Polygenic inheritance and its interplay with smoking history in predicting lung cancer diagnosis: a French-Canadian case-control cohort.

BACKGROUND: The most near-term clinical application of genome-wide association studies in lung cancer is a polygenic risk score (PRS). METHODS: A case-control dataset was generated consisting of 4002 lung cancer cases from the LORD project and 20,010 ethnically matched controls from CARTaGENE. A genome-wide PRS including >1.1 million genetic variants was derived and validated in UK Biobank (n = 5419 lung cancer cases). The predictive ability and diagnostic discrimination performance of the PRS was tested in LORD/CARTaGENE and benchmarked against previous PRSs from the literature. Stratified analyses were performed by smoking status and genetic risk groups defined as low (<20th percentile), intermediate (20-80th percentile) and high (>80th percentile) PRS. FINDINGS: The phenotypic variance explained and the effect size of the genome-wide PRS numerically outperformed previous PRSs. Individuals with high genetic risk had a 2-fold odds of lung cancer compared to low genetic risk. The PRS was an independent predictor of lung cancer beyond conventional clinical risk factors, but its diagnostic discrimination performance was incremental in an integrated risk model. Smoking increased the odds of lung cancer by 7.7-fold in low genetic risk and by 11.3-fold in high genetic risk. Smoking with high genetic risk was associated with a 17-fold increase in the odds of lung cancer compared to individuals who never smoked and with low genetic risk. INTERPRETATION: Individuals at low genetic risk are not protected against the smoking-related risk of lung cancer. The joint multiplicative effect of PRS and smoking increases the odds of lung cancer by nearly 20-fold. FUNDING: This work was supported by the CQDM and the IUCPQ Foundation owing to a generous donation from Mr. Normand Lord.

Pembrolizumab Every 6 Weeks Versus Every 3 Weeks in Advanced Non-Small Cell Lung Cancer.

BACKGROUND: The survival benefits and adverse effects of pembrolizumab 2 mg/kg intravenously (IV) every 3 weeks (Q3W) in advanced non-small lung cancer (NSCLC) are well documented in the literature. Based on pharmacokinetic models, a pembrolizumab 4 mg/kg IV every 6 weeks (Q6W) dosing regimen is also approved in some countries. To date, there is no direct comparison in the literature between these 2 regimens in advanced NSCLC. METHODS: This retrospective study included 80 patients with advanced NSCLC who received pembrolizumab monotherapy 4 mg/kg Q6W between March 1, 2020 and December 31, 2021 and 80 patients with advanced NSCLC who received pembrolizumab monotherapy 2 mg/kg Q3W between January 1, 2017 and January 15, 2019 at Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ). The primary outcomes of this study were to compare overall survival (OS), progression-free survival (PFS) as well as the occurrence and severity of immune-mediated adverse events (AEs) in patients with advanced NSCLC who received pembrolizumab Q6W vs Q3W. Data cutoff date was December 15, 2022. RESULTS: Median follow-up was 14.5 ± 8.6 months in the Q6W group and 18.3 ± 19.6 months in the Q3W group. Median PFS was 6.9 months (CI 95% 5.0-10.7) in the Q6W group vs 8.9 months (CI 95% 5.6-14.1) in the Q3W group (adjusted HR 1.27 (CI 95% 0.85-1.89), P = .25). Median OS was not reached in the Q6W group vs 20.5 months (CI 95% 13.7-29.8) in the Q3W group (adjusted HR 0.80 (CI 95% 0.50-1.29), P = .36). Immune-mediated AEs of grade ≥ 3 occurred in 18% of patients in the Q6W group and in 19% of those in the Q3W group. CONCLUSIONS: In this unicentric retrospective study, the pembrolizumab Q6W dosing regimen was comparable to the Q3W in terms of OS, PFS, and toxicity.

Retrospective Assessment of Complementary Liquid Biopsy on Tissue Single-Gene Testing for Tumor Genotyping in Advanced NSCLC.

Biomarker testing is key for non-small cell lung cancer (NSCLC) management and plasma based next-generation sequencing (NGS) is increasingly characterized as a non-invasive alternative. This study aimed to evaluate the value of complementary circulating tumor DNA (ctDNA) NGS on tissue single-gene testing (SGT). Ninety-one advanced stage NSCLC patients with tumor genotyping by tissue SGT (3 genes) followed by ctDNA (38 genes amplicon panel) were included. ctDNA was positive in 47% (n = 43) and identified a targetable biomarker in 19 patients (21%). The likelihood of positivity on ctDNA was higher if patients had extra-thoracic disease (59%) or were not under active treatment (59%). When compared to SGT, ctDNA provided additional information in 41% but missed a known alteration in 8%. Therapeutic change for targeted therapy based on ctDNA occurred in five patients (5%), while seven patients with missed alterations on ctDNA had EGFR mutations or ALK fusions. The median turnaround time of ctDNA was 10 days (range 6-25), shorter (p = 0.002) than the cumulative delays for the tissue testing trajectory until biomarker availability (13 d; range 7-1737). Overall, the results from this study recapitulate the potential and limitations of ctDNA when used complementarily to tissue testing with limited biomarker coverage.

Tumor Mutational Burden by Whole-Genome Sequencing in Resected NSCLC of Never Smokers.

BACKGROUND: Data are scarce about tumor mutational burden (TMB) as a biomarker in never smokers with non-small cell lung cancer (NSCLC). METHODS: TMB was assessed by whole-genome sequencing (WGS) and compared with in silico reduced whole-exome sequencing (WES) and targeted commercial next-generation sequencing (NGS) gene panels in 92 paired tumor-normal samples from never smokers who underwent NSCLC resection with curative intent. Analyses were performed to test for association with survival after surgery and to identify the optimal prognostic TMB cutoff. RESULTS: Tumors of never smokers with NSCLC had low TMB scores (median 1.57 mutations/Mb; range, 0.13-17.94). A TMB cutoff of 1.70 mutations/Mb was associated with a 5-year overall survival of 58% in the high-TMB (42% of cases) compared with 86% in low-TMB patients (Wald P = 0.0029). TMB scores from WGS and WES were highly correlated (Spearman ρ = 0.93, P < 2.2e-16). TMB scores from NGS panels demonstrated high intraindividual fluctuations and identified high-TMB patients with 65% concordance in average compared with WGS. CONCLUSIONS: In resected NSCLC of never smokers, high TMB was associated with worse prognosis. WES provided a good estimate of TMB while targeted NGS panels seem to lack adequate depth and resolution in the setting of low mutation burden. IMPACT: TMB is a prognostic indicator of survival in resected NSCLC from individuals who never smoked. In this setting of low mutation counts, TMB can be accurately measured by WGS or WES, but not NGS panels.

Transthoracic needle biopsy versus surgical diagnosis for solid pulmonary nodules.

Background: When investigating solitary pulmonary nodules (SPN), non-surgical [such as transthoracic needle biopsy (TTNB)] or surgical biopsies can be performed. There is a paucity of data comparing these two approaches. Methods: This descriptive study is a retrospective analysis of a cohort of 149 patients who underwent TTNB and/or surgery for a SPN >8 mm but ≤3 cm between January and December 2016, at Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ). Our primary objective was to evaluate the proportion of patients investigated with TTNB vs. surgical diagnosis in our center. Secondary objectives were to examine the distribution of diagnoses (malignancy vs. benign lesion), to evaluate the proportion of TTNB that would yield a benign diagnosis and permit to avoid surgery, to evaluate if delays to surgery were longer when preoperative TTNB was performed, and if operative times were longer with upfront surgery. Results: In our cohort, 87 patients (58%) underwent TTNB, while 62 (42%) had an upfront surgical procedure. One hundred and twenty-eight patients (86%) had a malignant diagnosis. Thirteen patients out of the 87 biopsied (15%) avoided surgery owing to a benign biopsy result, or a non-specific diagnosis and a physician reassured enough to decide for radiological surveillance, while 5/62 patients (8%) who underwent upfront surgery had a benign diagnosis. There was no significant difference in delays from imaging to surgery or in operative time between patients with or without prior TTNB. Conclusions: In this unicentric retrospective cohort of patients investigated for SPN, the malignancy rate was high (86%), which seemed to limit the applicability of prediction models. Adherence to guidelines for the investigation of SPN by physicians seemed suboptimal. More real-world prospective studies are needed to compare non-surgical and surgical biopsies. There is also a need for simpler nodule evaluation algorithms.

Wait Times and Survival in Lung Cancer Patients across the Province of Quebec, Canada.

Lung cancer is the leading cause of cancer death worldwide, with a five-year survival of 22% in Canada. Guidelines recommend rapid evaluation of patients with suspected lung cancer, but the impact on survival remains unclear. We reviewed medical records of all patients with newly diagnosed lung cancer in four hospital networks across the province of Quebec, Canada, between 1 February and 30 April 2017. Patients were followed for 3 years. Wait times for diagnosis and treatment were collected, and survival analysis using a Cox regression model was conducted. We included 1309 patients, of whom 39% had stage IV non-small cell lung cancer (NSCLC). Median wait times were, in general, significantly shorter in patients with stage III-IV NSCLC or SCLC. Surgery was associated with delays compared to other types of treatments. Median survival was 12.9 (11.1-15.7) months. The multivariate survival model included age, female sex, performance status, histology and stage, treatment, and the time interval between diagnosis and treatment. Longer wait times had a slightly protective to neutral effect on survival, but this was not significant in the stage I-II NSCLC subgroup. Wait times for the diagnosis and treatment of lung cancer were generally within targets. The shorter wait times observed for advanced NSCLC and SCLC might indicate a tendency for clinicians to act quicker on sicker patients. This study did not demonstrate the detrimental effect of longer wait times on survival.

Palliative Systemic Therapy Given near the End of Life for Metastatic Non-Small Cell Lung Cancer.

BACKGROUND: The use of chemotherapy near end of life (EOL) for various cancers is increasing and has been shown to be associated with delayed access to palliative care (PC) and increased aggressiveness in EOL care, without any benefit on survival. METHODS: This retrospective study included 90 patients with metastatic non-small cell lung cancer (NSCLC) who received at least one line of palliative systemic anticancer therapy (SACT) and died between 1 November 2014, and 31 October 2016, at Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ). Our primary objective was to evaluate the proportion of patients with NSCLC receiving SACT within 30 days of death. Secondary outcomes were to determine the mean and median delays between the administration of the last treatment and death, and to evaluate if there were differences in characteristics and outcomes (including overall survival (OS)) between patients treated or not within 30 days of death. RESULTS: In our cohort, 22% of patients received SACT within 30 days of death. For the entire cohort, the mean delay between the last treatment and death was 94 days, and the median was 57 days. There were no statistically significant differences between the two groups in terms of baseline characteristics. Use of SACT near EOL was associated with decreased access to PC, higher rates of in hospital death, decreased use of medical aid in dying (MAiD), and a shorter median OS (4.0 vs. 9.0 months). CONCLUSIONS: In this retrospective cohort of patients with metastatic NSCLC, 22% of patients received SACT within 30 days of death, with a negative impact on access to PC, higher rates of in hospital death, decreased use of MAiD and palliative sedation, and a shorter median OS.

Five-year absolute risk estimates of colorectal cancer based on CCRAT model and polygenic risk scores: A validation study using the Quebec population-based cohort CARTaGENE.

The objective was to evaluate the predictive performance of the Colorectal Cancer Risk Assessment Tool (CCRAT) and three polygenic risk scores (Hsu et al., 2015; Law et al., 2019, Archambault et al., 2020) to predict the occurrence of colorectal cancer at five years in a Quebec population-based cohort. By using the CARTaGENE cohort, we computed the absolute risk of colorectal cancer with the CCRAT model, the polygenic risk scores (PRS) and combined clinico-genetic models (CCRAT + PRS). We also tailored the CCRAT model by using the marginal age-specific colorectal incidence rates in Canada and the risk score distribution. We reported the calibration and the discrimination. Performances of the PRSs, combined and tailored CCRAT models were compared to the original CCRAT model. The expected-to-observed ratio of the original CCRAT model was 0.54 [0.43-0.68]. The c-index was 74.79 [68.3-80.5]. The tailored CCRAT model improved the expected-to-observed ratio (0.74 [0.59-0.94]) and c-index (76.39 [69.7-82.1]). All PRS improved the expected-to-observed ratios (around 0.83, confidence intervals including one). PRSs' c-indexes were not significantly different from CCRAT models. Results from the combined models were close to those from the PRS models, Archambault combined model's c-index being significantly higher than the original and tailored CCRAT models (78.67 [70.8-86.5]; p < 0.001 and p = 0.028, respectively). In this Quebec cohort, CCRAT model has a good discrimination with a poor calibration. While the tailored CCRAT provides some gain in calibration, clinico-genetic models improved both calibration and discrimination. However, better calibrations must be obtained before a practical use among the inhabitants of Quebec province.

Two-year survival with nivolumab in previously treated advanced non-small-cell lung cancer: A real-world pooled analysis of patients from France, Germany, and Canada.

OBJECTIVES: Immune checkpoint inhibitors have become the standard of care for metastatic non-small-cell lung cancer (NSCLC) progressing during or after platinum-based chemotherapy. Real-world clinical practice tends to represent more diverse patient characteristics than randomized clinical trials. We sought to evaluate overall survival (OS) outcomes in the total study population and in key subsets of patients who received nivolumab for previously treated advanced NSCLC in real-world settings in France, Germany, or Canada. MATERIALS AND METHODS: Data were pooled from two prospective observational cohort studies, EVIDENS and ENLARGE, and a retrospective registry in Canada. Patients included in this analysis were aged ≥18 years, had stage IIIB/IV NSCLC, and received nivolumab after at least one prior line of systemic therapy. OS was estimated in the pooled population and in various subgroups using the Kaplan-Meier method. Timing of data collection varied across cohorts (2015-2019). RESULTS: Of the 2585 patients included in this analyses, 1235 (47.8 %) were treated in France, 881 (34.1 %) in Germany, and 469 (18.1 %) in Canada. Median OS for the total study population was 11.3 months (95 % CI: 10.5-12.2); this was similar across France, Germany, and Canada. The OS rate was 49 % at 1 year and 28 % at 2 years for the total study population. In univariable Cox analyses, the presence of epidermal growth factor receptor mutations in nonsquamous disease, liver, or bone metastases were associated with significantly shorter OS, whereas tumor programmed death ligand 1 expression and Eastern Cooperative Oncology Group performance status 0-1 were associated with significantly prolonged OS. Similar OS was noted across subgroups of age and prior lines of therapy. CONCLUSION: OS rates in patients receiving nivolumab for previously treated advanced NSCLC in real-world clinical practice closely mirrored those in phase 3 studies, suggesting similar effectiveness of nivolumab in clinical trials and clinical practice.

Validation of breast cancer risk assessment tools on a French-Canadian population-based cohort.

OBJECTIVES: Evaluate the accuracy of the Breast Cancer Risk Assessment Tool (BCRAT), International Breast Cancer Intervention Study risk evaluation tool (IBIS), Polygenic Risk Scores (PRS) and combined scores (BCRAT+PRS and IBIS +PRS) to predict the occurrence of invasive breast cancers at 5 years in a French-Canadian population. DESIGN: Population-based cohort study. SETTING: We used the population-based cohort CARTaGENE, composed of 43 037 Quebec residents aged between 40 and 69 years and broadly representative of the population recorded on the Quebec administrative health insurance registries. PARTICIPANTS: 10 200 women recruited in 2009-2010 were included for validating BCRAT and IBIS and 4555 with genetic information for validating the PRS and combined scores. OUTCOME MEASURES: We computed the absolute risks of breast cancer at 5 years using BCRAT, IBIS, four published PRS and combined models. We reported the overall calibration performance, goodness-of-fit test and discriminatory accuracy. RESULTS: 131 (1.28%) women developed a breast cancer at 5 years for validating BCRAT and IBIS and 58 (1.27%) for validating PRS and combined scores. Median follow-up was 5 years. BCRAT and IBIS had an overall expected-to-observed ratio of 1.01 (0.85-1.19) and 1.02 (0.86-1.21) but with significant differences when partitioning by risk groups (p<0.05). IBIS' c-index was significantly higher than BCRAT (63.42 (59.35-67.49) vs 58.63 (54.05-63.21), p=0.013). PRS scores had a global calibration around 0.82, with a CI including one, and non-significant goodness-of-fit tests. PRS' c-indexes were non-significantly higher than BCRAT and IBIS, the highest being 64.43 (58.23-70.63). Combined models did not improve the results. CONCLUSIONS: In this French-Canadian population-based cohort, BCRAT and IBIS have good mean calibration that could be improved for risk subgroups, and modest discriminatory accuracy. Despite this modest discriminatory power, these tools can be of interest for primary care physicians for delivering a personalised message to their high-risk patients, regarding screening and lifestyle counselling.

Routine Neuroimaging in Patients with Stage IV Non-Small Cell Lung Cancer: A Single Center Experience.

BACKGROUND: There is a lack of consensus in current practice guidelines regarding routine neuroimaging in patients with stage IV non-small cell lung cancer (NSCLC) without neurologic symptoms, and there is a paucity of data on the impact of such imaging on overall survival (OS). METHODS: This retrospective study included 257 patients with stage IV NSCLC without neurologic symptoms diagnosed between January 1, 2013 and December 31, 2016 at Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ). The primary objective of this study was to compare the evolution of patients with stage IV NSCLC who had baseline brain imaging versus with who did not. Secondary objectives were to determine the proportion of patients who underwent brain imaging in their initial investigation and the proportion of patients who developed metachronous central nervous system (CNS) metastasis. RESULTS: CNS imaging, mainly with computed tomography (CT), was performed at diagnosis in 56% of patients, and the prevalence of synchronous CNS metastasis among these patients was 32%. There was no difference in median OS between patients who underwent initial CNS imaging and those who did not, but we did show a tendency for a higher cumulative incidence of metachronous CNS metastasis in patients without baseline imaging. These metachronous metastases were symptomatic and were more often not treated when compared to synchronous metastases. CONCLUSIONS: In this small, unicentric retrospective study, there was no benefit with routine neuroimaging in terms of median OS in stage IV NSCLC patients without neurologic symptoms.

Incidental findings suggestive of COVID-19 in asymptomatic cancer patients undergoing 18F-FDG PET/CT in a low prevalence region.

PURPOSE: To assess the rate and pattern of incidental interstitial lung abnormalities suggestive of COVID-19 on 18F-FDG PET/CT in asymptomatic cancer patients during the period of active COVID-19 circulation between March and April 2020 in a geographic area of low prevalence of the virus. METHODS: 1396 18F-FDG PET/CT performed between January 1, 2020, and February 21, 2020, and between March 16, 2020, and April 17, 2020 for routine oncological indication were retrospectively analyzed. No patients had symptoms suggestive of COVID-19 at the time of the 18F-FDG PET/CT. Incidental interstitial pneumonias suggestive of COVID-19 were identified, and the 18F-FDG PET/CT patterns were described. We compared the incidence of these lesions in the pre-COVID and pandemic phases. RESULTS: We observed a 1.6% increase in interstitial lung abnormalities during the period of COVID-19 circulation. All had < 50% lung involvement. We describe a case series with typical and atypical interstitial pneumonias suggestive of COVID-19 as unilateral or bilateral with ground-glass opacity, consolidation, or crazy-paving patterns. CONCLUSION: The relatively low increase in incidental findings suggestive of COVID-19 infection on 18F-FDG PET/CT in asymptomatic cancer patients was in accordance with the low COVID-19 transmission in our geographic region. Nevertheless, nuclear medicine physicians should familiarize themselves with typical and atypical 18F-FDG PET/CT patterns suggestive of COVID-19 pneumonia and initiate appropriate intervention where necessary.

Quantifying the Predictive Accuracy of a Polygenic Risk Score for Predicting Incident Cancer Cases : Application to the CARTaGENE Cohort.

With the increasing use of polygenic risk scores (PRS) there is a need for adapted methods to evaluate the predictivity of these tools. In this work, we propose a new pseudo-R 2 criterion to evaluate PRS predictive accuracy for time-to-event data. This new criterion is related to the score statistic derived under a two-component mixture model. It evaluates the effect of the PRS on both the propensity to experience the event and on the dynamic of the event among the susceptible subjects. Simulation results show that our index has good properties. We compared our index to other implemented pseudo-R 2 for survival data. Along with our index, two other indices have comparable good behavior when the PRS has a non-null propensity effect, and our index is the only one to detect when the PRS has only a dynamic effect. We evaluated the 5-year predictivity of an 18-single-nucleotide-polymorphism PRS for incident breast cancer cases on the CARTaGENE cohort using several pseudo-R 2 indices. We report that our index, which summarizes both a propensity and a dynamic effect, had the highest predictive accuracy. In conclusion, our proposed pseudo-R 2 is easy to implement and well suited to evaluate PRS for predicting incident events in cohort studies.

Initial Clinical Results of a Novel Immuno-PET Theranostic Probe in Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer.

This prospective study evaluated the imaging performance of a novel pretargeting immunologic PET (immuno-PET) method in patients with human epidermal growth factor receptor 2 (HER2)-negative, carcinoembryonic antigen (CEA)-positive metastatic breast cancer, compared with CT, bone MRI, and 18F-FDG PET. Methods: Twenty-three patients underwent whole-body immuno-PET after injection of 150 MBq of 68Ga-IMP288, a histamine-succinyl-glycine peptide given after initial targeting of a trivalent anti-CEA, bispecific, antipeptide antibody. The gold standards were histology and imaging follow-up. Tumor SUVs (SUVmax and SUVmean) were measured, and tumor burden was analyzed using total tumor volume and total lesion activity. Results: The total lesion sensitivity of immuno-PET and 18F-FDG PET were 94.7% (1,116/1,178) and 89.6% (1,056/1,178), respectively. Immuno-PET had a somewhat higher sensitivity than CT or 18F-FDG PET in lymph nodes (92.4% vs. 69.7% and 89.4%, respectively) and liver metastases (97.3% vs. 92.1% and 94.8%, respectively), whereas sensitivity was lower for lung metastases (48.3% vs. 100% and 75.9%, respectively). Immuno-PET showed higher sensitivity than MRI or 18F-FDG PET for bone lesions (95.8% vs. 90.7% and 89.3%, respectively). In contrast to 18F-FDG PET, immuno-PET disclosed brain metastases. Despite equivalent tumor SUVmax, SUVmean, and total tumor volume, total lesion activity was significantly higher with immuno-PET than with 18F-FDG PET (P = 0.009). Conclusion: Immuno-PET using anti-CEA/anti-IMP288 bispecific antibody, followed by 68Ga-IMP288, is a potentially sensitive theranostic imaging method for HER2-negative, CEA-positive metastatic breast cancer patients and warrants further research.

Efficacy of immune checkpoint inhibitors in older patients with non-small cell lung cancer: Real-world data from multicentric cohorts in Canada and France.

BACKGROUND: Age-related immune remodelling is thought to be associated with resistance to immune checkpoint inhibitors (ICIs) in cancer. Patients older than 70 years, representing >50% of the population with non-small cell lung cancer (NSCLC) according to SEER database, are underrepresented in clinical trials exploring ICIs. The objective of this study was to determine if patients with NSCLC older than ≥70 years had inferior clinical outcomes with ICIs. METHODS: We conducted a retrospective analysis of 381 patients treated with anti-PD-(L)1 ICI for advanced NSCLC at the Dijon Cancer Center (n = 177), University of Montreal Hospital (n = 106) and Quebec Heart and Lung Institute (n = 98). Age was considered as a categorical variable. Patients' baseline characteristics were compared using the Chi-squared test. Survival curves were estimated by the Kaplan-Meier method and compared with the Log-rank test in a univariate analysis. Multivariate cox regression model was used to determine hazard ratios and 95% confidence intervals for progression-free survival (PFS) and overall survival (OS) between the groups, adjusting for other clinicopathologic features. RESULTS: Among 381 patients included, 335 (88%) received ICI after platinum chemotherapy. The median age was 66 (range 37-89) and 33% were older than 70 years of age. Considering age as a categorical variable, differences in age were not associated with PFS or OS. Subgroup analysis and multivariate cox regression did not reveal significant interaction of age with outcomes. ECOG performance status was the only significant factor in the three cohorts. CONCLUSIONS: Unlike previously described in the era of chemotherapy, age was not associated with outcomes in NSCLC patients treated with ICI.

DNA methylation stability in fish spermatozoa upon external constraint: Impact of fish hormonal stimulation and sperm cryopreservation.

Highly differentiated mature spermatozoa carry not only genetic but also epigenetic information that is to be transmitted to the embryo. DNA methylation is one epigenetic actor associated with sperm nucleus compaction, gene silencing, and prepatterning of embryonic gene expression. Therefore, the stability of this mark toward reproductive biotechnologies is a major issue in animal production. The present work explored the impact of hormonal induction of spermiation and sperm cryopreservation in two cyprinids, the goldfish (Carassius auratus) and the zebrafish (Danio rerio), using LUminometric Methylation Assay (LUMA). We showed that while goldfish hormonal treatment did increase sperm production, it did not alter global DNA methylation of spermatozoa. Different sperm samples repeatedly collected from the same males for 2 months also showed the same global DNA methylation level. Similarly, global DNA methylation was not affected after cryopreservation of goldfish spermatozoa with methanol, whereas less efficient cryoprotectants (dimethylsulfoxide and 1,2-propanediol) decreased DNA methylation. In contrast, cryopreservation of zebrafish spermatozoa with methanol induced a slight, but significant, increase in global DNA methylation. In the less compact nuclei, that is, goldfish fin somatic cells, cryopreservation did not change global DNA methylation regardless of the choice of cryoprotectant. To conclude, global DNA methylation is a robust parameter with respect to biotechnologies such as hormonal induction of spermiation and sperm cryopreservation, but it can be altered when the best sperm manipulation conditions are not met.

Real-world health utility scores and toxicities to tyrosine kinase inhibitors in epidermal growth factor receptor mutated advanced non-small cell lung cancer.

BACKGROUND: As the treatment landscape in patients with non-small cell lung cancer (NSCLC) harboring mutations in the epidermal growth factor receptor (EGFRm) continues to evolve, real-world health utility scores (HUS) become increasingly important for economic analyses. METHODS: In an observational cohort study, questionnaires were completed in EGFRm NSCLC outpatients, to include demographics, EQ-5D-based HUS and patient-reported toxicity and symptoms. Clinical and radiologic characteristics together with outcomes were extracted from chart review. The impact of health states, treatment type, toxicities, and clinical variables on HUS were evaluated. RESULTS: Between 2014 and 2018, a total of 260 patients completed 994 encounters. Across treatment groups, patients with disease progression had lower HUS compared to controlled disease (0.771 vs 0.803; P = .01). Patients predominantly received gefitinib as the first-line EGFR tyrosine kinase inhibitor (TKI) (n = 157, mean-HUS = 0.798), whereas osimertinib (n = 62, mean-HUS = 0.806) and chemotherapy (n = 38, mean-HUS = 0.721) were more likely used in subsequent treatment lines. In longitudinal analysis, TKIs retained high HUS (>0.78) compared to chemotherapy (HUS < 0.74). There were no differences between the frequency or severity of toxicity scores in patients receiving gefitinib compared to osimertinib; however, TKI therapy resulted in fewer toxicities than chemotherapy (P < .05), with the exception of worse diarrhea and skin rash (P < .001). Severity in toxicities inversely correlated with HUS (P < .001). Clinico-demographic factors significantly affecting HUS included age, Eastern Cooperative Oncology Group Performance Score (ECOG PS), disease state, treatment group, and metastatic burden. CONCLUSIONS: In a real-world EGFRm population, patients treated with gefitinib or osimertinib had similar HUS and toxicities, scores which were superior to chemotherapy. Health utility scores inversely correlated with patient-reported toxicity scores. In the era of targeted therapies, future economic analyses should incorporate real-world HUS.