Publications by authors named "Laurence Gladieff"

75 Publications

Phase II study of the safety and efficacy of the anti-PD-1 antibody balstilimab in patients with recurrent and/or metastatic cervical cancer.

Gynecol Oncol 2021 Aug 24. Epub 2021 Aug 24.

Centre Léon Bérard, Lyon, France. Electronic address:

Objective: This phase II clinical trial evaluated the safety and antitumor activity of balstilimab, an anti-PD-1 antibody, in patients with previously-treated, recurrent/metastatic cervical cancer.

Methods: Eligible patients were 18 years or older with recurrent and/or metastatic cervical cancer and who had relapsed after a prior platinum-based treatment regimen for advanced disease. Balstilimab was administered intravenously at 3 mg/kg once every two weeks, for up to 24 months. The primary endpoint was objective response rate (ORR, RECIST v1.1) as assessed by an independent review committee.

Results: At data cutoff, 161 women (median age, 53 years [range 25-81]) were enrolled and treated with balstilimab. Of these, 140 had measurable disease at baseline and one prior line of platinum-based therapy in the metastatic, persistent, or recurrent setting; these patients were included in the efficacy analyses. The ORR was 15% (95% CI, 10.0%-21.8%) and included 5 patients with a complete response and 16 with a partial response. The median duration of response was 15.4 months. In patients with PD-L1-positive tumors the ORR was 20%, however patients with PD-L1-negative tumors also responded to balstilimab (ORR, 7.9%). Responses were not restricted to tumors of squamous cell histology, and an ORR of 12.5% was seen in the subset of patients with cervical adenocarcinoma. The disease control rate was 49.3% (95% CI, 41.1%-57.5%). Immune-mediated enterocolitis (3.1%) and diarrhea (1.9%) were the most common grade 3 or higher treatment-related adverse events.

Conclusion: Balstilimab demonstrated meaningful and durable clinical activity, with manageable safety, in patients with previously-treated, recurrent/metastatic cervical cancer.
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http://dx.doi.org/10.1016/j.ygyno.2021.08.018DOI Listing
August 2021

TUMOSPEC: A Nation-Wide Study of Hereditary Breast and Ovarian Cancer Families with a Predicted Pathogenic Variant Identified through Multigene Panel Testing.

Cancers (Basel) 2021 Jul 21;13(15). Epub 2021 Jul 21.

Centre Hospitalier de Troyes, Hôpital S. Veil, F-10000 Troyes, France.

Assessment of age-dependent cancer risk for carriers of a predicted pathogenic variant (PPV) is often hampered by biases in data collection, with a frequent under-representation of cancer-free PPV carriers. TUMOSPEC was designed to estimate the cumulative risk of cancer for carriers of a PPV in a gene that is usually tested in a hereditary breast and ovarian cancer context. Index cases are enrolled consecutively among patients who undergo genetic testing as part of their care plan in France. First- and second-degree relatives and cousins of PPV carriers are invited to participate whether they are affected by cancer or not, and genotyped for the familial PPV. Clinical, family and epidemiological data are collected, and all data including sequencing data are centralized at the coordinating centre. The three-year feasibility study included 4431 prospective index cases, with 19.1% of them carrying a PPV. When invited by the coordinating centre, 65.3% of the relatives of index cases (5.7 relatives per family, on average) accepted the invitation to participate. The study logistics were well adapted to clinical and laboratory constraints, and collaboration between partners (clinicians, biologists, coordinating centre and participants) was smooth. Hence, TUMOSPEC is being pursued, with the aim of optimizing clinical management guidelines specific to each gene.
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http://dx.doi.org/10.3390/cancers13153659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345200PMC
July 2021

Diagnostic chest X-rays and breast cancer risk among women with a hereditary predisposition to breast cancer unexplained by a BRCA1 or BRCA2 mutation.

Breast Cancer Res 2021 08 3;23(1):79. Epub 2021 Aug 3.

Institut Claudius Regaud - IUCT-Oncopole, Service d'Oncologie Médicale, Toulouse, France.

Background: Diagnostic ionizing radiation is a risk factor for breast cancer (BC). BC risk increases with increased dose to the chest and decreases with increased age at exposure, with possible effect modification related to familial or genetic predisposition. While chest X-rays increase the BC risk of BRCA1/2 mutation carriers compared to non-carriers, little is known for women with a hereditary predisposition to BC but who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation.

Methods: We evaluated the effect of chest X-rays from diagnostic medical procedures in a dataset composed of 1552 BC cases identified through French family cancer clinics and 1363 unrelated controls. Participants reported their history of X-ray exposures in a detailed questionnaire and were tested for 113 DNA repair genes. Logistic regression and multinomial logistic regression models were used to assess the association with BC.

Results: Chest X-ray exposure doubled BC risk. A 3% increased BC risk per additional exposure was observed. Being 20 years old or younger at first exposure or being exposed before first full-term pregnancy did not seem to modify this risk. Birth after 1960 or carrying a rare likely deleterious coding variant in a DNA repair gene other than BRCA1/2 modified the effect of chest X-ray exposure.

Conclusion: Ever/never chest X-ray exposure increases BC risk 2-fold regardless of age at first exposure and, by up to 5-fold when carrying 3 or more rare variants in a DNA repair gene. Further studies are needed to evaluate other DNA repair genes or variants to identify those which could modify radiation sensitivity. Identification of subpopulations that are more or less susceptible to ionizing radiation is important and potentially clinically relevant.
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http://dx.doi.org/10.1186/s13058-021-01456-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336294PMC
August 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

Correction to: Formulae recently proposed to estimate renal glomerular filtration rate improve the prediction of carboplatin clearance.

Cancer Chemother Pharmacol 2021 Jul;88(1):171

Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR1037, 2 Avenue Hubert Curien, CS53717, 31037, Toulouse CEDEX 1, France.

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http://dx.doi.org/10.1007/s00280-021-04268-4DOI Listing
July 2021

Risk factors for gastric perforation after cytoreductive surgery in patients with peritoneal carcinomatosis: Splenectomy and increased body mass index.

PLoS One 2021 4;16(3):e0248205. Epub 2021 Mar 4.

Department of Surgical Oncology, Institut Claudius Regaud - Institut Universitaire du Cancer de Toulouse - Oncopole, Toulouse, France.

Background: Gastric perforation after cytoreductive surgery (CRS) is an infrequent complication. There is lack of evidence regarding the risk factors for this postoperative complication. The aim of this study was to assess the prevalence of postoperative gastric perforation in patients undergoing CRS for peritoneal carcinomatosis (PC) and to evaluate risk factors predisposing to this complication.

Methods: We designed a unicentric retrospective study to identify all patients who underwent an open upfront or interval CRS after a primary diagnosis of PC of different origins between March 2007 and December 2018 at a French Comprehensive Cancer Center. The main outcome was the occurrence of postoperative gastric perforation.

Results: Five hundred thirty-three patients underwent a CRS for PC during the study period and 13 (2.4%) presented a postoperative gastric perforation with a mortality rate of 23% (3/13). Neoadjuvant chemotherapy was administered in 283 (53.1%) patients and 99 (18.6%) received hyperthermic intraperitoneal chemotherapy (HIPEC). In the univariate analysis, body mass index (BMI), peritoneal cancer index, splenectomy, distal pancreatectomy, and histology were significantly associated with postoperative gastric perforation. After multivariate analysis, BMI (OR [95%CI] = 1.13 [1.05-1.22], p = 0.002) and splenectomy (OR [95%CI] = 26.65 [1.39-509.67], p = 0.029) remained significantly related to the primary outcome.

Conclusions: Gastric perforation after CRS is a rare event with a high rate of mortality. While splenectomy and increased BMI are risk factors associated with this complication, HIPEC does not seem to be related. Gastric perforation is probably an ischemic complication due to a multifactorial process. Preventive measures such as preservation of the gastroepiploic arcade and prophylactic suture of the greater gastric curvature require further assessment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248205PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932550PMC
March 2021

Clinical practice guidelines for BRCA1 and BRCA2 genetic testing.

Eur J Cancer 2021 03 10;146:30-47. Epub 2021 Feb 10.

BRCA France Association, France. Electronic address:

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

Concordance of laparoscopic and laparotomic peritoneal cancer index using a two-step surgical protocol to select patients for cytoreductive surgery in advanced ovarian cancer.

Arch Gynecol Obstet 2021 05 3;303(5):1295-1304. Epub 2021 Jan 3.

Department of Surgical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse (IUCT)-Oncopole, 1 Avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France.

Purpose: The aim of our study was to assess concordance of staging laparoscopy and cytoreductive surgery (CRS) peritoneal cancer index (PCI) when applying a two-step surgical protocol. We also aimed to evaluate the accuracy of diagnostic laparoscopy to triage patients for complete cytoreduction, and to define optimal time between staging laparoscopy and CRS.

Methods: We designed a retrospective review of prospectively collected data from patients with advanced ovarian cancer who underwent a diagnostic laparoscopy followed by a CRS a few weeks later (two-step surgical protocol), from January 2010 to April 2019. Only patients selected for complete cytoreduction, and with available PCI score from both surgeries were included. PCI concordance was assessed using intraclass correlation coefficient (ICC).

Results: During the study period 543 patients underwent a laparoscopic staging for ovarian carcinomatosis. Among them, 43 patients fulfilled inclusion criteria. ICC between laparoscopic and laparotomic PCI was 0.54. After applying the linear regression equation: laparoscopic PCI + 0.2 x [days between surgeries] + 2, ICC increased to 0.79. Completeness cytoreduction score and laparoscopic PCI were significantly associated (OR 1.27, 95% CI 1.03-1.57, p = 0.03). AUC of laparoscopic PCI to predict complete cytoreduction was 0.90.

Conclusion: Concordance between laparoscopic PCI assessment and PCI score at the end of CRS is fair within a two-step surgical management. Laparoscopic assessment underestimates final PCI score by two points, and this difference increases with the delay between both surgeries. Diagnostic laparoscopy can adequately select patients for CRS, and optimal time to perform it is no more than 10 days after laparoscopy.
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http://dx.doi.org/10.1007/s00404-020-05874-yDOI Listing
May 2021

Gene- and pathway-level analyses of iCOGS variants highlight novel signaling pathways underlying familial breast cancer susceptibility.

Int J Cancer 2021 04 9;148(8):1895-1909. Epub 2021 Jan 9.

Département d'Anticipation et de Suivi des Cancers, Oncogénétique Clinique, Institut Paoli-Calmettes, Marseille, France.

Single-nucleotide polymorphisms (SNPs) in over 180 loci have been associated with breast cancer (BC) through genome-wide association studies involving mostly unselected population-based case-control series. Some of them modify BC risk of women carrying a BRCA1 or BRCA2 (BRCA1/2) mutation and may also explain BC risk variability in BC-prone families with no BRCA1/2 mutation. Here, we assessed the contribution of SNPs of the iCOGS array in GENESIS consisting of BC cases with no BRCA1/2 mutation and a sister with BC, and population controls. Genotyping data were available for 1281 index cases, 731 sisters with BC, 457 unaffected sisters and 1272 controls. In addition to the standard SNP-level analysis using index cases and controls, we performed pedigree-based association tests to capture transmission information in the sibships. We also performed gene- and pathway-level analyses to maximize the power to detect associations with lower-frequency SNPs or those with modest effect sizes. While SNP-level analyses identified 18 loci, gene-level analyses identified 112 genes. Furthermore, 31 Kyoto Encyclopedia of Genes and Genomes and 7 Atlas of Cancer Signaling Network pathways were highlighted (false discovery rate of 5%). Using results from the "index case-control" analysis, we built pathway-derived polygenic risk scores (PRS) and assessed their performance in the population-based CECILE study and in a data set composed of GENESIS-affected sisters and CECILE controls. Although these PRS had poor predictive value in the general population, they performed better than a PRS built using our SNP-level findings, and we found that the joint effect of family history and PRS needs to be considered in risk prediction models.
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http://dx.doi.org/10.1002/ijc.33457DOI Listing
April 2021

PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells.

JCI Insight 2021 01 25;6(2). Epub 2021 Jan 25.

Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.

Tumor antigen-specific CD4 T cells accumulate at tumor sites, evoking their involvement in antitumor effector functions in situ. Contrary to CD8 cytotoxic T lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic, and functional approaches, we characterized CD4 T cell exhaustion in patients with head and neck, cervical, and ovarian cancer. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low, evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression, suggesting divergence with CD8 T cell exhaustion. scRNA-Seq and further phenotypic analyses uncovered similarities with the CD8 T cell exhaustion program. In particular, PD-1hiCD39+ CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently higher tumor-specific CD8 T cell proliferation. Our data identify exhausted CD4 TILs as players in responsiveness to immune checkpoint blockade.
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http://dx.doi.org/10.1172/jci.insight.142513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934837PMC
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

Concordance between CA-125 and RECIST progression in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer treated in the SOLO2 trial with olaparib as maintenance therapy after response to chemotherapy.

Eur J Cancer 2020 11 23;139:59-67. Epub 2020 Sep 23.

Université Paris Descartes, Paris, France; ARCAGY-GINECO, France.

Background: Limited evidence exists to support CA-125 as a valid surrogate biomarker for progression in patients with ovarian cancer on maintenance PARP inhibitor (PARPi) therapy. We aimed to assess the concordance between CA-125 and Response Evaluation Criteria in Solid Tumours (RECIST) criteria for progression in patients with BRCA mutations on maintenance PARPi or placebo.

Methods: We extracted data on progression as defined by Gynecologic Cancer InterGroup CA-125, investigator- and independent central-assessed RECIST from the SOLO2/ENGOT-ov21(NCT01874353) trial. We excluded those with progression other than by RECIST, progression on date of randomisation, and no repeat CA-125 beyond baseline. We evaluated the concordance between CA-125 progression and RECIST progression, and assessed the negative (NPV) and positive predictive value (PPV).

Results: Of 295 randomised patients, 275 (184 olaparib, 91 placebo) were included. 171 patients had investigator-assessed RECIST progression. Of 80 patients with CA-125 progression, 77 had concordant RECIST progression (PPV 96%, 95% confidence interval 90-99%). Of 195 patients without CA-125 progression, 94 had RECIST progression (NPV 52%, 45-59%). Within treatment arms, PPV was similar (olaparib: 95% [84-99%], placebo: 97% [87-100%]) but NPV was lower in patients on placebo (olaparib: 60% [52-68%], placebo: 30% [20-44%]). Of 94 patients with RECIST but without CA-125 progression, 64 (68%) had CA-125 that remained within normal range. We observed similar findings using independent-assessed RECIST.

Conclusions: Almost half the patients without CA-125 progression had RECIST progression, and most of these had CA-125 within the normal range. Regular computed tomography imaging should be considered as part of surveillance in patients treated with or without maintenance olaparib rather than relying on CA-125 alone.
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http://dx.doi.org/10.1016/j.ejca.2020.08.021DOI Listing
November 2020

Avelumab in Patients With Gestational Trophoblastic Tumors With Resistance to Single-Agent Chemotherapy: Cohort A of the TROPHIMMUN Phase II Trial.

J Clin Oncol 2020 09 27;38(27):3129-3137. Epub 2020 Jul 27.

Centre de Référence des Maladies Trophoblastiques, Lyon, France.

Purpose: Women with gestational trophoblastic tumors (GTT) resistant to single-agent chemotherapy receive alternative chemotherapy regimens, which, although effective, cause considerable toxicity. All GTT subtypes express programmed death-ligand 1 (PD-L1), and natural killer (NK) cells are involved in trophoblast immunosurveillance. Avelumab (anti-PD-L1) induces NK cell-mediated cytotoxicity. The TROPHIMMUN trial assessed avelumab in women with chemotherapy-resistant GTT.

Methods: In this phase II multicenter trial (ClinicalTrials.gov identifier: NCT03135769), women with GTT who experienced disease progression after single-agent chemotherapy received avelumab 10 mg/kg intravenously every 2 weeks until human chorionic gonadotropin (hCG) normalization, followed by 3 consolidation cycles. Rate of hCG normalization was the primary endpoint (2-step Simon design).

Results: Between December 2016 and September 2018, 15 patients were treated. Median age was 34 years; disease stage was I or III in 53.3% and 46.7% of women, respectively; and International Federation of Gynecology and Obstetrics (FIGO) score was 0-4 in 33.3%, 5-6 in 46.7%, and ≥ 7 in 20% of patients. Prior treatment included methotrexate (100%) and actinomycin D (7%). Median follow-up was 25 months, and median number of avelumab cycles was 8 (range, 2-11). Grade 1-2 treatment-related adverse events occurred in 93% of patients, most commonly (≥ 25%) fatigue (33.3%), nausea/vomiting (33.3%), and infusion-related reaction (26.7%). One patient had grade 3 uterine bleeding (treatment unrelated). Eight patients (53.3%) had hCG normalization after a median of 9 avelumab cycles; none subsequently relapsed. Probability of normalization was not associated with disease stage, FIGO score, or baseline hCG. One patient subsequently had a healthy pregnancy. In avelumab-resistant patients (46.7%), hCG was normalized with actinomycin D (42.3%) or combination chemotherapy/surgery (57.1%).

Conclusion: In patients with single-agent chemotherapy-resistant GTT, avelumab had a favorable safety profile and cured approximately 50% of patients. Avelumab could be a new therapeutic option, particularly in patients who would otherwise receive combination chemotherapy.
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http://dx.doi.org/10.1200/JCO.20.00803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499607PMC
September 2020

A multivariate analysis of the prognostic impact of tumor burden, surgical timing and complexity after complete cytoreduction for advanced ovarian cancer.

Gynecol Oncol 2020 09 22;158(3):614-621. Epub 2020 Jul 22.

Department of Surgical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse (IUCT), Oncopole, Toulouse, France; INSERM CRCT 1, Toulouse, France. Electronic address:

Objective: To assess the survival benefit of primary debulking surgery (PDS) compared to interval debulking surgery (IDS) after complete cytoreduction (CC-0) or cytoreduction to minimal residual disease (CC-1) in advanced ovarian cancer. Secondary objective was to evaluate the effect of tumor load and surgical complexity on patients' survival.

Methods: A retrospective multicentric study was designed, including patients with IIIC-IV FIGO stage ovarian cancer who underwent PDS or IDS with CC-0 or CC-1 from January 2008 to December 2015 in four high-volume institutions. Patients were classified in three groups: PDS, IDS after 3-4 cycles of neoadjuvant chemotherapy (NACT), and IDS after 6 cycles. Disease-free survival (DFS) and overall survival (OS) were estimated. Univariable and multivariable analyses were conducted.

Results: We included 549 patients, 175 (31.9%) underwent PDS, 224 (40.8%) had IDS after 3-4 cycles of NACT, and 150 (27.3%) underwent IDS after 6 cycles. Median DFS in PDS, IDS at 3-4 cycles and IDS at 6 cycles were 23.0 months (95%CI = [20.0-29.3]), 18.0 months (95%CI = [15.9-20.0]) and 17.1 months (95%CI = [15.0-20.9]), respectively; p < .001. Median OS were 84.0 months (95%CI = [68.3-111.0]), 50.7 months (95%CI = [44.6-59.5]) and 47.5 months (95%CI = [39.3-52.9]), respectively; p < .001. In multivariable analysis, high peritoneal cancer index score and NACT were negatively associated to DFS and OS. Surgical complexity and CC-1 were negatively associated to DFS.

Conclusion: PDS offered a survival gain of almost three years compared to IDS in patients with minimal or no residual disease after surgery. PDS should remain the standard of care for advanced ovarian cancer.
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http://dx.doi.org/10.1016/j.ygyno.2020.06.495DOI Listing
September 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

Circulating CD14 CD16 intermediate blood monocytes as a biomarker of ascites immune status and ovarian cancer progression.

J Immunother Cancer 2020 06;8(1)

UMR152 Pharmadev, Université Toulouse III Paul Sabatier, Toulouse, Occitanie, France

Background: Besides the interest of an early detection of ovarian cancer, there is an urgent need for new predictive and prognostic biomarkers of tumor development and cancer treatment. In healthy patients, circulating blood monocytes are typically subdivided into classical (85%), intermediate (5%) and non-classical (10%) populations. Although these circulating monocyte subsets have been suggested as biomarkers in several diseases, few studies have investigate their potential as a predictive signature for tumor immune status,tumor growth and treatment adaptation.

Methods: In this study, we used a homogeneous cohort of 28 chemotherapy-naïve patients with ovarian cancer to evaluate monocyte subsets as biomarkers of the ascites immunological status. We evaluated the correlations between circulating monocyte subsets and immune cells and tumor burden in peritoneal ascites. Moreover, to validate the use of circulating monocyte subsets tofollow tumor progression and treatment response, we characterized blood monocytes from ovarian cancer patients included in a phase 1 clinical trial at baseline and following murlentamab treatment.

Results: We demonstrate here a robust expansion of the intermediate blood monocytes (IBMs) in ovarian cancer patients. We establish a significant positive correlation between IBM percentage and tumor-associate macrophages with a CCR2/CD163/CD206/CD86profile. Moreover, IBM expansion is associated with a decreased effector/regulatory T-cell ratio in ascites and with the presence of soluble immunosuppressive mediators. We also establish that IBM proportion positively correlates with the peritoneum tumor burden. Finally, the study of IBMs in patients with ovarian cancer under immunotherapy during the phase clinical trial supports IBMs to follow the evolution of tumor development and the treatment adaptation.

Conclusions: This study, which links IBM level with immunosuppression and tumor burden in peritoneum, identifies IBMs as apotential predictive signature of ascites immune status and as a biomarker ofovarian cancer development and treatment response.

Trial Registration Number: EudraCT: 2015-004252-22 NCT02978755.
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http://dx.doi.org/10.1136/jitc-2019-000472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279676PMC
June 2020

Dual Relief of T-lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies.

Cancer Immunol Res 2020 07 15;8(7):869-882. Epub 2020 Apr 15.

Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.

Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in patients with cancer could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8 T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor-specific CD8 T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors, leading, , to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison with their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor-specific CD8 T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated patients with head and neck cancer. Our results showed that PD-1 blockade-mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0855DOI Listing
July 2020

Clear cell adenocarcinoma arising from the abdominal wall after cesarean section in a patient with uterine adenomyosis.

J Surg Case Rep 2020 Apr 7;2020(4):rjaa070. Epub 2020 Apr 7.

Department of Surgical Oncology, Institut Claudius Regaud-Institut Universitaire du Cancer de Toulouse (IUCT)-Oncopole, Toulouse, France.

Malignant transformation of abdominal wall endometriosis lesions developed in a cesarean section scar is a rare event. Patients with uterine adenomyosis but without endometriosis can also develop abdominal wall malignant carcinoma after a gynecologic surgery. The treatment of abdominal wall clear cell adenocarcinoma combines tumor surgical excision with free margins, radiotherapy and chemotherapy. We report a case of clear cell carcinoma arising from an abdominal wall cesarean section scar in a patient without history of endometriosis.
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http://dx.doi.org/10.1093/jscr/rjaa070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136835PMC
April 2020

Formulae recently proposed to estimate renal glomerular filtration rate improve the prediction of carboplatin clearance.

Cancer Chemother Pharmacol 2020 03 9;85(3):585-592. Epub 2020 Jan 9.

Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR1037, 2 Avenue Hubert Curien, CS53717, 31037, Toulouse CEDEX 1, France.

Purpose: While doses of carboplatin are mostly individualized according to the Calvert equation based on estimated Glomerular Filtration Rate (eGFR), there is still uncertainty regarding the best formula to predict GFR. Since Janowitz et al. recently proposed a new equation predicting GFR in cancer patients, we aimed to compare this equation to other carboplatin clearance (carboCL) predicting formulae.

Methods: The actual carboCL of 491 patients was compared to predicted carboCL according to the Calvert formula using several equations to predict GFR (Janowitz, Cockcroft-Gault, MDRD, CKD-EPI, CKD-EPI with cystatin C (CKD-EPI-cysC)); and according to two others that directly predict carboCL (Chatelut and Thomas). The formulae were compared on Mean Percentage Error (MPE), Mean Absolute Percentage Error (MAPE) and percentage of patients with a prediction error above 20% (P20).

Results: The MPE, MAPE and P20 were, respectively, within the ranges - 5.2 to + 5.9%; 14.0-21.2% and 23-46%. The MAPE and P20 of Calvert-CKD-EPI-cysC were the lowest. The performance of Calvert-CKD-EPI was better than that of other creatinine-based formulae although not significantly different from the Calvert-Janowitz formula. Among formulae based on creatinine only, Calvert-CKD-EPI and Calvert-Janowitz are the least influenced by patient characteristics.

Conclusion: Whereas CysC improves carboplatin CL prediction, the Calvert-CKD-EPI equation seems the most suitable creatinine-based formula to predict carboCL homogeneously in all subgroups of patients.
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http://dx.doi.org/10.1007/s00280-019-04020-zDOI Listing
March 2020

Comparison of postoperative complications and quality of life between patients undergoing continent versus non-continent urinary diversion after pelvic exenteration for gynecologic malignancies.

Int J Gynecol Cancer 2020 02 2;30(2):233-240. Epub 2019 Dec 2.

Institut Claudius Regaud, Toulouse, Occitanie, France

Background: Pelvic exenteration and its reconstructive techniques have been associated with high postoperative morbidity and a negative impact on patient quality of life. The aim of our study was to compare postoperative complications and quality of life in patients undergoing continent compared with non-continent urinary diversion after pelvic exenteration for gynecologic malignancies.

Methods: We designed a multicenter study of patients from 10 centers who underwent an anterior or total pelvic exenteration with urinary reconstruction for histologically confirmed persistent or recurrent gynecologic malignancy after previous treatment with radiotherapy. From January 2005 to September 2008, we included patients retrospectively, and from September 2008 to May 2009, patients were included prospectively which allowed collection of quality of life data. Demographic, surgical, and follow-up data were analyzed. Postoperative complications were classified according to the Clavien-Dindo classification. Quality of life was assessed using the European Organization for Research and Treatment of Cancer (EORTC)-QLQ-C30 (V.3.0) and EORTC-QLQ-OV28 quality of life questionnaires. We compared patients who underwent a continent urinary diversion with those who underwent a non-continent reconstruction.

Results: We included 148 patients, 92 retrospectively and 56 prospectively. Among them, 77.4% had recurrent disease and 22.6% persistent disease after the primary treatment. In 70 patients, a urinary continent diversion was performed, and 78 patients underwent a non-continent diversion. Median age of the continent and incontinent groups was 53.5 (range 33-78) years and 57 (26-79) years, respectively. There were no significant differences between the continent and non-continent groups in median length of hospitalization (28.5 vs 26 days, P=0.19), postoperative grade III-IV complications (42.9% vs 42.3%, P=0.95), complications needing surgical (27.9% vs 34.6%, P=0.39) or radiological (14.7% vs 12.8%, P=0.74) intervention, and complication type (digestive (23.2% vs 16.7%, P=0.32) and urinary (15.9% vs 16.7%, P=0.91)). There were no significant differences between the groups in global health, global quality of life, and body image perception scores 1 year after surgery.

Conclusion: Continent and incontinent urinary reconstructions are equivalent in terms of postoperative complications and quality of life scores.
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http://dx.doi.org/10.1136/ijgc-2019-000863DOI Listing
February 2020

PIK3CA mutations early persistence in cell-free tumor DNA as a negative prognostic factor in metastatic breast cancer patients treated with hormonal therapy.

Breast Cancer Res Treat 2019 Oct 11;177(3):659-667. Epub 2019 Jul 11.

Institut d'Analyse Génomique, Imagenome-Inovie, Clinique BeauSoleil, Montpellier, France.

Purpose: The identification of biomarkers of hormonal therapy (HT) failure would allow tailored monitoring in metastatic breast cancer (mBC) patients. PIK3CA gene mutation is one of the most frequent events in mBC and is associated with HT resistance. We evaluated the early prognostic value of cell-free DNA (cfDNA) PIK3CA detection in first-line HT-treated mBC patients.

Methods: Between June 2012 and January 2014, 39 patients were prospectively included in a dedicated clinical trial (NCT01612871). Blood sampling was performed before (M0) and 4 weeks (M1), 3 months (M3) and 6 months (M6) after HT initiation, and at tumor progression. Patients were followed until progression or until the end of the study (2 years). Mutation detection was performed using droplet-based digital PCR (ddPCR). Progression-free survival (PFS) was used as primary endpoint.

Results: Median age at inclusion was 63 years (range 40-86). Most patients (34/39) received an aromatase inhibitor and presented a non-measurable disease (71.8%). PIK3CA mutations were reported in 10 (27.8%) and 5 (14.3%) cases at M0 and M1, respectively. The persistence of a detectable circulating mutation at M1 was highly correlated with a worse progression-free survival (PFS), rate at 1 year: 40% versus 76.7%; p = 0.0053).

Conclusions: Four-week persistence of cfDNA PIK3CA mutation appears highly correlated with PFS.

Trial Registration: NCT01612871, registered on June 6th, 2012; https://clinicaltrials.gov/ct2/show/NCT01612871 .
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http://dx.doi.org/10.1007/s10549-019-05349-yDOI Listing
October 2019

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With or Mutations.

JNCI Cancer Spectr 2018 Dec 8;2(4):pky078. Epub 2019 Mar 8.

Background: Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for and mutation carriers.

Methods: Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 and 3525 mutation carriers) and a prospective cohort (2276 and 1610 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.

Results: For mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HR] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HR = 0.79, 95% CI = 0.69 to 0.91; HR = 0.70, 95% CI = 0.59 to 0.82; HR = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort  = .0003). Relative to being nulliparous, uniparous mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HR] = 1.69, 95% CI = 1.09 to 2.62). For mutation carriers, being parous was associated with a 30% increase in BC risk (HR = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HR = 0.72, 95% CI = 0.54 to 0.98).

Conclusions: These findings suggest differential associations with parity between and mutation carriers with higher risk for uniparous carriers and parous carriers.
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http://dx.doi.org/10.1093/jncics/pky078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405439PMC
December 2018

Prognostic impact of celiac lymph node involvement in patients after frontline treatment for advanced ovarian cancer.

Eur J Surg Oncol 2019 Aug 19;45(8):1410-1416. Epub 2019 Feb 19.

Department of Surgical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse (IUCT), Oncopole, Toulouse, France; INSERM CRCT 1, Toulouse, France. Electronic address:

Introduction: Completeness of cytoreduction is the most important prognostic factor in patients with advanced ovarian cancer (OC). Extensive upper abdominal surgery has allowed to increase the rate complete cytoreduction and the feasibility of resection of celiac lymph nodes (CLN) and porta hepatis disease in these patients has been demonstrated. The aim of our study was to assess the prognostic impact of CLN involvement in patients with primary advanced OC undergoing a complete cytoreductive surgery (CRS).

Material And Methods: We designed a retrospective unicentric study. We reviewed data from patients who underwent CLN resection with or without porta hepatis disease resection, within upfront or interval complete CRS in the frontline treatment of advanced epithelial OC between January 2008 and December 2015. Patients were classified in two groups according to CLN status. Univariate and multivariate analyses were conducted. Survival rates were estimated using Kaplan-Meier method.

Results: Forty-three patients were included and positive CLN were found in 39.5% of them. The median disease-free survival in the group of patients with positive and negative CLN were 11.3 months and 25.8 months, respectively. In multivariable analysis, both CLN involvement and high peritoneal cancer index were independently associated with decreased disease-free survival. Computed tomography re-reading by an expert radiologist has good sensitivity for detection of positive CLN.

Conclusion: CLN involvement and high preoperative tumor burden are independently associated with decreased survival after complete cytoreduction for OC. CLN involvement is a marker of diffuse disease and an independent risk factor for early recurrent disease.
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http://dx.doi.org/10.1016/j.ejso.2019.02.018DOI Listing
August 2019

[Management of epithelial ovarian cancer. Short text drafted from the French joint recommendations of FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY and endorsed by INCa].

Bull Cancer 2019 Apr 6;106(4):354-370. Epub 2019 Mar 6.

CHU de Tours, service de chirurgie gynécologique, 37000 Tours, France.

Faced to an undetermined ovarian mass on ultrasound, an MRI is recommended and the ROMA score (combining CA125 and HE4) can be proposed (grade A). In case of suspected early stage ovarian or fallopian tube cancer, omentectomy (at least infracolonic), appendectomy, multiple peritoneal biopsies, peritoneal cytology (grade C) and pelvic and para-aortic lymphadenectomy are recommended (grade B) for all histological types, except for the expansive mucinous subtype where lymphadenectomy may be omitted (grade C). Minimally invasive surgery is recommended for early stage ovarian cancer, if there is no risk of tumor rupture (grade B). Adjuvant chemotherapy with carboplatin and paclitaxel is recommended for all high-grade ovarian or Fallopian tube cancers, stage FIGO I-IIA (grade A). In case of ovarian, Fallopian tube or primitive peritoneal cancer of FIGO III-IV stages, thoraco-abdomino-pelvic CT scan with injection (grade B) is recommended. Laparoscopic exploration for multiple biopsies (grade A) and to evaluate carcinomatosis score (at least using the Fagotti score) (grade C) are recommended to estimate the possibility of a complete surgery (i.e. no macroscopic residue). Complete medial laparotomy surgery is recommended for advanced cancers (grade B). It is recommended in advanced cancers to perform para-aortic and pelvic lymphadenectomy in case of clinical or radiological suspicion of metastatic lymph node (grade B). In the absence of clinical or radiological lymphadenopathy and in case of complete peritoneal surgery during an initial surgery for advanced cancer, it is possible not to perform a lymphadenectomy because it does not modify the medical treatment and the overall survival (grade B). Primary surgery is recommended when no tumor residue is possible (grade B). After a complete first surgery, it is recommended to deliver 6 cycles of intravenous (grade A) or to propose intraperitoneal (grade B) chemotherapy, to be discussed with patient, according to the benefit/risk ratio. After a complete interval surgery for a FIGO III stage, the hyperthermic intra peritoneal chemotherapy (HIPEC) can be proposed in the same conditions of the OV-HIPEC trial (grade B). In case of tumor residue after surgery or FIGO stage IV, chemotherapy associated with bevacizumab is recommended (grade A).
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http://dx.doi.org/10.1016/j.bulcan.2019.01.014DOI Listing
April 2019

Predictive risk factors of acute kidney injury after cytoreductive surgery and cisplatin-based hyperthermic intra-peritoneal chemotherapy for ovarian peritoneal carcinomatosis.

Int J Gynecol Cancer 2019 Feb 23;29(2):382-391. Epub 2019 Jan 23.

Department of Surgical Oncology, Institut Claudius Regaud - Institut Universitaire du Cancer de Toulouse (IUCT) - Oncopole, Toulouse, France

Objective: The aim of our study was to assess the incidence and identify the predictive risk factors of acute kidney injury after cytoreductive surgery and cisplatin-based hyperthermic intra-peritoneal chemotherapy.

Methods: This is a retrospective study from two centers evaluating patients with advanced or recurrent ovarian cancer who underwent cytoreductive surgery followed by cisplatin-based hyperthermic intra-peritoneal chemotherapy from January 2007 to December 2013. Patients were classified into two groups according to the occurrence of acute kidney injury, defined as a glomerular filtration rate at post-operative day 7 25% lower than at day 0. We also evaluated acute kidney injury following Risk, Injury, Failure, Lost and End-stage kidney function criteria. Univariate and multivariate analyses were conducted in order to assess the association between different variables and the occurrence of acute kidney injury.

Results: Sixty-six patients were included: 29 (44%) underwent first-line treatment and 37 (56%) were treated for recurrent disease. The incidence of post-operative acute kidney injury was 48%. After multivariate analysis, hypertension (OR 18.6; 95% CI 1.9 to 182.3; p=0.012) and low intra-operative diuresis (OR 0.5; 95% CI 0.4 to 0.8; p=0.001) were associated with acute kidney injury.

Conclusion: The incidence of acute kidney injury after cytoreductive surgery and cisplatin-based hyperthermic intra-peritoneal chemotherapy was high. Hypertension and low intra-operative diuresis were independent risk factors for this complication. Adequate peri-operative hydration, in order to maintain correct diuresis, could decrease the occurrence of acute kidney injury in patients undergoing cytoreductive surgery plus hyperthermic intra-peritoneal chemotherapy.
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http://dx.doi.org/10.1136/ijgc-2018-000099DOI Listing
February 2019

Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor-Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial.

J Clin Oncol 2019 01 26;37(2):105-114. Epub 2018 Nov 26.

2 Dana-Farber Cancer Institute, Boston, MA.

Purpose: Luminal breast cancer has a long natural history, with recurrences continuing beyond 10 years after diagnosis. We analyzed long-term follow-up (LTFU) of efficacy outcomes and adverse events in the Breast International Group (BIG) 1-98 study reported after a median follow-up of 12.6 years.

Patients And Methods: BIG 1-98 is a four-arm, phase III, double-blind, randomized trial comparing adjuvant letrozole versus tamoxifen (either treatment received for 5 years) and their sequences (2 years of one treatment plus 3 years of the other) for postmenopausal women with endocrine-responsive early breast cancer. When pharmaceutical company sponsorship ended at 8.4 years of median follow-up, academic partners initiated an observational, LTFU extension collecting annual data on survival, disease status, and adverse events. Information from Denmark was from the Danish Breast Cancer Cooperative Group Registry. Intention-to-treat analyses are reported.

Results: Of 8,010 enrolled patients, 4,433 were alive and not withdrawn at an LTFU participating center, and 3,833 (86%) had at least one LTFU report. For the monotherapy comparison of letrozole versus tamoxifen, we found a 9% relative reduction in the hazard of a disease-free survival event with letrozole (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.01). HRs for other efficacy end points were similar to those for disease-free survival. Efficacy of letrozole versus tamoxifen for contralateral breast cancer varied significantly over time (0- to 5-, 5- to 10-, and > 10-year HRs, 0.62, 0.47, and 1.35, respectively; treatment-by-time interaction P = .005), perhaps reflecting a longer carryover effect of tamoxifen. Reporting of specific long-term adverse events seemed more effective with national registry than with case-record reporting of clinical follow-up.

Conclusion: Efficacy end points continued to show trends favoring letrozole. Letrozole reduced contralateral breast cancer frequency in the first 10 years, but this reversed beyond 10 years. This study illustrates the value of extended follow-up in trials of luminal breast cancer.
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http://dx.doi.org/10.1200/JCO.18.00440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325353PMC
January 2019

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing.

Int J Cancer 2019 04 13;144(8):1962-1974. Epub 2018 Nov 13.

Institut Bergonié, Bordeaux, France.

Pathogenic variants in BRCA1 and BRCA2 only explain the underlying genetic cause of about 10% of hereditary breast and ovarian cancer families. Because of cost-effectiveness, multigene panel testing is often performed even if the clinical utility of testing most of the genes remains questionable. The purpose of our study was to assess the contribution of rare, deleterious-predicted variants in DNA repair genes in familial breast cancer (BC) in a well-characterized and homogeneous population. We analyzed 113 DNA repair genes selected from either an exome sequencing or a candidate gene approach in the GENESIS study, which includes familial BC cases with no BRCA1 or BRCA2 mutation and having a sister with BC (N = 1,207), and general population controls (N = 1,199). Sequencing data were filtered for rare loss-of-function variants (LoF) and likely deleterious missense variants (MV). We confirmed associations between LoF and MV in PALB2, ATM and CHEK2 and BC occurrence. We also identified for the first time associations between FANCI, MAST1, POLH and RTEL1 and BC susceptibility. Unlike other associated genes, carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (OR = 17.4 vs. OR = 1.6; p = 0.002). Hence, our approach allowed us to specify BC relative risks associated with deleterious-predicted variants in PALB2, ATM and CHEK2 and to add MAST1, POLH, RTEL1 and FANCI to the list of DNA repair genes possibly involved in BC susceptibility. We also highlight that different types of variants within the same gene can lead to different risk estimates.
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http://dx.doi.org/10.1002/ijc.31921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587727PMC
April 2019

Estimation of Unbound Carboplatin Clearance From Total Plasma Concentrations as a Means of Facilitating Therapeutic Drug Monitoring.

Ther Drug Monit 2019 02;41(1):66-74

Institut Claudius-Regaud, IUCT-Oncopole, Toulouse.

Background: Therapeutic drug monitoring of carboplatin is based on its unbound clearance (CLU) determined by Bayesian analysis on unbound (U) concentrations. However, the ultrafiltration of plasma samples presents technical and time constraints. Therefore, this study aims to estimate CLU using total plasma (P) concentrations.

Methods: U and P concentration data of 407 patients were obtained from 2 clinical studies in which actual CLU had been determined for each patient. The patients were then split into development (277 patients) and prospective data sets (130 patients). Two approaches were evaluated. PK-model-only approach: a 3-compartment pharmacokinetic (PK) model based on U and P concentrations and taking into account the protein binding process was developed. The model with patient covariates was also evaluated. Linear regression approach: an equation (CLU = aCLP + b) was obtained by linear regression analysis between actual CLU and CLP, which is the total plasma clearance obtained by analyzing P concentrations according to a 2-compartment PK model. Predictive performance was then assessed within the prospective data set by estimating CLU from P concentrations using each approach and computing the relative percentage error (PE) between estimated CLU and actual CLU.

Results: The linear regression equation was CLU (L/h) = 1.15 CLP (L/h) + 0.13. The mean PE (MPE) between CLU (estimated using the equation) and the actual CLU was +1.2% (ranging from -31% to +33%) and the mean absolute PE (MAPE) was 9.7%. With the 3-compartment PK model, the MPE was +2.3% (ranging from -41% to +31%) and the MAPE was 11.1%. Inclusion of covariates in the 3-compartment model did not improve the estimation of CLU [MPE = +6.3% (from -33% to +37%); MAPE = 11.4%].

Conclusions: The linear equation gives a relatively good estimation of CLU based on P concentrations, making PK-based carboplatin dose adaptation possible for centers without ultrafiltration facilities.
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http://dx.doi.org/10.1097/FTD.0000000000000569DOI Listing
February 2019

Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers.

Breast Cancer Res 2018 04 17;20(1):28. Epub 2018 Apr 17.

Laboratoire de Diagnostic Génétique, UF1422 Oncogénétique Moléculaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Background: The ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management.

Methods: To characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours. Morphology of ATM-associated tumours was compared with that of 599 patients with no BRCA1 and BRCA2 mutations from a hospital-based series, as well as with data from The Cancer Genome Atlas. Absolute copy number and loss of heterozygosity (LOH) profiles were obtained from the OncoScan SNP array. In addition, we performed whole-genome sequencing on four tumours from ATM loss-of-function variant carriers with available frozen material.

Results: We found that ATM-associated tumours belong mostly to the luminal B subtype, are tetraploid and show LOH at the ATM locus at 11q22-23. Unlike tumours in which BRCA1 or BRCA2 is inactivated, tumours arising in ATM deleterious variant carriers are not associated with increased large-scale genomic instability as measured by the large-scale state transitions signature. Losses at 13q14.11-q14.3, 17p13.2-p12, 21p11.2-p11.1 and 22q11.23 were observed. Somatic alterations at these loci may therefore represent biomarkers for ATM testing and harbour driver mutations in potentially 'druggable' genes that would allow patients to be directed towards tailored therapeutic strategies.

Conclusions: Although ATM is involved in the DNA damage response, ATM-associated tumours are distinct from BRCA1-associated tumours in terms of morphological characteristics and genomic alterations, and they are also distinguishable from sporadic breast tumours, thus opening up the possibility to identify ATM variant carriers outside the ataxia-telangiectasia disorder and direct them towards effective cancer risk management and therapeutic strategies.
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http://dx.doi.org/10.1186/s13058-018-0951-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905168PMC
April 2018
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