Exome-Based Genomic Markers Could Improve Prediction of Checkpoint Inhibitor Efficacy Independently of Tumor Type.

Immune checkpoint inhibitors (ICIs) have improved the care of patients in multiple cancer types. However, PD-L1 status, high Tumor Mutational Burden (TMB), and mismatch repair deficiency are the only validated biomarkers of efficacy for ICIs. These markers remain imperfect, and new predictive markers represent an unmet medical need. Whole-exome sequencing was carried out on 154 metastatic or locally advanced cancers from different tumor types treated by immunotherapy. Clinical and genomic features were investigated using Cox regression models to explore their capacity to predict progression-free survival (PFS). The cohort was split into training and validation sets to assess validity of observations. Two predictive models were estimated using clinical and exome-derived variables, respectively. Stage at diagnosis, surgery before immunotherapy, number of lines before immunotherapy, pleuroperitoneal, bone or lung metastasis, and immune-related toxicity were selected to generate a clinical score. KRAS mutations, TMB, TCR clonality, and Shannon entropy were retained to generate an exome-derived score. The addition of the exome-derived score improved the prediction of prognosis compared with the clinical score alone. Exome-derived variables could be used to predict responses to ICI independently of tumor type and might be of value in improving patient selection for ICI therapy.

MER4 endogenous retrovirus correlated with better efficacy of anti-PD1/PD-L1 therapy in non-small cell lung cancer.

BACKGROUND: Endogenous retroviruses (ERVs) are highly expressed in various cancer types and are associated with increased innate immune response and better efficacy of antiprogrammed death-1/ligand-1 (anti-PD1/PD-L1)-directed immune checkpoint inhibitors (ICI) in preclinical models. However, their role in human non-small cell lung cancer (NSCLC) remains unknown. METHODS: We conducted a retrospective study of patients receiving ICI for advanced NSCLC in two independent cohorts. ERV expression was determined by RNA sequencing. The primary endpoint was progression-free survival (PFS) under ICI. The secondary endpoint was overall survival (OS) from ICI initiation. We studied expression of 6205 ERVs. Multivariate Cox regression model with lasso penalty was estimated on the training set to select ERVs significantly associated with survival. The predictive power of these ERVs was compared with that of previously described transcriptomic signatures. RESULTS: We studied two independent cohorts of 89 and 70 patients, used as training and validation sets. Clinicopathological characteristics included 75% of patients with non-squamous NSCLC. We selected four ERVs significantly associated with PFS. Only high MER4 ERV was associated with better PFS and OS in both cohorts. From a biological point of view, high MER4 expression is associated with higher infiltration of eosinophils and inflammatory gene signatures, while low MER4 expression is associated with enrichment in metabolism and proliferation signatures. Adding MER4 to previously described transcriptomic signatures of response to ICI improved their predictive power. CONCLUSIONS: MER4 ERV expression is useful to stratify risk and predict PFS and OS in patients treated with ICI for NSCLC. It also improves the predictive power of other known transcriptomic signatures.

Uncommon EGFR mutations in lung carcinoma: features and treatment outcomes in a retrospective French cohort.

Background: The best management for rare epidermal growth factor receptor (EGFR) mutations in advanced non-small cell lung carcinoma (NSCLC) remains uncertain. The literature indicates that response to usual treatment could differ in certain subgroups such as exon 20 insertion/duplication (E20ID), other single uncommon mutation (OSUM), and EGFR complex mutation (ECM). Methods: In this observational, regional, multi-center, retrospective study, we gathered data on uncommon EGFR mutations in NSCLC from 2007 to 2021. We analyzed patient characteristics, prognostic factors and treatment outcomes [objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS)]. Results: Among 119 patients with an uncommon EGFR mutant, 34 harbored E20ID, 23 ECM, and 62 OSUM. There were significantly more non-smokers in E20ID. Female gender and performance status <2 were associated with a better prognosis. Among the 97 metastatic patients with available data for 1st line treatment, median estimated OS was 21 months (95% CI: 18-31 months), with better non-significant OS for ECM. Median estimated PFS was 7 months (95% CI: 4-9 months). We found significant differences in ORR, DCR and PFS favoring 1st line chemotherapy for E20ID, whereas the outcomes for OSUM and ECM were more favorable for tyrosine kinase inhibitor (TKI) (mainly 2nd and 3rd generation). Conclusions: There were variations in treatment outcomes among subgroups in our cohort. Exon 20 insertions showed better ORR and PFS with 1st line chemotherapy compared to TKI. Conversely, other rare EGFR mutations including ECM had better ORR and PFS with TKI than chemotherapy. There was no significant difference in OS among treatment groups overall or within rare mutation subgroups.

Parallel evolution and differences in seroprevalence of SARS-CoV-2 antibody between patients with cancer and health care workers in a tertiary cancer centre during the first and second wave of COVID-19 pandemic: canSEROcov-II cross-sectional study.

BACKGROUND: Patients with cancer are a population at high risk of severe infection from SARS-CoV-2. Patients with cancer regularly attend specialised healthcare centres for management and treatment, where they are in contact with healthcare workers (HCWs). Numerous recommendations target both patients with cancer and HCWs to minimise the spread of SARS-CoV-2 during these interactions. OBJECTIVE: To investigate the parallel evolution of the COVID-19 epidemic in these 2 populations over time, we studied the seroprevalence of anti-SARS-CoV-2 antibodies after both the first and second waves of the pandemic, and in both cancer patients and HCWs from a single specialised anti-cancer centre. Factors associated with seropositivity were identified in both populations. METHODS: We conducted a cross-sectional study after the second wave of the COVID pandemic in France. All participants were invited to undergo serological testing for SARS-CoV-2 and complete a questionnaire collecting data about their working conditions (for HCWs) or medical management (for patients) during this period. Results after the second wave were compared to those of a previous study among 1011 patients with cancer and 663 HCWs performed in the same centre after the first wave, using the same evaluations. FINDINGS: We included 502 HCWs and 507 patients with cancer. Seroprevalence of anti-SARS-CoV-2 antibodies was higher after the second wave than after the first wave in both HCWs (15.1% versus 1.8%; p < 0.001), and patients (4.1% versus 1.7%; p = 0.038). By multivariate analysis, the factors found to be associated with seropositivity after the second wave for HCWs were: working in direct patient care (p = 0.050); having worked in a dedicated COVID-19 unit (p = 0.0036); contact with a person with COVID-19-positive in the workplace (p = 0.0118) or outside of the workplace (p = 0.0297). Among patients with cancer, only a contact with someone who tested positive for COVID-19 was found to be significantly associated with positive serology. The proportion of reported contacts with individuals with COVID-19-positive was significantly lower among patients with cancer than among HCWs (7.6% versus 40.7%, respectively; p < 0.0001) INTERPRETATION: Between the first and second waves of the epidemic in France, the seroprevalence of anti-SARS-CoV-2 antibodies increased to a lesser extent among patients with cancer than among their HCWs, possibly due to better self-protection, notably social distancing. The risk factors for infection identified among HCWs plead in favour of numerous intra-hospital contaminations, especially for HCWs in contact with high-risk patients. This underlines the compelling need to pursue efforts to implement strict hygiene and personal protection measures (including vaccination) to protect HCWs and patients with cancer.

Splenic Volume as a Surrogate Marker of Immune Checkpoint Inhibitor Efficacy in Metastatic Non Small Cell Lung Cancer.

Monoclonal antibodies targeting PD1/PD-L1 are game changers in advanced non-small cell lung cancer (NSCLC), but biomarkers are lacking. We previously reported the prognostic role of splenic volume in digestive cancer and its correlation with the presence of immunosuppressive cells. The aim of this study was to evaluate the prognostic role of splenic volume in NSCLC patients treated with immune checkpoint inhibitors (ICIs). We conducted a retrospective study of 276 patients receiving ICIs for advanced NSCLC in the Georges François Leclerc Cancer Center. The association between splenic volume at baseline and at two months of therapy and progression-free survival (PFS) during ICI treatment or overall survival (OS) from ICI initiation was evaluated using univariate and multivariable Cox analyses. Splenic volume during treatment and the change in splenic volume were associated with poor PFS (respectively p = 0.02 and p = 0.001) and with OS (respectively p < 1.10-3 and p < 1.10-3). Baseline splenic volume at the first evaluation was also associated with poor OS (p = 0.001). LDH rate and dNLR were positively correlated with splenic volume, as well as with its evolution. After the adjustment of clinical variables, splenic volumes remained a predictive marker of immunotherapy efficacy. Splenic volume is a prognostic biomarker in patients with advanced NSCLC treated with ICIs.

Does large NGS panel analysed using exome tumour sequencing improve the management of advanced non-small-cell lung cancers?

INTRODUCTION: Non-small-cell lung cancer (NSCLC) is one of the most common and deadly cancers. Several molecular drivers of oncogene addiction are now known to be strong predictive biomarkers for target therapies. Advances in large Next Generation Sequencing (LNGS) have improved the ability to detect potentially targetable mutations. However, the integration of LNGS into clinical management in an individualized manner remains challenging. METHODS: In this single-center observational study we included all patients with advanced NSCLC who underwent LNGS. Somatic and germline exome analysis was performed with a restriction on 323 cancer related genes. Variants were classified and Molecular Tumour Board (MTB) made therapeutic propositions. RESULTS: We performed LNGS analysis in 281 patients with advanced NSCLC between March 2015 and January 2018. Technical failure occurred in only 3% of cases. Three hundred and fifty-six targetable mutations were detected. At least one targetable mutation was found in 209 patients. For all these patients, the MTB was able to recommend treatment with a targeted agent based on the evaluation of the tumour's genetic profile and treatment history. Twenty-nine patients (13.9%) were subsequently treated with an MTB-recommended targeted therapy. We did not observe any improvement in terms of clinical benefit for these patients. CONCLUSIONS: In this case series, we show that including LNGS into routine clinical management was feasible but does not appear to provide clinical benefit in the management of patients with advanced NSCLC.

Seroprevalence of SARS-CoV-2 among the staff and patients of a French cancer centre after first lockdown: The canSEROcov study.

BACKGROUND: In view of the potential gravity of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection for patients with cancer, epidemiological data are vital to assess virus circulation among patients and staff of cancer centres. We performed a prospective study to investigate seroprevalence of SARS-CoV-2 antibodies among staff and patients with cancer at a large cancer centre, at the end of the period of first national lockdown in France and to determine factors associated with the risk of SARS-CoV-2 infection. METHODS: After the first lockdown, all medical and non-medical staff, as well as all patients attending the medical oncology department were invited to undergo serological testing for SARS-CoV-2 between 11 May and 30 June 2020. All participants were also invited to complete a questionnaire collecting data about their living and working conditions, and for patients, medical management during lockdown. FINDINGS: A total of 1,674 subjects (663 staff members, 1011 patients) were included. Seroprevalence was low in both staff (1.8%) and patients (1.7%), despite more features of high risk for severe forms among patients. None of the risk factors tested in our analysis (working or living conditions, comorbidities, management characteristics during lockdown) was found to be statistically associated with seroprevalence in either staff or patients. There was no significant difference in the proportion of symptomatic and asymptomatic subjects between staff and patients. Only fever, loss of smell, and loss of taste were significantly more frequent among seropositive patients, in both staff and patients. INTERPRETATION: We report very low seroprevalence of antibodies against SARS-CoV-2 in the staff (caregiving and non-caregiving) and patients of a large cancer care centre in which strict hygiene, personal protection, and social distancing measures were implemented.