Evaluation of the TCR Repertoire as a Predictive and Prognostic Biomarker in Cancer : diversity or Clonality?

T cells play a vital role in the anti-tumoural response, and the presence of tumour-infiltrating lymphocytes has shown to be directly correlated with a good prognosis in several cancer types. Nevertheless, some patients presenting tumour-infiltrating lymphocytes do not have favourable outcomes. The TCR determines the specificities of T cells, so the analysis of the TCR repertoire has been recently considered to be a potential biomarker for patients' progression and response to therapies with immune checkpoint inhibitors. The TCR repertoire is one of the multiple elements comprising the immune system and is conditioned by several factors, including tissue type, tumour mutational burden, and patients' immunogenetics. Its study is crucial to understanding the anti-tumoural response, how to beneficially modulate the immune response with current or new treatments, and how to better predict the prognosis. Here, we present a critical review including essential studies on TCR repertoire conducted in patients with cancer with the aim to draw the current conclusions and try to elucidate whether it is better to encounter higher clonality with few TCRs at higher frequencies, or higher diversity with many different TCRs at lower frequencies

COVID-19 in breast cancer patients: a subanalysis of the OnCovid registry

COVID-19; SARS-CoV-2; Cáncer de mamaCOVID-19; SARS-CoV-2; Càncer de mamaCOVID-19; SARS-CoV-2; Breast cancerBackground: Cancer patients are at higher risk of COVID-19 complications and mortality than the rest of the population. Breast cancer patients seem to have better prognosis when infected by SARS-CoV-2 than other cancer patients. Methods: We report a subanalysis of the OnCovid study providing more detailed information in the breast cancer population. Results: We included 495 breast cancer patients with a SARS-CoV-2 infection. Mean age was 62.6 years; 31.5% presented more than one comorbidity. The most frequent breast cancer subtype was luminal-like (n = 245, 49.5%) and 177 (35.8%) had metastatic disease. A total of 332 (67.1%) patients were receiving active treatment, with radical intent in 232 (47.6%) of them. Hospitalization rate was 58.2% and all-cause mortality rate was 20.3%. One hundred twenty-nine (26.1%) patients developed one COVID-19 complication, being acute respiratory failure the most common (n = 74, 15.0%). In the multivariable analysis, age older than 70 years, presence of COVID-19 complications, and metastatic disease were factors correlated with worse outcomes, while ongoing anticancer therapy at time of COVID-19 diagnosis appeared to be a protective factor. No particular oncological treatment was related to higher risk of complications. In the context of SARS-CoV-2 infection, 73 (18.3%) patients had some kind of modification on their oncologic treatment. At the first oncological reassessment (median time: 46.9 days ± 36.7), 255 (51.6%) patients reported to be fully recovered from the infection. There were 39 patients (7.9%) with long-term SARS-CoV-2-related complications. Conclusion: In the context of COVID-19, our data confirm that breast cancer patients appear to have lower complications and mortality rate than expected in other cancer populations. Most breast cancer patients can be safely treated for their neoplasm during SARS-CoV-2 pandemic. Oncological treatment has no impact on the risk of SARS-CoV-2 complications, and, especially in the curative setting, the treatment should be modified as little as possible.D.J. Pinato is supported by grant funding from the Wellcome Trust Strategic Fund (PS3416) and acknowledges grant support from the Cancer Treatment and Research Trust (CTRT), infrastructural and grant support by the Cancer Research UK Imperial Centre and the NIHR Imperial Biomedical Research Centre. A. Gennari is supported by the AIRC IG Grant, No. 14230, Associazione Italiana per la Ricerca sul Cancro Foundation, Milan, Italy and acknowledge also support from the UPO Aging Project

Analysis of tumor infiltrating CD4+ and CD8+ CDR3 sequences reveals shared features putatively associated to the anti-tumor immune response

IntroductionTumor-infiltrating lymphocytes (TILs) have predictive and prognostic value in breast cancer (BC) and exert a protective function against tumor growth, indicating that it is susceptible to treatment using adoptive cell transfer of TILs or T cell receptor (TCR)-based therapies. TCR can be used to identify naturally tumor-reactive T cells, but little is known about the differences in the TCR repertoires of CD4+ and CD8+ TILs.MethodsTCR high-throughput sequencing was performed using TILs derived from the initial cultures of 11 BC biopsies and expanded and sorted CD4+ and CD8+ TILs as well as using PBMCs from healthy donors expanded and sorted using the same methodology.ResultsPhysicochemical TCR differences between T cell subsets were observed, as CD4+ TILs presented larger N(D)Nnt TRB sequences and with a higher usage of positively charged residues, although only the latest was also observed in peripheral T cells from healthy individuals. Moreover, in CD4+ TILs, a more restricted TCR repertoire with a higher abundance of similar sequences containing certain amino acid motifs was observed.DiscussionSome differences between CD4+ and CD8+ TCRs were intrinsic to T cell subsets as can also be observed in peripheral T cells from healthy individuals, while other were only found in TILs samples and therefore may be tumor-driven. Notably, the higher similarity among CD4+ TCRs suggests a higher TCR promiscuity in this subset

PANDORA II: campanya de comunicació d'un àlbum musical

[ES] Desarrollo de una campaña de comunicación gráfica asociada a un álbum musical de un artista emergente. Dicho álbum, dividido en dos versiones, presenta identidades gráficas diferentes pero complementarias; hecho que también se refleja en los propios ámbitos gráficos de la campaña y en todos los soportes empleados por la misma. El proyecto recibe el nombre de PANDORA y está realizado en colaboración con Enrique Ruiz.[EN] Development of a graphic communication campaign associated with a musical album by an emerging artist. This album, divided into two versions, presents different but complementary graphic identities; a fact that is also reflected in the graphic areas of the campaign and in all the supports used by it. The project is called PANDORA and is carried out in collaboration with Enrique Ruiz.Bonias Garrigós, L. (2023). PANDORA II: campaña de comunicación de un álbum musical. Universitat Politècnica de València. http://hdl.handle.net/10251/19539

Influència de factors clínics, radiològics i patològics en la valoració de resposta a la quimioteràpia neoadjuvant en càncer de mama

La importància d’una predicció acurada del tumor residual després de quimioteràpia neoadjuvant (QNA) radica en la planificació del tipus de cirurgia. Avui en dia es considera que la millor prova per a valorar la resposta a la QNA és la ressonància magnètica (RM); tot i això, estudis previs suggereixen que la fiabilitat de la RM pot estar alterada per diferents factors. En els últims anys la QNA ja no només s’utilitza amb intenció de millorar les opcions quirúrgiques de les pacients, sinó que s’ha ampliat a pacients amb tumors amb immunofenotips que tenen alta probabilitat d’assolir RCp, que en els subtipus triple negatiu (TN) i HER2(+), s’ha associat a millor pronòstic. Hem analitzat 186 pacients tractades amb QNA a l’Hospital del Mar entre 2006 i 2013. Totes les pacients disposaven de RM basal i de RM post-QNA. A la nostra sèrie predominaven tumors tipus Luminal (21% Luminal A i 33.3% Luminal B-HER2(-)). Hem assolit una taxa de Resposta Completa Patològica (RCp) total d’un 17.7%, que augmenta fins a un 66.7% en els tumors HER2(+) i que es redueix a un 0% en els tumors Luminal A. Hem objectivat que els principals factors predictors de RCp són estat de Receptors Hormonals (RH) i de HER2. Hem reportat una bona correlació entre mida de tumor residual valorada mitjançant RM i valorada per patologia, amb una mitjana de discrepança d’11.6 mm. L’immunofenotip on la mitjana de discrepança entre mides és menor és en el TN, de 3.2 mm versus un 15.4 mm en els tumors Luminal A, on trobem la major discrepança. Els factors que afecten a la precisió de la RM per a valorar mida tumoral residual són mida tumoral inicial i estat de HER2. Hem reportat una Sensibilitat de la RM per a predir RCp del 75.8%, una Especificitat del 79.7%, un Valor Predictiu Positiu del 44.6% i un Valor Predictiu Negatiu del 77.75%. La precisió de la RM per a detectar RCp és superior a mama que a aixella. La fiabilitat de la RM per a detectar RCp està influenciada pel valor basal de ki 67. L’immunofenotip on la RM valora de manera més precisa la resposta a la QNA és el TN. No hem identificat cap subgrup on la fiabilitat de la RM sigui del 100% i on es pogués plantejar eradicar el tractament quirúrgic. Les pacients que assoleixen RCp tenen major supervivència lliure de recaiguda. A la nostra cohort les pacients amb més recaigudes són aquelles amb tumors TN, sobretot les que no assoleixen RCp.In patients with breast cancer the assessment of the response to neoadjuvant chemotherapy (NAQ) is very important in order to plan the surgical treatment. Magnetic Resonance Imaging (MRI) is accepted as the best method to predict pathological response to NAQ. However, previous studies suggested that the accuracy of MRI in this situation can be altered by different factors. Initially NAQ was used to improve the surgical options of the patients, in recent years its used has been extended to patients with tumours with immunofenotypes that have a high probability of achieving pathological complete response (pCR), which is associated with better prognosis in triple negative (TN) and HER2 (+) subtypes. This retrospective study included 186 breast cancer patients treated with NAQ between January 2006 and June 2013 at Hospital del Mar. All patients underwent a baseline MRI and after NAQ. Luminal tumours predominated in our series (21% Luminal A and 33.3% Luminal B-HER2[-]). A pCR was achieved in 17.4% patients, 66.7% in HER(+) tumours, the highest, and 0% in Luminal A tumours, the lowest. The main predictors of pCR were Hormonal Receptors (RH) and HER2 status. We observed a good correlation between residual tumour size evaluated by MRI and tumour size evaluated by pathology, with a mean discrepancy of 11.6 mm. The size discrepancy was smaller in TN tumours, of 3.2 mm versus 15.4 mm in Luminal A tumors, where we find the greatest discrepancy. Initial tumor size and HER2 status were significantly correlated with the accuracy of MRI to asses residual tumour size. The overall sensitivity, specificity, positive predictive value and negative predictive value to predict pCR by using MRI were 75.8%, 79.7%, 44.6% and 77.75%. The accuracy of the MRI to detect pCR was superior in the breast that in the axilla. The accuracy of the MRI to detect pCR was influenced by the basal value of ki 67. The immunofenotype where the MRI better evaluated the response was the TN. We did not identified any subgroup where the reliability of MRI was 100% and where it could be considered to eradicate the surgical treatment. Patients who achieved pCR had a higher relapsing free survival rate. In our cohort, patients with most relapses were those with TN tumors, especially those that did not reach pCR

Influència de factors clínics, radiològics i patològics en la valoració de resposta a la quimioteràpia neoadjuvant en càncer de mama /

La importància d'una predicció acurada del tumor residual després de quimioteràpia neoadjuvant (QNA) radica en la planificació del tipus de cirurgia. Avui en dia es considera que la millor prova per a valorar la resposta a la QNA és la ressonància magnètica (RM); tot i això, estudis previs suggereixen que la fiabilitat de la RM pot estar alterada per diferents factors. En els últims anys la QNA ja no només s'utilitza amb intenció de millorar les opcions quirúrgiques de les pacients, sinó que s'ha ampliat a pacients amb tumors amb immunofenotips que tenen alta probabilitat d'assolir RCp, que en els subtipus triple negatiu (TN) i HER2(+), s'ha associat a millor pronòstic. Hem analitzat 186 pacients tractades amb QNA a l'Hospital del Mar entre 2006 i 2013. Totes les pacients disposaven de RM basal i de RM post-QNA. A la nostra sèrie predominaven tumors tipus Luminal (21% Luminal A i 33.3% Luminal B-HER2(-)). Hem assolit una taxa de Resposta Completa Patològica (RCp) total d'un 17.7%, que augmenta fins a un 66.7% en els tumors HER2(+) i que es redueix a un 0% en els tumors Luminal A. Hem objectivat que els principals factors predictors de RCp són estat de Receptors Hormonals (RH) i de HER2. Hem reportat una bona correlació entre mida de tumor residual valorada mitjançant RM i valorada per patologia, amb una mitjana de discrepança d'11.6 mm. L'immunofenotip on la mitjana de discrepança entre mides és menor és en el TN, de 3.2 mm versus un 15.4 mm en els tumors Luminal A, on trobem la major discrepança. Els factors que afecten a la precisió de la RM per a valorar mida tumoral residual són mida tumoral inicial i estat de HER2. Hem reportat una Sensibilitat de la RM per a predir RCp del 75.8%, una Especificitat del 79.7%, un Valor Predictiu Positiu del 44.6% i un Valor Predictiu Negatiu del 77.75%. La precisió de la RM per a detectar RCp és superior a mama que a aixella. La fiabilitat de la RM per a detectar RCp està influenciada pel valor basal de ki 67. L'immunofenotip on la RM valora de manera més precisa la resposta a la QNA és el TN. No hem identificat cap subgrup on la fiabilitat de la RM sigui del 100% i on es pogués plantejar eradicar el tractament quirúrgic. Les pacients que assoleixen RCp tenen major supervivència lliure de recaiguda. A la nostra cohort les pacients amb més recaigudes són aquelles amb tumors TN, sobretot les que no assoleixen RCp.In patients with breast cancer the assessment of the response to neoadjuvant chemotherapy (NAQ) is very important in order to plan the surgical treatment. Magnetic Resonance Imaging (MRI) is accepted as the best method to predict pathological response to NAQ. However, previous studies suggested that the accuracy of MRI in this situation can be altered by different factors. Initially NAQ was used to improve the surgical options of the patients, in recent years its used has been extended to patients with tumours with immunofenotypes that have a high probability of achieving pathological complete response (pCR), which is associated with better prognosis in triple negative (TN) and HER2 (+) subtypes. This retrospective study included 186 breast cancer patients treated with NAQ between January 2006 and June 2013 at Hospital del Mar. All patients underwent a baseline MRI and after NAQ. Luminal tumours predominated in our series (21% Luminal A and 33.3% Luminal B-HER2[-]). A pCR was achieved in 17.4% patients, 66.7% in HER(+) tumours, the highest, and 0% in Luminal A tumours, the lowest. The main predictors of pCR were Hormonal Receptors (RH) and HER2 status. We observed a good correlation between residual tumour size evaluated by MRI and tumour size evaluated by pathology, with a mean discrepancy of 11.6 mm. The size discrepancy was smaller in TN tumours, of 3.2 mm versus 15.4 mm in Luminal A tumors, where we find the greatest discrepancy. Initial tumor size and HER2 status were significantly correlated with the accuracy of MRI to asses residual tumour size. The overall sensitivity, specificity, positive predictive value and negative predictive value to predict pCR by using MRI were 75.8%, 79.7%, 44.6% and 77.75%. The accuracy of the MRI to detect pCR was superior in the breast that in the axilla. The accuracy of the MRI to detect pCR was influenced by the basal value of ki 67. The immunofenotype where the MRI better evaluated the response was the TN. We did not identified any subgroup where the reliability of MRI was 100% and where it could be considered to eradicate the surgical treatment. Patients who achieved pCR had a higher relapsing free survival rate. In our cohort, patients with most relapses were those with TN tumors, especially those that did not reach pCR

Vitamin D threshold to prevent aromatase inhibitor-related bone loss: the B-ABLE prospective cohort study

Aromatase inhibitor (AI)-related bone loss is associated with increased fracture rates. Vitamin D might play a role in minimising this effect. We hypothesised that 25-hydroxy-vitamin D concentrations [25(OH)D] after 3 months supplementation might relate to bone loss after 1 year on AItherapy. We conducted a prospective cohort study from January 2006 to December 2011 of a consecutive sample of women initiating AI for early breast cancer who were ineligible for bisphosphonate therapy and stayed on treatment for 1 year (N = 232). Serum 25(OH)D was measured at baseline and 3 months, and lumbar spine (LS) bone mineral density at baseline and 1 year. Subjects were supplemented with daily calcium (1 g) and vitamin D3 (800 IU) and additional oral 16,000 IU every 2 weeks if baseline 25(OH)D was ?30 ng/ml. Linear regression models were fitted to adjust for potential confounders. After 1 year on AI therapy, 232 participants experienced a significant 1.68 % [95 % CI 1.15–2.20 %] bone loss at LS (0.017 g/cm2 [0.012–0.024], P\0.0001). Higher 25(OH)D at 3 months protected against LS bone loss (-0.5 % per 10 ng/ml [95 % CI -0.7 to-0.3 %], adjusted P = 0.0001), and those who reached levels ?40 ng/ml had reduced bone loss by 1.70 % [95 % CI 0.4–3.0 %; adjusted P = 0.005] compared to those with low 25(OH)D levels (?30 ng/ml). We conclude that improved vitamin D status using supplementation is associated with attenuation of AI-associated bone loss. For this population, the current Institute of Medicine target recommendation of 20 ng/ml might be too low to ensure good bone health.<br/

Evolución de la DMO durante el tratamiento con inhibidores de aromatasa y su relación con el gen CYP11A1: estudio prospectivo de la cohorte B-ABLE

Objectives: The aim of this study was to analyze bone mineral density (BMD) changes throughout aromatase inhibitor (AI) treatment in clinical cases and also consider its association with the CYP11A1 gene and the BMD variation after treatment. Material and methods: The B-ABLE cohort is a prospective study of postmenopausal women with breast cancer, in AI treatment. BMD variation was analyzed during AI treatment, as well as the differences those patients who were treated and not treated previously with tamoxifen (TMX). Three polymorphisms (rs4077581, rs11632698 and rs900798) of the CYP11A1 gene were genotyped for their association with BMD variation. Results: TMX-treated patients presented more rapid BMD loss than those who did not undergo prior TMX treatment (60% less in spine and 46% in femur at 2 years and 70% less in the spine and 63% in the femur at 3 years). However, no significant BMD loss was detected after treatment in either group. The 3 CYP11A1 gene polymorphisms were significantly associated with BMD variation in the femur at the end of the treatment. Conclusions: BMD was reduced more rapidly in patients with prior TMX treatment than in those who only received AI, although no significant differences were detected after treatment. The 3 CYP11A1 gene polymorphisms were associated with BMD variation in response to AI treatment.Objetivos: El objetivo del estudio fue analizar los cambios en la densidad mineral ósea (DMO) a lo largo del tratamiento con inhibidores de aromatasa (IA) en la práctica clínica y evaluar la asociación entre el gen CYP11A1 y la variación de DMO al final del tratamiento. Material y métodos: La cohorte B-ABLE es un estudio prospectivo de mujeres postmenopáusicas con cáncer de mama, en tratamiento con IA. Se analizó la variación de DMO durante todo el tratamiento con IA, así como las diferencias entre las pacientes tratadas y no-tratadas previamente con tamoxifeno (TMX). Tres polimorfismos (rs4077581, rs11632698 y rs900798) del gen CYP11A1, fueron genotipados para su asociación con la variación de DMO. Resultados: Las pacientes tratadas con TMX mostraron pérdidas más aceleradas de DMO que las no tratadas previamente con TMX (60% menos en columna y 46% en fémur a los 2 años y 70% menos en columna y 63% en fémur a los 3 años). No obstante, al final del tratamiento no se detectaron diferencias significativas en la pérdida de DMO entre ambos grupos de pacientes. Los 3 polimorfismos del gen CYP11A1 resultaron significativamente asociados a la variación de DMO en fémur al final del tratamiento. Conclusiones: La DMO disminuyó de forma más acelerada en las pacientes con tratamiento previo con TMX que en las que solo recibieron AI, a pesar de que no se detectaron diferencias significativas al final de tratamiento. Polimorfismos en el gen CYP11A1 están relacionados con la variación de la DMO en respuesta al tratamiento con IA

Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: the DEBBRAH trial

[AHEAD] Data de publicació electrónica: 26-05-2022Background: trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in pretreated patients with HER2-positive advanced breast cancer (ABC), but its efficacy has not yet been evaluated in patients with active brain metastases (BMs). DEBBRAH aims to assess T-DXd in patients with HER2-positive or HER2-low ABC and central nervous system involvement. Methods: this ongoing, five-cohort, phase II study (NCT04420598) enrolled patients with pretreated HER2-positive or HER2-low ABC with stable, untreated, or progressing BMs and/or leptomeningeal carcinomatosis. Here, we report findings from HER2-positive ABC patients with non-progressing BMs after local therapy (n=8; cohort 1), asymptomatic untreated BMs (n=4; cohort 2), or progressing BMs after local therapy (n=9; cohort 3). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was 16-week progression-free survival (PFS) for cohort 1 and intracranial overall response rate (ORR-IC) for cohorts 2 and 3. Results: as of October 20, 2021, 21 patients received T-DXd. In cohort 1, 16-week PFS rate was 87.5% (95%CI, 47.3-99.7; P<.001). ORR-IC was 50.0% (95%CI, 6.7-93.2) in cohort 2 and 44.4% (95%CI, 13.7-78.8; P<.001) in cohort 3. Overall, the ORR-IC in patients with active BMs was 46.2% (95%CI, 19.2-74.9). Among patients with measurable intracranial or extracranial lesions at baseline, the ORR was 66.7% (12 out of 18 patients; 95%CI, 41.0-86.7), 80.0% (95%CI, 28.4-99.5) in cohort 1, 50.0% (95%CI, 6.7-93.2) in cohort 2, and 66.7% (95%CI, 29.9-92.5) in cohort 3. All responders had partial responses. The most common adverse events included fatigue (52.4%; 4.8% grade≥3), nausea (42.9%; 0% grade≥3), neutropenia (28.6%; 19% grade≥3), and constipation (28.6%; 0% grade≥3). Two (9.5%) patients suffered grade 1 interstitial lung disease/pneumonitis. Conclusions: T-DXd showed intracranial activity with manageable toxicity and maintained quality of life in pretreated HER2-positive ABC patients with stable, untreated, or progressing BMs. Further studies are needed to validate these results in larger cohorts