Cytotoxic chemotherapy has been the only systemic treatment of locally advanced and metastatic urothelial carcinoma for decades. Long-term survival remains stagnant around 12-14 months for patients ...with advanced disease who have progressed on or recurred after receiving first-line platinum-based chemotherapy. Improving clinical outcomes for patients with urothelial carcinoma in all disease settings requires the development of novel treatments, especially for patients who failed on first-line chemotherapy. Since the discovery of intravesical Bacillus-Calmette Guerin (BCG) in the 1970s for non-muscle invasive disease, there have not been any major breakthrough drugs that exploit the immune-sensitivity of bladder cancer until recently. Immune-checkpoint inhibitors targeting the programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways have shown significant anti-tumor activity, tolerable safety profiles and durable, long-term responses in clinical trials. Atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab are promising PD-1/PD-L1 blockade drugs under investigation that will redefine the standard of care for bladder cancer. CTLA-4 inhibitors are also under investigation in this setting. Atezolizumab, approved in May 2016, and nivolumab, approved in February 2017, are the first Food and Drug Administration (FDA)-approved immune-checkpoint inhibitors in bladder cancer for platinum-pretreated patients based on phase II data. On March 16, 2017, results from the phase III trial KEYNOTE-045 demonstrated that survival was significantly longer in patients treated with pembrolizumab when compared with the standard second-line chemotherapy. Research into biomarkers such as PD-L1 expression, messenger RNA subtype, mutational and neoantigen load and gene signature expression will be crucial to determining why some patients respond to immunotherapy and others do not. This review article describes the advances in immunotherapy since the development of BCG, presents results from clinical trials investigating immune-checkpoint inhibitors and discusses biomarkers and prognostic factors associated with response to these new drugs.
The purpose of this study is to characterize the mutational landscape across the spectrum of urothelial carcinoma (UC) to identify mutational features and potential therapeutic targets.
Using ...targeted exome sequencing (
= 237 genes), we analyzed the mutation spectra of 82 low-grade nonmuscle-invasive bladder cancers (LG-NMIBC), 126 high-grade (HG) NMIBC, 199 muscle-invasive bladder cancers (MIBC), 10 LG-upper tract urothelial cancers (LG-UTUC), and 55 HG-UTUC.
and
mutations were significantly more common in LG-NMIBC (72% and 44%, respectively) versus other bladder subtypes.
alterations were also enriched in LG-UTUC versus HG-UTUC tumors (80% vs. 16%). In contrast,
and
mutations were significantly more frequent in all 3 HG urothelial carcinoma subtypes than in LG-NIMBC (45%-58% vs. 4%; 9%-22% vs. 0; respectively). Among LG-NMIBC tumors,
mutations were more common in women than in men (71% vs. 38%). HG-NMIBC and MIBC had higher tumor mutational burden (TMB) than LG-NMIBC (
= 0.001 and
< 0.01, respectively). DNA-damage repair (DDR) alterations were associated with a higher TMB in HG-NMIBC and MIBC tumors, and these two tumor types were also enriched for an APOBEC mutational signature compared with LG-NMIBC and HG-UTUC. Alterations in
, and
correlated with worse overall survival in HG-UTUC and occurred concurrently.
Our analysis suggests that a fraction of MIBCs likely arise from precursor lesions other than LG-NMIBC.
mutations are twice as common in women with LG-NIMBC than those in men. DDR gene mutations and APOBEC mutagenesis drive mutations in HG-NMIBC and MIBC. UTUC has a distinct mutation profile from bladder cancer.
Pembrolizumab is a humanized monoclonal antibody that targets PD-1. In the Phase III trial KEYNOTE-045, pembrolizumab was associated with a significant overall survival benefit when compared with ...docetaxel, paclitaxel and vinflunine in second line metastatic urothelial carcinoma (UC). Additionally, in the first line, early results from an interim analysis of the Phase II trial Keynote-052 study indicated that pembrolizumab is efficacious for cisplatin-ineligible patients. Based on data from these trials, pembrolizumab was the most recent among the five checkpoint inhibitors tested in UC to be approved by the US FDA in May 2017. It was granted regular approval for patients with advanced-stage UC who progress after receiving platinum-based chemotherapy and accelerated approval in the first line for patients who are ineligible to receive cisplatin.
Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated the efficacy and safety of ...combination treatment with everolimus and pazopanib (E/P) in genomically profiled patients with mUC.
mUC patients enrolled on a Phase I dose escalation study and an expansion cohort treated with E/P were included. The primary end point was objective response rate (ORR); secondary end points were safety, duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Patients were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes using next-generation sequencing and findings were correlated with outcomes. Time-to-event data were estimated with Kaplan-Meier methods.
Of the 23 patients enrolled overall, 19 had mUC. ORR was 21% (one complete response (CR), three partial responses (PR), eight with stable disease (SD). DOR, PFS and OS were 6.5, 3.6, and 9.1 months, respectively. Four patients with clinical benefit (one CR, two PR, one SD) had mutations in TSC1/TSC2 or mTOR and a 5th patient with PR had a FGFR3-TACC3 fusion.
Combination therapy with E/P is safe in mUC and select patients with alterations in mTOR or FGFR pathways derive significant clinical benefit.
Metastatic UTUC is an aggressive disease. 45 patients with distant metastasis were analysed at the time of initiating chemotherapy in a risk score that includes anemia and receipt of cisplatin ...helping stratify overall survival patients for future clinical trials.
Upper tract urothelial carcinomas (UTUCs) are increasingly recognized as separate malignancies. Additional insight into clinical outcomes and key prognostic factors are needed.
To detail outcomes of patients with UTUCs recurring after radical nephroureterectomy (RNU) and to determine a risk score that predicts outcomes of patients with non–lymph node distant metastasis.
Chart review of all patients who had an extraurothelial recurrence after RNU for UTUC at Dana-Farber Cancer Institute between 2009 and 2014.
Median overall survival defined as time from chemotherapy for distant relapse to death. Prognostic relevance of performance status, hemoglobin, and receipt of cisplatin were assessed by Cox regression model.
A total of 102 patients were identified, 57 of whom had non–lymph node distant metastases at relapse; 45 received chemotherapy. Median follow-up was 29.8 months; median overall survival was 14.7 months. Objective response rate to any chemotherapy in the first-line setting was only 22%. Hemoglobin > 11 g/dL and receipt of cisplatin was associated with numerically longer median survival but did not reach statistical significance in univariate and multivariate analysis. Prognostic risk score scale including hemoglobin < 11 g/dL and receipt of cisplatin was inversely associated with survival, with scores of 0, 1, and 2 leading to median survival of 19.0, 14.9, and 7.2 months (P = .38), respectively.
Advanced UTUC portends a poor prognosis, and most patients cannot receive cisplatin-based chemotherapy. A risk score that includes anemia and receipt of cisplatin helps stratify patients with distant metastasis for inclusion into eventual clinical trials. More studies are needed to validate these findings.
Metastatic UTUC is an aggressive disease, where anemia and ineligibility to receive cisplatin are adverse features associated with shorter survival.
Zwitterionic platinum group metal complexes that feature formal charge separation between a cationic metal fragment and a negatively charged ancillary ligand combine the desirable reactivity profile ...of related cationic complexes with the broad solubility and solvent tolerance of neutral species. As such, zwitterionic complexes of this type have emerged as attractive candidates for a diversity of applications, most notably involving the breaking and/or forming of E---H and E---C σ bonds involving a main group element E. Important advances in ancillary ligand design are documented that have enabled the construction of platinum group metal zwitterions. Also summarized are the results of stoichiometric and catalytic investigations in which the reactivity of such zwitterions and their more traditionally employed cationic relatives in σ bond activation chemistry are compared and contrasted.
Arranging organisms into functional groups aids ecological research by grouping organisms (irrespective of phylogenetic origin) that interact with environmental factors in similar ways. Planktonic ...protists traditionally have been split between photoautotrophic “phytoplankton” and phagotrophic “microzooplankton”. However, there is a growing recognition of the importance of mixotrophy in euphotic aquatic systems, where many protists often combine photoautotrophic and phagotrophic modes of nutrition. Such organisms do not align with the traditional dichotomy of phytoplankton and microzooplankton. To reflect this understanding, we propose a new functional grouping of planktonic protists in an eco-physiological context: (i) phagoheterotrophs lacking phototrophic capacity, (ii) photoautotrophs lacking phagotrophic capacity, (iii) constitutive mixotrophs (CMs) as phagotrophs with an inherent capacity for phototrophy, and (iv) non-constitutive mixotrophs (NCMs) that acquire their phototrophic capacity by ingesting specific (SNCM) or general non-specific (GNCM) prey. For the first time, we incorporate these functional groups within a foodweb structure and show, using model outputs, that there is scope for significant changes in trophic dynamics depending on the protist functional type description. Accordingly, to better reflect the role of mixotrophy, we recommend that as important tools for explanatory and predictive research, aquatic food-web and biogeochemical models need to redefine the protist groups within their frameworks.
To investigate the complete clinical spectrum of individuals with paediatric tuberous sclerosis complex in southern Sweden and explore changes over time.
In this retrospective observational study, 52 ...individuals aged up to 18 years at the study start were followed-up at regional hospitals and centres for habilitation from 2000 to 2020.
Cardiac rhabdomyoma was detected prenatally/neonatally in 69.2% of the subjects born during the latest ten years of the study period. Epilepsy was diagnosed in 82.7% of subjects, and 10 (19%) were treated with everolimus, mainly (80%) for a neurological indication. Renal cysts were detected in 53%, angiomyolipomas in 47%, astrocytic hamartomas in 28% of the individuals. There was a paucity of standardized follow-up of cardiac, renal, and ophthalmological manifestations and no structured transition to adult care.
Our in-depth analysis shows a clear shift towards an earlier diagnosis of tuberous sclerosis complex in the latter part of the study period, where more than 60% of cases showed evidence of this condition already in utero due to the presence of a cardiac rhabdomyoma. This allows for preventive treatment of epilepsy with vigabatrin and early intervention with everolimus for potential mitigation of other symptoms of tuberous sclerosis complex.
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