Search

Purpose:This prespecified exploratory analysis evaluated the association between tumor mutational burden (TMB) status and outcomes of first-line pembrolizumab±chemotherapy versus chemotherapy in KEYNOTE-062.Patients and Methods:In patients with advanced gastric cancer and evaluable TMB data, we evaluated the association between TMB (continuous variable; square root scale) assessed with FoundationOne CDx and clinical outcomes [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] using logistic (ORR) and Cox proportional hazards (PFS, OS) regression models. Clinical utility of TMB was assessed using the prespecified cutoff of 10 mut/Mb.Results:TMB data were available for 306 of 763 patients (40.1%; pembrolizumab, 107; pembrolizumab+chemotherapy, 100; chemotherapy, 99). TMB was significantly associated with clinical outcomes in patients treated with pembrolizumab and pembrolizumab+chemotherapy (ORR, PFS, and OS; all P < 0.05) but not with chemotherapy (all P > 0.05). The overall prevalence of TMB ≥10 mut/Mb was 16% across treatment groups; 44% of patients who had TMB ≥10 mut/Mb had high microsatellite instability (MSI-H) tumors. Improved clinical outcomes (ORR, PFS, and OS) were observed in pembrolizumab-treated patients (pembrolizumab monotherapy and pembrolizumab+chemotherapy) with TMB ≥10 mut/Mb. When the analysis was limited to the non–MSI-H subgroup, both the positive association between clinical outcomes with pembrolizumab or pembrolizumab+chemotherapy and TMB as a continuous variable and the clinical utility of pembrolizumab (with or without chemotherapy) versus chemotherapy by TMB cutoff were attenuated.Conclusions:This exploratory analysis of KEYNOTE-062 suggests an association between TMB and clinical efficacy with first-line pembrolizumab-based therapy in patients with advanced gastric/gastroesophageal junction adenocarcinoma. However, after the exclusion of patients with MSI-H tumors, the clinical utility of TMB was attenuated.

Supplementary Figure from Association of Tumor Mutational Burden with Efficacy of Pembrolizumab±Chemotherapy as First-Line Therapy for Gastric Cancer in the Phase III KEYNOTE-062 Study

Chemotherapy-induced myelosuppression is an acute, dose-limiting toxicity of chemotherapy regimens used in the treatment of extensive-stage small cell lung cancer (ES-SCLC). Trilaciclib protects haematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection). To assess the totality of the myeloprotective benefits of trilaciclib, including analysis of several clinically relevant but low-frequency events, an exploratory composite endpoint comprising five major adverse haematological events (MAHE) was prospectively defined: all-cause hospitalisations, all-cause chemotherapy dose reductions, febrile neutropenia (FN), prolonged severe neutropenia (SN) and red blood cell (RBC) transfusions on/after week 5. MAHE and its individual components were assessed in three randomised, double-blind, placebo-controlled Phase 2 trials in patients receiving a platinum/etoposide or topotecan-containing chemotherapy regimen for ES-SCLC, and in data pooled from the three trials. A total of 242 patients were randomised across the three trials (trilaciclib, n = 123; placebo, n = 119). In the individual trials and the pooled analysis, administering trilaciclib prior to chemotherapy resulted in a statistically significant reduction in the cumulative incidence of MAHE compared with placebo. In the pooled analysis, the cumulative incidences of all-cause chemotherapy dose reductions, FN, prolonged SN and RBC transfusions on/after week 5 were significantly reduced with trilaciclib versus placebo; however, no significant difference was observed in rates of all-cause hospitalisations. Additionally, compared with placebo, trilaciclib significantly extended the amount of time patients remained free of MAHE. These data support the myeloprotective benefits of trilaciclib and its ability to improve the overall safety profile of myelosuppressive chemotherapy regimens used to treat patients with ES-SCLC. This article is protected by copyright. All rights reserved.

Purpose: This prespecified exploratory analysis evaluated the association between tumor mutational burden (TMB) status and outcomes of first-line pembrolizumab±chemotherapy versus chemotherapy in KEYNOTE-062. Patients and Methods: In patients with advanced gastric cancer and evaluable TMB data, we evaluated the association between TMB (continuous variable; square root scale) assessed with FoundationOne CDx and clinical outcomes [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] using logistic (ORR) and Cox proportional hazards (PFS, OS) regression models. Clinical utility of TMB was assessed using the prespecified cutoff of 10 mut/Mb. Results: TMB data were available for 306 of 763 patients (40.1%; pembrolizumab, 107; pembrolizumab+chemotherapy, 100; chemotherapy, 99). TMB was significantly associated with clinical outcomes in patients treated with pembrolizumab and pembrolizumab+chemotherapy (ORR, PFS, and OS; all P < 0.05) but not with chemotherapy (all P > 0.05). The overall prevalence of TMB ≥10 mut/Mb was 16% across treatment groups; 44% of patients who had TMB ≥10 mut/Mb had high microsatellite instability (MSI-H) tumors. Improved clinical outcomes (ORR, PFS, and OS) were observed in pembrolizumab-treated patients (pembrolizumab monotherapy and pembrolizumab+chemotherapy) with TMB ≥10 mut/Mb. When the analysis was limited to the non–MSI-H subgroup, both the positive association between clinical outcomes with pembrolizumab or pembrolizumab+chemotherapy and TMB as a continuous variable and the clinical utility of pembrolizumab (with or without chemotherapy) versus chemotherapy by TMB cutoff were attenuated. Conclusions: This exploratory analysis of KEYNOTE-062 suggests an association between TMB and clinical efficacy with first-line pembrolizumab-based therapy in patients with advanced gastric/gastroesophageal junction adenocarcinoma. However, after the exclusion of patients with MSI-H tumors, the clinical utility of TMB was attenuated.

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], pINTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.FUNDING: Merck Sharp & Dohme.

Trilaciclib is an intravenous CDK4/6 inhibitor administered prior to chemotherapy to preserve haematopoietic stem and progenitor cells and immune system function from chemotherapy‐induced damage (myelopreservation). The effects of administering trilaciclib prior to carboplatin, etoposide and atezolizumab (E/P/A) were evaluated in a randomised, double‐blind, placebo‐controlled Phase II study in patients with newly diagnosed extensive‐stage small cell lung cancer (ES‐SCLC) (NCT03041311). The primary endpoints were duration of severe neutropenia (SN; defined as absolute neutrophil count

BackgroundPrimary analysis of KEYNOTE-042 (NCT02220894), a global, randomized, phase 3 trial, showed that pembrolizumab significantly improved OS versus platinum-based chemotherapy in patients with locally advanced or metastatic non–small-cell lung cancer (NSCLC) without sensitizing EGFR/ALK alterations and with PD-L1 tumor proportion score (TPS) ≥50%, ≥20%, and ≥1% with fewer treatment-related AEs than chemotherapy. We report an updated analysis with ~5 years of follow-up.MethodsEligible adults were randomized 1:1 to receive pembrolizumab 200 mg Q3W for 35 cycles or investigator’s choice of chemotherapy (carboplatin + paclitaxel or pemetrexed) Q3W for 4–6 cycles with optional maintenance pemetrexed (nonsquamous only). Primary endpoints were OS in patients with PD-L1 TPS ≥50%, ≥20%, and ≥1%; secondary endpoints included PFS and ORR per RECIST v1.1 by central review, and safety (secondary). Eligible patients randomized to pembrolizumab who completed 35 cycles with SD or better or stopped treatment after confirmed CR could begin a second course of pembrolizumab at the time of progression.Results1274 patients were randomized to pembrolizumab or chemotherapy (n = 637 each). Median (range) time from randomization to data cutoff (Apr 28, 2021) was 61.1 (50.0–76.3) months. OS outcomes favored the pembrolizumab group (vs chemotherapy alone) regardless of PD-L1 TPS (HR [95% CI] for TPS ≥50%, 0.68 [0.57–0.81]; TPS ≥20%, 0.75 [0.64–0.87]; TPS ≥1%, 0.79 [0.70–0.89]), with estimated 5-year OS rates (95% CI) of 21.9% (17.3%–26.9%), 19.4% (15.6%–23.4%) and 16.6% (13.7%–19.6%), respectively, in the pembrolizumab group (table 1). Median duration of response (DOR) was 28.1 vs 10.8 months in PD-L1 TPS ≥50% group, 27.7 vs 10.8 months in PD-L1 TPS ≥20% group and, 26.5 vs 8.4 months in PD-L1 TPS ≥1% for pembrolizumab group vs chemotherapy. Treatment-related grade 3–5 AEs occurred in 120 patients (18.9%) in the pembrolizumab group and 257 (41.8%) in the chemotherapy group. Among 102 patients who completed 35 cycles of pembrolizumab: ORR was 84.3%; estimated 4-year OS rate after completion of 35 cycles of pembrolizumab (ie, approximately 6 years after randomization) was 61.8%. Among 33 patients who received second-course pembrolizumab, ORR was 15.2%.Abstract 363 Table 1Key efficacy outcomes in the KEYNOTE-042 ITT populationConclusionsWith 5 years of follow-up, first-line pembrolizumab monotherapy continued to show substantial clinical benefit with higher 5-year OS rates, and durable response over chemotherapy in patients with PD-L1–positive, locally advanced/metastatic NSCLC without EGFR/ALK alterations. First-line pembrolizumab remains a standard of care in patients with PD-L1 TPS ≥1%, as underscored by these long-term results.AcknowledgementsMedical writing assistance was provided by Kathleen Estes, PhD, of ICON plc (North Wales, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicaltrialsgov, NCT02220894Ethics ApprovalThe protocol and all amendments were approved by the appropriate ethics committee at each center, the study was conducted in accordance with the standards of Good Clinical Practice and in compliance with the Declaration of Helsinki. Patients provided written informed consent before enrollment.

Importance Safe and effective therapies for untreated, advanced gastric/gastroesophageal junction (G/GEJ) cancer remain an unmet need. Objective To evaluate the antitumor activity of pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone in patients with untreated, advanced G/GEJ cancer with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater. Design, Setting, and Participants The phase 3 KEYNOTE-062 randomized, controlled, partially blinded interventional trial enrolled 763 patients with untreated, locally advanced/unresectable or metastatic G/GEJ cancer with PD-L1 CPS of 1 or greater from 200 centers in 29 countries between September 18, 2015, and May 26, 2017. Interventions Patients were randomized 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin 80 mg/m2/d on day 1 plus fluorouracil 800 mg/m2/d on days 1 to 5 or capecitabine 1000 mg/m2twice daily), or chemotherapy plus placebo, every 3 weeks. Main Outcomes and Measures Primary end points were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 CPS of 1 or greater or 10 or greater. Results A total of 763 patients were randomized to pembrolizumab (n = 256), pembrolizumab plus chemotherapy (n = 257), or chemotherapy (n = 250). The median (range) age of all patients in the study cohort was 62 (20-87) years; 554 of 763 (72.6%) were men. At final analysis, after a median (range) follow-up of 29.4 (22.0-41.3) months, pembrolizumab was noninferior to chemotherapy for OS in patients with CPS of 1 or greater (median, 10.6 vs 11.1 months; hazard ratio [HR], 0.91; 99.2% CI, 0.69-1.18). Pembrolizumab monotherapy was not superior to chemotherapy in patients with CPS of 1 or greater. Pembrolizumab prolonged OS vs chemotherapy in patients with CPS of 10 or greater (median, 17.4 vs 10.8 months; HR, 0.69; 95% CI, 0.49-0.97), but this difference was not statistically tested. Pembrolizumab plus chemotherapy was not superior to chemotherapy for OS in patients with CPS of 1 or greater (12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.70-1.03;P = .05) or CPS of 10 or greater (12.3 vs 10.8 months; HR, 0.85; 95% CI, 0.62-1.17;P = .16) or for PFS in patients with CPS of 1 or greater (6.9 vs 6.4 months; HR, 0.84; 95% CI, 0.70-1.02;P = .04). Grade 3 to 5 treatment-related adverse event rates for pembrolizumab, pembrolizumab plus chemotherapy, and chemotherapy were 17%, 73%, and 69%, respectively. Conclusions and Relevance This phase 3 randomized clinical trial found that among patients with untreated, advanced G/GEJ cancer, pembrolizumab was noninferior to chemotherapy, with fewer adverse events observed. Pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for the OS and PFS end points tested. Trial Registration ClinicalTrials.gov Identifier:NCT02494583

Background Erlotinib is approved for the first line treatment of epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. Since the number of prospective studies in Caucasian patients treated in routine clinical setting is limited we conducted a multicenter, phase IV clinical trial to determine the efficacy and safety of erlotinib and to demonstrate the feasibility of the validated standardized companion diagnostic method of EGFR mutation detection. Methods 651 chemonaive, cytologically or histologically verified advanced stage lung adenocarcinoma patients from Hungary, Turkey and Latvia were screened for exon19 microdeletions and exon21 L858R EGFR mutations using the companion diagnostic EGFR test. EGFR mutation-positive, locally advanced or metastatic lung adenocarcinoma patients received as first line treatment erlotinib at 150 mg/day. The primary endpoint was progression-free survival (PFS). Results 62 EGFR mutation-positive patients (9.5% of screened) were included in the safety/intent-to-treat cohort. Median PFS was 12.8 months (95%CI, 9.9–15.8), objective response rate and one-year survival was 66.1% and 82.5%, respectively. Most frequent treatment related adverse events were diarrhoea and rash. Eastern Oncology Cooperative Group Performance Status (ECOG PS), smoking status and M1a/M1b disease stage were significant prognosticators of PFS (p = 0.017, p = 0.045 and p = 0.002, respectively). There was no significant difference in PFS between the subgroups stratified by gender, age or exon19 vs exon21 mutation. Conclusions Our study confirmed the efficacy and safety of first line erlotinib monotherapy in Caucasian patients with locally advanced or metastatic lung adenocarcinoma carrying activating EGFR mutations based on the screening with the approved companion diagnostic procedure. Trial registration ClinicalTrials.gov Identifier: NCT01609543.

Background KEYNOTE-062 (NCT02494583) was a randomized, study of 1L pembrolizumab (P) or pembro + chemo (P+C) vs chemo (C) in patients (pts) with PD-L1 combined positive score ≥1 (CPS ≥1), HER2-negative, advanced GC. Methods Eligible pts were randomized 1:1:1 to P 200mg Q3W for up to 2 y, P+C (cisplatin 80mg/m2 + 5-FU 800mg/m2/d on d1-d5 Q3W [or capecitabine 1000mg/m2 BID on d1-d14 Q3W per local guideline]) or placebo Q3W + C. Primary endpoints were OS in CPS ≥1 and CPS ≥10 for P+C vs C and P vs C and PFS (RECIST v1.1; central review) in CPS ≥1 for P+C vs C. ORR (RECIST v1.1; central review) in CPS ≥1 for P+C vs C was the secondary endpoint. The final analysis cutoff date was 26 Mar 2019. Results 763 pts (281 with CPS ≥10) were randomized to P+C (257), P (256), or C (250) (Table). Median follow-up was 11.3mo. P was noninferior to C for OS in CPS ≥1 per prespecified margins. P vs C prolonged OS in CPS ≥10 (median 17.4 vs 10.8mo; HR 0.69; 95% CI 0.49-0.97) but wasn't tested per analysis plan. P+C vs C was not superior for OS in CPS ≥1 or CPS ≥10, with a favorable trend for P+C. In an exploratory analysis of pts with MSI-H tumors with CPS ≥1 (N=50), median OS was not reached vs 8.5mo for both P vs C (HR 0.29; 95% CI 0.11-0.81) and P+C vs C (HR 0.37; 95% CI 0.14-0.97). PFS was longer with P vs C (HR 0.72; 95% CI 0.31-1.68) and P+C vs C (HR 0.45; 95% CI 0.18-1.11). ORR was higher with P (57%) and P + C (65%) vs C (37%). Median DOR was 21.2mo with P, not reached (P + C) vs 7.0mo (C). Grade 3-5 drug-related AE rates were 17% (P), 73% (P+C), and 69% (C). Conclusions As 1L therapy for advanced GC, P was noninferior to C for OS in CPS ≥1 with clinically meaningful improvement for OS in CPS ≥10. P+C did not show superior OS and PFS in CPS ≥1 and OS in CPS ≥10. Clinical benefit was substantially enhanced in a small subset of pts with MSI-H tumors. The safety profile was more favorable for P vs C.TableLBA44TableCPS ≥1P+CCPCaMedian, mo (95% CI)N=257N=250N=256N=250OSa12.5 (10.8-13.9)/ 11.1 (9.2-12.8)10.6 (7.7-13.8)/11.1 (9.2-12.8)HR (95% CI)/ b99.2% CI0.85 (0.70-1.03)0.91 (0.74-1.10)P=0.0460.91b (0.69-1.18); NI margin=1.2PFSa6.9 (5.7-7.3)/ 6.4 (5.7-7.0)2.0 (1.5-2.8)/6.4 (5.7-7.0)HR (95% CI)0.84 (0.70-1.02); P=0.0391.66 (1.37-2.01)MSI-HN=17/N=19N=14/N=19OSaNot reached (3.6-NR)/8.5 (5.3-20.8)Not reached (10.7-NR)/8.5 (5.3-20.8)ORR, %64.7/36.857.1/36.8PFSaNot reached (3.6-NR)/6.6 (4.4-8.3)11.2 (1.5-NR)/6.6 (4.4-8.3)DOR, median, mo (range)NR (1.6+ to 34.5+)/7.0 (2.0-30.4+)21.2 (1.4+ to 33.6+)/7.0 (2.0-30.4+) Clinical trial identification NCT02494583. Editorial acknowledgement Medical writing assistance was provided by Luana Atherly-Henderson, an employee of Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc, Kenilworth, NJ, USA. Legal entity responsible for the study Merck & Co., Inc. Funding Merck & Co., Inc. Disclosure K. Shitara: Honoraria (institution): Novartis; Honoraria (institution): AbbVie; Honoraria (institution): Yakult; Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical ; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Chugai Pharma. E. Van Cutsem: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Roche; Advisory / Consultancy: Servier; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Merck. Y. Bang: Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck Serano; Research grant / Funding (institution): Boehringer-Ingelheim; Advisory / Consultancy: Samyang Biopharma . C.S. Fuchs: Leadership role: CytomX Therapeutics; Advisory / Consultancy: Genentech; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Unum Therapeutics; Advisory / Consultancy: Merck; Advisory / Consultancy: Taiho. L. Wyrwicz: Honoraria (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Halozyme; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Servier; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): BMS; Licensing / Royalties: Cervico. K.W. Lee: Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Green Cross Corp.; Research grant / Funding (institution): ASLAN Pharmaceuticals; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution): Pfizer. M. Garrido: Advisory / Consultancy: MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Roche. H. Cheol Chung: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck-Serono; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (institution): Foundation medicine; Advisory / Consultancy: Taiho; Advisory / Consultancy: Celltrione; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Quintiles; Advisory / Consultancy: BMS; Research grant / Funding (institution): GSK; Research grant / Funding (institution): BMS-Ono; Research grant / Funding (institution): Taiho. H.R. Castro: Research grant / Funding (institution): Merck. W. Mansoor: Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Speaker Bureau / Expert testimony: BMS. M.I.F.M. Braghiroli: Honoraria (institution), Research grant / Funding (institution): Roche; Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Merck; Research grant / Funding (institution): AstraZeneca. E. Goekkurt: Advisory / Consultancy: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD. J. Chao: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Lilly; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy: FivePrime Therapeutics; Research grant / Funding (institution): Novonco Therapeutics. Z.A. Wainberg: Advisory / Consultancy: Aduro Bio; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): Five Prime Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Merck KGaA; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Sirtex Medical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Plexxikon. U. Kher: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. S. Shah: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. S..P. Kang: Shareholder / Stockholder / Stock options, Full / Part-time employment, Non-remunerated activity/ies, Patent: Merck & Co., Inc.. J. Tabernero: Advisory / Consultancy: Array Bio; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BeiGene; Advisory / Consultancy: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Summary Morbidity and mortality data of RCC (renal cell carcinoma) differs a lot among the European countries. In Latvia a growing trend in both incidence and mortality rates is still observed. The expanding availability of multiple treatment strategies has increased the importance of skilled individualized outcome prediction for patients. Several prognostic factors are available in RCC including anatomical, histological, clinical and molecular ones, but none of them is very precise, when used alone. Therefore increasing number of prognostic systems has been created in local and metastatic disease to increase predictive accuracy. In order to encourage the clinicians to use the available models in their routine practice, we tried to select the most relevant ones and include them in a simple algorithm to be used in common clinical scenarios throughout entire history of the disease in patients with RCC

Summary The existence of tumorigenic (stem) cells has been first described in acute myeloid leukemia (AML), and afterwards in some solid tumors. Recently, they were identified also in breast cancer showing high levels of CD44 surface marker and low level or lacking of CD24. Latest development revealed also significance of presence of ALDH1+ in this certain subpopulation of cells. These cells – CD44+/CD24- with ALDH1 have additional capability to induce tumors in NOD/SCID mice, have been extensively investigated in human tumors, and are claimed by some investigators to be responsible for cancer growth, relapse, resistance to chemotherapy, endocrine and radiation treatment, as well as widespread metastasis in breast cancer patients. However, the hope to solve the problem of breast cancer treatment focusing all attention to breast cancer stem cells (BCSC) has not yet been entirely successful and rather speculative. Investigations in animal models and human breast cancer cells grown as single cell suspensions or mammospheres in vitro have enlighted some of the latter problems, but the results until now are scarce and contradictory. In our review we have focused only on problems of vital interest for clinical practice, trying to elucidate the significance of breast cancer stem cells (or broadly speaking tumorigenic breast cancer cells) for prognostic and predictive significance in breast cancer treatment and prognosis. As a rule, BCSC are immunohistochemically detectable, having CD44+/CD24-/ low or ALDH1+ as a surface markers, they as a rule present a subpopulation of cells with intrinsic resistance to chemotherapy, some of them (CD44+/CD24 -/ low ) to radiotherapy; as to endocrine treatment, no satisfactory data are available until now. The BCSC problem remains unsolved, in vitro, in vivo or using them as indicators for treatment strategy. More data are to be needed for definite answers to many questions put forward by investigators and clinicians.