Spatial profiling of ovarian carcinoma and tumor microenvironment evolution under neoadjuvant chemotherapy.

PURPOSE: Immune tumor microenvironment (iTME) determines ovarian cancer development. This study investigates changes in HLA-I expression, CD8+/Foxp3 ratio, CD8+ cells and coregulators density at diagnosis and upon neoadjuvant chemotherapy (NACT), correlating changes with clinical outcomes. EXPERIMENTAL DESIGN: Multiplexed immune profiling and cell clustering analysis was performed on paired matched OC samples to characterize the iTME at diagnosis and under NACT from patients enrolled in the CHIVA trial (NCT01583322). RESULTS: Several immune cells (IC) subsets and immune coregulators were quantified pre-/post-NACT. At diagnosis, patients with higher CD8+ T cells and HLA-1+ enriched tumors were associated with -better outcome. The CD8+/Foxp3+ ratio increased significantly post-NACT in favor of increased immune surveillance and the influx of CD8+ T cells predicted better outcomes. Clustering analysis stratified pre-NACT tumors into 4 subsets: high Binf, enriched in B clusters; high Tinf, low Tinf, according to their CD8+ density; and desert clusters. At baseline, these clusters were not correlated with patient outcomes. Under NACT, tumors segregated into 3 clusters: high BinfTinf, low Tinf and desert. The high BinfTinf, more diverse in IC composition encompassing T, B and NK cell, correlated with improved survival. PD-L1 was rarely expressed, while TIM-3, LAG- and IDO-1 were more prevalent. CONCLUSIONS: Several iTMEs exist during tumor evolution and NACT impact on iTME is heterogeneous. Clustering analysis of patients, unravels several IC subsets within OC and can guide future personalized approaches. Targeting different checkpoints such as TIM-3, LAG-3 and IDO-1, more prevalent than PD-L1, could more effectively harness anti-tumor immunity in this anti-PD-L1 resistant malignancy.

Uterine adenosarcoma: Clinical significance of histological classification and SNP array analysis.

Mullerian adenosarcoma is a rare malignant biphasic tumor. The mesenchymal component may be low or high grade, with or without sarcomatous overgrowth (SO). Little is known about the molecular heterogeneity of these tumors. In this study, we aim to reclassify a large retrospective monocentric cohort of uterine adenosarcomas according to tumor grade and SO, to evaluate the clinical significance of pathological classification and to correlate with copy-number variations inferred from single nucleotide polymorphism array. Of the 67 uterine adenosarcomas, 18 (26.9%) were low grade without SO, 7 (10.4%) low grade with SO, 8 (11.9%) high grade without SO and 34 (50.7%) high grade with SO. SO, necrosis and RMS were more frequent in high grade than low grade adenosarcomas (p < 0.001). Low-rank test showed that recurrence-free survival was significantly shortened in high grade than low grade adenosarcomas (p = 0.035) and SO was associated with shortened overall and recurrence-free survival (p = 0.038 and p = 0.009, respectively). High-grade tumors displayed complex genomic profiles with multiple segmental losses including TP53, ATM and PTEN genes. The median genomic index was significantly higher in high grade than low grade tumors (27 [3-60] vs 5,3 [0-16], p < 0.0001) and was significantly higher in presence of SO in low grade tumors (12,8 [10-16] vs 2,6 [0-10], p = 0.0006). We propose to report sarcomatous overgrowth with the tumor grade for prognostication in adenosarcoma and representative sampling is crucial for evaluation of these histological criteria.

Correlation between peritoneal cancer index and survival in advanced epithelial ovarian cancer with complete resection.

OBJECTIVE: The aim of this study was to investigate the relation between the peritoneal cancer index, overall survival, and recurrence free survival, in patients with epithelial ovarian cancer. METHODS: Patients treated at the Gustave-Roussy Institute between December 2004 and November 2017 for advanced epithelial ovarian cancer in complete resection were included. The correlation between the peritoneal cancer index and survival was studied using statistical modeling. Multivariate analysis was performed with a logistic regression model. RESULTS: Of the 351 patients included, 94 (27%) had initial surgery and 257 (73%) had interval surgery. Median follow-up was 52.7 months (range 47.6-63.9). Median peritoneal cancer index was 10 (range 0-32). The linear model best represented the relationship between peritoneal cancer index and overall survival. Patients with neoadjuvant chemotherapy had a greater instantaneous risk of baseline death than those with initial surgery, as well as a more rapid increase in this risk as the peritoneal cancer index increased. Overall survival and recurrence free survival were better in the initial surgery group (103.4 months (79.1-not reached (NR)) vs 66.5 months (59.1-95.3) and 31.8 months (23.7-48.7) vs 25.9 months (23.2-29), respectively). Risk factors for death were body mass index, peritoneal cancer index, and need for neoadjuvant chemotherapy. CONCLUSION: The peritoneal cancer index is a prognostic indicator, but its linear relationship with survival precluded setting a unique peritoneal cancer index cut-off. Moreover, the prognostic impact of peritoneal cancer index was stronger in the setting of neoadjuvant chemotherapy.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy to Treat Pseudomyxoma Peritonei of Ovarian Origin: A Retrospective French RENAPE Group Study.

BACKGROUND: Ovarian pseudomyxoma peritonei (OPMP) are rare, without well-defined therapeutic guidelines. We aimed to evaluate cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) to treat OPMP. METHODS: Patients from the French National Network for Rare Peritoneal Tumors (RENAPE) database with proven OPMP treated by CRS/HIPEC and with histologically normal appendix and digestive endoscopy were retrospectively included. Clinical and follow-up data were collected. Histopathological and immunohistochemical features were reviewed. RESULTS: Fifteen patients with a median age of 56 years were included. The median Peritoneal Cancer Index was 16. Following CRS, the completeness of cytoreduction (CC) score was CC-0 for 9/15 (60%) patients, CC-1 for 5/15 (33.3%) patients, and CC-2 for 1/15 (6.7%) patients. The median tumor size was 22.5 cm. After pathological review and immunohistochemical studies, tumors were classified as Group 1 (mucinous ovarian epithelial neoplasms) in 3/15 (20%) patients; Group 2 (mucinous neoplasm in ovarian teratoma) in 4/15 (26.7%) patients; Group 3 (mucinous neoplasm probably arising in ovarian teratoma) in 5/15 (33.3%) patients; and Group 4 (non-specific group) in 3/15 (20%) patients. Peritoneal lesions were OPMP pM1a/acellular, pM1b/grade 1 (hypocellular) and pM1b/grade 3 (signet-ring cells) in 13/15 (86.7%), 1/15 (6.7%) and 1/15 (6.7%) patients, respectively. Disease-free survival analysis showed a difference (p = 0.0463) between OPMP with teratoma/likely-teratoma origin (groups 2 and 3; 100% at 1, 5, and 10 years), and other groups (groups 1 and 4; 100%, 66.6%, and 50% at 1, 5, and 10 years, respectively). CONCLUSION: These results suggested that a primary therapeutic strategy using complete CRS/HIPEC for patients with OPMP led to favorable long-term outcomes.

Integration of the Molecular Classification of Endometrial Carcinoma to Select Patients for Fertility Sparing Strategies.

Fertility-sparing treatment (FST) for endometrial carcinoma (EC) is an option for a subgroup of young women with low-risk disease. The low-risk group comprises patients with endometrioid EC stage IA, grade 1, with or without focal lymphovascular invasion. In the era of molecular subtyping, treatment de-escalation for some EC subtypes is recommended. Recommendations for fertility-preserving treatments were developed regardless of the molecular classification of EC. However, few studies have focused on this topic. In this review, we summarize the actual data available in the literature and discuss the impact of some molecular subtypes of FST.

[Current post-surgical treatment strategies in first-line ovarian cancer]. / Stratégies thérapeutiques post-chirurgicales actuelles dans les cancers de l'ovaire en première ligne de traitement.

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) stage I and II tumors, with some exceptions. For FIGO stage III/IV tumors, carboplatin- and paclitaxel-based chemotherapy are the standard of care, in combination with targeted therapies, especially bevacizumab and/or poly-(ADP-ribose) polymerase inhibitors, that have become a key milestone of first-line treatment. Our decision making for the maintenance therapy is based on the FIGO stage, tumor histology, timing of surgery (i.e. primary or interval debulking surgery), residual tumor, response to chemotherapy, BRCA mutation and homologous recombination (HR) status.

[Diagnosis of uterine sarcomas and rare uterine mesenchymal tumours with malignant potential. Guidelines of the French Sarcoma Group and Rare Gynaecological Tumours]. / Diagnostic des sarcomes utérins et tumeurs mésenchymateuses utérines rares à potentiel de malignité. Référentiels du Groupe Sarcome Français et des Tumeurs Rares Gynécologiques.

The landscape of uterine sarcomas is becoming more complex with the description of new entities associated with recurrent driver molecular alterations. Uterine sarcomas, in analogy with soft tissue sarcomas, are distinguished into complex genomic and simple genomic sarcomas. Leiomyosarcomas and undifferentiated uterine sarcomas belong to complex genomic sarcomas group. Low-grade and high-grade endometrial stromal sarcomas, other rare tumors associated with fusion transcripts (such as NTRK, PDGFB, ALK, RET ROS1) and SMARCA4-deficient uterine sarcoma are considered simple genomic sarcomas. The most common uterine sarcoma are first leiomyosarcoma and secondly endometrial stromal sarcomas. Three different histological subtypes of leiomyosarcoma (fusiform, myxoid, epithelioid) are identified, myxoid and epithelioid leiomyosarcoma being more aggressive than fusiform leiomyosarcoma. The distinction between low-grade and high-grade endometrial stromal sarcoma is primarily morphological and immunohistochemical and the detection of fusion transcripts can help the diagnosis. Uterine PEComa is a rare tumor, which is distinguished into borderline and malignant, according to a risk assessment algorithm. Embryonal rhabdomyosarcoma of the uterine cervix is more common in children but can also occur in adult women. Embryonal rhabdomyosarcoma of the uterine cervix is almost always DICER1 mutated, unlike that of the vagina which is wild-type DICER1, and adenosarcoma which can be DICER1 mutated but with less frequency. Among the emerging entities, sarcomas associated with fusion transcripts involving the NTRK, ALK, PDGFB genes benefit from targeted therapy. The integration of molecular data with histology and clinical data allows better identification of uterine sarcomas in order to better treat them.

Factors associated with the collection of isolated immature oocytes during ovarian tissue cryopreservation.

PURPOSE: To identify patient characteristics associated with successful isolated immature oocyte retrieval (IsO) during ovarian tissue cryopreservation (OTC) and to determine whether they are predictive of the collection of larger numbers of oocytes. METHODS: We retrospectively analyzed all patients undergoing OTC with IsO for fertility preservation over three years of activity at a university hospital. Univariate and multivariate analyses were used to identify the patients with the highest and lowest chances of oocyte recovery, and those with the largest numbers of oocytes. We also analyzed the correlation of IsO with the number of ovarian fragments collected and histological parameters. RESULTS: We analyzed 257 consecutive patients undergoing these procedures, at a median age of 17.1 years [0.3-38.3 years]. Isolated oocytes were obtained from 47.1% of patients, and IsO was more likely in patients with ovulatory cycles (63.0% vs. 38.6%; P≤ .001), without chemotherapy before OTC (61.4% vs. 33.1; P< .001) and with non-malignant diseases other than Turner syndrome (77.5%). Oocyte collection failure rates were highest in patients with Turner syndrome (OR 25.0, 95% CI 3.99-157.0; P< .001) or undergoing chemotherapy with alkylating agents before OTC (OR 37.6, 95% CI 8.36-168.8; P< .001). Prepubescent status (P= .043) and large numbers of ovarian fragments (P< .001) were associated with the retrieval of larger numbers of oocytes. Oocyte recovery was correlated with the presence of follicles in the medulla, but not with follicular density. CONCLUSION: The chances of IsO differ between patients. Identifying patients with the highest chances of success facilitates appropriate resource allocation.

Validation of the Clinical Use of GIScar, an Academic-developed Genomic Instability Score Predicting Sensitivity to Maintenance Olaparib for Ovarian Cancer.

PURPOSE: The optimal application of maintenance PARP inhibitor therapy for ovarian cancer requires accessible, robust, and rapid testing of homologous recombination deficiency (HRD). However, in many countries, access to HRD testing is problematic and the failure rate is high. We developed an academic HRD test to support treatment decision-making. EXPERIMENTAL DESIGN: Genomic Instability Scar (GIScar) was developed through targeted sequencing of a 127-gene panel to determine HRD status. GIScar was trained from a noninterventional study with 250 prospectively collected ovarian tumor samples. GIScar was validated on 469 DNA tumor samples from the PAOLA-1 trial evaluating maintenance olaparib for newly diagnosed ovarian cancer, and its predictive value was compared with Myriad Genetics MyChoice (MGMC). RESULTS: GIScar showed significant correlation with MGMC HRD classification (kappa statistics: 0.780). From PAOLA-1 samples, more HRD-positive tumors were identified by GIScar (258) than MGMC (242), with a lower proportion of inconclusive results (1% vs. 9%, respectively). The HRs for progression-free survival (PFS) with olaparib versus placebo were 0.45 [95% confidence interval (CI), 0.33-0.62] in GIScar-identified HRD-positive BRCA-mutated tumors, 0.50 (95% CI, 0.31-0.80) in HRD-positive BRCA-wild-type tumors, and 1.02 (95% CI, 0.74-1.40) in HRD-negative tumors. Tumors identified as HRD positive by GIScar but HRD negative by MGMC had better PFS with olaparib (HR, 0.23; 95% CI, 0.07-0.72). CONCLUSIONS: GIScar is a valuable diagnostic tool, reliably detecting HRD and predicting sensitivity to olaparib for ovarian cancer. GIScar showed high analytic concordance with MGMC test and fewer inconclusive results. GIScar is easily implemented into diagnostic laboratories with a rapid turnaround.

DICER1-mutated rhabdomyosarcoma of the ovary with teratoid features.

DICER1-mutated rhabdomyosarcoma is a rare, emerging entity with a predilection for the gynecologic and genitourinary tracts. We report here a case of DICER1-mutated rhabdomyosarcoma of the ovary in a 14 years old girl which displayed interspersed mature teratoid glands, neuroectodermal rosettes and immature blastematous-like tubes. Morphologically the sarcomatous component predominated, corresponding to a high grade spindle cell rhabdomyosarcoma with botryoid features. Islets of cartilage were present. The sarcomatous proliferation encased the teratoid glands, forming cambium layer-like arrangements. The sarcoma cells were Myogenin and MYOD1 positive, the neuroectodermal rosettes expressed SALL4 along with cytokeratins and EMA and were negative for Inhibin; immature blastematous-like tubes were negative for SALL4 and Inhibin. Whole RNA- and targeted DNA-sequencing revealed two DICER1 mutations in exon 26: c.5113G>A: p.(Glu1705Lys) and exon 12: c.1642C>T: p.(Gln548X). The sarcomatous component harbored a complex genetic profile while the teratoid component was diploid, none of the above displayed abnormality of 12p. DICER1-mutated sarcomas display pathological features similar to embryonal rhabdomyosarcomas, botryoid type. They also display heterogeneous features combining cartilage foci, teratoid mature glands, immature blastematous-like tubes and/or neuroectodermal components. Molecular testing remains necessary to confirm the diagnosis. Further studies need to clarify the nosology of DICER1-mutated sarcomas and devise specific therapeutic strategies.

Early-onset gynecological tumors in DNA repair-deficient xeroderma pigmentosum group C patients: a case series.

BACKGROUND: Xeroderma pigmentosum (XP) is a group of rare hereditary disorders with highly increased risk of skin tumors due to defective DNA repair. Recently we reported 34-fold increased risk of internal tumors in XP patients in comparison with general population. The molecular data and clinical practice on the internal tumors treatment in XP patients is limited and scarcely represented in the medical literature. In this work, we describe young patients with constitutive biallelic deactivation of the XPC gene developing gynecological tumors with somatic DICER1 mutations. METHODS: Whole genome sequencing was used to analyze in detail somatic mutational landscape and driver events of these rare tumors. RESULTS: We describe five early-onset gynecological tumors in four xeroderma pigmentosum group C (XP-C) young patients (11 to 19 years old) including vaginal embryonal rhabdomyosarcomas in monozygotic twin sisters, juvenile granulosa-cell tumor of the ovary and poorly differentiated stage IA Sertoli-Leydig cell tumor in 19-years old patient, and FIGO stage IC1 tumor of ovary in 13-years old patient. XP-C ovarian tumors harbor 4.4 times more single base substitutions than sporadic tissue-matched cancers and demonstrate XP-C specific mutation signature with strong transcriptional bias indicating inability of the cells to repair bulky DNA lesions of unknown etiology. A special mode of treatment was applied to avoid usage of chemotherapy which is toxic for XP patients. CONCLUSIONS: XP-C status should be accounted for prevention and specific treatment of gynecological tumors in young DNA repair-deficient XP patients.

Xeroderma pigmentosum group C (XP-C) is a rare inherited disorder resulting in a highly increased risk of skin and internal cancers due to the inability to efficiently repair DNA. In this study, we described four young XP-C patients who developed early-onset tumors affecting the female reproductive organs. We describe how we cared for these patients in the clinic. We looked at the genetic material within the tumors to better understand the mechanisms through which these tumors developed. We observed high numbers of specific types of changes in DNA, which are not typical for sporadic (non-inherited) gynecological tumors, but are characteristic of internal XP-C tumors. Further studies are needed to better understand the nature of these changes. Our findings highlight the important role of DNA repair in human tissues and cancer risk, and might inform future strategies for tumor prevention in XP-C patients.

A common [18F]-FDG PET radiomic signature to predict survival in patients with HPV-induced cancers.

Locally advanced cervical cancer (LACC) and anal and oropharyngeal squamous cell carcinoma (ASCC and OPSCC) are mostly caused by oncogenic human papillomaviruses (HPV). In this paper, we developed machine learning (ML) models based on clinical, biological, and radiomic features extracted from pre-treatment fluorine-18-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET) images to predict the survival of patients with HPV-induced cancers. For this purpose, cohorts from five institutions were used: two cohorts of patients treated for LACC including 104 patients from Gustave Roussy Campus Cancer (Center 1) and 90 patients from Leeds Teaching Hospitals NHS Trust (Center 2), two datasets of patients treated for ASCC composed of 66 patients from Institut du Cancer de Montpellier (Center 3) and 67 patients from Oslo University Hospital (Center 4), and one dataset of 45 OPSCC patients from the University Hospital of Zurich (Center 5). Radiomic features were extracted from baseline [18F]-FDG PET images. The ComBat technique was applied to mitigate intra-scanner variability. A modified consensus nested cross-validation for feature selection and hyperparameter tuning was applied on four ML models to predict progression-free survival (PFS) and overall survival (OS) using harmonized imaging features and/or clinical and biological variables as inputs. Each model was trained and optimized on Center 1 and Center 3 cohorts and tested on Center 2, Center 4, and Center 5 cohorts. The radiomic-based CoxNet model achieved C-index values of 0.75 and 0.78 for PFS and 0.76, 0.74, and 0.75 for OS on the test sets. Radiomic feature-based models had superior performance compared to the bioclinical ones, and combining radiomic and bioclinical variables did not improve the performances. Metabolic tumor volume (MTV)-based models obtained lower C-index values for a majority of the tested configurations but quite equivalent performance in terms of time-dependent AUCs (td-AUC). The results demonstrate the possibility of identifying common PET-based image signatures for predicting the response of patients with induced HPV pathology, validated on multi-center multiconstructor data.

Recommandations pour la pratique clinique Nice/Saint-Paul-de-Vence 2022­2023 : Prise en charge du cancer du col de l'utérus avancé.

French recommendations for clinical practice, Nice/Saint-Paul-de-Vence 2022-2023: Management of advanced cervical cancer The prognosis of cervical cancer remained pejorative until recently, first-line treatment consisting of platinum-based chemotherapy, associated with bevacizumab whenever possible, without any other therapeutic innovation for several years. However in 2022, immunotherapy appeared in the therapeutic landscape. Pembrolizumab can now be prescribed, thanks to the early access status granted by the HAS in September 2022, in patients with PD-L1 positive tumors. In parallel, bevacizumab generic is now reimbursed, allowing its association with chemotherapy on top of pembrolizumab, if indicated. For patient relapsing after platinium salts, and who never received immunotherapy, cemiplimab could be delivered and reimboursed since spring 2023, whatever could be PD-L1 status. Pretherapeutic work-up includes imaging combining MRI and PET/CT or CT of the chest, abdomen and pelvis, as well as evaluation of PD-L1 status on tumor and immune cells to define the CPS score that will determine eligibility to pembrolizumab treatment (CPS > 1). Possibilities of locoregional treatment depend on individual situations and are discussed on a case-by-case basis in multidisciplinary meetings. Early supportive care is always recommended and inclusion in clinical trials must be systematically considered.

Netrin-1 blockade inhibits tumor associated Myeloid-derived suppressor cells, cancer stemness and alleviates resistance to chemotherapy and immune checkpoint inhibitor.

Drug resistance and cancer relapse represent significant therapeutic challenges after chemotherapy or immunotherapy, and a major limiting factor for long-term cancer survival. Netrin-1 was initially identified as a neuronal navigation cue but has more recently emerged as an interesting target for cancer therapy, which is currently clinically investigated. We show here that netrin-1 is an independent prognostic marker for clinical progression of breast and ovary cancers. Cancer stem cells (CSCs)/Tumor initiating cells (TICs) are hypothesized to be involved in clinical progression, tumor relapse and resistance. We found a significant correlation between netrin-1 expression and cancer stem cell (CSC) markers levels. We also show in different mice models of resistance to chemotherapies that netrin-1 interference using a therapeutic netrin-1 blocking antibody alleviates resistance to chemotherapy and triggers an efficient delay in tumor relapse and this effect is associated with CSCs loss. We also demonstrate that netrin-1 interference limits tumor resistance to immune checkpoint inhibitor and provide evidence linking this enhanced anti-tumor efficacy to a decreased recruitment of a subtype of myeloid-derived suppressor cells (MDSCs) called polymorphonuclear (PMN)-MDSCs. We have functionally demonstrated that these immune cells promote CSCs features and, consequently, resistance to anti-cancer treatments. Together, these data support the view of both a direct and indirect contribution of netrin-1 to cancer stemness and we propose that this may lead to therapeutic opportunities by combining conventional chemotherapies and immunotherapies with netrin-1 interfering drugs.

Combined Tumor-Based BRCA1/2 and TP53 Mutation Testing in Ovarian Cancer.

Somatic/germline BRCA1/2 mutations (m)/(likely) pathogenic variants (PV) (s/gBRCAm) remain the best predictive biomarker for PARP inhibitor efficacy. As >95% of high-grade serous ovarian cancers (HGSOC) have a somatic TP53m, combined tumor-based BRCA1/2 (tBRCA) and TP53 mutation testing (tBRCA/TP53m) may improve the quality of results in somatic BRCAm identification and interpretation of the 'second hit' event, i.e., loss of heterozygosity (LOH). A total of 237 patients with HGSOC underwent tBRCA/TP53m testing. The ratio of allelic fractions (AFs) for tBRCA/TP53m was calculated to estimate the proportion of cells carrying BRCAm and to infer LOH. Among the 142/237 gBRCA results, 16.2% demonstrated a pathogenic/deleterious variant (DEL) gBRCA1/2m. Among the 195 contributive tumor samples, 43 DEL of tBRCAm (22.1%) were identified (23 gBRCAm and 20 sBRCAm) with LOH identified in 37/41 conclusive samples. The median AF of TP53m was 0.52 (0.01-0.93), confirming huge variability in tumor cellularity. Initially, three samples were considered as wild type with <10% cellularity. However, additional testing detected a very low AF (<0.05) in both BRCA1/2m and TP53m, thus reidentifying them as sBRCA1/2m. Combined tBRCA/TP53m testing is rapid, sensitive, and identifies somatic and germline BRCA1/2m. AF TP53m is essential for interpreting sBRCA1/2m in low-cellularity samples and provides indirect evidence for LOH as the 'second hit' of BRCA1/2-related tumorigenesis.

Normalized LST Is an Efficient Biomarker for Homologous Recombination Deficiency and Olaparib Response in Ovarian Carcinoma.

PURPOSE: The efficiency of the Myriad Homologous Recombination Deficiency (HRD) test to guide the use of poly (ADP-ribose) polymerase (PARP) inhibitors has been demonstrated in several phase III trials. However, a need exists for alternative clinically validated tests. METHODS: A novel biomarker for HRD was developed using The Cancer Genome Atlas database and, as part of the ENGOT HRD European Initiative, applied to 469 samples from the PAOLA-1/ENGOT-ov25 trial. Results were compared with the Myriad myChoice Genomic Instability Score (GIS) with respect to the progression-free survival in the olaparib + bevacizumab and placebo + bevacizumab arms. RESULTS: Analysis of the TCGA cohort revealed that a normalization of the number of large-scale state transitions by the number of whole-genome doubling events allows a better separation and classification of HRD samples than the GIS. Analysis of the PAOLA-1 samples, using the Geneva test (OncoScan + nLST), yielded a lower failure rate (27 of 469 v 59 of 469) and a hazard ratio of 0.40 (95% CI, 0.28 to 0.57) compared with 0.37 for Myriad myChoice (BRCAm or GIS+) in the nLST-positive samples. In patients with BRCAwt, the Geneva test identified a novel subpopulation of patients, with a favorable 1-year PFS (85%) but a poor 2-year PFS (30%) on olaparib + bevacizumab treatment. CONCLUSION: The proposed test efficiently separates HRD-positive from HRD-negative patients, predicts response to PARP inhibition, and can be easily deployed in a clinical laboratory for routine practice. The performance is similar to the available commercial test, but its lower failure rate allows an increase in the number of patients who will receive a conclusive laboratory result.

[Uterin adenosarcoma: French Guidelines of the French Sarcoma Group and the Rare Gynecologic Tumor Group]. / Adénosarcomes mullériens de l'utérus ­ référentiels de prise en charge du GSF-GETO/NETSARC+ et du groupe TMRG.

Uterine adenosarcoma is a very rare malignancy defined as a biphasic tumor composed of both benign epithelial component and a malignant sarcoma component. The stage of the disease is determined by the presence of myometrial invasion and the extent of extra-uterine disease. The most important histopronostic factors are the existence of a sarcomatous overgrowth defined by a sarcomatous contingent occupying more than 25 % of the volume of the tumor (directly correlated to the grade of the disease), the presence of a heterologous and/or a high-grade component. Stage I adenosarcomas without sarcomatous overgrowth have a good prognosis, with an overall 5-year survival of up to 80 %. In localized disease, complete surgical removal is recommended. The role of hormone therapy, chemotherapy and adjuvant radiotherapy is not established. If possible, relapses should be re-treated surgically, with the aim of achieving complete resection. In the advanced inoperable or metastatic setting, hormone therapy is an option for low-grade adenosarcomas with estrogen receptor (ER) and progesterone receptor (PR) overexpression. For high-grade tumors, the standard chemotherapies are doxorubicin-based combinations, although an integrated approach of surgery and medical treatment should also be considered in this setting.

Impact of surgery and chemotherapy in ovarian sex cord-stromal tumors from the multicentric Salomé study including 469 patients. A TMRG and GINECO group study.

OBJECTIVE: Identifying prognostic factors and evaluating the impact of adjuvant chemotherapy in patients with sex cord stromal tumors (SCST) is crucial. In this study, we aimed to address these challenges. METHODS: We conducted a retrospective analysis of data from 13 centers of the French Rare malignant gynecological tumors (TMRG) network. We enrolled 469 adult patients with malignant SCST who received upfront surgery since 2011 to July 2015. RESULTS: 75% were diagnosed with adult Granulosa cell tumors, and 23% had another subtype. With a median follow-up of 6.4 years, 154 patients (33%) developed a first recurrence, 82 (17%) two recurrences, and 49 (10%) three recurrences. Adjuvant chemotherapy was administered in 14.7% of patients at initial diagnosis. In relapse, perioperative chemotherapy was administered in 58.5%, 28.2%, and 23.8% of patients, respectively, in the first, second, and third relapse. In the first-line therapy, age under 70 years, FIGO stage, and complete surgery were associated with longer progression-free survival (PFS). Chemotherapy had no impact on PFS in early-stage disease (FIGO I-II). The PFS was similar using BEP or other chemotherapy regimens (HR 0.88 [0.43; 1.81]) in the first-line therapy. In case of recurrence, PFS was statistically prolonged by complete surgery, but perioperative chemotherapy use did not impact PFS. CONCLUSION: Chemotherapy use did not impact survival in the first-line or relapse setting in SCST. Only surgery and its quality demonstrated benefit for PFS in ovarian SCST in any lines of treatment.

Clinical Relevance of BRCA1 Promoter Methylation Testing in Patients with Ovarian Cancer.

PURPOSE: Homologous recombination deficiency (HRD) is closely related to PARP inhibitor (PARPi) benefit in ovarian cancer. The capacity of BRCA1 promoter methylation to predict prognosis and HRD status remains unclear. We aimed to correlate BRCA1 promoter methylation levels in patients with high-grade ovarian cancer to HRD status and clinical behavior to assess its clinical relevance. EXPERIMENTAL DESIGN: This is a retrospective monocentric analysis of patients centrally tested for genomic instability score (GIS) by MyChoice CDx (Myriad Genetics). The detection of BRCA1 promoter methylation and quantification of methylation levels were performed by quantitative droplet digital PCR methodology. High BRCA1 methylation was defined as ≥70% and deemed to be associated with homozygous silencing. RESULTS: Of 100 patients, 11% harbored a deleterious BRCA1/2 mutation. GIS was considered positive (score ≥ 42) for 52 patients and negative for 48 patients. Using a 70% cutoff, 19% (15/79) of BRCA wild-type ovarian cancer had high BRCA1 methylation levels. All of the highly methylated tumors were classified as HRD, achieving a positive predictive value of 100%. We detected 14% (11/79) low-methylated tumors (1%-69%), and all of them were also classified as HRD. Mean GIS was 61.5 for BRCAmut, 66.4 for high-BRCAmeth, 58.9 for low-BRCAmeth, and 33.3 for BRCAwt unmethylated (P < 0.001). Low methylation levels detected in samples previously exposed to chemotherapy appeared to be associated with poor outcome post-platinum. CONCLUSIONS: Patients with ovarian cancer with high levels of BRCA1 hypermethylation are very likely to have high GIS and therefore represent good candidates for PARPi treatment. These results may be highly relevant to other tumor types for HRD prediction. See related commentary by Garg and Oza, p. 2957.