor-positive, and pT1b tumors, but not in pT1a tumors.

Conclusions: Adjuvant chemotherapy ± trastuzumab is associated with a significantly reduced risk of recurrence in subcentimeter node-negative HER2+ breast cancers. Most of the benefit may be driven by pT1b tumors.
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http://dx.doi.org/10.1007/s10549-017-4136-5DOI Listing
April 2017

Prognostic impact of hormone receptor- and HER2-defined subtypes in inflammatory breast cancer treated with high-dose chemotherapy: a retrospective study.

J Cancer 2016 23;7(14):2077-2084. Epub 2016 Oct 23.

Aix-Marseille Université, Marseille, F-13284, France.; Centre de Thérapie Cellulaire, Département de Biologie du Cancer, Institut Paoli-Calmettes, Marseille, F-13273, France.; Centre d'Investigations Cliniques en Biothérapies, Inserm CBT-1409, Marseille, F-13009, France.

Studies examining high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDC-AHSCT) strategies in inflammatory breast cancer (IBC), showed encouraging results in terms of disease-free survival (DFS), and overall survival (OS). The lack of data regarding HER2 status in all of these studies prevented any prognostic analysis involving breast cancer subtypes. All consecutive female patients treated for IBC with HDC and AHSCT at Institut Paoli-Calmettes between 2003 and 2012 were included. Since 2005, trastuzumab was included in initial treatment. Patient, tumor and treatment characteristics were collected. 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 OS according to the IHC subtypes. Sixty-seven patients were included. Eleven patients received trastuzumab. Median follow up was 80.04 months (95% CI 73.2-88.08). Five-year OS and DFS for the whole population patients were 74% (95% CI 61-83) and 65 % (95% CI 52-75), respectively. OS differed across subtypes (p=0.057) : 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). In IBC patients receiving HDC-AHSCT, OS favorably compares with data available in the literature on similar groups of patients. TN patients carried the least favourable OS and HER2 patients, half of them also receiving trastuzumab, had the best outcome. These findings provide additional information and options for patients with IBC and who could potentially benefit of HDC-AHSCT.
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http://dx.doi.org/10.7150/jca.15797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118671PMC
October 2016

Targeted NGS, array-CGH, and patient-derived tumor xenografts for precision medicine in advanced breast cancer: a single-center prospective study.

Oncotarget 2016 Nov;7(48):79428-79441

Aix Marseille Univ, CNRS U7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Marseille, France.

Background: Routine feasibility and clinical impact of genomics-based tumor profiling in advanced breast cancer (aBC) remains to be determined. We conducted a pilot study to evaluate whether precision medicine could be prospectively implemented for aBC patients in a single center and to examine whether patient-derived tumor xenografts (PDX) could be obtained in this population.

Results: Thirty-four aBC patients were included. Actionable targets were found in 28 patients (82%). A targeted therapy could be proposed to 22 patients (64%), either through a clinical trial (n=15) and/or using already registered drugs (n=21). Ten patients (29%) eventually received targeted treatment, 2 of them deriving clinical benefit. Of 22 patients subjected to mouse implantation, 10 had successful xenografting (45%), mostly in triple-negative aBC.

Methods: aBC patients accessible to tumor biopsy were prospectively enrolled at the Institut Paoli-Calmettes in the BC-BIO study (ClinicalTrials.gov, NCT01521676). Genomic profiling was established by whole-genome array comparative genomic hybridization (aCGH) and targeted next-generation sequencing (NGS) of 365 candidate cancer genes. For a subset of patients, a sample of fresh tumor was orthotopically implanted in humanized cleared fat pads of NSG mice for establishing PDX.

Conclusions: Precision medicine can be implemented in a single center in the context of clinical practice and may allow genomic-driven treatment in approximately 30% of aBC patients. PDX may be obtained in a significant fraction of cases.
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http://dx.doi.org/10.18632/oncotarget.12714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346725PMC
November 2016

Corrigendum to "Immunohistochemical subtypes predict survival in metastatic breast cancer receiving high-dose chemotherapy with autologous haematopoietic stem cell transplantation" [Eur J Cancer 57 (April 2016) 118-126].

Eur J Cancer 2016 11 24;67:223. Epub 2016 Sep 24.

Département d'Oncologie Médicale, Institut Paoli-Calmettes (IPC), Marseille, F-13273, France; Centre de Recherches en Cancérologie de Marseille (CRCM), UMR Inserm 1068/CNRS 7258/AMU 105/IPC, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2016.09.002DOI Listing
November 2016

Invasive ductal breast carcinoma with predominant intraductal component: Clinicopathological features and prognosis.

Breast 2016 Jun 19;27:8-14. Epub 2016 Mar 19.

Department of Radiotherapy, Institut Paoli-Calmettes, Marseille, France.

Purpose: Invasive ductal carcinoma with predominant intraductal component (IDCPIC) represents almost 5% of breast cancers. Nevertheless few data exist concerning their characteristics and prognostic behaviour. Our objective was to describe IDCPIC's clinicopathological and prognostic features and compare them to that of invasive ductal carcinoma without predominant intraductal component (IDC).

Methods: Retrospective single centre study including all the localized invasive ductal carcinoma listed in our institutional database. Clinical, radiological and pathological criteria were collected as well as disease-free survival (DFS) data.

Results: From 1995 to 2008, 4109 invasive ductal breast cancers treated were included. Out of them 192 (4.7%) were IDCPIC. Most of IDCPIC (63%) were discovered by radiological screening whereas IDC suspicion was more often clinical (82.7% vs 49.5%, p < 0.001). Pathological lymph node involvement was less frequent in IDCPIC (35.8 vs 44.3%, p = 0.04). Invasive tumour median size was 2-fold smaller in IDCPIC (10 mm vs 20 mm, p<0.001). Hormone receptors expression was similar between both groups whereas HER2 overexpression was more frequent in IDCPIC (32% vs 14.3%, p<0.001). Mastectomy was more frequently performed for IDCPIC (67.7% vs 30.3%, p < 0.001) whereas chemotherapy and radiation therapy were less frequent (55.5% vs 68%, and 82.8% vs 95.5%, respectively, p < 0.001 for both). After matching for discriminant clinicopathological features (tumour size, lymph node involvement, vascular invasion, HER2), DFS was similar in both groups (5-year DFS of 87.4% vs 84.4%, p = 0.47).

Conclusion: IDCPIC and other IDC with invasive components showing similar clinicopathological features display a similar prognosis.
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http://dx.doi.org/10.1016/j.breast.2015.12.003DOI Listing
June 2016

Immunohistochemical subtypes predict survival in metastatic breast cancer receiving high-dose chemotherapy with autologous haematopoietic stem cell transplantation.

Eur J Cancer 2016 04 23;57:118-26. Epub 2016 Feb 23.

Département d'Oncologie Médicale, Institut Paoli-Calmettes (IPC), Marseille, F-13273, France; Centre de Recherches en Cancérologie de Marseille (CRCM), UMR Inserm 1068/CNRS 7258/AMU 105/IPC, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France. Electronic address:

Introduction: The objective of this study was to evaluate the outcome of patients affected with different subtypes of metastatic breast cancer (MBC) following treatment with high-dose chemotherapy (HDC) and autologous haematopoietic progenitor cell transplantation (AHSCT).

Methods: All consecutive female patients treated for MBC with HDC and AHSCT at the Institut Paoli-Calmettes between 2003 and 2012 were included. Patient, tumour and treatment characteristics were collected. Patients were categorised in three subtypes based on hormonal receptor (HR) and human epidermal growth factor receptor 2 (HER2) status of the primary tumour: luminal (L), (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 immunohistochemical (IHC) subtypes.

Results: A total of 235 patients were included, median age was 46 (range 21-62). Median follow up was 53.28 months (95% confidence interval [CI] 45.12-57.6). 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). In the multivariate analysis, the TN subtype retained an independent poor prognosis value compared to the luminal subtype, with a hazard ratio of 2.03 (95% CI 1.26-3.29, p = 0.037).

Conclusion: HDC-AHSCT does not change the prognostic value of IHC subtypes in MBC patients. OS favourably compares with data available in the literature on similar groups of patients. These findings provide additional information and options for patients with MBC and who could potentially benefit of HDC-AHSCT.
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http://dx.doi.org/10.1016/j.ejca.2016.01.005DOI Listing
April 2016

Ovarian cancer patients at high risk of BRCA mutation: the constitutional genetic characterization does not change prognosis.

Fam Cancer 2016 10;15(4):497-506

Department of Medical Oncology, Institut Paoli-Calmettes, 232 Boulevard Sainte-Marguerite, 13273, Marseille Cedex 09, France.

Ovarian neoplasms secondary to germline BRCA mutations had been described to have a more favourable survival. There is only few data concerning the prognosis of non mutated patients presenting clinical features evocative of BRCA alterations. We retrospectively collected data from patients treated in our institution for an invasive ovarian carcinoma between 1995 and 2011. Patients considered at high risk of BRCA mutation were tested for BRCA1/2 germline mutations. We described clinical, pathological and therapeutic features and compared prognosis of BRCA mutation carriers and non-mutated patients. Out of 617 ovarian cancer patients, we identified 104 patients who were considered at high risk of mutation. The 33 mutated patients were more likely to present a personal (33 vs. 10 %, p = 0.003) or a family (42 vs. 24 %, p = 0.06) history of breast/ovarian cancers. BRCA1/2 mutation carriers and wild type patients displayed similar prognosis: median progression-free survival (PFS) of 20.9 versus 37.7 months (p = 0.21); median overall survival (OS) of 151.2 versus 122.5 months (p = 0.52). Personal history of breast cancer increased both PFS [HR = 0.45 (95CI 0.25-0.81)] and OS [HR = 0.35 (95CI 0.16-0.75)]. In multivariate analysis, this parameter was an independent prognostic feature, whereas the identification of a BRCA1/2 mutation was not. In our cohort, all patients at high risk of BRCA mutation share a similar prognosis, whatever is their germline mutation status. Prognosis seems to be more influenced by clinical history than by germline mutations identification. If it is confirmed in larger and independent series, this result suggests that the hypothesis of other BRCA pathway alterations (BRCAness phenotype) deserves to be deeply explored.
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http://dx.doi.org/10.1007/s10689-016-9873-9DOI Listing
October 2016