While fibroblast growth factor receptor 3 (FGFR3) is frequently mutated or overexpressed in nonmuscle‐invasive urothelial carcinoma (UC), the prevalence of FGFR3 protein expression and mutation ...remains unknown in muscle‐invasive disease. FGFR3 protein and mRNA expression, mutational status, and copy number variation were retrospectively analyzed in 231 patients with formalin‐fixed paraffin‐embedded primary UCs, 33 metastases, and 14 paired primary and metastatic tumors using the following methods: immunohistochemistry, NanoString nCounterTM, OncoMap or Affymetrix OncoScanTM array, and Gain and Loss of Analysis of DNA and Genomic Identification of Significant Targets in Cancer software. FGFR3 immunohistochemistry staining was present in 29% of primary UCs and 49% of metastases and did not impact overall survival (P = 0.89, primary tumors; P = 0.78, metastases). FGFR3 mutations were observed in 2% of primary tumors and 9% of metastases. Mutant tumors expressed higher levels of FGFR3 mRNA than wild‐type tumors (P < 0.001). FGFR3 copy number gain and loss were rare events in primary and metastatic tumors (0.8% each; 3.0% and 12.3%, respectively). FGFR3 immunohistochemistry staining is present in one third of primary muscle‐invasive UCs and half of metastases, while FGFR3 mutations and copy number changes are relatively uncommon.
Fibroblast growth factor receptor 3 (FGFR3) is frequently mutated or overexpressed in nonmuscle‐invasive urothelial carcinoma (UC) where mutations are generally associated with lower rates of progression to invasive disease. In this report, we demonstrate that FGFR3 staining is present in nearly one third of muscle‐invasive UC and half of metastases (albeit at low levels), but IHC detection of FGFR3 does not appear to impact overall survival. While the FGFR3 mutation rate is less than 10% in our population, mutant tumors had an increase in FGFR3 mRNA and a trend toward increased protein expression, similar to nonmuscle‐invasive disease.
Background:
Erdafitinib is the first targeted therapy approved for the treatment of patients with metastatic urothelial carcinoma (mUC). Approval was based on a phase II single-arm trial that ...demonstrated significant activity of erdafitinib in patients with tumors harboring FGFR2/3 alterations. In Brazil, an Expanded Access Program (EAP) provided patients with early access to erdafitinib prior to market authorization. The current report describes characteristics and outcomes of patients with mUC on erdafitinib therapy.
Methods:
Patients with mUC that failed first- and second-line systemic therapies were screened for FGFR2/3 alterations in primary or metastatic tumor tissues. Patients with FGFR2/3 alterations were selected to receive erdafitinib at the standard dosing schedule and were followed prospectively to evaluate the efficacy and safety outcomes.
Results:
From 19 April 2019, through 13 March 2020, 47 patients with mUC from 10 Brazilian centers were tested for FGFR2/3 alterations. Alterations in FGFR2/3 were found in 12 patients (25.5%) and all of them were eligible for the EAP. Four patients (33%) had partial response, while two patients (17%) had stable disease. Progressive disease, the best response, was observed in five patients (42%). At a median follow-up of 16.2 months, the median time to treatment failure (TTF) was 2.8 months. When considering only patients with objective response, the median TTF was 5.3 months. Adverse events (AEs) were reported for any grade and grade 3 or higher in 10 patients (83%) and 5 patients (42%), respectively. The most common AE was hyperphosphatemia.
Conclusion:
This first real-world evidence report of heavily treated patients with mUC confirms the efficacy and safety of erdafitinib in a disease setting with a lack of treatment options.
•Largest cohort of patients with germ-cell tumors treated in Latin America.•LACOG 0515 showed OS rates comparable to other contemporary series.•No differences in outcomes were observed between public ...and private centers.
Germ-cell tumors (GCTs) are the most common malignancy in young men. There is a paucity of data on GCTs in developing countries. LACOG 0515 study aimed to evaluate clinical characteristics and treatment outcomes in patients with GCTs from Brazilian cancer centers.
This is a retrospective cohort study evaluating male patients diagnosed with GCTs from 2000 to 2018 in 13 Brazilian hospitals. We described baseline characteristics, progression-free survival (PFS), and overall survival (OS).
A total of 1232 patients were included, with a median age of 30 years. Histology was seminoma in 47.1% and non-seminoma GCT (NSGCT) in 52.9%. The primary tumor site was testis in 96.5%. At diagnosis, clinical stage I was present in 68.1% and 34.7% and clinical stages IS/II/III in 31.9% and 65.2% of patients with seminoma and NSCGT, respectively. Following orchiectomy, 55.2% of patients with clinical stage I were managed with surveillance. The 5-year disease-free survival rates among patients with stage I were 98.0% in seminoma and 92.3% in NSGCT, with 5-year OS of 99.6% and 97.6%, respectively. Among patients with advanced disease (IS, II, and III), the 5-year PFS were 88.7% in seminoma and 68.7% in NSGCT, with 5y-OS of 97.6% and 82.8%, respectively.
This is the largest Brazilian cohort of GCTs. Our results show a high rate of adjuvant chemotherapy in patients with clinical stage I. Although our data demonstrate slightly inferior PFS compared with the International Germ Cell Cancer Collaborative Group and other contemporary series, the OS rates were similar.
LACOG0515 is a multicenter database of patients with germ cell tumors treated in Brazil, with 1,232 patients..ßThe results showed a high rate of adjuvant chemotherapy in clinical stage I. For patients with advanced GCT, although our data demonstrate inferior PFS compared with the International Germ Cell Cancer Collaborative Group and other contemporary series, the survival rates were similar.
Vinca alkaloid agents have been widely used in several different types of malignancies. However, cancer cells, ultimately, develop resistance to these agents. Therefore, the development of new agents ...with improved efficacy is warranted. Recently, a new synthetic vinca alkaloid, vinflunine, was developed through the addition of two fluor molecules by superacidic chemistry.
The authors describe the development of the new vinca alkaloid vinflunine from preclinical studies to the late-stage clinical trials, highlighting the most important clinical and safety data of vinflunine. In vitro and in vivo studies have shown a superior efficacy of vinflunine over other vinca alkaloids and with an improved safety profile. Early clinical trials have demonstrated a significant activity of vinflunine against different malignancies. Phase III trials showed that vinflunine increases survival in patients with advanced transitional cell carcinoma of the urothelium (TCCU) tract treated in the second-line and is as effective as docetaxel in second-line NSCLC.
Vinflunine is currently approved in Europe for the treatment of second-line TCCU and is currently being developed in other malignancies. It has been shown to have predictable and manageable adverse effects, such as neutropenia, anemia, constipation and fatigue.
The presence of autoimmune events were recorded in patients receiving immune checkpoint inhibitors.
Retrospective study in patients receiving immune checkpoint inhibitors (ICIs) during the period of ...2012–2019.
A total of 554 patients received ICIs of which 123 developed an immune related adverse event. Twenty one (17%) with toxicity were identified as having a pre-existing autoimmune disease and 88 required treatment with corticosteroids or hormone replacement. Thirty two (26%) out of 123 had to temporarily discontinue ICIs due to autoimmune manifestations. Endocrine and skin manifestations were the most prevalent immune disorders in our cohort. In melanoma better efficacy was seen in patients with immune toxicity.
Autoimmune diseases appear in patients receiving ICIs in this real world experience. Our results differ from other series on the frequency of autoimmunity. Complete discontinuation of ICIs due to autoimmunity was rare.
The development of autoimmune events in patients receiving the modern forms of cancer immunotherapy are not unexpected since the presence of robust immune response against tumors relies on mechanisms of T-cell activation and release of cytotoxic cytokines that can also mediate autoimmune inflammatory conditions. In fact, some studies including ours points to better efficacy against tumor in patients that also develop autoimmune toxicity. Cancer therapy has now five consolidated forms of treatment, Chemotherapy, Radiotherapy, Surgery Biologic Therapy and second generation Immunotherapy.
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma Motzer, Robert J; Escudier, Bernard; McDermott, David F ...
New England journal of medicine/The New England journal of medicine,
11/2015, Letnik:
373, Številka:
19
Journal Article
Recenzirano
Odprti dostop
Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell ...carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.
A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety.
The median overall survival was 25.0 months (95% confidence interval CI, 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 95% CI, 3.68 to 9.72; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).
Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).
Prostate cancer still represents a major cause of morbidity, and still about 20% of men with the disease are diagnosed or will progress to the advanced stage without the possibility of curative ...treatment. Despite the recent advances in scientific and technological knowledge and the availability of new therapies, there is still considerable heterogeneity in the therapeutic approaches for metastatic prostate cancer.
This article presents a summary of the I Brazilian Consensus on Advanced Prostate Cancer, conducted by the Brazilian Society of Urology and Brazilian Society of Clinical Oncology.
Experts were selected by the medical societies involved. Forty issues regarding controversial issues in advanced disease were previously elaborated. The panel met for consensus, with a threshold established for 2/3 of the participants.
The treatment of advanced prostate cancer is complex, due to the existence of a large number of therapies, with different response profiles and toxicities. The panel addressed recommendations on preferred choice of therapies, indicators that would justify their change, and indicated some strategies for better sequencing of treatment in order to maximize the potential for disease control with the available therapeutic arsenal. The lack of consensus on some topics clearly indicates the absence of strong evidence for some decisions.
To present a summary of the treatment and follow-up recommendations for the biochemical recurrence in castration-sensitive prostate cancer (PCa) acquired through a questionnaire administered to 99 ...PCa experts from developing countries during the Prostate Cancer Consensus Conference for Developing Countries.
A total of 27 questions were identified as related to this topic from more than 300 questions. The clinician's responses were tallied and presented in a percentage format. Topics included the use of imaging for staging biochemical recurrence, treatment recommendations for three different clinical scenarios, the field of radiation recommended, and follow-up. Each question had 5-7 relevant response options, including "abstain" and/or "unqualified to answer," and investigated not only recommendations but also if a limitation in resources would change the recommendation.
For most questions, a clear majority (> 50%) of clinicians agreed on a recommended treatment for imaging, treatment scenarios, and follow-up, although only a few topics reached a consensus > 75%. Limited resources did affect several areas of treatment, although in many cases, they reinforced more stringent criteria for treatment such as prostate-specific antigen values > 0.2 ng/mL and STAMPEDE inclusion criteria as a basis for recommending treatment.
A majority of clinicians working in developing countries with limited resources use similar cutoff points and selection criteria to manage patients treated for biochemically recurrent castration-sensitive PCa.
PDF
