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1. Systemic pro-inflammatory response identifies patients with cancer with adverse outcomes from SARS-CoV-2 infection: the OnCovid Inflammatory Score

Author

Dettorre, Gino M., Dolly, Saoirse, Loizidou, Angela, Chester, John, Jackson, Amanda, Mukherjee, Uma, Zambelli, Alberto, Aguilar Company, Juan, Bower, Mark, Sng, Christopher C. T., Salazar Soler, Ramón, Bertuzzi, Alexia, Brunet, Joan, Mesia, Ricard, Sita-Lumsden, Ailsa, Seguí, Elia, Biello, Federica, Generali, Daniele, Grisanti, Salvatore, Seeva, Pavetha, Rizzo, Gianpiero, Libertini, Michela, Maconi, Antonio, Moss, Charlotte, Russell, Beth, Harbeck, Nadia, Vincenzi, Bruno, Bertulli, Rossella, Ottaviani, Diego, Liñan, Raquel, Marrari, Andrea, Carmona García, M. Carmen, Chopra, Neha, Tondini, Carlo Alberto, Mirallas, Oriol, Tovazzi, Valeria, Fotia, Vittoria, Cruz, Claudia Andrea, Saoudi González, Nadia, Felip, Eudald, Roqué, Ariadna, Lee, Alvin J. X., Newsom-Davis, Tom, García Illescas, David, Reyes, Roxana, Wong, Yien Ning Sophia, Ferrante, Daniela, Scotti, Lorenza, Marco Hernández, Javier, Ruiz Camps, Isabel, Patriarca, Andrea, Rimassa, Lorenza, Chiudinelli, Lorenzo, Franchi, Michela, Santoro, Armando, Prat Aparicio, Aleix, Gennari, Alessandra, Van Hemelrijck, Mieke, Tabernero Caturla, Josep, Diamantis, Nikolaos, Pinato, David J., OnCovid study group, Dettorre, G. M., Dolly, S., Loizidou, A., Chester, J., Jackson, A., Mukherjee, U., Zambelli, A., Aguilar-Company, J., Bower, M., Sng, C. C. T., Salazar, R., Bertuzzi, A., Brunet, J., Mesia, R., Sita-Lumsden, A., Segui, E., Biello, F., Generali, D., Grisanti, S., Seeva, P., Rizzo, G., Libertini, M., Maconi, A., Moss, C., Russell, B., Harbeck, N., Vincenzi, B., Bertulli, R., Ottaviani, D., Linan, R., Marrari, A., Carmen Carmona-Garcia, M., Chopra, N., Tondini, C. A., Mirallas, O., Tovazzi, V., Fotia, V., Cruz, C. A., Saoudi-Gonzalez, N., Felip, E., Roque, A., Lee, A. J. X., Newsom-Davis, T., Garcia-Illescas, D., Reyes, R., Wong, Y. N. S., Ferrante, D., Scotti, L., Marco-Hernandez, J., Ruiz-Camps, I., Patriarca, A., Rimassa, L., Chiudinelli, L., Franchi, M., Santoro, A., Prat, A., Gennari, A., Van Hemelrijck, M., Tabernero, J., Diamantis, N., Pinato, D. J., Wellcome Trust, Institut Català de la Salut, [Dettorre GM] Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK. [Dolly S] Medical Oncology, Guy’s and St Thomas’ NHS Foundation Trust (GSTT), London, UK. [Loizidou A] Department of Infectious Diseases, Internal Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. [Chester J] Medical Oncology, School of Medicine, Cardiff University, Cardiff, UK. Medical Oncology, Velindre Cancer Centre, Cardiff, UK. [Jackson A] Clinical Trials, Velindre Cancer Centre, Cardiff, UK. [Mukherjee U] Medical Oncology, Barts Health NHS Trust, London, UK. [Aguilar-Company J] Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei de Malalties Infeccioses, Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Mirallas O, Saoudi-Gonzalez N, García-Illescas D] Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Ruiz-Camps I] Servei de Malalties Infeccioses, Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Tabernero J] Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. IOB-Quiron, UVic-UCC, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, Comorbidity, Systemic inflammation, Otros calificadores::Otros calificadores::/complicaciones [Otros calificadores], COVID-19 Testing, 0302 clinical medicine, Neoplasms, Immunotherapy Biomarkers, virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], 80 and over, Immunology and Allergy, Medicine, Hypoalbuminemia, Young adult, Càncer, Multivariate Analysi, RC254-282, COVID-19 (Malaltia) - Complicacions, Cancer, Aged, 80 and over, OnCovid study group, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], Middle Aged, Prognosis, Inflamació, Systemic Inflammatory Response Syndrome, 030220 oncology & carcinogenesis, Cohort, Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation::Systemic Inflammatory Response Syndrome [DISEASES], Molecular Medicine, Female, medicine.symptom, Life Sciences & Biomedicine, Human, Adult, medicine.medical_specialty, Prognosi, Càncer - Epidemiologia, Immunology, neoplasias [ENFERMEDADES], inflammation mediator, Young Adult, 03 medical and health sciences, Internal medicine, Humans, afecciones patológicas, signos y síntomas::procesos patológicos::inflamación::síndrome de respuesta inflamatoria sistémica [ENFERMEDADES], Aged, Pharmacology, Science & Technology, business.industry, SARS-CoV-2, COVID-19, medicine.disease, inflammation, inflammation mediators, Blood Cell Count, Multivariate Analysis, Neoplasms [DISEASES], Systemic inflammatory response syndrome, 030104 developmental biology, Neoplasm, Lymphocytopenia, business, Other subheadings::Other subheadings::/complications [Other subheadings]
Abstract

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

Published
2021

2. Time-Dependent COVID-19 Mortality in Patients With Cancer: An Updated Analysis of the OnCovid Registry

Author

Gianpiero Rizzo, Eudald Felip, Annalisa Guida, Alessio Cortellini, Francesca Mazzoni, Rachel Sharkey, Alice Baggi, Emeline Colomba, Sabrina Rossi, Salvatore Grisanti, Federica Zoratto, David J. Pinato, Daniela Ferrante, Claudia Andrea Cruz, Giampero Porzio, Lorenzo Chiudinelli, Alessandra Gennari, Alexia Bertuzzi, Gianluca Gaidano, Joan Brunet, Johann Colomba, Alessia Dalla Pria, Nadia Harbeck, Raffaele Giusti, Alberto Zambelli, Angela Loizidou, Clara Martinez-Vila, Daniele Generali, Matteo Lambertini, Isabel Ruiz-Camps, Paola Queirolo, Michela Libertini, Ana Sanchez de Torre, Ailsa Sita-Lumsden, Laura Fox, Federica Biello, Javier Marco-Hernández, Nikolaos Diamantis, Elia Seguí, Lorenza Rimassa, Nadia Saoudi-Gonzalez, Ariadna Roqué Lloveras, Armando Santoro, John D. Chester, Mieke Van Hemelrijck, Carlo Tondini, Marco Krengli, Saoirse Dolly, Raquel Liñan, Elisa Roldán, Charlotte Moss, Diego Ottaviani, Fanny Pommeret, Uma Mukherjee, Andrea Patriarca, Aleix Prat, Joanne Evans, Rossana Berardi, Meera Patel, Mark Bower, Marco Tagliamento, Paolo Pedrazzoli, Juan Aguilar-Company, Lorenza Scotti, Bruno Vincenzi, Irina Earnshaw, M Carmen Carmona-García, Anna Pous, Thomas Newsom-Davis, Riccardo Bruna, Krishnie Srikandarajah, Rossella Bertulli, Josep Tabernero, Vittoria Fotia, Alessandro Parisi, Anna Sureda, Ramon Salazar, Beth Russell, Michela Franchi, Roxana Reyes, Pinato, D. J., Patel, M., Scotti, L., Colomba, E., Dolly, S., Loizidou, A., Chester, J., Mukherjee, U., Zambelli, A., Dalla Pria, A., Aguilar-Company, J., Bower, M., Salazar, R., Bertuzzi, A., Brunet, J., Lambertini, M., Tagliamento, M., Pous, A., Sita-Lumsden, A., Srikandarajah, K., Colomba, J., Pommeret, F., Segui, E., Generali, D., Grisanti, S., Pedrazzoli, P., Rizzo, G., Libertini, M., Moss, C., Evans, J. S., Russell, B., Harbeck, N., Vincenzi, B., Biello, F., Bertulli, R., Ottaviani, D., Linan, R., Rossi, S., Carmona-Garcia, M. C., Tondini, C., Fox, L., Baggi, A., Fotia, V., Parisi, A., Porzio, G., Queirolo, P., Cruz, C. A., Saoudi-Gonzalez, N., Felip, E., Roque Lloveras, A., Newsom-Davis, T., Sharkey, R., Roldan, E., Reyes, R., Zoratto, F., Earnshaw, I., Ferrante, D., Marco-Hernandez, J., Ruiz-Camps, I., Gaidano, G., Patriarca, A., Bruna, R., Sureda, A., Martinez-Vila, C., Sanchez De Torre, A., Berardi, R., Giusti, R., Mazzoni, F., Guida, A., Rimassa, L., Chiudinelli, L., Franchi, M., Krengli, M., Santoro, A., Prat, A., Tabernero, J., Van Hemelrijck, M., Diamantis, N., Gennari, A., and Cortellini, A.

Subjects
Male, Cancer Research, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), solid cancer, Internal medicine, Neoplasms, Tumor stage, COVID-19, real-world data, hematologic cancer, medicine, Humans, In patient, Registries, Pandemics, Aged, Original Investigation, business.industry, SARS-CoV-2, Hazard ratio, Outbreak, Cancer, Infant, medicine.disease, Female, Oncology, business, Case series
Abstract

IMPORTANCE Whether the severity and mortality of COVID-19 in patients with cancer have improved in terms of disease management and capacity is yet to be defined. OBJECTIVE To test whether severity and mortality from COVID-19 among patients with cancer have improved during the course of the pandemic. DESIGN, SETTING, AND PARTICIPANTS OnCovid is a European registry that collects data on consecutive patients with solid or hematologic cancer and COVID-19. This multicenter case series study included real-world data from 35 institutions across 6 countries (UK, Italy, Spain, France, Belgium, and Germany). This update included patients diagnosed between February 27, 2020, and February, 14, 2021. Inclusion criteria were confirmed diagnosis of SARS-CoV-2 infection and a history of solid or hematologic cancer. EXPOSURES SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES Deaths were differentiated at 14 days and 3 months as the 2 landmark end points. Patient characteristics and outcomes were compared by stratifying patients across 5 phases (February to March 2020, April to June 2020, July to September 2020, October to December 2020, and January to February 2021) and across 2 major outbreaks (February to June 2020 and July 2020 to February 2021). RESULTS At data cutoff, 2795 consecutive patients were included, with 2634 patients eligible for analysis (median [IQR] age, 68 [18-77] years ; 52.8% men). Eligible patients demonstrated significant time-dependent improvement in 14-day case-fatality rate (CFR) with estimates of 29.8% (95% CI, 0.26-0.33) for February to March 2020; 20.3% (95% CI, 0.17-0.23) for April to June 2020;12.5% (95% Cl, 0.06-22.90) for July to September 2020; 17.2% (95% CI, 0.15-0.21) for October to December 2020; and 14.5% (95% CI, 0.09-0.21) for January to February 2021(all P < .001) across the predefined phases. Compared with the second major outbreak, patients diagnosed in the first outbreak were more likely to be 65 years or older (974 of 1626 [60.3%] vs 564 of 1008 [56.1%]; P = .03), have at least 2 comorbidities (793 of 1626 [48.8%) vs 427 of 1008 [42.4%); P = .001), and have advanced tumors (708 of 1626 [46.4%) vs 536 of 1008 [56.1%]: P < .001). Complications of COVID-19 were more likely to be seen (738 of 1626 [45.4%) vs 342 of 1008 [33.9%]; P < .001) and require hospitalization (969 of 1626 [59.8%) vs 418 of 1008 [42.1%); P < .001) and anti-COVID-19 therapy (1004 of 1626 [61.7%) vs 501of 1008 [49.7%); P < .001) during the first major outbreak. The 14-day CFRs for the first and second major outbreaks were 25.6% (95% CI, 0.23-0.28) vs 16.2% (95% CI, 0.13-0.19; P < .001), respectively. After adjusting for country, sex, age, comorbidities, tumor stage and status, anti-COVID-19 and anticancer therapy, and COVID-19 complications, patients diagnosed in the first outbreak had an increased risk of death at 14 days (hazard ratio [HR], 1.85; 95% CI, 1.47-2.32) and 3 months (HR, 1.28; 95% CI, 1.08-1.51) compared with those diagnosed in the second outbreak. CONCLUSIONS AND RELEVANCE The findings of this registry-based study suggest that mortality in patients with cancer diagnosed with COVID-19 has improved in Europe; this improvement may be associated with earlier diagnosis, improved management, and dynamic changes in community transmission over time.

Published
2021

3. Clinical portrait of the SARS-CoV-2 epidemic in european patients with cancer

Author

David J. Pinato, Alberto Zambelli, Juan Aguilar-Company, Mark Bower, Christopher C.T. Sng, Ramon Salazar, Alexia Bertuzzi, Joan Brunet, Ricard Mesia, Elia Seguí, Federica Biello, Daniele Generali, Salvatore Grisanti, Gianpiero Rizzo, Michela Libertini, Antonio Maconi, Nadia Harbeck, Bruno Vincenzi, Rossella Bertulli, Diego Ottaviani, Anna Carbó, Riccardo Bruna, Sarah Benafif, Andrea Marrari, Rachel Wuerstlein, M. Carmen Carmona-Garcia, Neha Chopra, Carlo Tondini, Oriol Mirallas, Valeria Tovazzi, Marta Betti, Salvatore Provenzano, Vittoria Fotia, Claudia Andrea Cruz, Alessia Dalla Pria, Francesca D'Avanzo, Joanne S. Evans, Nadia Saoudi-Gonzalez, Eudald Felip, Myria Galazi, Isabel Garcia-Fructuoso, Alvin J.X. Lee, Thomas Newsom-Davis, Andrea Patriarca, David García-Illescas, Roxana Reyes, Palma Dileo, Rachel Sharkey, Yien Ning Sophia Wong, Daniela Ferrante, Javier Marco-Hernández, Anna Sureda, Clara Maluquer, Isabel Ruiz-Camps, Gianluca Gaidano, Lorenza Rimassa, Lorenzo Chiudinelli, Macarena Izuzquiza, Alba Cabirta, Michela Franchi, Armando Santoro, Aleix Prat, Josep Tabernero, Alessandra Gennari, Gian Carlo Avanzi, Mattia Bellan, Luigi Mario Castello, Maria Martinez, Meritxell Mollà, Mario Pirisi, Lorenza Scotti, Judith Swallow, Pinato, D. J., Zambelli, A., Aguilar-Company, J., Bower, M., Sng, C. C. T., Salazar, R., Bertuzzi, A., Brunet, J., Mesia, R., Segui, E., Biello, F., Generali, D., Grisanti, S., Rizzo, G., Libertini, M., Maconi, A., Harbeck, N., Vincenzi, B., Bertulli, R., Ottaviani, D., Carbo, A., Bruna, R., Benafif, S., Marrari, A., Wuerstlein, R., Carmona-Garcia, M. C., Chopra, N., Tondini, C., Mirallas, O., Tovazzi, V., Betti, M., Provenzano, S., Fotia, V., Cruz, C. A., Pria, A. D., D'Avanzo, F., Evans, J. S., Saoudi-Gonzalez, N., Felip, E., Galazi, M., Garcia-Fructuoso, I., Lee, A. J. X., Newsom-Davis, T., Patriarca, A., Garcia-Illescas, D., Reyes, R., Dileo, P., Sharkey, R., Wong, Y. N. S., Ferrante, D., Marco-Hernandez, J., Sureda, A., Maluquer, C., Ruiz-Camps, I., Gaidano, G., Rimassa, L., Chiudinelli, L., Izuzquiza, M., Cabirta, A., Franchi, M., Santoro, A., Prat, A., Tabernero, J., and Gennari, A.

Subjects
0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Population, MEDLINE, risk stratification, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SARS-CoV-2 pandemic, oncology practice, Internal medicine, Pandemic, medicine, education, education.field_of_study, Chemotherapy, Research Briefs, business.industry, Mortality rate, Cancer, medicine.disease, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, business
Abstract

Higher risk of death from COVID-19 among patients with cancer was correlated with male sex, greater age, presence of multiple comorbidities, advanced-stage disease, and active disease; there was no association between risk and anticancer treatment., The SARS-CoV-2 pandemic significantly affected oncology practice across the globe. There is uncertainty as to the contribution of patients' demographics and oncologic features to severity and mortality from COVID-19 and little guidance as to the role of anticancer and anti–COVID-19 therapy in this population. In a multicenter study of 890 patients with cancer with confirmed COVID-19, we demonstrated a worsening gradient of mortality from breast cancer to hematologic malignancies and showed that male gender, older age, and number of comorbidities identify a subset of patients with significantly worse mortality rates from COVID-19. Provision of chemotherapy, targeted therapy, or immunotherapy did not worsen mortality. Exposure to antimalarials was associated with improved mortality rates independent of baseline prognostic factors. This study highlights the clinical utility of demographic factors for individualized risk stratification of patients and supports further research into emerging anti–COVID-19 therapeutics in SARS-CoV-2–infected patients with cancer. Significance: In this observational study of 890 patients with cancer diagnosed with SARS-CoV-2, mortality was 33.6% and predicted by male gender, age ≥65, and comorbidity burden. Delivery of cancer therapy was not detrimental to severity or mortality from COVID-19. These patients should be the focus of shielding efforts during the SARS-CoV-2 pandemic. This article is highlighted in the In This Issue feature, p. 1426

Published
2020

4. Molecular profiling of long-term responders to immune checkpoint inhibitors in advanced non-small cell lung cancer

Author

Frigola Rissech, Joan, Navarro, Alejandro, Carbonell, Caterina, Callejo, Anna, Iranzo, Patricia, Cedrés, Susana, Martinez-Marti, Alex, Pardo Aranda, Nuria, Saoudi-Gonzalez, Nadia, Martinez, Débora, Jiménez, José, Sansano, Irene, Mancuso, Francesco M., Nuciforo, Paolo, Montuenga, Luis M., Sanchez-Cespedes, Montse, Prat, Aleix, Vivancos, Ana, Felip, Enriqueta, Amat, Ramón, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Frigola J, Carbonell C, Amat R] Thoracic Cancers Translational Genomics Unit, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Navarro A, Callejo A, Iranzo P, Cedrés S, Martinez-Marti A, Pardo N, Saoudi-Gonzalez N] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Jimenez J, Nuciforo P] Molecular Oncology Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Sansano I] Unitat de Patologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Mancuso FM, Vivancos A] Cancer Genomics Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Felip E] Thoracic Cancers Translational Genomics Unit, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Male, 0301 basic medicine, Oncology, Pulmons - Càncer - Prognosi, Cancer Research, Lung Neoplasms, Somatic cell, medicine.medical_treatment, Medicaments antineoplàstics - Ús terapèutic, NSCLC, B7-H1 Antigen, immune checkpoint inhibitors, Transcriptome, 0302 clinical medicine, Long-term benefit, Carcinoma, Non-Small-Cell Lung, Cytotoxic T cell, Other subheadings::/therapeutic use [Other subheadings], Research Articles, Aged, 80 and over, Chromosomal alterations burden, copy number alterations, biology, General Medicine, Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung [DISEASES], Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Diagnosis::Prognosis::Treatment Outcome::Progression-Free Survival [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Progression-Free Survival, 030220 oncology & carcinogenesis, Molecular Medicine, Female, Immunotherapy, Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS], Research Article, Adult, PD-L1, medicine.medical_specialty, Cell type, long‐term benefit, tumor mutational burden, DNA Copy Number Variations, diagnóstico::pronóstico::resultado del tratamiento::supervivencia libre de progresión [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], lcsh:RC254-282, 03 medical and health sciences, Immune checkpoint inhibitors, Immune system, chromosomal alterations burden, Internal medicine, Exome Sequencing, Biomarkers, Tumor, Genetics, medicine, Humans, Lung cancer, Aged, Otros calificadores::/uso terapéutico [Otros calificadores], business.industry, acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS], neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares::neoplasias de los bronquios::carcinoma broncogénico::carcinoma de pulmón de células no pequeñas [ENFERMEDADES], medicine.disease, Tumor mutational burden, 030104 developmental biology, PD‐L1, Copy number alterations, biology.protein, business, Pulmons - Càncer - Tractament
Abstract

We molecularly characterized tumors from non‐small cell lung cancer patients, focusing on long‐term responders to immune checkpoint inhibitors and showed that these patients present high tumor mutation burden and low somatic copy number alteration burden. PD‐L1 expression was also enriched in these patients. Finally, we validated our findings by reanalyzing two public datasets., Immunotherapy has transformed advanced non‐small cell lung cancer (NSCLC) treatment strategies and has led to unprecedented long‐lasting responses in some patients. However, the molecular determinants driving these long‐term responses remain elusive. To address this issue, we performed an integrative analysis of genomic and transcriptomic features of long‐term immune checkpoint inhibitors (ICIs)‐associated responders. We assembled a cohort of 47 patients with NSCLC receiving ICIs that was enriched in long‐term responders [>18 months of progression‐free survival (PFS)]. We performed whole‐exome sequencing from tumor samples, estimated the tumor mutational burden (TMB), and inferred the somatic copy number alterations (SCNAs). We also obtained gene transcription data for a subset of patients using Nanostring, which we used to assess the tumor immune infiltration status and PD‐L1 expression. Our results indicate that there is an association between TMB and benefit to ICIs, which is driven by those patients with long‐term response. Additionally, high SCNAs burden is associated with poor response and negatively correlates with the presence of several immune cell types (B cells, natural killers, regulatory T cells or effector CD8 T cells). Also, CD274 (PD‐L1) expression is increased in patients with benefit, mainly in those with long‐term response. In our cohort, combined assessment of TMB and SCNAs burden enabled identification of long‐term responders (considering PFS and overall survival). Notably, the association between TMB, SCNAs burden, and PD‐L1 expression with the outcomes of ICIs treatment was validated in two public datasets of ICI‐treated patients with NSCLC. Thus, our data indicate that TMB is associated with long‐term benefit following ICIs treatment in NSCLC and that TMB, SCNAs burden, and PD‐L1 are complementary determinants of response to ICIs.

Published
2020

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