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PURPOSE The PAOLA-1/ENGOT-ov25 trial of maintenance olaparib plus bevacizumab for newly diagnosed advanced high-grade ovarian cancer demonstrated a significant progression-free survival (PFS) benefit over placebo plus bevacizumab, particularly in patients with homologous recombination deficiency (HRD)–positive tumors. We explored whether mutations in non- BRCA1 or BRCA2 homologous recombination repair (non–BRCA HRRm) genes predicted benefit from olaparib plus bevacizumab in PAOLA-1. METHODS Eight hundred and six patients were randomly assigned (2:1). Tumors were analyzed using the Myriad MyChoice HRD Plus assay to assess non–BRCA HRRm and HRD status; HRD was based on a genomic instability score (GIS) of ≥ 42. In this exploratory analysis, PFS was assessed in patients harboring deleterious mutations using six non–BRCA HRR gene panels, three devised for this analysis and three previously published. RESULTS The non–BRCA HRRm prevalence ranged from 30 of 806 (3.7%) to 79 of 806 (9.8%) depending on the gene panel used, whereas 152 of 806 (18.9%) had non‐ BRCA1 or BRCA2 mutation HRD-positive tumors. The majority of tumors harboring non–BRCA HRRm had a low median GIS; however, a GIS of > 42 was observed for tumors with mutations in five HRR genes ( BLM, BRIP1, RAD51C, PALB2, and RAD51D). Rates of gene-specific biallelic loss were variable (0% to 100%) in non–BRCA HRRm tumors relative to BRCA1-mutated (99%) or BRCA2-mutated (86%) tumors. Across all gene panels tested, hazard ratios for PFS (95% CI) ranged from 0.92 (0.51 to 1.73) to 1.83 (0.76 to 5.43). CONCLUSION Acknowledging limitations of small subgroup sizes, non–BRCA HRRm gene panels were not predictive of PFS benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in PAOLA-1, irrespective of the gene panel tested. Current gene panels exploring HRRm should not be considered a substitute for HRD determined by BRCA mutation status and genomic instability testing in first-line high-grade ovarian cancer.

International audience; Abstract Aim: To provide practice guidelines about fertility preservation (FP) in oncology. 93Methods: We selected 400 articles after a PubMed review of the literature (1987e2019). Recommendations: Any child, adolescent and adult of reproductive age should be informed about the risk of treatment gonadotoxicity. In women, systematically proposed FP counselling between 15 and 38 years of age in case of treatment including bifunctional alkylating agents, above 6 g/m2 cyclophosphamide equivalent dose (CED), and for radiation doses on the ovaries 3 Gy. For postmenarchal patients, oocyte cryopreservation after ovarian stimulation is the firstline FP technique. Ovarian tissue cryopreservation should be discussed as a first-line approach in case of treatment with a high gonadotoxic risk, when chemotherapy has already started and in urgent cases. Ovarian transposition is to be discussed prior to pelvic radiotherapy involving a high risk of premature ovarian failure. For prepubertal girls, ovarian tissue cryopreservation should be proposed in the case of treatment with a high gonadotoxic risk. In pubertal males, sperm cryopreservation must be systematically offered to any male who isto undergo cancer treatment, regardless of toxicity. Testicular tissue cryopreservation must be proposed in males unable to cryopreserve sperm who are to undergo a treatment with intermediate or severe risk of gonadotoxicity. In prepubertal boys, testicular tissue preservation is: - recommended for chemotherapy with a CED 7500 mg/m2 or radiotherapy 3 Gy on both testicles. - proposed for chemotherapy with a CED 5.000 mg/m2 or radiotherapy 2 Gy. If several possible strategies, the ultimate choice is made by the patient.

International audience; Background: In spite of the frequency and clinical impact of BRCA1/2 alterations in high-grade epithelial ovarian cancer (HGEOC), real-world information based on robust data warehouse has been scarce to date. Methods: Consecutive patients with BRCA-mutated HGEOC treated between 2011 and 2016 within French comprehensive cancer centers from the Unicancer network were extracted from the ESME database. The main objective of the study was the assessment of clinicopathological and treatments parameters. Results: Out of the 8021 patients included in the ESME database, 266 patients matching the selection criteria were included. BRCA1 mutation was found in 191 (71.8%) patients, while 75 (28.2%) had a BRCA2 mutation only; 95.5% of patients received a cytoreductive surgery. All patients received a taxane/platinum-based chemotherapy (median = six cycles). Complete and partial response were obtained in 53.3% and 20.4% of the cases, respectively. Maintenance therapy was administered in 55.3% of the cases, bevacizumab being the most common agent. After a median follow up of 51.7 months, a median progression-free survival of 28.6 months (95% confidence interval (CI) [26.5; 32.7]) and an estimated 5-year median overall survival of 69.2% (95% CI [61.6; 70.3]) were reported. Notably, BRCA1- and BRCA2-mutated cases exhibited a trend towards different median progression-free survivals, with 28.0 (95% CI [24.4; 32.3]) and 33.3 months (95% CI [26.7; 46.1]), respectively (p-value = 0.053). Furthermore, five-year OS for BRCA1-mutated patients was 64.5% (95% CI [59.7; 69.2]), while it was 82.5% (95% CI [76.6; 88.5]) for BRCA2-mutated ones (p-value = 0.029). Conclusions: This study reports the largest French multicenter cohort of BRCA-mutated HGEOCs based on robust data from the ESME, exhibiting relevant real-world data regarding this specific population.

Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is a rare and rapidly lethal disease affecting young women. Cytoreductive surgery associated with chemotherapy followed by a high dose chemotherapy regimen (HDC) demonstrated improved outcomes in a unique prospective and several retrospective studies, and this report aimed to confirm these results in an independent and larger cohort.Between 2006 and 2018, we conducted a multicentric prospective study on 44 women diagnosed with SCCOHT. Patients were treated homogeneously with optimal cytoreductive surgery and chemotherapy protocol for four to six cycles (PAVEP). In case of complete response, patients received HDC with stem-cell support, followed by pelvic radiotherapy. The primary endpoint was the event-free survival (EFS) in the per-protocol cohort. Secondary analysis explored the effect of HDC with outcomes.Mean age at diagnosis was 33 years old (range 13.8-75.8). 14 patients presented with stage FIGO I, 21 with stage III and 9 with stage IV. Median follow-up was 53.4 months. 38 patients underwent optimal surgery with up to 6 cycles of PAVEP. 30 received HDC, and 21 pelvic radiotherapy. 21 relapses were reported leading to death for 18 patients. Median EFS in the per-protocol cohort was 18.2 months, and 2-year EFS rate was 40%. HDC was significantly associated with better overall survival (p .001). Grades 3/4 adverse events were frequent but, in most cases, manageable, although one grade-5 adverse-event occurred during HDC.Intensive regimen containing multidrug chemotherapy, HDC and pelvic radiotherapy, for the management of SCCOHT, demonstrated encouraging survival and should be proposed for all patients. However, the significant toxicity cost associated is of concern and it should be restricted to expert centers.

Background Trabectedin and pegylated liposomal doxorubicin (PLD) is an effective combination therapy for platinum-sensitive recurrent ovarian cancer (ROC), particularly for disease relapsing within 6-12 months of platinum therapy. The non-interventional PROSPECTYON study evaluated trabectedin/PLD in French clinical practice. Patients and methods Patients with ROC after at least one platinum-based regimen received 1.1 mg/m2 trabectedin plus 30 mg/m2 PLD every 3 weeks. Efficacy and safety were evaluated in subgroups according to platinum-free interval [6-12 versus ≥12 months (partially or fully platinum sensitive, respectively)]. Results Recurrent disease was partially platinum-sensitive in 58 patients and fully sensitive in 33 patients treated between July 2014 and June 2016. Patients in both subgroups received a median of six cycles of trabectedin and PLD. The most common grade 3 or more toxicities were haematological. Median progression-free survival was 6 months for both subgroups. Conclusion Trabectedin/PLD is a valuable treatment option for partially or fully platinum-sensitive ROC.

Objectives Description of fertility and prognosis of patients with borderline ovarian tumor (BOT) treated by fertility-sparing surgery through a longitudinal study from the French national cancer network. Methods All consecutive patients diagnosed with BOT from the French National Network dedicated to Ovarian Malignant Rare Tumors from 2010 and 2017 were selected. In 2018, an update was made by sending a questionnaire regarding recurrence and fertility to patients aged under 43 years at diagnosis and treated conservatively. We compared the characteristics of the patients with/without recurrence and with/without live birth. Results Fifty-two patients aged 18 to 42 years presented a desire of pregnancy. Thirty patients (58%) presented a FIGO IA tumor, and 20 patients were treated by bilateral cystectomies (38%). We observed at least one live birth for 33 patients (63%) and local recurrences in 20 patients (38%). Both recurrence and live birth in 17 patients (33%) were reported, with recurrence occurring before pregnancy, after a second fertility-sparing treatment, in half of the cases. No factors associated with recurrence or live birth in this study were identified. Moreover, in this population, both recurrence and live birth were independent of age, with a linear risk along time. Disease-free survival was worse for patients treated with bilateral cystectomy (n = 20, 38%), with no difference in terms of fertility. Conclusion Two third of the patients experienced life birth after conservation surgery. We did not highlight an age/time from surgery for which the risk of recurrence outweighs the chance of pregnancy and to radicalize surgery. Moreover, almost a quarter of the live birth occurred after recurrence, with no more further event to date in these patients. The results encourage to consider a second fertility-sparing surgery after local borderline recurrence in the case of pregnancy desire. All these decisions must be discussed in specialized multidisciplinary boards.

Anti-angiogenic rechallenge with bevacizumab plus chemotherapy is effective in recurrent ovarian cancer (rOC); however, data are limited on tyrosine kinase inhibitors after progression on maintenance bevacizumab.In the randomized phase II TAPAZ trial, patients with rOC during the first year of bevacizumab maintenance therapy were assigned 2:1 to either weekly paclitaxel 65 mg/mOverall, 116 patients were randomized and treated: 79 with combination therapy and 37 with single-agent paclitaxel. Median follow-up was 13.1 months. There was no difference between treatment arms in 4-month PFS rate (61% [95% CI, 51-73%] with the combination versus 68% [95% CI, 54-85%] with paclitaxel alone), median PFS (4.9 [95% CI, 4.1-6.1] versus 5.8 [95% CI, 4.8-7.4] months, respectively) or median overall survival (13.6 versus 12.9 months, respectively). The combination was associated with more grade 3/4 toxicities (87% versus 70%, respectively) and toxicity-related paclitaxel discontinuations (22% versus 11%). Pazopanib was discontinued for toxicity in 44% of patients, most commonly for gastrointestinal and vascular events. There were two treatment-related deaths, both in the combination arm (pulmonary embolism and gastrointestinal perforation). At month 4, patient-reported outcomes deteriorated from baseline in the combination arm, particularly for abdominal/gastrointestinal symptoms, which showed a clinically important difference versus paclitaxel alone.In rOC progressing during maintenance bevacizumab, adding pazopanib to paclitaxel did not improve efficacy, increased toxicity, and compromised chemotherapy delivery.govregistration:NCT02383251.

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.

Background The benefit of precision medicine based on relatively limited gene sets and often-archived samples remains unproven. PERMED-01 (NCT02342158) was a prospective monocentric clinical trial assessing, in adults with advanced solid cancer, the feasibility and impact of extensive molecular profiling applied to newly biopsied tumor sample and based on targeted NGS (t-NGS) of the largest gene panel to date and whole-genome array-comparative genomic hybridization (aCGH) with assessment of single-gene alterations and clinically relevant genomic scores. Methods Eligible patients with refractory cancer had one tumor lesion accessible to biopsy. Extracted tumor DNA was profiled by t-NGS and aCGH. We assessed alterations of 802 “candidate cancer” genes and global genomic scores, such as homologous recombination deficiency (HRD) score and tumor mutational burden. The primary endpoint was the number of patients with actionable genetic alterations (AGAs). Secondary endpoints herein reported included a description of patients with AGA who received a “matched therapy” and their clinical outcome, and a comparison of AGA identification with t-NGS and aCGH versus whole-exome sequencing (WES). Results Between November 2014 and September 2019, we enrolled 550 patients heavily pretreated. An exploitable complete molecular profile was obtained in 441/550 patients (80%). At least one AGA, defined in real time by our molecular tumor board, was found in 393/550 patients (71%, two-sided 90%CI 68–75%). Only 94/550 patients (17%, 95%CI 14–21) received an “AGA-matched therapy” on progression. The most frequent AGAs leading to “matched therapy” included PIK3CA mutations, KRAS mutations/amplifications, PTEN deletions/mutations, ERBB2 amplifications/mutations, and BRCA1/2 mutations. Such “matched therapy” improved by at least 1.3-fold the progression-free survival on matched therapy (PFS2) compared to PFS on prior therapy (PFS1) in 36% of cases, representing 6% of the enrolled patients. Within patients with AGA treated on progression, the use of “matched therapy” was the sole variable associated with an improved PFS2/PFS1 ratio. Objective responses were observed in 19% of patients treated with “matched therapy,” and 6-month overall survival (OS) was 62% (95%CI 52–73). In a subset of 112 metastatic breast cancers, WES did not provide benefit in term of AGA identification when compared with t-NGS/aCGH. Conclusions Extensive molecular profiling of a newly biopsied tumor sample identified AGA in most of cases, leading to delivery of a “matched therapy” in 17% of screened patients, of which 36% derived clinical benefit. WES did not seem to improve these results. Trial registration ID-RCB identifier: 2014-A00966-41; ClinicalTrials.gov identifier: NCT02342158.

International audience; Background: Hormone-resistant HER2-negative or triple-negative advanced breast cancers (ABC) are routinely treated with paclitaxel chemotherapy. LY2780301 is a dual inhibitor of p70 ribosomal protein S6 kinase and AKT. The TAKTIC study aimed at exploring the combination of paclitaxel and LY2780301 in this population.Methods: In this multicentric phase Ib/II trial, we enrolled patients with HER2-negative ABC, with (phase IB) or without (phase II) prior to cytotoxic treatment for advanced disease. Oral LY2780301 was administered once daily in combination with intravenous weekly paclitaxel. Primary endpoints were to determine the recommended phase II dose (RP2D) of the combination of LY2780301 with weekly paclitaxel (phase Ib), and to estimate a 6 months objective response rate (ORR) (phase II) in patients with HER2-negative ABC, both in the overall patient population and in cases with activation of the PI3K/AKT pathway (PI3KAKT+).Results: A total of 51 patients were enrolled; RP2D was LY2780301 500 mg QD+ paclitaxel 80 mg/m2. Main drug-related adverse events noted in phase Ib included neuropathy (75% of patients, grade 3-4 in 8%), asthenia (58% of patients, no grade 3-4), and ungual toxicity (50% of patients, grade 3-4 in 25%). They were similar in the phase II part, except that 14% of patients experienced pneumonia (grade 3-4 in 6%). In the phase II part, 6-month ORR in the overall population and in PI3KAKT+ subgroup were, respectively, 63.9% [48.8-76.8] and 55% [35-73.7].Conclusion: Combining LY2780301 and weekly paclitaxel in patients with HER2-negative ABC was feasible with preliminary evidence of efficacy in both the overall population and the PI3KAKT+ subgroup.Trial registration id: NCT01980277.

Resume Les cancers gynecologiques representent des pathologies frequentes, avec plus de 16 000 cas par an en France pour 6500 deces. Peu de modifications des methodes diagnostiques, des outils pronostiques, et des prises en charge therapeutiques ont eu lieu lors des deux dernieres decennies. Les analyses genomiques tumorales issues, entre autres, des donnees du Cancer Genome Atlas ont permis d’identifier une partie des alterations moleculaires a l’origine de ces tumeurs. Toutefois, ces donnees restent incompletes et n’ont pour l’instant pas permis de modifier la prise en charge de nos patientes. Par ailleurs, elles necessitent des prelevements invasifs non adaptes aux objectifs de diagnostic precoce, de suivi de l’effet d’un traitement, de suivi de la maladie residuelle, ou du diagnostic precoce des rechutes. Durant ces dernieres annees, l’analyse des biomarqueurs tumoraux circulants (aussi appeles « biopsies liquides ») qu’ils soient cellulaires (cellules tumorales circulantes) ou nucleotidiques (ADN ou ARN circulants) s’est massivement developpee a travers diverses indications, plateformes, objectifs ; les donnees concernant l’ADN tumoral circulant etant les plus importantes en volume de publication et en interet pour la pratique clinique. Cette revue de la litterature a pour but de decrire les methodes d’analyse et les observations issues de l’analyse de l’ADN tumoral circulant dans les tumeurs gynecologiques, depuis les donnees de depistage/diagnostic precoce jusqu’a l’adaptation des traitements en phase avancee, en passant par le choix des traitements et le suivi de la maladie residuelle.

5548 Background: Ovarian cancer is the leading cause of death by gynecological cancer. Complete surgery remains one of the main prognostic factors. Laparoscopic exploration is mandatory to assess surgical resectability at diagnosis or after neoadjuvant chemotherapy. However, there is no clinical or biological marker that can correctly predict resectability and may be able to avoid a second laparoscopic exploration for initially unresectable diseases. Our aim was to assess circulating tumor DNA (ctDNA) value as a predictive non-invasive marker of evolution towards resectability for patients with epithelial ovarian cancer receiving first-line chemotherapy. Methods: We explored in this work one of the secondary objectives of the CIDOC study (NCT03302884). CIDOC is a multicenter prospective study aiming to explore ctDNA value as early marker of disease relapse after first-line treatment for epithelial ovarian cancer. Patients with mucinous histology or early stages not requiring chemotherapy are excluded. Plasma samples are collected at diagnosis, during neoadjuvant chemotherapy, and during follow-up. After DNA extraction, panel-based next generation sequencing is performed on both tumor samples and germline DNA, and somatic mutations of interest are selected for ctDNA monitoring. ctDNA analyses are conducted using droplet digital PCR (BioRad QX200) by measuring the variant allele fraction (VAF) of previously identified mutations. Results: This intermediary analysis has included 47 patients diagnosed between March 2017 and December 2019. Median age was 69 years old (48 – 84). Most of the patients had advanced disease (89.4% stage FIGO III or IV), serous histology (94.8%), and high grade tumor (92.3%). Most of the patients underwent complete interval cytoreductive surgery (76.3% vs 17.4% complete upfront surgery). Most of the tumors had TP53 mutations (85.1%), following by alterations involving DNA repair genes (38.3%). Median cell-free DNA concentration at baseline was 0.38 ng/µL (0 – 12.8). ctDNA was identified in 92.1% of patients at baseline with a median VAF of 1.84% (0 – 42.52%). ctDNA VAF was correlated to the peritoneal dissemination ( p= 0.039) assessed with the peritoneal cancer index. ctDNA clearance after preoperative chemotherapy tended to be correlated to achievement of complete interval surgery for patients receiving neoadjuvant chemotherapy ( p= 0.108). Conclusions: ctDNA may be a promising non-invasive marker to assess peritoneal cancer spreading and to predict surgical resectability after neoadjuvant chemotherapy. If confirmed in larger populations, this may enable to avoid additional surgical explorations for patients who remain ctDNA positive after chemotherapy. Clinical trial information: NCT03302884.

International audience; The onset of brain metastases (BM) is a major turning point during advanced breast cancer (ABC) evolution, with only few treatment options when local therapies have failed. The therapeutic effect of eribulin, a wildly used drug in the treatment of ABC, remains unclear in this setting. Patients and Methods: We performed a retrospective observational study to assess eribulin efficacy in patients with ABC who displayed BM at time of eribulin initiation. We collected data from the medical files of all ABC patients who received eribulin at our institution from 2012 until 2020. Our main endpoint was the central nervous system (CNS) progression-free survival. (CNS-PFS). Other evaluation criteria were extra-cranial progression free survival (PFS) and overall survival (OS). Results: Twenty patients with BM monitoring data available were selected out of the 549 who received eribulin during the inclusion period. Fifteen patients (75%) had BM progressive as the best response, three patients (15%) had disease stabilization for more than 6 months and only one patient had a partial response according to RECIST 1.1 criteria. Median CNS-PFS was 3.39 months (95CI (3.02–3.76)). Cox univariate analysis identified molecular subtype as the only prognostic parameter in our cohort, with patients with hormone-receptor positive tumors less likely to experience CNS progression than those with triple-negative MBC (HR = 0.23 (95CI = 0.07–0.80), p = 0.021). Median extra-cranial PFS was 2.67 months (95CI (2.33–3.01)). Median OS was 7.68 months (95CI (0–17.41)). Conclusion: Eribulin seems to have only a limited impact on BM evolution. Hormone receptors expression may identify a subset of patients with better BM control.

International audience; Endometrial cancer (EC) can easily be cured when diagnosed at an early stage. However, advanced and metastatic EC is a common disease, affecting more than 15,000 patients per year in the United Sates. Only limited treatment options were available until recently, with a taxane–platinum combination as the gold standard in first-line setting and no efficient second-line chemotherapy or hormone therapy. EC can be split into four molecular subtypes, including hypermutated cases with POLE mutations and 25–30% harboring a microsatellite instability (MSI) phenotype with mismatch repair deficiency (dMMR). These tumors display a high load of frameshift mutations, leading to increased expression of neoantigens that can be targeted by the immune system, including (but not limited) to T-cell response. Recent data have demonstrated this impact of programmed death 1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors on chemo-resistant metastatic EC. The uncontrolled KEYNOTE-158 and GARNET trials have shown high response rates with pembrolizumab and dostarlimab in chemoresistant MSI-high tumors. Most responders experiment long responses that last more than one year. Similar, encouraging results were obtained for MMR proficient (MMRp) cases treated with a combination of pembrolizumab and the angiogenesis inhibitor lenvatinib. Approvals have, thus, been obtained or are underway for EC with immune checkpoint inhibitors (ICI) used as monotherapy, and in combination with antiangiogenic agents. Combinations with other targeted therapies are under evaluation and randomized studies are ongoing to explore the impact of ICI-chemotherapy triplets in first-line setting. We summarize in this review the current knowledge of the immune environment of EC, both for MMRd and MMRp tumors. We also detail the main clinical data regarding PD-1/PD-L1 inhibitors and discuss the next steps of development for immunotherapy, including various ICI-based combinations planned to limit resistance to immunotherapy.

Objectives: In the Phase III PAOLA-1/ENGOT-ov25 (NCT02477644) trial, the addition of the PARP inhibitor olaparib to bevacizumab maintenance therapy led to a significant progression-free survival (PFS) benefit in patients with newly diagnosed advanced ovarian cancer (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.49-0.72), particularly in patients who were homologous recombination deficiency (HRD) positive, both including patients with BRCA1 and/or BRCA2 mutations (BRCAm; HR 0.33; 95% CI 0.25-0.45) and patients without a BRCAm (HR 0.43; 95% CI 0.28-0.66; Ray-Coquard et al. NEJM 2019). We explored the role of mutations in genes involved in homologous recombination repair (HRRm) excluding BRCAm as a predictive biomarker in patients with newly diagnosed advanced ovarian cancer who received olaparib + bevacizumab maintenance therapy in PAOLA-1. Methods: Patients with newly diagnosed advanced high-grade serous or endometrioid ovarian cancer were randomized (2:1) to olaparib + bevacizumab maintenance or placebo + bevacizumab maintenance following response to platinum-based chemotherapy + bevacizumab. In an exploratory analysis, PFS was assessed in patients harboring a tumor mutation in a wide range of HRR gene panels (excluding tumor BRCAm [tBRCAm]): a panel with 13 pre-defined genes involved in HRR, an expanded panel with five additional genes involved in HRR, a restricted panel using five selected genes with the highest median genomic instability scores, and three published panels (Table). Tumors were analyzed using the Myriad myChoice HRD plus assay. Results: Of the 806 patients randomized in PAOLA-1, 235/806 (29.2%) had a tBRCAm. The percentage of patients harboring deleterious mutations involved in HRR excluding tBRCAm ranged from 3.7% to 9.8% depending on the HRR gene panel (Table). For each gene panel, the number of patients with an HRRm in each treatment arm and HRD status are shown in the Table. PFS using different gene panels for HRRm is summarized in the Table; using the 13-gene panel, in patients with an HRRm excluding tBRCAm (n=54), the HR for PFS was 0.95 (95% CI 0.49-1.94). Expansion of this panel to include five other genes (n=72) demonstrated an HR (95% CI) for PFS of 1.01 (0.55-1.95). Consistent results were seen in patients with HRRm excluding tBRCAm using the three other published HRR gene panels (Table). Conclusions: Acknowledging limitations of small subgroup sizes, HRRm (excluding tBRCAm) was not predictive of PFS benefit with maintenance olaparib in combination with bevacizumab, compared with bevacizumab alone, in PAOLA-1, regardless of the gene panel used. Mutation analysis using HRRm gene panels did not have utility beyond tBRCAm for selecting patients who may benefit from maintenance olaparib plus bevacizumab in PAOLA-1 and should not be considered a substitute for HRD determined by BRCA and/or genomic instability testing. Download : Download high-res image (309KB) Download : Download full-size image

Background Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms. Patients and methods PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments. Results A total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug–drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57–92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12–51%]). Conclusion Combining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population. Trial registration ID NCT01589861 .

Background PM01183 is a new compound that blocks active transcription, produces DNA breaks and apoptosis, and affects the inflammatory microenvironment. PM01183 showed strong antitumor activity in preclinical models of cisplatin-resistant epithelial ovarian cancer. Patients and methods Patients with platinum-resistant/refractory ovarian cancer were included in a two-stage, controlled, randomized (in a second stage), multicenter, phase II study. Primary endpoint was overall response rate (ORR) by RECIST and/or GCIG criteria. The exploratory first stage (n = 22) confirmed the activity of PM01183 as a single agent at 7.0 mg flat dose every 3 weeks (q3wk). The second stage (n = 59) was randomized and controlled with topotecan on days 1–5 q3wk or weekly (every 4 weeks, q4wk). Results ORR was 23% (95% CI, 13%–37%) for 52 PM01183-treated patients. Median duration of response was 4.6 months (95% CI, 2.5–6.9 months), and 23% (95% CI, 0%–51%) of responses lasted 6 months or more. Ten of the 12 confirmed responses were reported for 33 patients with platinum-resistant disease [ORR = 30% (95% CI, 16%–49%)]; for the 29 patients treated with topotecan in the second stage, no responses were found. Median PFS for all PM01183-treated patients was 4.0 months (95% CI, 2.7–5.6 months), and 5.0 months (95% CI, 2.7–6.9 months) for patients with platinum-resistant disease. Grade 3/4 neutropenia in 85% of patients; febrile neutropenia in 21% and fatigue (grade 3 in 35%) were the principal safety findings for PM01183. Conclusion PM01183 is an active drug in platinum-resistant/refractory ovarian cancer and warrants further development. The highest activity was observed in platinum-resistant disease. Its safety profile indicates the dose should be adjusted to body surface area (mg/m2). Trial code EudraCT 2011-002172-16.

Resume Introduction Les etudes evaluant la chimiotherapie a haute dose avec autogreffe de cellules-souches hematopoietiques (HDC-ACSH) dans la prise en charge des cancers du sein metastatiques (CSM), localement avances (CSLA) ou inflammatoires (CSI) ont pour point commun l’absence ou le manque de donnees sur la surexpression de la proteine human epidermal growth factor receptor-2 (Her2). Patientes et methodes Nous avons analyse retrospectivement les donnees des patientes ayant recu une HDC-ACSH pour la prise en charge d’un CS a l’institut Paoli-Calmettes entre 2003 et 2012. Les patientes ont ete classees en 3 sous-groupes selon l’expression des recepteurs hormonaux (RH) et/ou de Her2 : HER2 (Her2+ et RH+ ou−) ; luminal (RH+ et Her2−) ; triple negatif (TN) (RH− et Her2−). L’objectif principal etait l’analyse de la survie globale (SG) selon le sous-type IHC. Resultats Trois cent soixante-dix-sept patientes ont ete incluses. Pour les CSM, le sous-type TN apparaissait comme de moins bon pronostic avec une SG mediane de 19,68 mois (IC95 % 11,76–44,4) contre 44,64 mois (IC95 % 40,32–67,56) pour le sous-groupe luminal et une SG mediane non atteinte pour le sous-groupe HER2 (p Conclusion L’HDC-ACSH ne modifie pas le pronostic des sous-groupes IHC chez les patientes atteintes de CS.

Objective Time to adjuvant treatment could have an impact on cancer prognosis. It is possible that robotic surgery lengthens the healing time of vaginal cuff after minimally invasive hysterectomy. The objective of this study was to state the impact of time to RT (TTR) on prognosis in endometrial carcinoma (EC) patients and to assess variables associated with TTR. Study design We conducted a multicentric retrospective study in two cancer centers. We included EC patients, between January 1996 and January 2016. We searched variables associated with TTR and impact of TTR on end-points: local recurrence-free survival, metastatic-free survival, event-free survival and overall survival. Results 329 patients were included and 279 were analyzed for TTR impact. Robotic surgery was associated with shorter TTR (8 weeks, 8.9 w for laparotomy, 9.2 w for laparoscopy). Pelvic lymphadenectomy, para-aortic lymphadenectomy, discussion in multidisciplinary meeting and treatment center was independently associated with TTR. No impact of TTR was shown on metastatic-free survival, event-free survival and overall survival but there was a trend of a decreased local recurrence rate in case of prolonged TTR (HRcontinuous variable = 1.08; CI95 %: 0.97–1.2). Conclusion Our study did not show any impact of treatment delay on survival end-points although prolonged TTR could moderate the benefit of radiotherapy on local control rate. Surgical route was not associated with TTR, particularly robot-associated laparoscopy did not lengthen treatment delay. TTR seems dependent of health-care organization and could represent a quality criterion of EC care for institutions.

Introduction/Background In SOLO1 trial, maintenance therapy with olaparib considerably improved progression-free survival (PFS) among women with newly-diagnosed, advanced BRCA-mutated HGEOC. Based on the large real-life ESME ovarian cancer (OC) cohort, we aimed to describe the patient‘s characteristics and survival outcomes of a selected cohort of BRCA-mutated patients before the era of PARP inhibitors maintenance in first line. Methodology ESME OC is a national cohort including all patients (pts) with EOC managed in the 18 French Comprehensive Cancer Centres (NCT03275298). ESME Research program collected retrospective data from patient‘s medical records. BRCA1, BRCA2, or both mutated patients with de novo diagnosed advanced (FIGO stage III or IV) high-grade serous or endometrioid EOC were eligible. Primary objective was to describe patient‘s characteristics, clinical features and treatment patterns. Results Of the 4777 patients with OC treated in first line by platinum-based chemotherapy between 2011 and 2016, 266 were included. Median age was 57.0 (33–81). 187 pts (70.3%) harbored a BRCA1 mutation, and 75 (28.2%) a BRCA2 mutation. 66.9% of patients had FIGO stage III disease. Almost all patients (95.5%) underwent surgical resection, after neoadjuvant chemotherapy (48%), or primary debulking surgery (44.9%). 119 pts (44.7%) received maintenance therapy and majority with bevacizumab alone (78.9%). After a median follow-up of 51.7months, the median PFS (mPFS) was 28.6months [95 CI: 26.2–32.4]. Patients exhibited higher mPFS in case of FIGO stage III than stage IV (32.4 months and 25.4 months, respectively), or BRCA2 mutation than BRCA1 (33.3 months and 27.7 months, respectively). Although populations were non comparable, mPFS was close between patients treated with or without maintenance (28.3 and 29.5 months, respectively). Median PFS2 were 51.4 months and 50.4 months, respectively. Estimated 5-year OS for the whole population was 69.2% [95 CI: 65.3–73.0]. Conclusion This large ESME OC cohort described clinical features and real-life survival outcomes among pts with newly diagnosed advanced BRCA-mutated HGEOC treated in specialized centres. Disclosure This work was supported by UNICANCER. The ESME OC database is supported by an industrial consortium (Roche, Pfizer, AstraZeneca, MSD, Eisai and Daiichi Sankyo). Data collection, analyses and publications are totally managed by R&D UNICANCER independently of the industrial consortium. All the authors declare that there is no conflict of interest regarding the publication of this article.

Introduction/Background Surgery is the cornerstone of ovarian Granulosa Cell Tumor (GCT). Complete resection with adequate staging is the gold standard in 1st line setting. The aim of this study is to assess the impact of an appropriate surgery according to the guidelines. Methodology This is a nationwide five-year retrospective study, including 463 patients (of the 639 included patients) with a definitive diagnosis of GCT between 2011 and 2016. Medical and surgical practices were analyzed for conformity. Conformity to guidelines was defined by a conservative (unilateral salpingo-oophorectomy) or radical surgery (hysteretomy and bilateral salpingo-oophorectomy) including surgical staging (omentectomy, peritoneal biopsy and peritoneal cytology) according to the FIGO classification. Results Median age at diagnosis was 49 years old (range 10–89). The median size of tumor was 94 mm (range 5–400). Radical surgery was performed in 240 patients (51,8%), while a fertility-sparing surgery was performed in 98 cases (21,2%). A complete surgical staging was performed in only 76 cases (16,4%). 289 (62.4%) patients received an evaluation of the endometrium (hysterectomy or endometrial curettage). Surgery was fully compliant with the guidelines in 65 patients (14%), partially compliant in 213 patients (46%), non-compliant in 137 patients (29,6%) and not assessable in 48 cases (10,4%) respectively. A statistically significant improvement in the surgical management was observed among patients treated after 2012 compared to those treated before 2012. This Improvement included: endometrial evaluation (p=0,026), tumour rupture rate during surgery (p=0,010) and the global compliance of the surgery (p Conclusion Staging surgery provides a better assessment and an appropriate treatment of this rare tumors. According to this study, the implementation of a national network and guidelines dedicated to rare gynaecologic tumors seems to significantly improve the surgical management of the patients with GCT. Disclosure Nothing to disclose.

The French national rare gynecological tumor network has been established to improve the quality of care through offering expertise in double reading histological diagnosis, reviewing cases and guiding management of these tumors through specialized multidisciplinary tumor boards and online clinical guidelines (www.ovaire-rare.com). The aim of this study is to evaluate the impact of the development and implementation of this network by assessing the conformity of medical practice with the guidelines concerning the granulosa cell tumors (GCTs).This is a French nationwide study, including 463 patients (out of the 639 identified patients) with a definitive diagnosis of GCT between 2011 and 2016. Surgical practices were analyzed for conformity with the current guidelines (www.ovaire-rare.org). Medical records, surgical and pathological reports were systematically analyzed. Total conformity was defined by a conservative (unilateral salpingo-oophorectomy) or radical surgery (hysterectomy and bilateral salpingo-oophorectomy) including surgical staging (omentectomy, peritoneal biopsies and peritoneal cytology) according to the FIGO stage. Partial conformity referred to a conservative or radical surgery without surgical staging and non-conformity was defined as a non-optimal surgery as recommended by the guidelines.Median age at diagnosis was 49 years old (range 10-89). The median size of tumor was 94 mm (range 5-400). Radical surgery was performed in 240 patients (52%); while a fertility-sparing surgery was performed in 98 cases (21%). A surgical staging was performed in 76 cases (16%) and an evaluation of the endometrium in 289 cases (62%). Surgery was fully compliant with the guidelines in 65 patients (14%), partially compliant in 213 patients (46%), non-compliant in 137 patients (30%) and not assessable in 48 cases (10%). A statistically significant difference for compliance was observed in restaging surgery (p 0,001), radical surgery (p = 0,017) and the period (before or after) of the implementation of the network (p 0,001). Survival analyses did not allow us to demonstrate a significant difference in overall survival nor in PFS although there was a trend in favor of optimal surgery compared to incomplete/non optimal surgery.Surgical management's conformity to the guidelines increases over time from 2011 to 2016. According to this study, the implementation of a national network dedicated to rare gynecologic tumors seems to significantly improve the surgical management of the patients with ovarian granulosa cell tumors.

Ovarian cancers (OvC) are frequent, with more than 22,000 new cases each year for 14,000 deaths in the United States. Except for patients with BRCA1 or BRCA2 mutations, diagnostic methods, prognostic tools, and therapeutic strategies have not much improved in the last two decades. High throughput tumor molecular analyses have identified important alterations involved in ovarian carcinoma growth and spreading. However, these data have not modified the clinical management of most of patients. Moreover, tumor sample collection requires invasive procedures not adapted to objectives, such as the screening, prediction, or assessment of treatment efficacy, monitoring of residual disease, and early diagnosis of relapse. In recent years, circulating tumor biomarkers (also known as “liquid biopsies”) such as circulating tumor cells, circulating nucleotides (DNA or miRNA), or extracellular vesicles, have been massively explored through various indications, platforms, and goals, but their use has not yet been validated in routine practice. This review describes the methods of analysis and results related to liquid biopsies for ovarian epithelial cancer. The different settings that a patient can go through during her journey with OvC are explored: screening and early diagnosis, prognosis, prediction of response to systemic therapies for advanced stages, and monitoring of residual subclinical disease.

TPS5604 Background: Gynecological carcinosarcomas (CS) are rare and highly aggressive tumors with a 5-year overall survival (OS) < 10%. After initial treatment majority of patients (pts) relapse and receive diverse chemotherapies (CT) producing modest benefits. The median PFS in relapse after platinum based CT is less than 4 months and median OS less than 1 year. New innovative strategies are urgently needed. Since CS showed high DNA damage response activity and potentially a high tumor mutation load resulting in neo-antigens, a synergy between PARPi and anti-PD1 is expected. Methods: ROCSAN is a multicentric, randomized, open-label, integrated Phase II/III study. In the Phase II, 63 pts with recurrent or progressing endometrial or ovarian CS after at least a first line of platinum-based CT will be randomized (2:2:1) to receive either niraparib in monotherapy, niraparib in combination with dostarlimab or standard CT (paclitaxel, doxorubicine, gemcitabine, topotecan). Stratification factors include the number of previous CT lines (1 vs 2-3), FIGO stage at diagnosis (I-II vs III-IV), CS localisation (ovarian vs endometrial), and performance status (0-1 vs 2). The primary objective of the Phase II is to select the best experimental strategy between niraparib and dostarlimab/niraparib combination based on Response Rate at 4 months (RR-4M by RECIST1.1). A single stage design with a 10% unacceptable RR-4M and a 30% targeted RR-4M was used to determine Phase II sample size, assuming a 10% one sided alpha for each comparison and more than 90% power. A pick-the-winner selection design could be used in case of promising efficacy in each experimental arm. At the interim analysis, an Independent Data Monitoring Committee will make recommendation for the selection of the optimal experimental arm. The Steering committee could then support to continue enrolment for the international Phase III which is calibrated to detect an improvement in median OS from 7 months (Standard CT) to 11.7 months (best experimental arm). Assuming a 5% alpha level and 80% power, 133 additional pts could be randomized (2:1). Secondary endpoints include safety, PFS, PFS2, TTST, ORR, duration of response, patient report outcomes (assessed via EORTC QLQ-C30 OV28, HADS, PRO-CTCAE). A translational program supported by European Community is associated to the clinical study to identify predictive biomarkers of response/resistance to study treatments, to correlate with immune environment, a special focus on genetic instability and the EMT process will be included. Trial is currently recruiting only in France for the phase II part, the first pt was randomized in July 2020. Clinical trial information: NCT 03651206.

// Anthony Goncalves 1, 2, * , Francois Bertucci 1, 2, 3, * , Arnaud Guille 2, 3 , Severine Garnier 2, 3 , Jose Adelaide 2, 3 , Nadine Carbuccia 2, 3 , Oliver Cabaud 2, 3 , Pascal Finetti 2, 3 , Serge Brunelle 4 , Gilles Piana 4 , Jeanne Tomassin-Piana 5 , Maria Paciencia 5 , Eric Lambaudie 6 , Cornel Popovici 2, 7 , Renaud Sabatier 1, 2, 3 , Carole Tarpin 1 , Magali Provansal 1 , Jean-Marc Extra 1 , Francois Eisinger 2, 7 , Hagay Sobol 2, 7 , Patrice Viens 1, 2 , Marc Lopez 2, 3 , Christophe Ginestier 2, 3 , Emmanuelle Charafe-Jauffret 2, 3, 5 , Max Chaffanet 2, 3, # , Daniel Birnbaum 2, 3, # 1 Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France 2 Aix Marseille Univ, CNRS U7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Marseille, France 3 Department of Molecular Oncology, Institut Paoli-Calmettes, Marseille, France 4 Department of Imaging, Institut Paoli-Calmettes, Marseille, France 5 Department of Biopathology, Institut Paoli-Calmettes, Marseille, France 6 Department of Surgical Oncology, Institut Paoli-Calmettes, Marseille, France 7 Department of Oncogenetics, Institut Paoli-Calmettes, Marseille, France * both authors equally contributed # both authors equally supervised Correspondence to: Anthony Goncalves, email: goncalvesa@ipc.unicancer.fr Keywords: precision medicine, advanced breast cancer, NGS, CGH, patient-derived xenograft Received: July 10, 2016 Accepted: September 29, 2016 Published: October 18, 2016 ABSTRACT Background: Routine feasibility and clinical impact of genomics-based tumor profiling in advanced breast cancer (aBC) remains to be determined. We conducted a pilot study to evaluate whether precision medicine could be prospectively implemented for aBC patients in a single center and to examine whether patient-derived tumor xenografts (PDX) could be obtained in this population. Results: Thirty-four aBC patients were included. Actionable targets were found in 28 patients (82%). A targeted therapy could be proposed to 22 patients (64%), either through a clinical trial (n=15) and/or using already registered drugs (n=21). Ten patients (29%) eventually received targeted treatment, 2 of them deriving clinical benefit. Of 22 patients subjected to mouse implantation, 10 had successful xenografting (45%), mostly in triple-negative aBC. Methods: aBC patients accessible to tumor biopsy were prospectively enrolled at the Institut Paoli-Calmettes in the BC-BIO study ( ClinicalTrials.gov , NCT01521676). Genomic profiling was established by whole-genome array comparative genomic hybridization (aCGH) and targeted next-generation sequencing (NGS) of 365 candidate cancer genes. For a subset of patients, a sample of fresh tumor was orthotopically implanted in humanized cleared fat pads of NSG mice for establishing PDX. Conclusions: Precision medicine can be implemented in a single center in the context of clinical practice and may allow genomic-driven treatment in approximately 30% of aBC patients. PDX may be obtained in a significant fraction of cases.

Importance To our knowledge, this is the first randomized trial in sex cord-stromal tumors, and it establishes weekly paclitaxel as standard-of-care therapy after platinum-based therapy in this setting. Objective To determine the efficacy of weekly paclitaxel with or without bevacizumab as treatment for relapsed sex cord-stromal tumors and evaluate whether the addition of bevacizumab to weekly paclitaxel improves 6-month progression-free rate. Design, setting, and participants This open-label, academic, international, randomized phase 2 trial (ALIENOR) was conducted at 28 referral centers in France, Germany, Italy, Japan, and Belgium in collaboration with the Rare Tumor committee of the Gynecologic Cancer InterGroup and used an adaptive bayesian design. It included 60 women with sex cord-stromal tumors that had relapsed after at least 1 platinum-based chemotherapy. Enrollment occurred from 2013 to 2016, and the final analysis database lock was on March 27, 2020 (median follow-up, 38.9 months). Interventions Participants were randomized to receive either paclitaxel (80 mg/m2, days 1, 8, and 15 every 4 weeks) alone or paclitaxel with bevacizumab (10 mg/kg, every 2 weeks) for 6 cycles followed by maintenance bevacizumab (15 mg/kg, every 3 weeks) for up to 1 year or until progression or unacceptable toxicity. Crossover to bevacizumab was permitted after progression during or following paclitaxel alone. Main outcomes and measures Six-month progression-free rate. Results Sixty patients (predominantly with granulosa cell tumors) were randomized, 32 to receive single-agent paclitaxel (median [interquartile range] age at inclusion, 60 [53-64] years) and 28 to receive paclitaxel-bevacizumab (median [interquartile range] age at inclusion, 55 [47-61] years; 1 did not receive treatment). The estimated 6-month progression-free rate was 71% (95% credible interval, 55%-84%) with paclitaxel alone and 72% (95% credible interval, 55%-87%) with paclitaxel-bevacizumab. The bayesian estimate for the probability that the 6-month progression-free rate distribution was higher with the combination than with paclitaxel alone was 57%, less than the predefined superiority threshold. The objective response rate increased from 25% (95% CI, 12%-43%) to 44% (95% CI, 26%-65%) with the addition of bevacizumab. One patient discontinued combination therapy within 6 months because of toxicity. Conclusions and relevance Weekly paclitaxel is a new option for relapsed sex cord-stromal tumors. In this international randomized clinical trial of patients with relapsed sex cord-stromal tumors unsuitable for surgery, adding bevacizumab to weekly paclitaxel does not improve clinical benefit. Trial registration ClinicalTrials.gov Identifier: NCT01770301.

6023 Background: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and rapidly lethal disease affecting young women with over half dying within 2 years of diagnosis. We previously reported improved outcomes with cytoreductive surgery followed by HDC-aSCR in a prospective study, but these encouraging results needed to be confirmed in an independent and larger cohort. Methods: Between 2008 and 2019, out of 44 patients (pts) diagnosed with centrally confirmed SCCOHT in 16 referent centers of the TMRG network, 38 were treated prospectively according to the French recommendations of the network with complete surgery (primary or after neoadjuvant chemotherapy), 4 to 6 cycles of PAVEP chemotherapy (cisplatin, doxorubicin, vepeside, and cyclophosphamide), and for pts with complete response (CR), HDC-aSCR, followed by pelvic radiotherapy. The 6 patients who could not receive PAVEP (unfit or diagnostic delay) relapsed and died rapidly. The primary endpoint was the event-free survival (EFS) in the intention-to-treat cohort. Results: Median age at diagnosis was 33 years (14-76). 13 pts presented with FIGO stage I, 17 stage III and 6 stage IV, 2 unknown. Median follow-up was 55.5 months. 34 patients achieved CR with CT + surgery and 30 received HDC-aSCR (40%, 47% and 10% with stages I, III and IV diseases respectively) and 21 received also pelvic radiotherapy. Median overall and event-free survival was 36.4 and 15.9 months respectively, and 2-years event-free survival rate was 40% (CI95% 25-56). Median OS was respectively not reached, 18 and 9.6 months for FIGO I, III and IV patients. Among the pts (N = 14) who did not receive HDC-aSCR (rapid progression during or after PAVEP), the 2-yr EFS was 0% compared to 50.5% for the 30 patients receiving HDC. In multivariate analysis, HDC was significantly correlated with better outcomes (p < 0.001). For the 21 patients receiving also pelvic radiotherapy, 57% (12/21) are free of recurrence at 4 years. Grades 3/4 adverse events were frequent (78%) but, in most cases, manageable, although one toxic death (3%) occurred during HDC (fungal septic shock). Conclusions: Treatment of SCCOHT, with intensive multimodal therapy, is associated with a 40% 2-yr event-free survival. However, this protocol is associated with significant toxicity and should be restricted to good performance status patient and expert centers.

6039 Background: In PAOLA-1/ENGOT-ov25 (NCT02477644), adding the PARP inhibitor olaparib to maintenance bev after first-line platinum-based chemotherapy plus bev led to a statistically significant progression-free survival (PFS) benefit in pts with advanced HGOC (HR 0.59; 95% CI 0.49–0.72) (Ray-Coquard et al. 2019). Retrospective subgroup analysis in GOG-0218 (Norquist et al. 2018) suggested BRCA mutation (BRCAm) status did not significantly impact the PFS benefit provided by bev. We explored the efficacy of olaparib plus bev by BRCA1 mutation ( BRCA1m) or BRCA2 mutation ( BRCA2m) in PAOLA-1. Methods: PAOLA-1 is a randomized, double-blind, Phase III trial in pts with newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid OC, fallopian tube or primary peritoneal cancer receiving platinum-based chemotherapy plus bev then maintenance bev. Pts unrestricted by surgical outcome or BRCAm status and in response to first-line therapy were randomized to maintenance olaparib tablets (300 mg bid for up to 24 months) plus bev (15 mg/kg q3w for up to 15 months in total) or placebo plus bev, stratified by first-line treatment outcome and tumor BRCAm status. Investigator-assessed PFS (modified RECIST v1.1) by BRCAm was a predefined analysis. Results: Of 806 randomized pts, 160 (20%) had tumor BRCA1m, 76 (9%) had tumor BRCA2m and 1 (

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.

Background Carboplatin and pegylated liposomal doxorubicin combination is a standard regimen in platinum-sensitive recurrent ovarian cancer patients. The pegylated liposomal doxorubicin shortage from 2011 to 2013 urged assessment of the efficacy and tolerance of non-pegylated liposomal doxorubicin in combination with carboplatin. Methods MYCA was a multicenter 2-step phase Ib-II single arm trial meant to assess the safety and efficacy of carboplatin AUC 5 mg/min.mL combined with non-pegylated liposomal (dose escalation from 40 to 50 mg/m2 during phase Ib step; and 50 mg/m2 during phase II step), every 4 weeks in patients with platinum-sensitive relapse. The primary objective was disease control rate (DCR) at 12 months. Results From 2012 to 2014, 87 patients were enrolled. They were treated as second (78%) or third line (22%) treatment. Total of 67 patients (78%) completed 6 cycles. G-CSF support was prescribed to 58% patients. The DCR at 12 months was 30.0% (95% CI, 20.3–39.7); the median PFS was 10.0 months (95% CI, 8.6–11.0). The median overall survival was 28.1 months (95% CI, 22.3–32.5); and the objective response rate was 58% (95% CI, 47–68). Grade 3–4 neutropenia, anemia and thrombocytopenia were observed in 17%, 13% and 1%, respectively; febrile neutropenia in 6%. One patient who did not receive GCSF support died from febrile neutropenia. Conclusion Non-pegylated liposomal doxorubicin-carboplatin combination exhibits an acceptable safety profile, with GCSF prophylaxis. Acknowledging the lack of direct comparison, efficacy in terms of 12 month DCR was comparable with standard treatments.

Background Breast cancer diagnosed during pregnancy (BCP) is rare, but the prevalence is expected to rise. Long-term follow-up data regarding this clinically challenging condition are scarce. The main objective of this multicentre case-control French study was to compare the survival between pregnant patients and matched controls. Methods Patients from 27 centres diagnosed between 2000 and 2009 with histologically proven invasive breast cancer occurring during pregnancy were retrospectively included. Controls were matched to BCP patients on age, clinical T stage, hormone receptor, HER2, administration of neo-adjuvant chemotherapy and pathological node involvement in the absence of neo-adjuvant chemotherapy. Five-year overall survival (OS), disease-free survival (DFS) and metastasis-free survival (MFS) rates were estimated using the Kaplan–Meier method. Results One hundred and eleven BCP patients and 253 controls were included. Median age was 33 and 35 years, respectively. Both populations were managed similarly, except for less frequent sentinel node dissection (p = 0.026) and taxane administration (p = 0.03) among BCP patients. Median follow-up was 7.5 years. Survival rates were similar between both BCP and control patients: 5-year OS rates were 83.1% (95% CI: 74.5–89.0) vs 85.5% (95% CI: 80.4–89.4), respectively, p = 0.31; 5-year DFS rates 60.0% (95% CI: 50.1–68.6) vs 68.5% (95% CI: 62.3–73.9), respectively, p = 0.12 and 5-year MFS rates 71.0% (95% CI: 61.3–78.6) and 74.5% (95% CI: 68.6–79.5), respectively, p = 0.21. Conclusion Our study showed that the survival outcomes of patients diagnosed with BCP were not significantly different as compared to those of matched non-pregnant controls. A proper management of women diagnosed with BCP is crucial.

Background Genomic-based approaches in advanced breast cancer (ABC) were recently demonstrated as feasible in the clinical practice, but only a limited number of patients were actually treated with targeted therapies matching genomic alterations, with low antitumor activity. We conducted a pilot study to evaluate whether precision medicine using NGS and aCGH could be implemented prospectively at a single center in ABC patients. In addition, we examined whether PDX could be derived from ABC and thus could help inform therapeutic decision. Methods ABC patients accessible to tumor biopsy were prospectively enrolled at the Institut Paoli-Calmettes in the BC-BIO study (ClinicalTrials.gov, NCT01521676). Tumor tissue from locally recurrent or metastatic disease was immediately frozen after dedicated biopsy. Genomic profiling included high-resolution 4x180K aCGH (Agilent Technologies, Massy, France) and DNA sequencing, using a library of 365 cancer candidate genes (HaloPlex target enrichment kit, Agilent technologies, Santa Clara, CA, USA) and MiSeq analyzer (Illumina, San Diego, CA, USA) with 2x150-bp, paired-end at about 300x coverage. In a subset of patients, fresh tumor was implanted orthotopically in humanized cleared fat pads of NSG mice for establishing xenotransplants. Results A total of 34 ABC patients were included, with the following characteristics: median age 54 years (35-77); molecular subtypes: 11 triple-negative (32%), 12 luminal non-HER2 (35%), 4 luminal HER2 (12%), 3 HER2 non-luminal (9%), and 4 unknown (12%); 33 with previous chemotherapy (97%); 22 with previous endocrine treatment (35%); 7 with previous anti-HER2 (21%). Tumor biopsies were obtained from liver (15), skin (6), peritoneum (4), breast (3), node (3), lung (1), pleura (1), and ascitis (1), with a median tumor cellularity of 70% (range 10-90%). aCGH and NGS were available from 34 and 33 patients, respectively. An actionable target was found in 28 patients (82%), corresponding to 66 targets, including 37 mutations (8 in PIK3CA, 7 TP53, 4 ESR1, 2 AKT1, 2 BRCA2, 2 HER2), 22 amplifications (7 for CCND1, 2 CCNE1, 2 FGFR1, 2 IGF1R) and 7 homozygous deletions (3 for PTEN, 2 CDKN2A/B,1 BRCA2, 1 STK11). A targeted therapeutic proposal was possible, either in a clinical trial (N=18, 52%) or using already registered drugs (N=17, 50%). Ten patients actually received a targeted treatment, 1 of them experienced objective response and 1 showed stable disease for more than 6 months. Of 26 patients subjected to mouse implantation, 10 had successful xenografting (6 triple-negative, 2 HER2, 1 luminal non-HER2, 1 subtype non-attributed), with a median time to reach 10 mm of 148 days. These PDX will be used as models to understand the patient's therapeutic response. Conclusion Precision medicine using high-throughput DNA sequencing and aCGH can be implemented at a single center in the context of clinical practice and may allow direct therapeutic proposal in 1/3 of patients, but antitumor activity was minimal. PDX may be obtained in a significant fraction of patients, especially in triple-negative and HER2 subtypes, and could phenotypically complement genomic data. Citation Format: Gonçalves A, Bertucci F, Chaffanet M, Guille A, Garnier S, Adelaide J, Carbuccia N, Brunelle S, Piana G, Cabaud O, Thomassin-Piana J, Paciencia-Gros M, Chereau-Ewald E, Lambaudie E, Sabatier R, Tarpin C, Provansal M, Jalaguier-Coudray A, Extra J-M, Sarran A, Pakradouni J, Viens P, Lopez M, Ginestier C, Charafe-Jauffret E, Birnbaum D. Next-generation sequencing (NGS), array comparative genomic hybridization (aCGH) and patient-derived tumor xenograft (PDX) for precision medicine in advanced breast cancer: A single-center prospective study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-23.

Background: Breast cancer (BC) during pregnancy (BCP) is a rare situation that requires collaboration between oncologists, surgeons and obstetricians. The main objectives of this study were to compare the overall survival (OS) and disease free survival (DFS) of a multicenter cohort of pregnant patients (pts) with those of matched control pts. Methods: Patients from 27 centers and diagnosed between 2000 and 2006 with histological confirmed M0 invasive BC were included in this retrospective study. For the cohort of BCP, pts whose pregnancy was interrupted were not eligible. Controls were matched to BCP pts on 5 criteria: clinical T (of TNM), hormonal receptor (HR) status, HER2 status, administration of neo-adjuvant chemotherapy and pathological nodal status in the absence of neo-adjuvant chemotherapy. Survival times were estimated from the date of diagnosis using Kaplan-Meier method. OS was calculated until death from every cause, DFS was calculated until relapse or death from every cause; patients alive were censored at the date of last news. Results: 100 BCP pts were identified. Their clinical and pathological characteristics were described on a previous presentation (SABCS 2013 P6-06-07). Matched controls could not be found for 12 BCP pts. 88 BCP pts were matched with 204 controls. The only differences between the 2 populations in terms of characteristics or treatment were more radical mastectomy (p=0.036) and fewer taxane administrations in the BCP group (p=0.06). The median duration of follow-up was 8.2 years for cases and 7.7 years for controls. There were no differences between BCP pts and controls in 5-year OS: 83.4%, IC 95% (73.5-89.8) vs 83.8%, IC 95% (77.9-88.3) nor 7-year OS: 76.5% (65.5-84.4) vs 78.1% (71.5-83.3) (p=0.52). The 5-year DFS was 58.6% IC 95% (47.3-68.3) vs 67.2% IC 95% (60.2-73.2) (p= 0.16). However, 5-year DFS was lower in HR+ BCP pts subgroup than in HR+ control group (56.7% IC 95% (40.7-69.8) vs 70.9% IC 95% (61.4-78.5) (p=0.023). Conclusion: This multicenter French large study confirmed that there are no differences on OS and DFS between pregnant and no pregnant pts, though this might not be true for HR subgroup. Citation Format: Vanlemmens L, Ploquin A, Delaloge S, Rouzier R, Lesur A, Frenel J-S, Loustalot C, Bachelot T, Provansal M, Ferrero J-M, Coussy F, Debled M, Kerbrat P, Vinceneux A, Djelila A, Baron M, Jebert S, Decoupigny E, Tresch E, Bonneterre J. 5-year overall survival of early breast cancer during pregnancy: A multicenter French case control study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-02.

International audience; Purpose: Studies examining high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDC-AHSCT) strategies in inflammatory breast cancer (IBC), showed encouraging results in terms of disease-free survival (DFS), and overall survival (OS). The lack of data regarding HER2 status in all of these studies prevented any prognostic analysis involving breast cancer subtypes. Methods: All consecutive female patients treated for IBC with HDC and AHSCT at Institut Paoli-Calmettes between 2003 and 2012 were included. Since 2005, trastuzumab was included in initial treatment. Patient, tumor and treatment characteristics were collected. Patients were categorized in three subtypes based on hormonal receptor (HR) and HER2 status of the primary tumor: Luminal, (HR+/HER2-), HER2 (HER2+, any HR), and triple negative (TN) (HER2-and HR-). The main objective was the analysis of OS according to the IHC subtypes. Results: Sixty-seven patients were included. Eleven patients received trastuzumab. Median follow up was 80.04 months (95% CI 73.2-88.08). Five-year OS and DFS for the whole population patients were 74% (95% CI 61-83) and 65 % (95% CI 52-75), respectively. OS differed across subtypes (p=0.057) : HER2 subgroup appeared to have the best prognosis with a 5-year OS of 89% (95% CI 64-97) compared to 57% (95% CI 33-76) for the TN subgroup (HR 5.38, 95% CI 1.14-25.44; p=0.034). Conclusions: In IBC patients receiving HDC-AHSCT, OS favorably compares with data available in the literature on similar groups of patients. TN patients carried the least favourable OS and HER2 patients, half of them also receiving trastuzumab, had the best outcome. These findings provide additional information and options for patients with IBC and who could potentially benefit of HDC-AHSCT.

Ovarian cancer is the leading cause of mortality by gynecologic cancers in Western countries. Many publications have suggested that age may be an independent prognostic factor in ovarian carcinoma. There are only few data concerning the impact of treatments and geriatric features within the elderly population.We collected data of older (≥ 70 years old) patients treated in our institution for an invasive ovarian carcinoma between 1995 and 2011. First we described usual clinical and pathological features for these patients, as well as their outcome. We compared these parameters with that of young (70 years old) patients treated during the same period. We then observed geriatric features in our set: Eastern Cooperative Oncology Group performance status, number of medications, Charlson index, body mass index, hemoglobin, and glomerular filtration rate. We finally looked for prognostic factors specific of the elderly population.One hundred nine elderly patients were identified and compared with 488 younger cases. There was no difference concerning clinicopathologic data. Surgery was more frequently complete in young women (58% vs 41.7%), and older patients received less chemotherapy courses and less taxanes (38.4% vs 67.1%). Young patients had a longer overall survival (median, 65.2 vs 26.2 months, P = 8.5E-10, log-rank test). Multivariate analyses confirmed that age was an independent prognostic factor and that within the elderly set the International Federation of Gynecology and Obstetrics stage, surgery results, number of chemotherapy cycles administered and performance status had a significant prognostic value. No clear correlation could be observed between geriatric characteristics and treatments administration.Ovarian cancer prognosis is poorer for older women, but they are more frequently suboptimally treated. No correlation could be observed between geriatric factors and surgery or chemotherapy achievement. Treatment decision should be based on objective geriatric assessment in order to improve outcome in this population.

International audience; PURPOSE:Eribulin is approved for advanced breast cancers refractory to anthracyclines and taxanes. Efficacy according to sensitivity to previous therapies has been poorly explored.MATERIALS AND METHODS:Safety data were collected prospectively and we retrospectively collected efficacy data from the five French centres that participated in the Eribulin E7389-G000-398 expanded access program. Our main objectiveswere exploration of safety and analysis of eribulin efficacy (progression-free survival [PFS] and overall survival [OS]) according to sensitivity to the last microtubule-inhibiting agent administered.RESULTS:Median eribulin treatment duration was 3.3 months for the 250 patients included in this prospective single-arm study. Two hundreds and thirty-nine patients (95.6%) experienced an adverse event (AE) related to treatment including 129 (51.6%) with grade ≥ 3 AEs. The most frequently observed toxicities were cytopenias (59.6% of included patients), gastrointestinal disorders (59.2%), and asthenia (56.4%). The most frequent grade 3-4 AE was neutropenia (37.2% with 4.8% febrile neutropenia). Median PFS and OS were 4.6 and 11.8 months, respectively. Patients classified as responders to the last microtubule-inhibiting therapy had a longer OS (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.51 to 0.94; p=0.017), and tended to display a better PFS (HR, 0.78; 95% CI, 0.58 to 1.04; p=0.086). OS improvement was still significant in multivariate analysis (adjusted HR, 0.53; 95% CI, 0.35 to 0.79; p=0.002).CONCLUSION:This work based on a prospective study suggests that identification of patients likely to be more sensitive to eribulin could be based on their previous response to microtubules inhibitors.

1091 Background: Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-pathway is frequently activated in HER2-negative breast cancer and may play a role in taxane-resistance. LY is a dual inhibitor of p70 S6 kinase and AKT. TAKTIC study aimed to determine the recommended phase II dose (RP2D) of the combination of LY with wP (phase Ib) and to estimate overall response rate (ORR) of this regimen (phase II) in HER2-negative LA or MBC patients, both in the overall patient population and in patients with activation of PI3K/AKT pathway (PI3KAKT+). Methods: HER2-negative inoperable LA or MBC patients (pts), with (phase Ib) or without (phase II) previous cytotoxic treatment for advanced disease were eligible. Oral LY (400 or 500mg) was administered daily in combination with intravenous wP (70 or 80mg/m2). A modified CRM using an adaptive Bayesian model guided the dose escalation of both agents. PI3KAKT+ was defined as activating mutation of PIK3CA and/or AKT by targeted NGS or homozygous loss of PTEN by array comparative genomic hybridization (aCGH) or loss of PTEN by immunohistochemistry, as evaluated on available fresh tumor tissue. Results: A total of 12 and 35 patients (pts) were included in the phase Ib and II, respectively. In phase Ib, only 1 dose-limiting toxicity (confusion) was observed at the last dose level (LY, 500 + wP, 80), which was determined as RP2D. Main drug-related adverse events (AE) in phase Ib were skin toxicity (92% of pts, G3-4 in 33%), and paresthesia (50% of pts, G3-4 in 8%). In the phase II study, ORR was 62.9 % [44.9,78.5] including 1 CR and 21 PR in the overall population and 55.6 % [30.8,78.5] in PI3KAKT+ pts (10 PR in 18 pts). Median progression-free survival was 12.4 months [7.9,17.9] and 6-month clinical benefit rate was 82.9% [66.4,93.4]. AEs in phase II were similar to phase I part, except that 17% of pts experienced pneumonia (G3-4 in 9%). Conclusions: Combining LY and wP in HER2-negative LA or MBC was feasible with preliminary evidences of efficacy, independently of PI3K/AKT activation. Clinical trial information: NCT01980277.

Triple-negative breast cancer (TNBC), as defined by the absence of estrogen and progesterone receptor expression, as well as the lack of HER2 overexpression/amplification, corresponds to 15% of breast cancer and represents an aggressive form of the disease. TNBC are frequently confounded with basal subtype in the molecular classification of breast cancer and also share some similarities with BRCA1-mutated tumors. Epidemiological and clinical characteristics are distinct from other subtypes, including a younger age at diagnosis, a higher risk of relapse in spite of increased chemosensitivity, and a higher incidence of lung and brain metastatic relapses. Conventional cytotoxics remain the mainstay of current systemic management but recent evaluation of more targeted therapeutics, including specific cytotoxics (such as the use of platinum salts), PARP and EGFR inhibition, and antiangiogenics have been performed, providing contrasted but rather disappointing results. Recent data indicate that TNBC represent a heterogeneous entity composed of multiple and distinct molecular subtypes, which should deserve specific targeted therapeutics.

International audience