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Recurrent cervical cancer; Combination therapy; Immunotherapy Cáncer cervical recurrente; Terapia de combinación; Inmunoterapia Càncer cervical recurrent; Teràpia combinada; Immunoteràpia Introduction: Recurrent or primary advanced metastatic cervical cancer (R/M CC) has a poor prognosis with a 5-year-survival rate of 16.5%, demanding novel and improved therapies for the treatment of these patients. The first-line standard of care for R/M CC now benefits from the addition of the immune checkpoint inhibitor, pembrolizumab, to platinum-based chemotherapy with paclitaxel and bevacizumab. Additionally, new options for second-line treatment have become available in recent years. Areas covered: Here, we review current investigational drugs and discuss their relative targets, efficacies, and potential within the R/M CC treatment landscape. This review will focus on recently published data and key ongoing clinical trials in patients with R/M CC, covering multiple modes of action, including immunotherapies, antibody-drug conjugates, and tyrosine kinase inhibitors. We searched clinicaltrials.gov for ongoing trials and pubmed.ncbi.nih.gov for recently published trial data, as well as recent years' proceedings from the annual conferences of the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), European Society of Gynaecological Oncology (ESGO), and the International Gynecologic Cancer Society (IGCS). Expert opinion: Therapeutics currently attracting attention include novel immune checkpoint inhibitors, therapeutic vaccinations, antibody-drug conjugates, such as tisotumab vedotin, tyrosine kinase inhibitors targeting HER2, and multitarget synergistic combinations.

BACKGROUND: PAOLA-1/ENGOT-ov25 (NCT02477644) demonstrated a significant progression-free survival (PFS) benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in newly diagnosed, advanced ovarian cancer. We report the prespecified main second progression-free survival (PFS2) analysis for PAOLA-1. METHODS: This randomised, double-blind, phase III trial was conducted in 11 countries. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were in response after first-line platinum-based chemotherapy plus bevacizumab. Patients were randomised 2:1 to olaparib (300 mg twice daily) or placebo for up to 24 months; all patients received bevacizumab (15 mg/kg every 3 weeks) for up to 15 months. Primary PFS end-point was reported previously. Time from randomisation to second disease progression or death was a key secondary end-point included in the hierarchical-testing procedure. RESULTS: After a median follow-up of 35.5 months and 36.5 months, respectively, median PFS2 was 36.5 months (olaparib plus bevacizumab) and 32.6 months (placebo plus bevacizumab), hazard ratio 0.78; 95% confidence interval (CI) 0.64-0.95; P = 0.0125. Median time to second subsequent therapy or death was 38.2 months (olaparib plus bevacizumab) and 31.5 months (placebo plus bevacizumab), hazard ratio 0.78; 95% CI 0.64-0.95; P = 0.0115. Seventy-two (27%) patients in the placebo plus bevacizumab group received a poly(ADP-ribose) polymerase inhibitor as first subsequent therapy. No new safety signals were observed for olaparib plus bevacizumab. CONCLUSION: In newly diagnosed, advanced ovarian cancer, maintenance olaparib plus bevacizumab provided continued benefit beyond first progression, with a significant PFS2 improvement and a time to second subsequent therapy or death delay versus placebo plus bevacizumab. ispartof: EUROPEAN JOURNAL OF CANCER vol:174 pages:221-231 ispartof: location:England status: published

BackgroundWhile great advances in clinical and pathological description of tenosynovial giant cell tumors (TGCT) have been made, TGCT molecular heterogeneity represents an ongoing challenge. The canonical oncogenic fusion CSF1::COL6A3 is not systematically observed, suggesting that other oncogenic mechanisms are involved in tumorigenesis. This study aims to explore by RNA sequencing a retrospective series of tumors diagnosed as TGCT, in order to provide a better description of their molecular landscape and to correlate molecular features with clinical data.MethodsWe analyzed clinicopathological data and performed whole-exome RNA sequencing on 41 TGCT samples.ResultsRNAseq analysis showed significant higher CSF1 and CSF1-R expression than a control panel of 2642 solid tumors. RNA sequencing revealed fusion transcripts in 14 patients including 6 not involving CSF1 and some previously unreported fusions. Unsupervised clustering on the expression profiles issued from this series suggested two distinct subgroups: one composed of various molecular subtypes including CSF1 and FN1 rearranged samples and one composed of four tumors harboring an HMGA2::NCOR2 fusion, suggesting distinct tumor entities. Overall, 15 patients received at least one systemic anti-CSF1R treatment and clinical improvement was observed in 11 patients, including patients from both clusters.DiscussionThis study reported molecular heterogeneity in TGCT, contrasting with the clinical and pathological homogeneity and the ubiquitous high CSF1 and CSF1R expression levels. Whether molecular diversity may impact the efficacy of systemic treatments needs to be further investigated.

Additional file 1. Black-box model. Displays the results from the black-box model, which consists of a probit model with instrumented hospital volume, are indicative of the causal impact of hospital volume on outcomes.

Additional file 2. Propensity score analysis. Displays the results from a propensity score analysis, used as a robustness check. Use of a propensity score is indeed an alternative approach to an instrumental variable to estimate a causal effect in the presence of selection bias, which is based on different theoretical assumptions regarding the selection process.

Additional file 3. Share of patients that had at least ���N��� hospitals treating gynecologic cancer to choose from in a radius of ���K��� kilometers. Displays the share of patients that had at least ���N��� hospitals treating gynecologic cancer to choose from in a radius of ���K��� kilometers around the municipalities.

Additional file 4. Patient and municipality characteristics. Provides a comparison of patient and municipality characteristics between patients treated in low- and high-volume providers.

Contains fulltext : 218867.pdf (Publisher’s version ) (Closed access) AGO-OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front-line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression-free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB-IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m(2) ) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2-21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83-1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh-risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75-0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports.

The use of radiolabeled non-natural amino acids can provide high contrast SPECT/PET metabolic imaging of solid tumors. Among them, radiohalogenated tyrosine analogs (i.e., [123I]IMT, [18F]FET, [18F]FDOPA, [123I]8-iodo-L-TIC(OH), etc.) are of particular interest. While radioiodinated derivatives, such as [123I]IMT, are easily available via electrophilic aromatic substitutions, the production of radiofluorinated aryl tyrosine analogs was a long-standing challenge for radiochemists before the development of innovative radiofluorination processes using arylboronate, arylstannane or iodoniums salts as precursors. Surprisingly, despite these methodological advances, no radiofluorinated analogs have been reported for [123I]8-iodo-L-TIC(OH), a very promising radiotracer for SPECT imaging of prostatic tumors. This work describes a convenient synthetic pathway to obtain new radioiodinated and radiofluorinated derivatives of TIC(OH), as well as their non-radiolabeled counterparts. Using organotin compounds as key intermediates, [125I]5-iodo-L-TIC(OH), [125I]6-iodo-L-TIC(OH) and [125I]8-iodo-L-TIC(OH) were efficiently prepared with good radiochemical yield (RCY, 51–78%), high radiochemical purity (RCP, >98%), molar activity (Am, >1.5–2.9 GBq/µmol) and enantiomeric excess (e.e. >99%). The corresponding [18F]fluoro-L-TIC(OH) derivatives were also successfully obtained by radiofluorination of the organotin precursors in the presence of tetrakis(pyridine)copper(II) triflate and nucleophilic [18F]F− with 19–28% RCY d.c., high RCP (>98.9%), Am (20–107 GBq/µmol) and e.e. (>99%).

PurposeGene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features.Experimental designAdopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting.ResultsGene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations.ConclusionsWe validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications.See related commentary by McMullen et al., p. 5271.

Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and highly aggressive ovarian malignancy. In almost all cases, it is associated with somatic and often germline pathogenic variants in SMARCA4, which encodes for the SMARCA4 protein (BRG1), a subunit of the SWI/SNF chromatin remodeling complex. Approximately 20% of human cancers possess pathogenic variants in at least one SWI/SNF subunit. Because of their role in regulating many important cellular processes including transcriptional control, DNA repair, differentiation, cell division, and DNA replication, SWI/SNF complexes with mutant subunits are thought to contribute to cancer initiation and progression. Fewer than 500 cases of SCCOHT have been reported in the literature and approximately 60% are associated with hypercalcemia. SCCOHT primarily affects females under 40 years of age who usually present with symptoms related to a pelvic mass. SCCOHT is an aggressive cancer, with long-term survival rates of 30% in early-stage cases. Although various treatment approaches have been proposed, there is no consensus on surveillance and therapeutic strategy. An international group of multidisciplinary clinicians and researchers recently formed the International SCCOHT Consortium to evaluate current knowledge and propose consensus surveillance and therapeutic recommendations, with the aim of improving outcomes. Here, we present an overview of the genetics of this cancer, provide updates on new treatment targets, and propose management guidelines for this challenging cancer.

Additional file 1: Table S1. Treatment modalities. BSC: best supportive care; MD: missing data; SRS: stereotactic radiosurgery; WBRT: whole-brain radiotherapy

Additional file 2: Table S2. Treatment modalities per histology group BSC: best supportive care; SRS: stereotactic radiosurgery; WBRT: whole-brain radiotherapy.

Additional file 4: Figure S3. Sarcoma trends and annual percentage change (APC) of world age-standardized incidence rate according to topographic group. FRANCIM network data 2000–2013 (11 registries).

Additional file 1. Complementary information on data collection and statistical analyses.

Additional file 5: Figure S4. Sarcoma trends and annual percentage change (APC) of world age-standardized incidence rate according to histologic group. FRANCIM network data 2000–2013 (11 registries).

Additional file 2: Figure S1. Age-specific incidence rates of sarcomas per 100,000 person-years according to histologic groups. FRANCIM network data 2010–2013 (19 registries).

Additional file 3: Figure S2. Age-specific incidence rates of sarcomas per 100,000 person-years according to genomic groups. FRANCIM network data 2010–2013 (19 registries).

Figure S2. Baseline biomarker values according to medical history (de novo versus radio-induced angiosarcoma). (PPTX 290 kb)

Figure S1. Location map of the tumors in each treatment arm (A/B). (PPTX 117 kb)

Figure S3. Forest plot: evaluation of the predictive value of clinical factors and biomarkers for the treatment effect in terms of PFS. Biomarkers were categorized as binary variables using the observed median value as the cut-off to illustrate the results. (PPTX 415 kb)

Common support of the distribution of the propensity score. Displays the distribution of the propensity score for treated and untreated patients (threshold of 12 cases). The common support seems to be sufficient to allow for use of the matching method. (PDF 6Â kb)

Table S1. All Grade ≥ 3 drug-related adverse events. (DOCX 13 kb)

Log-Log progression free survival curves comparing LVH and HVH. Displays the log-log survival curves (threshold of 12 cases), which are a transformation of the standard Kaplan Meier estimator. These curves can be used to test the proportional hazard assumption. Indeed, the hazard is proportional if the two curves look parallel, meaning that the hazard ratio is constant over time. In our case, the two curves doesnâ t looks parallel and even cross each other at the bottom right of the plot, meaning that the hazard is not proportional. (PDF 77Â kb)

In this work, we aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in patients with ovarian cancer who were treated within the phase III randomized European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG) 55041 study comparing erlotinib with observation in patients with no evidence of disease progression after first-line platinum-based chemotherapy. Somatic mutations in KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN were determined in 318 (38 %) and expression of EGFR, pAkt, pMAPK, E-cadherin and Vimentin, and EGFR and HER2 gene copy numbers in 218 (26 %) of a total of 835 randomized patients. Biomarker data were correlated with progression-free survival (PFS) and overall survival (OS). Only 28 mutations were observed among KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN (in 7.5 % of patients), of which the most frequent were in KRAS and PIK3CA. EGFR mutations occurred in only three patients. When all mutations were pooled, patients with at least one mutation in KRAS, NRAS, BRAF, PIK3CA, or EGFR had longer PFS (33.1 versus 12.3 months; HR 0.57; 95 % CI 0.33 to 0.99; P = 0.042) compared to those with wild-type tumors. EGFR overexpression was detected in 93 of 218 patients (42.7 %), and 66 of 180 patients (36.7 %) had EGFR gene amplification or high levels of copy number gain. Fifty-eight of 128 patients had positive pMAPK expression (45.3 %), which was associated with inferior OS (38.9 versus 67.0 months; HR 1.81; 95 % CI 1.11 to 2.97; P = 0.016). Patients with positive EGFR fluorescence in situ hybridization (FISH) status had worse OS (46.1 months) than those with negative status (67.0 months; HR 1.56; 95 % CI 1.01 to 2.40; P = 0.044) and shorter PFS (9.6 versus 16.1 months; HR 1.57; 95 % CI 1.11 to 2.22; P = 0.010). None of the investigated biomarkers correlated with responsiveness to erlotinib. In this phase III study, increased EGFR gene copy number was associated with worse OS and PFS in patients with ovarian cancer. It remains to be determined whether this association is purely prognostic or is also predictive.

Characteristics of included sarcomas. (DOCX 15 kb)

Cause of death. (DOCX 35 kb)

Characteristics of included sarcomas. (DOCX 15 kb)

Additional file 2. CNIL (Comité National d’Information et Libertés) French committee in charge of watching that the computing is in the service of the citizen and that it strikes a blow neither at the human identity, nor at the human rights, nor at the private life, nor at the personal or public freedoms.

Additional file 1. CCTIRS (Comité Consultatif sur le traitement de l’information en matière de recherché dans le domaine de la santé) approved the relevance of the personal name specific data with regard to the objective of the research.

Cause of death. (DOCX 35 kb)

Contains fulltext : 139063.pdf (Publisher’s version ) (Closed access)

Characteristics of currently used antibodies. (DOC 33 kb)

International audience; BACKGROUND: Metastatic soft tissue sarcoma (STS) prognosis remains poor and few cytotoxic agents offer proven efficacy. This randomized open phase III study examines whether high-dose (HD) chemotherapy with peripheral blood stem cells (PBSCs) could improve overall survival (OS) of chemosensitive patients. PATIENTS AND METHODS: Advanced STS patients aged 18-65 years received four courses of standard mesna, adryamycin, ifosfamide and dacarbazine (MAID) treatment. Chemotherapy-responding patients and patients with at least stable disease amenable to complete surgical resection were randomized to receive standard dose (SD) with two successive MAID cycles or HD treatments of one MAID then MICE intensification: mesna (3.6 g/m(2), day 1-5), ifosfamide (2.5 g/m(2), day 1-4), carboplatin [area under the curve (AUC) 5/day 2-4] and etoposide (300 mg/m(2), day 1-4) with PBSC reinjection at day 7. RESULTS: From 2000 to 2008, 207 patients received four cycles of MAID and 87 assessable patients were randomly assigned to receive the following: 46 SD, 41 HD, with 45 and 38 maintained for analyses after secondary centralized histological review. Futility analyses led to study closure in November 2008. Three-year OS was 49.4% for the SD group versus 32.7% for HD arm, hazard ratio= 1.26, 95% confidence interval 0.70-2.29; progression-free survival was 32.4% and 14.0%, respectively. HD treatment led to higher grades 3-4 toxicity. CONCLUSION: This study failed to show an OS advantage for advanced STS patients treated with dose-intensified chemotherapy with PBSC.

Background: Total and CD4 lymphopenia is observed in 25% of advanced cancers patients and is a predictive factor of chemotherapy (CT)-induced death, febrile neutropenia, thrombocytopenia, anemia, as well as an independent prognostic factor for survival and tumor progression. CYT107 is a glycosylated recombinant human IL-7 (CYTHERIS, France) emerging as a promising immuno-restorative agent well tolerated in Phase 1 trials. To date, it is unknown whether IL-7 can correct lymphopenia during CT and whether this could translate into clinical benefit in advanced cancer patients. Methods: A placebo-controlled, monocentric, Phase 2a (NCT01368107) was conducted in lymphopenic metastatic breast cancer (MBC) patients to be treated by capecitabine (2500mg/m2/d, pers os, 21-day cycle from D21 after randomization). Using a 2x2 factorial design, patients were randomly allocated to 4 arms to receive 1) before the 1st cycle of CT : r-hIL-7 (CYT107:10µg/kg, subcutaneously, weekly at D0, D7, D14, groups 2 & 4) or placebo (groups 1 & 3), then 2) during the 3rd cycle of CT: r-hIL-7 (weekly at D57, D64, D71, groups 3 & 4) or placebo (groups 1 & 2). The primary endpoint, CD4 count evolution, was evaluated before (D0 to D21) and during CT (D57 to D78). Secondary endpoints include risks of severe hematological AE, safety and progression free survival (PFS). An ancillary study has evaluated the quantitative and functional changes in circulating immune cells (see abstract Ménétrier-Caux). Results: From Nov. 2011 to Jun. 2013, 20 patients (median age [range]: 60 [39-76 y.]; median CD4 count on D0: 242 [22-522 cells/µL]) with MBC (mainly with bone and liver metastasis) were enrolled. Before CT (n=20), r-hIL-7 treatment induced a significant increase of CD4 count (median relative evolution: +148.1% [41.8-763.9 cells/µL] in r-hIL-7 groups vs +9.9% [-50.3-102.2 cells/µL] in placebo [Wilcoxon, p=0.002]). During CT (n=11), r-hIL-7 treatment also increased CD4 count (+58.6%[-15.2-281.5 cells/µL] in r-hIL-7 groups vs -2.4% [-27.6-112.5 cells/µL] in placebo [p=0.121]). Overall, r-hIL-7 was well tolerated with reactions related to injection as the main specific AE, no binding or neutralizing antibodies, and no r-hIL-7-related ≥ Grade 3 AE except 1 fatal SAE for which one a relationship to r-hIL-7 cannot be ruled out. Interestingly, r-hIL-7 treatment during CT reduced the incidence of Grade 3 hematological AE compared to placebo (0 vs 5 events, respectively). PFS data will be available by Feb. 2014. Conclusion: In this exploratory trial, r-hIL-7 treatment was safe at biologically active dose, able to correct CD4 lymphopenia and associated with lower incidence of severe hematological toxicity during CT. These early results are encouraging and warrant further investigations of IL-7 clinical applications in the oncology field. Citation Format: Ray-Coquard Isabelle, Olivier Tredan, Gwenaele Garin, Christine Ménétrier-Caux, Sylvie Chabaud, Thomas Bachelot, Claire Cropet, Pierre-Etienne Heudel, Paul Rebattu, Patricia Dupont, Estelle Verronese, Anne-claire Cadore, Valérie Fouillat, Olfa Derbel, Nathalie Bonnin, Thérèse Croughs, Michel Morre, Nicolas Pasqual, Manuari Manuel, Gilles Clapisson, Christophe Caux, David Pérol, Jean-Yves Blay. Elypse-7: A randomized, placebo-controlled, Phase 2a evaluating the impact of IL-7 immunotherapy on CD4 count, risks of severe haematological toxicity and tumor progression in metastatic breast cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT333. doi:10.1158/1538-7445.AM2014-CT333

Background Aggressive angiomyxoma (AA) is a rare, locally aggressive tumor usually arising from pelvis or perineum, with a high local-recurrence rate after complete surgery. Anecdotal responses to hormone therapy have been reported. In the present study we aimed at studying surgical treatment outcomes and sensitivity to hormone therapy of AA. Materials and Methods We conducted a multicenter, international retrospective effort including patients with AA treated at three European referral centers (Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy and the Italian Rare Cancer Network; Centre Léon Bérard, Lyon, France; and Hospital Universitario Virgen del Rocio, Seville, Spain). Results A total of 36 patients were included. Median follow-up was 51.3 months. Thirty-three patients (92%) underwent complete (R0 + R1) surgery, with a local relapse rate of 50% and a median relapse-free survival of 39 months (95% confidence interval [CI], 27–68.1). Thirteen patients received a first-line systemic treatment with hormone therapy for locally advanced disease, with an overall response rate of 62% and a median progression-free survival of 24.6 months (95% CI, 11.0–39.7). In two patients, adding an aromatase inhibitor (AI) on progression to first-line GnRH agonist (GnRHa) resulted in a new tumor response. Conclusion Our findings confirm that in AA, surgical local control may be challenging, with a significant rate of local relapse despite complete surgery. Hormone therapy is an active treatment option, with a potential of disease control and of being combined with surgery. The addition of an AI to first-line GnRHa could be an effective second-line systemic therapy in premenopausal female patients with AA.