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Germline; Tumour-only sequencing Línia germinal; Seqüenciació només de tumors Línea germinal; Secuenciación solo de tumors Background The European Society for Medical Oncology Precision Medicine Working Group (ESMO PMWG) was reconvened to update its 2018/19 recommendations on follow-up of putative germline variants detected on tumour-only sequencing, which were based on an analysis of 17 152 cancers. Methods We analysed an expanded dataset including 49 264 paired tumour-normal samples. We applied filters to tumour-detected variants based on variant allele frequency, predicted pathogenicity and population variant frequency. For 58 cancer-susceptibility genes, we then examined the proportion of filtered tumour-detected variants of true germline origin [germline conversion rate (GCR)]. We conducted subanalyses based on the age of cancer diagnosis, specific tumour types and ‘on-tumour’ status (established tumour-gene association). Results Analysis of 45 472 nonhypermutated solid malignancy tumour samples yielded 21 351 filtered tumour-detected variants of which 3515 were of true germline origin. 3.1% of true germline pathogenic variants were absent from the filtered tumour-detected variants. For genes such as BRCA1, BRCA2 and PALB2, the GCR in filtered tumour-detected variants was >80%; conversely for TP53, APC and STK11 this GCR was

Artificial intelligence; Precision oncology Intel·ligència artificial; Oncologia de precisió Inteligencia artificial; Oncología de precisión R.P.L. is supported by LaCaixa Foundation, a CRIS Foundation Talent Award (TALENT19-05), the FERO Foundation, the Instituto de Salud Carlos III-Investigacion en Salud (PI18/01395 and PI21/01019), the Prostate Cancer Foundation (18YOUN19) and the Asociación Española Contra el Cancer (AECC) (PRYCO211023SERR, funding C.M.). J.N.K. is supported by the German Federal Ministry of Health (DEEP LIVER, ZMVI1-2520DAT111) and the Max-Eder-Program of the German Cancer Aid (grant #70113864), the German Federal Ministry of Education and Research (PEARL, 01KD2104C; CAMINO, 01EO2101; SWAG, 01KD2215A; TRANSFORM LIVER, 031L0312A; TANGERINE, 01KT2302 through ERA-NET Transcan), the German Academic Exchange Service (SECAI, 57616814), the German Federal Joint Committee (Transplant.KI, 01VSF21048) the European Union’s Horizon Europe and innovation program (ODELIA, 101057091; GENIAL, 101096312) and the National Institute for Health and Care Research (NIHR, NIHR213331) Leeds Biomedical Research Centre. JSR-F is funded in part by the Breast Cancer Research Foundation, a Susan G Komen Leadership grant, an NIH/NCI P50 CA247749 01 grant, and an NIH/NCI grant No. P30CA008748. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.

Marcadors; Fàrmacs; Programa d'oncologia de precisió Marcadores; Fármacos; Programa de oncología de precisión Markers; Medicines; Precision oncology program La determinació molecular en determinats contextos clínics permet la selecció de pacients amb característiques moleculars que en estudis clínics s'han associat a una millor resposta a tractaments dirigits específics, en comparació amb pacients sense aquestes característiques. Aquesta aproximació permet una major probabilitat d'èxit, millorant les taxes de resposta i minimitzant l'ús de medicaments d'elevada toxicitat en situacions de resposta clínica improbable.

Cancer; Drug development; Gene amplifications Cáncer; Desarrollo de fármacos; Amplificaciones de genes Càncer; Desenvolupament de medicaments; Amplificacions de gens The identification of novel therapeutic targets for specific cancer molecular subtypes is crucial for the development of precision oncology. In the last few years, CRISPR/Cas9 screens have accelerated the discovery and validation of new targets associated with different tumor types, mutations, and fusions. However, there are still many cancer vulnerabilities associated with specific molecular features that remain to be explored. Here, we used data from CRISPR/Cas9 screens in 954 cancer cell lines to identify gene dependencies associated with 16 common cancer genomic amplifications. We found that high-copy-number genomic amplifications generate multiple collateral dependencies within the amplified region in most cases. Further, to prioritize candidate targets for each chromosomal region amplified, we integrated gene dependency parameters with both druggability data and subcellular location. Finally, analysis of the relationship between gene expression and gene dependency led to the identification of genes, the expression of which may constitute predictive biomarkers of dependency. In conclusion, our study provides a set of druggable targets specific for each amplification, opening the possibility to specifically target amplified tumors on this basis. This research was funded by grants from Institut Català d’Oncologia (ICO), Instituto de Salud Carlos III (PI21/00640), AGAUR (2021 FI_B 00088), Fundació BOSCH, Iniciativa Tot per tu, Fundació Amics Joan Petit, and Mi compañero de viaje.

Abstract MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered “ready for routine use.” Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies—56% of them within early clinical trials—mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA). Significance: MAPPYACTS underlines the feasibility of molecular profiling at cancer recurrence in children on a multicenter, international level and demonstrates benefit for patients with selected key drivers. The use of cfDNA deserves validation in prospective studies. Our study highlights the need for innovative therapeutic proof-of-concept trials that address the underlying cancer complexity. This article is highlighted in the In This Issue feature, p. 1171

Cancer therapy; Predictive markers; Translational research Terapia del cáncer; Marcadores predictivos; Investigación traslacional Teràpia del càncer; Marcadors predictius; Recerca translacional Precision medicine is starting to incorporate functional assays to evaluate anticancer agents on patient-isolated tissues or cells to select for the most effective. Among these new technologies, dynamic BH3 profiling (DBP) has emerged and extensively been used to predict treatment efficacy in different types of cancer. DBP uses synthetic BH3 peptides to measure early apoptotic events (‘priming’) and anticipate therapy-induced cell death leading to tumor elimination. This predictive functional assay presents multiple advantages but a critical limitation: the cell number requirement, that limits drug screening on patient samples, especially in solid tumors. To solve this problem, we developed an innovative microfluidic-based DBP (µDBP) device that overcomes tissue limitations on primary samples. We used microfluidic chips to generate a gradient of BIM BH3 peptide, compared it with the standard flow cytometry based DBP, and tested different anticancer treatments. We first examined this new technology’s predictive capacity using gastrointestinal stromal tumor (GIST) cell lines, by comparing imatinib sensitive and resistant cells, and we could detect differences in apoptotic priming and anticipate cytotoxicity. We then validated µDBP on a refractory GIST patient sample and identified that the combination of dactolisib and venetoclax increased apoptotic priming. In summary, this new technology could represent an important advance for precision medicine by providing a fast, easy-to-use and scalable microfluidic device to perform DBP in situ as a routine assay to identify the best treatment for cancer patients. Ramon y Cajal Programme, Ministerio de Economia y Competitividad grant RYC-2015–18357. (J.M.). Ministerio de Ciencia, Innovación y Universidades grant RTI2018-094533-A-I00 (J.M.). CELLEX foundation (J.M., A.M.). Beca Trienal Fundación Mari Paz Jiménez Casado (J.M.). European Research Council, grant ERC-StG-DAMOC 714317 (J.R.-A.). European Research Council, H2020 EU framework FET-open BLOC 863037 (J.R.-A.). Spanish Ministry of Economy and Competitiveness, “Severo Ochoa” Program for Centers of Excellence in R&D SEV-2020-2023 (J.R.-A.). Generalitat de Catalunya. CERCA Programme 2017-SGR-1079 (J.R.-A., J.S.). Fundación Bancaria “la Caixa”- Obra Social “la Caixa” (project IBEC-La Caixa Health Ageing) (J.R.-A.). Fero Foundation (C.S.). Networking Biomedical Research Center (CIBER). CIBER is an initiative funded by the VI National R&D&i Plan 2008–2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions, and the Instituto de Salud Carlos III (RD16/0006/0012), with the support of the European Regional Development Fund (J.S.).

Immunotherapy; Metastatic colorectal cancer; Precision medicine Inmunoterapia; Cáncer colorrectal metastásico; Medicina de precisión Immunoteràpia; Càncer colorectal metastàtic; Medicina de precisió Colorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major efforts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the improvements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complexity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the comprehensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the application of the resulting dynamic changes to a precision medicine-based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC. Fortunato Ciardiello was supported by a grant from Regione Campania (I-Cure Research Project Cup 21C17000030007). Andres Cervantes was supported by grants from the Instituto de Salud Carlos III (PI18/01909 and PI21/00689). Fortunato Ciardiello reports institutional research grants from Amgen, Merck KGaA, Merck Sharp & Dohme, Pfizer, Pierre Fabre, Roche, and Servier; and service on advisory boards for Bayer, Merck KGaA, Merck Sharp & Dohme, Pierre Fabre, Roche, and Servier outside the submitted work. Davide Ciardiello reports a travel grant from Sanofi outside the submitted work. Stefania Napolitano reports honoraria from Bristol Myers Squibb and Novartis outside the submitted work. Josep Tabernero reports advisory board or scientific consultancy fees from Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck KGaA, Merus, Merck Sharp & Dohme, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, SotioBiotech, Taiho, Tessa Therapeutics, and TheraMyc outside the submitted work. Andres Cervantes reports institutional research grants from Genentech, Merck KGaA, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas, Takeda, and Fibrogen; and honoraria or speaker’s fees from Amgen, Merck KGaA, Roche, Bayer, Servier, and Pierre Fabre outside the submitted work. Giulia Martini reports no conflicts of interest.

Oncología de precisión; Datos clinicogenómicos Oncologia de precisió; Dades clinicogenòmiques Precision oncology; Clinicogenomic data Precision oncology, where patients are given therapies based on their genomic profile and disease trajectory, is rapidly evolving to become a pivotal part of cancer management, supported by regulatory approvals of biomarker-matched targeted therapies and cancer immunotherapies. However, next-generation sequencing (NGS)–based technologies have revealed an increasing number of molecular-based cancer subtypes with rare patient populations, leading to difficulties in executing/recruiting for traditional clinical trials. Therefore, approval of novel therapeutics based on traditional interventional studies may be difficult and time consuming, with delayed access to innovative therapies. Real-world data (RWD) that describe the patient journey in routine clinical practice can help elucidate the clinical utility of NGS-based genomic profiling, multidisciplinary case discussions, and targeted therapies. We describe key learnings from the setup of WAYFIND-R (NCT04529122), a first-of-its-kind global cancer registry collecting RWD from patients with solid tumors who have undergone NGS-based genomic profiling. The meaning of ‘generalizability’ and ‘high quality’ for RWD across different geographic areas was revisited, together with patient recruitment processes, and data sharing and privacy. Inspired by these learnings, WAYFIND-R’s design will help physicians discuss patient treatment plans with their colleagues, improve understanding of the impact of treatment decisions/cancer care processes on patient outcomes, and provide a platform to support the design and conduct of further clinical/epidemiologic research. WAYFIND-R demonstrates user-friendly, electronic case report forms, standardized collection of molecular tumor board-based decisions, and a dashboard providing investigators with access to local cohort-level data and the ability to interact with colleagues or search the entire registry to find rare populations. Overall, WAYFIND-R will inform on best practice for NGS-based treatment decisions by clinicians, foster global collaborations between cancer centers and enable robust conclusions regarding outcome data to be drawn, improve understanding of disparities in patients’ access to advanced diagnostics and therapies, and ultimately drive advances in precision oncology.

Gender; Toxicity; Tumour biology Gènere; Toxicitat; Biologia tumoral Género; Toxicidad; Biología tumoral Historically women were frequently excluded from clinical trials and drug usage to protect unborn babies from potential harm. As a consequence, the impact of sex and gender on both tumour biology and clinical outcomes has been largely underestimated. Although interrelated and often used interchangeably, sex and gender are not equivalent concepts. Sex is a biological attribute that defines species according to their chromosomal makeup and reproductive organ, while gender refers to a chosen sexual identity. Sex dimorphisms are rarely taken into account, in either preclinical or clinical research, with inadequate analysis of differences in outcomes according to sex or gender still widespread, reflecting a gap in our knowledge for a large proportion of the target population. Underestimation of sex-based differences in study design and analyses has invariably led to 'one-drug' treatment regimens for both males and females. For patients with colorectal cancer (CRC), sex also has an impact on the disease incidence, clinicopathological features, therapeutic outcomes, and tolerability to anticancer treatments. Although the global incidence of CRC is higher in male subjects, the proportion of patients presenting right-sided tumours and BRAF mutations is higher among females. Concerning sex-related differences in treatment efficacy and toxicity, drug dosage does not take into account sex-specific differences in pharmacokinetics. Toxicity associated with fluoropyrimidines, targeted therapies, and immunotherapies has been reported to be more extensive for females with CRC than for males, although evidence about differences in efficacy is more controversial. This article aims to provide an overview of the research achieved so far into sex and gender differences in cancer and summarize the growing body of literature illustrating the sex and gender perspective in CRC and their impact in relation to tumour biology and treatment efficacy and toxicity. We propose endorsing research on how biological sex and gender influence CRC as an added value for precision oncology.

Local excision Organ preservation; Rectal cancer Escisión local; Preservación de órganos; Cáncer de recto Excisió local; Preservació d'òrgans; Càncer de recte Background and Aim Total mesorectal excision (TME) remains the treatment of choice in T2N0 tumors. However, evidence suggest that one-size-fits-all approach is not always beneficial for this group of patients. The aim of this study is to synthesize data on long-term outcomes after neoadjuvant therapy (NAT) followed by local excision (LE) in T2N0 rectal cancer patients in the perspective of a rectal-preserving strategy. Methods A systematic search of PubMed/MEDLINE, SCOPUS, and Web of Science databases was conducted until October 2021 to identify studies comparing LE after NAT and TME or reporting oncologic outcomes after conservative approach. A pooled analysis was conducted using a fixed-effect model in the case of non-significant heterogeneity (P > 0.1), and a random effect model (DerSimonian–Laird method) when significant heterogeneity was present (P < 0.1) CRD42022300344. Results Nine studies were included in the analysis. Three of them were comparative studies. The pooled 3-year DFS, 5-year DFS, 3-year OS, 5-year OS, local and distant recurrence rates were 92.8% (95% CI 81.6–99.5%), 91.3% (95% CI 88.3–94.3%), 96.1% (95% CI 90.5–100%), 72.6% (95% CI 57.5–87.7%), 4% (95% CI 18–63%), and 4.9% (95% CI 2–7.8%), respectively, in subjects treated with NAT followed by LE. No heterogeneity was found for all these analyses, except for the 5-year OS sub-analysis (I2 95.5%, P < 0.001). Complete pathological response (ypT0) rate after NAT and LE ranges from 26.7% to 59%. Conclusion LE following neoadjuvant CRT may provide comparable survival benefit to radical surgery for patients with clinical stage T2N0 in selected patients although the evidence is still limited to provide solid recommendations. A personalized therapeutic approach taking into account tumor and patient-related factors should be considered. Open Access Funding provided by Universita degli Studi della Campania Luigi Vanvitelli within the CRUI-CARE Agreement.

Teràpia dirigida; Proves; Càncer de tiroide Targeted therapy; Testing; Thyroid cancer Terapia dirigida; Pruebas; Cáncer de tiroides Most malignant thyroid tumours are initially treated with surgery or a combination of surgery and radioactive iodine (RAI) therapy. However, in patients with metastatic disease, many tumours become refractory to RAI, and these patients require alternative treatments, such as locoregional therapies and/or systemic treatment with multikinase inhibitors. Improvements in our understanding of the genetic alterations that occur in thyroid cancer have led to the discovery of several targeted therapies with clinical efficacy. These alterations include NTRK (neurotrophic tyrosine receptor kinase) gene fusions, with the tropomyosin receptor kinase inhibitors larotrectinib and entrectinib both approved by the European Medicines Agency and in other markets worldwide. Inhibitors of aberrant proteins resulting from alterations in RET (rearranged during transfection) and BRAF (B-Raf proto-oncogene) have also shown promising efficacy, and so far have received approval by the US Food and Drug Administration. Selpercatinib, a RET kinase inhibitor, was approved for use in Europe in early 2021. With the discovery of multiple actionable targets, it is imperative that effective testing strategies for these genetic alterations are integrated into the diagnostic armamentarium to ensure that patients who could potentially benefit from targeted treatments are identified. In this review, we offer our recommendations on the optimal testing strategies for detecting genetic alterations in thyroid cancer that have the potential to be targeted by molecular therapy. We also discuss the future of treatments for thyroid cancers, including the use of immune checkpoint inhibitors, and new generations of targeted treatments that are being developed to counter acquired tumour resistance.

Biomarkers; Brain barriers immunotherapy; Multiple sclerosis Biomarcadores; Inmunoterapia de barreras cerebrales; Esclerosis múltiple Biomarcadors; Immunoteràpia de barreres cerebrals; Esclerosi múltiple MS is the most common autoimmune demyelinating disease of the CNS. For the past decades, several immunomodulatory disease-modifying treatments with multiple presumed mechanisms of action have been developed, but MS remains an incurable disease. Whereas high efficacy, at least in early disease, corroborates underlying immunopathophysiology, there is profound heterogeneity in clinical presentation as well as immunophenotypes that may also vary over time. In addition, functional plasticity in the immune system as well as in the inflamed CNS further contributes to disease heterogeneity. In this review, we will highlight immune-pathophysiological and associated clinical heterogeneity that may have an implication for more precise immunomodulatory therapeutic strategies in MS. We thank our lab teams and clinical coworkers for their dedication. We thank people with MS that we have the privilege to counsel for their continuous support. Part of the work cited was funded by the Swiss National Fund (SNF no. 310030_172952) to AC. Open access funding provided by Inselspital Universitatsspital Bern

Endotype; Organ dysfunction; Sepsis Endotipo; Disfunción de órganos; Sepsis Endotip; Disfunció d'òrgans; Sèpsia Sepsis is a heterogeneous disease with variable clinical course and several clinical phenotypes. As it is associated with an increased risk of death, patients with this condition are candidates for receipt of a very well-structured and protocolized treatment. All patients should receive the fundamental pillars of sepsis management, which are infection control, initial resuscitation, and multiorgan support. However, specific subgroups of patients may benefit from a personalized approach with interventions targeted towards specific pathophysiological mechanisms. Herein, we will review the framework for identifying subpopulations of patients with sepsis, septic shock, and multiorgan dysfunction who may benefit from specific therapies. Some of these approaches are still in the early stages of research, while others are already in routine use in clinical practice, but together will help in the effective generation and safe implementation of precision medicine in sepsis.

Circulating tumour DNA (ctDNA); Liquid biopsy; Precision medicine DNA tumoral circulant (ctDNA); Biòpsia líquida; Medicina de precisió ADN tumoral circulante (ctDNA); Biopsia líquida; Medicina de precisión Circulating tumour DNA (ctDNA) assays conducted on plasma are rapidly developing a strong evidence base for use in patients with cancer. The European Society for Medical Oncology convened an expert working group to review the analytical and clinical validity and utility of ctDNA assays. For patients with advanced cancer, validated and adequately sensitive ctDNA assays have utility in identifying actionable mutations to direct targeted therapy, and may be used in routine clinical practice, provided the limitations of the assays are taken into account. Tissue-based testing remains the preferred test for many cancer patients, due to limitations of ctDNA assays detecting fusion events and copy number changes, although ctDNA assays may be routinely used when faster results will be clinically important, or when tissue biopsies are not possible or inappropriate. Reflex tumour testing should be considered following a non-informative ctDNA result, due to false-negative results with ctDNA testing. In patients treated for early-stage cancers, detection of molecular residual disease or molecular relapse, has high evidence of clinical validity in anticipating future relapse in many cancers. Molecular residual disease/molecular relapse detection cannot be recommended in routine clinical practice, as currently there is no evidence for clinical utility in directing treatment. Additional potential applications of ctDNA assays, under research development and not recommended for routine practice, include identifying patients not responding to therapy with early dynamic changes in ctDNA levels, monitoring therapy for the development of resistance mutations before clinical progression, and in screening asymptomatic people for cancer. Recommendations for reporting of results, future development of ctDNA assays and future clinical research are made. This project was funded by the European Society for Medical Oncology (no grant number).

Medicina de precisió; Farmacogenòmica; Teràpies avançades; Nanomedicina Medicina de precisión; Farmacogenómica; Terapias avanzadas; Nanomedicina Precision medicine; Pharmacogenomics; Advanced therapies; Nanomedicine La medicina de precisió té com a repte utilitzar el medicament adequat, en la persona concreta i en el moment adequat, el que suposa un canvi d’enfocament en la medicina: d’una visió poblacional a una visió individual. La variabilitat interindividual de la resposta a un fàrmac pot implicar el fracàs terapèutic, fet que suposa una minva de la qualitat de vida dels pacients i un alt impacte econòmic per al sistema sanitari. La resposta a la teràpia farmacològica ve determinada en bona part pels factors genètics, els quals expliquen gran part de la variabilitat interindividual. La farmacogenòmica, les teràpies avançades o la nanomedicina són tres àrees que s’engloben dintre de la medicina de precisió. La farmacogenòmica permet la detecció de biomarcadors que ens poden predir la resposta o toxicitat d’un determinat tractament. Aquesta àrea és molt utilitzada en oncologia atesa la base genètica de les neoplàsies malignes. També s’utilitza en altres patologies, com en determinats fàrmacs per a la !brosi quística, l’ús de la codeïna per a la tos o en fàrmacs antidepressius. Les teràpies avançades són medicaments que es basen en la teràpia gènica, la teràpia de cèl·lules somàtiques, la teràpia d’enginyeria de teixits i els medicaments combinats de teràpies avançades per al maneig d’algunes malalties. El desenvolupament d’aquests medicaments és molt complex com a conseqüència de la pròpia naturalesa d’aquestes teràpies. Actualment a Espanya en tenim tres de comercialitzades. Per últim, la nanomedicina estudia i desenvolupa nanomaterials per a la prevenció, el diagnòstic o el tractament de la malaltia a escala cel·lular o molecular. Avui dia disposem de nanomaterials que s’utilitzen a la pràctica clínica diària, com són els biosensors de glucosa, i també de nanofàrmacs comercialitzats en el nostre país. Aquestes tres àrees han creat grans avenços que han permès millorar el diagnòstic i/o tractament de les malalties de forma “individual”, sobretot en l’àmbit de l’oncologia i de les malalties minoritàries. La medicina de precisión tiene como reto utilizar el medicamento adecuado, en la persona concreta y en el momento apropiado, lo que supone un cambio de enfoque en la medicina: de una visión poblacional a una visión individual. La variabilidad interindividual de la respuesta a un fármaco puede implicar el fracaso terapéutico, hecho que supone una disminución en la calidad de vida de los pacientes y un alto impacto económico para el sistema sanitario. La respuesta a la terapia farmacológica viene determinada en buena parte por los factores genéticos, los cuales explican gran parte de la variabilidad interindividual. La farmacogenómica, las terapias avanzadas o la nanomedicina son tres áreas que se engloban dentro de la medicina de precisión. La farmacogenómica permite la detección de biomarcadores que nos pueden predecir la respuesta o toxicidad de un determinado tratamiento. Esta área es muy utilizada en oncología dada la base genética de las neoplasias malignas. También se utiliza en otras patologías, como en determinados fármacos para la !brosis quística, el uso de la codeína para la tos o en fármacos antidepresivos. Las terapias avanzadas son medicamentos que se basan en la terapia génica, la terapia de células somáticas, la terapia de ingeniería de tejidos y los medicamentos combinados de terapias avanzadas para el manejo de determinadas enfermedades. El desarrollo de estos medicamentos es muy complejo como consecuencia de la propia naturaleza de estas terapias. Actualmente en España hay tres comercializadas. Por último, la nanomedicina estudia y desarrolla nanomateriales para la prevención, el diagnóstico o el tratamiento de los trastornos a escala celular o molecular. Hoy en día disponemos de nanomateriales que se utilizan en la práctica clínica diaria, como los biosensores de glucosa, y también de nanofármacos ya comercializados en nuestro país. Estas tres áreas han supuesto grandes avances que han permitido mejorar el diagnóstico y/o tratamiento de las enfermades de forma “individual”, sobre todo en el ámbito de la oncología y de las enfermedades minoritarias.

Programa d’oncologia de precisió; Implantació; Sistema sanitari públic Programa de oncología de precisión; Implantación; Sistema sanitario público Precision oncology Program; Implementation; Public health system El Programa d’oncologia de precisió comprèn un àmbit d’actuació que afecta totes aquelles alteracions moleculars o genètiques vinculades amb marcadors de pronòstic, predictors de la resposta terapèutica, la determinació de les quals condiciona la indicació d’un fàrmac més efectiu per al pacient, i també aquelles determinacions que comporten la identificació de alteracions relacionades amb la predisposició hereditària al càncer. El Programa de oncología de precisión comprende un ámbito de actuación que afecta a todas aquellas alteraciones moleculares o genéticas vinculadas con marcadores de pronóstico, predictores de la respuesta terapéutica, la determinación se condiciona la indicación de un fármaco más efectivo para el paciente , y también aquellas determinaciones que conllevan la identificación de alteraciones relacionadas con la predisposición hereditaria al cáncer. The Precision Oncology Program includes a field of action that affects all those molecular or genetic alterations linked to prognostic markers, predictors of the therapeutic response, the determination of which conditions the indication of a more effective drug for the patient, and also those determinations that involve the identification of alterations related to the hereditary predisposition to cancer.

Biomarcadors; Diagnòstic; Avaluació de tractaments Biomarcadores; Diagnóstico; Evaluación de tratamientos Biomarkers; Diagnosis; Treatment evaluation Amb l’objectiu d’avaluar la tecnologia nCounter®, es va dur a terme una revisió sistemàtica de la literatura a la base de dades Pubmed, en el període temporal entre 2015 y març de 2021. La finalitat d’aquesta revisió sistemàtica va ser identificar els estudis de diagnòstic, pronòstic i tractament en pacients amb indicacions oncològiques i no oncològiques de qualsevol edat, en els que s’hagués comparat la tecnologia nCounter® amb altres tècniques existents (immunohistoquímica, FISH, RT-qPCR, RT-PCR, entre altres). Els dissenys d’estudi que es van cercar van ser revisions sistemàtiques, assaigs clínics aleatoritzats, estudis observacionals (de proves diagnòstiques, entre altres) i avaluacions econòmiques. In order to evaluate the nCounter® technology, a systematic literature review was conducted in the Pubmed database in the period between 2015 and March 2021. The purpose of this systematic review was to identify diagnostic, prognostic and treatment studies in patients with oncological and non-oncological indications of any age in which nCounter® technology was compared to other existing techniques (immunohistochemistry, FISH, RT-qPCR, RTPCR, among others). The study designs were systematic reviews, randomised clinical trials, observational studies (of diagnostic tests, among others) and economic evaluations. Con el objetivo de evaluar la tecnología nCounter®, se llevó a cabo una revisión sistemática de la literatura en la base de datos Pubmed en el periodo temporal entre 2015 y marzo de 2021. La finalidad de esta revisión sistemática fue identificar los estudios de diagnóstico, pronóstico y tratamiento en pacientes con indicaciones oncológicas y no oncológicas de cualquier edad en los que hubieran comparado la tecnología nCounter® con otras técnicas existentes (inmunohistoquímica, FISH, RT-qPCR, RT-PCR, entre otras). Los diseños de estudio que se buscaron fueron revisiones sistemáticas, ensayos clínicos aleatorizados, estudios observacionales (de pruebas diagnósticas, entre otros) y evaluaciones económicas.

Cancer treatment; Personalized medicine; Precision oncology Tratamiento del cáncer; Medicina personalizada; Oncología de precisión Tractament del càncer; Medicina personalitzada; Oncologia de precisió Cancer treatment options have evolved significantly in the past few years. From the initial surgical procedures, to the latest next-generation technologies, we are now in the position to analyze and understand tumors in a one-by-one basis and use that to our advantage to provide with individualized treatment options that may increase patient survival. In this review, we will focus on how tumor profiling has evolved over the past decades to deliver more efficient and personalized treatment options, and how novel technologies can help us envisage the future of precision oncology toward a better management and, ultimately, increased survival. This work was funded by AECC grant GC16173720CARR to ÁC, ML, and AC. Also, other sources of funding include the Fundación Ramón Areces; the Spanish Ministry of Science, Innovation and Universities (MCIU- I+D+i 2018), Spanish Research State Agency (AEI), the European Fund for Regional Development (MCIU/AEI/FEDER-UE): grants RTI2018-097455-B-I00 and RED2018-102723-T; CIBER-Onc (grant number CB16/12/00275) and the Economy, Business and Universities Council of the Junta de Andalucia (grant number P18-RT-2501)—to AC; and the Instituto de Salud Carlos III (ISCIII) co-financed by the European Regional Fund (ERDF): grant numbers PI16/01057—to AC and PI15/01262 and CP03/00101—to ML.

Medicina de precisió; Farmacogenòmica; Teràpies avançades; Nanomedicina Medicina de precisión; Farmacogenómica; Terapias avanzadas; Nanomedicina Precision medicine; Pharmacogenomics; Advanced therapies; Nanomedicine La medicina de precisió té com a repte utilitzar el medicament adequat, en la persona concreta i en el moment adequat, el que suposa un canvi d’enfocament en la medicina: d’una visió poblacional a una visió individual. La variabilitat interindividual de la resposta a un fàrmac pot implicar el fracàs terapèutic, fet que suposa una minva de la qualitat de vida dels pacients i un alt impacte econòmic per al sistema sanitari. La resposta a la teràpia farmacològica ve determinada en bona part pels factors genètics, els quals expliquen gran part de la variabilitat interindividual. La farmacogenòmica, les teràpies avançades o la nanomedicina són tres àrees que s’engloben dintre de la medicina de precisió. La farmacogenòmica permet la detecció de biomarcadors que ens poden predir la resposta o toxicitat d’un determinat tractament. Aquesta àrea és molt utilitzada en oncologia atesa la base genètica de les neoplàsies malignes. També s’utilitza en altres patologies, com en determinats fàrmacs per a la !brosi quística, l’ús de la codeïna per a la tos o en fàrmacs antidepressius. Les teràpies avançades són medicaments que es basen en la teràpia gènica, la teràpia de cèl·lules somàtiques, la teràpia d’enginyeria de teixits i els medicaments combinats de teràpies avançades per al maneig d’algunes malalties. El desenvolupament d’aquests medicaments és molt complex com a conseqüència de la pròpia naturalesa d’aquestes teràpies. Actualment a Espanya en tenim tres de comercialitzades. Per últim, la nanomedicina estudia i desenvolupa nanomaterials per a la prevenció, el diagnòstic o el tractament de la malaltia a escala cel·lular o molecular. Avui dia disposem de nanomaterials que s’utilitzen a la pràctica clínica diària, com són els biosensors de glucosa, i també de nanofàrmacs comercialitzats en el nostre país. Aquestes tres àrees han creat grans avenços que han permès millorar el diagnòstic i/o tractament de les malalties de forma “individual”, sobretot en l’àmbit de l’oncologia i de les malalties minoritàries. La medicina de precisión tiene como reto utilizar el medicamento adecuado, en la persona concreta y en el momento apropiado, lo que supone un cambio de enfoque en la medicina: de una visión poblacional a una visión individual. La variabilidad interindividual de la respuesta a un fármaco puede implicar el fracaso terapéutico, hecho que supone una disminución en la calidad de vida de los pacientes y un alto impacto económico para el sistema sanitario. La respuesta a la terapia farmacológica viene determinada en buena parte por los factores genéticos, los cuales explican gran parte de la variabilidad interindividual. La farmacogenómica, las terapias avanzadas o la nanomedicina son tres áreas que se engloban dentro de la medicina de precisión. La farmacogenómica permite la detección de biomarcadores que nos pueden predecir la respuesta o toxicidad de un determinado tratamiento. Esta área es muy utilizada en oncología dada la base genética de las neoplasias malignas. También se utiliza en otras patologías, como en determinados fármacos para la !brosis quística, el uso de la codeína para la tos o en fármacos antidepresivos. Las terapias avanzadas son medicamentos que se basan en la terapia génica, la terapia de células somáticas, la terapia de ingeniería de tejidos y los medicamentos combinados de terapias avanzadas para el manejo de determinadas enfermedades. El desarrollo de estos medicamentos es muy complejo como consecuencia de la propia naturaleza de estas terapias. Actualmente en España hay tres comercializadas. Por último, la nanomedicina estudia y desarrolla nanomateriales para la prevención, el diagnóstico o el tratamiento de los trastornos a escala celular o molecular. Hoy en día disponemos de nanomateriales que se utilizan en la práctica clínica diaria, como los biosensores de glucosa, y también de nanofármacos ya comercializados en nuestro país. Estas tres áreas han supuesto grandes avances que han permitido mejorar el diagnóstico y/o tratamiento de las enfermades de forma “individual”, sobre todo en el ámbito de la oncología y de las enfermedades minoritarias.

Precision oncology relies on accurate discovery and interpretation of genomic variants, enabling individualized diagnosis, prognosis and therapy selection. We found that six prominent somatic cancer variant knowledgebases were highly disparate in content, structure and supporting primary literature, impeding consensus when evaluating variants and their relevance in a clinical setting. We developed a framework for harmonizing variant interpretations to produce a meta-knowledgebase of 12,856 aggregate interpretations. We demonstrated large gains in overlap between resources across variants, diseases and drugs as a result of this harmonization. We subsequently demonstrated improved matching between a patient cohort and harmonized interpretations of potential clinical significance, observing an increase from an average of 33% per individual knowledgebase to 57% in aggregate. Our analyses illuminate the need for open, interoperable sharing of variant interpretation data. We also provide a freely available web interface (search.cancervariants.org) for exploring the harmonized interpretations from these six knowledgebases., This analysis presents a harmonized meta-knowledgebase to facilitate clinical interpretation of somatic genomic variants in cancer. This community-based project highlights the need for cooperative efforts to curate clinical interpretations of somatic variants for robust practice of precision oncology.

Molecular profiling of personal cancer genomes, and the identification of actionable vulnerabilities and drug-response biomarkers, are the basis of precision oncology. Tumors often present several driver alterations that might be connected by cross-talk and feedback mechanisms, making it difficult to mark single oncogenic variations as reliable predictors of therapeutic outcome. In the current work, we uncover and exploit driver alteration co-occurrence patterns from a recently published in vivo screening in patient-derived xenografts (PDXs), including 187 tumors and 53 drugs. For each treatment, we compare the mutational profiles of sensitive and resistant PDXs to statistically define Driver Co-Occurrence (DCO) networks, which capture both genomic structure and putative oncogenic synergy. We then use the DCO networks to train classifiers that can prioritize, among the available options, the best possible treatment for each tumor based on its oncogenomic profile. In a cross-validation setting, our drug-response models are able to correctly predict 66% of sensitive and 77% of resistant drug-tumor pairs, based on tumor growth variation. Perhaps more interesting, our models are applicable to several tumor types and drug classes for which no biomarker has yet been described. Additionally, we experimentally validated the performance of our models on 15 new tumor samples engrafted in mice, achieving an overall accuracy of 75%. Finally, we adapted our strategy to derive drug-response models from continuous clinical outcome measures, such as progression free survival, which better represent the data acquired during routine clinical practice and in clinical trials. We believe that the computational framework presented here could be incorporated into the design of adaptive clinical trials, revealing unexpected connections between oncogenic alterations and increasing the clinical impact of genomic profiling.

Medicina personalitzada; Càncer pediàtric; Bioinformàtica Personalized medicine; Pediatric cancer; Bioinformatics Medicina personalizada; Cáncer pediátrico; Bioinformática La medicina personalitzada s’adapta a les necessitats particulars de cada pacient. El càncer en pediatria és diferent del càncer de l’adult, tant pel que fa a l’origen i els seus tipus com en la seva evolució. Els tumors pediàtrics són el resultat d’alteracions genètiques i moleculars específiques de cada pacient que es produeixen de forma primerenca durant el desenvolupament o en les primeres etapes de la vida, per la qual cosa, a diferència dels tumors d’adults, no s’associen amb l’estil de vida o amb factors de risc ambientals. El Servei d’Oncologia Pediàtrica de l’Hospital Universitari Vall d’Hebron va posar en marxa el 2016 el programa Comik (Cancer Omics for Kids —Medicina Òmica en Nens—) de medicina personalitzada en tumors sòlids infantils. Aquest programa possibilita realitzar una anàlisi genètica exhaustiva dels tumors en aquells casos en què els pacients no responen als tractaments actuals o que estan en situació de recaiguda. D’aquesta manera, es pot obtenir una signatura molecular específica de cada tumor. Una signatura que és única i singular per al tumor de cada pacient, i que pot permetre l’ús de teràpies dirigides basades en les anomalies moleculars detectades.

Medicina personalitzada; Malaltia pulmonar obstructiva crònica; MPOC Personalized medicine; Chronic obstructive pulmonary disease; COPD Medicina personalizada; Enfermedad pulmonar obstructiva crónica; EPOC Comunicació sobre la medicina personalitzada i la seva aplicació en el tractament de la malaltia pulmonar obstructiva crònica (MPOC).