Publications by authors named "Thibault De la Motte Rouge"

53 Publications

Development of multiplex digital PCR assays for the detection of PIK3CA mutations in the plasma of metastatic breast cancer patients.

Sci Rep 2021 Aug 27;11(1):17316. Epub 2021 Aug 27.

Department of Medical Oncology, Centre Eugène Marquis, Unicancer, Rennes, France.

With the approval of new therapies targeting the PI3K pathway, the detection of PIK3CA mutations has become a key factor in treatment management for HR+/HER2- metastatic breast cancer (MBC). We developed multiplex digital PCR (dPCR) assays to detect and quantify PIK3CA mutations. A first screening assay allows the detection of 21 mutations, with a drop-off system targeting the 542-546 hotspot mutations combined with the simultaneous detection of N345K, C420R, H1047L and H1047R mutations. In the case of a positive result, a sequential strategy based on other assays that we have developped allows for precise mutation identification. Clinical validity was determined by analyzing plasma circulating free DNA (cfDNA) from 213 HR+/HER2- MBC samples, as well as DNA extracted from 97 available matched tumors from 89 patients. Our assays have shown reliable specificity, accuracy and reproducibility, with limits of blank of three and four droplets for the screening assay. Sixty-eight patients (32%) had at least one PIK3CA mutation detectable in their plasma, and we obtained 83.1% agreement between the cfDNA analysis and the corresponding tumors. The high sensitivity and robustness of these new dPCR assays make them well-suited for rapid and cost-effective detection of PIK3CA mutations in the plasma of MBC patients.
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http://dx.doi.org/10.1038/s41598-021-96644-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397758PMC
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

Impact of EPclin on adjuvant therapeutic decision making and comparison of EPclin to the PREDICT tool.

Int J Biol Markers 2021 Jun 22;36(2):57-63. Epub 2021 May 22.

Centre Eugène Marquis, Unicancer, Rennes, France.

Purpose: Genomic signatures, such as EndoPredict, may help clinicians to decide which adjuvant treatment is the most appropriate.

Methods: We propose the EndoPredict assay for unclear cases of adjuvant treatment in patients treated in our comprehensive cancer center. We prospectively and retrospectively report the decision of adjuvant treatment before and after the EndoPredict assay, respectively, compared to the PREDICT's tool scores.

Results: From November 2016 to March 2019, 159 breast cancer tumors were analyzed and presented before and after the EndoPredict assay. Before the EndoPredict results, clinicians recommended chemotherapy for 57 patients (57/159, 36%). A total of 108 patients (108/159, 68%) were classified as EPclin high-risk score. There was only a slight agreement between clinicians' decisions and EPclin risk score. The EPclin score led to 37% changes in treatment (59/159); chemotherapy was favored in 80% of cases (47/59). The PREDICT tool recommended chemotherapy for 16 high-risk patients (16/159, 10%).

Conclusion: Although genomic tests were developed in order to de-escalate adjuvant treatment, in our comprehensive cancer center the use of the EndoPredict assay led to an increase in prescribed chemotherapy.
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http://dx.doi.org/10.1177/17246008211012424DOI 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

Outcome beyond third-line chemotherapy for metastatic triple-negative breast cancer in the French ESME program.

Breast 2021 Apr 30;56:18-25. Epub 2021 Jan 30.

Curie, Saint Cloud, France.

Purpose: Among metastatic breast cancer (MBC) patients, those with a triple-negative breast cancer phenotype (mTNBC) have the worst prognosis, but the benefit of chemotherapy beyond second line on outcome remains uncertain. The purpose of this study was to identify predictive factors of outcome after third- or fourth-line chemotherapy.

Methods: The ESME-MBC database is a French prospective real-life cohort with homogeneous data collection, including patients who initiated first-line treatment for MBC (2008-2016) in 18 cancer centers. After selection of mTNBC cases, we searched for independent predictive factors (Cox proportional-hazards regression models) for overall survival (OS) on third- and fourth-line chemotherapy (OS3, OS4). We built prognostic nomograms based on the main prognostic factors identified.

Results: Of the 22,266 MBC cases in the ESME cohort, 2903 were mTNBC, 1074 (37%) and 598 (20%) of which had received at least 3 or 4 lines of chemotherapy. PFS after first- and second-line chemotherapy (PFS1, PFS2) and number of metastatic sites ≥3 at baseline were identified by multivariate analysis as prognostic factors for both OS3 (HR = 0.76 95%CI[0.66-0.88], HR = 0.55 95%CI[0.46-0.65], HR = 1.36 95%CI[1.14-1.62], respectively), and OS4 (HR = 0.76 95%CI[0.63-0.91], HR = 0.56 95%CI[0.45-0.7], HR = 1.37 95%CI[1.07-1.74]), respectively. In addition, metastasis-free interval was identified as a prognostic factor for OS3 (p = 0.01), while PFS3 influenced OS4 (HR = 0.75 95%CI[0.57-0.98]). Nomograms predicting OS3 and OS4 achieved a C-index of 0.62 and 0.61, respectively.

Conclusion: The duration of each previous PFS is a major prognostic factor for OS in mTNBC patients receiving third- or fourth-line chemotherapy. The clinical utility of nomograms including this information was not demonstrated.
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http://dx.doi.org/10.1016/j.breast.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873471PMC
April 2021

Knowledge of bladder cancer in the French population: results of the EDIFICE 6 survey.

Eur J Cancer Care (Engl) 2021 May 17;30(3):e13392. Epub 2020 Dec 17.

Centre Eugène-Marquis, Rennes, France.

Objective: To assess awareness of bladder cancer (BCa) in France.

Methods: The French nationwide observational survey EDIFICE 6 was conducted online (26 June-28 July 2017) in 12,046 individuals (age, 18-69 years). The present analysis focuses on laypersons' knowledge of the severity and frequency of BCa, signs and symptoms, associated risk factors and screening tests. Quantitative data were expressed as means and standard deviation, and categorical data as percentages.

Results: Analyses were conducted on 11,313 questionnaires. Among the top five acknowledged risk factors for BCa, tobacco was ranked as having the second lowest impact (5.9/10 [2.5]). Only 28% of the study population were aware that active tobacco smoking is a major risk factor for BCa (rating ≥8/10); 61% of the study population was unaware of the existence of any signs or symptoms of BCa, and 69% was not able to cite any of the most widely used diagnostic tests.

Conclusions: We found that the French population has a poor knowledge of BCa risk factors, early signs and diagnostic tests. Effective prevention of BCa requires dissemination of clear information and prevention messages to the lay population, focusing particularly on tobacco consumption and early signs of the disease.
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http://dx.doi.org/10.1111/ecc.13392DOI Listing
May 2021

Borderline ovarian tumors: French guidelines from the CNGOF. Part 1. Epidemiology, biopathology, imaging and biomarkers.

J Gynecol Obstet Hum Reprod 2021 Jan 4;50(1):101965. Epub 2020 Nov 4.

Centre Clinico-Biologique d'AMP, Pôle Femmes - Parents- Enfants, AP-HM, Hôpital de La Conception, 147 Bd Baille, 13005 Marseille, France.

The incidence (rate per 100 000) of borderline ovarian tumors (BOTs) increases progressively with age, starting at 15-19 years and peaking at around 4.5 cases per 100 000 at an age of 55-59 years (LE3) with a median age of 46 years. The five year survival for FIGO stages I, II, III and IV is 99.7 % (95 % CI: 96.2-100 %), 99.6 % (95 % CI: 92.6-100 %), 95.3 % (95 % CI: 91.8-97.4 %) and 77.1 % (95 % CI: 58.0-88.3 %), respectively (LE3). An epidemiological association exists between the individual risk of BOT and family history of BOT and certain other cancers (pancreatic, lung, bone, leukemia) (LE3), a personal history of benign ovarian cyst (LE2), a personal history of tubo-ovarian infection (LE3), the use of a levonorgestrel intrauterine device (LE3), oral contraceptive use (LE3), multiparity (LE3), Hormonal replacement therapy (LE3), high consumption of Coumestrol (LE4), medical treatment for infertility with progesterone (LE3) and non-steroidal anti-inflammatory drug use (LE3). Screening for BOTs is not recommended for patients (Grade C). The overall risk of recurrence of BOTs varies between 2% and 24 %, with an overall survival greater than 94 % at 10 years, and the risk of an invasive recurrence of a BOT ranges from 0.5 % to 3.8 %. The use of scores and nomograms can be useful in assessing the risk of recurrence, and providing patients with information (Grade C). The WHO classification is recommended for classifying BOTs. It is recommended that the presence of a microinvasive focus (<5 mm) and microinvasive carcinoma (<5 mm with an atypical nuclei and a desmoplastic stroma reaction) within a BOT be reported. In cases of serous BOT, it is recommended to specify the classic histological subtype or micropapillary / cribriform type (Grade C). When confronted with a BOT, it is recommended that the invasive or non-invasive nature of peritoneal implants can be investigated based solely on the invasion and destruction of underlying adipose or peritoneal tissue which has a desmoplastic stromal reaction where in contact with the invasive clusters (Grade B). For bilateral mucinous BOTs and / or in cases with peritoneal implants or peritoneal pseudomyxoma, it is recommended to also look for a primitive digestive or pancreato-biliary cancer (Grade C). It is recommended to sample ovarian tumors suspected of being BOTs by focusing samples on vegetations and solid components, with at least 1 sample per cm in tumors with a size less than 10 cm and 2 samples per cm in tumors with a size greater than 10 cm (Grade C). In cases of BOTs and in the absence of macroscopic omental involvement after careful macroscopic examination, it is recommended to perform at least 4-6 systematic sampling blocks and to include all peritoneal implants (Grade C). It is recommended to consult an expert pathologist in gynecology when a BOT suspicion requires intraoperative extemporaneous histology (grade C). Endo-vaginal and suprapubic ultrasonography are recommended for the analysis of an ovarian mass (Grade A). In case of an undetermined ovarian lesion on ultrasonography, it is recommended that a pelvic MRI be performed (Grade A). To analyze an adnexal mass with MRI, it is recommended to use an MRI protocol with T2, T1, T1 Fat Sat, dynamic and diffusion sequences as well as gadolinium injection (Grade B). To characterize an adnexal mass with MRI, it is recommended to include a score system for malignancy (ADNEX MR/O-RADS) (Grade C) in the report and to formulate a histological hypothesis (Grade C). Pelvic MRI is recommended to characterize a tumor suspected of being a BOT (Grade C). Macroscopic MRI features should be analyzed to differentiate BOT subtypes (Grade C). Pelvic ultrasound is the first-line examination for the detection and characterization of adnexal masses during pregnancy (Grade C). Pelvic MRI is recommended from 12 weeks of gestation in case of an indeterminate adnexal mass and should provide a diagnostic score (Grade C). Gadolinium injection must be minimized as fetal impairment has been proven (Grade C). It is recommended that serum levels of HE4 and CA125 be evaluated and that the ROMA score for the diagnosis of an indeterminate ovarian mass on imaging be used (grade A). In case of suspicion of a mucinous BOT on imaging, dosage of serum levels of CA 19-9 can be considered (Grade C). If the determination of tumor markers is normal preoperatively, routine dosage of tumor markers in BOT follow-up is not recommended (Grade C). In case of preoperative elevation in tumor markers, the determination of serum CA 125 levels is recommended in the follow-up of BOT (Grade B). When conservative treatment of a BOT has been adopted, the use of endovaginal and transabdominal ultrasonography is recommended during follow-up (Grade B).
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http://dx.doi.org/10.1016/j.jogoh.2020.101965DOI Listing
January 2021

Factors associated with compliance to cervical cancer screening in France: The EDIFICE 6 survey.

Gynecol Oncol 2021 01 4;160(1):112-117. Epub 2020 Nov 4.

Hôpital Paul Brousse, Villejuif, France.

Introduction: A nationwide cervical cancer (CC) screening program was implemented in France in 2018. Asymptomatic women are invited for a cytological test once every 3 years (age, 25-29 years), and an HPV test every 5 years (age, 30-65 years). We investigated the characteristics of women who are resistant to CC screening.

Methods: Since 2005, the EDIFICE survey program has assessed attitudes toward cancer screening in France. The 6th edition (2017) included 12,046 representative women (age, 18-69 years). Social vulnerability was assessed using the EPICES score. Multivariate stepwise logistic regression analysis identified factors correlated with nonuptake of CC screening.

Results: Questionnaires from 4499 women (age, 25-65 years) with no history of cancer were analyzed; 88% (N = 3960) reported at least one test in their lifetime, and 73% (N = 3262) did the test in the previous 3 years. Compared to ever-screened women, never-screened women were younger (38 ± 11 yrs. vs 44 ± 12 yrs., P < 0.05), and more likely to be single (48% vs 20%, P < 0.05) and/or socially vulnerable (59% vs 38%, P < 0.05). In multivariate analysis, items significantly (P < 0.05) associated with never screening included living alone (OR = 2.26, 95% CI [1.85-2.75]) and social vulnerability (OR = 1.95 [1.59-2.40]). Women who were not compliant with recommendations were more likely to be older (mean age, 49.2 yrs. vs. 43.2 yrs), living alone (single, widowed or divorced, 40% vs. 30%, P < 0.05), and/or socially vulnerable (55% vs. 35%, P < 0.05; OR = 1.78, 95% CI [1.49-2.12]).

Conclusion: This analysis identified several factors associated with never screening and under-screening. Effective prevention messages should specifically target these populations.
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http://dx.doi.org/10.1016/j.ygyno.2020.10.032DOI Listing
January 2021

Borderline ovarian tumors: French guidelines from the CNGOF. Part 2. Surgical management, follow-up, hormone replacement therapy, fertility management and preservation.

J Gynecol Obstet Hum Reprod 2021 Jan 2;50(1):101966. Epub 2020 Nov 2.

Service de gynécologie obstétrique, Hopital Saint Joseph, 13005, Marseille, France.

In the Early Stages (ES) of Borderline Ovarian Tumor (BOT), if surgery without risk of tumor rupture is possible, then laparoscopy with protected extraction is recommended over laparotomy (Grade C). In case of bilateral serous ES BOT treatment with a strategy to preserve fertility and/or endocrine function, bilateral cystectomy is recommended if possible (Grade B). In case of mucinous BOT treatment with a strategy to preserve fertility and/or endocrine function, unilateral adnexectomy is recommended (grade C). In the case of a mucinous BOT in a patient who has had an initial cystectomy, unilateral adnexectomy is recommended (grade C). In the case of treatment of a serous ES BOT in a patient who has had an initial cystectomy, with a strategy to preserve fertility and/or endocrine function, restaging surgery for adnexectomy is not recommended in the absence of suspicious residual lesions at the time of surgery and/or postoperative imaging (reference ultrasonography or pelvic MRI) (grade C). For serous or mucinous ES BOTs, routine hysterectomy is not recommended (Grade C). In cases of ES BOTs, lymphadenectomy is not recommended (Grade C). For ES BOTs, appendectomy is recommended only if there is a macroscopically pathological aspect to the appendix (Grade C). Restaging surgery is recommended in case of a serous BOT with a micropapillary aspect and an unsatisfactory inspection of the abdominal cavity during initial surgery (Grade C). Restaging surgery is recommended in cases of mucinous BOT if only a cystectomy has been performed or if the appendix has not been evaluated (Grade C). If restaging surgery is decided for an ES BOT, the following procedures should be performed: peritoneal cytology (grade C), omentectomy (there is no data in literature to recommend which type of omentectomy should be performed) (grade B), complete exploration of the abdominal cavity with peritoneal biopsies (grade C), visualization of the appendix +/- appendectomy in case of pathological macroscopic appearance (grade C) and unilateral adnexectomy in case of a mucinous BOT (grade C). In advanced stages of BOT it is not recommended to perform a lymphadenectomy as a routine procedure (Grade C). In cases of an advanced stage BOT, in a patient with a desire to fall pregnant, conservative treatment involving preservation of the uterus and all or part of the ovary may be proposed after a multidisciplinary meeting (Grade C). Second surgery aimed at removing all lesions, if not performed initially, is recommended in cases of advanced stage BOT (Grade C). It is not recommended to perform completion surgery after conservative treatment (preservation of the ovaries and the uterus) and after the achievement of fertility desire for a serous BOT (Grade B). After treatment for a BOT, follow-up beyond 5 years is recommended due to the median time to recurrence (Grade B). It is recommended that a systematic clinical examination be carried out during follow-up of a treated BOT (Grade B). In the particular case of an initial elevation of CA 125 levels, it is recommended to monitor CA 125 during follow up (Grade B). In cases treated conservatively (ovarian and uterine conservation), it is recommended to use endovaginal and transabdominal ultrasonography during the follow up period (Grade B). In the event of a recurrence of a BOT, in a woman of childbearing age, a conservative treatment strategy can again be proposed (Grade C). In the presence of non-invasive BOT implants, conservative treatment may be considered after a first non-invasive recurrence in women who wish to preserve their fertility (Grade C). Pelvic MRI is recommended after 12 weeks of amenorrhea in case of an undetermined adnexal mass and should be concluded with a diagnostic score (Grade C). The injection of gadolinium, in case of pregnancy, should be discussed on a case-by-case basis due to the proven risks for the foetus (Grade C). If feasible, a laparoscopic approach should be preferred during pregnancy (Grade C). A consultation with a specialist reproductive physician should be offered to patients with a BOT and of childbearing age (Grade C). It is recommended that patients be provided with full information on the risk of decreased ovarian reserve following to surgical treatment. It is recommended that the ovarian reserve be evaluated prior to surgical management of a suspected BOT (Grade C). When possible, a conservative surgical strategy is recommended to preserve fertility in women of childbearing age (Grade C). There is no specific data on the management of infertility following to conservative treatment of BOT. In case of durable infertility following to conservative treatment of BOT, a consultation with a specialist reproductive physician is required (Grade C). In the case of optimally treated BOT, there is no evidence in literature to contraindicate the use of Assisted Reproductive Techniques (ART). The use of hormonal contraception after serous or mucinous BOT is not contraindicated (Grade C). After treatment of a mucinous BOT, for women aged under 45 years, given the benefit of hormonal replacement therapy (HRT) on cardiovascular and bone risks, and the lack of hormone-sensitivity of mucinous BOTs, it is recommended to offer HRT (Grade C). After treatment of a mucinous BOT, for women over 45 years of age, there is no argument to contraindicate the use of HRT. HRT can be prescribed in case of a climacteric syndrome, as part of an individual benefit to risk assessment (Grade C).
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http://dx.doi.org/10.1016/j.jogoh.2020.101966DOI Listing
January 2021

The Landscape and Therapeutic Implications of Molecular Profiles in Epithelial Ovarian Cancer.

J Clin Med 2020 Jul 15;9(7). Epub 2020 Jul 15.

Service de Chirurgie gynécologique, CHU de Rennes, 35000 Rennes, France.

Epithelial ovarian cancer (EOC) affects 43,000 women worldwide every year and has a five-year survival rate of 30%. Mainstay treatment is extensive surgery and chemotherapy. Outcomes could be improved by molecular profiling. We conducted a review of the literature to identify relevant publications on molecular and genetic alterations in EOC. Approximately 15% of all EOCs are due to or mutations. Four histologic subtypes characterized by different mutations have been described: serous, endometrioid, mucinous, and clear-cell. Between 20-30% of high-grade serous EOCs have a mutation. Tumors with mutations are unable to repair double-strand DNA breaks, making them more sensitive to platinum-based chemotherapy and to PolyAdenosine Diphosphate-Ribose Polymerase (PARP) inhibitors. Olaparib is a PARP inhibitor with proven efficacy in -mutated ovarian cancer, but its effectiveness remains to be demonstrated in tumors with a BRCAness (breast cancer) profile (i.e., also including sporadic tumors in patients with deficient DNA repair genes). A universally accepted molecular definition of BRCAness is required to identify optimal theranostic strategies involving PARP inhibitors. Gene expression analyses have led to the identification of four subgroups of high-grade serous EOC: mesenchymal, proliferative, differentiated, and immunoreactive. These subtypes are not mutually exclusive but are correlated with prognosis. They are not yet used in routine clinical practice. A greater understanding of EOC subtypes could improve patient management.
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http://dx.doi.org/10.3390/jcm9072239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408825PMC
July 2020

How and when to refer patients for oncogenetic counseling in the era of PARP inhibitors.

Ther Adv Med Oncol 2020 28;12:1758835919897530. Epub 2020 Feb 28.

Oncology Department, Centre François Baclesse, Caen, France.

Poly(ADP-ribose)polymerase (PARP) inhibitors are targeted therapy for cancers with homologous repair deficiency (HRD). They were first approved for ovarian cancer and have changed current treatment strategies. They have also demonstrated efficacy in HER2-negative metastatic breast cancer and advanced prostate cancer with or mutations. Patients with somatic and/or germline mutations benefit more from these treatments than other patients. Nowadays, the diagnosis of HRD is largely based on germline genetic testing, which is performed after an in-person genetic counseling session, even for patients without any family history of cancer. However, with the increasing number of PARP inhibitor indications across different tumor types, rapid access to oncogenetic consultations will become a challenge. To meet this demand, tumor genomic testing could be offered at initial diagnosis. Telephone counseling and other referral systems could replace in-person consultations for certain subgroups of patients deemed to have a low risk of harboring a germline mutation. This article reviews international guidelines for genetic counseling testing. We herein propose new care pathways for breast, prostate and ovarian cancers, including tumor genomic testing at initial diagnosis in order to help triage genetic counseling referrals.
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http://dx.doi.org/10.1177/1758835919897530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052467PMC
February 2020

Predictive factors of 5-year relapse-free survival in HR+/HER2- breast cancer patients treated with neoadjuvant endocrine therapy: pooled analysis of two phase 2 trials.

Br J Cancer 2020 03 31;122(6):759-765. Epub 2020 Jan 31.

Institut Bergonié, Bordeaux, France.

Background: Few data are available on survival and predictive factors in early breast cancer (BC) patients treated with neoadjuvant endocrine therapy (NET).

Methods: This is a pooled analysis of two multicentre, randomised non-comparative phase 2 clinical trials evaluating neoadjuvant anastrozole and fulvestrant efficacy for postmenopausal HR+/HER2- breast cancer patients: HORGEN (NCT00871858) and CARMINA02 (NCT00629616) studies.

Results: In total, 236 patients were included in CARMINA02 and HORGEN trials. Modified intention-to-treat analysis was available for 217 patients. Median follow-up was 65.2 months. Relapse-free survival (RFS) and overall survival (OS) at 5 years were 83.7% (95% CI: 77.9-88) and 92.7% (95% CI: 88.2-95.6), respectively, with no difference between treatment arms. On univariate analysis, tumour staging (T2 vs T3-4; p = 0.0001), Ki-67 at surgery (≤10% vs >10%; p = 0.0093), pathological tumour size (pT1-2 vs pT3-4; p = 0.0012) and node status (pN negative vs positive; p = 0.007), adjuvant chemotherapy (p = 0.0167) and PEPI score (PEPI group I + II vs III; p = 0.0004) were associated with RFS. No events were observed in patients with pathological response according to the Sataloff classification. Multivariate analysis showed that preoperative endocrine prognostic index (PEPI) group III was associated with significantly worse RFS (p = 0.0069, hazard ratio = 3.33 (95% CI: 1.39-7.98)).

Conclusions: Postmenopausal HR+/HER2- breast cancer patients receiving NET generally have a favourable outcome. The PEPI score identifies a subset of patients of poorer prognosis who are candidates for further additional treatment.
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http://dx.doi.org/10.1038/s41416-020-0733-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078275PMC
March 2020

Radiation therapy to the primary tumor for de novo metastatic breast cancer and overall survival in a retrospective multicenter cohort analysis.

Radiother Oncol 2020 04 10;145:109-116. Epub 2020 Jan 10.

Medical Oncology Department, Claudius Regaud Institute, IUCT-Oncopole, Toulouse, France.

Background: The impact of locoregional treatment (LRT) on overall survival (OS) in de novo metastatic breast cancer (dnMBC) is still under debate, with very few data available regarding exclusive radiotherapy (ERT) as a therapeutic modality.

Methods: We evaluated the impact of ERT, exclusive surgery, or a combination of surgery plus radiotherapy (bimodality therapy, BMT) on survival outcomes in a national real-life dnMBC cohort. The primary and secondary end points were OS and progression free survival (PFS) according to LRT (ERT, exclusive surgery, BMT) and no LRT. Sensitivity analyses were performed using propensity score matched analyses.

Results: From 2008 to 2014, 4507 dnMBC patients were identified. Only patients alive and free from progression under systemic therapy at least 1 year after diagnosis were included (n = 1965). Forty-five percent of patients (891/1965) underwent LRT: 41.1% (n = 366) ERT, 13.7% (n = 122) exclusive surgery, and 45.2% (n = 403) BMT. OS adjusted for major prognostic factors was significantly longer in the ERT and BMT group compared with no-LRT group, but not exclusive surgery (hazard ratio (HR) = 0.63, 95% confidence interval (CI) [0.49, 0.80], p < 0.001, HR = 0.61, 95%CI [0.47, 0.78], p < 0.001 and HR = 0.87, 95%CI [0.61, 1.26], p = 0.466 respectively). Results were similar after matching on a propensity score. ERT, surgery and BMT were all associated with a significantly better PFS in multivariable analysis.

Conclusion: ERT was significantly associated with better OS in dnMBC, in the same magnitude as BMT, compared with no-LRT. However, even with statistical models adjusted for known prognostic factors and propensity score analysis, selection biases cannot be eliminated from observational studies.
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http://dx.doi.org/10.1016/j.radonc.2019.12.019DOI Listing
April 2020

Clinical factors associated with prolonged response and survival under olaparib as maintenance therapy in BRCA mutated ovarian cancers.

Gynecol Oncol 2019 11 8;155(2):262-269. Epub 2019 Oct 8.

Department of Medical Oncology, Centre Léon Bérard, Lyon, France; University Claude Bernard (UCBL Lyon1), Lyon, France.

Objective: To investigate clinical factors associated with prolonged progression-free survival (PFS) and overall survival (OS) in relapsing epithelial ovarian cancer (EOC) patients with BRCA mutations and receiving olaparib as maintenance therapy in daily practice.

Methods: Multicenter (8 hospitals) European retrospective study of relapsing EOC patients having germline or somatic mutations of BRCA1/BRCA2 genes and treated with olaparib as maintenance therapy after platinum-based chemotherapy.

Results: One hundred and fifteen patients were included. Median age was 54 years. There were 90 BRCA1 carriers, 24 BRCA2 carriers and one patient had germline mutation of BRCA1 and BRCA2. Six patients had somatic mutations (all BRCA1) and 109 had germline mutations. Ninety percent had serous carcinomas and were platinum-sensitive. Following ultimate platinum-based chemotherapy, 69% of the patients had normalization of CA-125 levels and 87% had RECIST objective responses, either partial (53%) or complete (34%). After a median follow-up of 21 months, median PFS was 12.7 months and median OS was 35.4 months. In multivariate analysis, factors associated with prolonged PFS under olaparib were: platinum-free interval (PFI) ≥ 12 months, RECIST complete response (CR) or partial response (PR) and normalization of CA-125 upon ultimate platinum-based chemotherapy. Factors associated with prolonged OS were PFI ≥ 12 months, CR and normalization of CA-125.

Conclusions: Platinum-free interval ≥ 12 months, complete response and normalized CA-125 levels after ultimate platinum-based chemotherapy are associated with prolonged PFS and OS in relapsing BRCA1/BRCA2 mutated ovarian cancer patients who received olaparib as maintenance therapy.
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http://dx.doi.org/10.1016/j.ygyno.2019.09.008DOI Listing
November 2019

Serum CD95L Level Correlates with Tumor Immune Infiltration and Is a Positive Prognostic Marker for Advanced High-Grade Serous Ovarian Cancer.

Mol Cancer Res 2019 12 19;17(12):2537-2548. Epub 2019 Sep 19.

INSERM, UMR 1242, COSS - Chemistry Oncogenesis Stress and Signaling, Rennes, France.

Soluble CD95L (s-CD95L) is a chemoattractant for certain lymphocyte subpopulations. We examined whether this ligand is a prognostic marker for high-grade serous ovarian cancer (HGSOC) and whether it is associated with accumulation of immune cells in the tumor. Serum s-CD95L levels in 51 patients with advanced ovarian cancer were tested by ELISA. IHC staining of CD3, CD4, CD8, CD20, CD163, CD31, FoxP3, CCR6, IL-17, Granzyme B, PD-L1, and membrane CD95L was used to assess tumor-infiltrating immune cells. Although the intensity of CD3, CD8, CD4, CD20, and CD163 in tumor tissues remained constant regardless of membrane CD95L expression, tumors in patients with HGSOC with s-CD95L levels ≥516 pg/mL showed increased infiltration by CD3 T cells ( = 0.001), comprising both cytotoxic CD8 ( = 0.01) and CD4 ( = 0.0062) cells including FoxP3 regulatory T cells ( = 0.0044). Also, the number of tumor-infiltrating CD20 B cells ( = 0.0094) increased in these patients. Multivariate analyses revealed that low s-CD95L concentrations [<516 pg/mL, HR, 3.54; 95% confidence interval (CI), 1.13-11.11), and <1,200 activated CD8 (Granzyme B) cells (HR, 2.63; 95% CI, 1.16-5.95) were independent poor prognostic factors for recurrence, whereas >6,000 CD3 cells (HR, 0.34; 95% CI, 0.15-0.79) was a good prognostic factor. Thus, low levels of s-CD95L (<516 pg/mL) are correlated with lower numbers of tumor-infiltrating lymphocytes (CD3 and CD8, and also CD4 and FoxP3 T cells) in advanced HGSOC and are a poor prognostic marker. IMPLICATIONS: Serum s-CD95L is correlated with a number of tumor-infiltrating immune cells in HGSOC and could be used as a noninvasive marker of tumor immune infiltration to select patients referred for immunotherapy trials that evaluate checkpoint inhibitor treatment.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0449DOI Listing
December 2019

From Targeting Somatic Mutations to Finding Inherited Cancer Predispositions: The Other Side of the Coin.

Diagnostics (Basel) 2019 Jul 26;9(3). Epub 2019 Jul 26.

Department of pathology, Centre Jean Perrin, 63000 Clermont-Ferrand, France.

The expanding use of tumor genome analysis by next generation sequencing to drive target therapies has led to increased germline findings in genes predisposing to hereditary cancer. These putative germline findings obtained from theranostic analyses, such as gene testing, large panels, whole-exome, or whole-genome sequencing, need to be managed carefully and in an anticipated way with the patient. Before the genetic analysis of a tumor, specific information should be given to patients, who should be aware that the results may have extra-therapeutic medical issues for themselves and relatives. We previously published a list of 36 actionable genes predisposing to cancer for which informing the patient is recommended prior to pangenomic germline analysis because of available screening or preventive strategies. Here, we report clinical practice considerations and schemes for managing germline findings in tumor analyses, including written informed consent and a multidisciplinary approach involving an oncologist, molecular biologist/pathologist, and geneticist in case of germline findings. A somatic result showing a deleterious mutation in a known predisposing gene in a patient who has consented to this purpose should result in referral to a geneticist who is part of the multidisciplinary team. At any time of the somatic analysis process, the patient may have access to a geneticist consultation if additional information is required. This framework will optimally manage both personalized theranostic issues and specific preventive strategies for individuals and relatives; it will also simplify and accelerate the process of genetic testing.
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http://dx.doi.org/10.3390/diagnostics9030083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787697PMC
July 2019

Fertility preservation, contraception and menopause hormone therapy in women treated for rare ovarian tumours: guidelines from the French national network dedicated to rare gynaecological cancers.

Eur J Cancer 2019 07 3;116:35-44. Epub 2019 Jun 3.

Recommandations pour La Pratique Clinique, Nice-Saint-Paul, 06000, France.

Introduction: Rare ovarian tumours include complex borderline ovarian tumours, sex-cord tumours, germ cell tumours and rare epithelial tumours. Indications and modalities of fertility preservation (FP), infertility management, contraindications for hormonal contraception or menopause hormone therapy are frequent issues in clinical practice. A panel of experts from the French national network dedicated to rare gynaecological cancers, and experts in reproductive medicine and gynaecology have built guidelines on FP, contraception and menopause hormone therapy in women treated for ovarian rare tumours.

Material And Methods: A panel of 35 experts from different specialties contributed to the preparation of the guidelines, following the DELPHI method (formal consensus method). Statements were drafted after a systematic literature review and then rated through two successive rounds.

Results: Thirty-five recommendations were identified, concerning indications for FP, contraindications for ovarian stimulation, contraceptive options and menopause hormone therapy for each tumour type.

Discussion: Overall, caution has been recommended in the case of potentially hormone-sensitive tumours such as sex-cord tumours, serous and endometrioid low-grade adenocarcinomas, as well as for high-risk serous borderline ovarian tumours.

Conclusion: In the context of a scarce literature, a formal consensus method allowed the elaboration of guidelines, which will help clinicians in the management of these patients.
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http://dx.doi.org/10.1016/j.ejca.2019.04.018DOI Listing
July 2019

Therapeutic innovations in breast cancer.

Presse Med 2019 Oct 29;48(10):1131-1137. Epub 2019 May 29.

Centre Eugène-Marquis, avenue Bataille Flandres-Dunkerque, 35000 Rennes, France. Electronic address:

Managing endocrine resistance and resistance to endocrine therapy for ER+ HER2- breast cancer with the CDK 4/6 inhibitors in the metastatic setting. New antibodies drug conjugates for HER2+ and TNBC. Targeting DNA damage and synthetic lethality strategies with PARP inhibitors for breast cancer patients harboring BRCA mutation. Immunotherapies in 1st line metastatic setting of TNBC.
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http://dx.doi.org/10.1016/j.lpm.2019.04.005DOI Listing
October 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

Survival Impact of Locoregional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancers in a Large Multicentric Cohort Study: A Propensity Score-Matched Analysis.

Ann Surg Oncol 2019 Feb 11;26(2):356-365. Epub 2018 Dec 11.

Department of Medical Oncology, Claudius Regaud Institute, IUCT-Oncopole, Toulouse Cedex 09, France.

Introduction: Improvement in overall survival (OS) by locoregional treatment (LRT) of the primary tumor in de novo metastatic breast cancer (MBC) patients remains controversial.

Objective: The aim of our study was to evaluate the impact of LRT on OS in a large retrospective cohort of de novo MBC patients, with regard to immunohistochemical characteristics and pattern of metastatic dissemination.

Methods: We conducted a multicentric retrospective study of patients diagnosed with de novo MBC selected from the French Epidemiological Strategy and Medical Economics MBC database (NCT03275311) between 2008 and 2014. Overall, 4276 women were included in the study. LRT comprised either radiotherapy, surgery, or both.

Results: LRT was used in 40% of patients. Compared with no LRT, patients who received LRT were younger (p < 0.0001) and were more likely to have only one metastatic site (p < 0.0001) or bone-only metastases (p < 0.0001). LRT was associated with a significantly better OS based on landmark multivariate analysis at 1-year (hazard ratio 0.65, 95% confidence interval 0.55-0.76, p < 0.001). Similar results were observed in all sensitivity analyses, including propensity score matching. In subgroup analysis, LRT was associated with better OS in patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (61.6 vs. 45.9 months, p < 0.001) and HER2-positive tumors (77.2 vs. 52.6 months, p = 0.008), but not in triple-negative tumors (19 vs. 18.6 months, p = 0.54), and was also associated with a reduction in the risk of death in visceral metastatic patients (p < 0.001).

Conclusions: LRT was associated with a significantly better OS in de novo MBC patients, including patients with visceral involvement at diagnosis; however, LRT did not impact OS in triple-negative MBC.
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http://dx.doi.org/10.1245/s10434-018-6831-9DOI Listing
February 2019

Tumor analysis: freeze-thawing cycle of triple-negative breast cancer cells alters tumor CD24/CD44 profiles and the percentage of tumor-infiltrating immune cells.

BMC Res Notes 2018 Jun 20;11(1):401. Epub 2018 Jun 20.

COSS (Chemistry Oncogenesis Stress Signaling)-UMR 1242, Inserm, Univ Rennes, CLCC Eugène Marquis, Rue Bataille Flandres Dunkerque, 35042, Rennes, France.

Objective: The use of novel methods to characterize living tumor cells relies on well-conceived biobanks. Herein, we raised the question of whether the composition of fresh and freeze/thawed dissociated tumor samples is comparable in terms of quantitative and qualitative profiling.

Results: Breast cancer is a heterogeneous disease, encompassing luminal A and B, basal/triple-negative breast cancer (TNBC), and ERBB2-like tumors. We examined living cells dissociated from TNBC and found that a classical freeze/thaw protocol leads to a marked reduction in the number of CD45CD44CD24 tumor cells. This, in turn, changed the percentage of tumor cells with certain CD44/CD24 expression patterns and changed the percentage of tumor-infiltrating immune cells. These cryopreservation-driven alterations in cellular phenotype make it impossible to compare fresh and frozen samples from the same patient directly. Moreover, the freeze/thaw process changed the transcriptomic signatures of triple-negative cancer stem cells in such a manner that hierarchical clustering no longer ranked them according to expected inter-individual differences. Overall, this study suggests that all analyses of living tumor cells should be conducted only using freshly dissociated tumors if we are to generate a robust scoring system for prognostic/predictive markers.
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http://dx.doi.org/10.1186/s13104-018-3504-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011598PMC
June 2018

[Expectation about maintenance therapy among the GINECO French ovarian cancer cohort from the European NOGGO/ENGOT-ov22 Expression IV survey].

Bull Cancer 2018 May 12;105(5):465-474. Epub 2018 Mar 12.

Centre Francois-Baclesse, oncologie médicale, 3, avenue du Général-Harris, 14000 Caen, France. Electronic address:

Background: Expression IV survey evaluated the patients' expectations to a maintenance therapy.

Methods: From January 2015 to March 2016, 401 French patients, in first line or recurrent disease, answered a 24-items anonymous questionnaire. The results were specifically analyzed according to the demographic characteristics and treatment lines.

Results: Among the patients, 62% had already been informed about maintenance therapy. Thirty-seven percent of patients received a maintenance treatment: 111 patients during first line and 39 patients in relapse. Expectations of patients were: 1) the chance of cure (73%), 2) the tumor shrinkage (36%), 3) quality of life improvement (35%) and 4) tumor growth reduction (27%). Among the responders, 42% were willing to take the treatment for 6-24 months, 20% for 24-60 months and 38% until tumor progression. 64% of patients expected more than a 6 months progression-free survival. Patients older than 70 years were less informed than their younger counterparts (48% vs 66%) and had lesser hope for cure with maintenance treatment (60% vs 77%). Patients in relapse had more expectation than patients in remission (tumor shrinkage: 47% vs 22%, slowing of tumor growth: 37% vs 15%, improving the progression-free survival of more than 6 months: 71% vs 53%, respectively). Among patients, 48% in relapse consented to take a treatment until progression vs 24% of patients in remission.

Conclusion: This sub-analysis in French patients demonstrate a gap between the efficacy of maintenance therapy and the patients' expectations in ovarian cancer, particularly in relapsing disease justifying better information and explanations.
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http://dx.doi.org/10.1016/j.bulcan.2018.01.015DOI Listing
May 2018

Fluctuating Behavior of the French Population in Cancer Screening: 5th Edition of the EDIFICE Survey.

Curr Oncol Rep 2018 03 5;20(Suppl 1):14. Epub 2018 Mar 5.

INSERM, IRD, SESSTIM, Aix Marseille University, 23 rue Stanislas Torrents, 13006, Marseille, France.

Background: The EDIFICE surveys have assessed cancer screening behavior in the French population since 2005.

Methods: The 2016 edition was conducted among a representative sample of 1501 individuals (age, 50-75 years). The current analysis focuses on breast, colorectal, prostate, lung, and cervical cancer screening.

Results: The rate of women (50 to 74 years) declaring having had at least one breast cancer screening test in their lifetime remained stable and high between 2005 and 2016. Compliance with recommended screening intervals improved between 2005 and 2011 from 75 to 83%, respectively, then decreased significantly to 75% in 2016 (P = 0.02). Uptake of at least one lifetime colorectal cancer screening test procedure declared (individuals aged 50-74 years) increase from 25% in 2005 to 59% in 2011, stabilized at 60% in 2014, then reached 64% in 2016. Opportunistic prostate cancer screening (men aged 50-75 years) rose between 2005 and 2008 from 36 to 49%, plateaued until 2014 then dropped to 42% in 2016. The proportion of women aged 50-65 declaring having undergone one cervical cancer screening test dropped significantly between 2014 and 2016 from 99 to 94% (P < 0.01). Lastly, 11% of our survey population in 2014 and 2016 (55-74 years) declared having already undergone lung cancer screening.

Conclusion: Cancer screening behavior fluctuates in France, regardless of the context, i.e., organized programs or opportunistic screening. This observation highlights the need for constant analysis of population attitudes to optimize public awareness campaigns.
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http://dx.doi.org/10.1007/s11912-017-0646-xDOI Listing
March 2018

[Fertility preservation, contraception and menopause hormone therapy in women treated for rare ovarian tumors: Guidelines from the French national network dedicated to rare gynaecological cancer].

Bull Cancer 2018 Mar;105(3):299-314

Centre François-Baclesse, 3, avenue du Général-Harris, 14076 Caen cedex 5, France.

Introduction: Rare ovarian tumors include complex borderline ovarian tumors, sex-cord tumors, germ cell tumors, and rare epithelial tumors. Indications and modalities of fertility preservation, infertility management and contraindications for hormonal contraception or menopause hormone therapy are frequent issues in clinical practice. A panel of experts from the French national network dedicated to rare gynaecological cancers, and of experts in reproductive medicine and gynaecology have worked on guidelines about fertility preservation, contraception and menopause hormone therapy in women treated for ovarian rare tumors.

Methods: A panel of 39 experts from different specialties contributed to the preparation of the guidelines, following the DELPHI method (formal consensus method). Statements were drafted after a systematic literature review, and then rated through two successive rounds.

Results: Thirty-five recommendations were selected, and concerned indications for fertility preservation, contraindications for ovarian stimulation (in the context of fertility preservation or for infertility management), contraceptive options (especially hormonal ones), and menopause hormone therapy for each tumor type. Overall, prudence has been recommended in the case of potentially hormone-sensitive tumors such as sex cord tumors, serous and endometrioid low-grade adenocarcinomas, as well as for high-risk serous borderline ovarian tumors.

Discussion: In the context of a scarce literature, a formal consensus method allowed the elaboration of guidelines, which will help clinicians in the management of these patients.
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http://dx.doi.org/10.1016/j.bulcan.2017.10.032DOI Listing
March 2018

Cancer de l’ovaire : la rechute précoce.

Bull Cancer 2017 May;104 Suppl 1:S32-S38

Département de cancérologie gynécologique, centre Oscar-Lambret, Lille, France.

Ovarian Cancer: EARLY RELAPSE: Early relapse (primary or secondary) is defined by relapse of disease less than 6 months before the last infusion of chemotherapy (with a platinum compound). There is no carcinological surgical indication. Disease should be treated with a non-platinum single agent (pegylated liposomal doxorubicin, weekly paclitaxel, gemcitabine or topotecan). Bevacizumab can be added if patients have not already received it (level of proof 1, grade A).
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http://dx.doi.org/10.1016/S0007-4551(17)30160-1DOI Listing
May 2017

Prognostic significance of an early decline in serum alpha-fetoprotein during chemotherapy for ovarian yolk sac tumors.

Gynecol Oncol 2016 09 8;142(3):452-7. Epub 2016 Jul 8.

Department of Cancer Medicine, Institut Gustave-Roussy, 114 rue Edouard Vaillant, F-94805 Villejuif, France. Electronic address:

Background: The ovarian yolk sac tumor (OYST) is a very rare malignancy arising in young women. Our objective was to determine whether an early decline in serum alpha-fetoprotein (AFP) during chemotherapy has a prognostic impact.

Methods: This retrospective study is based on prospectively recorded OYST cases at Gustave Roussy (Cancer Treatment Center). Survival curves were estimated using the Kaplan-Meier method. The serum AFP decline was calculated with the formula previously developed and validated in male patients with poor prognosis non-seminomatous germ cell tumors. Univariate and multivariate analyses were performed using the log-rank test and logistic regression, respectively.

Results: Data on AFP were available to calculate an early AFP decline in 57 patients. All patients had undergone surgery followed by chemotherapy. The 5-year overall survival (OS) and event-free survival (EFS) rates were 86% (95% CI: 74%-93%) and 84% (95% CI: 73%-91%), respectively. The disease stage, presence of ascites at presentation, use of the BEP regimen, serum AFP half-life and an early AFP decline were significantly predictive factors for OS and EFS in the univariate analysis. The OS rate was 100% and 49% (95% CI: 26%-72%) in patients with a favorable AFP decline and in those with an unfavorable decline, respectively (p<0.001). In the multivariate analysis, only the presence of ascites at diagnosis (RR=7.3, p=0.03) and an unfavorable early AFP decline (RR=16.9, p<0.01) were significant negative predictive factors for OS.

Conclusions: An early AFP decline during chemotherapy is an independent prognostic factor in patients with OYSTs.

Conflict Of Interest Statement: No conflict of interest.
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http://dx.doi.org/10.1016/j.ygyno.2016.07.005DOI Listing
September 2016

Dynamic Analysis of CA125 Decline During Neoadjuvant Chemotherapy in Patients with Epithelial Ovarian Cancer as a Predictor for Platinum Sensitivity.

Anticancer Res 2016 Apr;36(4):1865-71

Department of Breast and Gynecological Surgery, Institut Curie, Paris, France Versailles-St-Quentin-en-Yvelines University, EA 7285: Risques Cliniques et Sécurité en Santé des Femmes et en Santé Périnatale, Montigny-Le-Bretonneux, France.

Aim: Our objective was to evaluate the kinetic parameters of serum CA125 during neoadjuvant platinum-based chemotherapy (NAC), in patients with epithelial ovarian cancer, in order to identify a surrogate marker of sensitivity to platinum.

Materials And Methods: Patients diagnosed between 2002 and 2009, and treated with NAC and interval debulking surgery, were included in the study.

Results: One hundred and forty-two patients met the study inclusion criteria. Fifty-four patients (38%) were platinum-sensitive (PFI >12 months). A CA125 level after the 3rd NAC cycle <35 UI/ml was significantly associated with improved overall survival (OS) and relapse-free survival (RFS). In the multivariate model, patients with a CA125 level after the 3rd NAC cycle >35 UI/ml were 3.8-times more at risk for PFI <12 months (95% CI=1.7-8.5, p<0.001).

Conclusion: A CA125 level after the 3rd NAC <35 UI/ml is an independent predictor for tumor platinum-sensitivity.
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April 2016

Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628.

Cancer Discov 2016 05 14;6(5):492-500. Epub 2016 Mar 14.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Unlabelled: The antineoplastic, prodifferentiative effects of bromodomain and extra-terminal (BET) bromodomain (BRD) inhibitors were initially discovered in NUT midline carcinoma (NMC), an aggressive subtype of squamous cancer driven by the BRD4-NUT fusion oncoprotein. BRD4-NUT blocks differentiation and maintains tumor growth through a potent chromatin-modifying mechanism. OTX015/MK-8628, a novel oral BET inhibitor, targets BRD2/3/4/T with preclinical activity in NMC and several other tumor types and is currently in clinical development. Antitumor activity was evaluated in four patients with advanced-stage NMC with confirmed BRD4-NUT fusions who were treated with 80 mg OTX015/MK-8628 once daily in a compassionate-use context. Two patients responded rapidly with tumor regression and symptomatic relief, and a third had meaningful disease stabilization with a minor metabolic response. The main side effects were mild to moderate gastrointestinal toxicity and fatigue, and reversible grade 3 thrombocytopenia. This is the first proof-of-concept evidence of clinical activity of a BRD inhibitor in targeting BRD4-NUT.

Significance: We present the first clinical proof-of-concept that targeting BRD4-NUT with a BET inhibitor results in impressive and rapid antitumor activity in NMC. It offers strong potential for future clinical application in this rare patient population as either a single agent or in combination with other agents. Cancer Discov; 6(5); 492-500. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 461.
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http://dx.doi.org/10.1158/2159-8290.CD-15-1335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854801PMC
May 2016

[Fertility sparing treatment in women affected by cervical cancer larger than 2cm].

Bull Cancer 2016 Feb 8;103(2):173-9. Epub 2015 Dec 8.

Hôpital, institut Curie, département de chirurgie, 5248 Paris, France.

Objective: We report our experience on fertility sparing treatment in young women affected by cervical cancer of more than 2cm.

Methods: Between July 2012 and February 2014, five patients presenting cervical tumors larger than 2cm (IB1>2cm) (23-35) and wishing to preserve fertility have been treated at our institution. Laparoscopic pelvic and para-aortic lymphadenectomy was performed for all patients. When lymph nodes were free of disease, patients had neoadjuvant chemotherapy followed by surgical conservative treatment.

Results: Four patients underwent a cisplatin based neoadjuvant chemotherapy before conservative surgery: radical trachelectomy or simple trachelectomy. One patient with nodal involvement underwent a 3cycle chemotherapy followed by concurrent radiochemotherapy. Hematologic toxicity grade 3 was observed in one patient leading to a change of chemotherapy. Two patients showed complete disappearance of tumor and two a partial response to neoadjuvant treatment. After a mean follow up of 20.5months (14-33), no relapse was observed. To date, no pregnancy was obtained.

Conclusion: Lymph node staging followed by neoadjuvant chemotherapy and radical trachelectomy seems to be a promising treatment scheme for patients with cervical tumors IB1>2cm pN0 seeking parenthood.
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http://dx.doi.org/10.1016/j.bulcan.2015.11.005DOI Listing
February 2016

Anticancer treatment and fertility: Effect of therapeutic modalities on reproductive system and functions.

Crit Rev Oncol Hematol 2016 Jan 8;97:328-34. Epub 2015 Aug 8.

Oncology Department, Attikon Hospital, University of Athens, 1 Rimini, 12462, Greece.

The significant improvement of cancer treatments entailed a longer life in cancer survivors and raised expectations for higher quality of life with minimized long-term toxicity. Infertility and gonadal dysfunction are adverse effects of anticancer therapy or may be related to specific tumors. In female cancer survivors, premature ovarian failure is common after antineoplastic treatments resulting in infertility and other morbidities related to oestrogen deficiency such as osteoporosis. In male cancer survivors, infertility and persistent a zoospermia is a more common long-term adverse effect than hypogonadism because germ cells are more sensitive to chemotherapy and radiotherapy than leydig cells. Gonadal toxicity and compromise of reproductive functions will be more efficiently prevented and treated if addressed before treatment initiation. This review focuses on these issues in young cancer survivors of childbearing age, where methods of protecting or restoring endocrine function and fertility need to be considered.
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http://dx.doi.org/10.1016/j.critrevonc.2015.08.002DOI Listing
January 2016
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