Perioperative Nivolumab in Resectable Lung Cancer.

BACKGROUND: Standard treatment with neoadjuvant nivolumab plus chemotherapy significantly improves outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative treatment (i.e., neoadjuvant therapy followed by surgery and adjuvant therapy) with nivolumab may further improve clinical outcomes. METHODS: In this phase 3, randomized, double-blind trial, we assigned adults with resectable stage IIA to IIIB NSCLC to receive neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary outcome was event-free survival according to blinded independent review. Secondary outcomes were pathological complete response and major pathological response according to blinded independent review, overall survival, and safety. RESULTS: At this prespecified interim analysis (median follow-up, 25.4 months), the percentage of patients with 18-month event-free survival was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (hazard ratio for disease progression or recurrence, abandoned surgery, or death, 0.58; 97.36% confidence interval [CI], 0.42 to 0.81; P<0.001). A pathological complete response occurred in 25.3% of the patients in the nivolumab group and in 4.7% of those in the chemotherapy group (odds ratio, 6.64; 95% CI, 3.40 to 12.97); a major pathological response occurred in 35.4% and 12.1%, respectively (odds ratio, 4.01; 95% CI, 2.48 to 6.49). Grade 3 or 4 treatment-related adverse events occurred in 32.5% of the patients in the nivolumab group and in 25.2% of those in the chemotherapy group. CONCLUSIONS: Perioperative treatment with nivolumab resulted in significantly longer event-free survival than chemotherapy in patients with resectable NSCLC. No new safety signals were observed. (Funded by Bristol Myers Squibb; CheckMate 77T ClinicalTrials.gov number, NCT04025879.).

CD8+ NKs as a potential biomarker of complete response and survival with lenalidomide plus R-GDP in the R2-GDP-GOTEL trial in recurrent/refractory diffuse large B cell lymphoma.

Background: Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. DLBCL is an aggressive disease that can be cured with upfront standard chemoimmunotherapy schedules. However, in approximately 35-40% of the patients DLBCL relapses, and therefore, especially in this setting, the search for new prognostic and predictive biomarkers is an urgent need. Natural killer (NK) are effector cells characterized by playing an important role in antitumor immunity due to their cytotoxic capacity and a subset of circulating NK that express CD8 have a higher cytotoxic function. In this substudy of the R2-GDP-GOTEL trial, we have evaluated blood CD8+ NK cells as a predictor of treatment response and survival in relapsed/refractory (R/R) DLBCL patients. Methods: 78 patients received the R2-GDP schedule in the phase II trial. Blood samples were analyzed by flow cytometry. Statistical analyses were carried out in order to identify the prognostic potential of CD8+ NKs at baseline in R/R DLBCL patients. Results: Our results showed that the number of circulating CD8+ NKs in R/R DLBCL patients were lower than in healthy donors, and it did not change during and after treatment. Nevertheless, the level of blood CD8+ NKs at baseline was associated with complete responses in patients with R/R DLBCL. In addition, we also demonstrated that CD8+ NKs levels have potential prognostic value in terms of overall survival in R/R DLBCL patients. Conclusion: CD8+ NKs represent a new biomarker with prediction and prognosis potential to be considered in the clinical management of patients with R/R DLBCL. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001620-29 EudraCT, ID:2014-001620-29.

Identification of non-actionable mutations with prognostic and predictive value in patients with advanced or metastatic non-small cell lung cancer.

INTRODUCTION: Lung cancer is one of the most prevalent cancers and the leading cause of cancer death. Advanced non-small cell lung cancer (aNSCLC) patients frequently harbor mutations that impact their survival outcomes. There are limited data regarding the prognostic and predictive significance of these mutations on survival outcomes in the real-world setting. METHODS: This observational retrospective study analyzed de-identified electronic medical records from the Flatiron Health Clinico-Genomic and FoundationCore® databases to identify patients with aNSCLC who initiated first-line immune checkpoint inhibitors (ICI; alone or in combination) or chemotherapy under routine care between 2016 and 2021. The primary objectives were to assess the prevalence of non-actionable mutations and to determine their association with overall survival (OS). Real-world progression-free survival (rwPFS) and real-world response (rwR) were investigated as secondary exploratory outcomes. RESULTS: Based on an assessment of 185 non-actionable mutations in 2999 patients, the most prevalent mutations were TP53 (70%), KRAS (42%), CDKN2A/B (31%), and STK11 (21%). STK11, KEAP1, and CDKN2A/B mutations were significantly associated with lower rwR, shorter rwPFS and OS. KRAS mutations were clinically associated with shorter rwPFS in CIT-treated patients. Subgroup analysis revealed that fast progressors were significantly more likely to harbor STK11, KEAP1, and CDKN2A/B mutations. Accordingly, long-term survivors (LTS) showed a significantly lower prevalence of these mutations. CONCLUSION: Our results provide evidence on the prognostic value of STK11, KEAP1, and CDKN2A/B mutations in patients with aNSCLC. Further research is required to better understand the implications of these findings on patient management and future trial design and treatment selection.

Sexual dysfunction in patients with cancer, a challenge in oncology practice: results of the CLARIFY project.

BACKGROUND: Sexual dysfunction (SD) associated with oncological treatment is a common and understudied disorder. Our aim was to characterize SD in a cohort of Spanish patients. METHODS: Analytic observational study in patients included in the CLARIFY H2020 project at the Hospital Universitario Puerta de Hierro. Clinical variables and validated measures of sexual function were collected from October 2020 to May 2022. Frequency and quality of sexual activity were assessed. Descriptive, trend associations, and logistic regression analyses were performed. RESULTS: A total of 383 patients were included: breast cancer 68.14% (261), lung cancer 26.37% (101), and lymphoma 5.50% (21). Mean age was 56.5 years (range 33-88). 19.58% (75) were men and 80.42% (308) were women. 69% and 31% of men and women, respectively, reported being sexually active. The absolute frequency of overall sexual dissatisfaction was 76% in women and 24% in men. Women with breast cancer were most likely to have severe sexual dysfunction. Those with early disease had resolved complaints after 5 years. In multinomial logistic regression, significant associations were found in women with metastatic breast cancer and severe disorders of arousal (p 0.000), lubrication (p 0.002), orgasm (p 0.000), as well as dissatisfaction with sexual performance (p 0.000) and global sexual dissatisfaction (p 0.000). Women with lung cancer have severe arousal dysfunction (p 0.016) and global sexual dissatisfaction (p 0.044). CONCLUSIONS: Our population has a high prevalence of SD, which supports the need to increase awareness of this disorder among the medical oncology team and the importance of including sexual health assessment in oncological patient follow-up.

ROSEWOOD: A Phase II Randomized Study of Zanubrutinib Plus Obinutuzumab Versus Obinutuzumab Monotherapy in Patients With Relapsed or Refractory Follicular Lymphoma.

PURPOSE: The combination of zanubrutinib plus obinutuzumab (ZO) was found to be well tolerated with an early signal of efficacy in a phase Ib study. ROSEWOOD is a phase II, randomized study that assessed the efficacy and safety of ZO versus obinutuzumab in patients with relapsed/refractory (R/R) follicular lymphoma (FL). METHODS: Patients with R/R FL who had received ≥2 lines of therapy, including an anti-CD20 antibody and an alkylating agent, were randomly assigned 2:1 to receive ZO or obinutuzumab (O). The primary end point was overall response rate (ORR) by independent central review (ICR). Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival, and safety. RESULTS: A total of 217 patients were randomized (ZO, 145; O, 72). Median study follow-up was 20.2 months. The study met its primary end point: ORR by ICR was 69% (ZO) versus 46% (O; P = .001). Complete response rate was 39% (ZO) versus 19% (O); 18-month DOR rate was 69% (ZO) versus 42% (O). Median PFS was 28.0 months (ZO) versus 10.4 months (O; hazard ratio, 0.50 [95% CI, 0.33 to 0.75]; P < .001). The most common adverse events with ZO were thrombocytopenia, neutropenia, diarrhea, and fatigue; incidences of atrial fibrillation and major hemorrhage were 3% and 1%, respectively. CONCLUSION: The combination of ZO met its primary end point of a superior ORR versus O, and demonstrated meaningful activity and a manageable safety profile in patients with R/R FL. ZO had a favorable benefit-risk profile compared with O, and represents a potential combination therapy for patients with R/R FL.

Lenalidomide plus R-GDP (R2-GDP) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Final Results of the R2-GDP-GOTEL Trial and Immune Biomarker Subanalysis.

PURPOSE: New therapeutic options are needed in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Lenalidomide-based schedules can reverse rituximab refractoriness in lymphoma. PATIENTS AND METHODS: In the phase II R2-GDP trial, 78 patients unsuitable for autologous stem cell transplant received treatment with the following schedule: lenalidomide 10 mg Days (D)1-14, rituximab 375 mg/m2 D1, cisplatin 60 mg/m2 D1, gemcitabine 750 mg/m2 D1 and D8, and dexamethasone 20 mg D1-3, up to 6 cycles (induction phase), followed by lenalidomide 10 mg (or last lenalidomide dose received) D1-21 every 28 days (maintenance phase). Primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and monitorization of key circulating immune biomarkers (EU Clinical Trials Register number: EudraCT 2014-001620-29). RESULTS: After a median follow-up of 37 months, ORR was 60.2% [37.1% complete responses (CR) and 23.1% partial responses (PR)]. Median OS was 12 months (47 vs. 6 months in CR vs. no CR); median PFS was 9 months (34 vs. 5 months in CR vs. no CR). In the primary refractory population, ORR was 45.5% (21.2% CR and 24.3% PR). Most common grade 3-4 adverse events were thrombocytopenia (60.2%), neutropenia (60.2%), anemia (26.9%), infections (15.3%), and febrile neutropenia (14.1%). Complete responses were associated with a sharp decrease in circulating myeloid-derived suppressor cells and regulatory T cells. CONCLUSIONS: R2-GDP schedule is feasible and highly active in R/R DLBCL, including the primary refractory population. Immune biomarkers showed differences in responders versus progressors.

Radon, Tobacco Exposure and Non-Small Cell Lung Cancer Risk Related to BER and NER Genetic Polymorphisms / El radón, la exposición al tabaco y el riesgo de desarrollar cáncer de pulmón de células no pequeñas en relación con polimorfismos genéticos de BER y NER

Introduction: Tobacco consumption and radon exposure are considered the first and second most common causes of lung cancer, respectively. The aim of this study was to analyze both whether selected genetic polymorphisms in loci that are in DNA repair pathways, are related to non-small-cell lung cancer (NSCLC) and whether they may modulate the association between residential radon exposure and lung cancer in both smokers and never smokers.Methods: A multicentre, hospital-based, case–control study with 826 cases and 1201 controls was designed in a radon-prone area. Genotyping was determined in whole blood and residential radon exposure was measured in participants’ dwellings.Results: Attending to tobacco exposure, the variant in the gene NBN (rs1805794) was associated with lung cancer in never smokers (OR 2.72; 95%1.44–5.2) and heavy smokers (OR 3.04; 95%CI 1.21–7.69). The polymorphism with the highest lung cancer association was OGG1 (rs125701), showing an OR of 8.04 (95%CI 1.64–58.29) for its homozygous variant genotype in heavy smokers. Attending to indoor radon exposure (>200Bq/m3), rs1452584, for its homozygous variant genotype, showed the highest association (OR 3.04 (95%CI 1.15–8.48).Conclusion: The genes analyzed seem to have no association with the fully adjusted model, but they might modulate lung cancer association when different categories of tobacco consumption are considered (i.e. heavy smokers). This association may similarly be elevated for those individuals having high indoor radon exposures, though at a minor extent. (AU)

Introducción: El consumo de tabaco y la exposición al radón se consideran la primera y la segunda causa más frecuentes de cáncer de pulmón, respectivamente. El objetivo de este estudio fue analizar si determinados polimorfismos genéticos en los loci que forman parte de la cascada de reparación del ADN se asocian con el cáncer de pulmón de célula no pequeña, y también si es posible que modifiquen la asociación entre la exposición al radón en el hogar y el cáncer de pulmón tanto en fumadores como en no fumadores.Métodos: Se diseñó un estudio multicéntrico hospitalario de casos y controles con 826 casos y 1.201 controles en un área proclive a la presencia de radón. Se determinó el genotipo en sangre y se midió la exposición al radón en el lugar de residencia de los participantes.Resultados: Analizando la exposición al tabaco, la variante del gen NBN (rs1805794) se asoció con el cáncer de pulmón en no fumadores (OR 2,72; IC 95% 1,44-5,2) y grandes fumadores (OR 3,04; IC 95% 1,21-7,69). El polimorfismo con mayor asociación con el cáncer de pulmón fue OGG1 (rs125701), con una OR de 8,04 (IC 95% 1,64-58,29) para la variante genotípica en homocigosis en grandes fumadores. En cuanto a la exposición al radón en interiores (>200Bq/m3), rs1452584 en homocigosis mostró la asociación más fuerte (OR 3,04; IC 95% 1,15-8,48).Conclusión: Los genes que se analizaron no muestran asociación con el modelo completamente ajustado, pero podrían modificar la asociación con el cáncer de pulmón cuando se consideran diferentes categorías de consumo de tabaco (esto es, grandes fumadores). Esta asociación podría aumentar de forma similar en aquellos individuos que están expuestos al radón en interiores, aunque en menor medida. (AU)

Radon, Tobacco Exposure and Non-Small Cell Lung Cancer Risk Related to BER and NER Genetic Polymorphisms.

INTRODUCTION: Tobacco consumption and radon exposure are considered the first and second most common causes of lung cancer, respectively. The aim of this study was to analyze both whether selected genetic polymorphisms in loci that are in DNA repair pathways, are related to non-small-cell lung cancer (NSCLC) and whether they may modulate the association between residential radon exposure and lung cancer in both smokers and never smokers. METHODS: A multicentre, hospital-based, case-control study with 826 cases and 1201 controls was designed in a radon-prone area. Genotyping was determined in whole blood and residential radon exposure was measured in participants' dwellings. RESULTS: Attending to tobacco exposure, the variant in the gene NBN (rs1805794) was associated with lung cancer in never smokers (OR 2.72; 95%1.44-5.2) and heavy smokers (OR 3.04; 95%CI 1.21-7.69). The polymorphism with the highest lung cancer association was OGG1 (rs125701), showing an OR of 8.04 (95%CI 1.64-58.29) for its homozygous variant genotype in heavy smokers. Attending to indoor radon exposure (>200Bq/m3), rs1452584, for its homozygous variant genotype, showed the highest association (OR 3.04 (95%CI 1.15-8.48). CONCLUSION: The genes analyzed seem to have no association with the fully adjusted model, but they might modulate lung cancer association when different categories of tobacco consumption are considered (i.e. heavy smokers). This association may similarly be elevated for those individuals having high indoor radon exposures, though at a minor extent.

Prospective Exploratory Analysis of Angiogenic Biomarkers in Peripheral Blood in Advanced NSCLC Patients Treated With Bevacizumab Plus Chemotherapy: The ANGIOMET Study.

Finding angiogenic prognostic markers in advanced non-small-cell lung cancer is still an unmet medical need. We explored a set of genetic variants in the VEGF-pathway as potential biomarkers to predict clinical outcomes of patients with non-small-cell lung cancer treated with chemotherapy plus bevacizumab. We prospectively analyzed the relationship between VEGF-pathway components with both pathological and prognostic variables in response to chemotherapy plus bevacizumab in 168 patients with non-squamous non-small-cell lung cancer. Circulating levels of VEGF and VEGFR2 and expression of specific endothelial surface markers and single-nucleotide polymorphisms in VEGF-pathway genes were analyzed. The primary clinical endpoint was progression-free survival. Secondary endpoints included overall survival and objective tumor response. VEGFR-1 rs9582036 variants AA/AC were associated with increased progression-free survival (p = 0.012 and p = 0.035, respectively), and with improved overall survival (p = 0.019) with respect to CC allele. Patients with VEGF-A rs3025039 harboring allele TT had also reduced mortality risk (p = 0.049) compared with the CC allele. The VEGF-A rs833061 variant was found to be related with response to treatment, with 61.1% of patients harboring the CC allele achieving partial treatment response. High pre-treatment circulating levels of VEGF-A were associated with shorter progression-free survival (p = 0.036). In conclusion, in this prospective study, genetic variants in VEGFR-1 and VEGF-A and plasma levels of VEGF-A were associated with clinical benefit, progression-free survival, or overall survival in a cohort of advanced non-squamous non-small-cell lung cancer patients receiving chemotherapy plus antiangiogenic therapy.

Outcomes of surgical resection after neoadjuvant chemoimmunotherapy in locally advanced stage IIIA non-small-cell lung cancer.

OBJECTIVES: This analysis aimed to evaluate perioperative outcomes of surgical resection following neoadjuvant treatment with chemotherapy plus nivolumab in resectable stage IIIA non-small-cell lung cancer. METHODS: Eligible patients received neoadjuvant chemotherapy (paclitaxel + carboplatin) plus nivolumab for 3 cycles. Reassessment of the tumour was carried out after treatment and patients with at least stable disease as best response underwent pulmonary resection. After surgery, patients received adjuvant treatment with nivolumab for 1 year. Surgical data were collected from the NADIM database and patient charts were reviewed for additional surgical details. RESULTS: Among 46 patients who received neoadjuvant treatment, 41 (89.1%) underwent surgery. Two patients rejected surgery and 3 did not fulfil resectability criteria. There were 35 lobectomies (85.3%), 3 of which were sleeve lobectomies (9.4%), 3 bilobectomies (7.3%) and 3 pneumonectomies (7.3%). Video-assisted thoracoscopy was the initial approach in 51.2% of cases, with a conversion rate of 19% (n = 4). There was no operative mortality at either 30 or 90 days. The most common complications were prolonged air leak (n = 8), pneumonia (n = 5) and arrhythmia (n = 4). Complete resection (R0) was achieved in all patients who underwent surgery, downstaging was observed in 37 patients (90.2%) and major pathological response in 34 patients (82.9%). CONCLUSIONS: Surgical resection following induction therapy with chemotherapy plus nivolumab appears to be safe and offers appropriate oncological outcomes. Perioperative morbidity and mortality rates in our study were no higher than previously reported in this setting. A minimally invasive approach is, therefore, feasible.

Polymorphisms in the BER and NER pathways and their influence on survival and toxicity in never-smokers with lung cancer.

Polymorphisms in DNA repair pathways may play a relevant role in lung cancer survival in never-smokers. Furthermore, they could be implicated in the response to chemotherapy and toxicity of platinum agents. The aim of this study was to evaluate the influence of various genetic polymorphisms in the BER and NER DNA repair pathways on survival and toxicity in never-smoker LC patients. The study included never-smokers LC cases diagnosed from 2011 through 2019, belonging to the Lung Cancer Research In Never Smokers study. A total of 356 never-smokers cases participated (79% women; 83% adenocarcinoma and 65% stage IV). Survival at 3 and 5 years from diagnosis was not associated with genetic polymorphisms, except in the subgroup of patients who received radiotherapy or chemo-radiotherapy, and presented with ERCC1 rs3212986 polymorphism. There was greater toxicity in those presenting OGG1 rs1052133 (CG) and ERCC1 rs11615 polymorphisms among patients treated with radiotherapy or chemo-radiotherapy, respectively. In general, polymorphisms in the BER and NER pathways do not seem to play a relevant role in survival and response to treatment among never-smoker LC patients.

Lung cancer survival in never-smokers and exposure to residential radon: Results of the LCRINS study.

We aimed to evaluate lung cancer survival in never-smokers, both overall and specifically by sex, exposure to residential-radon, age, histological type, and diagnostic stage. We included lung cancer cases diagnosed in a multicentre, hospital-based, case-control-study of never-smoker patients, diagnosed from January-2011 to March-2015 (Lung Cancer Research In Never Smokers study). 369 never-smokers (79% women; median age 71 years; 80% adenocarcinoma; 66% stage IV) were included. Median overall survival, and at one, 3 and 5 years of diagnosis was 18.3 months, 61%, 32% and 22%, respectively. Higher median survival rates were obtained for: younger age, adenocarcinoma, actionable mutations, and earlier-stage at diagnosis. Higher indoor radon showed a higher risk of death in multivariate analysis. Median lung cancer survival in never-smokers seems higher than that in ever-smokers. Patients with actionable mutations have a significantly higher survival. Higher indoor-radon exposure has a negative effect on survival.

Fomento de las estrategias antitabaco como la manera más efectiva y eficiente de reducir el cáncer de pulmón (y otras enfermedades) / Promotion of Anti-Smoking Strategies as the Most Effective and Efficient Way to Reduce Lung Cancer (and Other Diseases)

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Lung cancer risk and do-it-yourself activities. A neglected risk factor for lung cancer.

BACKGROUND: The aim of this study was to assess the relationship between do-it-yourself activities entailing the exposure to carcinogenic substances and the risk of lung cancer. METHODS: We pooled individual data from different case-control studies conducted in Northwestern Spain which investigated residential radon and lung cancer. Cases had an anatomopathologically confirmed primary lung cancer and controls were selected at the pre-surgery unit with uncomplicated surgeries. Both cases and controls were older than 30 years with no previous cancer history. All participants were interviewed face-to-face using a specific questionnaire. Painting, model building, furniture refinishing and woodworking or home carpentry were the do-it-yourself activities considered risky due to exposure to carcinogenic agents. RESULTS: We included 1528 cases and 1457 controls. Practicing do-it-yourself risk activities was more frequent among cases: 16.0% were exposed to carcinogenic exposures during leisure time, compared to 11.8% for controls. The overall adjusted OR for lung cancer risk among individuals who practiced do-it-yourself risk activities, was 1.77 (95% CI: 1.36-2.31); this was 2.17 (95% CI: 1.51-3.11) when the analysis was restricted to individuals who performed these activities for at least 10 years. These risks were greater when the analyses were carried out exclusively among never-smokers, with the respective ORs being 2.04 (95% CI: 1.38-3.01) and 3.10 (95% CI: 1.78-5.40). CONCLUSION: These results support the hypothesis that do-it-yourself activities involving exposure to certain carcinogens are associated with an increased risk of lung cancer, both in ever and never-smokers.

Radon exposure: a major cause of lung cancer.

Introduction: Lung cancer is the most important cause of cancer mortality. It is a multifactorial disease with multiple risk factors, including residential radon exposure. Areas covered: The aim of this paper was to review the epidemiology of residential radon exposure and its impact on lung cancer risk. While tobacco is the main risk factor of lung cancer, residential radon is the first cause in never-smokers and the second in ever-smokers. Moreover, the synergistic effect between tobacco consumption and radon exposure should be considered. However, the biological mechanism by which radon and its decay products induce lung cancer is not entirely known. Expert opinion: Residential radon is usually neglected by clinicians. In fact, no lung cancer risk score (predicting incidence or mortality) includes radon as a variable. Further studies are needed to find out the molecular pathways of radon that cause lung cancer and whether this radioactive gas is also involved in the development of other diseases other than lung cancer. There is a clear need to increase awareness among administrations, health professionals and the general population in order to take the necessary measures to reduce this harmful exposure, particularly in radon-prone areas.

Cribado de cáncer de pulmón con tomografía computarizada de baja dosis. No es cuestión de logística / Lung Cancer Screening With Low-Dose Computed Tomography is not a Question of Logistics

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