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Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Inflamació; Mediadors d'inflamació Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Inflamación; Mediadores de la inflamación Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Inflammation; Inflammation mediators Background Patients with cancer are particularly susceptible to SARS-CoV-2 infection. The systemic inflammatory response is a pathogenic mechanism shared by cancer progression and COVID-19. We investigated systemic inflammation as a driver of severity and mortality from COVID-19, evaluating the prognostic role of commonly used inflammatory indices in SARS-CoV-2-infected patients with cancer accrued to the OnCovid study. Methods In a multicenter cohort of SARS-CoV-2-infected patients with cancer in Europe, we evaluated dynamic changes in neutrophil:lymphocyte ratio (NLR); platelet:lymphocyte ratio (PLR); Prognostic Nutritional Index (PNI), renamed the OnCovid Inflammatory Score (OIS); modified Glasgow Prognostic Score (mGPS); and Prognostic Index (PI) in relation to oncological and COVID-19 infection features, testing their prognostic potential in independent training (n=529) and validation (n=542) sets. Results We evaluated 1071 eligible patients, of which 625 (58.3%) were men, and 420 were patients with malignancy in advanced stage (39.2%), most commonly genitourinary (n=216, 20.2%). 844 (78.8%) had ≥1 comorbidity and 754 (70.4%) had ≥1 COVID-19 complication. NLR, OIS, and mGPS worsened at COVID-19 diagnosis compared with pre-COVID-19 measurement (p

Background: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC. Methods: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival. Findings: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0·010, 95% CI 3·29 × 10 −4–0·0282; p=0·0067) and overall survival (0·080, 0·017–0·373; p=0·0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0·330, 0·149–0·727; p=0·0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0·415, 0·209–0·802; p=0·0063) and overall survival (0·409, 0·220–0·780; p=0·0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy. Interpretation: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies.

La implementación de programas de cribaje y/o de prevención junto a terapias innovadoras está disminuyendo la mortalidad por cáncer de mama. Ahora bien, más de 120.000 muertes anuales ocurren en Estados Unidos y en Europa por esta causa. Una explicación de este hecho es que aún nos falta obtener una fotografía completa de la heterogeneidad biológica del cáncer de mama con respeto a sus alteraciones moleculares, sensibilidad al tratamiento, y composición celular. De hecho, esta complejidad no se halla reflejada por los principales parámetros clínicos (edad, afectación ganglionar, tamaño tumoral, grado histológico) o los marcadores patológicos (receptor de estrógeno [ER], progesterona [PR] y el receptor del factor de crecimiento epidérmico tipo 2 [HER2]), los cuales están siendo utilizados hoy en día en la clínica para estratificar las pacientes en grupos pronósticos y/o terapéuticos. Los estudios basados en expresión global de genes han proporcionado una mayor comprensión de este escenario tan complejo. Durante los últimos 10 años, seis subtipos moleculares de cáncer de mama (Luminal A, Luminal B, HER2-enriched, Claudin-low, Normal Breast-like and Basal-like) han sido identificados y estudiados extensamente. Conocidos como los subtipos intrínsecos, este grupo de tumores ha revelado diferencias críticas en incidencia, supervivencia y respuesta a los tratamientos. De forma muy importante, la información proporcionada por los subtipos intrínsecos complementa y expande la información proporcionada por las variables clínico-patológicas clásicas. En esta tesis doctoral, presento los resultados de tres proyectos independientes sobre la caracterización molecular de los subtipos intrínsecos de cancer de mama y la implementación clínica de test basados en expresión génica. En global, los resultados sugieren que la información que proporciona los subtipos intrínsecos, combinados con los datos clínico-patológicos, nos ayuda a entender mejor la complejidad biológica del cáncer de mama, mejora la eficacia de los tratamientos actuales y los tratamientos novedosos, y finalmente mejora la supervivencia de las pacientes con cáncer de mama., Implementation of screening/prevention programs and novel treatment strategies is decreasing breast cancer mortality. However, more than 120,000 estimated deaths due to breast cancer are expected annually in the US and Europe combined. A plausible explanation for this scenario is, in part, that we still lack a complete enough picture of the biologic heterogeneity of breast cancers with respect to molecular alterations, treatment sensitivity, and cellular composition. Importantly, this complexity is not entirely reflected by the main clinical parameters (age, node status, tumor size, histological grade) and pathological markers (estrogen receptor [ER], progesterone receptor [PR] and human epidermal growth factor receptor 2 [HER2]), all of which are routinely used in the clinic to stratify patients for prognostic predictions and to select treatments. Studies based on global gene expression analyses have provided additional insights into this complex scenario. During the last 10 years, four molecular ‘intrinsic’ subtypes of breast cancer (Luminal A, Luminal B, HER2-enriched, and Basal-like) and a Normal Breast-like group have been identified and intensively studied. Known as the ‘intrinsic subtypes of breast cancer’, these groups of tumors have revealed critical differences in incidence, survival, and response to treatment. Importantly, the information provided by the intrinsic subtypes complements and expands the information provided by classical clinical-pathological markers. In this doctoral thesis, I am presenting the results of three independent projects regarding the molecular characterization of the intrinsic subtypes of breast cancer and the implementation of gene expression-based tests in the clinical setting. Overall, the results suggest that the information provided by the intrinsic subtypes, when combined with the current clinical-pathological markers, helps to further explain the biological complexity of breast cancer, increases the efficacy of current and novel therapies, and ultimately improves outcomes for breast cancer patients.

[eng] Breast cancer (BC) is the most common cancer in women and it represents the most common cause of cancer-­‐related death in women worldwide1. Advances in early detection, prevention, risk stratification, and therapeutic strategies as well as supportive care for patients have resulted in important improvements in mortality and reduction of cancer relapse. However, around 20% of the patients will present metastatic disease. Advanced breast cancer is still an incurable disease with a median overall survival (OS) of ∼3 years, while the 5-­‐year survival of only ∼25%2. Thus, the deeper understanding of cancer biology, inter-­‐ and intra-­‐tumor heterogeneity, and as well as, the biology behind the progression of tumor cells toward metastasis is urgent. To date, evidence suggests that both intrinsic properties of breast cancer cells and host organ microenvironment participate actively to this matter3. In general, detectable distant breast cancer metastases occur years, or even decades, after primary tumor diagnosis. Metastatic lesions are supposed to originate from disseminated tumor cells that underwent a period of dormancy4. Nevertheless, the molecular factors that promote the formation of detectable metastasis from disseminated tumor cells are largely unknown. Nowadays, the genomic revolution has transformed the landscape of cancer, leading possible an improvement in understanding of tumor biology. To try to explore BC capability in producing metastases, a molecular analysis consisting on transcriptome study was performed among a retrospective cohort of metastatic breast cancer patients. Paired tissue samples from primary and metastatic tumor were available to be analyzed., [spa] El cáncer de mama (CM) es el cáncer más común en las mujeres y representa la causa más común de muerte relacionada con el cáncer en las mujeres en todo el mundo. Los avances en la detección temprana, la prevención, la estratificación del riesgo y las estrategias terapéuticas, así como la atención de apoyo para los pacientes, han dado como resultado mejoras importantes en la mortalidad y la reducción de la recaída del cáncer. Sin embargo, alrededor del 20% de las pacientes presentarán enfermedad metastásica. El cáncer de mama avanzado sigue siendo una enfermedad incurable con una mediana de supervivencia general (SG) de ∼3 años, mientras que la supervivencia a 5 años de solo ∼25%. Por lo tanto, es urgente una comprensión más profunda de la biología del cáncer, la heterogeneidad inter e intratumoral y la biología detrás de la progresión de las células tumorales hacia la metástasis. Hasta la fecha, la evidencia sugiere que tanto las propiedades intrínsecas de las células como el microambiente del órgano huésped participan activamente en este asunto.

[cat] El tractament de quimioteràpia associada a fàrmacs anti-EGFR representa un estàndard de tractament oncològic per a un subgrup de pacients amb Càncer colorectal metastàtic (CCRm). Malgrat això, no tots el pacients que reben aquesta combinació se’n beneficien plenament. És per tant del nostre interès, i justificació d’aquesta tesi, optimitzar l’ús d’aquest recurs terapèutic. En la cerca d’aquest objectiu van promoure tres assajos clínics. En un primer assaig, la nostra estratègia per optimitzar l’ús dels agents anti-EGFRs va ser substituir la pauta d’administració estàndard setmanal de cetuximab per una d’administració bisetmanal. Hem liderat un estudi fase II multicèntric a nivell nacional, l’estudi OPTIMIX, amb l’objectiu d’avaluar resultats en termes de supervivència i seguretat per un esquema de tractament de quimioteràpia més cetuximab bisetmanal i poder comparar-ne els resultats amb històrics previs amb pauta setmanal. Vam objectivar per la pauta bisetmanal una taxa de resposta del 60%, una mitjana de supervivència lliure de progressió de 10.1 mesos i una mitjana supervivència global 20.8 mesos. Tots aquests resultats són similars als reportats per la pauta de cetuximab en règim setmanal en estudis previs. Així mateix van descriure un perfil de toxicitat amb la pauta bisetmanal similar al descrit per la pauta setmanal convencional. En els darrers anys s’han descrit biomarcadors pronòstics i predictius de resposta a tractaments anti-EGFRs que s’han incorporat a les guies de pràctica clínica. Amb ells podem seleccionar bons candidats a tractaments anti-EGFRs, com ho són els pacients RAS-wild type, però no tots aquests pacients es beneficien plenament d’un tractament amb quimioteràpia associada a un tractament anti-EGFR. Per tant, ens calen més biomarcadors. Amb l’objectiu de millorar la selecció dels candidats a teràpia anti-EGFR vam avaluar com a nou biomarcador, la coexpressió de p-IGF-1R i de MMP-7 de forma prospectiva en el marc de 2 assajos prospectius fase II multicèntrics nacionals. Són l’estudi PULSE-panitumumab i l’estudi POSIBA-cetuximab en que cetuximab va ser administrat en pauta bisetmanal d’acord als resultats de l’estudi OPTIMIX, entre d’altres. La doble positivitat per p-IGF-1R i de MMP-7 es va associar a una disminució de SLP i SG en l’estudi POSIBA de quimioteràpia associada a cetuximab bisetmanal (HR: 1.39, p=.20). En contraposició, es va associar a un augment de SLP i SG en l’estudi PULSE de FOLFOX més panitumumab (HR: 0.33; p=.0017). Posant els resultats en perspectiva i en primer lloc, els resultats de SLP presentats en la segona publicació d’aquesta tesi per la pauta de quimioteràpia més cetuximab bisetmanal estan en consonància amb els resultats del nostre primer estudi (estudi OPTIMIX). En segon lloc, cal destacar que la doble positivitat per p-IGF-1R i de MMP-7 s’associa a una disminució de SG quan els pacients reben quimioteràpia més cetuximab bisetmanal. Es confirmen així els resultats d’un estudi previ del grup. Finalment, els nostres resultats suggereixen que hi ha un benefici en SG pel subgrup que no coexpressa p-IGF-1R i de MMP-7 (No-DP) quan són tractats amb FOLFOX més cetuximab bisetmanal així com en el subgrup que sí coexpressa p-IGF-1R i de MMP-7 (DP) quan són tractats amb FOLFOX més panitumumab. La disparitat de resultats probablement té una explicació biològica, que és discutida en aquesta tesi. A la llum dels resultats publicats en aquesta tesi considerem que la pauta bisetmanal de cetuximab és un nou estàndard per l’administració d’aquest agent anti-EGFR en CCRm. Fruit del nostre treball de recerca, considerem la coexpressió de p-IGF-1R i MMP-7 com un potencial biomarcador pronòstic i predictiu per tractaments anti-EGFRs que ens pot permetre optimitzar l’ús dels agents anti-EGFRs., [eng] The current thesis is based on 2 articles published in a scientific journal. The objective of our research was the optimization of the oncological treatment for RAS wild-type metastatic colorectal cancer (mCRC) patients. In our first publication, we determined the efficacy of a biweekly administration schedule of cetuximab compared to a weekly schedule. We expected that the biweekly schedule would be more convenient and equally efficient. After leading a multicenter phase II study, we were able to demostrate a similar tumor response rate (around 60%) and tumor progression-free survival, both for the biweekly schedule and the weekly regimen. The weekly schedule has been the most frequently used in common practice. Our results have change the standard of care of many healthcare centers that nowadays prefer the biweekly schedule over the weekly cetuximab administration. In our second publication, our goal was to determine which patients could benefit most from an anti-EGFR treatment. For this purpose, we evaluated the co-expression of p-IGF-1R and MMP-7, also called Double Positive (DP), as a biomarker of response to anti-EGFR drugs. We designed two phase II multicenter clinical trials, the POSIBA and de PULSE trials to evaluate our biomarker. We published a joint analysis result of both studies. We analyzed 67 patients in the PULSE trial and 181 patients in the POSIBA trial. Response rates and PFS were similar between groups in both studies. DP was associated with prolonged OS in PULSE-panitumumab trial (HR: 0.23; p=.0004) and with shorter OS in POSIBA-cetuximab trial (HR: 1.67; p=.07). We were able to report that the coexpression of p-IGF-1R and MMP-7 is a biomarker of poor prognosis and poor response for cetuximab. In contrast, is a potential biomarker of good response for panitumumab. The biological basis that can justify these results was discussed and our proposal is to carry out a study to confirm our results.

El carcinoma basocelular (CBC) es el tumor maligno más frecuente en el ser humano y su incidencia está en aumento. Existe un subgrupo de CBC que presentan un comportamiento más agresivo, son más destructivos e invasivos y tienen un mayor riesgo de recurrencia y de metástasis. Desconocemos los mecanismos moleculares que condicionan las diferentes formas clínico-patológicas y las implicaciones que pueden tener en la respuesta a los diferentes tratamientos. En este trabajo hemos estudiado 25 CBC (superficiales, nodulares, morfeiformes e infiltrantes), para investigar su heterogeneidad molecular mediante análisis de expresión de ARNm. Hemos identificado un grupo de 120 genes relacionados con el sistema inmune que presentan una elevada expresión en la mayoría de CBC infiltrantes, una expresión intermedia en los superficiales y baja en los morfeiformes y nodulares. Para corroborar estos datos hemos analizado la expresión de estos 120 genes y hallado que la expresión de PD-L1 es significativamente superior en el grupo de CBC infiltrantes en comparación con el resto (p=0,01). Estos resultados sugieren que el eje PD-1/PD-L1 desempeña un papel importante en la mayor agresividad intrínseca de los CBC infiltrantes y, por lo tanto, su bloqueo podría ser útil como tratamiento de este subtipo de CBC. Basal cell carcinomas (BCC) are the most common cancers worldwide and their incidence is increasing annualy. A subset of BCC behaves more aggressively and are associated with a higher risk of recurrence, local tissue destruction, deeper invasion, subclinical spread, morbidity and distant metastasis risk. The molecular basis for the aggressive behavior, for the different clinical and pathological forms of BCC and their response to the treatments available remains to be elucidated. In this study we evaluated 25 BCC (superficial, nodular, morpheaform and infiltrative) to delineate their molecular heterogeneity by means of mRNA expression analysis. We identified 120 immune-related genes linked to immune response with high expression in most of infiltrative CBC, medium expression in superficial CBC and low in morpheaform and nodular. To corroborate these findings we analyzed these 120 genes and discovered that PD-L1 expression was associated with infiltrative BCC samples compared to nodular, superficial, morpheaform and basosquamous BCC (p=0,01). Overall, our results suggest that the PD-1/PD-L1 axis may play an important role in locally infiltrative BCC and provide support for PD-1/PD-L1 blockade.

En la última década, la incidencia de los tumores escamosos de cabeza y cuello relacionados con el virus del Papiloma Humano (HPV), principalmente en los tumores de orofaringe, ha aumentado considerablemente, siendo considerados una entidad clínica asociada a características etiológicas, clínicas y pronósticas diferenciadas del subgrupo de tumores HPV negativos. Los tumores HPV positivos, comparados con los tumores HPV negativos, presentan mejor pronóstico sin embargo el impacto pronóstico de HPV en localizaciones diferentes a la orofaringe no está claramente establecido. Diferentes estrategias se han desarrollado para el tratamiento de los tumores de cabeza y cuello localmente avanzados e irresecables, incluyendo la quimioradioterapia concomitante, la quimioterapia de inducción seguida de tratamiento radical o el tratamiento anti-EGFR concomitante con radioterapia. La identificación de los factores clínicos y moleculares que caractericen a los pacientes con tumores HPV positivos y negativos podría favorecer el desarrollo de nuevas estrategias terapéuticas específicas. En nuestro trabajo de tesis, realizado sobre una serie de 83 pacientes con tumores de cavidad oral y orofaringe localmente avanzados e irresecables, hemos confirmado el impacto pronóstico de la positividad de HPV en términos de beneficio en supervivencia libre de progresión y supervivencia global, principalmente en tumores de orofaringe. Por otro lado tanto la positividad de HPV en tumores de orofaringe y cavidad oral, como la concordancia entre HPV-PCR e inmunohistoquímica de p16 resultaron similares a lo reportado en la literatura. Paralelamente, nuestros estudios de expresión génica han demostrado como la expresión de genes de la firma Basal se correlaciona con peor pronóstico en la población global del estudio, siendo capaces además, de describir genes diferentemente expresados en tumores de cavidad oral y orofaringe. Sin embargo, no hemos podido describir un patrón de expresión génica diferenciado entre tumores HPV positivos y negativos, probablemente en relación con el limitado número de tumores HPV positivos., Over the past decade, there has been a significant increase in the incidence of HPV positive head and neck cancers (HNC), particularly in tumors arising in the oropharynx, comprising approximately 60% of all cases. HPV positive represents a distinct molecular and clinical entity from HPV negative disease. HPV positivity is strongly correlated with a significantly superior outcome indicating that such tumors should have a distinct management approach. However, its prognostic impact on non-oropharyngeal tumors is not stablished. Current treatment regimens for unresectable, locally advanced, HNC are aggressive and several treatment strategies, including concomitant chemoradiotherapy, induction chemotherapy or anti-EGFR and radiotherapy are standard treatment options. Refining clinical and molecular features that separate HPV-associated and non-associated tumors will undoubtedly improve HNC management. Our research project was conducted in a total of 83 patients with diagnosis of unresectable, locally advanced oropharyngeal and oral cavity tumors. We have demonstrated the impact value of HPV positivity on progression free survival and overall survival, particularly in oropharyngeal cancer patients. The concordance of HPV-PCR and p16 immunohistochemistry diagnostic methods, was significant within the total patient population and similar to previous reports. Our gene expression studies demonstrated that Basal-Like signature correlated with poor prognosis, and also we were able to confirm several genes that were differently expressed within oral cavity and oropharyngeal tumors, without differences among HPV positive and negative tumors, probably due to the limited number of HPV positive patients enrolled in our study.