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Recent advances in molecular profiling, have reclassified medulloblastoma, an undifferentiated tumor of the posterior fossa, in at least four diseases, each one with differences in prognosis, epidemiology and sensibility to different treatments. The recommended management of a lesion with radiological characteristics suggestive of MB includes maximum safe resection followed by a post-surgical MR 1.5 cm2, presence of micro- or macroscopic dissemination, and age > 3 years as well as pathological (presence of anaplastic or large cell features) and molecular findings (group, 4, 3 or p53 SHH mutated subgroup) determine the risk of relapse and should guide adjuvant management. Although there is evidence that both high-risk patients and to a lesser degree, standard-risk patients benefit from adjuvant craneoespinal radiation followed by consolidation chemotherapy, tolerability is a concern in adult patients, leading invariably to dose reductions. Treatment after relapse is to be considered palliative and inclusion on clinical trials, focusing on the molecular alterations that define each subgroup, should be encouraged. Selected patients can benefit from surgical rescue or targeted radiation or high-dose chemotherapy followed by autologous self-transplant. Even in patients that are cured by chemorradiation presence of significant sequelae is common and patients must undergo lifelong follow-up.

Coronavirus disease 2019 (COVID‐19) pandemic is affecting a high percentage of the population at an unprecedented rate. Cancer patients comprise a subgroup especially vulnerable to this infection. Herein, we present a prospective analysis of epidemiological, clinical, radiological and laboratory data of consecutive adult cancer patients seen in the Clínico San Carlos University Hospital (Madrid, Spain), and admitted to hospital and tested for COVID‐19 between 21 February 2020 and 8 May 2020 due to clinical suspicion of infection. Data from 73 patients with confirmed COVID‐19 and active solid tumors or diagnosed within the previous 5 years were analyzed. The most frequent malignancy was lung cancer (19%) and 54 patients (74%) were on active cancer treatment. Most common findings on presentation included cough (55%), fever (52%) and dyspnea (45%), and 32 (44%) patients showed oxygen saturation levels below 95%. Radiologically, 54 (73%) patients presented an abnormal pattern, the most frequent being infiltrates (64%). 18 (24.7%) patients died in hospital and 55 (75.3%) were discharged with clinical resolution of the event. Multivariable logistic regression adjusted for age and tumor stage showed higher odds of in‐hospital death associated with a history of cardiovascular disease, hospitalization in the previous 30 days, and several features on admission including dyspnea, higher qSOFA score, higher C‐reactive protein levels and an abnormal neutrophil count. We present prospective, real‐world evidence that can help articulate cancer care protocols for patients infected with SARS‐CoV‐2, with special focus on features on admission that can stratify patients with a higher risk of death from COVID‐19., What's new? This report provides prospective data about cancer patients with COVID‐19 in a situation of maximum pressure on the healthcare system of a large urban area in Western Europe. Despite a milder clinical profile on presentation, in‐hospital mortality of COVID‐19 was higher in cancer patients than in the general population. The mortality risk was associated with a history of cardiovascular disease and several variables on admission, but seemed not to be influenced by tumor type or anti‐tumor therapy. The evidence could help articulate cancer care protocols for patients infected with SARS‐CoV‐2 and identify patients with a higher risk of in‐hospital death.

Funder: Funding details are provided in the Supplementary Material, Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, ���select and shrink for summary statistics��� (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28���1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08���1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30���1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

[Background and objective]: Integrins are a family of adhesion receptor proteins that provide signaling from the extracellular matrix to the cytoplasm. They have been associated with cancer by promoting migration, invasion, metastasis, and survival. ¿¿ß6 integrin is upregulated in several tumors. Here, we evaluate the prognostic impact of ¿¿ß6 integrin protein expression in solid tumors. [Methods]: A systematic search of electronic databases identified publications exploring the effect of ¿¿ß6 integrin on overall survival (OS). Hazard ratios (HRs) were pooled in a meta-analysis using generic inverse variance and random effects modeling. Subgroup analyses were conducted based on tumor site, tumor stage, antibody used for immunohistochemistry (IHC) and method for extraction of the HR. A meta-regression explored the influence of clinical variables on the magnitude of effect of ¿¿ß6 integrins on OS. [Results]: Seventeen studies comprising 5795 patients met the inclusion criteria. High ¿¿ß6 integrin expression in tumors was associated with worse OS (HR 1.65, 95% confidence interval [CI] 1.32-2.06; Cochran's Q p < 0.001, I2 = 81%). Adverse outcomes were similar in all tumor sites (subgroup difference p = 0.10), with the strongest association between ¿¿ß6 integrins and OS in gastric cancer (HR 2.20, 95% CI 1.71-2.83) and the lowest in head and neck cancer (HR 1.21, 95% CI 0.79-1.83). There was no significant difference between early-stage and metastatic cancer, type of IHC antibodies, and analysis methods. [Conclusions]: High expression of ¿¿ß6 integrins is associated with adverse survival outcome in several tumors. Prospective studies evaluating the prognostic impact of ¿¿ß6 integrin and its role as a therapeutic target are warranted.

Breast and prostate cancer risks; Pathogenic variant Riscos de càncer de mama i pròstata; Variants patogèniques Riesgos de cáncer de mama y próstata; Variantes patogénicas Background Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. Methods 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)–negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. Results PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. Conclusions Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management. The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861 and PPRPGM-Nov20\100002. The research leading to these results has received funding from the Italian Association for Cancer Research (AIRC) under IG 2018 - ID. 21389 and the Italian League for the Fight Against Cancer (LILT) under IG 2019 projects, P.I. Ottini Laura and Italian Ministry of Education, Universities and Research-Dipartimenti di Eccellenza-L. 232/2016. CIMBA: GCT is a National Health and Medical Research Council (NHMRC) Research Fellow. iCOGS and OncoArray data: the European Community’s Seventh Framework Programme under grant agreement No. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (NIH) (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Personalized Risk Stratification for Prevention and Early Detection of Breast Cancer (PERSPECTIVE) and PERSPECTIVE I&I projects were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy and Innovation through Genome Québec, and The Quebec Breast Cancer Foundation and the Ontario Research Fund. Breast Cancer Family Registry (BCFR): UM1 CA164920 from the National Cancer Institute (NCI). Baltic Familial Breast Ovarian Cancer Consortium (BFBOCC): Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015. Beth Israel Deaconess Medical Center (BIDMC): Breast Cancer Research Foundation. BRCA-gene mutations and breast cancer in South African women (BMBSA): Cancer Association of South Africa (PI Elizabeth J. van Rensburg). Spanish National Cancer Centre (CNIO): Spanish Ministry of Health PI16/00440 supported by Fondo Europeo de Desarrollo Regional (FEDER) funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). City of Hope - Clinical Cancer Genomics Community Research Network (COH-CCGCRN): Research reported in this publication was supported by the NCI of the NIH under grant No. R25CA112486, and RC4CA153828 (PI: J. Weitzel) from the NCI and the Office of the Director, NIH. CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella (CONSIT TEAM): Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 No.15547) to P. Radice. Funds from Italian citizens who allocated the 5x1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5x1000’) to S. Manoukian. Associazione CAOS Varese to M.G. Tibiletti. AIRC (IG2015 No.16732) to P. Peterlongo. National Centre for Scientific Research Demokritos (DEMOKRITOS): European Union (European Social Fund—ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. German Cancer Research Center (DFKZ): German Cancer Research Center. Epidemiological Study of Familial Breast Cancer (EMBRACE): Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an National Institute for Health Research (NIHR) grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden National Health Service (NHS) Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Fox Chase Cancer Center (FCCC): The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. AKG was in part funded by the NCI (R01 CA214545 and R01 CA140323), The Kansas Institute for Precision Medicine (P20 GM130423), and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. is the Chancellors Distinguished Chair in Biomedical Sciences Professor. Fundación Pública Galega de Medicina Xenómica (FPGMX): FISPI05/2275 and Mutua Madrileña Foundation (FMMA). German Familial Breast Group (GC-HBOC): German Cancer Aid (grant No. 110837, Rita K. Schmutzler) and the European Regional Development Fund and Free State of Saxony, Germany (LIFE—Leipzig Research Centre for Civilization Diseases, project No. 713-241202, No. 713-241202, No. 14505/2470, and No. 14575/2470). Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO): Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award, the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program and the French National Institute of Cancer (INCa grants 2013-1-BCB-01-ICH-1 and SHS-E-SP 18-015). Georgetown University (GEORGETOWN): the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing Fore the Cure. Ghent University Hospital (G-FAST): Bruce Poppe is a senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. Hospital Clinico San Carlos (HCSC): Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. Helsinki Breast Cancer Study (HEBCS): Helsinki University Hospital Research Fund, the Finnish Cancer Society and the Sigrid Juselius Foundation. Hereditary Breast and Ovarian cancer study the Netherlands (HEBON): the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of Dutch Cancer Registry (IKNL; S. Siesling, J. Verloop) and the Dutch Pathology database (PALGA; L. Overbeek) for part of the data collection. Study of Genetic Mutations in Breast and Ovarian Cancer patients in Hong Kong and Asia (HRBCP): Hong Kong Sanatorium and Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, National Institute of Health1R 03CA130065, and North California Cancer Center. Molecular Genetic Studies of Breast- and Ovarian Cancer in Hungary (HUNBOCS): Hungarian Research Grants KTIA-OTKA CK-80745 and NKFI_OTKA K-112228. Institut Català d’Oncologia (ICO): The authors would like to particularly acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad) and “FEDER, una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563 and CIBERONC) and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338 and PERIS Project MedPerCan). International Hereditary Cancer Centre (IHCC): PBZ_KBN_122/P05/2004. Iceland Landspitali – University Hospital (ILUH): Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility (INHERIT): Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program—grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade—grant No. PSR-SIIRI-701. Istituto Oncologico Veneto (IOVHBOCS): Ministero della Salute and “5x1000” Istituto Oncologico Veneto grant. Portuguese Oncology Institute-Porto Breast Cancer Study (IPOBCS): Liga Portuguesa Contra o Cancro. Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab): The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Korean Hereditary Breast Cancer Study (KOHBRA): the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 1020350; 1420190). Mayo Clinic (MAYO): NIH grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer Research Foundation. McGill University (MCGILL): Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. Marc Tischkowitz is supported by the funded by the European Union Seventh Framework Program (2007Y2013)/European Research Council (Grant No. 310018). Modifier Study of Quantitative Effects on Disease (MODSQUAD): MH CZ—DRO (MMCI, 00209805), MEYS—NPS I—LO1413 to LF, and by Charles University in Prague project UNCE204024 (MZ). Memorial Sloane Kettering Cancer Center (MSKCC): the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). Women’s College Research Institute Hereditary Breast and Ovarian Cancer Study (NAROD): 1R01 CA149429-01. National Cancer Institute (NCI): the Intramural Research Program of the US NCI, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc, Rockville, MD. National Israeli Cancer Control Center (NICCC): Clalit Health Services in Israel, the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. N.N. Petrov Institute of Oncology (NNPIO): the Russian Foundation for Basic Research (grants 17-54-12007, 17-00-00171 and 18-515-12007). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. The Ohio State University Comprehensive Cancer Center (OSUCCG): Ohio State University Comprehensive Cancer Center. Università di Pisa (PBCS): AIRC [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. South East Asian Breast Cancer Association Study (SEABASS): Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. Sheba Medical Centre (SMC): the Israeli Cancer Association. Swedish Breast Cancer Study (SWE-BRCA): the Swedish Cancer Society. University of Chicago (UCHICAGO): NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women’s Cancer Research Alliance and the Breast Cancer research Foundation. OIO is an American Cancer Society (ACS) Clinical Research Professor. University of California Los Angeles (UCLA): Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. University of California San Francisco (UCSF): UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UK Familial Ovarian Cancer Registry (UKFOCR): Cancer Research UK. University of Pennsylvania (UPENN): NIH (R01-CA102776 and R01-CA083855); Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. Cancer Family Registry University of Pittsburg (UPITT/MWH): Hackers for Hope Pittsburgh. Victorian Familial Cancer Trials Group (VFCTG): Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. Women’s Cancer Program at Cedars-Sinai Medical Center (WCP): Dr Karlan is funded by the ACS Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. TN-D is a recipient of a Career Development Fellow from the National Breast Cancer Foundation (Australia, ECF-17-001).

Identification of membrane proteins expressed exclusively on tumor cells is a goal for cancer drug development. The receptor tyrosine kinase-like orphan receptor type 1 and 2 (ROR1/2), are type-I transmembrane proteins expressed in cancer but not in adult normal tissue. Here, we explore the prognostic role ROR1/2 expression on patient outcome.A systematic search of electronic databases identified publications exploring the effect of ROR1/2 on overall survival (OS). Hazard ratios (HR) from collected data were pooled in a meta-analysis using generic inverse-variance and random effects modeling. Subgroup analyses were conducted based on disease site or tumor type.Twenty five studies met the inclusion criteria. ROR1 was associated with worse overall survival (HR 2.13, 95% confidence interval (CI) 1.62-2.80; P 0.001) with subgroup analysis showing the strongest association between ROR1 and OS was in lung cancer. There was no significant difference between solid tumors and hematological malignancies (HR 2.15, 95% CI 1.52-3.06 vs. HR 2.02, 95% CI 1.46-2.84; subgroup difference P = 0.80). ROR2 was also associated with worse OS (HR 1.84, 95% CI 1.43-2.38; P 0.001). There was no significant difference between disease sites although the highest association seen was in head and neck cancers (HR 3.19, 95% CI 1.13-8.97) and the lowest in gynecological cancers (HR 1.19, 95% CI 0.71-2.00; subgroup difference P = 0.10).ROR1 and ROR2 expression is associated with adverse outcome in several tumors. ROR1/2 warrants study as a target for developmental therapeutics.

Many patients with recurrent/metastatic squamous cell cancer of the head and neck (SCCHN) are old or fragile and, despite deserving rapid and deep responses due to symptoms or a high tumor burden, they are not candidates for the current standard in the first-line setting of pembrolizumab plus platinum-5-FU. Other chemoimmunotherapy combinations substituting the 5-FU infusion by a taxane, may allow for less toxic effects without the need for a central venous catheter placement while maintaining efficacy. We present the case of an oral cavity cancer progressing with bulky disease to first-line cetuximab-paclitaxel in a frail and malnourished patient, where second-line treatment with pembrolizumab and reduced-dose 3-weekly carboplatin-paclitaxel achieved a deep and durable response. This is, to our knowledge, the first reported case of such combination being used in the R/M setting of SCCHN. Clinical trials should try to investigate the feasibility of this potentially less toxic and convenient combination in patients with SCCHN.

Previous works seem to agree in the higher mortality of cancer patients with COVID-19. Identifying potential prognostic factors upon admission could help identify patients with a poor prognosis.We aimed to explore the characteristics and evolution of COVID-19 cancer patients admitted to hospital in a multicenter international registry (HOPE COVID-19).Our primary objective is to define those characteristics that allow us to identify cancer patients with a worse prognosis (mortality within 30 days after the diagnosis of COVID-19).5838 patients have been collected in this registry, of whom 770 had cancer among their antecedents. In hospital mortality reached 258 patients (33.51%). The median was 75 years (65-82). Regarding the distribution by sex, 34.55% of the patients (266/770) were women.The distribution by type of cancer: genitourinary 238/745 (31.95%), digestive 124/745 (16.54%), hematologic 95/745 (12.75%).In multivariate regression analysis, factors that are independently associated with mortality at admission are: renal impairment (OR 3.45, CI 97.5% 1.85-6.58), heart disease (2.32, 1.47-3.66), liver disease (4.69, 1.94-11.62), partial dependence (2.41, 1.34-4.33), total dependence (7.21, 2.60-21.82), fatigue (1.84, 1.16-2.93), arthromialgias (0.45, 0.26-0.78), SatO2 92% (4.58, 2.97-7.17), elevated LDH (2.61, 1.51-4.69) and abnormal decreased Blood Pressure (3.57, 1.81-7.15). Analitical parameters are also significant altered.In patients with cancer from the HOPE registry, 30-day mortality from any cause is high and is associated with easily identifiable clinical factors upon arrival at the hospital. Identifying these patients can help initiate more intensive treatments from the start and evaluate the prognosis of these patients.Trabajos previos parecen coincidir en la mayor mortalidad de los pacientes con cáncer y COVID-19. La identificación de posibles factores pronósticos en el momento del ingreso podría ayudar a identificar a los pacientes con mal pronóstico.Nos propusimos explorar las características y la evolución de los pacientes con cáncer y COVID-19 ingresados en un registro internacional multicéntrico (HOPE COVID-19).Nuestro objetivo principal es definir aquellas características que nos permitan identificar a los pacientes con cáncer de peor pronóstico (mortalidad en los 30 días siguientes al diagnóstico de COVID-19).En este registro se ha recogido a 5.838 pacientes, de los cuales 770 tenían cáncer entre sus antecedentes. La mortalidad hospitalaria alcanzó a 258 pacientes (33,51%). La mediana fue de 75 años (65-82). En cuanto a la distribución por sexo, el 34,55% de los pacientes eran mujeres (266/770).La distribución por tipo de cáncer: genitourinario 238/745 (31,95%), digestivo 124/745 (16,54%) y hematológico 95/745 (12,75%).En el análisis de regresión multivariante, los factores que se asocian de forma independiente con la mortalidad al ingreso son: insuficiencia renal (OR 3,45; IC 97,5%: 1,85-6,58), cardiopatía (2,32; 1,47-3,66), hepatopatía (4,69; 1,94-11,62), dependencia parcial (2,41; 1,34-4,33), dependencia total (7,21; 2,60-21,82), fatiga (1,84, 1;16-2,93), artromialgias (0,45; 0,26-0,78), SatOEn los pacientes con cáncer del registro HOPE, la mortalidad a los 30 días por cualquier causa es elevada y se asocia a factores clínicos fácilmente identificables a su llegada al hospital. La identificación de estos pacientes puede ayudar a iniciar tratamientos más intensivos desde el principio y evaluar el pronóstico de estos pacientes.

Background: Coronavirus disease 2019 (COVID-19) pandemic is affecting a high percentage of the population at an unprecedented rate Cancer patients comprise a subgroup especially vulnerable to this infection However, to date, there is a critical need of medical data to optimize the management of these patients Methods: We present a prospective analysis of epidemiological, clinical, radiological and laboratory data of consecutive adult cancer patients seen in the Medical Oncology Department of the Hospital Universitario Clinico San Carlos (Madrid, Spain), and admitted to hospital and tested for COVID-19 between February 21 and April 9, 2020 due to clinical suspicion of infection Results: 193 patients with suspected COVID-19 were prospectively followed Data from 58 patients with confirmed COVID-19 and active cancer or diagnosed within the last 5 years were analyzed The most frequent malignancy was lung cancer (22%) 45 patients (78%) were on active cancer treatment, of which 36 (84%) had their last dose administered within 14 days before admission Most common findings on presentation included fever (59%), cough (53%), and dyspnea (48%), and 25 (43%) patients showed oxygen saturation levels below 95% Radiologically, 41 (71%) patients presented an abnormal pattern, the most frequent being infiltrates (62%) 17 (29 3%) patients died in hospital and 41 (61 7%) were discharged with clinical resolution of the event Multivariable logistic regression showed higher odds of in-hospital death associated with a history of cardiovascular disease (odds ratio 5 14, 1 28-22 55;p=0 023), lower oxygen saturation levels (1 12, 1 01-1 30;p=0 049), and neutropenia (9 01, 1 08-100;p=0 047) on admission Conclusions: The data presented here captures the course of COVID-19 in cancer patients during the initial phase of the outbreak and may help identify patients with a higher risk of death from COVID-19 at the time of diagnosis so that earlier and more intensive measures can be articulated Legal entity responsible for the study: Hospital Clinico San Carlos Funding: Has not received any funding Disclosure: All authors have declared no conflicts of interest

Background: There is growing evidence that cancer patients may be more susceptible to contracting coronavirus disease 2019 (COVID-19) infection, show a more aggressive course and associate a poorer prognosis than the general population An unbalanced inflammatory response and systemic coagulopathy seem to define the pathological hallmark underlying severe presentations However, the complex immune cell interplay and the role of the tumor-associated pro-coagulative state in COVID-19 remain a challenge Methods: We prospectively evaluated cancer patients presenting to the emergency department of the Hospital Clinico San Carlos (Madrid, Spain) with severe pneumonia, and compared a comprehensive coagulation and immunological profile from blood samples on admission between those with SARS-CoV-2 positive and negative RT-PCR tests Results: 14 patients with suspected COVID-19 and receiving in-hospital care were prospectively followed SARS-CoV-2 RT-PCR was positive on admission in 6 patients, and negative on admission and on re-test in 8 patients Peripheral blood samples were drawn on admission In spite of the modest sample size, patients with SARS-CoV-2 positive showed higher levels of D-dimer (median 6,355 vs 1,964 ng/ml, p=0 025), a decreased CD4+/CD8+ ratio (1 2 vs 2 2, p=0 17) at the expense of CD4+ T lymphocytopenia (305 vs 467, p=0 18), and NK cell expansion (17 vs 9%, p=0 13) Several monocyte activation markers were found to be elevated in RT-PCR positive patients, including CD86 (2 8-fold increase in classic monocytes, p=0 06) and CCR2 (2 9-fold in intermediate monocytes, p=0 17;11-fold in non-classic monocytes, p=0 03) Conclusions: In cancer patients presenting with severe SARS-CoV-2 positive pneumonia, the infection may cause a hypercoagulable state, as suggested by higher levels of D-dimer, and unleash a pro-inflammatory response Marked CD4+ T lymphocytopenia and NK expansion may reflect lymphocyte exhaustion and dysregulated cytotoxicity Monocyte activation and recruitment also seem to be strongly upregulated Legal entity responsible for the study: Hospital Clinico San Carlos Funding: Cris Cancer Foundation Disclosure: All authors have declared no conflicts of interest

Importance The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participants Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Results Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P

Introduction Venous thromboembolism (VTE) is common in non-small cell lung cancer (NSCLC) patients undergoing systemic chemotherapy. The usefulness of Khorana score (KRS) to predict risk in lung cancer patients is limited, and the identification of patients who would benefit most from thromboprophylaxis is challenging. We aimed to identify variables whose values before chemotherapy helped in predicting VTE occurrence, and build a model to assess VTE risk. Materials and methods A cohort of newly diagnosed NSCLC patients to undergo outpatient chemotherapy, not under anticoagulant treatment, was recruited. Pre-chemotherapy demographic, clinical, analytical and tumor-specific variables were collected. Patients were prospectively followed-up for 12 months to record VTE events. Bivariate and multivariate analyses were performed to identify VTE-associated variables, and a prediction model was built and compared with KRS. Results 90 patients were recruited, 18 of whom had a VTE event during follow-up. High baseline levels of factor VIII (FVIII) and, especially, soluble P-selectin (sP-selectin), were independently associated with VTE risk (hazard ratio [HR] 4.15, 95% confidence interval [CI] 1.17–14.71, and 66.40 [8.70–506.69], respectively). Our so-called Thrombo-NSCLC risk score, which assigns 1 and 3 points to high FVIII and sP-selectin values, respectively, was significantly better than KRS in predicting VTE (area under the curve [AUC] 0.93 vs. 0.55, sensitivity 94.4 vs. 35.0%, specificity 93.1 vs. 60.0%). Our prediction model showed significant discriminating capacity between high risk vs. intermediate/low risk patients, while KRS did not. Conclusions The Thrombo-NSCLC risk score may be useful to identify those NSCLC patients who would benefit most from thromboprophylaxis.

BACKGROUND AND RATIONALE: Thromboembolic complications are a serious, preventable and common event in cancer patients that contributes to increasing morbidity and mortality. Despite increasing knowledge on cancer-associated thrombosis (CAT), there are still several aspects of diagnosis, clinical management, treatment and prognosis with uncertainties that are under-represented in randomized clinical trials. For this reason, the Spanish Society of Medical Oncology (SEOM) launched in June 2018 a registry of CAT. METHODS/DESIGN: TESEO is an ongoing prospective, non-interventional, multicentric study in consecutive cancer patients with newly diagnosed of thromboembolic event (TEE). Eligibility criteria include being > 18 years with a histologically confirmed diagnosis of cancer and a symptomatic or incidental TEE confirmed with an imaging technique in the previous month or any time after the cancer diagnosis and signing of informed consent. The study consists of two types of integrated but independent prospective registries. Regular CAT sub-registry includes information on patient's cancer´s characteristics, anticoagulant treatment provided and outcome data. Special CAT sub-registry includes variables related to special situations of CAT that comprise patients with severe kidney failure, thrombocytopenia, high risk of bleeding related to the cancer or with coexistence of bleeding and patients who receive new treatments such a targeted therapy, antiangiogenics agents and immunotherapy. The registry considers the status of the cancer and the time to assess how the prognosis is changed based on when the thrombus occurs. Some outcomes such as rethrombosis, major bleeding, tumor progression and survival will be valued in various time intervals including 1, 3, 6 and 12 months after the even in the first year; and then every 6 months until the patient's death. RESULTS: After 18 months and with 35 centers and researchers, the registry has 1128 patients. CONCLUSION: TESEO registry will provide clinical real-world evidence for prevention, treatment and complications of CAT in different scenarios that are under-represented in randomized clinical trials.

Background Standard treatment for glioblastoma is radiation with concomitant and adjuvant temozolomide for 6 cycles, although the optimal number of cycles of adjuvant temozolomide has long been a subject of debate. We performed a phase II randomized trial investigating whether extending adjuvant temozolomide for more than 6 cycles improved outcome. Methods Glioblastoma patients treated at 20 Spanish hospitals who had not progressed after 6 cycles of adjuvant temozolomide were centrally randomized to stop (control arm) or continue (experimental arm) temozolomide up to a total of 12 cycles at the same doses they were receiving in cycle 6. Patients were stratified by MGMT methylation and measurable disease. The primary endpoint was differences in 6-month progression-free survival (PFS). Secondary endpoints were PFS, overall survival (OS), and safety (Clinicaltrials.gov NCT02209948). Results From August 2014 to November 2018, 166 patients were screened, 7 of whom were ineligible. Seventy-nine patients were included in the stop arm and 80 in the experimental arm. All patients were included in the analyses of outcomes and of safety. There were no differences in 6-month PFS (control 55.7%; experimental 61.3%), PFS, or OS between arms. MGMT methylation and absence of measurable disease were independent factors of better outcome. Patients in the experimental arm had more lymphopenia (P Conclusions Continuing temozolomide after 6 adjuvant cycles is associated with greater toxicity but confers no additional benefit in 6-month PFS. Key Points 1. Extending adjuvant temozolomide to 12 cycles did not improve 6-month PFS. 2. Extending adjuvant temozolomide did not improve PFS or OS in any patient subset. 3. Extending adjuvant temozolomide was linked to increased toxicities.

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Background: The ever-growing complexity of cancer-associated thrombosis (CAT), with new antineoplastic drugs and anticoagulants, distinctive characteristics, and decisions with low levels of evidence, justifies this registry. Method: TESEO is a prospective registry promoted by the Spanish Society of Medical Oncology to which 34 centers contribute cases. It seeks to provide an epidemiological description of CAT in Spain. Results: Participants (N=939) with CAT diagnosed between July 2018 and December 2019 were recruited. Most subjects had advanced colon (21.4%), non-small cell lung (19.2%), and breast (11.1%) cancers, treated with dual-agent chemotherapy (28.4%), monochemotherapy (14.4%), or immune checkpoint inhibitors (3.6%). Half (51%) were unsuspected events, albeit only 57.1% were truly asymptomatic. Pulmonary embolism (PE) was recorded in 571 (58.3%); in 120/571 (21.0%), there was a concurrent deep venous thromboembolism (VTE). Most initially received low molecular weight heparin (89.7%). Suspected and unsuspected VTE had an OS rate of 9.9 (95% CI, 7.3-non-computable) and 14.4 months (95% CI, 12.6-non-computable) (p=0.00038). Six-month survival was 80.9%, 55.9%, and 55.5% for unsuspected PE, unsuspected PE admitted for another reason, and suspected PE, respectively (p

Head and neck cancers are increasingly being diagnosed in elderly patients, where standard curative-intent, therapeutic options are often too aggressive for frail, malnourished and heavily comorbid patients. Since the incorporation of immune checkpoint inhibitors (ICIs) a few small studies have reported promising safety and efficacy with ICIs in the neoadjuvant locally-advaced setting. We present the case of an elderly, frail and comorbid patient, with a high-PDL1 expressing and very locally-advanced unresectable oral cavity cancer, that was treated with the combination of pembrolizumab and weekly carboplatin and paclitaxel, achieving a major pathological response, that permitted to de-escalate adjuvant therapy after surgery and is free of locoregional relapse 7 months after surgery. This is, to our knowledge, the first patient treated with neoadjuvant chemo-immunotherapy outside a clinical trial in SCCHN.

[Introduction]: Therapeutic targeting of inhibitors of the immune response has reached the clinical setting. Inhibitors of the novel receptor LAG3, which negatively regulates T-cell activation, are under investigation. Here we explore the presence and prognostic role of LAG3 in cancer., [Methods]: A systematic search of electronic databases identified publications exploring the effect of LAG3 on overall survival (OS) and (for early-stage cancers) disease-free survival (DFS). Hazard ratios (HR) were pooled in a meta-analysis using generic inverse-variance and random effect modeling. Subgroup analyses were conducted based on disease site and tumor type., [Results]: Fifteen studies met the inclusion criteria. LAG3 was associated with better overall survival [HR 0.81, 95% confidence interval (CI) 0.66–0.99; P = 0.04], with subgroup analysis showing no significant differences between disease-site subgroups. The beneficial effect of LAG3 on OS was of greater magnitude in early-stage malignancies (HR 0.73, 95% CI 0.60–0.88) than in the metastatic setting (HR 1.20, 95% CI 0.70–2.05), but this difference was not statistically significant (subgroup difference p = 0.18). LAG3 did not have a significant association with DFS [HR 1.02, 95% confidence interval (CI) 0.77–1.37; P = 0.87], with subgroup analysis showing worse DFS in patients with lymphoma and improved DFS in those with breast cancer., [Conclusions]: High expression of LAG3 is associated with favorable overall survival in several solid tumors. A trend toward an association in early-stage disease suggests the importance of immune surveillance in this setting.

© 2019 Pérez-Pena, Tibor Fekete, Páez, Baliu-Piqué, García-Saenz, García-Barberán, Manzano, Pérez-Segura, Esparis-Ogando, Pandiella, Gyorffy and Ocaña., Limited therapeutic options exist for the treatment of patients with triple negative breast cancer (TNBC). Neoadjuvant chemotherapy is currently the standard of care treatment in the early stages of the disease, although reliable biomarkers of response have been scarcely described. In our study we explored whether immunologic signatures associated with inflamed tumors or hot tumors could predict the outcome to neoadjuvant chemotherapy. Publicly available transcriptomic data of more than 2,000 patients were evaluated. ROC plots were generated to assess the response to therapy. Cox proportional hazards regression was computed. Kaplan-Meier plots were drawn to visualize the survival differences. Higher expression of IDO1, CXCL9, CXCL10, HLA-DRA, HLA-E, STAT1, and GZMB were associated with a higher proportion without relapse in the first 5 y after chemotherapy in TNBC. The expression of these genes was associated with a high presence of CD8 T cells in responder patients using the EPIC bioinformatic tool. The strongest effect was observed for STAT1 (p = 1.8e-05 and AUC 0.69, p = 2.7e-06). The best gene-set signature to predict favorable RFS was the combination of IDO1, LAG3, STAT1, and GZMB (HR = 0.28, CI = 0.17–0.46, p = 9.8 E-08, FDR = 1%). However, no influence on pathological complete response (pCR) was observed. Similarly, no benefit was identified in any other tumor subtype: HER2 or estrogen receptor positive. In conclusion, we describe a set of immunologic genes that predict the outcome to neoadjuvant chemotherapy in TNBC, but not pCR, suggesting that this non-time to event endpoint is not a good surrogate marker to detect the long term outcome for immune activated tumors., This work was supported by the Instituto de Salud Carlos III (PI16/01121), ACEPAIN; Diputación de Albacete, CIBERONC and the CRIS Cancer Foundation (to AO). The Ministry of Economy and Competitiveness of Spain (BFU2015-71371-R), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003) and CIBERONC, the scientific foundation of the AECC and the CRIS Foundation (to AP). The work carried out in our laboratories received support from the European Community through the regional development funding program (FEDER). BG was supported by the NVKP_16-1-2016-0037, 2018-1.3.1-VKE-2018-00032, and KH-129581 grants.

Background Standard treatment of glioblastoma (GBM) is focal radiation with concomitant and adjuvant temozolomide (TMZ) for 6 cycles. The GEINO-14-01 trial (NCT02209948) investigated the role of extending adjuvant TMZ to 12 cycles in a randomized multicenter study. Methods Between Aug/2014 and Nov/2018, 166 patients (p) were screened and 159 randomized to extend (80p) or not (79p) TMZ treatment to 12 cycles after proving lack of progression of the disease in the MRI performed before inclusion. The trial was stratified by MGMT status and presence or absence of residual disease (defined as a residual enhancement larger than 1cm on the MRI). The primary endpoint was differences in 6monthsPFS, secondary endpoints were differences in PFS, OS, toxicity, between arms and per stratification factors. Results Median age was 60.4 (range 29-83), all p had ECOG≤1 and 86.2% were without DXM treatment. MGMT status: Met: 97 (61%) UnMet:62 (39%). RD yes: 83 (52.2%) and no: 76 (47.8%). At the time of the abstract report 3 patients are still on treatment or control without a documented progression and 5 patients have not been yet 6m in the study: 31 patients (19.5) are still free of progression and 60 patients (37.7%) are still alive. Median (m) PFS has been reached: 7.9 months (95%CI: 6.1-9.8) as well as mOS: 20.9 (95%CI: 17.6-24.1). A methylated status was a factor of better PFS (HR = 0.29, 95% CI 0.46-0.95; p = 0.029) and better OS (HR = 0.43: 95% CI 0.28-0.66; p = 0.000) as well as the absence of residual disease (PFS: HR = 0.84: 95% CI = 0.71-1.01; p = 0.068; OS: HR = 0.77, 95%CI 0.63-0.96; p = 0.019). We didn’t find any difference in PFS (HR = 1.02, 95%CI 0.85-1.21; p = 0.82), or OS (HR = 0.90; 0.73-1.11; p = 0.34) on extending treatment with temozolomide longer than 6 cycles. Toxicity data and final results are expected for the congress. Conclusions There is no benefit of continuing TMZ treatment for more than 6 cycles in the adjuvant treatment of glioblastoma. Met status and absence of RD are factors of better SLP after adjuvant treatment. Supported by a Grant of the ISCIII: PI13/01751. Clinical trial identification NCT02209948. Legal entity responsible for the study GEINO (Grupo Espanol de Investigacion en Neurooncologia). Funding Supported by a Grant of the ISCIII. Disclosure M.A.V. Salgado: Advisory / Consultancy: Lilly; Research grant / Funding (institution): Pfizer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: pharmamar; Advisory / Consultancy: eisai; Advisory / Consultancy: Celgene. All other authors have declared no conflicts of interest.

e19219 Background: In the Genitourinary (GU) Cancer Unit of Clínico San Carlos Hospital the inclusion rate in Clinical-Trials (CTs) from January-October 2018 was 39%. However, in bladder cancer patients it was only 24%. We identified improvement areas in order to increase the inclusion rate of these patients up to 30% from November 2018-March 2019. Methods: We used as an instrument the American Society of Clinical Oncology (ASCO) Quality Training Program (QTP). We collected the number of proposals and available CTs, the number of bladder cancer patients evaluated for the first time and the patients enrolled in CTs. We also identified the causes of non-enrollment and elaborated a list of possible solutions. Results: We developed a cause-effect diagram showing that the most relevant causes of non-enrollment in CTs were the eligibility criteria (60%) and the absence of available CTs (35%). We created a list of measures and identified which would have a higher impact. On November 2018 we started a protocolized Supportive-Care evaluation by our Oncology nurses to increase the number of eligible patients. We also initiated the diffusion of CTs in the Investigation Unit and in the GU-board to increase the number of available CTs and recruitment. In January 2019 we implemented a Geriatric evaluation for the elderly, also to increase the number of eligible patients. With these measures the number of accepted trials increased from 5 in January-October 2018 to 12 in November 2018-March 2019. Also, in January-October 2018, 46% of patients were not-enrolled in a CT due to ineligibility, which decreased to 25% from November 2018-March 2019. As a result, the enrollment rate increased to 43, 75% from November 2018-March 2019. We maintained the measures, and achieved an enrollment rate of 54, 83% from May-December 2019. Conclusions: The implementation of a Supportive-Care and a Geriatric evaluation, and the diffusion of CTs helped increase the percentage of eligible patients and the number of available CTs. With these improvements, we were able to increase the enrollment rate in CTs from 24 to 58, 83%.

69 Background: Plasma immune biomarkers such as soluble plasma PD-L1 (sPD-L1) may serve as surrogates of the immune condition of cancer patients and be potential markers of response to different immunotherapy modalities. Very few data exist regarding sPD-L1 in patients with primary brain tumors. Our aim was to study the levels of sPD-L1 in patients with gliomas according to histologic grade and IDH mutation status. Methods: Patients (pts) with grade II to IV gliomas were prospectively enrolled. Single-time-point plasma samples were obtained prior to adjuvant radiotherapy +/- chemotherapy. sPD-L1 determined using ELISA with a rabbit polyclonal anti-PDL1/CD274 antibody as capture reagent. Results: Between February 2017 and August 2019, 44 patients (pts) with gliomas and 12 healthy controls (HC) were enrolled. N=11 grade II, n=9 grade III, n=24 grade IV; n=26 IDHwt, n=18 IDHmut. Higher sPD-L1 levels in glioma pts compared to HC (60.8 vs 47.8 ng/ml, p=0.05). Higher sPD-L1 levels in grade II vs grades III-IV (73.3 vs 60 ng/ml, p=0.09). Higher sPD-L1 in IDHmut grades II-III vs IDHwt grades II-III + IDHmut/wt grade IV (73 vs 59 ng/ml, p=0.07). Non-significantly higher sPD-L1 in grades II-III vs grade IV (73 vs 59 ng/ml, p=0.46). No difference in sPD-L1 in IDHmut vs IDHwt (63.3 vs 59.1 ng/ml, p=0.496), nor in IDHwt vs HC (59.1 vs 47.8 ng/ml, p=0.109). Trend to significance in IDHmut vs HC (63.3 vs 47.8, p=0.062). Conclusions: sPD-L1 levels were significantly higher in glioma pts compared to HC. A trend was seen towards higher sPD-L1 levels in lower-grade (grades II, III) IDHmut gliomas. These findings may indicate a different systemic immune profile for currently defined glioma groups based on histologic grade and IDH status and merit confirmation in a larger sample.

Patients with metastatic squamous cell cancer of the head and neck (SCCHN) have a poor prognosis, with most patients surviving less than a year. Immunotherapy (IO) is changing the natural history of the disease and programmed death-ligand 1 (PD-L1) inhibitors are showing notable improvements in survival with a more favourable toxicity profile than chemotherapy. To our knowledge, there are no data regarding how checkpoint blockade inhibitors may behave at rechallenge in SCCHN. We present the case of a metastatic hypopharyngeal cancer patient who after progressing clinically and radiologically to PD-L1-based IO and then to second-line cetuximab-based chemotherapy, achieved a partial response to third-line nivolumab. Our case shows that PD(L)1 rechallenge after interval chemotherapy may be worth considering in SCCHN. Studies should try to address which is the optimal treatment sequence in the era of IO in SCCHN.

The SEOM/GEINO clinical guidelines provide recommendations for radiological, and molecular diagnosis, treatment and follow-up of adult patients with anaplastic gliomas (AG). We followed the 2016 WHO classification which specifies the major diagnostic/prognostic and predictive value of IDH1/IDH2 missense mutations and 1p/19q codeletions in AG. The diagnosis of anaplastic oligoastrocytoma is discouraged. Surgery, radiotherapy and chemotherapy with PCV or TMZ are the first-line standard of care for AG with slight modifications according to molecular variables. A multidisciplinary team is highly recommended in the management of these tumors.

The treatment of recurrent high-grade gliomas (HGG) is controversial. There are different therapeutic schedules but without a clear orientation about which of them should be used in each clinical situation. In addition, when patients suffer a second recurrence or they have poor performance status, they are excluded from clinical trials, although second recurrences and poor performance status are indeed more and more real and common situations in the clinical setting. In this study, we assessed the efficacy and safety of fotemustine (FTM) in HGG [fundamentally, glioblastomas (GB)], independent of time of recurrence or performance status. Retrospective study in HGG patients treated with FTM in second or further line according to standard, the Addeo or any other scheme, starting treatment prior to 30 November 2012. Included patients reflect the regular situation in which the drug is used in terms of comorbidities and analytic situation (hematologic, renal and hepatic functions). Response assessment was performed by MRI and according to the clinical protocols of each center (every 8–12 weeks). Clinical situation and supportive care drugs were evaluated in each medical consultation. Clinical end-points analyzed, among others, were: PFS-6, PFS, OS, response rates, toxicity, quality of life and neurocognitive impact. In terms of activity, an overall response rate of 8 % was observed: partial response 6 % (7 patients) and complete response 2 % (2 patients). The median time to achieve the greater response with FTM was 73 days (4–841 days). Patients treated according to the Addeo schedule had a shorter time to greater response in comparison with other schedules (85.9 vs 114 days), although without statistical significance. There were no significant differences in progression-free survival (PFS) when comparing different FTM schedules or using FTM in first or second recurrence. Median PFS: 3 months. PFS-6: 30.3 %. Overall survival (OS): although without significant differences, a tendency to better survival when using the Addeo schedule versus other schedules was observed (at 6 months, 44.6 vs 34.5 %; at 12 months, 25 vs 23.6 %; at 18 months, 11.5 vs 7.9 %), as well as if earlier use (second vs third line) concerning OS-12 (33.7 vs 18.2 %). Median OS: 5.2 months. Grades 3–4 toxicity was 28 % (31 patients), being neutropenia (4 %) and thrombocytopenia (17 %) the most frequent adverse reactions. From quality of life and neuro-cognitive function perspectives, 11 patients (10 %) and 16 (14 %) improved the Karnofsky Index and neurological impairment, respectively, after FTM treatment. This study has shown that FTM is safe and has a comparable activity with other available therapeutic options of use in the treatment of recurrent HGG.

The aim of this prospective and multicentric phase II study was to evaluate the efficacy and safety of temozolomide (TMZ) and bevacizumab (BV) in patients (pts) with recurrent glioblastoma (GB), previously treated with chemoradiotherapy and at least three cycles of adjuvant TMZ. Patients with GB at first relapse received BV 10 mg/kg day every 2 weeks and TMZ 150 mg/m(2) days 1-7 and 15-21, every 28 days. Patients underwent brain magnetic resonance imaging every 8 weeks. Thirty-two evaluable pts were recruited in 8 sites. Fourteen pts (44 %) had gross total resection. O-6-methylguanine-DNA methyltransferase (MGMT) promoter was methylated in 12 pts, unmethylated in 6 pts, and missing in 14 pts. The estimated 6-month progression free survival (PFS) rate was 21.9 % (95 % CI 9.3-40.0 %). The median PFS and overall survival (OS) were 4.2 months (95 % CI 3.6-5.4 months) and 7.3 months (95 % CI 5.8-8.8 months), respectively. No significant association with MGMT status was found in terms of OS or PFS. Six of 32 pts (19 %; 95 % CI 7.2-36.4) were long-term survivors, with a median PFS and OS (50 % events) of 9.5 months (95 % CI 7.9-23.6) and 15.4 (95 % CI 8.9-NA), respectively: no differences in baseline characteristics were identified in comparison with total population. No unexpected toxicities or treatment-related deaths were observed. This regimen showed to be feasible and well tolerated in pts with recurrent GB pretreated with TMZ. Further investigation is warranted to identify subpopulations that are more likely to benefit from addition of BV to GB therapy.

Background We conducted a multicenter, 2-stage, open-label, phase II trial to assess the efficacy and safety of dacomitinib in adult patients with recurrent glioblastoma (GB) and epidermal growth factor receptor gene (EGFR) amplification with or without variant III (EGFRvIII) deletion. Methods Patients with first recurrence were enrolled in 2 cohorts. Cohort A included patients with EGFR gene amplification without EGFRvIII mutation. Cohort B included patients with EGFR gene amplification and EGFRvIII mutation. Dacomitinib was administered (45 mg/day) until disease progression/unacceptable adverse events (AEs). Primary endpoint was progression-free survival (PFS; RANO criteria) at 6 months (PFS6). Results Thirty patients in Cohort A and 19 in Cohort B were enrolled. Median age was 59 years (range 39-81), 65.3% were male, and Eastern Cooperative Oncology Group Performance Status 0/1/2 were 10.2%/65.3%/24.5%, respectively. PFS6 was 10.6% (Cohort A: 13.3%; Cohort B: 5.9%) with a median PFS of 2.7 months (Cohort A: 2.7 mo; Cohort B: 2.6 mo). Four patients were progression free at 6 months and 3 patients were so at 12 months. Median overall survival was 7.4 months (Cohort A: 7.8 mo; Cohort B: 6.7 mo). The best overall response included 1 complete response and 2 partial responses (4.1%). Stable disease was observed in 12 patients (24.5%: eight in Cohort A and four in Cohort B). Diarrhea and rash were the most common AEs; 20 (40.8%) patients experienced grade 3-4 drug-related AEs. Conclusions Dacomitinib has a limited single-agent activity in recurrent GB with EGFR amplification. The detailed molecular characterization of the 4 patients with response in this trial can be useful to select patients who could benefit from dacomitinib.

International audience; Leptomeningeal metastases are a late manifestation of systemic cancer which affects up to 10% of patients with solid tumors. Prognosis is poor, and overall survival at 1 year is only approximately 10%. Management depends mainly on general and neurological condition, primary tumor, and patterns of metastasis, notably absence or presence of concurrent systemic or solid brain metastases. Here we set out to characterize current practice patterns of diagnosis and treatment of patients with leptomeningeal metastasis in Europe. We prepared a web-based survey including 25 simple or multiple choices questions on best practice supplemented by eight case vignettes with various diagnosis and management options. The survey was sent to the membership of the European Association of Neuro-Oncology and the European Organisation for Research and Treatment of Cancer Brain Tumor Group. Between April 7, 2016 and August 8, 2016, 224 colleagues from 26 countries initiated the survey, 115 colleagues completed the whole survey. There were major differences both in the general diagnostic and therapeutic approach, e.g., regarding the use of cerebrospinal fluid (CSF) flow studies, intra-CSF chemotherapy, various types of radiotherapy, and even more so when selecting decisions on diagnostic and therapeutic measures for single case vignettes. Diagnosis and treatment decisions for patients with leptomeningeal metastasis from solid tumors vary widely across Europe. Standardization of diagnosis and evaluation tools as well as controlled studies to improve the level of evidence for all therapeutic approaches to LM are required.

Revisión, © 2014 SEAP y SEC. The publication of this consensus statement is a joint initiative of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM), which aims to revise and update the diagnostic and treatment recommendations published two years ago on biomarker use and the management of patients with colorectal carcinoma, with the intention of improving healthcare efficiency and use of resources. This group of experts recommends testing for KRAS and NRAS status in all patients with metastatic colorectal carcinoma being considered for anti-epidermal growth factor receptor (anti-. EGFR) therapy, as this type of treatment should only be used in patients not harbouring mutations in these genes. In contrast, testing for BRAF, EGFR, PI3K and PTEN mutation status is not necessary for therapeutic decision-making and therefore does not need to be done routinely.

Early-onset diagnosis is an eligibility criterion for BRCA1 and BRCA2 (BRCA) testing in sporadic breast cancer patients. Limited family structure has been proposed as a predictor of BRCA mutation status in this group of patients. An overwhelming amount of data supports a strong association between BRCA1 mutations and triple-negative breast cancer (TNBC). Here, we analyze the feasibility of using limited family structure and TNBC as predictors of BRCA mutation status in early-onset breast cancer patients attending genetic counseling units. We have conducted the study in a cohort of sporadic early-onset (≤35 years) breast cancer patients (N = 341) previously selected for BRCA genetic testing in Academic Hereditary Cancer Clinics from Spain. A retrospective review of medical records available at the time of risk assessment allowed us classifying patients according to family structure and TNBC. In addition, BRCAPRO score was calculated for all patients. Association between categorical variables was investigated using the Fisher’s exact test. Binary Logistic Regression Analysis was used for multivariate analysis. Limited family structure (OR 3.61, p = 0.013) and TNBC (OR 3.14, p = 0.013) were independent predictors of BRCA mutation status. Mutation prevalence in the subgroup of patients with at least one positive predictor was 14 %, whereas it dropped to 3 % in non-TNBCs with adequate family history (OR 5.31, 95 % CI 1.38–23.89, p = 0.006). BRCAPRO correctly discerned between limited and adequate family structures. Limited family structure and TNBC are feasible predictors of BRCA mutation status in sporadic early-onset (≤35 years) breast cancer patients attending genetic counseling units. The low prevalence of mutations observed in non-TNBCs with adequate family structure suggests that this subgroup of patients might be excluded from genetic testing., This work was supported by research Grants (PI12/00539) to M. de la Hoya, Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation & Eurpean Regional Development Fund (ERDF) ‘‘A way to make Europe’’, research grants (RD06/0020/1051 and RD12/0036/008) from Red Temática de Investigación Cooperativa en Cáncer (RTICC) to E. Diaz-Rubio, Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation & Eurpean Regional Development Fund (ERDF) ‘‘A way to make Europe’’, research Grant (10PXIB 9101297PR), Xunta de Galicia, and research grant FMM Foundation to A. Vega.

Background Limited therapeutic options exist for the treatment of patients with triple negative breast cancer (TNBC) tumors beyond the administration of chemotherapy, and very recently, the approval of the anti PD-L1 inhibitor atezolizumab. Neoadjuvant chemotherapy is currently the standard of care treatment in the early stage disease, although reliable biomarkers of response have been scarcely described. In our study we explored whether immunologic signatures associated with inflamed tumors or hot tumors could predict outcome to neoadjuvant chemotherapy. Methods Publicly available transcriptomic data of more than 2,000 patients were evaluated. ROC plots were generated to assess response to therapy. Cox proportional hazards regression was computed to explore the association between gene expression and outcomes. Kaplan-Meier plots were drawn to visualize the survival differences. Results Higher expression of IDO1, CXCL9, CXCL10, HLA-DRA, ISGF-3 from the IFN gamma signature, CXCL13, HLA-E, LAG3 and STAT1 from the expanded gene signature and GZMB from the CTL-level signature were associated with higher proportion without relapse in the first five years after chemotherapy in TNBC. The strongest effect was observed for STAT1 (p value =1.8e-05 and AUC 0.69, p = 2.7e-06). The best gene-set signature to predict favorable RFS was the combination of IDO1, LAG3, STAT1 and GZMB (HR 0.28 CI 0.17-0.46 p = 9.8 E-08). However, no influence on pathological complete response (pCR) was observed. Similar, no benefit was identified in any other tumor subtype: HER2 or estrogen receptor positive. Conclusions In conclusion, we describe a set of immunologic genes that predict outcome to neoadjuvant chemotherapy in TNBC. Legal entity responsible for the study The authors. Funding Instituto de Salud Carlos III. Disclosure All authors have declared no conflicts of interest.

BACKGROUND Standard treatment of glioblastoma (GBM) is focal radiation with concomitant and adjuvant temozolomide (TMZ) for 6 cycles. The GEINO-14-01 trial (NCT02209948) investigated the role of extending adjuvant TMZ to 12 cycles in a randomized multicenter study. MATERIAL AND METHODS Between Aug/2014 and Nov/2018, 166 patients (p) were screened and 159 randomized to extend (80p) or not (79p) TMZ treatment to 12 cycles after proving stable disease in the MRI performed before inclusion. The trial was stratified by MGMT status and presence or absence of residual disease (defined as a residual enhancement larger than 1cm on the MRI). The primary endpoint was differences in 6monthsPFS, secondary endpoints were differences in PFS, OS, toxicity, between arms and per stratification factors. RESULTS Median age was 60.4 (range 29–83), 97p (61%) were methylated and 83 p (52.2%) were reported with residual disease. Median (m) PFS was 7.9 months (95%CI: 6.1–9.8) and mOS: 20.9 (95%CI: 17.6–24.1). A methylated status was a factor of better PFS (HR=0.29, 95% CI 0.46–0.95; p=0.029) and better OS (HR= 0.43: 95% CI 0.28–0.66; p=0.000) as well as the absence of residual disease (PFS: HR = 0.84: 95% CI =0.71–1.01; p=0.068; OS: HR=0.77, 95%CI 0.63–0.96; p=0.019). We didn’t find any difference in PFS (HR=1.02, 95%CI 0.85–1.21; p=0.82), or OS (HR=0.90; 0.73–1.11; p=0.34) on extending treatment with temozolomide longer than 6 cycles. CONCLUSION There is no benefit of continuing TMZ treatment for more than 6 cycles in the adjuvant treatment of glioblastoma. Final data will be presented at the congress. Supported by a Grant of the ISCIII: PI13/01751

2001 Background: The GEINO-14-01 trial (NCT02209948) investigated the role of extending temozolomide (TMZ) for 6 cycles after the standard 6 cycles to improve 6m-PFS, SLP and OS in newly diagnosed glioblastoma (GBM) patients (p). Methods: Between 08/2014 and 11/2018, 166 p were screened and 159 randomized to extend (80p) or not (79p) TMZ treatment for 6 cycles after proving stable disease in the MRI performed before inclusion. Centralized review of histology and determination of MGMT status, if not previously available, were performed before randomizing patients. Two criteria of stratification were used: MGMT status and presence/absence of residual disease on the basal MRI (defined as a residual enhancement larger than 1cm in one). The primary endpoint was differences in 6mPFS, secondary endpoints were differences in PFS, OS, toxicity, between arms and per stratification factors. Results: Median age was 60.3 (range 29-83), 97p (61%) were methylated, basal MRI showed residual disease in 57p (35.8%). After a median follow up of 14.0 months, with 121 p(76.1%) already progressed and 81p (50.9%) already dead, median PFS is presented. Median (m) PFS is 8.0 months (95%CI: 5.7-10.2). There is no difference in mPFS between arms (adjusted HR = 0.98, 95% CI: 0.82-1.18, P = 0.907). Methylated tumors had longer mPFS (HR=0.57, 95% CI: 0.39-0.83, P=0.004) irrespectively to the study treatment. Conclusions: There is not apparent benefit of continuing TMZ treatment for more than 6 cycles. Data will be actualized for the congress.Supported by a Grant of the ISCIII: PI13/01751. Clinical trial information: NCT02209948.

69 Background: Immunotherapy (IO) has shown to improve survival in recurrent or metastatic (R/M) squamous cell cancer of the head and neck (SCCHN) with a better toxicity profile than chemotherapy (CT). An increased objective response rate (ORR) to CT has been shown after PD(L)1 blockade in SCCHN and other solid tumors. However, there are no data regarding the safety and efficacy of PD(L)1 rechallenge in SCCHN. Methods: Retrospective study of patients with R/M SCCHN treated with PD-1 inhibitors after an overt clinical and radiological progression to PD(L)1 blockade. Post-IO CT regimens, overall survival (OS), objective response rates (ORR) and percentage of tumor reduction (PTR) with post-IO CT and toxicity of IO rechallenge were recorded. Results: Eight patients treated between October 2016 and October 2018, were included. All patients received the first IO (1st-IO) treatment within clinical trials (anti-PDL1: 7; anti-PD1: 1), and received rescue cetuximab-based CT at progression (PD) (ERBITAX: 7; EXTREME: 1). ORR to post-IO 1st rescue CT (1RCT): 7 partial responses (PR), 1 stable disease (SD). PTR to 1RCT (median): 45% (range: 40-80). All second IO (2nd-IO) treatments consisted of PD1 inhibitors (nivolumab) and 6 received rescue CT (2RCT) at PD (ERBITAX: 1; wkCDDP-Cetuximab: 2; EXTREME: 3). Only 1of 6 evaluable patients responded to 2nd-IO with 5 PD as best response. Median duration of 2nd-IO: 3 months (range: 1-6). ORR to 2RCT (5 evaluable): 4 PR, 1 PD. PTR to 2RCT (median): 30% (range: 30-80). No G3/4 toxicities were detected during 2nd-IO. Conclusions: No new safety signals were encountered during PD-1 blockade in patients with SCCHN previously treated with PD-(L)1 inhibitors. First and second IO treatments associated with increased response rates to subsequent CT compared with historical data. Clinical trials should try to address the optimal treatment sequence in the IO era.

BRCA1-associated breast cancers have been associated to a triple-negative phenotype. The prevalence of BRCA1 germline mutations in young onset TNBC based on informativeness of family history has not been reported. From January 2008 to May 2009 were collected blood and tumor samples from patients with TNBC younger than 50 years and without a family history of breast and ovarian cancer in first- and second-degree relatives. Analysis of BRCA1 germline mutations was made. Age at diagnosis and informativeness of family history (presence of female in first- and second-degree relatives alive until age 45) was collected in all cases. Immunohistochemistry of basal-like features was performed centrally in all available tumors. Seven pathogenic mutations were detected in 92 patients (7.6 %), two of them in patients younger than 35 years (28.6 %) (Fisher's exact test, p = 0.631). Three non-classified variants were detected (3.2 %). Family history was informative in two patients with a pathogenic mutation (28.6 %) and not informative in five (71.4 %) (Fisher's exact test, p = 0.121). Of the seven patients with a pathogenic mutation, four had a basal-like phenotype. Patients with apparently sporadic TNBC younger than 50 years and a non-informative family history are candidates for germline genetic testing of BRCA1.

The standard adjuvant treatment for glioblastoma is temozolomide concomitant with radiotherapy, followed by a further six cycles of temozolomide. However, due to the lack of empirical evidence and international consensus regarding the optimal duration of temozolomide treatment, it is often extended to 12 or more cycles, even in the absence of residual disease. No clinical trial has shown clear evidence of clinical benefit of this extended treatment. We have explored the economic impact of this practice in Spain.Spanish neuro-oncologists completed a questionnaire on the clinical management of glioblastomas in their centers. Based on their responses and on available clinical and demographic data, we estimated the number of patients who receive more than six cycles of temozolomide and calculated the cost of this extended treatment.Temozolomide treatment is continued for more than six cycles by 80.5 % of neuro-oncologists: 44.4 % only if there is residual disease; 27.8 % for 12 cycles even in the absence of residual disease; and 8.3 % until progression. Thus, 292 patients annually will continue treatment beyond six cycles in spite of a lack of clear evidence of clinical benefit. Temozolomide is covered by the National Health Insurance System, and the additional economic burden to society of this extended treatment is nearly 1.5 million euros a year.The optimal duration of adjuvant temozolomide treatment merits investigation in a clinical trial due to the economic consequences of prolonged treatment without evidence of greater patient benefit.

Background: Renal angiomyolipomas (AML) are usual manifestations of tuberous sclerosis complex (TSC) that may cause aneurism-related haemorrhages and renal impairment. Everolimus has emerged as an alternative to surgery/embolization. We provide further insight into everolimus safety and efficacy for TSC-related AML. Methods: This was a Spanish expanded access trial including patients aged ≥18 years with TSC-related AML. They received 10 mg everolimus once daily until AML progression, unacceptable toxicity, death/withdrawal, commercialisation for TSC-related AML, or 1 year after first patient enrolment. The primary outcome was dose-limiting safety according to grade 3/4 adverse events, serious adverse events, or adverse events leading to treatment modification. Secondary outcomes included overall safety and efficacy. Results: Nineteen patients were enrolled and received everolimus for a median of 6.6 (5.3-10.9) months. Eleven (57.9 %) remained on 10 mg/day throughout the study and eight (42.1 %) required treatment modifications due to adverse events; none permanently discontinued treatment. Adverse events were overall grade 1/2 and most frequently included aphthous stomatitis/mucosal inflammation, hypercholesterolaemia/hypertriglyceridaemia, urinary tract infection, hypertension, dermatitis acneiform, and insomnia. Four (21.1 %) patients experienced grade 3 adverse events, none was grade 4, and only one (5.3 %) was serious (pneumonia). AML volume was reduced ≥30 % in 11 (57.9 %) patients and ≥50 % in 9 (47.4 %); none progressed. Right and left kidney sizes decreased in 16 and 14 patients, respectively. Conclusions: These findings support the benefit of everolimus for renal AML due to a manageable safety profile accompanied by reduced AML and kidney volumes. Trial registration: EudraCT number 2012-005397-63; date of registration 22 Nov 2012., This work was funded by Novartis Farmacéutica S.A., which was involved in study design, data analysis and interpretation, and writing of the manuscript

This phase II study was conducted to determine the efficacy and safety of metronomic temozolomide (TMZ) in combination with irinotecan in glioblastoma (GB) at first relapse. Patients with GB at first relapse received TMZ 50 mg/m(2)/day divided into three doses, except for a single 100 mg/m(2) dose, administered between 3 and 6 h before every irinotecan infusion. Irinotecan was given intravenously at the previously established dose of 100 mg/m(2) on days 8 and 22 of 28-day cycles. Treatment was given for a maximum of nine cycles or until progression or unacceptable toxicity occurred. Vascular endothelial growth factor and its soluble receptor 1, thrombospondin-1, microparticles, and microparticle-dependent procoagulant activity were measured in blood before treatment. The primary objective was 6-month progression-free survival (PFS). Twenty-seven evaluable patients were enrolled. Six-month PFS was 20.8%. Median PFS was 11.6 weeks (95% confidence interval: 7.5-15.7). Stable disease was the best response for nine (37.5%) patients, with a median duration of 11.2 weeks (4.2-35.85 weeks). No differences in PFS or response were observed among patients who relapsed during or after completion of adjuvant TMZ. Grade 3/4 adverse events included lymphopenia (15%), fatigue, diarrhea and febrile neutropenia (3.7% each), lymphopenia, neutropenia, and nausea/vomiting (11.1% each). One patient died from pneumonia and one patient died from pulmonary thromboembolism. Pretreatment levels of angiogenesis biomarkers, microparticles, and microparticle-related procoagulant activity were elevated in patients compared with healthy volunteers. This regimen is feasible, but failed to improve the results obtained with other second-line therapies in recurrent GB.

There is a current unmet medical need for treatment of leptomeningeal metastases (LMD). To analyze the efficacy and safety of systemic temozolomide (TMZ) for first-line treatment of patients with LMD associated with solid tumors, a phase II, non-randomized, multicenter, prospective study was conducted. The planned duration of treatment was a maximum of six cycles (24 weeks) or until unacceptable toxicity was reported. One cycle of oral TMZ (100 mg/m(2) daily) consisted of one week on treatment/one week off treatment for four weeks. The study was stopped early because of poor accrual. Nineteen patients (median age 51(33-72); 32 % male) were enrolled. The LMD source was breast cancer (53 %) and non-small-cell lung cancer (37 %). Previous treatment was chemotherapy (100 %), surgery 74 %, radiotherapy 79 %, and hormone therapy 42 %. The average last dose of TMZ received by patients was 171 mg and only one patient required dose reduction. Three of 19 patients (15.8 %) had clinical benefit and 16 of 19 patients (84.2 %) progressed. Of the two patients completing the study (six cycles, 24 weeks), one had a partial response and the other stable disease. Median survival was 43 days (95 % CI 28.7-57.3); there were 18 deaths. Median TTP was 28 days (95 % CI 14-42). The most common adverse event was vomiting (52.6 %); nine patients (47.4 %) reported at least one serious adverse event but only one episode of thrombocytopenia was drug related. Median Karnofsky score remained at or above 70 % throughout the study, and was 75 % at the end of the study. First-line TMZ was well tolerated, and did not adversely affect the quality of life of patients with LMD. Future studies are needed to verify the efficacy results of this pilot trial.

The Yin-Yang haplotype is defined as two mismatched haplotypes (Yin and Yang) representing the majority of the existing haplotypes in a particular genomic region. The human adenomatous polyposis coli (APC) gene shows a Yin-Yang haplotype pattern accounting for 84% of all of the haplotypes existing in the Spanish population. Several association studies have been published regarding APC gene variants (SNPs and haplotypes) and colorectal cancer (CRC) risk. However, no studies concerning diplotype structure and CRC risk have been conducted. The aim of the present study was to investigate whether the APC Yin-Yang homozygote diplotype is over-represented in patients with sporadic CRC when compared to its distribution in controls, and its association with CRC risk. TaqMan(®) assays were used to genotype three tagSNPs selected across the APC Yin-Yang region. Frequencies of the APC Yin-Yang tagSNP alleles, haplotype and diplotype of 378 CRC cases and 642 controls were compared. Two Spanish CRC group samples were included [Hospital Clínico San Carlos in Madrid (HCSC) and Instituto Catalán de Oncología in Barcelona (ICO)]. Analysis of 157 consecutive CRC patients and 405 control subjects from HCSC showed a significative effect for the risk of CRC (OR=1.93; 95% CI 1.32-2.81; P=0.001). However, this effect was not confirmed in 221 CRC patients and 237 control subjects from ICO (OR=0.89; 95% CI 0.61-1.28; P=0.521). We found a significant association between the APC homozygote Yin-Yang diplotype and the risk of colorectal cancer in the HCSC samples. However, we did not observe this association in the ICO samples. These observations suggest that a study with a larger Spanish cohort is necessary to confirm the effects of the APC Yin-Yang diplotype on the risk of CRC.

Background: Germline mutation screening of BRCA1 and BRCA2 genes is performed in suspected familial breast cancer cases, but a causative mutation is found in only 30% of patients. The development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would therefore increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1—or BRCA2—mutated breast cancers. Materials and Methods: Array-cgh (comparative genomic hybridization) and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the basis of at least 3 affected first-degree relatives or at least 2 affected first-degree relatives with breast cancer at an average age of 45 years. Array-cgh analyses were performed on a 4407 BAC-array (CIT-V8) manufactured by IntegraGen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Results: Using supervised clustering analyses we identified two transcriptomic signatures: one for BRCA1-mutated breast cancers consisting of 600 probe sets and another for BRCA2-mutated breast cancers also consisting of 600 probes sets. We also defined cgh-array signatures, based on the presence of specific genomic rearrangements, one for BRCA1-mutated breast cancers and one for BRCA2-mutated breast cancers. Conclusions: This study identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. We also identified specific genomic rearrangements in these breast cancers, which could be screened for in a diagnostic setting using fluorescence in situ hybridization, thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis.

Neutropenia is a common complication of cancer chemotherapy. Colony-stimulating factors (CSF) may be used to avoid neutropenia-associated complications. The Spanish Society of Medical Oncology (SEOM) recently constituted a working group to review the main issues concerning the use of CSF and carried out a consensus process about the use of CSF in cancer patients, held in Madrid on 26 May 2006. The group concluded the following recommendations: prophylactic use of CSF is recommended when a rate of febrile neutropenia (FN) higher than 20% is expected without the use of CSF or when additional risk factors for neutropenia exist; therapeutic use of CSF is recommended in order to treat FN episodes but not to treat afebrile neutropenic episodes. In addition, the use of CSF is considered effective when used to mobilise stem cells before high-dose chemotherapy and when used for chemotherapy schedule optimisation in dose-dense and in dose-intense regimens.

BACKGROUND: Phase I, two-stage study of buparlisib combined with standard-of-care (RT + TMZ followed by adjuvant TMZ) in newly diagnosed GBM. METHODS: Stage I evaluated buparlisib with adjuvant TMZ in 28-day treatment cycles after prior RT + TMZ treatment. Stage II evaluated buparlisib with concomitant RT + TMZ and then adjuvant TMZ. In the concomitant phase, buparlisib was administered at two schedules: 60mg/40mg/QD or 40mg D1–5/Q7, in combination with RT (2.5 Gy/day) + TMZ 75mg/m2/day over 42 days. In the adjuvant phase, buparlisib was administered at 80mg/QD during Cycle 1 with TMZ 150mg/m2 D1–D5/Q28 (A1), and at 60mg/80mg/QD during Cycles 2–12 with TMZ 200mg/m2 on D1–D5/Q28 (A2). Dose-escalation was guided by a Bayesian logistic regression model with overdose control principle. Primary study objectives were to identify buparlisib dose-limiting toxicities (DLTs) and to determine the recommended Phase II dose (RP2D). RESULTS: Adjuvant: Of 16 patients treated, six developed DLTs, including three DLTs in A1: Grade(G) 3-hyperglycemia, G3-anxiety, G3-intermittent confusion (1 patient each) at 80mg/QD; and three in A2: G2-hyperglycemia (1 patient) at 60mg/QD, G4-platelet count decrease and G4-thrombocytopenia (1 patient each) at 80mg/QD. Concomitant: Of 22 patients treated, seven developed DLTs: G4-thrombocytopenia (2 patients) at 60mg/QD, G4-lipase elevation (2 patients) and G2-thrombocytopenia (1 patient) at 40mg/QD, G3-decreased mood (1 patient) and G4-decreased platelet count (1 patient) at 40mg D1–5/Q7. Twenty-three patients (60.5%) experienced study-drug-related G3/4 adverse events (AEs) including hyperglycemia, neutropenia, thrombocytopenia (13.2% each), and lipase increase (10.5%). Twenty-nine patients discontinued treatment due to AEs (44.7%), disease progression (26.3%), and withdrawal of consent (5.3%). CONCLUSION: RP2D of buparlisib for the adjuvant phase in combination with TMZ was defined as 80mg/QD. RP2D of buparlisib plus RT + TMZ was not determined due to challenging safety at all doses/schedules. Exposure of buparlisib with RT + TMZ was slightly lower than that of single-agent buparlisib. Anti-tumor activity is under evaluation and will be reported.

If we had to classify the risk factors making us more prone to develop cancer we could simply divide them into endogenous and exogenous factors. Among the endogenous factors we could find all those relating to heredity (genetic predisposition) or with non-hereditary molecular alterations that make our cells become malignant more easily. These factors are not modifiable; however, exogenous factors depend on lifestyle choices, which are. These factors have an influence on a large percentage of the most prevalent cancers nowadays, such as colon, breast and lung cancer. Taking action on tobacco and obesity would reduce the incidence of cancer by 30-40% in the industrialised countries. This article reviews the role of negative lifestyle choices in the development of cancer., Si tuviésemos que clasificar los factores de riesgo que nos hacen más proclives a desarrollar cáncer podríamos hacerlo, de una manera sencilla, en factores endógenos y exógenos. Dentro de los primeros estarían todos aquellos que tienen que ver con la herencia (genes de predisposición) o con alteraciones moleculares no hereditarias que hacen que nuestras células se “vuelvan” malignas con más facilidad, estos factores son inmodificables. Sin embargo, los factores exógenos dependen de los llamados “hábitos de vida”, son factores modificables e influyen en un porcentaje importante de los cánceres más prevalentes en la actualidad, como son el de colon, mama y pulmón. Actuando sobre el tabaco y la obesidad se reduciría entre un 30%y 40% la incidencia de cáncer en los países industrializados. Este artículo es una revisión del papel de los hábitos de vida negativos en la producción del cáncer.

Prostate cancer is the most common neoplasm in men in western countries. The use of strategies for primary prevention and early diagnosis is a usual procedure, but there is considerable controversy on their benefits. Recent data from several remarkable studies have contributed more uncertainty toward this issue. We review the available evidence and suggest some general recommendations for prostate cancer primary prevention and screening.

In the last few years, many prospective studies have demonstrated a clear association between obesity and cancers of the colon and rectum, breast in post-menopausal women, endometrium, kidney, oesophagus and pancreas. Obesity is also associated with a high risk of recurrence and cancer-related death. The pathophysiology of obesity involves various changes that may be implicated in the relationship between obesity and cancer, such as excess inflammatory cytokines and chronic inflammation, hyperinsulinaemia, insulin resistance, and raised leptin and oestrogens. The Spanish Society for the Study of Obesity and the Spanish Society of Medical Oncology have signed a cooperation agreement to work together towards reducing the impact of obesity in cancer. Preventing obesity prevents cancer.

INTRODUCTION: Mammographic density (MD) is one of the strongest determinants of sporadic breast cancer (BC). In this study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2 mutation carriers per type of mutation and tumor subtype. METHODS: The study was carried out in 1039 female members of BRCA1 and BRCA2 mutation-positive families followed at 16 Spanish Genetic Counseling Units. Participants' density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (75 %). In BC cases, we selected mammograms taken prior to diagnosis or from the contralateral breast, whereas, in non-cases, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype. RESULTS: We identified and scored mammograms from 341 BRCA1, 350 BRCA2 mutation carriers and 229 non-carriers. Compared to non-carriers, MD was significantly lower among BRCA2 mutation carriers (odds ratio (OR) =0.71; P-value=0.04), but not among BRCA1 carriers (OR=0.84; P-value=0.33). MD was associated with subsequent development BC (OR per category of MD=1.45; 95 % confidence interval=1.18-1.78, P-value

Index cases from a clinically relevant cohort of 102 Spanish families with at least 3 cases of breast and/or ovarian cancer (at least 1 case diagnosed before age 50) in the same lineage were screened for germline mutations in the entire coding sequence and intron boundaries of the breast cancer susceptibility genes BRCA1 and BRCA2. Overall, the prevalence of mutations was 43% in female breast/ovarian cancer families, 15% in female breast cancer families and 100% in male breast cancer families. Three recurrent mutations (185delAG, 589delCT and A1708E) explained 63% of BRCA1-related families. Early age at diagnosis of breast cancer, ovarian cancer, bilateral breast cancer, concomitant breast/ovarian cancer in a single patient and prostate cancer but not unilateral breast cancer were associated with BRCA1 and BRCA2 mutations. Male breast cancer was associated with BRCA2 mutations. The presence of male breast cancer was the only cancer phenotype that distinguished BRCA2- from BRCA1-related families. We have developed a logistic regression model for predicting the probability of harbouring a mutation in either BRCA1 or BRCA2 as a function of the cancer phenotype present in the family. The predictive positive and negative values of this model were 77.4% and 79%, respectively (probability cutoff of 30%). The findings of our work may be a useful tool for increasing the cost-effectiveness of genetic testing in familial cancer clinics.