Publications by authors named "Patricia Pautier"

159 Publications

Lurbinectedin versus pegylated liposomal doxorubicin or topotecan in patients with platinum-resistant ovarian cancer: A multicenter, randomized, controlled, open-label phase 3 study (CORAIL).

Gynecol Oncol 2021 Sep 11. Epub 2021 Sep 11.

Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, and Fondazione Policlinico Gemelli IRCCS, Rome, Italy.

Objective: The randomized phase 3 CORAIL trial evaluated whether lurbinectedin improved progression-free survival (PFS) compared to pegylated liposomal doxorubicin (PLD) or topotecan in patients with platinum-resistant ovarian cancer.

Methods: Patients were randomly assigned (1:1) to lurbinectedin 3.2 mg/m 1-h i.v. infusion q3wk (experimental arm), versus PLD 50 mg/m 1-h i.v. infusion q4wk or topotecan 1.50 mg/m 30-min i.v. infusion Days 1-5 q3wk (control arm). Stratification factors were PS (0 vs. ≥1), prior PFI (1-3 months vs. >3 months), and prior chemotherapy lines (1-2 vs. 3). The primary endpoint was PFS by Independent Review Committee in all randomized patients. This study was registered with ClinicalTrials.gov, NCT02421588.

Results: 442 patients were randomized: 221 in lurbinectedin arm and 221 in control arm (127 PLD and 94 topotecan). With a median follow-up of 25.6 months, median PFS was 3.5 months (95% CI, 2.1-3.7) in the lurbinectedin arm and 3.6 months (95% CI, 2.7-3.8) in the control arm (stratified log-rank p = 0.6294; HR = 1.057). Grade ≥ 3 treatment-related adverse events (AEs) were most frequent in the control arm: 64.8% vs. 47.9% (p = 0.0005), mainly due to hematological toxicities. The most common grade ≥ 3 AEs were: fatigue (7.3% of patients) and nausea (5.9%) with lurbinectedin; mucosal inflammation (8.5%) and fatigue (8.0%) in the control arm.

Conclusions: The primary endpoint of improvement in PFS was not met. Lurbinectedin showed similar antitumor efficacy and was better tolerated than current standard of care in patients with platinum-resistant ovarian cancer.
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http://dx.doi.org/10.1016/j.ygyno.2021.08.032DOI Listing
September 2021

[Fertility preservation in cervical cancer, analysis of 30 years of practice and immersion in future developments.]

Gynecol Obstet Fertil Senol 2021 Sep 3. Epub 2021 Sep 3.

Département de chirurgie gynécologique, Institut Gustave Roussy, Villejuif, France; Unité INSERM U 10-30, Gustave Roussy, Villejuif, France et université Paris-Sud (Paris XI), Le Kremlin Bicêtre, France. Electronic address:

Objectives: The strategy of fertility preservation (FP) in cervical cancer has been challenged for several years and a therapeutic de-escalation seems to be necessary. In this context, we evaluated the oncological, fertility and obstetric outcomes of surgical techniques performed in our centre for FP.

Methods: This retrospective uni centric trial included 75 patients, managed at the Gustave Roussy Institute between 1995 and 2020, for cervical cancer (stage IB1 FIGO 2018) and having conducted a fertility preservation project after a complete pre-therapy work-up. The objective of this study was to understand our results on fertility and obstetrical outcomes and to correlate them with oncological data and finally to evaluate the evolution of our surgical practices.

Results: 54 patients benefited from an extended trachelectomy and no lymph node involvement was found. 1 patient received a complementary treatment postoperatively which did not allow to preserve her fertility. The recurrence rate was 4.8% (4/75) with one death described. 31 pregnancies were obtained, representing a pregnancy rate of 50%. 74% of pregnancies were obtained spontaneously and 60% of pregnancies were carried to term.

Conclusion: Our results are similar to those in the literature. Despite a fertility preservation project, only half of the patients were able to achieve a pregnancy.
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http://dx.doi.org/10.1016/j.gofs.2021.09.001DOI Listing
September 2021

Association between Olaparib Exposure and Early Toxicity in BRCA-Mutated Ovarian Cancer Patients: Results from a Retrospective Multicenter Study.

Pharmaceuticals (Basel) 2021 Aug 16;14(8). Epub 2021 Aug 16.

Department of Medical Oncology, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.

Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from "real life" data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95%CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients.
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http://dx.doi.org/10.3390/ph14080804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399031PMC
August 2021

Outcomes of patients with cancer and sarcoid-like granulomatosis associated with immune checkpoint inhibitors: A case-control study.

Eur J Cancer 2021 Oct 20;156:46-59. Epub 2021 Aug 20.

Département d'Innovation Thérapeutique et d'Essais Précoces, Institute Gustave Roussy, Université Paris-Saclay, Villejuif, F-94805, France. Electronic address:

Purpose: Sarcoid-like granulomatosis (SLG) reaction caused by immunotherapy remains poorly understood. This study aims to investigate the outcome of patients with cancer and SLG associated with immunotherapy.

Patients And Methods: Between April 2016 and June 2020, 434 patients with immunological adverse events were screened from the ImmunoTOX assessment board of Gustave Roussy, an academic cancer centre in France. Among them, 28 patients had SLG associated with immunotherapy (SLG cohort) and 406 patients had other immunological adverse events (control cohort). Clinical characteristics and outcome of patients were compared from SLG and control cohort.

Results: The SLG cohort consisted of 28 patients, 14 women and 14 men, with the median (range) age of 56.5 (28.7-75.3) years. Patients in the SLG cohort with sarcoidosis were asymptomatic (only radiographical finding) in 13 (46.4%) cases; otherwise, the most frequent symptoms were dyspnoea in 8 (28.6%) patients and cough in 5 (17.8%) patients. The computerised tomography scan found sarcoidosis localisations in mediastinal or peri-hilar thoracic lymph nodes in 26 (92.9%) patients, and lung parenchymal involvement was found in 14 (50.0%) patients. The radiographic Scadding stages for sarcoidosis classification were distributed in stages 0, I, II, III and IV in 2 patients (7.1%), 13 patients (46.4%), 11 patients (39.3%), 1 patient (3.6%) and 1 patient (3.6%), respectively. Compared with patients with other immunological toxicities (cohort control), patients with sarcoidosis presented most frequently with melanoma (75.0% versus 21.9% of patients; p < 0.001) and more often received combined therapies of anti-programmed cell death 1 plus anti-cytotoxic T-lymphocyte antigen 4 protein (46.4% versus 12.6% of patients; p = 0.002). Patients with sarcoidosis had an improved overall survival (OS); the median OS was not reached in the SLG cohort and 40.4 months in the control cohort, hazard ratio = 0.232 (95% confidence interval: 0.086-0.630) (p = 0.002).

Conclusion: Sarcoidosis-like reactions in patients receiving immunotherapy were reported as non-severe immunological reactions in most cases and were correlated with improved OS. SLG should not be misdiagnosed as tumour progression in patients receiving immunotherapy treatment for cancer.
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http://dx.doi.org/10.1016/j.ejca.2021.07.015DOI Listing
October 2021

Clinicopathological characterization of a real-world multicenter cohort of endometrioid ovarian carcinoma: Analysis of the French national ESME-Unicancer database.

Gynecol Oncol 2021 Jul 19. Epub 2021 Jul 19.

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

Background: Prognostic significance of endometrioid epithelial ovarian cancer (EOC) is controversial. We compared clinical, pathological, and biological features of patients with endometrioid and serous EOC, and assessed the independent effect of histology on outcomes.

Methods: We conducted a multicenter retrospective analysis of patients with EOC selected from the French Epidemiological Strategy and Medical Economics OC database between 2011 and 2016. Our main objective was to compare overall survival (OS) in endometrioid and serous tumors of all grades. Our second objectives were progression-free survival (PFS) and prognostic features.

Results: Out of 10,263 patients included, 3180 cases with a confirmed diagnosis of serous (N = 2854) or endometrioid (N = 326) EOC were selected. Patients with endometrioid histology were younger, more often diagnosed at an early stage, with lower-grade tumors, more frequently dMMR/MSI-high, and presented more personal/familial histories of Lynch syndrome-associated cancers. BRCA1/2 mutations were more frequently identified in the serous population. Endometrioid patients were less likely to receive chemotherapy, with less bevacizumab. After median follow-up of 51.7 months (95CI[50.1-53.6]), five-year OS rate was 81% (95CI[74-85]) in the endometrioid subgroup vs. 55% (95CI[53-57] in the serous subset (p < 0.001, log-rank test). In multivariate analyses including [age, ECOG-PS, FIGO, grade, and histology], the endometrioid subtype was independently associated with better OS (HR = 0.38, 95CI[0.20-0.70], p= 0.002) and PFS (HR = 0.53, 95CI[0.37-0.75], p < 0.001).

Conclusions: Clinicopathological features at diagnosis are not the same for endometrioid and serous EOC. Endometrioid histology is an independent prognosis factor in EOC. These observations suggest the endometrioid population requires dedicated clinical trials and management.
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http://dx.doi.org/10.1016/j.ygyno.2021.07.019DOI Listing
July 2021

Metabolic features of cancer cells impact immunosurveillance.

J Immunother Cancer 2021 Jun;9(6)

Equipe 11 labellisée par la Ligue contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, INSERM, Paris, France

Background: Tumors rewire their metabolism to achieve robust anabolism and resistance against therapeutic interventions like cisplatin treatment. For example, a prolonged exposure to cisplatin causes downregulation of pyridoxal kinase (PDXK), the enzyme that generates the active vitamin B6, and upregulation of poly ADP-ribose (PAR) polymerase-1 (PARP1) activity that requires a supply of nicotinamide (vitamin B3) adenine dinucleotide. We investigated the impact of the levels of PDXK and PAR on the local immunosurveillance (ie, density of the antigen presenting cells and adaptive immune response by CD8 T lymphocytes) in two different tumor types.

Methods: Tumors from patients with locally advanced cervical carcinoma (LACC) and non-small cell lung cancer (NSCLC) were stained for PAR, PDXK, dendritic cell lysosomal associated membrane glycoprotein (DC-LAMP) and CD8 T cell infiltration. Their correlations and prognostic impact were assessed. Cisplatin-resistant NSCLC cell clones isolated from Lewis-lung cancer (LLC) cells were evaluated for PAR levels by immunoblot. Parental (PAR) and cisplatin-resistant (PAR) clones were subcutaneously injected into the flank of C57BL/6 mice. Tumors were harvested to evaluate their immune infiltration by flow cytometry.

Results: The infiltration of tumors by CD8 T and DC-LAMP cells was associated with a favorable overall survival in patients with LACC (p=0.006 and p=0.008, respectively) and NSCLC (p<0.001 for both CD8 T and DC-LAMP cells). We observed a positive correlation between PDXK expression and the infiltration by DC-LAMP (R=0.44, p=0.02 in LACC, R=0.14, p=0.057 in NSCLC), and a negative correlation between PAR levels and CD8 T lymphocytes (R=-0.39, p=0.034 in LACC, R=-0.18, p=0.017 in NSCLC). PARP1 is constitutively hyperactivated in cisplatin-resistant LLC cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR). Tumors formed by such cancer cells injected into immunocompetent mice were scarcely infiltrated by CD8 T (p=0.028) and antigen presenting cells (p=0.086).

Conclusions: Oncometabolic features can impact local immunosurveillance, providing new functional links between cisplatin resistance and therapeutic failure.
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http://dx.doi.org/10.1136/jitc-2021-002362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231002PMC
June 2021

Effects of local laser treatment on vulvovaginal atrophy among women with breast cancer: a prospective study with long-term follow-up.

Breast Cancer Res Treat 2021 Jul 23;188(2):501-509. Epub 2021 Apr 23.

Department of Cancer Medicine/Gynecology, Gustave Roussy, 114 rue Edouard Vaillant, 94800, Villejuif, France.

Purpose: Women with breast cancer (BC) often suffer from severe vulvovaginal atrophy (VVA) which ultimately leads to poor sexual and urinary quality of life. We conducted a prospective study among women with BC and VVA, in order to evaluate the long-term effect of laser therapy on VVA.

Methods: Women with BC and VVA were proposed to have fractional microablative CO laser therapy (MonaLisaTouch®, DEKA) once per month for 3 months. Efficacy of laser therapy was assessed at baseline, 6 months and 18 months after treatment, using Female Sexual Function Index (FSFI) score, Ditrovie score and vaginal pH. A pap smear was also performed and the epithelial maturation pattern was noted. Paired statistical tests were used to compare results between baseline, 6 months and 18 months.

Results: 46 women with BC (median age [interquartile range] 56.5 years [47.0 - 59.4]) were included between May and October 2018. PH level slightly decreased over time (mean Δ at 18 months -0.3, SD = 0.7, p = 0.02) whereas maturation pattern on pap smear did not change. Sexual quality of life was significantly improved at 6 months and 18 months (mean Δ at 6 months 8.3, SD = 6.2 (p < 0.0001) and mean Δ at 18 months 4.3, SD = 8.4 (p = 0.01)). Ditrovie total score improved at 6 months (mean Δ -1.2, SD = 2.7, p = 0.01) but returned to baseline afterwards. Side effects were very mild. Three women developed low (2)- and high (1)-grade HPV-linked cervical lesions during follow-up.

Conclusion: Among women with BC, fractional microablative CO laser is effective on the long term on VVA symptoms and gynaecological quality of life.

Trial Registration Number: ID-RCB 2018-A01500-55.
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http://dx.doi.org/10.1007/s10549-021-06226-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062616PMC
July 2021

Brenner Borderline Ovarian Tumor: A Case Series and Literature Review.

Ann Surg Oncol 2021 Oct 25;28(11):6714-6720. Epub 2021 Mar 25.

Department of Gynaecologic Surgery, Gustave-Roussy, Villejuif, France.

Background: Most frequent borderline ovarian tumors are serous and mucinous subtypes. Less frequent borderline diseases are endometrioid, clear-cell, and Brenner tumors (BBOT). Very little is known about the latter subtype, and most studies include very short series or case reports. The aim of this study is to determine the prognosis of a continuous series of BBOT and analyze data published in the literature on this rare entity.

Patients And Methods: A retrospective review of patients with BBOT treated or referred to our institutions was conducted. A centralized histological review by a reference pathologist and data on the clinical characteristics, management, and outcomes of patients were required for inclusion.

Results: Overall, 17 patients were identified. Median age was 62 (range 42-85) years. Six patients underwent unilateral salpingo-oophorectomy, and 11 bilateral salpingo-oophorectomy +/- hysterectomy and/or staging surgery. In total, 16 patients had unilateral tumor, and all patients had stage I disease. Stromal microinvasion was observed in three cases. Median follow-up was 60 months (range 7-118 months). One patient developed a recurrence in contralateral ovary after unilateral salpingo-oophorectomy. One patient had previous history of urothelial tumor.

Conclusions: Peritoneal staging surgery is not required because all patients reported had stage I disease. One recurrence occurred. When reviewing all the 82 cases reported in the literature (including ours), 9% had previous history or synchronous urothelial tumor, suggesting the need to carefully check for urological disease in patients with BBOT.
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http://dx.doi.org/10.1245/s10434-021-09879-yDOI Listing
October 2021

False negative rate at F-FDG PET/CT in para-aortic lymphnode involvement in patients with locally advanced cervical cancer: impact of PET technology.

BMC Cancer 2021 Feb 6;21(1):135. Epub 2021 Feb 6.

Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Paris Saclay, 114 Rue Edouard Vaillant, 94800, Villejuif, France.

Background: The identification of factors responsible for false negative (FN) rate at F- Fluorodeoxyglucose (FDG) Positron Emission Tomography /Computed Tomography (PET/CT) in para-aortic (PA) lymph nodes in the presurgical staging of patients with locally advanced cervical cancer (LACC) is challenging. The aim of this study was to evaluate the impact of PET/CT technology.

Methods: A total of 240 consecutive patients with LACC (International Federation of Gynecology and Obstetrics, FIGO, stage IB2-IVA) and negative Magnetic Resonance Imaging (MRI) and/or Computed Tomography (CT) and negative F-FDG PET/CT in the PA region, undergoing laparoscopic PA lymphadenectomy before chemoradiotherapy were included. The FN rate in patients studied with Time of flight (TOF) PET/CT (TOF PET) or non-Time of flight PET/CT (no-TOF PET) technology was retrospectively compared.

Results: Patients presented with FIGO stage IB (n = 78), stage IIA-B (n = 134), stage III (n = 18) and stage IVa (n = 10), squamous cell carcinoma (n = 191) and adenocarcinoma (n = 49). 141/240 patients were evaluated with no-TOF PET/CT and 99/240 with TOF PET/CT. Twenty-two patients (9%) had PA nodal involvement at histological analysis and considered PET/CT FN findings. The FN rate was 8.5% for no-TOF PET and 10% for TOF PET subgroup respectively (p = 0.98). Ninety patients (38%) presented with pelvic node uptakes at PET/CT. The FN rate in the PA region was 18% (16/90) and 4% (6/150) in patients with and without pelvic node involvement at PET/CT respectively (19 vs 3% for no-TOF PET and 17 vs 5% for TOF PET subgroup).

Conclusions: In LACC, FN rate in PA lymph nodes detection is a clinical issue even for modern PET/CT, especially in patients with pelvic uptake. Surgical lymphadenectomy should be performed in case of negative PET/CT at PA level in these patients, while it could be discussed in the absence of pelvic uptake.
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http://dx.doi.org/10.1186/s12885-021-07821-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866875PMC
February 2021

Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial.

Lancet Oncol 2021 02;22(2):267-276

Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Ginecologia Oncologica-Fondazione Policlinico Universitario Gemelli, Università Cattolica del Sacro Cuore di Roma, Rome, Italy.

Background: Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug.

Methods: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB-IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0-2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin-carboplatin, or 15 mg/kg every 21 days combined with gemcitabine-carboplatin or paclitaxel-carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17.

Findings: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4-9·3) in the standard chemotherapy group and 11·8 months (10·8-12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41-0·65; log-rank p<0·0001). Most common grade 3-4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related.

Interpretation: Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice.

Funding: Hoffmann-La Roche and Associazione Italiana per la Ricerca sul Cancro.
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http://dx.doi.org/10.1016/S1470-2045(20)30637-9DOI Listing
February 2021

Distribution of novel immune-checkpoint targets in ovarian cancer tumor microenvironment: A dynamic landscape.

Gynecol Oncol 2021 01 6;160(1):279-284. Epub 2020 Nov 6.

Gynecological Cancer Unit, Department of Medicine, Gustave Roussy, France; INSERM U981, Gustave Roussy, Villejuif, France. Electronic address:

Background: The disappointing activity of single agent immune-checkpoint inhibitors in epitherlial ovarian cancer (EOC) has been attributed in part to its unique tumor microenvironment (TME). IDO, PDL1, LAG3 and TIM3 have been implicated in the immunotolerance of EOC. We investigated the expression of these co-regulators, their change with neoadjuvant chemotherapy (NACT), and their association with outcome.

Method: We identified 98 patients with EOC treated with NACT and performed IDO, PDL1, LAG3 and TIM3 immunohistochemistry on samples obtained before and after NACT. The cut-off threshold to consider a positive sample was set at 5%.

Results: In our cohort, TIM3 was the most prevalent co-regulator, with more than 75% of the samples being TIM3 positive. In comparison, only 22%, 28% and 17% of the samples were considered IDO, PDL1 and LAG3 positive. More than half of ovarian tumors expressed 2, 3 or even all 4 co-inhibitory molecules. However, biomarkers were not correlated with each other. NACT had a marked impact on immune co-regulator expression with over 70% of patients showing a change in biomarker status from negative to positive or vice versa. There was no significant difference in the pattern of co-regulator expression between platinum-sensitive and resistant patients. Co-expression of multiple inhibitory molecules did not appear to affect overall and progression-free survival.

Conclusion: TIM3 is the most abundant co-inhibitory molecule in OC and may represent an attractive target. In addition, OC frequently co-expressed 2 or more markers supporting ICI combinatorial approaches. Finally, NACT significantly altered the expression of immunosuppressive molecules suggesting that the choice of ICI combinations should be adapted to the composition of the post-NACT immune TME.
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http://dx.doi.org/10.1016/j.ygyno.2020.09.045DOI Listing
January 2021

Results After Conservative Surgery of Stage II/III Serous Borderline Ovarian Tumors.

Ann Surg Oncol 2021 Jul 2;28(7):3597-3604. Epub 2020 Nov 2.

Department of Gynaecologic Surgery, Institut Gustave-Roussy, Villejuif, France.

Objective: The aim of this study was to assess the outcomes of a large series of patients treated conservatively for stage II or III serous borderline tumors of the ovary (SBOTs) with a long-term follow-up.

Methods: Patients with SBOTs and peritoneal implants, treated in or referred to our institution, were retrospectively reviewed. Outcomes of patients treated conservatively (preservation of the uterus and at least a part of one ovary) to promote subsequent fertility were specifically analyzed.

Results: Between 1971 and 2017, 212 patients were identified and followed-up. Among these patients, 65 underwent conservative treatment; eight patients had invasive implants. Among patients treated conservatively, 38 (58%) patients recurred. Twenty-eight recurrences were observed under the form of borderline tumor on the spared ovary and/or noninvasive implants, but eight patients had a recurrence under the form of invasive disease. Compared with radical surgery, the use of conservative treatment (p < 0.0001) was a prognostic factor on disease-free survival (DFS), but without an impact on overall survival (OS). Nevertheless, three deaths occurred. Twenty-four pregnancies (13 spontaneous) were observed in 20 patients (29 patients wanted to become pregnant).

Conclusion: In this series collecting the largest number of patients undergoing conservative surgery for stage II/III SBOTs, spontaneous pregnancies can be achieved after conservative treatment of advanced-stage disease, but the recurrence rate is high and three deaths were observed. These patients were spared their fertility but with a high rate of recurrence. Uncertainties regarding the safety of conservative treatment should be exposed to these patients.
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http://dx.doi.org/10.1245/s10434-020-09250-7DOI Listing
July 2021

Impact of young age on platinum response in women with epithelial ovarian cancer: Results of a large single-institution registry.

Gynecol Oncol 2021 01 12;160(1):77-82. Epub 2020 Oct 12.

Department of Medical Oncology, Gustave-Roussy, Villejuif, France.

Objective: In young women, EOC is a rare disease with an uncertain genetic and biological substrate.

Methods: We report a long follow-up of EOC patients treated at Gustave Roussy between 1990 and 2009. We matched young patients aged ≤30 years to randomly selected older patients aged ≥40 years according to known prognostic factors (i.e. FIGO stage, histology and surgical residual disease) and the date of diagnosis with a threshold at the year 2000 to balance the treatment procedures.

Results: EOC was diagnosed in 68 patients aged ≤30 years matched with 111 patients aged ≥40 years. Low-grade (LG) (i.e. serous and endometrioid) (52%, n = 35) and mucinous (i.e. 23%, n = 16 infiltrative and 12% n = 8 expansile) tumors are prevalent. High-grade (HG) tumors are rare (7%, n = 5). Early stage diseases (53%, n = 36 FIGO I/II) are predominant. Response to platinum based chemotherapy is observed to be inferior in young patients as compared to matched older patients (ORR, 29 vs 84% p = 0.0002). For HG tumors the PFS is of 0% at 5 and 10 years in younger as compared to 30% in older patients. No difference in PFS (median 4.9 vs 9.8 ms, p = 0.58) and OS (not reached vs 15.3 ms, p = 0.47) is found overall among younger and older patients respectively. The median follow-up was 72 months (range, 11-288 months). No genetic abnormalities were found.

Conclusions: Young EOC patients are most often diagnosed at an early FIGO stage with LG serous or mucinous histology. Tumors are significantly more resistant to platinum-based chemotherapy in younger patients.
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http://dx.doi.org/10.1016/j.ygyno.2020.09.050DOI Listing
January 2021

Effect of Weekly Paclitaxel With or Without Bevacizumab on Progression-Free Rate Among Patients With Relapsed Ovarian Sex Cord-Stromal Tumors: The ALIENOR/ENGOT-ov7 Randomized Clinical Trial.

JAMA Oncol 2020 Dec;6(12):1923-1930

GINECO and Centre Léon Bérard, Lyon, France.

Importance: To our knowledge, this is the first randomized trial in sex cord-stromal tumors, and it establishes weekly paclitaxel as standard-of-care therapy after platinum-based therapy in this setting.

Objective: To determine the efficacy of weekly paclitaxel with or without bevacizumab as treatment for relapsed sex cord-stromal tumors and evaluate whether the addition of bevacizumab to weekly paclitaxel improves 6-month progression-free rate.

Design, Setting, And Participants: This open-label, academic, international, randomized phase 2 trial (ALIENOR) was conducted at 28 referral centers in France, Germany, Italy, Japan, and Belgium in collaboration with the Rare Tumor committee of the Gynecologic Cancer InterGroup and used an adaptive bayesian design. It included 60 women with sex cord-stromal tumors that had relapsed after at least 1 platinum-based chemotherapy. Enrollment occurred from 2013 to 2016, and the final analysis database lock was on March 27, 2020 (median follow-up, 38.9 months).

Interventions: Participants were randomized to receive either paclitaxel (80 mg/m2, days 1, 8, and 15 every 4 weeks) alone or paclitaxel with bevacizumab (10 mg/kg, every 2 weeks) for 6 cycles followed by maintenance bevacizumab (15 mg/kg, every 3 weeks) for up to 1 year or until progression or unacceptable toxicity. Crossover to bevacizumab was permitted after progression during or following paclitaxel alone.

Main Outcomes And Measures: Six-month progression-free rate.

Results: Sixty patients (predominantly with granulosa cell tumors) were randomized, 32 to receive single-agent paclitaxel (median [interquartile range] age at inclusion, 60 [53-64] years) and 28 to receive paclitaxel-bevacizumab (median [interquartile range] age at inclusion, 55 [47-61] years; 1 did not receive treatment). The estimated 6-month progression-free rate was 71% (95% credible interval, 55%-84%) with paclitaxel alone and 72% (95% credible interval, 55%-87%) with paclitaxel-bevacizumab. The bayesian estimate for the probability that the 6-month progression-free rate distribution was higher with the combination than with paclitaxel alone was 57%, less than the predefined superiority threshold. The objective response rate increased from 25% (95% CI, 12%-43%) to 44% (95% CI, 26%-65%) with the addition of bevacizumab. One patient discontinued combination therapy within 6 months because of toxicity.

Conclusions And Relevance: Weekly paclitaxel is a new option for relapsed sex cord-stromal tumors. In this international randomized clinical trial of patients with relapsed sex cord-stromal tumors unsuitable for surgery, adding bevacizumab to weekly paclitaxel does not improve clinical benefit.

Trial Registration: ClinicalTrials.gov Identifier: NCT01770301.
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http://dx.doi.org/10.1001/jamaoncol.2020.4574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545353PMC
December 2020

Histological classification of mucinous ovarian tumors: inter-observer reproducibility, clinical relevance, and role of genetic biomarkers.

Virchows Arch 2021 May 3;478(5):885-891. Epub 2020 Oct 3.

Department of Pathology, Université Claude Bernard Lyon 1, Villeurbanne, France.

The morphological distinction between the various types of mucinous ovarian tumors has major prognostic implications but may be challenging. The aims of our study were to describe inter-observer reproducibility in the morphological diagnosis of mucinous ovarian tumors, to evaluate the clinical relevance of possible diagnostic discrepancies, and to identify molecular abnormalities correlated with the histological type. Seventy-nine ovarian mucinous borderline tumors (MOB) and either expansile or infiltrative carcinomas (MOC) were independently reviewed by two gynecological pathologists. Molecular analysis was performed in 32 cases. Concordance between the two pathologists was reached in 67 cases (k: 0.78). The main discrepancies (8/12) were the evaluation of nuclear grade 3 or that of microfoci (< 5 mm) of infiltrative-type carcinoma in an otherwise typical expansile MOC. Our follow-up analysis showed that infiltrative MOC had a lower overall survival (OS) (p < 0.0024) and progression-free survival (PFS) (p = 0.0060) as compared with MOB and expansile MOC. The presence of nuclear grade 3 or microfoci (< 5 mm) of infiltrative-type pattern of invasion in an otherwise typical expansile MOC did not alter the prognosis as compared with expansile MOC without these features, in terms of OS (p < 0.0028) and PFS (p = 0.0074). KRAS mutations were more frequent in MOB (71%), than in expansile (50%) and infiltrative MOC (14%). In contrast, the prevalence of TP53 mutation was lower in MOB (43%), than in expansile (58%) and infiltrative MOC (71%). Our results confirm that in MOC, the expansile pattern of invasion is associated with a better prognosis than extensive (> 5 mm) infiltrative-type pattern of invasion. No specific or sensitive molecular profile might help in the differential diagnosis of mucinous ovarian tumors.
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http://dx.doi.org/10.1007/s00428-020-02939-wDOI Listing
May 2021

Neoadjuvant chemotherapy alters the balance of effector to suppressor immune cells in advanced ovarian cancer.

Cancer Immunol Immunother 2021 Feb 27;70(2):519-531. Epub 2020 Aug 27.

Pathology Department, Institut Gustave Roussy, Villejuif, France.

Background: At diagnosis, tumor-infiltrating lymphocytes (TILs) are prognostic in epithelial ovarian cancer (EOC). We recently demonstrated that neoadjuvant chemotherapy (NACT) significantly increased stromal TILs. Here, we investigated the impact of NACT on immune subpopulations with a particular focus on the balance of immune-reactive to tolerant subpopulations.

Materials And Methods: Tissue microarrays of EOC (145 pre-NACT, 139 post-NACT) were analyzed for CD3+, CD8+, FOXP3+, CD68+, and CD163+ by immunohistochemistry and CD4+ cells from deduction. Stromal TILs scored as percentage of stromal area, while intra-epithelial TILs scored as number of TILs in contact with tumor cells/HPF. Differences were evaluated by Wilcoxon or Chi square tests, Wilcoxon signed-rank for paired analyses, and cox model for PFS and OS.

Results: NACT significantly increased stromal CD3+ (p = 0.003) and CD8+ (p = 0.001) and intra-epithelial CD8+ (p = 0.022) and CD68+ (p = 0.0003) infiltration in unmatched samples and among paired samples for stromal CD3+ and CD8+. Neither CD3+, CD8+, CD4+, and CD68+ nor CD163+ expression correlated with outcome at diagnosis or post NACT. Using median value as a cut-off, high stromal CD8+/FOXP3+ ratio (HR = 0.59; p = 0.017) and high stromal CD3+/FOXP3+ ratio post NACT were associated with prolonged PFS (p = 0.0226). The more the balance shifted in favor of effector versus regulatory TILs, the better the survival. Similarly, high CD68+/CD163+ ratio post NACT improved PFS (p = 0.0445).

Conclusion: NACT has a significant impact on the balance of immune-reactive to immune-tolerant subpopulations and a high ratio of CD8+/FOXP3+, CD3+/FOXP3+, and CD68+/CD163+ post NACT was significantly associated with improved outcomes. Whether this could select patients for immunotherapy in the post-operative setting should be investigated.
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http://dx.doi.org/10.1007/s00262-020-02670-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889679PMC
February 2021

A new score based on biomarker values to predict the prognosis of locally advanced cervical cancer.

Gynecol Oncol 2020 11 19;159(2):534-538. Epub 2020 Aug 19.

Department of Gynecologic Surgery, Gustave Roussy, Villejuif, France; Unit INSERM 1030, Villejuif, France. Electronic address:

Objective: To define a prognostic score based on pretreatment values of leucocyte, platelet and hemoglobin in locally advanced cervical cancer (LACC).

Material And Methods: We conducted a prospective study of 238 patients for LACC with negative PET imaging in the para-aortic (PA) area and who were undergoing laparoscopic PA lymphadenectomies. All patients were treated with chemo-radiation and brachytherapy.

Results: Patients had clinical International Federation of Gynecology and Obstetrics stages IB2 (n = 76), IIA (n = 13), IIB (n = 122), III (n = 18) or IVA (n = 9). We identified three biological parameters (at the time of diagnosis) with three cut-offs which impacted disease free survival (DFS) and overall survival (OS): <12 g/dL for hemoglobin, >10,000/μL for leucocyte and >300 × 109/L for platelet. A score is calculated, as shown in the table below, by adding the scores of all three biological parameters together (with a maximum score of three). DFS at 36 months was 87.3% [78.3-97.4], 58% [45-74.6], 79.1% [71.1-88], 58% [45-74.6] and 56.8% [37.8-85.4] for scores of 0, 1, 2 and 3 respectively. OS at 36 months was 92.6% [84.9-100], 84% [76.6-92.1], 62.5% [48.9-79.9] and 67% [46.8-96] for scores of 0, 1, 2 and 3 respectively.

Conclusion: This score includes three biomarkers with easily remembered cut-offs that allow us to identify, at the time of diagnosis, those patients with a high risk of relapse (scores of two or three) and those requiring dose escalation.
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http://dx.doi.org/10.1016/j.ygyno.2020.08.002DOI Listing
November 2020

Dose-intensive regimen treatment for small-cell carcinoma of the ovary of hypercalcemic type (SCCOHT).

Gynecol Oncol 2020 10 25;159(1):129-135. Epub 2020 Jul 25.

Gynecology Unit, Institut Gustave-Roussy, 114 rue Édouard-Vaillant, 94800 Villejuif, France. Electronic address:

Purpose: Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is a rare and rapidly lethal disease affecting young women. Cytoreductive surgery associated with chemotherapy followed by a high dose chemotherapy regimen (HDC) demonstrated improved outcomes in a unique prospective and several retrospective studies, and this report aimed to confirm these results in an independent and larger cohort.

Methods: Between 2006 and 2018, we conducted a multicentric prospective study on 44 women diagnosed with SCCOHT. Patients were treated homogeneously with optimal cytoreductive surgery and chemotherapy protocol for four to six cycles (PAVEP). In case of complete response, patients received HDC with stem-cell support, followed by pelvic radiotherapy. The primary endpoint was the event-free survival (EFS) in the per-protocol cohort. Secondary analysis explored the effect of HDC with outcomes.

Results: Mean age at diagnosis was 33 years old (range 13.8-75.8). 14 patients presented with stage FIGO I, 21 with stage III and 9 with stage IV. Median follow-up was 53.4 months. 38 patients underwent optimal surgery with up to 6 cycles of PAVEP. 30 received HDC, and 21 pelvic radiotherapy. 21 relapses were reported leading to death for 18 patients. Median EFS in the per-protocol cohort was 18.2 months, and 2-year EFS rate was 40%. HDC was significantly associated with better overall survival (p < .001). Grades 3/4 adverse events were frequent but, in most cases, manageable, although one grade-5 adverse-event occurred during HDC.

Conclusion: Intensive regimen containing multidrug chemotherapy, HDC and pelvic radiotherapy, for the management of SCCOHT, demonstrated encouraging survival and should be proposed for all patients. However, the significant toxicity cost associated is of concern and it should be restricted to expert centers.
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http://dx.doi.org/10.1016/j.ygyno.2020.07.019DOI Listing
October 2020

GINECO Prospective Non-interventional PROSPECTYON Study: Trabectedin Plus Pegylated Liposomal Doxorubicin for Platinum-sensitive Recurrent Ovarian Cancer.

Anticancer Res 2020 Jul;40(7):3939-3945

ORACLE-Centre d'Oncologie de Gentilly, Nancy, France.

Background: Trabectedin and pegylated liposomal doxorubicin (PLD) is an effective combination therapy for platinum-sensitive recurrent ovarian cancer (ROC), particularly for disease relapsing within 6-12 months of platinum therapy. The non-interventional PROSPECTYON study evaluated trabectedin/PLD in French clinical practice.

Patients And Methods: Patients with ROC after at least one platinum-based regimen received 1.1 mg/m trabectedin plus 30 mg/m PLD every 3 weeks. Efficacy and safety were evaluated in subgroups according to platinum-free interval [6-12 versus ≥12 months (partially or fully platinum sensitive, respectively)].

Results: Recurrent disease was partially platinum-sensitive in 58 patients and fully sensitive in 33 patients treated between July 2014 and June 2016. Patients in both subgroups received a median of six cycles of trabectedin and PLD. The most common grade 3 or more toxicities were haematological. Median progression-free survival was 6 months for both subgroups.

Conclusion: Trabectedin/PLD is a valuable treatment option for partially or fully platinum-sensitive ROC.
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http://dx.doi.org/10.21873/anticanres.14385DOI Listing
July 2020

ESGO-SIOPE guidelines for the management of adolescents and young adults with non-epithelial ovarian cancers.

Lancet Oncol 2020 07;21(7):e360-e368

Paediatric Oncology, University Hospital Bonn, Bonn, Germany.

The European Society of Gynaecological Oncology and the European Society for Paediatric Oncology jointly developed clinically relevant and evidence-based guidelines for the management of adolescents and young adults aged 15 to 25 years with non-epithelial ovarian cancers, including malignant ovarian germ cell tumours, sex cord-stromal tumours, and small cell carcinoma of the ovary of hypercalcaemic type. The developmental process of these guidelines is based on a systematic literature review and critical appraisal process involving an international multidisciplinary developmental group consisting of experts from relevant disciplines (paediatric oncology, paediatric surgery, medical oncology, pathology, psycho-oncology, gynaecological oncology, and reproductive endocrinology). Given the specific and often complex issues involved in treating this group of patients, fertility sparing surgery and decrease of acute and long-term toxicities from treatment were important criteria for guidelines definition. Prior to publication, the guidelines were reviewed by 54 independent international practitioners in cancer care delivery.
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http://dx.doi.org/10.1016/S1470-2045(20)30091-7DOI Listing
July 2020

Atezolizumab in combination with bevacizumab and chemotherapy versus bevacizumab and chemotherapy in recurrent ovarian cancer - a randomized phase III trial (AGO-OVAR 2.29/ENGOT-ov34).

Int J Gynecol Cancer 2020 12 30;30(12):1997-2001. Epub 2020 Jun 30.

AGO & University Mannheim, Mannheim, Germany.

Background: Improvement in clinical outcomes of patients with platinum-resistant disease is an unmet medical need and trials in this population are urgently needed. Checkpoint-inhibitors have already shown activity in multiple other tumor entities and ovarian cancer, especially in the combination with anti-angiogenic treatment.

Primary Objective: To test if the activity of non-platinum-based chemotherapy and bevacizumab could be improved by the addition of atezolizumab.

Study Hypothesis: The addition of atezolizumab to standard non-platinum combination of chemotherapy and bevacizumab improves median overall survival from 15 to 20 months.

Trial Design: Patients are randomized to chemotherapy (paclitaxel weekly or pegylated liposomal doxorubicin) + bevacizumab + placebo vs chemotherapy + bevacizumab + atezolizumab. Stratification factors are: number of prior lines, planned type of chemotherapy, prior use of bevacizumab, and tumor programmed death-ligand 1 (PD-L1) status.

Major Inclusion/exclusion Criteria: Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer with up to three prior therapies and a treatment-free interval after platinum of less than 6 months. Patients with three prior lines of chemotherapy are eligible irrespective of the platinum free-interval. A de novo tumor tissue sample biopsy for determination of PD-L1 status prior to randomization for stratification is mandatory. Major exclusion criteria consider bevacizumab-specific and immunotherapy-specific criteria.

Primary Endpoint: Overall survival and progression-free survival are co-primary endpoints.

Sample Size: It is planned to randomize 664 patients.

Trial Registration: NCT03353831.
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http://dx.doi.org/10.1136/ijgc-2020-001572DOI Listing
December 2020

Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) beyond Mutations: A Comprehensive Genomic Analysis.

Cells 2020 06 19;9(6). Epub 2020 Jun 19.

Medical Oncologist, Gynecology Unit, Lead Translational Research Team, INSERM U981, Gustave Roussy, 94805 Villejuif, France.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive malignancy that occurs in young women, is characterized by recurrent loss-of-function mutations in the gene, and for which effective treatments options are lacking. The aim of this study was to broaden the knowledge on this rare malignancy by reporting a comprehensive molecular analysis of an independent cohort of SCCOHT cases. We conducted Whole Exome Sequencing in six SCCOHT, and RNA-sequencing and array comparative genomic hybridization in eight SCCOHT. Additional immunohistochemical, Sanger sequencing and functional data are also provided. SCCOHTs showed remarkable genomic stability, with diploid profiles and low mutation load (mean, 5.43 mutations/Mb), including in the three chemotherapy-exposed tumors. All but one SCCOHT cases exhibited 19p13.2-3 copy-neutral LOH. deleterious mutations were recurrent and accompanied by loss of expression of the paralog. Variants in a few other genes located in 19p13.2-3 (e.g., ) were detected. Putative therapeutic targets, including , and , were found to be overexpressed in SCCOHT by RNA-seq as compared to benign ovarian tissue. Lastly, we provide additional evidence for sensitivity of SCCOHT to HDAC, DNMT and EZH2 inhibitors. Despite their aggressive clinical course, SCCOHT show remarkable inter-tumor homogeneity and display genomic stability, low mutation burden and few somatic copy number alterations. These findings and preliminary functional data support further exploration of epigenetic therapies in this lethal disease.
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http://dx.doi.org/10.3390/cells9061496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349095PMC
June 2020

Long term follow-up of a large series of stage-II/III atypical proliferative serous ovarian tumors.

Gynecol Oncol 2020 09 20;158(3):659-665. Epub 2020 Jun 20.

Department of Surgery, Gustave-Roussy Cancer Campus, Villejuif, France; Unit INSERM U10-30, Villejuif, France; University Paris Sud, Le Kremlin-Bicêtre, France. Electronic address:

Background: The aim of this study was to assess prognostic factors and implications on further management in a large series of stage-II or III Atypical Proliferative Serous Tumors (APST) with a long-term follow-up.

Patients And Methods: Patients with APSTs and peritoneal implants treated in, or referred to, our institution were retrospectively reviewed. Prognostic factors on invasive recurrence, disease-free (DFS) and overall survival (OS) were analyzed.

Results: Between 1971 and 2017, 212 patients were identified and followed (33 having invasive implants). After a median follow-up of 115 months, 70 recurrences were observed, 28 of them under the form of invasive disease. DFS at 5 years and 10 years was 73% and 62% respectively. The use of a conservative treatment (HR = 5.5[3.33-9.08], p < .0001), the presence of ≥3 peritoneal sites with implants (HR = 1.65[1.01-2.72], p = .045) were unfavorable prognostic factors for DFS. The presence of ≥3 peritoneal sites with implants (HR = 3.02[0.96-9.53], p = .049) and the presence of stromal microinvasion (HR = 3.19[1.12-9.1], p = .022) were unfavorable prognostic factors for OS. Non-conservative surgery (HR = 7[2.35-20.87], p = .0002), invasive implants (HR = 5.37[1.29-22.26], p = .013), and ≥ 3 peritoneal sites with implants (HR = 3.56 [1.11-11.39], p = .024) were identified as predictors of recurrence in the form of an invasive disease. Invasive implants were not associated with DFS (HR = 1.39[0.77-2.51], p = .27), nor OS (HR = 1.76[0.57-5.47], p = .32).

Conclusion: After a long-term follow-up, type of peritoneal implants is no longer a prognostic factor for OS. Implants ≥3 peritoneal sites seem to impact significantly OS and then require a specific follow-up in this subgroup of patients.
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http://dx.doi.org/10.1016/j.ygyno.2020.06.489DOI Listing
September 2020

Interaction between the Number of Chemotherapy Cycles and Brachytherapy Dose/Volume Parameters in Locally Advanced Cervical Cancer Patients.

J Clin Med 2020 Jun 1;9(6). Epub 2020 Jun 1.

Brachytherapy Unit, Gustave Roussy Cancer Campus, F-94800 Villejuif, France.

Scarce data exist on concurrent chemotherapy in locally advanced cervical cancer (LACC) patients (pts) treated with image-guided adaptive brachytherapy (IGABT). We examined the effect of a number of chemotherapy cycles and their interaction with brachytherapy dose/volume parameters. Clinical records of 209 consecutive pts treated for a LACC were reviewed. Pts received CRT concurrently with cisplatin 40 mg/m² or carboplatin AUC2. An additional cycle could have been delivered during the pulse-dose rate (PDR)-IGABT. The impact of a number of chemotherapy cycles on outcome was examined, as well as the interactions with dose volume parameters. The number of cycles was four in 55 (26.3%) pts, five in 154 (73.7%) including 101 receiving the fifth cycle during IGABT. Median follow-up was 5.5 years. Pts receiving five cycles had a better outcome on all survival endpoints, including three year local control rate (93.9% vs. 77.2%; < 0.05). In the subgroup, only pts with tumor FIGO (Fédération Internationale de Gynécologie Obstétrique) stage ≤IIB or with CTV > 25 cm had a better outcome. Pts receiving four cycles with DCTV > 80Gy had the same locoregional control-(LRC) as those receiving five cycles and achieving DCTV ≤ 80 Gy ( = 0.75). An optimal propensity score matching the balance for the FIGO stage, CTV volume and DCTV confirmed the effect, with the largest life expectancy benefit for locoregional failure-free survival (absolute gain: 1.5 years; = 0.017). Long-term radiation-induced toxicity was not increased. Increasing the total number of cycles from 4 to 5 improved LFS, suggesting a place for systemic strategies aimed at in-field cooperation. Delivering an additional cycle at the time of brachytherapy did not increase morbidity and there permitted an increase in chemotherapy dose intensity.
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http://dx.doi.org/10.3390/jcm9061653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356737PMC
June 2020

Analysis of Systemic Inflammatory Factors and Survival Outcomes in Endometrial Cancer Patients Staged I-III FIGO and Treated with Postoperative External Radiotherapy.

J Clin Med 2020 May 12;9(5). Epub 2020 May 12.

Radiotherapy Department, Gustave Roussy Cancer Campus, 94800 Villejuif, France.

Background: The causal link between elevated systemic inflammation biomarkers and poor survival has been demonstrated in cancer patients. However, the evidence for this correlation in endometrial cancer (EC) is too weak to influence current criteria of risk assessment. Here, we examined the role of inflammatory indicators as a tool to identify EC patients at higher risk of death in a retrospective observational study.

Methods: A total of 155 patients surgically diagnosed with EC stage I-III FIGO 2009 and treated with postoperative External Beam Radiotherapy (EBRT) ± brachytherapy and chemotherapy according to ESMO-ESTRO-ESGO recommendation for patients at high risk of recurrence at the Gustave Roussy Institut, France, and Hospital Clínic, Spain, between 2008 and 2017 were evaluated. The impact of pre-treatment Neutrophil-to-Lymphocyte Ratio (NLR ≥ 2.2), Monocyte-to-Lymphocyte Ratio (MLR ≥ 0.18), Systemic Immune-Inflammatory Index (SII ≥ 1100) and lymphopenia (<1.0×10/L) on overall survival (OS), cancer-specific survival and progression-free survival was evaluated. Subsequently, a cohort of 142 patients within high-advanced risk groups according to ESMO-ESGO-ESTRO classification was evaluated.

Results: On univariate analysis, NLR (HR = 2.2, IC 95% 1.1-4.7), SII (HR = 2.2, IC 95% 1.1-4.6), MLR (HR = 5.0, IC 95% 1.1-20.8) and lymphopenia (HR = 3.8, IC 95% 1.6-9.0) were associated with decreased OS. On multivariate analysis, NLR, MLR, SII and lymphopenia proved to be independent unfavorable prognostic factors.

Conclusions: lymphopenia and lymphocytes-related ratio are associated with poorer outcome in surgically staged I-III FIGO EC patients classified as high risk and treated with adjuvant EBRT and could be considered at cancer diagnosis. External validation in an independent cohort is required before implementation for patients' stratification.
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http://dx.doi.org/10.3390/jcm9051441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291051PMC
May 2020

Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian Cancer.

Cancers (Basel) 2020 Mar 17;12(3). Epub 2020 Mar 17.

INSERM U981, Gustave Roussy Cancer Center, 94805 Villejuif, France.

Ovarian cancer (OC) is sensitive to upfront chemotherapy, which is likely attributable to defects in DNA damage repair (DDR). Unfortunately, patients relapse and the evolution of DDR competency are poorly described. We examined the expression of proposed effectors in homologous recombination (HR: RAD51, ATM, FANCD2), error-prone non-homologous end-joining (NHEJ: 53BP1), and base excision repair pathways (BER: PAR and PARP1) in a cohort of sequential OC samples obtained at diagnosis, after neoadjuvant chemotherapy (NACT), and/or at relapse from a total of 147 patients. Immunohistochemical (IHC) expression was quantified using the H-score (0-300), where H ≤ 10 defined negativity. Before NACT, a significant number of cases lacked the expression of some effectors: 60%, 60%, and 24% were PAR-, FANCD2-, or RAD51-negative, with a reassuringly similar proportion of negative biomarkers after NACT. In multivariate analysis, there was a poorer progression-free survival (PFS) and overall survival (OS) for cases with competent HR at diagnosis (PRE-NACT 53BP1-/RAD51+, hazard ratio (HR) 3.13, = 0.009 and HR 2.78, = 0.024) and after NACT (POST-NACT FANCD2+/RAD51+ HR 1.89, = 0.05 and HR 2.38, = 0.02; POST-NACT PARP-1+/RAD51+ HR 1.79, = 0.038 and HR 2.04, = 0.034), reflecting proficient DNA repair. Overall, HR-competent tumors appeared to have a dismal prognosis in comparison with tumors utilizing NHEJ, as assessed either at baseline or post-NACT. Accurate knowledge of the HR status during treatment is clinically important for the efficient timing of platinum-based and targeted therapies with poly(ADP-ribose) polymerase inhibitors (PARPi).
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http://dx.doi.org/10.3390/cancers12030707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140046PMC
March 2020

Small-Cell Carcinoma of the Ovary, Hypercalcemic Type-Genetics, New Treatment Targets, and Current Management Guidelines.

Clin Cancer Res 2020 08 10;26(15):3908-3917. Epub 2020 Mar 10.

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.

Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and highly aggressive ovarian malignancy. In almost all cases, it is associated with somatic and often germline pathogenic variants in , which encodes for the SMARCA4 protein (BRG1), a subunit of the SWI/SNF chromatin remodeling complex. Approximately 20% of human cancers possess pathogenic variants in at least one SWI/SNF subunit. Because of their role in regulating many important cellular processes including transcriptional control, DNA repair, differentiation, cell division, and DNA replication, SWI/SNF complexes with mutant subunits are thought to contribute to cancer initiation and progression. Fewer than 500 cases of SCCOHT have been reported in the literature and approximately 60% are associated with hypercalcemia. SCCOHT primarily affects females under 40 years of age who usually present with symptoms related to a pelvic mass. SCCOHT is an aggressive cancer, with long-term survival rates of 30% in early-stage cases. Although various treatment approaches have been proposed, there is no consensus on surveillance and therapeutic strategy. An international group of multidisciplinary clinicians and researchers recently formed the International SCCOHT Consortium to evaluate current knowledge and propose consensus surveillance and therapeutic recommendations, with the aim of improving outcomes. Here, we present an overview of the genetics of this cancer, provide updates on new treatment targets, and propose management guidelines for this challenging cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415570PMC
August 2020

Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer.

N Engl J Med 2019 12;381(25):2416-2428

From Centre Léon Bérard (I.R.-C., D.P.), University Claude Bernard Lyon 1 (I.R.-C.), and Centre Hospitalier Lyon-Sud (B.Y.), Lyon, Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) (I.R.-C., P.P., F.S., C.L.-P., A.L., P.C., M.R., C.D., B.Y., E.P.-L.), Groupe Hospitalier Diaconesses Croix Saint-Simon (F.S.), Hôpital Européen Georges Pompidou (P.C.), Institut Curie, Hôpital Claudius Régaud (M.R.), and Association de Recherche Cancers Gynécologiques (ARCAGY) (E.P.-L.), Paris, Gustave Roussy, Villejuif (P.P.), Centre Eugène Marquis, Rennes (C.L.-P.), Centre Catherine de Sienne Hôpital Privé du Confluent, Nantes (A.L.), and Institut Curie, Hôpital René Huguenin, Saint Cloud (C.D.) - all in France; the Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, and Multicenter Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO), Naples (S.P.), University of Milan-Bicocca and European Institute of Oncology IRCCS, and Mario Negri Gynecologic Oncology Group (MANGO) (N.C.), and Fondazione IRCCS Istituto Nazionale Tumori and MITO (D.L.), Milan, and Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica, and MITO, Rome (G.S.) - all in Italy; M.D. Anderson Cancer Center Madrid (A.G.-M.), Grupo Español de Investigación en Cáncer de Ovario (GEICO) (A.G.-M., E.M.G.A.), and Hospital Universitario Ramón y Cajal (E.M.G.A.) - all in Madrid; Medical University of Innsbruck, University Clinic for Gynecology and Obstetrics (R.B.), and Arbeitsgemeinschaft Gynäkologische Onkologie Study Group (AGO)-Austria (R.B., A.R.), Innsbruck, and Medical University of Vienna, Vienna (A.R.) - all in Austria; Saitama Medical University International Medical Center, Hidaka (K.F.), Gynecologic Oncology Trial and Investigation Consortium (GOTIC), Moroyama-cho (K.F., S.N.), and Hyogo Cancer Center, Akashi (S.N.) - all in Japan; University Hospital Leuven, Leuven Cancer Institute, and Belgium and Luxembourg Gynecologic Oncology Group (BGOG) - both in Leuven, Belgium (I.V.); Tampere University and University Hospital, Tampere, Finland (J.M.); the Nordic Society of Gynecologic Oncology (NSGO), Copenhagen (J.M.); and Charité-Medical University of Berlin (Campus Virchow Klinikum), Berlin (J.S.), German Society of Gynecologic Oncology (AGO) (J.S., U.C., F.M., N.G., P.B., A.B., P.H.), Universitätsklinikum Essen (P.B.), and Kliniken Essen Mitte (P.H.), Essen, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden (U.C.), Universitätsklinikum Heidelberg, Heidelberg (F.M.), Universitätsklinikum Ulm, Ulm (N.G.), and Klinikum der Universität München, Munich (A.B.) - all in Germany.

Background: Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a mutation. The effect of combining maintenance olaparib and bevacizumab in patients regardless of mutation status is unknown.

Methods: We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death.

Results: Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab.

Conclusions: In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.).
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December 2019

Clinical utility of SMARCA4 testing by immunohistochemistry in rare ovarian tumours.

Br J Cancer 2020 02 17;122(4):564-568. Epub 2019 Dec 17.

Groupe des Investigateurs Nationaux des Cancers de l'Ovaire (GINECO)-GINECO Group for Early Phase Studies (GINEGEPS), Paris, France.

Background: Ovarian small cell carcinoma, hypercalcaemic type (SCCOHT) is a rare and lethal disease affecting young women. As histological diagnosis is challenging and urgent, there is a clear need for a robust diagnostic test. While mutations in the chromatin-remodelling gene, SMARCA4, appear to be typical, it may not be feasible routinely to be clinically relevant.

Methods: Previous studies have described the value of SMARCA4 IHC to differentiate SCCOHT from ovarian neoplasms (ON), with similar histologic appearances. We aimed to evaluate its clinical utility among a cohort of 44 SCCOHT and 94 rare ON frequently misdiagnosed as SCCOHT.

Results: Forty-three percent (16/36) of SCCOHT had been classified locally as non-SCCOHT confirming the diagnosis challenge. Sensitivity and specificity of SMARCA4 IHC were excellent at 88% and 94%, respectively. In a community setting with a much lower prevalence of the disease, estimated PPV is 40% while NPV remained high at 99%. Finally, among the 16 SCCOHT misclassified locally, SMARCA4 IHC testing would have resulted in corrected diagnosis in 88% of cases.

Conclusions: SMARCA4 IHC is a highly sensitive, and specific test for the diagnosis of SCCOHT and is of huge clinical utility in providing a timely and accurate diagnosis of this challenging disease.
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http://dx.doi.org/10.1038/s41416-019-0687-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028983PMC
February 2020
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