Alexandra Leary

Institut de Cancérologie Gustave Roussy | IGR · Department of Adult Medicine

Rationale: Homologous recombination deficiency (HRD), defined as BRCA1/2 mutation (BRCAmut) or high genomic instability, is used to identify ovarian cancer (OC) patients most likely to benefit from PARP inhibitors. While these tests are useful, they are imperfect. Another approach is to measure the capacity of tumor cells to form RAD51 foci in the...

Although the management of epithelial ovarian cancer has evolved significantly over the past few years, it remains a public health issue, as most patients are diagnosed at an advanced stage and relapse after first line treatment. Chemotherapy remains the standard adjuvant treatment for International Federation of Gynecology and Obstetrics (FIGO) st...

(Abstracted from J Clin Oncol 2022; doi: 10.1200/JCO.22.01549) Because of nonspecific symptoms at disease presentation and inadequate screening methods, ovarian cancer is often advanced at the time of diagnosis results in a 10-year survival of 17% in patients with advanced epithelial ovarian cancer. The poly(ADP-ribose) polymerase (PARP) inhibitor...

BACKGROUND: The endometrial cancer molecular classification has been integrated into the 2020 World Health Organization (WHO) diagnostic classification and European treatment guidelines, and provides direction towards more effective and less toxic adjuvant treatment strategies for women with endometrial cancer. PRIMARY OBJECTIVES: The RAINBO progra...

Purpose Kinase inhibitors (KI) and antibodies targeting the VEGF pathway are approved in a broad spectrum of cancers and associated with an increased risk of bleeding and thromboembolic events (TE). The use of direct oral anticoagulants (DOACs) apixaban and rivaroxaban is increasing in cancer patients, but limited data are available for patients re...

Background: Around 15% of metastatic endometrial carcinoma (EC) are MMRd/MSI-H improving response to immune checkpoint inhibitors (ICI). So far, few data existed considering the chemotherapy (CT) sensitivity in MMRd/MSI-H EC, especially response to first-line platinum-based treatment. Patients and methods: We performed a multicentric retrospecti...

Objectives In ARIEL3 (NCT01968213), rucaparib maintenance treatment significantly improved progression-free survival (PFS) vs placebo. We present updated PFS2 and preplanned final overall survival (OS) analyses. Methods Patients were randomized to receive rucaparib 600 mg BID or placebo. Efficacy was analyzed across the 3 protocol-defined nested c...

Background Endometrial cancer can be molecularly classified into POLEmut, mismatch repair deficient (MMRd), p53 abnormal (p53abn), and no specific molecular profile (NSMP) subgroups. We aimed to develop an interpretable deep learning pipeline for whole-slide-image-based prediction of the four molecular classes in endometrial cancer (im4MEC), to ide...

Introduction/Background In 2021, the ESGO-ESTRO-ESP endometrial cancer (EC) guideline was updated and the molecular classification was added to the clinicopathological prognostic factors to classify women with EC in risk groups. The risk stratification is based on consensus of a multitude of studies investigating a variety of EC subgroups. To date,...

Introduction/Background Endometrial Cancer (EC) are molecularly classified into polymerase-ε mutated (POLEmut), mismatch repair deficient (MMRd), p53 abnormal (p53abn) and no specific molecular profile (NSMP). With the incorporation of the molecular classification in risk-assessment of EC patients, clinical relevance of histopathological features b...

Introduction/Background Platinum sensitivity and homologous recombinaison deficiency (HRD) are predictive biomarkers for PARP inhibitors (PARPi) benefit in HGOC patients. The only validated assays to assess HRD are BRCA-mutation (BRCAmut) analysis and genomic instability scores (GIS) designed to detect genomic ‘scars’ in tumor DNA. However, these t...

Introduction/Background Endometrioid Borderline Ovarian Tumor (EBOT) is a rare subtype of borderline ovarian malignancies. This study aimed to determine the prognosis of a series of EBOT. Methodology A retrospective review of patients with EBOT treated in or referred to our institutions. A centralized histological review by a reference pathologist...

Introduction/Background In this preliminary evaluation of the first 324 patients enrolled in the OVAL-1 study (NCT04532645), we report real-world characteristics and first-year therapy management among tumour or germline (t/g) BRCA1/BRCA2-mutated (t/gBRCAm) newly diagnosed advanced ovarian cancer (OC) patients who received maintenance olaparib acro...

Introduction/Background Six different techniques can be proposed to preserve the uterine corpus in early stage cervical cancer. Oncologic results (particularly recurrence rates) are the first aim of this review in order to evaluate the best strategy according both to the tumor size (< or > 20 mm) and the lympho-vascular space involvement status. Wh...

Introduction/Background The vast majority of mismatch repair-deficient (MMRd) endometrial carcinomas (EC) are due MLH1 promoter hypermethylation. Here, we aimed to investigate the prevalence, prognosis and underlying causes (including Lynch syndrome (LS)) of MMRd EC other than MLH1 promoter hypermethylation. Methodology From the 409 MMRd ECs that...

Introduction/Background The aim of this study was to assess the outcomes of a large series of patients treated conservatively for stage II or III serous borderline tumors of the ovary (SBOTs) with a long-term follow-up. Methodology Patients with SBOTs and peritoneal implants, treated in or referred to our institution, were retrospectively reviewed...

Introduction/Background FIGO grading of endometrioid-type endometrial cancers (EEC) is standard clinical practice. Upon the incorporation of the molecular classification in the risk-assessment of EC patients, the role of grading is debated. Here, we assessed the prognostic value of grading in molecularly classified high-risk EC (HREC). Methodology...

Introduction/Background Numerous studies showed that elderly women with endometrial cancer (EC) have a higher risk of recurrence and cancer-related death. It is unclear whether ageing is a risk factor by itself, or whether other risk factors become increasingly common at older age. We addressed to this using the large PORTEC collection of molecular...

Introduction/Background In ARIEL3 (NCT01968213), progression-free survival (PFS) improved significantly with rucaparib maintenance treatment versus placebo. We present updated PFS2 and preplanned final overall survival (OS) analyses. Methodology ARIEL3 enrolled patients with platinum-sensitive, high-grade ovarian carcinoma who had received ≥2 prev...

Purpose: To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi). Experimental design: In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 ovarian cancer (OC) patients referred to hematology consultation for cytopenia under P...

Objective ARIEL3 (NCT01968213) is a placebo-controlled randomized trial of the poly(ADP-ribose) polymerase inhibitor rucaparib as maintenance treatment in patients with recurrent high-grade ovarian carcinoma who responded to their latest line of platinum therapy. Rucaparib improved progression-free survival across all predefined subgroups. Here, we...

Background Risk-assessment of endometrial cancer (EC) is based on clinicopathological factors and molecular subgroup. It is unclear whether adding hormone receptor expression, L1CAM expression or CTNNB1 status yields prognostic refinement. Methods Paraffin-embedded tumour samples of women with high-risk EC (HR-EC) from the PORTEC-3 trial (n=424),...

PURPOSE In SOLO1/GOG 3004 (ClinicalTrials.gov identifier: NCT01844986 ), maintenance therapy with the poly(ADP-ribose) polymerase inhibitor olaparib provided a sustained progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 (BRCA) mutation. We report overall survival (OS) after a 7-year...

Background Survival outcomes for cervical cancer differ between countries and world regions. Locally advanced cervical cancer (LACC) is associated with poorer outcomes than early-stage disease. Country-specific variations in diagnostic and treatment recommendations might contribute to differences in LACC outcomes among countries. Objective We comp...

Background Neoadjuvant chemotherapy (NAC) followed by interval debulking does not present inferior results to those of primary cytoreduction and offers the opportunity to evaluate chemo-sensitivity in vivo. Chemotherapy response score (CRS) have been shown to correlate with outcome with a complete or near-complete (CRS3) response predicting improve...

Background Clinical studies have highlighted the efficacy of anti-programmed death 1 (αPD-1) monoclonal antibodies in patients with DNA mismatch repair-deficient (MMRD) tumors. However, the responsiveness of MMRD cancers to αPD-1 therapy is highly heterogeneous, and the origins of this variability remain not fully understood. Methods 4T1 and CT26...

Objectives: In patients with recurrent advanced endometrial carcinomas (EC), innovative treatments are needed after platinum chemotherapy. EC are characterized by frequent defective DNA repair, along with alterations of PI3K-AKT-mTor, and IGF1R pathways. In preclinical studies, the activity of PARP inhibitor is increased by the inhibition of PI3K-A...

TPS5614 Background: Besides PARP inhibitors and bevacizumab, there are no approved maintenance therapies after platinum based chemotherapy for patients with a platinum sensitive relapsed epithelial ovarian cancer (OC). Immune checkpoint inhibitors (ICI) as single agents have limited activity in OC. One attractive strategy is to turn OC from immunog...

5575 Background: Few platinum resistant ovarian cancer (PROvC) patients respond to anti-PD1 monotherapy (ORR 7.6%) with little impact on survival (OS 10.1 mo). Among responders the median duration of response is impressive (18.7 mo) (Hamanishi 2021). Methods: We have evaluated the combination of pembrolizumab (200mg), with bevacizumab (400mg) for 6...

5557 Background: We have shown that neoadjuvant carboplatin and paclitaxel (NACP) increased tumor infiltrating lymphocytes and PDL1 expression in OC pts. INEOV evaluated NACP with durvalumab (D) +/- tremelimumab (T) in pts with unresectable OC. We previously reported that NACP with D+/-T was feasible and safe but the addition of T did not improve i...

Standard molecular classification of endometrial cancers (EC) is now endorsed by the WHO and identifies p53-abnormal (p53abn) EC as the subgroup with the poorest prognosis and the most likely to benefit from adjuvant chemo(radio)therapy. P53abn EC are POLE wildtype, mismatch repair proficient and show abnormal immunohistochemical (IHC) staining for...

7057 Background: PARPi have shown promising results in several cancers, especially breast (BC) and ovarian cancer (OC), but may be associated with an increased risk of t-MNs. A careful monitoring of hematologic toxicity to exclude this risk is necessary. Here we described, in a real-life setting, the management of these adverse effect. Methods: Fir...

5544 Background: In ARIEL3 (NCT01968213), rucaparib maintenance treatment led to significant improvement vs placebo for the primary endpoint of investigator-assessed progression-free survival (PFS) in patients (pts) with platinum-sensitive, recurrent ovarian carcinoma responsive to the last line of platinum therapy (Coleman et al. Lancet. 2017;390:...

5554 Background: Antibodies targeting PDL1 or PD1 have been disappointing so far in the treatment of ovarian cancer (OC). A greater understanding of the complex iTME and of the impact of chemotherapy on immune features could uncover promising immune targets. We previously reported that neoadjuvant chemotherapy (NACT) increased CD4+ and CD8+ immune...

DNA double-strand breaks are the most critical DNA damage to cells, and their repair is tightly regulated to maintain cellular integrity. Some cancers exhibit homologous recombination deficiency (HRD), a faithful double-strand break repair system, making them more sensitive to poly (ADP ribose) polymerase inhibitors (PARPi). PARPi have shown substa...

Background: Endometrioid borderline ovarian tumor (EBOT) is a rare subtype of borderline ovarian malignancies. This study was designed to determine the prognosis of a series of EBOT. Methods: This is a retrospective review of patients with EBOT treated in or referred to our institutions and a centralized, histological review by a reference patho...

Background The prognosis of patients with advanced soft-tissue sarcomas (STS) remains dismal, and systemic therapeutic options are limited. Early phase trials are becoming increasingly safe and effective. This study aimed to identify the prognostic factors for progression-free survival (PFS). Patients and methods This retrospective analysis includ...

Background In ovarian carcinomas, the likelihood of disease cure following first-line medical-surgical treatment has been poorly addressed. The objective was to: (a) assess the likelihood of long-term disease-free (LDF) > 5 years; and (b) evaluate the impact of the tumour primary chemosensitivity (assessed with the modelled CA-125 KELIM) with respe...

B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid structures (TLS). Here, we investigate the role of B-cells and TLS in endometrial cancer (EC). Single cell RNA-sequencing of B-cells shows presence of naïve B-cells, cycling/germinal center B-cells and antibody-secreting cells. Differential gene express...

Standard treatment of locally advanced gynecological cancers relies mainly on platinum-based concurrent chemoradiotherapy followed by brachytherapy. Current chemotherapeutic drugs are only transiently effective and patients with advanced disease often develop resistance and subsequently, distant metastases despite significant initial responses of t...

Background: Several techniques can be proposed as fertility sparing surgery in young patients treated for cervical cancer but uncertaincies remain concerning their outcomes. Analysis of oncological issues is then the first aim of this review in order to evaluate the best strategy. Results: Data were identified from searches of MEDLINE, Current C...

Background: Following disappointing results with PD-1/PD-L1 inhibitors in ovarian cancer, it is essential to explore other immune targets. The aim of this study is to describe the tumor immune microenvironment (TME) according to genomic instability in high grade serous ovarian carcinoma (HGSOC) patients receiving primary debulking surgery followed...

Background There are limited treatment options for ovarian cancer patients with early relapse after platinum chemotherapy. In preclinical studies, we previously demonstrated the promising activity of ABT-737, a Bcl-2/Bcl-xL anti-apoptotic protein inhibitor, in chemo-resistant ovarian cancer cells and tumors, suggesting its potential activity in pla...

Background: Endometrial Cancer (EC) is molecularly classified into the POLE-mutated (POLEmut), mismatch-repair deficient (MMRd), p53 abnormal (p53abn) and no specific molecular profile (NSMP) subgroups. We aimed to develop an interpretable DL pipeline for image-based prediction of the four-class molecular EC classification (im4MEC), to identify mor...

Ovarian cancer (OC) is the most lethal gynecologic malignancy, affecting approximately 1 in 70 women with only 45% surviving 5 years after diagnosis. This disease typically presents at an advanced stage, and optimal debulking with platinum-based chemotherapy remains the cornerstone of management. Although most ovarian cancer patients will respond e...

B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid structures (TLS). Here, we investigated the role of B-cells and TLS in endometrial cancer (EC). Single cell RNA-sequencing of B-cells showed presence of naïve B-cells, cycling/germinal center B-cells and antibody-secreting cells. Differential gene expre...

Résumé Dans les stades précoces, le traitement adjuvant standard est une chimiothérapie, consistant en une association à base de platine pour une durée de 6 cycles dans les carcinomes séreux et endométrioïdes de haut grade. Dans les stades avancés, la chimiothérapie néoadjuvante doit être discutée au cas par cas en réunion de concertation pluridisc...

Objectives ARIEL3 is a placebo-controlled randomized trial of the PARP inhibitor (PARPi) rucaparib as maintenance treatment in HGOC patients who responded to the latest line of platinum therapy (NCT01968213). Rucaparib improved progression-free survival (PFS) across all predefined subgroups. Here, we present an exploratory analysis of characteristi...

Objectives Globally, cervical cancer is a leading cause of death. Lack of international consensus on standard-of-care (SoC) treatment for locally advanced cervical cancer (LACC) (Stages IB2-IVA) may contribute to inconsistent treatment. We compared LACC treatment recommendations from international guidelines. Methods Literature databases (1999–202...

Objective Maintenance olaparib provided a progression-free survival benefit in the phase III SOLO2 trial (NCT01874353) in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (BRCAm). However, questions remain regarding tumor versus germline BRCA testing and the impact of heterozygous versus bi-allelic loss of BRCA1 or BRCA2...

Background There is a medical need in platinum resistant ovarian cancer patients. Median progression-free survival (PFS) is 3.4 months with chemotherapy and 6.7 months with chemotherapy-bevacizumab combination regimens. ¹ RECIST overall response rate (ORR) is 11.8% and 27.3%, respectively. The ORR is 15.9% for bevacizumab as a monotherapy with a me...

(Abstracted from Lancet Oncol 2021;22:1034–1046) The majority of patients with ovarian cancer will experience relapse and develop platinum-resistant disease after being treated with frontline platinum-based chemotherapy. Treatment options for platinum-resistance or platinum-refractory disease are very limited, usually involving nonplatinum chemothe...

Objective: Tropomyosin-related kinase B receptor (TrkB) is a receptor tyrosine kinase (RTK) that regulates the follicular growth and oocyte survival in the ovaries and is overexpressed in various cancers. Previously, we reported the increased expression of the TrkB isoform with tyrosine kinase (TrkB-TK) in Japanese clear cell ovarian cancer (CCOC)...

Résumé L’évolution des connaissances en oncologie gynécologique conduit progressivement vers une désescalade chirurgicale dans plusieurs domaines, notamment dans celui de la chirurgie ganglionnaire. L’indication du ganglion sentinelle (GS) dans le cancer de l’endomètre, initialement réservé aux risques bas et intermédiaire, est maintenant élargie à...

Background Clear cell borderline ovarian tumor (CCBOT) is one of the rarest subtypes of borderline ovarian malignancies. The aim of this study was to determine the prognosis of a series of CCBOT.Patients and MethodsA retrospective review of patients with CCBOT treated or referred to our institutions. A centralized histological review by a reference...

Introduction/Background* From our previously conducted global systematic literature review (SLR) assessing recommended treatment for locally advanced cervical cancer (LACC) it was observed that there was international consensus on the use of concurrent chemoradiotherapy (cCRT) as standard of care (SoC) for Stage IIB-IVA LACC, but recommendations fo...

Introduction/Background* Most frequent borderline ovarian tumors are serous and mucinous subtypes. Less frequent borderline diseases are endometrioid, clear cell and Brenner tumors (BBOT). Very few are known about this later subtype and most of reports concerns very short series or case reports. The aim of this study was to determine the prognosis...

Introduction/Background* The TransPORTEC Consortium was established in 2013 by the PIs and translational science representatives of the PORTEC-3 trial groups from the Netherlands, United Kingdom, Australia, Canada and France. Purpose of the collaboration is to improve treatment of endometrial cancer (EC) patients. Here, we evaluate our experience w...

Introduction/Background* The identification of factors responsible for false negative (FN) rate at 18F- Fluorodeoxyglucose (FDG) Positron Emission Tomography/Computed Tomography (PET/CT) in para-aortic (PA) lymph nodes in the presurgical staging of patients with locally advanced cervical cancer (LACC) is challenging. The aim of this study was to ev...

Introduction/Background* The molecular endometrial cancer (EC) classification has proven prognostic value and can direct adjuvant treatment decisions. Despite this, a relatively large group of EC is still molecularly unclassified (NSMP-EC). In this study we aimed to identify biomarkers among high-risk NSMP-EC patients with prognostic and/or predict...

Introduction/Background* In the randomized phase 3 JAVELIN Ovarian 200 trial (N=566), avelumab alone or combined with pegylated liposomal doxorubicin (PLD) did not significantly prolong progression-free survival (PFS; blinded independent central review) or overall survival (OS) vs PLD alone in patients with platinum-resistant/refractory ovarian can...

Introduction/Background* As stated by ESGO-ESMO, there is a need for indicators of chemotherapy efficacy in ovarian carcinoma patients treated in first-line setting (Colombo et al, IGCS, 2020). The pathological chemotherapy response score (CRS) and the modeled CA-125 KELIM during neo-adjuvant chemotherapy were reported as potential markers. Moreove...

Introduction/Background* In the randomized phase 3 JAVELIN Ovarian 200 trial (N=566), avelumab alone or combined with pegylated liposomal doxorubicin (PLD) did not significantly prolong progression-free survival (PFS; blinded independent central review) or overall survival (OS) vs PLD alone in patients with platinum-resistant/refractory ovarian can...

Introduction/Background* Most frequent borderline ovarian tumors are serous and mucinous subtypes. Clear Cell Borderline Ovarian Tumor (CCBOT) is one of the rarest subtypes of borderline ovarian malignancies. Very few are known about this subtype and most of reports concerns very short series or case reports. The aim of this study was to determine...

Introduction/Background* The aim of this study was to investigate the relation between the PCI and overall survival (OS) and recurrence-free survival (RFS). The peritoneal cancer index (PCI) is one of the main prognostic factor for the evaluation of ovarian peritoneal carcinosis. Different thresholds have been reported in terms of prognosis and to...

Introduction/Background* Tertiary lymphoid structures (TLS) are ectopic lymphoid tissues that form in and around cancers. TLS consist of a germinal centre (GC) with proliferating B-cells and follicular dendritic cells (FDCs), as well