Real-world Data and Economic Evaluation of Nivolumab in Previously Treated Non-small Cell Lung Cancer Greek Patients.

BACKGROUND/AIM: Nivolumab is an FDA-approved immune checkpoint inhibitor (ICI) for patients with advanced, pre-treated non-small cell lung cancer (NSCLC). However, treatment profiles and patient outcomes often differ in routine clinical practice while the financial impact of approved therapies is largely unknown. In this study, we investigated the efficacy, tolerability, and economic impact of nivolumab in real-world settings (RWS) in Greece. PATIENTS AND METHODS: Patients diagnosed with advanced pre-treated NSCLC, receiving nivolumab were recruited from October 2015 until November 2019 across 18 different clinical centers in Greece. Endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety. Cost analysis was conducted using a third-party public-payer perspective (National Organization for Healthcare Services Provision; EOPYY). RESULTS: A total of 346 patients, median age 66.5 years, were included. With 43.4 months median follow-up, median PFS was 7.8 months and median OS 15.8 months. The 1-year OS rate was 56.5%, 2-year OS 38.8%, and 3-year OS 27.3%. The ORR was 29.5% and DCR 58.7%, with a median response duration of 26.8 months. Patients with objective response were more likely to experience long-term survival (HR=0.14, p<0.001). Only 8.4% of patients experienced grade 3-4 adverse events. The presence of immune-related adverse events was associated with improved OS (HR=0.77, p=0.043). Nivolumab-associated economic burden accounted for €2,214.10 per cycle for each patient, mainly attributed to drug-acquisition costs. CONCLUSION: This is the first report of real-world efficacy, safety, and economic burden of nivolumab in pre-treated patients with NSCLC in Greece. Indirectly compared to clinical trials, nivolumab was associated with improved efficacy in RWS, further supporting its use in clinical practice and providing insights on clinical prognosticators. The main cost component affecting the nivolumab economic burden was drug-acquisition costs, while toxicity-associated cost was negligible.

Molecular Epidemiology and Treatment Patterns of Patients With EGFR Exon 20-Mutant NSCLC in the Precision Oncology Era: The European EXOTIC Registry.

Introduction: Real-world evidence regarding molecular epidemiology and management patterns of patients with EGFR exon-20 mutated, advanced NSCLC outside the context of clinical trials is lacking. Methods: We created a European registry for patients with advanced EGFR exon 20-mutant NSCLC diagnosed from January 2019 to December 2021. Patients enrolled in clinical trials were excluded. Clinicopathologic and molecular epidemiology data were collected, and treatment patterns were recorded. Clinical end points according to treatment assignment were assessed using Kaplan-Meier curves and Cox regression models. Results: Data on 175 patients from 33 centers across nine countries were included in the final analysis. Median age was 64.0 (range: 29.7-87.8) years. Main features included female sex (56.3%), never or past smokers (76.0%), adenocarcinoma (95.4%), and tropism for bone (47.4%) and brain (32.0%) metastases. Mean programmed death-ligand 1 tumor proportional score was 15.8% (range: 0%-95%) and mean tumor mutational burden was 7.06 (range: 0-18.8) mutations per megabase. Exon 20 was detected in the tissue (90.7%), plasma (8.7%), or both (0.6%), using mostly targeted next-generation sequencing (64.0%) or polymerase chain reaction (26.0%). Mutations were mainly insertions (59.3%), followed by duplications (28.1%), deletions-insertions (7.7%), and the T790M (4.5%). Insertions and duplications were located mainly in the near loop (codons 767-771, 83.1%) and the far loop (codons 771-775, 13%) and only in 3.9% within the C helix (codons 761-766). Main co-alterations included mutations in TP53 (61.8%) and MET amplifications (9.4%). Treatment on mutation identification included chemotherapy (CT) (33.8%), CT-immunotherapy (IO) (18.2%), osimertinib (22.1%), poziotinib (9.1%), mobocertinib (6.5%), mono-IO (3.9%), and amivantamab (1.3%). Disease control rates were 66.2% with CT plus or minus IO, 55.8% with osimertinib, 64.8% with poziotinib, and 76.9% with mobocertinib. Corresponding median overall survival was 19.7, 15.9, 9.2, and 22.4 months, respectively. In multivariate analysis, type of treatment (new targeted agents versus CT ± IO) affected progression-free survival (p = 0.051) and overall survival (p = 0.03). Conclusions: EXOTIC represents the largest academic real-world evidence data set on EGFR exon 20-mutant NSCLC in Europe. Indirectly compared, treatment with new exon 20-targeting agents is likely to confer survival benefit than CT plus or minus IO.

Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: final long-term results of the Hellenic Cooperative Oncology Group Phase III HE10/05 Trial.

BACKGROUND: Dose-dense sequential chemotherapy with anthracyclines and taxanes achieved an 18% reduction of recurrence risk in early breast cancer (BC). The optimal chemotherapy schedule and interval between cycles remain under investigation. METHODS: Overall, 990 patients were randomised to receive either three cycles of epirubicin (E, 110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by three cycles of intensified CMF (Control Arm A, E-T-CMF) that was previously used in BC or three cycles of epirubicin followed by three cycles of CMF followed by nine consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Arm B, E-CMF-wD) or nine consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Arm C, E-CMF-wT). Trastuzumab was administered for HER2-positive disease. RESULTS: At a median follow-up of 13.3 years, 330 disease-free survival (DFS) events (33.3%) were reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus arm A either in the entire cohort (HR = 0.90, P = 0.38 and HR = 0.85, P = 0.20) or among trastuzumab-treated patients (HR = 0.69, P = 0.13 and HR = 0.67, P = 0.13). Thirty-four patients (3.4%) developed secondary neoplasms. CONCLUSIONS: Overall, no significant differences in survival were found amongst the studied regimens after a long-term observational period. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000151033.

Artificial intelligence supporting cancer patients across Europe-The ASCAPE project.

INTRODUCTION: Breast and prostate cancer survivors can experience impaired quality of life (QoL) in several QoL domains. The current strategy to support cancer survivors with impaired QoL is suboptimal, leading to unmet patient needs. ASCAPE aims to provide personalized- and artificial intelligence (AI)-based predictions for QoL issues in breast- and prostate cancer patients as well as to suggest potential interventions to their physicians to offer a more modern and holistic approach on cancer rehabilitation. METHODS AND ANALYSES: An AI-based platform aiming to predict QoL issues and suggest appropriate interventions to clinicians will be built based on patient data gathered through medical records, questionnaires, apps, and wearables. This platform will be prospectively evaluated through a longitudinal study where breast and prostate cancer survivors from four different study sites across the Europe will be enrolled. The evaluation of the AI-based follow-up strategy through the ASCAPE platform will be based on patients' experience, engagement, and potential improvement in QoL during the study as well as on clinicians' view on how ASCAPE platform impacts their clinical practice and doctor-patient relationship, and their experience in using the platform. ETHICS AND DISSEMINATION: ASCAPE is the first research project that will prospectively investigate an AI-based approach for an individualized follow-up strategy for patients with breast- or prostate cancer focusing on patients' QoL issues. ASCAPE represents a paradigm shift both in terms of a more individualized approach for follow-up based on QoL issues, which is an unmet need for cancer survivors, and in terms of how to use Big Data in cancer care through democratizing the knowledge and the access to AI and Big Data related innovations. TRIAL REGISTRATION: Trial Registration on clinicaltrials.gov: NCT04879563.

Genetic Variation in the Vascular Endothelial Growth Factor (VEGFA) Gene at rs13207351 Is Associated with Overall Survival of Patients with Head and Neck Cancer.

Head and neck cancer (HNC) is a significantly heterogeneous disease and includes malignancies arising from different anatomical sites, such as nasopharyngeal cancer (NPC) and laryngeal cancer (LC). In the current study, polymorphisms located in angiogenesis- and apoptosis-related genes (VEGFA, FAS, EDNRA and NBS1) were evaluated regarding their clinical significance in HNC patients. In total, 333 HNC patients were enrolled in this study and 34 variants located on the aforementioned genes were genotyped via Sanger sequencing. LC patients, homozygous A for VEGFA rs13207351, had shorter overall survival (OS) as opposed to homozygous G (Hazard ratio (HR) = 2.06, Wald's p = 0.017) upon adjustment for age, disease stage, and surgery. Following the dominant model, LC patients carrying the A allele had a marginally significantly higher risk for death (HR = 1.72, p = 0.059). NPC patients heterozygous (CT) for FAS rs2234768 had a marginal but significantly higher risk of death compared to those with homozygosity for the T allele (HR = 2.22, p = 0.056). In conclusion, rs13207351 (VEGFA) and rs2234768 (FAS) polymorphisms seem to have prognostic significance in HNC, with VEGFA rs13207351 showing the most promise in this subgroup of LC patients.

Androgen Receptor and PIM1 Expression in Tumor Tissue of Patients With Triple-negative Breast Cancer.

BACKGROUND/AIM: Effective targeted therapies for triple-negative breast cancer (TNBC) are limited. In a subset of TNBC, androgen receptor (AR) plays an important role, while the human proviral integration site for Moloney murine leukemia virus-1 (PIM1) overexpression is also implicated. PIM1 kinases phosphorylate AR, thus regulating its transcriptional activity, regardless of the presence or not of androgens. We evaluated the expression of AR and PIM1 and their prognostic significance in TNBC. MATERIALS AND METHODS: AR and PIM1 transcripts were quantified by quantitative reverse transcription polymerase chain reaction in formalin-fixed paraffin-embedded tumor from 141 patients with TNBC. RESULTS: AR was expressed in 38.3%, PIM1 in 10.6%, while co-expression of AR and PIM1 was detected in 7/141 cases (5.0%). No prognostic significance of AR or PIM1 was reached for overall or disease-free survival. CONCLUSION: Co-expression of AR and PIM1 exists in only in a small percentage of patients with TNBC. The implications of this finding in the therapeutic management of patients with TNBC should be investigated in larger patient cohorts.

Clinical Significance of Germline Cancer Predisposing Variants in Unselected Patients with Pancreatic Adenocarcinoma.

Our aim was to determine the prevalence, prognostic and predictive role of germline pathogenic/likely pathogenic variants (P/LPVs) in cancer predisposing genes in patients with pancreatic ductal adenocarcinoma (PDAC). Germline testing of 62 cancer susceptibility genes was performed on unselected patients diagnosed from 02/2003 to 01/2020 with PDAC, treated at Hellenic Cooperative Oncology Group (HeCOG)-affiliated Centers. The main endpoints were prevalence of P/LPVs and overall survival (OS). P/LPVs in PDAC-associated and homologous recombination repair (HRR) genes were identified in 22 (4.0%) and 42 (7.7%) of 549 patients, respectively. P/LPVs were identified in 16 genes, including ATM (11, 2.0%) and BRCA2 (6, 1.1%), while 19 patients (3.5%) were heterozygotes for MUTYH P/LPVs and 9 (1.6%) carried the low-risk allele, CHEK2 p.(Ile157Thr). Patients carrying P/LPVs had improved OS compared to non-carriers (22.6 vs. 13.9 months, p = 0.006). In multivariate analysis, there was a trend for improved OS in P/LPV carriers (p = 0.063). The interaction term between platinum exposure and mutational status of HRR genes was not significant (p-value = 0.35). A significant proportion of patients with PDAC carries clinically relevant germline P/LPVs, irrespectively of age, family history or disease stage. The predictive role of these P/LPVs has yet to be defined. ClinicalTrials.gov Identifier: NCT03982446.

Steroid Use Independently Predicts for Poor Outcomes in Patients With Advanced NSCLC and High PD-L1 Expression Receiving First-Line Pembrolizumab Monotherapy.

BACKGROUND: Real-world data have suggested a detrimental effect of steroid use in patients with advanced non-small-cell lung cancer (NSCLC) receiving immunotherapy. However, previous studies included heterogeneous cohorts of patients receiving different lines of treatment with several immuno-oncology agents and various combinations of chemotherapy and immuno-oncology agents. PATIENTS AND METHODS: A comprehensive clinicopathologic database of patients with NSCLC and programmed cell death ligand 1 >50% treated with frontline pembrolizumab monotherapy was constructed in 14 centers in Italy, Spain, Greece, and Switzerland. A multivariate analysis adjusting for the established prognostic factors was performed using a Cox regression model. RESULTS: For the 265 eligible patients, the median age at diagnosis was 67 years, 66% were male, 90% were current or former smokers, 18% had had an Eastern Cooperative Oncology Group performance status of 2 or 3. Of the NSCLC subtypes, 64% were adenocarcinoma and 25% were squamous cell. Of the patients, 18% had had brain metastases at diagnosis and 24% had received steroids before or during pembrolizumab treatment. The median time to progression was 4.4 months with and 13.7 months without steroid use (hazard ratio [HR], 2.55; 95% confidence interval [CI], 1.69-3.85; log-rank P < .001). The median survival was 22.5 months for the whole cohort, 7.7 months for the steroid group, and not reached for the non-steroid group (HR, 3.64; 95% CI, 2.34-5.68; log-rank P < .001). On multivariate analysis accounting for all established prognostic variables, steroid use was still independently associated with a high risk of progression (HR, 1.864; 95% CI, 1.179-2.949; P = .008) and death (HR, 2.292; 95% CI, 1.441-3.644; P < .001) CONCLUSIONS: In patients with advanced NSCLC and programmed cell death ligand 1 expression > 50% receiving frontline pembrolizumab monotherapy, any use of steroids before or during treatment was associated with an 86% increase in the risk of progression and a 2.3-fold increase in the risk of death, even accounting for palliative indication-related bias, including the presence of central nervous system metastasis. The use of steroids for palliative indications should be restricted to absolutely necessary for patients receiving immuno-oncology monotherapy.

Efficacy of Pembrolizumab Monotherapy in Patients With or Without Brain Metastases From Advanced Non-Small Cell Lung Cancer With a PD-L1 Expression ≥50%.

The authors conducted a multicenter retrospective study on the outcome of programmed death-ligand 1 tumor proportion score≥50% advanced non-small cell lung cancer patients treated with first-line pembrolizumab according to the presence/absence of brain metastases. A total of 282 patients were included, of whom 56 had brain metastases that were treated with upfront local radiation therapy in 80.3% of cases. The overall response rate was 39.2% and 44.4% in patients with and without brain metastases (P=0.48), respectively, while intracranial response rate and intracranial disease control rate were 67.5% and 85.0%, respectively. The median time-to-treatment failure (TTF) and overall survival (OS) were 4.2 and 9.9 months versus 10.8 and 26.5 months for patients with and without brain metastases (P=0.06 and 0.05, respectively). Drug discontinuation rate due to treatment-related adverse events was 10.7% and 10.2% in patients with and without brain metastases, respectively. Multivariate analysis showed that baseline steroids was an independent predictor for a worse OS (P<0.001), while performance status (PS)≥2 was an independent predictor for a poorer TTF (P<0.001) and OS (P<0.001). In patients with brain metastases, only PS ≥2 was predicted for a worse TTF (P=0.02) and OS (P=0.03). Pembrolizumab has activity against brain metastases from non-small cell lung cancers with programmed death-ligand 1≥50%. Presence of brain metastases per se does not appear to be prognostic, and PS ≥2 seems to be the only factor associated with a worse outcome in patients with brain metastases.

Impact of performance status on non-small-cell lung cancer patients with a PD-L1 tumour proportion score ≥50% treated with front-line pembrolizumab.

Objectives: We retrospectively analysed patients with advanced non-small-cell lung cancer (NSCLC) harbouring high PD-L1 expression (>50%) and treated with front-line pembrolizumab, comparing outcomes of patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to those with PS 0-1.Methods: Data were collected by 16 participating centres. All patients with NSCLC and high PD-L1, treated with first-line pembrolizumab were included. We collected medical data from patient files, pathology and laboratory reports. Patient characteristics, comorbidities, PS, and tumour characteristics were reported. Overall survival (OS), progression-free survival (PFS) and response rate (RR) were calculated.Results: 302 patients were included, 246 with PS 0-1, 56 with PS 2. RR was 72% among patients with PS 0-1 compared to 45% with PS2 (odds ratio (OR) 0.31 (95% CI: 0.17-0.57), p < .001). Median PFS was 2.6 months (95% CI: 1.9-5.1) among patients with PS2 and 11.3 months (95% CI: 8.5-14.4) among those with PS 0-1. Median OS was 7.8 months (95% CI: 2.5-10.7) in the PS2 group, not reached in the PS 0-1 group. PS 2 remained predictive of poor outcomes in multivariate analysis.Conclusion: PS 2 is a strong independent predictor of poor response and survival in NSCLC patients with high PD-L1, treated with front-line pembrolizumab. Prospective randomised trials comparing immunotherapy to chemotherapy in this population would be welcome.

Impact of Bevacizumab Versus Erlotinib on Tumor Metrics in Patients With Previously Untreated Advanced Non-small Cell Lung Cancer: A Study by the Hellenic Cooperative Oncology Group.

BACKGROUND: The mechanism of action of bevacizumab and erlotinib is quite different in the treatment of advanced non-small cell lung cancer (NSCLC). This study sought to compare the two targeted therapies in terms of sequential tumor response metrics. PATIENTS AND METHODS: Parameters of radiological tumor response evaluation were assessed at baseline and periodically in 58 patients receiving either bevacizumab plus platinum-based chemotherapy (N=25) or erlotinib (N=33). RESULTS: Bevacizumab-treated patients had lower longest diameter at best response compared to the erlotinib group (p=0.011). The longest diameter, tumor volume and density significantly decreased from baseline to best response for the entire cohort and bevacizumab-treated patients; no difference was found in the erlotinib group. CONCLUSION: Treatment with bevacizumab substantially improved tumor metrics between baseline and each cycle of treatment, as well as between baseline and best response, in patients with advanced NSCLC.

Pathogenic mutations and overall survival in 3,084 patients with cancer: the Hellenic Cooperative Oncology Group Precision Medicine Initiative.

Background: We evaluated the association between pathogenic mutations and overall survival (OS) in patients with cancer referred to Hellenic Cooperative Oncology Group-affiliated Departments. Patients and methods: Patients referred from 12/1980 to 1/2017 had molecular testing (for research) of archival tumor tissue collected at the time of first diagnosis (non-metastatic, 81%; metastatic, 19%). Tumor-specific gene panels (16-101 genes) were used to identify pathogenic mutations in clinically relevant genes. NGS genotyping was performed at the Laboratory of Molecular Oncology, Aristotle University of Thessaloniki. Annotation of mutations was performed at MD Anderson Cancer Center. Results: We analyzed 3,084 patients (median age, 57 years; men, 22%) with sequencing data. Overall, 1,775 (58% of 3,084) patients had pathogenic mutations. The median follow-up was 7.52 years (95% CI, 7.39-7.61). In patients with non-metastatic tumors, after stratification by tumor type, increasing age, higher grade, and histology other than adenocarcinoma were associated with shorter OS. OS was also shorter in patients with pathogenic TP53 (HR=1.36; p<0.001), MLL3 (HR=1.64; p=0.005), and BRCA1 (HR=1.46; p=0.047) mutations compared to wild-type genes. In multivariate analyses, independent prognostic factors predicting shorter OS were pathogenic mutations in TP53 (HR=1.37, p=0.002) and MLL3 (HR=1.50, p=0.027); increasing age (HR=1.02, p<0.001); and increasing grade (HR=1.46, p<0.001). In patients with metastatic cancer, older age and higher grade were associated with shorter OS and maintained their independent prognostic significance (increasing age, HR=1.03, p<0.001 and higher grade, HR=1.73, p<0.001). Conclusions: Analysis of molecular data reveals prognostic biomarkers, regardless of tissue or organ of origin to improve patient management.

Genetic Variations of VEGFA Gene Are Associated With Infiltration of Adjacent Tissues and the Clinical Outcome of Patients With Nasopharyngeal Carcinoma.

BACKGROUND/AIM: The aim of the present study was to investigate the clinical significance of 7 single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor A (VEGFA), endothelin receptor type A (EDNRA), nibrin (NBS1) and Fas cell surface death receptor (FAS) genes in patients with nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Genomic DNA was extracted from the peripheral blood specimens of 60 patients. Genotyping of 4 VEGFA polymorphisms, namely VEGFA -1154 G/A (rs1570360), -2578 A/C (rs699947), -1498 C/T (rs833061) and +936 C/T (rs3025039), as well as EDNRA SNP p.His323 (rs5333), NBS1 p.E185Q (rs1805794) and FAS -671 A/G (rs1800682) was performed by using Sanger sequencing. RESULTS: The VEGFA +936 CC genotype was more frequent in tumors with bilateral infiltration of pterygoid plates compared to those with ipsilateral (76.9% vs. 69.6%, p=0.008) and no infiltration of pterygoid plates (76.9% vs. 68.8%, p=0.023). VEGFA -2578, VEGFA -1154 and VEGFA +936 were significantly associated with infiltration to the pterygoid processes (p=0.011, p=0.041 and p=0.032, respectively). EDNRA H323H TT genotype was marginally associated with infiltration to the ipsilateral medial pterygoid muscles (p=0.045). A trend towards longer overall survival was observed for VEGFA -2578 CC as compared to AC (HR=0.24, p=0.060). CONCLUSION: The studied VEGFA SNPs seem to be associated with the local extension of the NPC and maybe with the clinical outcome of this patient group.

Recurrence-free Survival and Safety of Imatinib in Patients With Gastrointestinal Stromal Tumour (GIST) in Greece.

AIM: The purpose of the Imadje study was to confirm the efficacy and safety of imatinib, following resection of kit-positive gastrointestinal stromal tumour (GIST), in the adjuvant setting in the Greek population. PATIENTS AND METHODS: A total of 34 adult patients already receiving imatinib were enrolled. Recurrence-free (RFS) and overall survival, as well as time to treatment failure and safety were assessed. RESULTS: Overall survival could not be estimated in the present study, as no death occurred. Overall, 91.2% of patients were recurrence-free at 36 months, while the median time to treatment failure was 35 months. No new or unexpected safety findings were observed. Mutation analysis in 14 patients showed that the most frequent mutations were located in KIT exon 11 (64.3%) and exon 9 (28.6%). Univariate analysis showed that only surgical resection with a margin classification of R0 was associated with better RFS. CONCLUSION: Adjuvant treatment with imatinib for 3 years in patients with intermediate to high risk of recurrence was proven to prolong RFS, while being well-tolerated and not exhibiting a negative impact on patient compliance with therapy.

Genotyping KRAS and EGFR Mutations in Greek Patients With Non-small-cell Lung Cancer: Incidence, Significance and Implications for Treatment.

BACKGROUND/AIM: KRAS mutations are reported in 20-25% of non-small cell lung cancer (NSCLC) and their prognostic role is unclear. We studied KRAS and EGFR genotyping in Greek NSCLC patients. PATIENTS AND METHODS: KRAS and EGFR genotypes were centrally evaluated in 421 NSCLC patients (diagnosed September 1998 -June 2013) and associated with clinicopathological parameters. Outcome comparisons were performed in 288 patients receiving first line treatment. RESULTS: Most patients were male (78.6%), >60 years old (63.9%), current smokers (51.1%), with adenocarcinoma histology (63.9%). EGFR and KRAS mutations were found in 10.7% and 16.6% of all histologies, respectively, and in 14.9% and 21.9% of adenocarcinomas. At 4.5 years median follow-up, KRAS status was an independent negative prognostic factor for overall survival (OS, p=0.016). KRAS mutations conferred 80% increased risk of death in patients receiving first-line treatment (p=0.002). CONCLUSION: The presence of KRAS mutations is an independent negative prognosticator among Greek NSCLC patients and an independent response predictor to first line treatment.

Outcomes from salvage chemotherapy or pembrolizumab beyond progression with or without local ablative therapies for advanced non-small cell lung cancers with PD-L1 ≥50% who progress on first-line immunotherapy: real-world data from a European cohort.

BACKGROUND: In this real-world multicenter study we addressed the activity of post-progression anticancer treatments after first-line pembrolizumab in advanced non-small cell lung cancer (NSCLC) patients with PD-L1 ≥50%. METHODS: Clinico-pathological data of PD-L1 ≥50% advanced NSCLCs who failed first-line pembrolizumab were collected in 14 Oncologic Centers from different European countries. Types of subsequent anticancer treatment and outcomes on salvage chemotherapy or pembrolizumab beyond progression with or without the addition of local ablative therapies were reported. RESULTS: Out of 173 patients, 100 had progressed on pembrolizumab, of which 60 patients (60%) met eligibility criteria and were treated with either salvage chemotherapy (42/60, 70%) or pembrolizumab beyond progression (18/60, 30%). Overall, median age was 66 years, 63.3% were male, 60.0% had a performance status of 0-1, 88.3% were smokers and 61.7% had adenocarcinoma histology. In patients evaluable for response, objective response rate to salvage chemotherapy was 41.9%, with no significant difference according to the type of regimen (42.9% for platinum-based and 40.0% for single-agent chemotherapy). Median progression-free survival (PFS) to salvage chemotherapy was 4.5 months. Among patients treated with pembrolizumab beyond progression, 13 out of 18 patients (72.2%) had progressive disease in ≤2 organ sites, of whom 9 (69.2%) were managed with the addition of local ablative therapies consisting of radiation at progressive lesion(s). No significant difference was noted in terms of post-progression survival between the salvage chemotherapy and the pembrolizumab beyond progression groups of patients (6.9 versus 8.1 months, respectively, P=0.08). CONCLUSIONS: In PD-L1 ≥50% advanced NSCLCs who progress on first-line pembrolizumab, salvage chemotherapy is associated with a remarkable anticancer activity, while select patients may benefit from continuation of pembrolizumab beyond progression, with the possible addition of local ablative radiotherapy in oligoprogressive cases.

Evaluation of the prognostic value of CD3, CD8, and FOXP3 mRNA expression in early-stage breast cancer patients treated with anthracycline-based adjuvant chemotherapy.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) have been shown to be of prognostic value in several cancer types. In early breast cancer, TILs have a prognostic utility, as well, especially in HER2-positive and triple-negative breast cancer. TILs presence is broadly associated with improved survival; however, there is controversy regarding TILs subpopulations. PATIENTS AND METHODS: Early-stage breast cancer patients treated with anthracycline-based chemotherapy within two randomized trials were included in the study. We evaluated, by qRT-PCR, 826 tumor tissue samples for mRNA expression of CD3, CD8, and FOXP3 for potential prognostic significance in terms of disease-free survival (DFS) and overall survival (OS). RESULTS: After a median follow-up of 133.0 months, 255 patients (30.9%) had died and 314 (38.0%) had disease progression. In the univariate analysis, high CD3 and CD8 mRNA expression was found to be of favorable prognostic value for DFS (P = 0.007 and P = 0.016, respectively). In multivariate analyses, the association of high CD8 mRNA expression with increased DFS was retained (HR = 0.77, 95% CI 0.60-0.998, Wald's P = 0.048), whereas that of high CD3 mRNA expression was of marginal statistical significance (HR = 0.77, 95% CI 0.59-1.01, P = 0.059). Moreover, a significant interaction was observed between HER2 status and CD3 mRNA expression with respect to DFS (interaction P = 0.032). In the HER2-positive subgroup, the hazard ratio associated with high CD3 mRNA expression was of greater magnitude (HR = 0.48, 95% CI 0.30-0.76, P = 0.002) compared with the hazard ratio presented above, for the entire cohort. No significant findings were observed for FOXP3 in terms of DFS, while none of the studied markers were of prognostic value for OS. CONCLUSIONS: High CD3 and CD8 mRNA expression in early-stage breast cancer patients is of prognostic value for decreased risk of relapse and, in the future, could potentially be of importance in deciding the most appropriate therapeutic strategy in light of the recent immune-related treatment developments.

Associations of angiogenesis-related proteins with specific prognostic factors, breast cancer subtypes and survival outcome in early-stage breast cancer patients. A Hellenic Cooperative Oncology Group (HeCOG) trial.

Several studies support an important role of angiogenesis in breast cancer growth and metastasis. The main objectives of the study were to investigate the immunohistochemical expression of vascular endothelial growth factor (VEGF) family ligands (VEGF-A and VEGF-C) and receptors (VEGFR1, VEGFR2 and VEGFR3) in breast cancer and their associations with clinicopathological parameters, cancer subtypes/subgroups and patient outcome. Formalin-fixed paraffin-embedded tumor tissue samples were collected from early-stage breast cancer patients treated with anthracycline-based chemotherapy within a randomized trial. Immunohistochemistry was performed on serial 2.5 µm thick tissue sections from tissue microarray blocks. High VEGF-A, VEGF-C, VEGFR1, VEGFR2 and VEGFR3 protein expression was observed in 11.8% (N = 87), 80.8% (N = 585), 28.1% (N = 202), 64.6% (N = 359) and 71.8% (N = 517) of the cases, respectively. Significant associations were observed among all proteins (all p-values <0.05), with the exception of the one between VEGF-C and VEGFR1 (chi-square test, p = 0.15). Tumors with high VEGF-A protein expression, as compared to tumors with low expression were more frequently ER/PgR-negative (33.3% vs. 20.8%, chi-square test, p = 0.009) and HER2-positive (44.8% vs. 20.6%, p<0.001). In addition, tumors with high VEGFR1 expression, were more frequently HER2-positive (32.8% vs. 19.6%, p<0.001), while tumors with high VEGFR3 expression were more frequently ER/PgR-negative (24.9% vs. 17.0%, p = 0.024) and HER2-positive (26.9% vs. 14.8%, p = 0.001). High VEGF-A and VEGF-C protein expression was associated with increased DFS in the entire cohort (HR = 0.57, 95% CI 0.36-0.92, Wald's p = 0.020 and HR = 0.71, 95% CI 0.52-0.96, p = 0.025, respectively), as well as in specific subtypes/subgroups, such as HER2-positive (VEGF-A, HR = 0.32, 95% CI 0.14-0.74, p = 0.008) and triple-negative (VEGF-C, HR = 0.44, 95% CI 0.21-0.91, p = 0.027) patients. High vs. low VEGFR1 expression was an unfavorable factor for DFS in triple-negative patients (HR = 2.74, 95% CI 1.26-5.98, p = 0.011), whereas the opposite was observed among the ER/PgR-positive patients (HR = 0.69, 95% CI 0.48-0.98, p = 0.041). Regarding OS, high VEGF-C protein expression was associated with increased OS in the entire cohort (HR = 0.64, 95% CI 0.46-0.89, Wald's p = 0.008), as well as in in specific subtypes/subgroups, such as ER/PgR-negative (HR = 0.37, 95% CI 0.20-0.71, p = 0.003) and triple-negative (HR = 0.42, 95% CI 0.19-0.90, p = 0.026) patients. In conclusion, high expression of angiogenesis-related proteins is associated with adverse clinicopathological parameters in early-stage breast cancer patients and may be surrogate markers of biologically distinct subgroups of ER/PgR-negative or triple-negative tumors with superior outcome. Further validation of our findings in independent cohorts is needed.

Correlation of MYC Gene and Protein Status With Breast Cancer Subtypes and Outcome of Patients Treated With Anthracycline-Based Adjuvant Chemotherapy. Pooled Analysis of 2 Hellenic Cooperative Group Phase III Trials.

BACKGROUND: The prognostic/predictive value of aberrant MYC gene copies and protein expression is not clear in breast cancer. PATIENTS AND METHODS: Early breast cancer patients were treated with anthracycline-containing chemotherapy within 2 randomized adjuvant trials. MYC gene and centromere-8 status, as well as Myc protein expression were investigated on 1060 paraffin tumors with fluorescence in situ hybridization and immunohistochemistry, respectively. RESULTS: MYC amplification was present in 45% and polysomy-8 in 23% of the tumors. Cytoplasmic staining was observed in 60% and nuclear staining in 26% of the tumors, strongly correlating with each other but not with MYC gene status. MYC gene amplification in the absence of polysomy-8 was associated with adverse disease-free survival (DFS) and overall survival (OS), and remained as an independent unfavorable prognostic factor in multivariate analysis (Wald P = .022 for DFS; P = .032 for OS), whereas patients with MYC amplification and polysomy-8, with polysomy-8 only, and with normal MYC without polysomy-8 performed significantly better compared with those with MYC gene amplification only. Nuclear Myc protein expression benefitted patients treated with paclitaxel (interaction P = .052 for DFS; P = .049 for OS). This interaction remained independently significant in multivariate analysis for OS (overall P = .028). CONCLUSION: The effect of MYC gene status on breast cancer patient outcome seems to depend on the underlying chromosomal instability and appears unfavorable for tumors with MYC amplification without polysomy. Nuclear Myc protein expression seems predictive for benefit from adjuvant paclitaxel. These data might aid in the interpretation of relevant findings from large clinical trials.

Protein expression patterns of cell cycle regulators in operable breast cancer.

BACKGROUND-AIM: To evaluate the prognostic role of elaborate molecular clusters encompassing cyclin D1, cyclin E1, p21, p27 and p53 in the context of various breast cancer subtypes. METHODS: Cyclin E1, cyclin D1, p53, p21 and p27 were evaluated with immunohistochemistry in 1077 formalin-fixed paraffin-embedded tissues from breast cancer patients who had been treated within clinical trials. Jaccard distances were computed for the markers and the resulted matrix was used for conducting unsupervised hierarchical clustering, in order to identify distinct groups correlating with prognosis. RESULTS: Luminal B and triple-negative (TNBC) tumors presented with the highest and lowest levels of cyclin D1 expression, respectively. By contrast, TNBC frequently expressed Cyclin E1, whereas ER-positive tumors did not. Absence of Cyclin D1 predicted for worse OS, while absence of Cyclin E1 for poorer DFS. The expression patterns of all examined proteins yielded 3 distinct clusters; (1) Cyclin D1 and/or E1 positive with moderate p21 expression; (2) Cyclin D1 and/or E1, and p27 positive, p53 protein negative; and, (3) Cyclin D1 or E1 positive, p53 positive, p21 and p27 negative or moderately positive. The 5-year DFS rates for clusters 1, 2 and 3 were 70.0%, 79.1%, 67.4% and OS 88.4%, 90.4%, 78.9%, respectively. CONCLUSIONS: It seems that the expression of cell cycle regulators in the absence of p53 protein is associated with favorable prognosis in operable breast cancer.