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Purpose: To evaluate atezolizumab combined with platinum-based chemotherapy (CT) followed by maintenance niraparib for late-relapsing recurrent ovarian cancer., Methods: The multicenter placebo-controlled double-blind randomized phase III ENGOT-OV41/GEICO 69-O/ANITA trial (ClinicalTrials.gov identifier: NCT03598270) enrolled patients with measurable high-grade serous, endometrioid, or undifferentiated recurrent ovarian cancer who had received one or two previous CT lines (most recent including platinum) and had a treatment-free interval since last platinum (TFIp) of >6 months. Patients were stratified by investigator-selected carboplatin doublet, TFIp, BRCA status, and PD-L1 status in de novo biopsy and randomly assigned 1:1 to receive either atezolizumab or placebo throughout standard therapy comprising six cycles of a carboplatin doublet followed (in patients with response/stable disease) by maintenance niraparib until progression. The primary end point was investigator-assessed progression-free survival (PFS) per RECIST v1.1., Results: Between November 2018 and January 2022, 417 patients were randomly assigned (15% BRCA- mutated, 36% PD-L1-positive, 66% TFIp >12 months, 11% previous poly [ADP-ribose] polymerase inhibitor after frontline CT, and 53% previous bevacizumab). Median follow-up was 28.6 months (95% CI, 26.6 to 30.5 months). Atezolizumab did not significantly improve PFS (hazard ratio, 0.89 [95% CI, 0.71 to 1.10]; P = .28). Median PFS was 11.2 months (95% CI, 10.1 to 12.1 months) with atezolizumab versus 10.1 months (95% CI, 9.2 to 11.2 months) with standard therapy. Subgroup analyses generally showed consistent results, including analyses by PD-L1 status. The objective response rate (ORR) was 45% (95% CI, 39 to 52) with atezolizumab and 43% (95% CI, 36 to 49) with standard therapy. The safety profile was as expected from previous experience of these drugs., Conclusion: Combining atezolizumab with CT and maintenance niraparib for late-relapsing recurrent ovarian cancer did not significantly improve PFS or the ORR.

Purpose: Prognostic biomarkers remain necessary in sporadic desmoid tumor (DT) because the clinical course is unpredictable. DT location along with gene expression between thoracic and abdominal wall locations was analyzed., Method: Sporadic DT patients (GEIS Registry) diagnosed between 1982 and 2018 who underwent upfront surgery were enrolled retrospectively in this study. The primary endpoint was relapse-free survival (RFS). Additionally, the gene expression profile was analyzed in DT localized in the thoracic or abdominal wall, harboring the most frequent CTNNB1 T41A mutation., Results: From a total of 454 DT patients, 197 patients with sporadic DT were selected. The median age was 38.2 years (1.8-89.1) with a male/female distribution of 33.5/66.5. Most of them harbored the CTNNB1 T41A mutation (71.6 %), followed by S45F (17.8 %) and S45P (4.1 %). A significant worse median RFS was associated with males (p = 0.019), tumor size ≥ 6 cm (p = 0.001), extra-abdominal DT location (p < 0.001) and the presence of CTNNB1 S45F mutation (p = 0.013). In the multivariate analysis, extra-abdominal DT location, CTNNB1 S45F mutation and tumor size were independent prognostic biomarkers for worse RFS. DTs harboring the CTNNB1 T41A mutation showed overexpression of DUSP1, SOCS1, EGR1, FOS, LIF, MYC, SGK1, SLC2A3, and IER3, and underexpression of BMP4, PMS2, HOXA9, and WISP1 in thoracic versus abdominal wall locations., Conclusion: Sporadic DT location exhibits a different prognosis in terms of RFS favoring the abdominal wall compared to extra-abdominal sites. A differential gene expression profile under the same CTNNB1 T41A mutation is observed in the abdominal wall versus the thoracic wall, mainly affecting the Wnt/β-catenin, TGFβ, IFN, and TNF pathways., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.C.G. report institutional research grants from Pharmamar and Karyopharm. D.S.M. reports institutional research grants from PharmaMar, Eisai, Immix BioPharma and Novartis outside the submitted work; travel support from PharmaMar, Eisai, Celgene, Bayer and Pfizer. N.H. reports grants, personal fees and nonfinancial support from PharmaMar, research grants from Eisai, Immix BioPharma and Novartis outside the submitted work and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, Forma, Amgen and Daichii-Sankyo. J.M.B. reports research grants from PharmaMar, Eisai, Immix BioPharma and Novartis outside the submitted work; honoraria for advisory board participation and expert testimony from PharmaMar, honoraria for advisory board participation from Eli Lilly and Company, Bayer and Eisai; and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, Forma, Amgen and Daichii-Sankyo. M.C., M.A.S., A.U., A.L.P., S.B., I.S., L.V., R.R., J.M.T., M.C.G.M., J.C., C.N.H.L., A.R., M.M., J.M.G., J.E.H., R.A., C.A., A.J.F., C.V., J.M.C., L.M.S., J.A.P.F., J.L., D.M. and A. G. have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Periosteal Ewing sarcoma (ES) is an exceedingly rare topographic subtype of the ES. To our knowledge, only 60 patients have been reported in the medical English language literature. It predominantly affects men in the second decade of life and arises in the long tubular bone diaphysis. Periosteal ES rarely develops distant metastases. We report two patients of this rare ES location that were found on the distal tibial shaft and proximal femoral diaphysis of a 21-year-old man and an 8-year-old boy, respectively. Both patients were treated with neoadjuvant chemotherapy, wide resection, and adjuvant chemotherapy. One of our patients had lung metastases at the time of diagnosis and died 5 years later. The other patient presented intramedullary humeral bone metastasis 19 years after diagnosis. There has been no evidence of disease in the 26 years of follow-up. Close follow-up of periosteal ES is recommended because distant metastases may exceptionally occur, even several years after diagnosis., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Our aim was to reach a consensus on the management of the most controversial issues of advanced ovarian cancer., Methods: Nominal group and Delphi techniques were used. A steering committee of 5 experts analyzed current management of advanced ovarian cancer, identified controversies, critically analyzed the evidence, and formulated guiding statements for clinicians. Subsequently, a panel of 15 experts was selected to test agreement with the statements through two Delphi rounds. Items were scored on a 4-point Likert scale from 1 (totally disagree) to 4 (totally agree). In the first and second rounds, consensus was considered if ≥70% of answers pertained to category 1 or category 4., Results: Overall, 112 statements were incorporated in the following areas: 1) biomarkers and hereditary ovarian cancer; 2) first-line treatment; 3) recurrent disease when platinum might be the best option; and 4) post-poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors setting. In the first Delphi round, 37 statements reached consensus and did thus not pass to the second round. After the second round, another 18 statements reached consensus. Forty-six of the consensus were with the agreement and 9 with the disagreement., Conclusion: Through the methodology used, a consensus was reached in approximately half of the statements. The results of this work may be useful in addressing the most controversial issues on the management of advanced ovarian cancer., Competing Interests: Andrés Redondo has received support for the present manuscript from Pharmamar; Consulting fees from Astra-Zeneca, MSD, GSK, Pharmamar, Clovis; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astra-Zeneca, MSD, GSK, Pharmamar, Clovis; Support for attending meetings and/or travel from Astra-Zeneca, Pharmamar, Clovis., (© 2023. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Purpose: To report updated long-term efficacy and safety from the double-blind, placebo-controlled, phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016)., Methods: Patients with newly diagnosed advanced ovarian cancer with complete or partial response (CR or PR) to first-line platinum-based chemotherapy received niraparib or placebo once daily (2:1 ratio). Stratification factors were best response to first-line chemotherapy regimen (CR/PR), receipt of neoadjuvant chemotherapy (yes/no), and homologous recombination deficiency (HRD) status (deficient [HRd]/proficient [HRp] or not determined). Updated (ad hoc) progression-free survival (PFS) data (as of November 17, 2021) by investigator assessment (INV) are reported., Results: In 733 randomised patients (niraparib, 487; placebo, 246), median PFS follow-up was 3.5years. Median INV-PFS was 24.5 versus 11.2months (hazard ratio, 0.52; 95% confidence interval [CI], 0.40-0.68) in the HRd population and 13.8 versus 8.2months (hazard ratio, 0.66; 95% CI, 0.56-0.79) in the overall population for niraparib and placebo, respectively. In the HRp population, median INV-PFS was 8.4 versus 5.4months (hazard ratio, 0.65; 95% CI, 0.49-0.87), respectively. Results were concordant with the primary analysis. Niraparib-treated patients were more likely to be free of progression or death at 4years than placebo-treated patients (HRd, 38% versus 17%; overall, 24% versus 14%). The most common grade ≥ 3 treatment-emergent adverse events in niraparib patients were thrombocytopenia (39.7%), anaemia (31.6%), and neutropenia (21.3%). Myelodysplastic syndromes/acute myeloid leukaemia incidence rate (1.2%) was the same for niraparib- and placebo-treated patients. Overall survival remained immature., Conclusions: Niraparib maintained clinically significant improvements in PFS with 3.5years of follow-up in patients with newly diagnosed advanced ovarian cancer at high risk of progression irrespective of HRD status. No new safety signals were identified., Competing Interests: Declaration of Competing Interest Dr. González-Martín reports support for the manuscript funding from GSK; grants or contracts from GSK and Roche; consulting fees from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Merck Sharp & Dohme, MacroGenics, Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Roche, Sotio, and Sutro; honoraria fees from AstraZeneca, Clovis, GSK, PharmaMar, and Roche; and support for attending meetings from AstraZeneca, GSK, PharmaMar, and Roche. Dr. Pothuri reports institutional grant support from AstraZeneca, Celsion, Genentech/Roche, Karyopharm, Merck, Mersana, GSK, Sutro, Toray, Incyte, Imab, Onconova, VBL Therapeutics, and Clovis Oncology; consulting fees from AstraZeneca, GSK, SeaGen, and Merck; advisory board fees from Eisai, Lily, Merck, Sutro Biopharma, Tesaro/GSK, Astra Zeneca, and GOG Foundation. Dr. Vergote reports institutional payments for corporate sponsorship research from Amgen and Roche and contracted research from Genmab and Oncoinvent AS; institutional consulting fee payments from Amgen (Europe) GmbH, AstraZeneca, Carrick Therapeutics, Clovis Oncology Inc, Deciphera Pharmaceuticals, Elevar Therapeutics, F. Hoffmann–La Roche Ltd, Genmab, GSK, Immunogen Inc, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Oncoinvent AS, Octimet Oncology, Sotio, Verastem Oncology, and Zentalis; consulting fees from Deciphera Pharmaceuticals, Jazz Pharmaceuticals, and Oncoinvent AS; honoraria payments from Agenus, Aksebio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, F. Hoffmann–La Roche Ltd, Genmab, GSK, Immunogen Inc, Jazz Pharmaceuticals, Karyopharm, MSD, Novartis, Novocure, Oncoinvent AS, Seagen, and Sotio; institutional travel support from Amgen, AstraZeneca, MSD, Roche, and Tesaro; advisory board fees from Agenus, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals (2021), Eisai, F. Hoffmann–La Roche Ltd, Genmab, GSK, Immunogen Inc, MSD, Novartis, Novocure, Seagen (2021), and Sotio. Dr. Graybill reports advisory board and speaker fees from GSK. Dr. Lorusso reports personal fees from Amgen, AstraZeneca, Clovis Oncology, Genmab, Immunogen, Merck, and PharmaMar; and grants from Merck and PharmaMar. Dr. McCormick reports advisory role fees from AstraZeneca, Clovis, GSK, ImmunoGen, and Merck. Dr. Freyer reports personal fees from AstraZeneca, Biogaran, Bristol Myers Squibb, Clovis Oncology, MSD, Novartis, Pfizer Inc., Roche Holding AG, S.A.S., and Tesaro; grants from AstraZeneca, Mylan, and Roche Holding AG. Dr. Backes reports personal fees from Agenus, CEC Oncology, Clovis, Eisai, Merck, AstraZeneca and GSK. ImmunoGen, Myriad; grants from Clovis, Eisai, Immunogen, and Merck, Beigene, Natera. Dr. Heitz reports honoraria from Roche, AstraZeneca, GSK, NovoCure, and PharmaMar; advisory board fees from NovoCure; and leadership role with AGO study group. Dr. Redondo reports institutional grants from Eisai, PharmaMar, and Roche; honoraria fees from AstraZeneca, MSD, Clovis, GSK, PharmaMar, and Eisai; advisory board roles at AstraZeneca, MSD, Clovis, GSK, PharmaMar, and Eisai; and travel support from AstraZeneca, GSK, and PharmaMar. Dr. Moore reports personal fees from Abcodia Inc, Fujirebio Diagnostics Inc, and Humphries Pharmaceutical; and institutional grants from Angle Plc. Dr. Vulsteke reports medical writing support to GSK; consulting fees from Atheneum Partners, Bristol Myers Squibb, GSK, Janssen-Cilag, Leo-Pharma, Merck Sharp & Dohme, and Roche; advisory board fees from AstraZeneca, Bayer, GSK, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme; and travel support from Pfizer and Roche. Dr. O'Cearbhaill reports participating in advisory boards with 2seventy bio, Bayer, Carina Biotech, Fresenius Kabi, Immunogen, GSK, Miltenyi Biotec, Regeneron, and Seattle Genetics; personal fees from GOG Foundation; travel fees from Hitech Health and Gathering Around Cancer, Ireland; service as a noncompensated steering committee member for the PRIMA and Moonstone (niraparib) and DUO-O (olaparib) studies; institutional research support grants from Acrivon Therapeutics, AstraZeneca/Merck, Atara Biotherapeutics/Bayer, Genentech, Genmab, GSK, Gynecologic Oncology Group Foundation, Juno Therapeutics, Kite/Gilead, Ludwig Institute for Cancer Research, Lyell Immunopharma, Regeneron, Sellas Life Sciences, StemcentRx, Syndax, TapImmune Inc, and TCR2 Therapeutics. Drs. Malinowska and Shtessel are employees of GSK. Ms. Compton is a former employee of GSK and currently receiving consulting fees from GSK. Dr. Mirza reports consulting and advisory role fees from AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, and Zai Lab; speakers’ bureau fees from AstraZeneca and GSK; institutional research funding from Apexigen, AstraZeneca, Deciphera (trial chair), GSK, and Ultimovacs; and personal financial interest in Karyopharm (stocks/shares, member of board of directors). Dr. Monk reports consulting fees from Agenus, Akeso Bio, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, Macrogenics, Mersana, Myriad, Novocure, Novartis, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, and VBL; and speakers’ bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: the association between ovarian endometriosis (OE) and endometriosis-associated ovarian cancer (EAOC) is extensively documented, and misfunction of the immune system might be involved. The primary objective of this study was to identify and compare the spatial distribution of tumour-infiltrating lymphocytes (TILs) and tumour-associated macrophages (TAMs) in OE and EAOC. Secondary objectives included the analysis of the relationship between immunosuppressive populations and T-cell exhaustion markers in both groups., Methods: TILs (CD3, CD4, and CD8) and macrophages (CD163) were assessed by immunochemistry. Exhaustion markers (PD-1, TIM3, CD39, and FOXP3) and their relationship with tumour-associated macrophages (CD163) were assessed by immunofluorescence on paraffin-embedded samples from n = 43 OE and n = 54 EAOC patients., Results: we observed a predominantly intraepithelial CD3+ distribution in OE but both an intraepithelial and stromal pattern in EAOC ( p < 0.001). TILs were more abundant in OE ( p < 0.001), but higher TILs significantly correlated with a longer overall survival and disease-free survival in EAOC ( p < 0.05). CD39 and FOXP3 significantly correlated with each other and CD163 ( p < 0.05) at the epithelial level in moderate/intense CD4 EAOC, whereas in moderate/intense CD8+, PD-1+ and TIM3+ significantly correlated ( p = 0.009). Finally, T-cell exhaustion markers FOXP3-CD39 were decreased and PD-1-TIM3 were significantly increased in EAOC ( p < 0.05)., Conclusions: the dysregulation of TILs, TAMs, and T-cell exhaustion might play a role in the malignization of OE to EAOC.

Early stages are under-represented in studies on the molecular and immune features of high-grade serous ovarian carcinoma (HGSOC), and specific studies focused on early-stage HGSOC are required for a better prognostic stratification and to personalize chemotherapy. The aim of this study was to determine the prognostic significance of CD8+ and CD4+ tumor-infiltrating lymphocytes (TILs), tumoral cell PD-L1 expression, BRCA mutational status and tumor mutation burden (TMB) in early-stage HGSOC. A retrospective study was performed on stage I and II HGSOC from the Molecular Reclassification of Early Stages of Ovarian Cancer (RECLAMO) cohort from the Spanish Group of Ovarian Cancer Research (GEICO). Centralized histological typing was performed based on morphological and immunohistochemical features. Intraepithelial (i) and stromal (s) CD8+ and CD4+ T cells and PD-L1 were evaluated on tissue microarrays by immunohistochemistry. BRCA1 and BRCA2 mutation status and TMB were analyzed in tumor DNA using next-generation sequencing. The study included 124 tumors. High iCD8+ (>20 TILs/core), low/intermediate CD4+ (<20 TILs/core) and high CD8+/CD4+ ratio (>35/core) were associated with favorable outcomes. Tumor cell PD-L1 expression (TPS ≥ 1) was present in only 8% of tumors. In total, 11 (16%) and 6 (9%) out of 69 HGSOC tested carried pathogenic or likely pathogenic BRCA1 or BRCA2 mutations, respectively. Median TMB of 40 tumors analyzed was 5.04 mutations/Mb and only 6 tumors had 10 or more mutations/Mb. BRCA status and TMB were not associated with TILs or prognosis. When compared with studies on advanced HGSOC, our results suggested that prognostic variables differed according to stage and that more studies focused on early stages of HGSOC are needed to better stratify these tumors.

In this analysis, we examined the relationship between progression-free survival (PFS) and mutation status of 18 homologous recombination repair (HRR) genes in patients in the non-germline BRCA -mutated (non-g BRCA m) cohort of the ENGOT-OV16/NOVA trial (NCT01847274), which evaluated niraparib maintenance therapy for patients with recurrent ovarian cancer. This post hoc exploratory biomarker analysis was performed using tumor samples collected from 331 patients enrolled in the phase III ENGOT-OV16/NOVA trial's non-g BRCA m cohort. Niraparib demonstrated PFS benefit in patients with either somatic BRCA- mutated (s BRCA m; HR, 0.27; 95% confidence interval, CI, 0.08-0.88) or BRCA wild-type ( BRCA wt; HR, 0.47; 95% CI, 0.34-0.64) tumors. Patients with BRCA wt tumors with other non- BRCA HRR mutations also derived benefit from niraparib (HR, 0.31; 95% CI, 0.13-0.77), as did patients with BRCA wt/HRRwt (HRR wild-type) tumors (HR, 0.49; 95% CI, 0.35-0.70). When patients with BRCA wt/HRRwt tumors were further categorized by genomic instability score (GIS), clinical benefit was observed in patients with homologous recombination-deficient (GIS ≥ 42; HR, 0.33; 95% CI, 0.18-0.61) and in patients with homologous recombination-proficient (HRp; GIS < 42; HR, 0.60; 95% CI, 0.36-0.99) disease. Although patients with s BRCA m, other non- BRCA HRR mutations, or GIS ≥ 42 benefited the most from niraparib treatment, PFS benefit was also seen in HRp (GIS < 42) patients without HRR mutations. These results support the use of niraparib in patients with recurrent ovarian cancer regardless of BRCA /HRR mutation status or myChoice CDx GIS., Significance: We retrospectively evaluated the mutational profile of HRR genes in tumor samples from 331 patients from the non-germline BRCA -mutated cohort of the phase III NOVA trial of patients with platinum-sensitive high-grade serous ovarian cancer. Patients with non- BRCA HRR mutations generally benefited from second-line maintenance treatment with niraparib compared with placebo., Competing Interests: G. Lindahl reports personal fees from Honoraria for lectures outside the submitted work. S. Mahner reports grants, personal fees, and other from AbbVie, AstraZeneca, Clovis, Eisai, GSK, Hubro, Medac, MSD, Novartis, Nykode, Olympus, PharmaMar, Pfizer, Roche, Sensor Kinesis, Teva, and Tesaro outside the submitted work. A. Redondo reports personal fees from GSK, MSD; personal fees and other from AstraZeneca; other from Clovis; grants and personal fees from Pharmamar; and grants from Eisai outside the submitted work. M. Fabbro reports personal fees from GSK and AstraZeneca outside the submitted work. B.J. Rimel reports other from GSK, Merck, Immunogen, and personal fees from Deep6AI outside the submitted work. A.M. Oza reports PI and Steering Committees with AstraZeneca, GSK, and Clovis; advisory Board member with AstraZeneca and Morphosys. U. Canzler reports personal fees from AstraZeneca, Lilly, and Roche outside the submitted work. J.S. Berek reports grants from Tesaro during the conduct of the study. A. González-Martín reports personal fees from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Merck Sharp & Dohme, MacroGenics, Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Roche, Sotio, Sutro and grants from GSK and Roche outside the submitted work. P. Follana reports personal fees from GSK, AstraZeneca, and Clovis outside the submitted work. R. Lord reports personal fees from GSK outside the submitted work. Z. Wang reports other from GSK during the conduct of the study; other from GSK outside the submitted work. D. Gupta reports other from GSK during the conduct of the study; other from GSK outside the submitted work; and D. Gupta is an employee of GSK which sponsored the NOVA trial. U. Matulonis reports personal fees from GSK, AstraZeneca, Merck, Novartis, Next Cure, Agenus, 2X oncology, Symphogen, Alkermes, and Morphosys during the conduct of the study; personal fees from Clearity Foundation and Ovarian Cancer Research Alliance outside the submitted work. B. Feng is an employee of GSK. No disclosures were reported by the other authors., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Background: The PRIMA phase 3 trial showed niraparib significantly prolongs median progression-free survival (PFS) versus placebo in patients with advanced ovarian cancer (OC) responsive to first-line platinum-based chemotherapy, including those who had tumors with homologous recombination deficiency (HRd). This analysis of PRIMA examined the quality-adjusted PFS (QA-PFS) and quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) of patients on maintenance niraparib versus placebo., Methods: Patients were randomized 2:1 to receive once-daily maintenance niraparib ( n  = 487) or placebo ( n  = 246). QA-PFS was defined as the PFS of patients adjusted for their health-related quality of life (HRQoL) prior to disease progression, measured using European Quality of Life Five-Dimension (EQ-5D) questionnaire index scores from the PRIMA trial. Q-TWiST was calculated by combining data on PFS, duration of symptomatic grade ⩾2 adverse events (fatigue or asthenia, nausea, vomiting, abdominal pain, and abdominal bloating) prior to disease progression, and EQ-5D index scores. Analyses used data collected up to the last date of PFS assessment (May 17, 2019)., Results: The restricted mean QA-PFS was significantly longer with niraparib versus placebo in the HRd ( n  = 373) and overall intention-to-treat (ITT; n  = 733) populations (mean gains of 6.5 [95% confidence interval; CI, 3.9-8.9] and 4.1 [95% CI, 2.2-5.8] months, respectively). There were also significant improvements in restricted mean Q-TWiST for niraparib versus placebo (mean gains of 5.9 [95% CI, 3.5-8.6] and 3.5 [95% CI, 1.7-5.6] months, respectively) in the HRd and ITT populations., Conclusions: In patients with advanced OC, first-line niraparib maintenance was associated with significant gains in QA-PFS and Q-TWiST versus placebo. These findings demonstrate that niraparib maintenance treatment is associated with a PFS improvement and that treatment benefit is maintained even when HRQoL and/or toxicity data are combined with PFS in a single measure., Trial Registration: ClinicalTrials.gov: NCT02655016; trial registration date: January 13, 2016., Plain Language Summary: Background: In a large clinical trial called PRIMA, patients with advanced cancer of the ovary (ovarian cancer) were given either niraparib (a type of cancer medicine) or placebo (a pill containing no medicine/active substances) after having chemotherapy (another type of cancer medicine). Taking niraparib after chemotherapy is called maintenance therapy and aims to give patients more time before their cancer returns or gets worse than if they were not given any further treatment. In the PRIMA trial, patients who took niraparib did have more time before their cancer progressed than if they took placebo. However, it is important to consider patients' quality of life, which can be made worse by cancer symptoms and/or side effects of treatment. Here, we assessed the overall benefit of niraparib for patients in PRIMA. Methods: Both the length of time before disease progression (or survival time) and quality of life were considered using two different analyses:● The first analysis was called quality-adjusted PFS (QA-PFS) and looked at how long patients survived with good quality of life.● The second analysis was called quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) and looked at how long patients survived without cancer symptoms or treatment side effects. Results: The PRIMA trial included 733 patients; 487 took niraparib and 246 took placebo. Around half of the patients in both groups had a type of ovarian cancer that responds particularly well to drugs like niraparib - they are known as homologous recombination deficiency (HRd) patients.● When information on quality of life (collected from patient questionnaires) and survival was combined in the QA-PFS analysis, HRd patients who took niraparib had approximately 6.5 months longer with a good quality of life before disease progression than those who took placebo. In the overall group of patients (including HRd patients and non-HRd patients), those who took niraparib had approximately 4 months longer than with placebo.● Using the second analysis (Q-TWiST) to combine information on survival with cancer symptoms and treatment side effects, the HRd patients taking niraparib had approximately 6 months longer without cancer symptoms or treatment side effects (such as nausea or vomiting) than patients taking placebo. In the overall group of patients, those taking niraparib had approximately 3.5 months longer without these cancer symptoms/side effects than patients receiving placebo. Conclusions: These results show that the survival benefits of niraparib treatment remain when accounting for patients' quality of life. These benefits were seen not only in HRd patients who are known to respond better to niraparib, but in the overall group of patients who took niraparib., Competing Interests: Competing interests: MPBG reports receiving lecture fees, advisory board fees, and travel support from AstraZeneca, Clovis Oncology, GSK, Merck, PharmaMar, Roche, and Tesaro. BJM has received honoraria and lecture fees from Tesaro. BP has received institutional grant support from AstraZeneca, Celsion, Clovis Oncology, Genentech/Roche, Merck, Mersana, Tesaro/GSK, Toray, I-Mab, Incyte, and Seagen; and advisory board compensation from Arquer, AstraZeneca, Eisai, Elevar, Lilly, Merck, Mersana, Tesaro/GSK, I-Mab, ImmunoGen, InxMed, Onconova Therapeutics, Seagen, and Toray. AAu reports receiving consulting fees from GSK. DMC reports personal fees from GSK; has received honoraria from Roche; has served as a consultant to AstraZeneca and Mateon Therapeutics; and has received research grants to her institution from Genentech. DL reports receiving advisory board fees from Amgen, AstraZeneca, Clovis Oncology, Genmab, and ImmunoGen; grant support, paid to her institution, and consulting fees from PharmaMar; and grant support, paid to her institution, and advisory board fees from Merck. EIB reports receiving consulting fees, lecture fees, and travel support from AstraZeneca, Clovis, GSK, Tesaro, Roche, Roche Diagnostics, Eisai, and Merck Sharp & Dohme; and grant support to their institution from Roche Diagnostics, Merck Sharp & Dohme, and Bayer. AR has received grant support, advisory fees, and travel support from PharmaMar and Roche; advisory fees and travel support from AstraZeneca and Tesaro/GSK; advisory fees from Clovis; and grant support from Eisai. RS is an employee of Open Health Evidence and Access, which received research funding from GSK for this study. NK was an employee of Open Health Evidence and Access at the time of the study. CH and DG are employees of GSK. TW is a former employee of GSK. DMO reports grants and personal fees from Clovis; has served on advisory boards for Agenus, AstraZeneca, Eisai, Genentech/Roche, ImmunoGen, Iovance Biotherapeutics, Janssen/Johnson & Johnson, Merck, Mersana, Myriad, Novartis Pharmaceuticals, Novocure, Regeneron Pharmaceuticals, Seagen, Tarveda, and Tesaro/GSK; has served on steering committees for Amgen; has served as a consultant to AbbVie, Agenus, Ambry, AstraZeneca, Eisai, Genentech/Roche, GOG Foundation, ImmunoGen, Iovance Biotherapeutics, Merck, Mersana, Novartis Pharmaceuticals, Novocure, Seagen, and Tesaro/GSK; and has received research support to his institution from AbbVie, Agenus, Ajinomoto, Amgen, Array BioPharma, AstraZeneca, Bristol-Myers Squibb, Cerulean Pharma, Eisai, EMD Serono, Ergomed Clinical Research, Genentech/Roche, Genmab, GOG Foundation, ImmunoGen, INC Research, inVentiv Health Clinical, Iovance Biotherapeutics, Janssen/Johnson & Johnson, Ludwig Institute for Cancer Research, Merck, Mersana, New Mexico Cancer Care Alliance, Novocure, PRA International, Regeneron Pharmaceuticals, Seagen, Serono, Stemcentrx, Tesaro/GSK, TRACON Pharmaceuticals, VentiRx, and Yale University. AGM reports receiving consulting fees from Alkermes, Amgen, AstraZeneca, Clovis, Genmab, GSK, Immunogen, Mersana, Merck Sharp & Dohme, Oncoinvent, PharmaMar, Roche, SOTIO, and Takeda; lecture fees from AstraZeneca, Clovis, GSK, Merck Sharp & Dohme, PharmaMar, and Roche; travel support from AstraZeneca, GSK, and PharmaMar; grant support to their institution from Roche Holding and Tesaro. SH, CA, SAL, NC, and AAm have no conflicts to disclose., (© The Author(s), 2022.)

Pazopanib was assessed prospectively in the GEIS-32 phase II study (NCT02066285) on advanced solitary fibrous tumour (SFT), resulting in a longer progression-free survival (PFS) and overall survival (OS) compared with historical controls treated with chemotherapy. A retrospective analysis of peripheral inflammatory indexes in patients enrolled into GEIS-32 was performed to evaluate their prognostic and predictive value. Patients received pazopanib 800 mg/day as the first antiangiogenic line. The impacts of baseline neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and red cell distribution width (RDW) on PFS, OS, and Choi response were evaluated by univariate and multivariate analysis. Metastasis-free interval (MFI), mitotic count, and ECOG were also included as potential prognostic factors. Sixty-seven SFT patients, enrolled in this study, showed a median age of 63 years and a female/male distribution of 57/43. The median follow-up from treatment initiation was 16.8 months. High baseline NLR, PLR, and standardised RDW were significantly associated with worse PFS and OS. NLR, RDW, MFI, and mitotic count were independent variables for PFS, while RDW and ECOG were independent for OS. Further, NLR and mitotic count were independent factors for Choi response. High baseline NLR and RDW values were independent prognostic biomarkers for worse outcome in advanced SFT patients treated with pazopanib.

Blackground: The COVID-19 pandemic has over-burdened the Spanish health service and, as a result, affected the treatment and management of oncological patients. The aim of this study is to make a descriptive analysis of the management of oncological patients and the functioning of the tumour committees in the University Hospital La Paz (Madrid) during the first wave of the pandemic., Materials and Methods: A descriptive analysis was made, based on the results of a questionnaire given to all 18 adult tumour committees and 3 paediatric tumour committees in the University Hospital La Paz. Further information was obtained from all the hospital services involved in the diagnosis and treatment of oncological patients., Results: During the first wave of the pandemic, there was a significant decrease in diagnostic tests. For many weeks, the majority of oncological surgical procedures were delayed or referred to other hospitals. Highly beneficial systemic and radiotherapeutic treatments were maintained and preoperative treatment was increased. The diagnosis and treatment of paediatric tumours was unaltered. Tumour committees were affected but each one adjusted in a different way. All the departments involved in the diagnosis and treatment of oncological patients made contingency plans to minimalize the effect on patients., Conclusion: This study shows how the management of oncological patients and the functioning of tumour committees was affected during the COVID-19 pandemic., (Copyright © 2022. Publicado por Elsevier España, S.L.U.)

Ovarian cancer (OC) is a life-threatening tumor and the deadliest among gynecological cancers in developed countries. First line treatment with a carboplatin/paclitaxel regime is initially effective in the majority of patients, but most advanced OC will recur and develop drug resistance. Therefore, the identification of alternative therapies is needed. In this study, we employed a panel of high-grade serous ovarian cancer (HGSOC) cell lines, in monolayer and three-dimensional cell cultures. We evaluated the effects of a novel tubulin-binding agent, plocabulin, on proliferation, cell cycle, migration and invasion. We have also tested combinations of plocabulin with several drugs currently used in OC in clinical practice. Our results show a potent antitumor activity of plocabulin, inhibiting proliferation, disrupting microtubule network, and decreasing their migration and invasion capabilities. We did not observe any synergistic combination of plocabulin with cisplatin, doxorubicin, gemcitabine or trabectedin. In conclusion, plocabulin has a potent antitumoral effect in HGSOC cell lines that warrants further clinical investigation., Competing Interests: AG reports honoraria (Clovis, MSD, AstraZeneca, GSK, PharmaMar and Roche) and travel/accommodation/expenses (Merck Sharp and Dohme, PharmaMar, Roche, Eisai, Pfizer, Pierre-Fabre and Tesaro-A GSK Company), outside the submitted work. MM-D is employee and shareholder of PharmaMar S.A. (Madrid, Spain). AR reports honoraria and advisory/consultancy (MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar, Lilly, Amgen), research grant/funding to his institution (Eisai, PharmaMar, Roche), travel/accommodation/expenses (AstraZeneca, Tesaro: A GSK Company, PharmaMar, Roche), and speakers bureau (MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar), outside the submitted work. MMe reports honoraria (MSD, AstraZeneca and GSK), research grant/funding to her institution (Eisai and PharmaMar), travel/accommodation/expenses (AstraZeneca, GSK, PharmaMar, Roche and Pfizer), outside the submitted work. The authors declare that this study received funding from PharmaMar S.A. (MM-D). The funder had the following involvement with the study: performed immunofluorescence experiments and reviewed draft preparation., (Copyright © 2022 Heredia-Soto, Escudero, Miguel, Ruiz, Gallego, Berjón, Hernández, Martínez-Díez, Zheng, Tang, Hardisson, Feliu, Redondo and Mendiola.)

Objective: To estimate the cost-effectiveness of olaparib after being funded by the Spanish National Health Service (SNHS) as first-line monotherapy maintenance treatment in patients with advanced high-grade serous ovarian carcinoma (HGSOC) and BRCA mutations in Spain., Methods: A semi-Markov model with one-month cycles was adapted to the Spanish healthcare setting, using the perspective of the SNHS, and a time horizon of 50 years. Two scenarios were compared: receiving olaparib vs. no maintenance treatment. The model comprised four health states and included the clinical results of the SOLO1 study, along with the direct healthcare costs associated with the use of first-line and subsequent treatment resources (2020 €). A discount rate of 3% was applied for future cost and quality-of-life outcomes. A probabilistic sensitivity analysis (PSA) was also carried out and a cost-effectiveness threshold of €25,000 per quality adjusted life year (QALY) was considered., Results: The introduction of olaparib as a first-line maintenance treatment for advanced HGSOC patients with BRCA mutations implied a cost of €131,614.98 compared to €102,369.54 without olaparib (difference: €29,245.44), with an improvement of 2.00 QALYs (5.56 and 3.57, respectively). Therefore, olaparib is cost-effective for advanced HGSOC patients with BRCA mutations, with an incremental cost-effectiveness ratio of €14,653.2/QALY. The results from the PSA showed that 92.1% of the simulations fell below the €25,000/QALY threshold. The model showed that olaparib could improve the overall survival by 2 years, vs. no maintenance treatment., Conclusions: Olaparib as first-line maintenance treatment is cost-effective in advanced HGSOC patients with BRCA mutations in Spain., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Long-term cancer survivors (LTCS) are a vulnerable and continued growing population. To date, only few studies have been conducted in the Spanish population; none of them with a comprehensive analysis of the most common problems identified for cancer survivors in order to improve their care and quality of life., Methods: We conducted an observational descriptive study in 347 patients recruited between January 2015 and December 2016 from our newly created medical office for the specific care and follow-up of LTCS. Variables that describe the medical history were completed by the oncologist and measures on common problems previously reported for LTCS, related to cancer diagnosis and treatment, function, lifestyle, and emotional concerns, were collected from the patient., Results: The mean age of our patients was 65.1 years at the time of the study and a median time without any antitumor treatment of 5.7 years. At the time of cancer diagnosis, 298 patients (85.9%) had at least one related chronic disease and 184 patients (53%) were retired. In addition, in 17.9% of those who continued working, income had been reduced. The incidence of health problems showed an increase during follow-up, even after 5 years, and required evaluation in an emergency department in 157 cases (45.3%). Regardless of age or sex, 239 patients (68.9%) had a significant decrease in sexual activity and 120 (34.6%) were diagnosed with clinical depression., Conclusions: LTCS are patients with significantly high socioeconomic, labor, sexual, health, and psychological problems, 5 years after completion of cancer treatment, especially in older survivors., Implications for Cancer Survivor: Common concerns of LTCS were identified and are consistent across many countries. It is important to realize that even 5 or so years following treatment, both medical and non-medical problems can exist and may need attention by an expert., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Low-grade and early-stage endometrioid endometrial carcinomas (EECs) have an overall good prognosis but biomarkers identifying patients at risk of relapse are still lacking. Recently, CTNNB1 exon 3 mutation has been identified as a potential risk factor of recurrence in these patients. We evaluate the prognostic value of CTNNB1 mutation in a single-centre cohort of 218 low-grade, early-stage EECs, and the correlation with beta-catenin and LEF1 immunohistochemistry as candidate surrogate markers. CTNNB1 exon 3 hotspot mutations were evaluated by Sanger sequencing. Immunohistochemical staining of mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6), p53, beta-catenin, and LEF1 was performed in representative tissue microarrays. Tumours were also reviewed for mucinous and squamous differentiation, and MELF pattern. Nineteen (8.7%) tumours harboured a mutation in CTNNB1 exon 3. Nuclear beta-catenin and LEF1 were significantly associated with CTNNB1 mutation, showing nuclear beta-catenin a better specificity and positive predictive value for CTNNB1 mutation. Tumours with CTNNB1 exon 3 mutation were associated with reduced disease-free survival (p = 0.010), but no impact on overall survival was found (p = 0.807). The risk of relapse in tumours with CTNNB1 exon 3 mutation was independent of FIGO stage, tumour grade, mismatch repair protein expression, or the presence of lymphovascular space invasion. CTNNB1 exon 3 mutation has a negative impact on disease-free survival in low-grade, early-stage EECs. Nuclear beta-catenin shows a higher positive predictive value than LEF1 for CTNNB1 exon 3 mutation in these tumours., (© 2021. The Author(s).)

Background: Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue factor-directed antibody-drug conjugate, in this patient population., Methods: This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396., Findings: 102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1-13·0). The confirmed objective response rate was 24% (95% CI 16-33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 [38%] of 101 patients), epistaxis (30 [30%]), nausea (27 [27%]), conjunctivitis (26 [26%]), fatigue (26 [26%]), and dry eye (23 [23%]). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three [3%] patients), fatigue (two [2%]), ulcerative keratitis (two [2%]), and peripheral neuropathies (two [2%] each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two [2%] patients) and pyrexia (two [2%]). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes., Interpretation: Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer., Funding: Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups., Competing Interests: Declaration of interests RLC has received funding for consulting from AstraZeneca, Merck, Tesaro, Medivation, Clovis, GamaMabs, Genmab, Roche, Janssen, Agenus, Regeneron, and OncoQuest, and grant support from AstraZeneca, Merck, Clovis, Genmab, Roche, and Janssen. DL reports advisory board membership for Roche, Tesaro/GlaxoSmithKline, Clovis, Merck, PharmaMar, ImmunoGen, Genmab, Amgen, and AstraZeneca; grant support from Tesaro/GlaxoSmithKline, Merck, Roche, PharmaMar, and Clovis; consultancy for Clovis; travel support from Roche, PharmaMar, AstraZeneca, Tesaro/GlaxoSmithKline, AstraZeneca, and Amgen; and acting as principal investigator for registrational clinical trials for Roche, PharmaMar, Tesaro, Clovis, ImmunoGen, Genmab, AstraZeneca, and Merck. CG has received clinical trial institutional support from Genmab; is an advisory board member for Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Novartis, and Lilly; has received consultancy fees from GlaxoSmithKline and Roche; has received institutional grant support from Roche, PharmaMar, Merck Sharp & Dohme, and AstraZeneca; and has received travel support from Pfizer, PharmaMar, Ipsen, and Roche. AG-M has received consultancy fees or honoraria from AstraZeneca, Clovis, Genmab, ImmunoGen, Merck Sharp & Dohme, Amgen, Oncoinvent, Merck/Pfizer, Roche, Sotio, and Tesaro/GlaxoSmithKline, and institutional grant support from Roche and Tesaro/GlaxoSmithKline. LW has received honoraria from Genmab and Tesaro; travel support from Genmab, Tesaro, and medac; institutional grant support from Genmab and Roche; and fees for development of educational presentations from Roche, Pfizer, and medac. SP has received honoraria from Genmab, Roche, AstraZeneca, Merck Sharp & Dohme, GlaxoSmithKline, PharmaMar, Incyte, Pfizer, Merck, and Clovis, and research funding from Roche, AstraZeneca, Merck Sharp & Dohme, and Pfizer. FF has received institutional funding from Genmab for travel. AR has received consultancy fees from AstraZeneca, GlaxoSmithKline, Roche, PharmaMar, Clovis, and Amgen; institutional grant support from Roche, PharmaMar, and Eisai; honoraria from AstraZeneca, GlaxoSmithKline, Roche, PharmaMar, and Clovis; and travel support from Roche, AstraZeneca, and PharmaMar. SDV, MC, JRH, and MS are employees of and own stock in Genmab. LVN and MSLT are employees of and own stock in Seagen. RR is a former employee of and owns stock in Genmab. LM has received consultancy fees from Roche, Novartis, Pfizer, AstraZeneca, and GlaxoSmithKline, and institutional grant support from Tesaro. MM has received consultancy fees or honoraria from Genmab. BJM has received consultancy fees or honoraria from AbbVie, Advaxis, Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Asymmetric Therapeutics, Boston Biomedical, ChemoID, Clovis, Deciphera, Eisai, Geistlich, Genmab, GOG Foundation, ImmunoGen, Immunomedics, Incyte, Iovance, Laekna Health Care, Merck, Mersana, Myriad, NuCana, OncoMed, OncoQuest, OncoSec, Perthera, Pfizer, Puma, Regeneron, Roche/Genentech, Seagen, Senti Biosciences, Starton Therapeutics, Takeda, Tesaro/GlaxoSmithKline, Vavotar Life Sciences, VBL, and Vigeo. IV has received institutional funding for the following: consultancy or honoraria from Amgen, AstraZeneca, Clovis Oncology, Carrick Therapeutics, Debiopharm, F Hoffmann-La Roche, Genmab, GlaxoSmithKline, ImmunoGen, Medical University of Vienna (Vienna, Austria), Millennium Pharmaceuticals, Merck Sharp & Dohme Belgium, Octimet Oncology, Oncoinvent, PharmaMar-Doctaforum Servicios SL, Roche, Sotio, Tesaro, Deciphera, and Verastem Oncology; institutional grant support from Amgen and Roche; institutional research support from Oncoinvent and Genmab; and institutional travel support from Amgen, AstraZeneca, Merck, Sharp & Dohme, Roche, and Tesaro. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Low-grade, early-stage endometrial carcinoma (EC) is the most frequent malignant tumor of the uterine corpus. However, the molecular alterations that underlie these tumors are far from being fully understood. The purpose of this study is to describe dysregulated molecular pathways from EC patients. Sixteen samples of tumor tissue and paired healthy controls were collected and both were subjected to mass spectrometry (MS)/MS proteomic analysis. Gene ontology and pathway analysis was performed to discover dysregulated pathways and/or proteins using different databases and bioinformatic tools. Dysregulated pathways were cross-validated in an independent external cohort. Cell signaling, immune response, and cell death-associated pathways were robustly identified. The SLIT/ROBO signaling pathway demonstrated dysregulation at the proteomic and transcriptomic level. Necroptosis and ferroptosis were cell death-associated processes aberrantly regulated, in addition to apoptosis. Immune response-associated pathways showed a dominance of innate immune responses. Tumor immune infiltrates measured by immunofluorescence demonstrated diverse lymphoid and myeloid populations. Our results suggest a role of SLIT/ROBO, necroptosis, and ferroptosis, as well as a prominent role of innate immune response in low-grade, early-stage EC. These results could guide future research in this group of tumors.

Background: The phase 3 KATHERINE trial demonstrated significantly improved invasive disease-free survival with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab in patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy., Methods: Patients who received taxane- and trastuzumab-containing neoadjuvant therapy (with/without anthracyclines) and had residual invasive disease (breast and/or axillary nodes) at surgery were randomly assigned to 14 cycles of adjuvant T-DM1 (3.6 mg/kg intravenously every 3 weeks) or trastuzumab (6 mg/kg intravenously every 3 weeks). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and breast cancer module (QLQ-BR23) were completed at screening, at day 1 of cycles 5 and 11, within 30 days after study drug completion, and at 6- and 12-month follow-up visits., Results: Of patients who were randomly assigned to T-DM1 (n = 743) and trastuzumab (n = 743), 612 (82%) and 640 (86%), respectively, had valid baseline and ≥1 postbaseline assessments. No clinically meaningful changes (≥10 points) from baseline in mean QLQ-C30 and QLQ-BR23 scores occurred in either arm. More patients receiving T-DM1 reported clinically meaningful deterioration at any assessment point in role functioning (49% vs 41%), appetite loss (38% vs 28%), constipation (47% vs 38%), fatigue (66% vs 60%), nausea/vomiting (39% vs 30%), and systemic therapy side effects (49% vs 36%). These differences were no longer apparent at the 6-month follow-up assessment, except for role functioning (23% vs 16%)., Conclusion: These data suggest that health-related quality of life was generally maintained in both study arms over the course of treatment., (© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Sarcomas are tumours of mesenchymal origin, which can arise in bone or soft tissues. They are rare but frequently quite aggressive and with a poor outcome. New approaches are needed to characterise these tumours and their resistance mechanisms to current therapies, responsible for tumour recurrence and treatment failure. This review is focused on the potential of three-dimensional (3D) in vitro models, including multicellular tumour spheroids (MCTS) and organoids, and the latest data about their utility for the study on important properties for tumour development. The use of spheroids as a particularly valuable alternative for compound high throughput screening (HTS) in different areas of cancer biology is also discussed, which enables the identification of new therapeutic opportunities in commonly resistant tumours., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Niraparib, an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), has been associated with significantly increased progression-free survival among patients with recurrent ovarian cancer after platinum-based chemotherapy, regardless of the presence or absence of BRCA mutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown., Methods: In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival., Results: Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred., Conclusions: Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.)., (Copyright © 2019 Massachusetts Medical Society.)

Low-grade and early Federation for Gynecology and Obstetrics (FIGO) stage endometrioid endometrial carcinomas (EEC) have an excellent prognosis. However, approximately 10% of patients develop recurrence, which cannot be correctly predicted at diagnosis. We evaluated myoinvasive patterns as a prognostic factor of relapse in low-grade, early-stage EEC. Two-hundred and fifty-eight cases were selected according to the following inclusion criteria: (i) endometrioid endometrial carcinomas, (ii) grade 1 or 2 with (iii) FIGO stage I or II, and (iv) clinical follow-up. Slides were reviewed to annotate the myoinvasive pattern present in each case (infiltrative glands, microcystic, elongated and fragmented -MELF-, broad front, adenomyosis-like and adenoma malignum). Microsatellite instability was studied by immunoexpression of mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6). There were 29 recurrences (11.2%) among the 258 cases analysed. A predominant broad front myoinvasive pattern was significantly associated with tumour relapse ( p = 0.003). The presence of a pattern of infiltrative glands ( p = 0.001) and microsatellite instability ( p = 0.004) were associated with lower disease-free survival, without having an impact on overall survival. Our observations suggest the potential value of the pattern of myoinvasion as a prognostic factor in low-grade, early-stage endometrioid endometrial carcinoma.

Introduction: The PENELOPE trial evaluated pertuzumab added to chemotherapy for biomarker-selected platinum-resistant ovarian cancer. As previously reported, pertuzumab did not statistically significantly improve progression-free survival (primary end point: HR 0.74, 95% CI 0.50 to 1.11), although results in the paclitaxel and gemcitabine cohorts suggested activity. Here, we report final overall survival and patient-reported outcomes., Patients and Methods: Eligible patients had ovarian carcinoma that progressed during/within 6 months of completing ≥4 platinum cycles, low tumor human epidermal growth factor receptor 3 (HER3) mRNA expression, and ≤2 prior chemotherapy lines. Investigators selected single-agent topotecan, gemcitabine or weekly paclitaxel before patients were randomized to either placebo or pertuzumab (840→420 mg every 3 weeks), stratified by selected chemotherapy, prior anti-angiogenic therapy, and platinum-free interval. Final overall survival analysis (key secondary end point) was pre-specified after 129 deaths. Patient-reported outcomes (secondary end point) were assessed at baseline and every 9 weeks until disease progression., Results: At database lock (June 9, 2016), 130 (83%) of 156 randomized patients had died. Median follow-up was 27 months in the pertuzumab arm versus 26 months in the control arm. In the intent-to-treat population there was no overall survival difference between treatment arms (stratified HR 0.90, 95% CI 0.61 to 1.32; p=0.60). Results in subgroups defined by stratification factors indicated heterogeneity similar to previous progression-free survival results. Updated safety was similar to previously published results. Compliance with patient-reported outcomes questionnaire completion was >75% for all validated patient-reported outcomes measures. Pertuzumab demonstrated neither beneficial nor detrimental effects on patient-reported outcomes compared with placebo, except for increased diarrhea symptoms., Discussion: Consistent with the primary results, adding pertuzumab to chemotherapy for low tumor HER3 mRNA-expressing platinum-resistant ovarian cancer did not improve overall survival, but showed trends in some cohorts. Except for increased diarrhea symptoms, pertuzumab had no impact on patient-reported outcomes. ClinicalTrials.gov: ClinicalTrials.gov: NCT01684878., Competing Interests: Competing interests: DL has participated in advisory boards for Roche, AstraZeneca, Clovis, Merck and Tesaro; her institution has received research support from Clovis, PharmaMar and Merck. FH has a consultant and advisory relationship with Roche, AstraZeneca and MSD. AGM has consulting and advisory relationships with Roche, Tesaro, AstraZeneca, Pfizer, Clovis, PharmaMar and ImmunoGen. PO has a consulting or advisory role with Novartis, GSK, MSD, Clovis and Tesaro. FS has served as a consultant for Roche and Tesaro. NC has received personal fees from AstraZeneca, Clovis, Tesaro, Roche, PharmaMar, Takeda and Pfizer. BP has participated in advisory boards for Clovis and Tesaro. IV has participated in advisory boards for Advaxis Inc, Eisai Inc, MSD Belgium, Roche NV, Genmab A/S, F. Hoffmann-La Roche Ltd, PharmaMar, Millennium Pharmaceuticals, Clovis Oncology Inc, AstraZeneca NV, Novocure GMBH, Morphotek Inc, Mateon Therapeutics Inc, Immunogen Inc, Eli Lilly Benelux NV, Amgen Inc, Pfizer Inc, Vifor Pharma België NV, Novartis Pharma AG, Oxigene Inc, Nektar Therapeutics and Bayer Pharma AG, has contract research (via K U Leuven) with Oncoinvent AS and Genmab A/S – Genmab B.V., has received grants for corporate-sponsored research from Amgen and Roche, and has received accommodation/travel expenses from Takeda Oncology, PharmaMar, Genmab, Roche and AstraZeneca. AR has consultant and advisory roles with Roche, Tesaro, AstraZeneca, Clovis, PharmaMar, Amgen, Lilly and Novartis, and research funding from Roche, PharmaMar and Eisai. AC and LB-T are employees of and shareholders in Roche. AdB has a consulting and advisory relationship with AstraZeneca, Roche, Tesaro, Pfizer, Clovis, PharMar and Genmab. CK has a consultant and advisory relationships with Roche, AstraZeneca, Tesaro and Genomic Health. All remaining authors have declared no conflicts of interest., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Randomized controlled trials of the first-line combination of bevacizumab and chemotherapy in patients with metastatic breast cancer (MBC) have shown improvements in tumor response and progression-free survival (PFS)., Objective: The aim of this ambispective, observational study (LORENA) was to describe the clinical characteristics of long-term responders to bevacizumab-based therapy., Patients and Methods: This study consisted of a retrospective and a prospective phase. During the retrospective phase, patients with HER2-negative MBC who were treated with bevacizumab-based first-line therapy were included. During the prospective phase, patients with PFS of ≥12 months were treated according to routine clinical practice procedures. Overall survival (OS) and PFS were estimated using the Kaplan-Meier method. Univariate and multivariate analyses of prognostic factors were performed., Results: In total, 148 women were included (median age: 50 years; range: 29-81 years). The mean duration of exposure to bevacizumab was 18 months. The majority of patients experienced objective response (complete: 23%; partial: 57%). Median PFS was 22.7 months and median OS was 58.2 months. In multivariate analyses, patients receiving maintenance hormonal therapy (MHT) had longer PFS ( P =0.002; hazard ratio [HR] =1.8) and OS ( P =0.009; HR=2.0), while patients not previously treated with taxanes had longer OS ( P <0.0001; HR =3.3). No unexpected adverse events were observed., Conclusion: The results of this study suggest, that among long-term responders, first-line bevacizumab-based therapy is more effective in patients who had not been previously treated with taxanes, and that MHT provides additional therapeutic benefits by extending PFS and OS., Competing Interests: Disclosure Andrés Redondo served as an advisor for, and received honoraria and research funding from Roche. Miguel J Gil Gil served as advisors and received honoraria from Roche. Elisa García-Garre has received honoraria from Roche for lectures. The other authors report no conflicts of interest in this work.

Background/aim: Predicting response to treatment in high-grade serous ovarian carcinoma (HGSOC) still remains a clinical challenge. The standard-of-care for first-line chemotherapy, based on a combination of carboplatin and paclitaxel, achieves a high response rate. However, the development of drug resistance is one of the major limitations to efficacy. Therefore, identification of biomarkers able to predict response to chemotherapy in patients with HGSOC is a critical step for prognosis and treatment of the disease. Several studies suggest that angiogenesis is an important process in the development of ovarian carcinoma and chemoresistance. The aim of this study was to identify a profile of angiogenesis-related genes as a biomarker for response to first-line chemotherapy in HGSOC., Materials and Methods: Formalin-fixed paraffin-embedded samples from 39 patients with HGSOC who underwent surgical cytoreduction and received a first-line chemotherapy with carboplatin and paclitaxel were included in this study. Expression levels of 82 angiogenesis-related genes were measured by quantitative real-time polymerase chain reaction using TaqMan low-density arrays., Results: Univariate analysis identified five genes [angiopoietin 1 (ANGPT1), aryl hydrocarbon receptor nuclear translocator (ARNT), CD34, epidermal growth factor (EGF) and matrix metallopeptidase 3 (MMP3)] as being statistically associated with response to treatment. Multivariable analysis by Lasso-penalized Cox regression generated a model with the combined expression of seven genes [angiotensinogen (AGT), CD34, EGF, erythropoietin receptor (EPOR), interleukin 8 (IL8), MMP3 and MMP7)]. The area under the receiver operating characteristics curve (0.679) and cross-validated Kaplan-Meier survival curves were used to estimate the accuracy of these predictors., Conclusion: An angiogenesis-related gene expression profile useful for response prediction in HGSOC was identified, supporting the important role of angiogenesis in HGSOC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Glycosyltransferase enzyme GCNT3, has been proposed as a biomarker for prognosis in colorectal cancer (CRC). Our study goes in depth into the molecular basis of GCNT3 role in tumorigenesis and drug resistance, and it explores its potential role as biomarker in epithelial ovarian cancer (EOC). High levels of GCNT3 are associated with increased sensibility to 5-fluoracil in metastatic cells. Accordingly, GCNT3 re-expression leads to the gain of anti-carcinogenic cellular properties by reducing cell growth, invasion and by changing metabolic capacities. Integrated transcriptomic and proteomic analyses reveal that GCNT3 is linked to cellular cycle, mitosis and proliferation, response to drugs and metabolism pathways. The vascular epithelial growth factor A (VEGFA) arises as an attractive partner of GCNT3 functions in cell invasion and resistance. Finally, GCNT3 expression was analyzed in a cohort of 56 EOC patients followed by a meta-analysis of more than one thousand patients. This study reveals that GCNT3 might constitute a prognostic factor also in EOC, since its overexpression is associated with better clinical outcome and response to initial therapy. GCNT3 emerges as an essential glycosylation-related molecule in CRC and EOC progression, with potential interest as a predictive biomarker of response to chemotherapy.

Background: Recent reports have identified distinct genomic patterns in ovarian carcinoma, including proliferative and mesenchymal-like groups, with worse outcome. The exact mechanisms driving the onset and progression of these tumors are still poorly understood. Additionally, researchers are concerned about the correct subtype stratification of the available cell line models, and the exploration of alternatives to monolayer culture. Identification of biomarkers to stratify cell lines, characterization of important processes as epithelial-mesenchymal transition (EMT), and the use of three-dimensional (3D) cultures as alternative models could be useful for cell line classification., Methods and Results: In this work, we present a descriptive analysis of 16 commonly used ovarian cancer cell lines. We have studied their morphology in 2- and 3D culture, and their response to cisplatin, observing in the majority of them an increased resistance in 3D. We have also performed an immunohistochemical analysis for proliferation marker Ki-67, and EMT related markers to establish phenotypes. Epithelial cells tend to show higher proliferative rates, and mesenchymal cells show an increase in EMT related markers, especially when cultured in 3D conditions., Conclusions: We have stated the complex heterogeneity of ovarian cancer models, resembling primary tumors, agreeing with the argument that the cell line model for in vitro experiments must be carefully chosen. Our results also support that tridimensional culture could be a very helpful alternative in ovarian cancer research. Regarding EMT, a very important process for the development of this disease, some related biomarkers might be further characterized for their role in this disease development., Competing Interests: CONFLICTS OF INTEREST The authors declare no potential conflicts of interest related to this work.

Background: Gemcitabine plus sirolimus enhances apoptosis in vitro and increases anti-tumor efficacy in vivo in soft-tissue sarcoma (STS) models., Objective: The objective of this study was to evaluate the activity and toxicity of the combination of gemcitabine plus sirolimus in patients with STS after failure of standard chemotherapy., Patients and Methods: Advanced STS patients, previously treated with doxorubicin and/or ifosfamide, were included in this single-arm phase II study. Patients received gemcitabine 800 mg/m 2 intravenously (iv) at 10 mg/m 2 /min on days 1 and 8 every 3 weeks plus sirolimus 5 mg daily orally (po). After enrolment of the first 12 patients, the study protocol was amended due to toxicity and the starting dose of sirolimus was reduced to 3 mg daily po. Archival tumor samples were analyzed for extracellular signal-regulated kinase 1 and 2 (ERK1/2) expression and correlated with outcome. The primary endpoint was progression-free rate (PFR) at 3 months., Results: From May 2012 to May 2013, 28 patients were enrolled at eight centers. PFR at 3 and 6 months was 44% and 20%, respectively, with 12 patients being free of progression at 3 months. Median progression-free survival (PFS) was 1.85 months (95% confidence interval [CI] 0.73-2.97) and median overall survival (OS) was 9.2 months (95% CI 5.8-12.5). No responses were observed. The most common grade 3-4 hematologic toxicities were neutropenia (48%) and leukopenia (41%) and the most frequent grade 3 non-hematologic toxicities were infection (18.5%), transaminitis (15%), fatigue (11%), and pneumonitis (11%). ERK1/2 expression was significantly correlated with PFS (p = 0.026)., Conclusions: The combination of gemcitabine and sirolimus is an active treatment in STS. Further investigation is warranted. ClinicalTrials.gov identifier: NCT01684449.

Primary malignant bone tumors are uncommon and heterogeneous malignancies. This document is a guideline developed by the Spanish Group for Research on Sarcoma with the participation of different specialists involved in the diagnosis and treatment of bone sarcomas. The aim is to provide practical recommendations with the intention of helping in the clinical decision-making process. The diagnosis and treatment of bone tumors requires a multidisciplinary approach, involving as a minimum pathologists, radiologists, surgeons, and radiation and medical oncologists. Early referral to a specialist center could improve patients' survival. The multidisciplinary management of osteosarcoma, chondrosarcoma, chordoma, giant cell tumor of bone and other rare bone tumors is reviewed in this guideline. Ewing's sarcoma will be the focus of a separate guideline because of its specific biological, clinical and therapeutic features. Each statement has been accompanied by the level of evidence and grade of recommendation on the basis of the available data. Surgical excision is the mainstay of treatment of a localized bone tumor, with various techniques available depending on the histologic type, grade and location of the tumor. Chemotherapy plays an important role in some chemosensitive subtypes (such as high-grade osteosarcoma). In other subtypes, historically considered chemoresistant (such as chordoma or giant cell tumor of bone), new targeted therapies have emerged recently, with a very significant efficacy in the case of denosumab. Radiation therapy is usually necessary in the treatment of chordoma and sometimes of other bone tumors.

Purpose: To compare the concordance in risk classification between the EndoPredict and the MammaPrint scores obtained for the same cancer samples on 40 estrogen-receptor positive/HER2-negative breast carcinomas., Methods: Formalin-fixed, paraffin-embedded invasive breast carcinoma tissues that were previously analyzed with MammaPrint as part of routine care of the patients, and were classified as high-risk (20 patients) and low-risk (20 patients), were selected to be analyzed by the EndoPredict assay, a second generation gene expression test that combines expression of 8 genes (EP score) with two clinicopathological variables (tumor size and nodal status, EPclin score)., Results: The EP score classified 15 patients as low-risk and 25 patients as high-risk. EPclin re-classified 5 of the 25 EP high-risk patients into low-risk, resulting in a total of 20 high-risk and 20 low-risk tumors. EP score and MammaPrint score were significantly correlated (p = 0.008). Twelve of 20 samples classified as low-risk by MammaPrint were also low-risk by EP score (60%). 17 of 20 MammaPrint high-risk tumors were also high-risk by EP score. The overall concordance between EP score and MammaPrint was 72.5% (κ = 0.45, (95% CI, 0.182 to 0.718)). EPclin score also correlated with MammaPrint results (p = 0.004). Discrepancies between both tests occurred in 10 cases: 5 MammaPrint low-risk patients were classified as EPclin high-risk and 5 high-risk MammaPrint were classified as low-risk by EPclin and overall concordance of 75% (κ = 0.5, (95% CI, 0.232 to 0.768))., Conclusions: This pilot study demonstrates a limited concordance between MammaPrint and EndoPredict. Differences in results could be explained by the inclusion of different gene sets in each platform, the use of different methodology, and the inclusion of clinicopathological parameters, such as tumor size and nodal status, in the EndoPredict test.

Purpose: Neuropathy is the dose-limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, the major causes for interindividual differences remain unexplained. In this study, we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes. Experimental Design: We sequenced the coding region of 4 EPHA genes, 5 genes involved in paclitaxel pharmacokinetics, and 30 Charcot-Marie-Tooth genes, in 228 cancer patients with no/low neuropathy or high-grade neuropathy during paclitaxel treatment. An independent validation series included 202 paclitaxel-treated patients. Variation-/gene-based analyses were used to compare variant frequencies among neuropathy groups, and Cox regression models were used to analyze neuropathy along treatment. Results: Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced neuropathy. Low-frequency nonsynonymous variants in EPHA6 were present exclusively in patients with high neuropathy, and all affected the ligand-binding domain of the protein. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for EPHA5/6/8 low-frequency nonsynonymous variant carriers [HR, 14.60; 95% confidence interval (CI), 2.33-91.62; P = 0.0042], and an independent cohort confirmed an increased neuropathy risk (HR, 2.07; 95% CI, 1.14-3.77; P = 0.017). Combining the series gave an estimated 2.5-fold higher risk of neuropathy (95% CI, 1.46-4.31; P = 9.1 × 10 -4 ). Conclusions: This first study sequencing EPHA genes revealed that low-frequency variants in EPHA6, EPHA5 , and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy. Furthermore, EPHA's neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs. Clin Cancer Res; 23(5); 1227-35. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Background: Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer., Methods: In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival., Results: Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P<0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications., Conclusions: Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274 .).

Purpose: Trebananib, a peptibody that blocks binding of angiopoietin-1 and -2 to Tie2, significantly prolonged progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer in the phase 3 TRINOVA-1 study. We report overall survival (OS) in the intent-to-treat population and clinically relevant subgroups and time to second disease progression (PFS-2)., Patients and Methods: Women with recurrent disease (platinum-free interval<12months) were randomized to receive intravenous paclitaxel 80mg/m(2) (3weeks on/1week off) plus intravenous trebananib 15mg/kg or placebo, weekly. OS in the intent-to-treat population was a key secondary endpoint. Exploratory analysis of PFS-2 was conducted according to guidance by the European Medicines Agency., Results: Median OS was not significantly improved with trebananib compared with placebo (19.3 versus 18.3months; HR, 0.95; 95% CI, 0.81-1.11; P=0.52) in the intent-to-treat population (n=919). In subgroup analysis, trebananib improved median OS compared with placebo (14.5 versus 12.3months; HR, 0.72; 95% CI, 0.55-0.93; P=0.011) in patients with ascites at baseline (n=295). In the intent-to-treat population, trebananib significantly improved median PFS-2 compared with placebo (12.5 versus 10.9months; HR, 0.85; 95% CI, 0.74-0.98; P=0.024). The incidence and type of adverse events in this updated analysis was consistent with that described in the primary analysis; no new safety signals were detected., Conclusions: OS was not significantly longer in the intent-to-treat population, although there was an improvement in OS in patients with ascites receiving trebananib. PFS-2 confirmed that the PFS benefit associated with trebananib was maintained through the second disease progression independent of the choice of subsequent therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Doxorubicin and trabectedin are considered active drugs in soft tissue sarcoma (STS). The combination of both drugs was hypothesized to be advantageous and safe on the basis of preclinical evidence and a previous phase I trial, respectively. The aim of this study was to compare the clinical outcome of trabectedin plus doxorubicin with doxorubicin as first-line treatment of advanced STS patients., Patients and Methods: In this open-label randomized phase II trial, the main end point was progression-free survival (PFS). Trabectedin 1.1 mg/m(2) in a 3-hour infusion plus doxorubicin 60 mg/m(2) as the experimental arm and doxorubicin 75 mg/m(2) as the control arm were administered for up to six cycles. Translational research was planned to correlate the expression of apoptotic and DNA repair genes with clinical outcome., Results: In 115 randomly assigned patients, the median PFS was 5.5 months in the control arm and 5.7 months in the experimental arm (hazard ratio, 1.16; 95% CI, 0.79 to 1.71; P = .45) in the intent-to-treat analysis. The trial was stopped for futility after the interim analysis, because the results in the experimental arm showed the risk reduction for the main end point to be < 9.64%. The proportion of patients with grade 3 or 4 thrombocytopenia, asthenia, and liver toxicity was significantly higher in the experimental arm. FAS and p53 were shown to be prognostic factors for PFS (7.0 months if FAS+ and p53-; 3.4 months if FAS+/p53+ or FAS-/p53-; and 0.7 months if FAS- and p53+; P < .001) and for overall survival., Conclusion: Trabectedin plus doxorubicin did not show superiority over doxorubicin alone as first-line treatment of advanced STS. The prognostic role of apoptotic key genes, FAS and p53, was shown to be robust enough to continue this research line., (© 2016 by American Society of Clinical Oncology.)

Background: Most GISTs have mutations in KIT or PDGFRA. Patients with advanced GIST with KIT exon 9, PDGFRA mutation or WT for KIT and PDGFRA have a worse progression-free survival (PFS) compared to patients with KIT exon 11 mutated tumors. We evaluated the immunohistochemical (IHC) expression of p-IGF1R (Y1316) and MMP3 as predictors of PFS or overall survival (OS)., Methods: Ninety-two advanced GIST patients included in GEIS-16 study with KIT and PDGFRA mutational information were examined for p-IGF1R (Y1316) and MMP3 expression in a tissue micro-array. To study activation of the IGF1R system, we have used an antibody (anti-pY1316) that specifically recognizes the active phosphorylated form of the IGF1R. DNA was extracted from paraffin-embedded tissues and intronic PCR primers were used to amplify exons 9, 11, 13 and 17 of KIT, 12 and 18 of PDGFRA. Bidirectional sequencing with specific primers was performed on a ABI3100 sequencer using the Big Dye Terminator v3.1 kit. Multivariate model was built using a stepwise automated variable selection approach with criterion to enter the variable in the model of p < 0.10 and criterion to keep the variable in the model of p < 0.05. PFS was computed as the date of imatinib initiation to progression or death. Overall survival was defined as the time from imatinib initiation to death., Results: Phospho-IGF1R was expressed only in 9 % (2/22) of cases without KIT mutation. MMP3 expression was detected in 2/5 patients (40 %) with PDGFRA mutation, 1/16 patients (6 %) with WT genotype and 7/71 patients (10 %) of KIT mutant patients. At univariate analysis KIT exon 11/13 mutation had better PFS than patients with exon 9 mutation, PDGFRA mutation or WT genotype (p = 0.021; HR: 0.46; 95 %CI (0.28-0.76). Less than 24 months disease free-interval (HR 24.2, 95 % CI 10.5-55.8), poor performance status (PS) (HR 6.3, 95 % CI 2.5-15.9), extension of disease; >1 organ (HR 1.89; 95 % CI 1.03-3.4) and genotype analysis (HR 0.57, 95 % CI 0.37-0.97) but not immunophenotype analysis (HR 1.53; 95 % CI 0.76-3.06) were the strongest prognostic factors for PFS in the multivariate analysis., Conclusions: Our results do not support p-IGF-1R and MMP3 evaluation in non-selected GIST patients but evaluation of this immunophenotype in WT and mutant PDGFR mutation in larger group of GIST patients, deserve merits.

Bevacizumab plus weekly paclitaxel improves progression-free survival (PFS) in HER2-negative metastatic breast cancer (mBC), but its use has been questioned due to the absence of a predictive biomarker, lack of benefit in overall survival (OS) and increased toxicity. We examined the baseline tumor angiogenic-related gene expression of 60 patients with mBC with the aim of finding a signature that predicts benefit from this drug.Multivariate analysis by Lasso-penalized Cox regression generated two predictive models: one, named G-model, including 11 genes, and the other one, named GC-model, including 13 genes plus 5 clinical covariates. Both models identified patients with improved PFS (HR (Hazard Ratio) 2.57 and 4.04, respectively) and OS (HR 3.29 and 3.43, respectively). The G-model distinguished low and high risk patients in the first 6 months, whereas the GC-model maintained significance over time., Competing Interests: The authors declare no conflicts of interest, with the exception of Dr. Redondo (honoraria, advisory role and research funding from Roche Farma).

Objective: We aimed to evaluate the prognostic and predictive value of the nucleotide excision repair-related gene GTF2H5, which is localized at the 6q24.2-26 deletion previously reported by our group to predict longer survival of high-grade serous ovarian cancer patients., Methods: In order to test if protein levels of GTF2H5 are associated with patients' outcome, we performed GTF2H5 immunohistochemical staining in 139 high-grade serous ovarian carcinomas included in tissue microarrays. Upon stratification of cases into high- and low-GTF2H5 staining categories (> and ≤ median staining, respectively) Kaplan-Meier and log-rank test were used to estimate patients' survival and assess statistical differences. We also evaluated the association of GTF2H5 with survival at the transcriptional level by using the on-line Kaplan-Meier plotter tool, which includes gene expression and survival data of 855 high-grade serous ovarian cancer patients from 13 different datasets. Finally, we determined whether stable short hairpin RNA-mediated GTF2H5 downregulation modulates cisplatin sensitivity in the SKOV3 and COV504 cell lines by using cytotoxicity assays., Results: Low expression of GTF2H5 was associated with longer 5-year survival of patients at the protein (hazard ratio [HR], 0.52; 95% CI, 0.29 to 0.93; p=0.024) and transcriptional level (HR, 0.80; 95% CI, 0.65 to 0.97; p=0.023) in high-grade serous ovarian cancer patients. We confirmed the association with 5-year overall survival (HR, 0.55; 95% CI, 0.38 to 0.78; p=0.0007) and also found an association with progression-free survival (HR, 0.72; 95% CI, 0.54 to 0.96; p=0.026) in a homogenous group of 388 high-stage (stages III-IV using the International Federation of Gynecology and Obstetrics staging system), optimally debulked high-grade serous ovarian cancer patients. GTF2H5-silencing induced a decrease of the half maximal inhibitory concentration upon cisplatin treatment in GTF2H5-silenced ovarian cancer cells., Conclusion: Low levels of GTF2H5 are associated with enhanced prognosis in high-grade serous ovarian cancer patients and may contribute to cisplatin sensitization.

Background: Recurrent, metastatic, and locally advanced gastrointestinal stromal tumors (GISTs) can be treated successfully with imatinib mesylate. Surgery for residual disease has been suggested for nonrefractory metastatic GISTs to reduce the probability of resistant recurrent clones, although no randomized Phase III trial has been performed to answer the question about its benefit. We carried out an analysis of the outcome of patients with recurrent unresectable locally advanced or metastatic imatinib-sensitive priamary GIST in 14 institutions in Spain. We compared two cohorts: treated or not treated with surgery after partial response or stabilization by imatinib., Patients and Methods: Data were obtained from the online GIST registry of the Spanish Group for Research in Sarcomas. Selected patients were then divided into two groups: group A, treated initially only with imatinib, and group B, treated additionally with metastasectomy. Baseline characteristics between groups were compared, and univariate and multivariate analysis for progression-free survival and overall survival (OS) were performed., Results: Analysis was undertaken in 171 patients considered nonrefractory to imatinib. The median follow-up time was 56.6 months. Focusing on OS, the Eastern Cooperative Oncology Group performance status different than 0, extent of disease limited to one metastatic organ, and comparison between groups A or B achieved statistical difference in the multivariate analysis. Median survival was 59.9 months in group A and 87.6 months in group B., Conclusions: Based in its benefit in OS, our study supports surgery of metastatic disease in GIST patients who respond to imatinib therapy.

VEGF-targeted therapies have shown activity in ovarian cancer, and one of them, bevacizumab, has been recently approved in this disease. Aflibercept is an antiangiogenic soluble fusion protein that inhibits VEGF-mediated signaling. In ovarian cancer, phase II trials with aflibercept have shown a significant benefit in the control of malignant ascites but with a lower response rate than expected.We report the case of a patient with relapsed ovarian cancer treated with aflibercept in fourth line, who experienced a prolonged response during more than two years with good tolerance. The duration of response to aflibercept was longer than that of the three previous lines of therapy (including the initial carboplatin-paclitaxel regimen) and ascites did not reappear. Further clinical research with this drug in ovarian cancer to identify patients who benefit most is warranted.

Background: Bevacizumab plus taxane chemotherapy improves progression-free survival (PFS) versus taxane monotherapy in the first-line treatment of HER2-negative metastatic breast cancer (MBC) and appears promising in the second-line setting. This retrospective analysis evaluated the efficacy and safety of this combination in a real-world setting., Patients and Methods: Eligible patients received bevacizumab (10 mg/kg days 1 and 15, every 28 days) plus paclitaxel (80 mg/m(2) days 1, 8, and 15, every 28 days) as first-line therapy for MBC, or as subsequent lines, including bevacizumab continuation therapy, at La Paz University Hospital between August 2007 and October 2012. End points included objective response rate (ORR), PFS, overall survival (OS), and safety., Results: Seventy-eight patients were included. Median PFS was 12.8 months for patients receiving first-line treatment and 9.3 months for subsequent lines. Forty-five patients (57.7%) continued bevacizumab after stopping paclitaxel, and had significantly longer PFS and OS than those who did not (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.248-0.653, P<0.001; HR 0.39, 95% CI 0.218-0.710, P=0.002; respectively). In the continuation phase, estrogen receptor-positive patients had longer PFS and OS when receiving hormone therapy plus bevacizumab versus patients receiving only bevacizumab (HR 0.50, 95% CI 0.24-1.04, P=0.06; HR 0.43, 95% CI 0.16-1.16, P=0.09; respectively). Thirty-five patients (44.9%) reported grade 3-4 adverse events., Conclusion: Bevacizumab plus paclitaxel was effective in HER2-negative MBC. Continuation of bevacizumab and addition of hormone therapy following paclitaxel therapy could be beneficial.

Background: Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival., Methods: For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m(2)) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT01204749, and is no longer accruing patients., Findings: 919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7·2 months [5·8-7·4] vs 5·4 months [95% CI 4·3-5·5], respectively, hazard ratio 0·66, 95% CI 0·57-0·77, p<0·0001). Incidence of grade 3 or higher adverse events was similar between treatment groups (244 [54%] of 452 patients in the placebo group vs 258 [56%] of 461 patients in the trebananib group). Trebananib was associated with more adverse event-related treatment discontinuations than was placebo (77 [17%] patients vs 27 [6%], respectively) and higher incidences of oedema (294 [64%] patients had any-grade oedema in the trebananib group vs 127 [28%] patients in the placebo group). Grade 3 or higher adverse events included ascites (34 [8%] in the placebo group vs 52 [11%] in the trebananib group), neutropenia (40 [9%] vs 26 [6%]), and abdominal pain (21 [5%] vs 22 [5%]). We recorded serious adverse events in 125 (28%) patients in the placebo group and 159 (34%) patients in the trebananib group. There was a difference of 2% or less in class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, wound-healing complications, thrombotic events, gastrointestinal perforations), except bleeding, which was more common in the placebo group than in the trebananib group (75 [17%] vs 46 [10%])., Interpretation: Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti-VEGF associated adverse events were not prominent., Funding: Amgen., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Context: The sodium iodide symporter (NIS) mediates active transport of iodide into the thyroid and the lactating mammary glands and is highly expressed in thyroid and breast carcinomas. NIS is clinically very relevant because it allows the treatment with radioiodine of thyroid cancer patients., Objective: In this study we wanted to explore whether NIS is expressed in the ovary and in ovarian cancer., Methods/patients: Methods included NIS and paired box 8 expression and function in ovarian cancer patients and rats by immunochemistry, immunoblot, RT-PCR, and iodide uptake., Results: Here we demonstrate for the first time that NIS is expressed in the ovary and fallopian tube and actively accumulates significant levels of radioiodide in vivo. In a large survey of menstruating women receiving radioiodide for medical purposes, 15% showed significant uptake in the normal reproductive tract. Ovarian NIS activity is influenced by the estrous cycle stage in rats, being up-regulated during peak levels of estrogens occurring immediately before the ovulation. We unveil that the regulatory mechanism underlying this phenomenon is based on the functional cooperation of estrogen receptor-α and paired box 8. We also show that NIS is highly expressed in ovarian cancer, predicting a poor prognosis in these patients., Conclusions: These results provide the basis that will help minimize the impact of therapeutic doses of radioiodide on gonadal function. We also suggest that NIS is a new ovarian cancer marker, opening a door for the use of radioiodide in the diagnosis and treatment of ovarian cancer patients.

Prostate cancer is the most common malignancy in men in Western countries. Until the last decade, the main available therapeutic options were based on hormonal therapy. For castration-refractory prostate carcinoma, from 2004, the combination of chemotherapy with docetaxel and prednisone has shown to improve survival in this subset of patients. Many agents have been tested either alone or in combination with this standard therapy, trying to find synergistic effects between drugs, and to target specific pathways that influence tumor growth, invasiveness, angiogenesis, and the development of distant metastasis. Endothelin antagonists have been recently studied, as they can get involved in many of these oncogenic pathways, and results are encouraging; nevertheless, the right setting to use them, whether to use them in monotherapy or in combination with other agents, and if they really improve the survival of our patients, are questions that remain to be addressed. In this review, we summarize the role of endothelins in tumoral biology and specifically in prostate carcinoma natural history, and the results obtained in the clinical trials involving this new therapeutic group.

Gene signatures may complement clinical and pathological factors to predict prognosis and response to therapy in patients with breast cancer, and can also sub-classify these tumours into entities with different biology and treatment requirements. A number of prognostic gene signatures are commercially available at this moment and two of them have entered phase III evaluation. Specific signatures are also being assessed to predict response to a number of drug therapies. The combined use of prognostic, predictive and subtype-defining signatures will guide therapeutic decisions in the future and will facilitate development of targeted drugs in specific groups of patients. However, cost-utility issues and some technical limitations have hindered widespread adoption of gene profiling. Gene signatures will become part of the routine clinical workup only if they help making clinical decisions. The first step to achieve this will consist of the inclusion of gene signatures in the design of clinical trials with new drugs., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objectives: The objective of the study was to assess the feasibility, toxicity, and reasons for early discontinuation of a modified outpatient intraperitoneal/intravenous (IP/IV) chemotherapy regimen for the treatment of patients with optimally debulked stage III ovarian cancer., Methods: Between February 2006 and November 2008, 51 consecutive patients from Institutions of the Spanish Ovarian Cancer Group (GEICO) were treated with a modified outpatient IP chemotherapy regimen. Patients received IV paclitaxel 175 mg/m over 3 hours on day 1, followed by IP cisplatin 100 mg/m (or 75 mg/m according to the principal investigator's criteria) on day 2. On day 8, patients received IP paclitaxel 60 mg/m. To homogenize the IP administration and supportive measures, a GEICO guideline for IP chemotherapy was established. Patients were treated with the intention to receive 6 courses of chemotherapy every 21 days., Results: The median age of the patients was 49 years (range, 36-75 years), and most of them had papillary serous ovarian cancer (78%), International Federation of Gynecology and Obstetrics stage IIIC (76%). Thirty-nine patients completed 4 or more IP cycles, and 28 (61%) completed all 6 IP cycles. Twenty-two patients discontinued the IP/IV treatment, mainly because of chemotherapy toxicity (10 patients) and catheter-related complications (5 patients). The most prevalent grade 3/4 toxicities were neutropenia (14 patients; 30%) and gastrointestinal events (12 patients; 26%)., Conclusions: The GEICO outpatient modified regimen resulted in a lesser toxicity and a greater rate of treatment completion than previously reported. The accurate selection of patients and the administration following well-defined guidelines can increase the feasibility of IP chemotherapy administration.

Ovarian cancer remains one of the leading causes of cancer deaths. Thus, new biomarkers predictive of response to the standard paclitaxel-carboplatin treatment are needed to improve chemotherapy strategies. MicroRNAs have the potential to modify drug outcomes. Based on this, we have demonstrated in this study that patients with a high expression of the miR-200 family show low levels of β-tubulin class III in ovarian carcinoma. In addition, we have established the clinical relevance of these microRNAs for ovarian cancer patients' treatment response and survival. In a well-characterized series of 72 ovarian carcinomas, the expressions of miR-141, miR-200a, miR-200b, miR-200c, and miR-429 were quantified by quantitative reverse transcription-PCR, and the protein content of β-tubulin isotypes I, II, and III was determined by immunohistochemistry. The relationship between these microRNAs, β-tubulin expression, response to paclitaxel-based treatment, progression-free survival (PFS) and overall survival was determined. While isotype I had constant high levels, protein expression of β-tubulins II and III was mutually exclusive. Low tumoral miR-200 expression was significantly associated with high β-tubulin III protein content (P values range, 0.047-<0.0001), and patients without complete response (CR) had lower miR-200c levels than patients with CR (hazard ratio (HR)=1.43, 95% confidence interval (CI)=1.02-1.99, P=0.037, multivariate analysis). Additionally, low miR-200 family expression had a trend toward poor PFS (HR>2.0, P values 0.051, 0.054, and 0.079 for miR-200c, miR-141, and miR-429 respectively, multivariate analysis). In conclusion, miR-200 family members affect the final β-tubulin III protein content of ovarian carcinomas. Furthermore, these microRNAs might constitute the biomarkers of response to paclitaxel-based treatments and relapse/progression of advanced stage ovarian carcinoma patients.

In the last few years, angiogenesis has confirmed its critical role in the development of malignant neoplasms. Antiangiogenic drugs, mainly bevacizumab, sorafenib, or sunitinib, are currently approved in a wide number of tumor types, such as breast, colorectal, liver, or kidney cancer, and have changed dramatically the evolution of our patients. Unfortunately, in urothelial carcinoma, which is a very common neoplasm, antiangiogenic agents are still in a very preliminary phase of clinical research. In this study, we focus on the biological basis of angiogenesis in urothelial tumors, its influence in the prognosis of these malignancies, and the available evidence about the use of antiangiogenic drugs in urothelial carcinoma.

Background: Gene expression profiling may improve prognostic accuracy in patients with early breast cancer. Our objective was to demonstrate that it is possible to develop a simple molecular signature to predict distant relapse., Methods: We included 153 patients with stage I-II hormonal receptor-positive breast cancer. RNA was isolated from formalin-fixed paraffin-embedded samples and qRT-PCR amplification of 83 genes was performed with gene expression assays. The genes we analyzed were those included in the 70-Gene Signature, the Recurrence Score and the Two-Gene Index. The association among gene expression, clinical variables and distant metastasis-free survival was analyzed using Cox regression models., Results: An 8-gene prognostic score was defined. Distant metastasis-free survival at 5 years was 97% for patients defined as low-risk by the prognostic score versus 60% for patients defined as high-risk. The 8-gene score remained a significant factor in multivariate analysis and its performance was similar to that of two validated gene profiles: the 70-Gene Signature and the Recurrence Score. The validity of the signature was verified in independent cohorts obtained from the GEO database., Conclusions: This study identifies a simple gene expression score that complements histopathological prognostic factors in breast cancer, and can be determined in paraffin-embedded samples.