Publications by authors named "Isabelle Ray-Coquard"

343 Publications

Maintenance Treatment of Newly Diagnosed Advanced Ovarian Cancer: Time for a Paradigm Shift?

Cancers (Basel) 2021 Nov 17;13(22). Epub 2021 Nov 17.

US Oncology Research, The Woodlands, Houston, TX 77380, USA.

Recent data have demonstrated substantial efficacy with poly (ADP-ribose) polymerase (PARP) inhibitors as treatment and/or maintenance therapy in patients with newly diagnosed advanced epithelial ovarian cancer (EOC). Here, we review efficacy and safety results from four recent Phase III trials in newly diagnosed EOC: SOLO1 (olaparib), PAOLA-1 (olaparib in combination with bevacizumab), PRIMA (niraparib), and VELIA (veliparib). The implications of these data for current clinical practice and areas for future research are discussed, including ongoing studies of targeted agents in the newly diagnosed setting. Data from SOLO1, PAOLA-1, PRIMA, and VELIA confirm the benefit of PARP inhibitors (olaparib, niraparib, veliparib) for women with newly diagnosed EOC. The greatest benefit was seen in patients with a and/or mutation or in the homologous recombination deficiency (HRD)-test positive subgroup. These four well-conducted studies have generated practice-changing data. However, deciding how to apply these results in clinical practice is challenging, and substantial differences in trial design impede cross-trial comparisons. Recent PARP inhibitor approvals (olaparib, niraparib) in the newly diagnosed EOC setting have provided new maintenance treatment options for a broader patient population. The results of these studies call for personalized medicine based on biomarker profile and other factors, including tolerability, cost considerations, and physician and patient preference. Important areas for future research include appropriate use of both BRCA mutation and HRD testing to inform magnitude of PARP inhibitor benefit as well as exploring further options for patients who are HRD-test negative and for those who become PARP inhibitor resistant.
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http://dx.doi.org/10.3390/cancers13225756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616471PMC
November 2021

Precision medicine for patients with gastro-oesophageal cancer: A subset analysis of the ProfiLER program.

Transl Oncol 2021 Nov 15;15(1):101266. Epub 2021 Nov 15.

Département de Cancérologie Médicale, Centre Léon Bérard, 28 rue Laennec, Lyon 69008, France.

Background: Chemotherapy, anti-HER2 and PD-1 antibodies are standard treatments but only a minority of patients derive long-term benefit from these agents.

Methods: In this report we describe the mutational landscape and outcome of patients with gastroesophageal cancers enroled in the ProfiLER program.

Results: Adenocarcinoma (n = 86, 59%), signet-cell (n = 37, 25%) and squamous-cell (n = 21, 14%) were the dominant histology amongst 147 patients. Genomic analyses could be performed for 114 (78%) patients. The most common genomic alterations involved ERBB2 (15%), KRAS (12%), CCND1 (7%), FGFR1-3 (8%), EGFR (5%) and MET (3%), TP53 (51%) and CDKN2A/B (10%). ERBB2, MET and FGFR alterations were found exclusively in the adenocarcinoma and signet-cell subtypes, while CCND1 amplification, TP53 mutations and CDKN2A/B loss were found in both adenocarcinoma and squamous-cell subtypes. Nine patients (8%) received therapy matched to their genomic alteration, with 5 of them achieving disease control. In an exploratory analysis, patients with stage IV disease at diagnosis who had an actionable alteration had longer overall survival compared to those without.

Conclusion: Genomic profiling for patients with advanced gastroesophageal cancers allows the identification of actionable alterations in large proportion of patients. Increased accessibility to molecularly matched therapy may improve survival in this disease.
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http://dx.doi.org/10.1016/j.tranon.2021.101266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605190PMC
November 2021

Treatment Perspectives for Ovarian Cancer in Europe and the United States: Initial Therapy and Platinum-Sensitive Recurrence after PARP Inhibitors or Bevacizumab Therapy.

Curr Oncol Rep 2021 Nov 9;23(12):148. Epub 2021 Nov 9.

Gynecologic Oncology, US Oncology Research, The Woodlands, TX, USA.

Purpose Of Review: Although the survival rate of patients with ovarian cancer (OC) has significantly improved, OC is still one of the most common causes of gynecologic cancer death in women worldwide. The current advances in primary treatment are based on recent regulatory approvals and recurrency of such treatments, challenging the development of a unified approach to care. Herein, we examine how integration of these new approaches is applied to patient's treatment.

Recent Findings: We and others have recently reported clinical trials using bevacizumab and/or inhibitors of Poly (ADP-ribose) polymerase (PARP), which have greatly affected the change in first-line treatments for OC. As first-line therapy has evolved, therapeutic agents once designated for recurrent disease are increasingly being incorporated, changing our standard of care following previously indexed trials. Here, we provide an overview of the current treatment for OC patients, and we highlight practice patterns in Europe and in the USA with corresponding opinions on current and future treatments for platinum-sensitive recurrent OC.
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http://dx.doi.org/10.1007/s11912-021-01128-5DOI Listing
November 2021

"Chronic fatigue, quality of life and long-term side-effects of chemotherapy in patients treated for non-epithelial ovarian cancer: national case-control protocol study of the GINECO-Vivrovaire rare tumors INCa French network for rare malignant ovarian tumors".

BMC Cancer 2021 Oct 26;21(1):1147. Epub 2021 Oct 26.

Clinical Research Department, Baclesse Cancer Center, 3 av. general Harris, 14076, Caen, France.

Background: Germ cell tumors and sex cord stromal tumors are rare cancers of the ovary. They mainly affect young women and are associated with a high survival rate. The standard treatment mainly involves conservative surgery combined with chemotherapy [bleomycin, etoposide and cisplatin (BEP)] depending on the stage and the prognostic factors, as for testicular cancers. As reported in testicular cancer survivors, chemotherapy may induce sequelae impacting quality of life, which has not yet been evaluated in survivors of germ cell tumors and sex cord stromal tumors. The GINECO-VIVROVAIRE-Rare tumor study is a two-step investigation aiming to assess i) chronic fatigue and quality of life and ii) long-term side-effects of chemotherapy with a focus on cardiovascular and pulmonary disorders.

Methods: Using self-reported questionnaires, chronic fatigue and quality of life are compared between 134 ovarian cancer survivors (cancer-free ≥2 years after treatment) treated with surgery and chemotherapy and 2 control groups (67 ovarian cancer survivors treated with surgery alone and 67 age-matched healthy women). Medical data are collected from patient records. In the second step evaluating the long-term side-effects of chemotherapy, a subgroup of 90 patients treated with chemotherapy and 45 controls undergo the following work-up: cardiovascular evaluation (clinical examination, non-invasive cardiovascular tests to explore heart disease, blood tests), pulmonary function testing, audiogram, metabolic and hormonal blood tests. Costs of sequelae will be also assessed. Patients are selected from the registry of the INCa French Network for Rare Malignant Ovarian Tumors, and healthy women by the 'Seintinelles' connected network (collaborative research platform).

Discussion: This study will provide important data on the potential long-term physical side-effects of chemotherapy in survivors of Germ Cell Tumors (GCT) and Sex Cord Stromal Tumors (SCST), especially cardiovascular and pulmonary disorders, and neurotoxicity. The identification of long-term side-effects can contribute to adjusting the treatment of ovarian GCT or SCST patients and to managing follow-up with adapted recommendations regarding practices and chemotherapy regimens, in order to reduce toxicity while maintaining efficacy. Based on the results, intervention strategies could be proposed to improve the management of these patients during their treatment and in the long term.

Trial Registration: This trial was registered at clinicaltrials.gov : 03418844 , on 1 February 2018. This trial was registered on 25 October 2017 under the unique European identification number (ID-RCB): 2017-A03028-45. Recruitment Status: Recruiting.

Protocol Version: Version n° 4.2 dated from Feb 19, 2021.

Trial Sponsor: Centre François Baclesse, 3 avenue du Général Harris, F-14076 Caen cedex 05, France.
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http://dx.doi.org/10.1186/s12885-021-08864-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549373PMC
October 2021

Regorafenib or Tamoxifen for platinum-sensitive recurrent ovarian cancer with rising CA125 and no evidence of clinical or RECIST progression: A GINECO randomized phase II trial (REGOVAR).

Gynecol Oncol 2021 Oct 22. Epub 2021 Oct 22.

Département d'Oncologie Médicale, Centre Léon Bérard, Lyon, France; University Claude Bernard, GINECO, Lyon, France.

Objective: To evaluate the efficacy and safety of regorafenib versus tamoxifen in platinum-sensitive ovarian cancer biological recurrence, defined by CA-125 increase without radiological (RECIST criteria) or symptomatic evidence of progression.

Patients And Methods: 116 patients with platinum-sensitive ovarian cancer presenting an isolated increase of CA-125 were planned to be randomized. Regorafenib was administered orally at 160 or 120 mg daily, 3 weeks on/1 week off or tamoxifen at 40 mg daily, until disease progression or development of unacceptable toxicity. The primary endpoint was Progression-Free Survival, assessed by progression according to RECIST 1.1 or death (by any cause). Secondary endpoints included Overall Survival, Best Response and CA-125 response rate.

Results: 68 patients were randomized. Median age was 67 years (range: 30-87). Primary site of cancer was ovarian for most patients (92.6%). Tumors were predominantly serous / (89.7%), high grade (83.6%) and initial FIGO staging was III for 69.6% of the patients. Most (79.4%) patients were included after the first line of platinum-based treatment. After a median follow-up of 32 months, there was no difference of progression-free survival (PFS) between regorafenib and tamoxifen groups (p = 0.72), with median PFS of 5.6 months (CI 90%: 3.84-7.52) for the tamoxifen arm and 4.6 months (CI 90%: 3.65-7.33) for the regorafenib arm. There was also no difference in term of overall survival, best response or CA-125 response, delay to next therapy. Regorafenib presented a less favorable safety profile than tamoxifen, with grade 3/4 events occurring for 90.9% of the patients compared to 54.3% for tamoxifen. The most frequent were cutaneous, digestive, and biological events. Notably, hand-foot syndrome occurred in 36.4% of these patients.

Conclusion: Regorafenib presented an unfavorable toxicity profile compared to tamoxifen, with no superior efficacy in this population of patients.
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http://dx.doi.org/10.1016/j.ygyno.2021.09.024DOI Listing
October 2021

Preexisting TP53-Variant Clonal Hematopoiesis and Risk of Secondary Myeloid Neoplasms in Patients With High-grade Ovarian Cancer Treated With Rucaparib.

JAMA Oncol 2021 Oct 14. Epub 2021 Oct 14.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle.

Importance: A total of 1% to 3% of patients treated with a poly(adenosine diphosphate-ribose) polymerase inhibitor for high-grade ovarian cancer (HGOC) develop therapy-related myeloid neoplasms (t-MNs), which are rare but often fatal conditions. Although the cause of these t-MNs is unknown, clonal hematopoiesis of indeterminate potential (CHIP) variants can increase the risk of primary myeloid malignant neoplasms and are more frequent among patients with solid tumors.

Objectives: To examine whether preexisting CHIP variants are associated with the development of t-MNs after rucaparib treatment and how these CHIP variants are affected by treatment.

Design, Setting, And Participants: This retrospective genetic association study used peripheral blood cell (PBC) samples collected before rucaparib treatment from patients in the multicenter, single-arm ARIEL2 (Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer) (n = 491; between October 30, 2013, and August 9, 2016) and the multicenter, placebo-controlled, double-blind ARIEL3 (Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients With Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer) (n = 561; between April 7, 2014, and July 19, 2016), which tested rucaparib as HGOC therapy in the treatment and maintenance settings, respectively. The follow-up data cutoff date was September 1, 2019. Of 1052 patients in ARIEL2 and ARIEL3, PBC samples from 20 patients who developed t-MNs (cases) and 44 randomly selected patients who did not (controls) were analyzed for the presence of CHIP variants using targeted next-generation sequencing. Additional longitudinal analysis was performed on available ARIEL2 samples collected during treatment and at the end of treatment.

Main Outcomes And Measures: Enrichment analysis of preexisting variants in 10 predefined CHIP-associated genes in cases relative to controls; association with clinical correlates.

Results: Among 1052 patients (mean [SE] age, 61.7 [0.3] years) enrolled and dosed in ARIEL2 and ARIEL3, 22 (2.1%) developed t-MNs. The t-MNs were associated with longer overall exposure to prior platinum therapies (13.2 vs 9.0 months in ARIEL2, P = .04; 12.4 vs 9.6 months in ARIEL3, P = .003). The presence of homologous recombination repair gene variants in the tumor, either germline or somatic, was associated with increased prevalence of t-MNs (15 [4.1%] of 369 patients with HGOC associated with an HRR gene variant vs 7 [1.0%] of 683 patients with wild-type HGOC, P = .002). The prevalence of preexisting CHIP variants in TP53 but not other CHIP-associated genes at a variant allele frequency of 1% or greater was significantly higher in PBCs from cases vs controls (9 [45.0%] of 20 cases vs 6 [13.6%] of 44 controls, P = .009). TP53 CHIP was associated with longer prior exposure to platinum (mean 14.0 months of 15 TP53 CHIP cases vs 11.1 months of 49 non-TP53 CHIP cases; P = .02). Longitudinal analysis showed that preexisting TP53 CHIP variants expanded in patients who developed t-MNs.

Conclusions And Relevance: The findings of this genetic association study suggest that preexisting TP53 CHIP variants may be associated with t-MNs after rucaparib treatment.
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http://dx.doi.org/10.1001/jamaoncol.2021.4664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517887PMC
October 2021

Characterization of patients with long-term responses to rucaparib treatment in recurrent ovarian cancer.

Gynecol Oncol 2021 Dec 30;163(3):490-497. Epub 2021 Sep 30.

Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.

Objective: To describe molecular and clinical characteristics of patients with high-grade recurrent ovarian carcinoma (HGOC) who had long-term responses to the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib.

Methods: This post hoc analysis pooled patients from Study 10 (NCT01482715; Parts 2A and 2B; n = 54) and ARIEL2 (NCT01891344; Parts 1 and 2; n = 491). Patients with investigator-assessed complete or partial response per RECIST were classified based on duration of response (DOR): long (≥1 year), intermediate (6 months to <1 year), or short (<6 months). Next-generation sequencing was used to detect deleterious mutations and loss of heterozygosity (LOH) in tumors.

Results: Overall, 25.3% (138/545) of enrolled patients were responders. Of these, 27.5% (38/138) had long-term responses; 28.3% (39/138) were intermediate- and 34.8% (48/138) were short-term responders. Most of the long-term responders harbored a BRCA1 or BRCA2 (BRCA) mutation (71.1%, 27/38), and BRCA structural variants were most frequent among long-term responders (14.8%; 4/27). Responders with HGOC harboring a BRCA structural variant (n = 5) had significantly longer DOR than patients with other mutation types (n = 81; median not reached vs 0.62 years; HR, 0.21; 95% CI, 0.10-0.43; unadjusted p = 0.014). Among responders with BRCA wild-type HGOC, most long- and intermediate-term responders had high genome-wide LOH: 81.8% (9/11) and 76.9% (10/13), respectively, including 7 with deleterious RAD51C, RAD51D, or CDK12 mutations.

Conclusion: Among patients who responded to rucaparib, a substantial proportion achieved responses lasting ≥1 year. These analyses demonstrate the relationship between DOR to PARP inhibitor treatment and molecular characteristics in HGOC, such as presence of reversion-resistant BRCA structural variants.
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http://dx.doi.org/10.1016/j.ygyno.2021.08.030DOI Listing
December 2021

Population-adjusted indirect treatment comparison of the SOLO1 and PAOLA-1/ENGOT-ov25 trials evaluating maintenance olaparib or bevacizumab or the combination of both in newly diagnosed, advanced BRCA-mutated ovarian cancer.

Eur J Cancer 2021 11 28;157:415-423. Epub 2021 Sep 28.

Women & Infants Hospital, Providence, RI, USA.

Background: In the absence of randomised head-to-head trials, we conducted a population-adjusted indirect treatment comparison (PA-ITC) of phase III trial data to evaluate the relative efficacy and safety of maintenance olaparib and bevacizumab alone and in combination in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation (BRCAm).

Methods: An unanchored PA-ITC was performed on investigator-assessed progression-free survival (PFS) data. Individual patient data from SOLO1 (olaparib versus placebo) and from BRCA-mutated patients in PAOLA-1/ENGOT-ov25 (olaparib plus bevacizumab versus placebo plus bevacizumab) were pooled. Each arm of PAOLA-1 was weighted so that key baseline patient characteristics were similar to the SOLO1 cohort. Analyses were performed in patients with complete baseline data. Weighted Cox regression analysis was used to estimate the comparative efficacy of different maintenance therapy strategies, supplemented by weighted Kaplan-Meier analyses.

Results: Data from SOLO1 patients (olaparib, n = 254; placebo, n = 126) were compared with data from BRCA-mutated PAOLA-1 patients (olaparib plus bevacizumab, n = 151; placebo plus bevacizumab, n = 71). Adding bevacizumab to olaparib was associated with a numerical improvement in PFS compared with olaparib alone (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.45-1.09). Statistically significant improvements in PFS were seen with olaparib alone versus placebo plus bevacizumab (HR 0.48; 95% CI 0.30-0.75), olaparib plus bevacizumab versus placebo (0.23; 0.14-0.34), and placebo plus bevacizumab versus placebo (0.65; 0.43-0.95).

Conclusions: Results of this hypothesis-generating PA-ITC analysis support the use of maintenance olaparib alone or with bevacizumab in patients with newly diagnosed, advanced ovarian cancer and a BRCAm.
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http://dx.doi.org/10.1016/j.ejca.2021.08.023DOI Listing
November 2021

SLFN11 captures cancer-immunity interactions associated with platinum sensitivity in high-grade serous ovarian cancer.

JCI Insight 2021 09 22;6(18). Epub 2021 Sep 22.

Department of Internal Medicine and Medical Specialties and.

Large independent analyses on cancer cell lines followed by functional studies have identified Schlafen 11 (SLFN11), a putative helicase, as the strongest predictor of sensitivity to DNA-damaging agents (DDAs), including platinum. However, its role as a prognostic biomarker is undefined, partially due to the lack of validated methods to score SLFN11 in human tissues. Here, we implemented a pipeline to quantify SLFN11 in human cancer samples. By analyzing a cohort of high-grade serous ovarian carcinoma (HGSOC) specimens before platinum-based chemotherapy treatment, we show, for the first time to our knowledge, that SLFN11 density in both the neoplastic and microenvironmental components was independently associated with favorable outcome. We observed SLFN11 expression in both infiltrating innate and adaptive immune cells, and analyses in a second, independent, cohort revealed that SLFN11 was associated with immune activation in HGSOC. We found that platinum treatments activated immune-related pathways in ovarian cancer cells in an SLFN11-dependent manner, representative of tumor-immune transactivation. Moreover, SLFN11 expression was induced in activated, isolated immune cell subpopulations, hinting that SLFN11 in the immune compartment may be an indicator of immune transactivation. In summary, we propose SLFN11 is a dual biomarker capturing simultaneously interconnected immunological and cancer cell-intrinsic functional dispositions associated with sensitivity to DDA treatment.
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http://dx.doi.org/10.1172/jci.insight.146098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492341PMC
September 2021

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 Nov 11;163(2):237-245. 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
November 2021

TCR Clonality and Genomic Instability Signatures as Prognostic Biomarkers in High Grade Serous Ovarian Cancer.

Cancers (Basel) 2021 Aug 31;13(17). Epub 2021 Aug 31.

Platform of Transfer in Biological Oncology, Georges François Leclerc Cancer Center-UNICANCER, 1 rue du Professeur Marion, 21000 Dijon, France.

Purpose: Immune infiltration is a prognostic factor in high-grade serous ovarian carcinoma (HGSC) but immunotherapy efficacy is disappointing. Genomic instability is now used to guide the therapeutic value of PARP inhibitors. We aimed to investigate exome-derived parameters to assess the tumor microenvironment according to genomic instability profile.

Methods: We used the HGSC TCGA (the cancer genome atlas) dataset with genomic characteristics, including homologous recombination deficiency (HRD), copy number variant (CNV) signatures, TCR (T cell receptor) clonality and abundance of tissue-infiltrating immune and stromal cell populations. We then investigated the relationship with survival data.

Results: In 578 HGSC patients, HRD status, CNV signature 7 and TCR clonality were associated with longer survival. The combination of high CNV signature 7 expression and HRD status or high CNV signature 3 expression and high TCR clonality was associated with a trend towards longer survival compared to each variable alone. Combining T cell infiltrate and TCR clonality improved the prognostic value compared to T cells infiltration alone. Prognostic value of TCR clonality was confirmed in an independent cohort.

Conclusions: TCR clonality is an emerging prognostic biomarker that improves T cell infiltrate information. Analysis of TCR clonality combined with genomic instability could be an interesting prognostic biomarker.
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http://dx.doi.org/10.3390/cancers13174394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430641PMC
August 2021

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 Nov 25;163(2):274-280. Epub 2021 Aug 25.

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
November 2021

Dedicated Program for Adolescent and Young Adults With Cancer: A Better Way to Inform About Sexual and Fertility Issues.

JCO Oncol Pract 2021 10 26;17(10):642. Epub 2021 Aug 26.

Amandine Bertrand, MD, Department of Pediatric Oncology, Institut d'Hématologie et d'Oncologie Pédiatrique, Lyon, France, RESHAPE U1290, Lyon, France, Department of Human and Social Sciences, Centre Léon Bérard, Lyon, France; Simon Aho, MD, Department of Medical Oncology, Centre Léon Bérard, Lyon, France; Christine Rousset-Jablonski, PhD, RESHAPE U1290, Lyon, France, Department of Surgical Oncology, Centre Léon Bérard, Lyon, France; Marion Cessot, MD, Department of Surgical Oncology, Centre Léon Bérard, Lyon, France; Véronique Christophe, PhD, Department of Human and Social Sciences, Centre Léon Bérard, Lyon, France; Véronique Christophe, PhD, Department of Human and Social Sciences, Centre Léon Bérard, Lyon, France; Perrine Marec-Bérard, MD, Department of Pediatric Oncology, Institut d'Hématologie et d'Oncologie Pédiatrique, Lyon, France; and Isabelle Ray-Coquard, PhD, RESHAPE U1290, Lyon, France, Department of Medical Oncology, Centre Léon Bérard, Lyon, France.

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http://dx.doi.org/10.1200/OP.21.00452DOI Listing
October 2021

Olaparib plus bevacizumab as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer: Japan subset from the PAOLA-1/ENGOT-ov25 trial.

J Gynecol Oncol 2021 09;32(5):e82

Centre Léon BERARD and University Claude Bernard Lyon I, GINECO, Lyon, France.

Objective: The addition of maintenance olaparib to bevacizumab demonstrated a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the PAOLA-1/ENGOT-ov25 trial (NCT02477644). We evaluated maintenance olaparib plus bevacizumab in the Japan subset of PAOLA-1.

Methods: PAOLA-1 was a randomized, double-blind, phase III trial. Patients received maintenance olaparib tablets 300 mg twice daily or placebo twice daily for up to 24 months, plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total. This prespecified subgroup analysis evaluated investigator-assessed PFS (primary endpoint).

Results: Of 24 randomized Japanese patients, 15 were assigned to olaparib and 9 to placebo. After a median follow-up for PFS of 27.7 months for olaparib plus bevacizumab and 24.0 months for placebo plus bevacizumab, median PFS was 27.4 versus 19.4 months, respectively (hazard ratio [HR]=0.34; 95% confidence interval [CI]=0.11-1.00). In patients with tumors positive for homologous recombination deficiency, the HR for PFS was 0.57 (95% CI=0.16-2.09). Adverse events in the Japan subset were generally consistent with those of the PAOLA-1 overall population and with the established safety and tolerability profiles of olaparib and bevacizumab.

Conclusion: Results in the Japan subset of PAOLA-1 support the overall conclusion of the PAOLA-1 trial demonstrating that the addition of maintenance olaparib to bevacizumab provides a PFS benefit in patients with newly diagnosed, advanced ovarian cancer.

Trial Registration: ClinicalTrials.gov Identifier: NCT02477644.
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http://dx.doi.org/10.3802/jgo.2021.32.e82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362816PMC
September 2021

PARP-inhibitors in epithelial ovarian cancer: Actual positioning and future expectations.

Cancer Treat Rev 2021 Sep 15;99:102255. Epub 2021 Jul 15.

Centre Léon Bérard, Lyon, France; University Claude Bernard Lyon 1, France. Electronic address:

Poly-(ADP)-ribose polymerase inhibitors (PARPi) are a class of oral anticancer drugs first developed as "synthetically lethal" in cancers harboring BRCA1/BRCA2 inactivating mutations. In high-grade serous or endometrioid ovarian cancers (HGOC), PARPi demonstrated benefit as maintenance therapy in relapsing BRCA-mutated and non-mutated tumors. Recently, they extended their indications to frontline maintenance therapy. This review summarizes the current place of PARPi (i) as maintenance or single agent in recurrent disease and (ii) frontline maintenance with different settings. We reviewed the course of biomarker identification, the challenge of overcoming resistance to PARPi and future combinations with targeted therapies, including anti-angiogenic, immune checkpoint inhibitors and DNA damage response inhibitors.
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http://dx.doi.org/10.1016/j.ctrv.2021.102255DOI Listing
September 2021

Management of Patients with Pancreatic Ductal Adenocarcinoma in the Real-Life Setting: Lessons from the French National Hospital Database.

Cancers (Basel) 2021 Jul 14;13(14). Epub 2021 Jul 14.

Agence Régionale de Santé (ARS) AuRA, 241 Rue Garibaldi, 69003 Lyon, France.

Pancreatic ductal adenocarcinoma (PDAC) remains a major public health challenge, and faces disparities and delays in the diagnosis and access to care. Our purposes were to describe the medical path of PDAC patients in the real-life setting and evaluate the overall survival at 1 year. We used the national hospital discharge summaries database system to analyze the management of patients with newly diagnosed PDAC over the year 2016 in Auvergne-Rhône-Alpes region (AuRA) (France). A total of 1872 patients met inclusion criteria corresponding to an incidence of 22.6 per 100,000 person-year. Within the follow-up period, 353 (18.9%) were operated with a curative intent, 743 (39.7%) underwent chemo- and/or radiotherapy, and 776 (41.4%) did not receive any of these treatments. Less than half of patients were operated in a high-volume center, defined by more than 20 PDAC resections performed annually, mainly university hospitals. The 1-year survival rate was 47% in the overall population. This study highlights that a significant number of patients with PDAC are still operated in low-volume centers or do not receive any specific oncological treatment. A detailed analysis of the medical pathways is necessary in order to identify the medical and territorial determinants and their impact on the patient's outcome.
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http://dx.doi.org/10.3390/cancers13143515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306072PMC
July 2021

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

Gynecol Oncol 2021 Oct 19;163(1):64-71. 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
October 2021

Mutation as a Prognostic and Predictive Marker in Sarcoma: Pooled Analysis of MOSCATO and ProfiLER Precision Medicine Trials.

Cancers (Basel) 2021 Jul 5;13(13). Epub 2021 Jul 5.

Centre Léon Bérard, Medical Oncology Department, 69008 Lyon, France.

(1) Background: locally resected high-grade sarcomas relapse in 40% of cases. There is no prognostic or predictive genomic marker for response to peri-operative chemotherapy. (2) Methods: MOSCATO and ProfiLER are pan-tumor prospective precision medicine trials for advanced tumors. Molecular analysis in both trials comprised targeted next-generation sequencing and comparative genomic hybridization array. We investigated if molecular alterations identified in these trials in sarcomas were associated with disease-free survival (DFS) and response to anthracyclines. (3) Results: this analysis included 215 sarcomas, amongst which 53 leiomyosarcomas, 27 rhabdomyosarcomas, 20 undifferentiated pleomorphic sarcomas, and 17 liposarcomas. The most frequently altered gene was (46 mutations and eight deletions). There were 149 surgically resected localized sarcomas. Median DFS in wild type (WT), deleted, and mutated sarcomas was 16, 10, and 10 months, respectively ( = 0.028; deletions: HR = 1.55; 95% CI = 0.75-3.19; mutations: HR = 1.70; 95%CI = 1.13-2.64). In multivariate analysis, mutations remained associated with shorter DFS ( = 0.027; HR = 2.30; 95%CI = 1.10-4.82). There were 161 localized and advanced sarcomas evaluable for response to anthracyclines. Objective response rates were 35% and 55% in WT and mutated sarcomas, respectively (OR = 2.24; 95%CI = 1.01-5.03; = 0.05). In multivariate analysis, mutations remained associated with increased response (OR = 3.24; 95%CI = 1.30-8.45; = 0.01). (4) Conclusions: mutations are associated with shorter DFS and increased response to anthracyclines. Post-validation, these findings could assist in decision-making for peri-operative treatments.
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http://dx.doi.org/10.3390/cancers13133362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268242PMC
July 2021

Genetic Analysis in Anal and Cervical Cancer: Exploratory Findings About Radioresistance in the ProfiLER Database.

Cancer Genomics Proteomics 2021 Jul-Aug;18(4):515-520

Department of Medical Oncology, Léon Bérard Cancer Centre, Lyon, France.

Background/aim: This study aimed to describe genomic alterations on squamous cell cervical and anal carcinomas.

Materials And Methods: From 2013 to 2019, 3,269 patients were included in the molecular screening ProfiLER trial. Only patients with non-metastatic cervical or anal cancer, and those initially treated with radiotherapy in a curative intent were selected. Genetic analyses were performed by next generation sequencing (NGS).

Results: Genomic alterations were observed in most patients: 5 patients out of 15 (33.3%) had at least one mutation on NGS and 4 out of 15 (26.7%) had at least one aberration of the number of copies of genes in the comparative genomic hybridation (CGH) analysis. The most common mutated gene was PIK3CA.

Conclusion: All omic approaches must be integrated in the locally advanced cancer setting by new clinical trial design to develop two routes in the treatment strategy: intensification or de-escalation treatment strategy according to omic markers.
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http://dx.doi.org/10.21873/cgp.20276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404730PMC
November 2021

Importance of guidelines and networking for the management of rare gynecological cancers.

Curr Opin Oncol 2021 09;33(5):442-446

Centre Léon Bérard, University Claude Bernard Lyon I, Lyon.

Purpose Of Review: Guidelines are essential to support appropriate medical management. The objective of our paper is to highlight the need for such recommendations, to reinforce strategies in place and to promote the creation of multidisciplinary networks to provide the most appropriate care to patients and to improve it.

Recent Findings: Gynecological rare cancers are not that rare since they represent around 50% of all gynecological cancers. Surgery remains the cornerstone of management for all subtypes. Apart from malignant ovarian germ-cell tumors for which conventional chemotherapy was proven to be efficient, response to standard systemic treatment for other gynecological cancers are disappointing. Better understanding of these pathologies is needed and requires more adapted management.

Summary: Rare cancers are substantially heterogeneous but raise the need of integrating new cases in dedicated networks to enhance and homogenize medical practices. Centralized diagnosis, improved medical practice based on regularly updated international guidelines, and inclusion in innovative clinical trials linked to preclinical studies are essential to contribute to the promotion of improvement in patient care.
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http://dx.doi.org/10.1097/CCO.0000000000000760DOI Listing
September 2021

Determinants of the access to remote specialised services provided by national sarcoma reference centres.

BMC Cancer 2021 May 29;21(1):631. Epub 2021 May 29.

Lille University Medical School and Centre Oscar Lambret, Lille, France.

Background: Spatial inequalities in cancer management have been evidenced by studies reporting lower quality of care or/and lower survival for patients living in remote or socially deprived areas. NETSARC+ is a national reference network implemented to improve the outcome of sarcoma patients in France since 2010, providing remote access to specialized diagnosis and Multidisciplinary Tumour Board (MTB). The IGéAS research program aims to assess the potential of this innovative organization, with remote management of cancers including rare tumours, to go through geographical barriers usually impeding the optimal management of cancer patients.

Methods: Using the nationwide NETSARC+ databases, the individual, clinical and geographical determinants of the access to sarcoma-specialized diagnosis and MTB were analysed. The IGéAS cohort (n = 20,590) includes all patients living in France with first sarcoma diagnosis between 2011 and 2014. Early access was defined as specialised review performed before 30 days of sampling and as first sarcoma MTB discussion performed before the first surgery.

Results: Some clinical populations are at highest risk of initial management without access to sarcoma specialized services, such as patients with non-GIST visceral sarcoma for diagnosis [OR 1.96, 95% CI 1.78 to 2.15] and MTB discussion [OR 3.56, 95% CI 3.16 to 4.01]. Social deprivation of the municipality is not associated with early access on NETSARC+ remote services. The quintile of patients furthest away from reference centres have lower chances of early access to specialized diagnosis [OR 1.18, 95% CI 1.06 to 1.31] and MTB discussion [OR 1.24, 95% CI 1.10 to 1.40] but this influence of the distance is slight in comparison with clinical factors and previous studies on the access to cancer-specialized facilities.

Conclusions: In the context of national organization driven by reference network, distance to reference centres slightly alters the early access to sarcoma specialized services and social deprivation has no impact on it. The reference networks' organization, designed to improve the access to specialized services and the quality of cancer management, can be considered as an interesting device to reduce social and spatial inequalities in cancer management. The potential of this organization must be confirmed by further studies, including survival analysis.
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http://dx.doi.org/10.1186/s12885-021-08393-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164290PMC
May 2021

Gynecological sarcomas: literature review of 2020.

Curr Opin Oncol 2021 07;33(4):345-350

Department of Medical Oncology, Centre Léon Bérard, Lyon Cedex.

Purpose Of Review: This article, focus on recently published data of the last 18 months on the management of gynecologic sarcomas.

Recent Findings: Different tools have been studied to identify the differences between benign from malignant uterine conjonctive tumor.Molecular biology impact more and more on the diagnosis of uterine sarcoma with new definitions of very specific groups. This will make it possible to better define the last group of endometrial sarcoma which has been defined as undifferentiated.In several articles, surgical approaches and fertility-sparing surgery were described including the role of surgery for recurrences.Some other articles have evaluated the potential benefice of adjuvant therapy for uterine sarcoma with early stages.Several new targeted therapies are in development. Notably deoxyribonucleic acid repair machinery in uterine leiomyosarcoma and also immune therapies, transforming growth factor beta pathway, mechanistic target of rapamycin inhibitor, anti angiogenics, etc.

Summary: This last year the potential interest for uterine sarcoma increased, demonstrated by the increasing number of publications in the literature compared to previous years. Despite this greater interest over time, the standard of care for uterine sarcoma does not change and we are always waiting for new innovative therapies able to change routine practice and survival of patients. Currently, the result of different clinical trials, which include new options as targeted molecular approach or immune checkpoint inhibitors are closed to be reported.
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http://dx.doi.org/10.1097/CCO.0000000000000753DOI Listing
July 2021

Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2).

Nat Commun 2021 05 3;12(1):2487. Epub 2021 May 3.

Clovis Oncology, Inc., Boulder, CO, USA.

ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.
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http://dx.doi.org/10.1038/s41467-021-22582-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093258PMC
May 2021

Uterine serous carcinoma.

Gynecol Oncol 2021 07 30;162(1):226-234. Epub 2021 Apr 30.

Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy.

Serous endometrial cancer represents a relative rare entity accounting for about 10% of all diagnosed endometrial cancer, but it is responsible for 40% of endometrial cancer-related deaths. Patients with serous endometrial cancer are often diagnosed at earlier disease stage, but remain at higher risk of recurrence and poorer prognosis when compared stage-for-stage with endometrioid subtype endometrial cancer. Serous endometrial cancers are characterized by marked nuclear atypia and abnormal p53 staining in immunohistochemistry. The mainstay of treatment for newly diagnosed serous endometrial cancer includes a multi-modal therapy with surgery, chemotherapy and/or radiotherapy. Unfortunately, despite these efforts, survival outcomes still remain poor. Recently, The Cancer Genome Atlas (TCGA) Research Network classified all endometrial cancer types into four categories, of which, serous endometrial cancer mostly is found within the "copy number high" group. This group is characterized by the increased cell cycle deregulation (e.g., CCNE1, MYC, PPP2R1A, PIKCA, ERBB2 and CDKN2A) and TP53 mutations (90%). To date, the combination of pembrolizumab and lenvatinib is an effective treatment modality in second-line therapy, with a response rate of 50% in advanced/recurrent serous endometrial cancer. Owing to the unfavorable outcomes of serous endometrial cancer, clinical trials are a priority. At present, ongoing studies are testing novel combinations of various targeted and immunotherapeutic agents in newly diagnosed and advanced/recurrent endometrial cancer - an important strategy for serous endometrial cancer, whereby tumors are usually p53+ and pMMR, making response to PD-1 inhibitor monotherapy unlikely. Here, the rare tumor working group (including members from the European Society of Gynecologic Oncology (ESGO), Gynecologic Cancer Intergroup (GCIG), and Japanese Gynecologic Oncology Group (JGOG)), performed a narrative review reporting on the current landscape of serous endometrial cancer and focusing on standard and emerging therapeutic options for patients affected by this difficult disease.
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http://dx.doi.org/10.1016/j.ygyno.2021.04.029DOI Listing
July 2021

Cutting Edge: mTORC1 Inhibition in Metastatic Breast Cancer Patients Negatively Affects Peripheral NK Cell Maturation and Number.

J Immunol 2021 05 30;206(10):2265-2270. Epub 2021 Apr 30.

Centre International de Recherche en Infectiologie, Equipe Activation et Transduction du Signal dans les Lymphocytes, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Lyon, France

NK cells are cytotoxic lymphocytes displaying strong antimetastatic activity. Mouse models and in vitro studies suggest a prominent role of the mechanistic target of rapamycin (mTOR) kinase in the control of NK cell homeostasis and antitumor functions. However, mTOR inhibitors are used as chemotherapies in several cancer settings. The impact of such treatments on patients' NK cells is unknown. We thus performed immunophenotyping of circulating NK cells from metastatic breast cancer patients treated with the mTOR inhibitor everolimus over a three-month period. Everolimus treatment resulted in inhibition of mTORC1 activity in peripheral NK cells, whereas mTORC2 activity was preserved. NK cell homeostasis was profoundly altered with a contraction of the NK cell pool and an overall decrease in their maturation. Phenotype and function of the remaining NK cell population was less affected. This is, to our knowledge, the first in vivo characterization of the role of mTOR in human NK cells.
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http://dx.doi.org/10.4049/jimmunol.2001215DOI Listing
May 2021

The Expression of Anti-Müllerian Hormone Type II Receptor (AMHRII) in Non-Gynecological Solid Tumors Offers Potential for Broad Therapeutic Intervention in Cancer.

Biology (Basel) 2021 Apr 7;10(4). Epub 2021 Apr 7.

GamaMabs Pharma, Centre Pierre Potier, F-31100 Toulouse, France.

The anti-Müllerian hormone (AMH) belongs to the TGF-β family and plays a key role during fetal sexual development. Various reports have described the expression of AMH type II receptor (AMHRII) in human gynecological cancers including ovarian tumors. According to qRT-PCR results confirmed by specific In-Situ Hybridization (ISH) experiments, AMHRII mRNA is expressed in an extremely restricted number of normal tissues. By performing ISH on tissue microarray of solid tumor samples AMHRII mRNA was unexpectedly detected in several non-gynecological primary cancers including lung, breast, head and neck, and colorectal cancers. AMHRII protein expression, evaluated by immunohistochemistry (IHC) was detected in approximately 70% of epithelial ovarian cancers. Using the same IHC protocol on more than 900 frozen samples covering 18 different cancer types we detected AMHRII expression in more than 50% of hepato-carcinomas, colorectal, lung, and renal cancer samples. AMHRII expression was not observed in neuroendocrine lung tumor samples nor in non-Hodgkin lymphoma samples. Complementary analyses by immunofluorescence and flow cytometry confirmed the detection of AMHRII on a panel of ovarian and colorectal cancers displaying comparable expression levels with mean values of 39,000 and 50,000 AMHRII receptors per cell, respectively. Overall, our results suggest that this embryonic receptor could be a suitable target for treating AMHRII-expressing tumors with an anti-AMHRII selective agent such as murlentamab, also named 3C23K or GM102. This potential therapeutic intervention was confirmed in vivo by showing antitumor activity of murlentamab against AMHRII-expressing colorectal cancer and hepatocarcinoma Patient-Derived tumor Xenografts (PDX) models.
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http://dx.doi.org/10.3390/biology10040305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067808PMC
April 2021

Population exposure-efficacy and exposure-safety analyses for rucaparib in patients with recurrent ovarian carcinoma from Study 10 and ARIEL2.

Gynecol Oncol 2021 Jun 19;161(3):668-675. Epub 2021 Mar 19.

Clinical Pharmacology, Clovis Oncology, Inc., Boulder, CO, USA.

Objective: To evaluate correlations between rucaparib exposure and selected efficacy and safety endpoints in patients with recurrent ovarian carcinoma using pooled data from Study 10 and ARIEL2.

Methods: Efficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had received ≥2 prior lines of chemotherapy. Safety was evaluated in all patients who received ≥1 rucaparib dose. Steady-state daily area under the concentration-time curve (AUC) and maximum concentration (C) for rucaparib were calculated for each patient and averaged by actual dose received over time (AUC and C) using a previously developed population pharmacokinetic model.

Results: Rucaparib exposure was dose-proportional and not associated with baseline patient weight. In the exposure-efficacy analyses (n = 121), AUC was positively associated with independent radiology review-assessed RECIST response in the subgroup of patients with platinum-sensitive recurrent disease (n = 75, p = 0.017). In the exposure-safety analyses (n = 393, 40 mg once daily to 840 mg twice daily [BID] starting doses), most patients received a 600 mg BID rucaparib starting dose, with 27% and 21% receiving 1 or ≥2 dose reductions, respectively. C was significantly correlated with grade ≥2 serum creatinine increase, grade ≥3 alanine transaminase/aspartate transaminase increase, platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease (p < 0.05).

Conclusion: The exposure-response analyses provide support for the approved starting dose of rucaparib 600 mg BID for maximum clinical benefit with subsequent dose modification only following the occurrence of a treatment-emergent adverse event in patients with BRCA-mutated recurrent ovarian carcinoma.
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http://dx.doi.org/10.1016/j.ygyno.2021.03.015DOI Listing
June 2021

Poly(ADP-ribose) polymerase inhibitors in combination with anti-angiogenic agents for the treatment of advanced ovarian cancer.

Future Oncol 2021 06 17;17(18):2291-2304. Epub 2021 Mar 17.

Department of Medical Oncology, Centre Léon Bérard, 28 Prom. Léa et Napoléon Bullukian, Lyon, 69008, France.

Homologous recombination deficiency and VEGF expression are key pathways in high-grade ovarian cancer. Recently, three randomized practice changing trials were published: the PAOLA-1, PRIMA and VELIA trials. The use of PARP inhibitors (PARPi) following chemotherapy has become standard of care in first line. Combination of PARPi with anti-angiogenic agents has demonstrated synergistic activity in preclinical study. This review summarizes the body of evidence supporting the efficacy and safety of the combination of PARPi and anti-angiogenic drugs in first-line homologous recombination deficiency high-grade ovarian cancer leading to US FDA and EMA approvals. This double maintenance is supported by: a large benefit with bevacizumab + olaparib compared with olaparib alone, a rationale for additive effect, and a good safety and cost-effective profile.
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http://dx.doi.org/10.2217/fon-2021-0059DOI Listing
June 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

Bringing Greater Accuracy to Europe's Healthcare Systems: The Unexploited Potential of Biomarker Testing in Oncology.

Biomed Hub 2020 Sep-Dec;5(3):182-223. Epub 2020 Sep 14.

Digestive Cancers Europe, Brussels, Belgium.

Rapid and continuing advances in biomarker testing are not being matched by take-up in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. This paper sets out the potential of biomarker testing, the unfolding precision and range of possible diagnosis and prediction, and the many obstacles to adoption. It offers case studies of biomarker testing in breast, ovarian, prostate, lung, thyroid and colon cancers, and derives specific lessons as to the potential and actual use of each of them. It also draws lessons about how to improve access and alignment, and to remedy the data deficiencies that impede development. And it suggests solutions to outstanding issues - notably including funding and the tangled web of obtaining reimbursement or equivalent coverage that Europe's fragmented health system implies. It urges a European evolution towards an initial minimum testing scenario, which would guarantee universal access to a suite of biomarker tests for the currently most common conditions, and, further into the future, to an optimum testing scenario in which a much wider range of biomarker tests would be introduced and become part of a more sophisticated health system articulated around personalised medicine. For exploiting genomics to the full, it argues the need for a new policy framework for Europe. Biomarker testing is not an issue that can be treated in isolation, since the purpose of testing is to improve health. Its use is therefore always closely linked to specific health challenges and needs to be viewed in the broader policy context in the EU and more widely. The paper is the result of extensive engagement with experts and decision makers to develop the framework, and consequently represents a wide consensus of views on how healthcare systems should respond from push and pull factors at local, national and cross-border and EU level. It contains strong views and clear recommendations springing from the convictions of patients, clinicians, academics, medicines authorities, HTA bodies, payers, the diagnostic, pharmaceutical and ICT industries, and national policy makers.
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http://dx.doi.org/10.1159/000511209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841733PMC
September 2020
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