Challenges in oncology career: are we closing the gender gap? Results of the new ESMO Women for Oncology Committee survey

Discrimination; Gender equity; OncologyDiscriminació; Equitat de gènere; OncologiaDiscriminación; Equidad de género; OncologíaBackground Following a European Society for Medical Oncology Women for Oncology (ESMO W4O) survey in 2016 showing severe under-representation of female oncologists in leadership roles, ESMO launched a series of initiatives to address obstacles to gender equity. A follow-up survey in October 2021 investigated progress achieved. Materials and methods The W4O questionnaire 2021 expanded on the 2016 survey, with additional questions on the impact of ethnicity, sexual orientation and religion on career development. Results were analysed according to respondent gender and age. Results The survey sample was larger than in 2016 (n = 1473 versus 482), especially among men. Significantly fewer respondents had managerial or leadership roles than in 2016 (31.8% versus 51.7%). Lack of leadership development for women and unconscious bias were considered more important in 2021 than in 2016. In 2021, more people reported harassment in the workplace than in 2016 (50.3% versus 41.0%). In 2021, ethnicity, sexual orientation and religion were considered to have little or no impact on professional career opportunities, salary setting or related potential pay gap. However, gender had a significant or major impact on career development (25.5% of respondents), especially in respondents ≤40 years of age and women. As in 2016, highest ranked initiatives to foster workplace equity were promotion of work–life balance, development and leadership training and flexible working. Significantly more 2021 respondents (mainly women) supported the need for culture and gender equity education at work than in 2016. Conclusions Gender remains a major barrier to career progression in oncology and, although some obstacles may have been reduced since 2016, we are a long way from closing the gender gap. Increased reporting of discrimination and inappropriate behaviour in the workplace is a major, priority concern. The W4O 2021 survey findings provide new evidence and highlight the areas for future ESMO interventions to support equity and diversity in oncology career development.This work was supported by the European Society for Medical Oncology (no grant number)

Has COVID-19 had a greater impact on female than male oncologists? Results of the ESMO Women for Oncology (W4O) Survey

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Desigualtats; DonaCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Desigualdades; MujerCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV Inequalities; WomanBackground European Society for Medical Oncology Women for Oncology (ESMO W4O) research has previously shown under-representation of female oncologists in leadership roles. As early reports suggested disproportionate effects of the COVID-19 pandemic on women, the ESMO W4O Committee initiated a study on the impact of the pandemic on the lives of female and male oncologists. Methods A questionnaire was sent to ESMO members and put on the ESMO website between 8 June 2020 and 2 July 2020. Questions focused on the working (hospital tasks, laboratory tasks, science) and home (household management, childcare, parent care, personal care) lives of oncologists during and after COVID-19-related lockdowns. Results Of 649 respondents, 541 completed the questionnaire. Of these, 58% reported that COVID-19 had affected their professional career, 83% of whom said this was in a negative way (85% of women versus 76% of men). Approximately 86% reported that COVID-19 had changed their personal life and 82% their family life. Women were again significantly more affected than men: personal life (89% versus 78%; P = 0.001); family life (84% versus 77%; P = 0.037). During lockdowns, women reported increased time spent on hospital and laboratory tasks compared with men (53% versus 46% and 33% versus 26%, respectively) and a significantly higher proportion of women than men spent less time on science (39% versus 25%) and personal care (58% versus 39%). After confinement, this trend remained for science (42% versus 23%) and personal care (55% versus 36%). Conclusions The COVID-19 pandemic has adversely affected the professional and home lives of oncologists, especially women. Reduced research time for female oncologists may have long-lasting career consequences, especially for those at key stages in their career. The gender gap for promotion to leadership positions may widen further as a result of the pandemic.This work was supported by the European Society for Medical Oncology (ESMO)

Characterizing Prostate Cancer Risk Through Multi-Ancestry Genome-Wide Discovery of 187 Novel Risk Variants

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

RON kinase inhibition reduces renal endothelial injury in sickle cell disease mice

Sickle cell disease patients are at increased risk of developing a chronic kidney disease. Endothelial dysfunction and inflammation associated with hemolysis lead to vasculopathy and contribute to the development of renal disease. Here we used a Townes sickle cell disease mouse model to examine renal endothelial injury. Renal disease in Townes mice was associated with glomerular hypertrophy, capillary dilation and congestion, and significant endothelial injury. We also detected substantial renal macrophage infiltration, and accumulation of macrophage stimulating protein 1 in glomerular capillary. Treatment of human cultured macrophages with hemin or red blood cell lysates significantly increased expression of macrophage membrane-associated protease that might cleave and activate circulating macrophage stimulating protein 1 precursor. Macrophage stimulating protein 1 binds to and activates RON kinase, a cell surface receptor tyrosine kinase. In cultured human renal glomerular endothelial cells, macrophage stimulating protein 1 induced RON downstream signaling, resulting in increased phosphorylation of ERK and AKT kinases, expression of Von Willebrand factor, increased cell motility, and re-organization of F-actin. Specificity of macrophage stimulating protein 1 function was confirmed by treatment with RON kinase inhibitor BMS-777607 that significantly reduced downstream signaling. Moreover, treatment of sickle cell mice with BMS-777607 significantly reduced glomerular hypertrophy, capillary dilation and congestion, and endothelial injury. Taken together, our findings demonstrated that RON kinase is involved in the induction of renal endothelial injury in sickle cell mice. Inhibition of RON kinase activation may provide a novel approach for prevention of the development of renal disease in sickle cell disease

Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci