Screening for EGFR Mutations in Patients with Head and Neck Cancer Treated with Gefitinib on a Compassionate-Use Program: A Hellenic Cooperative Oncology Group Study

Background and Aim. EGFR is commonly expressed in cancers of the head and neck (H and N), and anti-EGFR agents have demonstrated improvements in outcomes (TTP and OS). The aim of this study was to determine EGFR gene status in H and N cancer patients treated with gefitinib and to correlate mutational status with clinico-pathological data and response. Patients and Methods. Patients with histologically confirmed H and N cancer having failed prior treatment for advanced disease entered this compassionate-use-program. Nineteen patients received gefitinib. EGFR expression was assessed by IHC, gene copy number by FISH, and mutation analysis was conducted for EGFR (18-21), KRAS, BRAF (V600E), and HER-2 exon 20. An additional TKI naive cohort of 73 patients was also screened. Results. Mutations were detected in 6/19 patients (3× EGFR, 1× KRAS, and 2× HER2-exon 20). There were no significant differences in TTP or OS for patients with somatic EGFR mutations. No BRAF mutations were detected. Conclusions. The incidence of EGFR mutations in H and N cancer in this study was 5.3%. No statistically relevant correlations between mutation or gene gain and response or survival were observed. Due to the limited number of patients and low incidence of genetic aberrations in the genes analyzed, additional studies are warranted

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)

Predicting the Role of DNA Polymerase β Alone or with KRAS Mutations in Advanced NSCLC Patients Receiving Platinum-Based Chemotherapy

: Clinical data suggest that only a subgroup of non-small cell lung cancer (NSCLC) patients has long-term benefits after front-line platinum-based therapy. We prospectively investigate whether KRAS status and DNA polymerase β expression could help identify patients responding to platinum compounds. Prospectively enrolled, advanced NSCLC patients treated with a first-line regimen containing platinum were genotyped for KRAS and centrally evaluated for DNA polymerase β expression. Overall survival (OS), progression-free survival (PFS), and the objective response rate (ORR) were recorded. Patients with KRAS mutations had worse OS (hazard ratio (HR): 1.37, 95% confidence interval (95% CI): 0.70-2.27). Negative DNA polymerase β staining identified a subgroup with worse OS than patients expressing the protein (HR: 1.43, 95% CI: 0.57-3.57). The addition of KRAS to the analyses further worsened the prognosis of patients with negative DNA polymerase β staining (HR: 1.67, 95% CI: 0.52-5.56). DNA polymerase β did not influence PFS and ORR. KRAS may have a negative role in platinum-based therapy responses in NSCLC, but its impact is limited. DNA polymerase β, when not expressed, might indicate a group of patients with poor outcomes. KRAS mutations in tumors not expressing DNA polymerase β further worsens survival. Therefore, these two biomarkers together might well identify patients for whom alternatives to platinum-based chemotherapy should be used

Immunotherapy in non-small cell lung cancer: the clinical impact of immune response and targeting

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. In recent years, through a better understanding of the interactions between the immune system and tumor cells (TC), immunotherapy has emerged as a promising therapeutic strategy. Chemotherapy has long been reported to interfere with the immune response to the tumor and conversely, anti-tumor immunity may add to those effects. Anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, tumor cell vaccines and dendritic cell (DC) vaccines emerged as potent inducers of the immune response against the tumor. More recently the approval of the anti-programmed cell death 1 (anti-PD-1) monoclonal antibodies nivolumab and pembrolizumab for previously treated advanced squamous and non-squamous NSCLC, as well as other immune checkpoint inhibitors delivering promising results, has radically transformed the therapeutic landscape of NSCLC. Combination strategies now appear as the next step. Notwithstanding these successes, immunotherapy still holds significant drawbacks and currently several improvements are needed before routine use in clinical practice, including identification of robust biomarkers for optimal patient selection, as well as defining the best way to evaluate response

TP53 Arg72Pro Polymorphism and Colorectal Cancer Risk: A Systematic Review and Meta-Analysis

Background: The TP53 rs1042522 polymorphism (c.215C>G, Arg72Pro) has been extensively investigated as a potential risk factor for colorectal cancer, but the results have thus far been inconclusive. Methods: We searched multiple electronic databases to identify studies investigating the association between the Arg72Pro polymorphism and colorectal cancer. Individual study odds ratios (OR) and their confidence intervals were estimated using allele-frequency, recessive, and dominant genetic models. Summary ORs where estimated using random effects models. Results: We identified 23 eligible case-control studies, investigating 6,514 cases and 9,334 controls. There was significant between-study heterogeneity for all genetic models. The control group in one of the studies was not in Hardy-Weinberg equilibrium; only three studies reported that genotyping was blinded to case/control status and five studies used tumor tissue for case genotyping. Overall, we did not identify any association between rs1042522 and colorectal cancer risk under an allele-frequency comparison (OR, 0.99; 95% confidence interval, 0.89-1.09). Likewise, no association was evident under dominant or recessive models. Studies using tumor tissue for case genotyping found a protective effect for the Pro allele, compared with studies using somatic DNA (P-interaction = 0.03). Results were also inconsistent between different genotyping methods (P-interaction = 0.03). Conclusion: We did not identify an association between TP53 rs1042522 and colorectal cancer. Published results seem to be driven by technical artifacts rather than true biological effects. Impact: Future genetic association studies should use more rigorous genotyping methods and avoid the use of tumor tissue as a source of DNA to prevent genotype misclassification due to loss of heterozygosity. Cancer Epidemiol Biomarkers Prev; 19(7); 1840-7. (C) 2010 AACR

Somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor and tyrosine kinase inhibitor response to TKIs in non-small cell lung cancer: An analytical database

Background: After the discovery of somatic mutations in the tyrosine kinase domain (exons 18-24) of the epidermal growth factor receptor (EGFR) correlating with responses of non-srnall cell lung cancer (NSCLC) to the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, there has been increasing interest in utilizing this molecular marker for treatment selection. We aimed to analytically catalogue the Mutational spectrum of somatic Mutations in EGFR and format a database allowing correlation of specific mutations with clinico-pathologic factors and response to TKIs. Methods: A computerized search of MEDLINE (January I 2004 to,June 30, 2007) was performed to identify articles reporting on NSCLC patients harboring somatic mutations in EGFR. Demographic, clinico-pathologic, Mutational, and response data were extracted and tabulated. Results: A total of 202 eligible articles were identified. We report data on 12,244 patients with 3381 somatic EGFR mutations. The majority Of mutations have been reported on only one occasion (158 of 254, 62.2%), and only nine Mutations occur at a rate of L858R and delE746-A750 account for 32.84% and 24.28% of all mutations, respectively; with 50% of mutations being exon 19 deletions or “deletional-insertions.” There is a clear association between the presence of Mutations and response to TKI. Conclusions: We have generated a free access, nonprofit online analytical database of somatic EGFR mutations in NSCLC. Cumulative information will be made available through a routine update of both database tables and associated graphical representations. Direct updates and Submissions through the online site (www.somaticmutations-EGFR.org) are encouraged, as are comments and suggestions

Lung Cancer Screening in Greece: A Modelling Study to Estimate the Impact on Lung Cancer Life Years

(1) Background: Lung cancer causes a substantial epidemiological burden in Greece. Yet, no formal national lung cancer screening program has been introduced to date. This study modeled the impact on lung cancer life years (LCLY) of a hypothetical scenario of comprehensive screening for lung cancer with low-dose computed tomography (LDCT) of the high-risk population in Greece, as defined by the US Preventive Services Taskforce, would be screened and linked to care (SLTC) for lung cancer versus the current scenario of background (opportunistic) screening only; (2) Methods: A stochastic model was built to monitor a hypothetical cohort of 100,000 high-risk men and women as they transitioned between health states (without cancer, with cancer, alive, dead) over 5 years. Transition probabilities were based on clinical expert opinion. Cancer cases, cancer-related deaths, and LCLYs lost were modeled in current and hypothetical scenarios. The difference in outcomes between the two scenarios was calculated. 150 iterations of simulation scenarios were conducted for 100,000 persons; (3) Results: Increasing SLTC to a hypothetical 100% of eligible high-risk people in Greece leads to a statistically significant reduction in deaths and in total years lost due to lung cancer, when compared with the current SLTC paradigm. Over 5 years, the model predicted a difference of 339 deaths and 944 lost years between the hypothetical and current scenario. More specifically, the hypothetical scenario led to fewer deaths (−24.56%, p < 0.001) and fewer life years lost (−31.01%, p < 0.001). It also led to a shift to lower-stage cancers at the time of diagnosis; (4) Conclusions: Our study suggests that applying a 100% screening strategy amongst high-risk adults aged 50–80, would result in additional averted deaths and LCLYs gained over 5 years in Greece