Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies ...across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.
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•Evolutionary study of matched primary metastasis biopsies from 100 ccRCC cases•Metastasis competence is afforded by chromosome complexity, but not driver mutation load•The hallmark genomic drivers of ccRCC metastasis are loss of 9p and 14q•Punctuated and branched evolution result in distinct patterns of metastases
A multi-center prospective study and two validation cohorts of matched primary metastasis biopsies from 100 patients with clear-cell renal cell carcinoma provides a comprehensive picture of the genetic underpinnings and the evolutionary patterns of metastasis.
Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies ...across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5′ UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor’s most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.
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•Novel hotspot of driver mutations in 5′-UTR repressor of TERT, expanding telomeres•Most common cause of 3p loss is a chromothripsis event, generating concurrent 5q gain•t(3;5) event occurs in childhood or adolescence, decades before tumor diagnosed•Initial clonal expansion after 3p loss starts from only a few hundred cells
Combination of whole-genome sequencing analysis and a multi-region sampling approach provides insights into the nature and timing of key oncogenic events in clear cell renal cell carcinoma, depicts the evolutionary trajectories of tumors in patients and highlights the opportunity for early intervention.
•Stereotactic ablative body radiotherapy.•Stereotactic ablative radiotherapy.•Renal Cell Carcinoma Oligometastasis.•Renal Cell Carcinoma Oligoprogression.•Patient selection for stereotactic ablative ...radiotherapy.
Stereotactic ablative body radiotherapy (SABR) aims to accurately deliver a higher than conventional dose of radiotherapy to a well-defined target tumour incorporating advanced immobilisation and imaging techniques. SABR is an emerging treatment option for primary kidney cancer especially when surgery is contraindicated. Increasingly, SABR is being incorporated into the management of low-volume stage IV kidney cancers to delay the need for systemic therapy or to prolong the duration of ongoing systemic treatment. This review will evaluate the evidence and limitations of SABR for oligometastatic renal cell carcinoma.
BackgroundImmune-related diarrhoea/colitis (ir-D/C) is a common adverse event of immune checkpoint inhibitor (ICI) therapy. Guidelines recommend corticosteroid (CS) treatment; however, the average ...treatment duration for ir-D/C remains poorly defined.MethodsAll advanced melanoma patients treated with ICI therapy at the Royal Marsden Hospital between 2011 and 2016 were reviewed to identify ir-D/C cases alongside clinical variables.Results117 any-grade ir-D/C episodes occurred in 109 (21%) patients out of a total of 519 patients treated (ipilimumab=77 episodes, anti-PD1=17 (nivolumab or pembrolizumab), ipilimumab and nivolumab=23 (ipi+nivo)) (seven patients had ir-D/C more than once on different lines of treatment) and >/=grade 3 ir-D/C occurred most frequently (63/519 patients (12%) vs 29/519 (5%) grade 1, and 25/519 (5%) grade 2). Median onset (days) of all-grade ir-D/C after starting ICI therapy was 41 for ipilimumab (IQR 24 to 59, n=77), 91 for anti-PD1 (IQR 46 to 355, n=17) and 45 for ipi+nivo (IQR 24 to 67, n=23). In 71/117 (61%) patients, ir-D/C episodes were treated with CS (17% grade 2; 79% grade 3/4): 54 being steroid-responsive; 17 being steroid-refractory and received additional anti-tumor necrosis factor (TNF) treatment. Median grade 3 ir-D/C CS duration was similar across treatments, averaging 58 days. Median overall CS duration (days) was longer in the grade 3/4 D/C steroid-refractory group (94 vs 45 days). Infection developed in 11/71 (15%) CS recipients and in 6/17 (35%) anti-TNF recipients. In 65/117 (55%) patients, ir-D/C episodes were investigated with flexible sigmoidoscopy. Of these patients, 38/65 (58%) had macroscopic colitis and 12/65 (18%) had microscopic colitis. The steroid-refractory group had more macroscopic changes, 13/17 (76%), than the steroid-responsive group, 22/41 (54%).ConclusionRates of grade 3 ir-D/C were higher than reported in clinical trials. The 58-day median duration of CS therapy for grade 3 ir-D/C places a significant number of patients at risk of complications. We demonstrate that microscopic colitis is an important subgroup, advocating biopsies in ir-D/C even with macroscopically normal bowel.
Combined LAG-3 and PD-1 blockade is an emerging strategy for the treatment of melanoma. Tawbi et al. and Amaria et al. report in The New England Journal of Medicine and Nature respectively on two ...clinical trials evaluating relatlimab and nivolumab as front-line treatment for metastatic, and resectable, high-risk, node-positive melanoma.
Combined LAG-3 and PD-1 blockade is an emerging strategy for the treatment of melanoma. Tawbi et al. and Amaria et al. report in The New England Journal of Medicine and Nature respectively on two clinical trials evaluating relatlimab and nivolumab as front-line treatment for metastatic, and resectable, high-risk, node-positive melanoma.
The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the ...multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.
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•ccRCC evolutionary subtypes correlate with clinical phenotypes•Genetic diversity and chromosome complexity contribute to patient outcomes•Early fixation of multiple driver events leads to rapid growth and metastases•Subclonal diversification is linked with slower growth and attenuated metastases
A multi-center prospective study on 101 patients with clear-cell renal cell carcinoma resolves the evolutionary features and subtypes underpinning the diverse clinical phenotypes of the disease and suggests these features as potential biomarkers for guiding intervention and surveillance.
Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes
. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation ...necessary for tumour evolution
. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2
breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.
Evolution of Renal Cell Carcinoma Tippu, Zayd; Au, Lewis; Turajlic, Samra
European urology focus,
January 2021, 2021-01-00, 20210101, Letnik:
7, Številka:
1
Journal Article
Recenzirano
A diverse range of clinical phenotypes are observed in clear-cell renal cell carcinoma (ccRCC) with resultant therapeutic implications. Molecular characterisation underpinning the diversity observed ...has been qualified, where the near ubiquitous loss of the short arm of chromosome 3 precedes distinct evolutionary trajectories involving different sequences and combinations of genetic events. Primary tumours are characterised by varying degrees of intratumoural heterogeneity and chromosomal complexity associated with distinct metastatic phenotypes. An evolutionary understanding reconciles the diverse clinical phenotypes observed in metastatic ccRCC and has the potential to impact patient management.
Re-tracing the evolutionary paths taken by clear-cell kidney cancer through analyses at the gene level gives an insight into genetic changes that are correlated to metastatic potential. This may provide a framework to guide therapeutic interventions, especially in identifying candidates for surgical intervention.
Molecular characterisation has qualified the diversity of metastatic phenotypes seen in clear-cell renal cell carcinoma. Evolutionary subtypes have been characterised by variations in chromosomal complexity and intratumoral heterogeneity affording differing metastatic competencies. This may provide a framework to guide therapeutic interventions, most pertinently by identifying patients appropriate for surgical intervention.
Melanoma therapies have evolved rapidly, and initial successes have translated into survival gains for patients with advanced melanoma. Both targeted and immune-therapy now have evidence in earlier ...stage disease. There are many new agents and combinations of treatments in development as potential future treatment options. This highlights the need for a reflection on current treatment practice trends that are guiding the development of potential new therapies.
In this review, the authors discuss the evidence for currently approved therapies for cutaneous melanoma, including adjuvant therapy, potential new biomarkers, and emerging treatments with early phase clinical trial data. The authors have searched both the PubMed and clinicaltrials.gov databases for published clinical trials and discuss selected landmark trials of current therapies and of investigational treatment strategies with early evidence for the treatment of melanoma.
Significant efficacy has been demonstrated with both immune checkpoint inhibitors and targeted therapies in treating advanced melanoma. A multitude of novel therapies are in development and there is need for instructive biomarker assessment to identify patients likely to respond or be refractory to current therapies, to identify mechanisms of resistance and to direct further treatment options to patients based on individual disease biology.
The SARS-CoV-2 pandemic has posed a significant challenge for risk evaluation and mitigation among cancer patients. Susceptibility to and severity of COVID-19 in cancer patients has not been studied ...in a prospective and broadly applicable manner. CAPTURE is a pan-cancer, longitudinal immune profiling study designed to address this knowledge gap.
The SARS-CoV-2 pandemic has posed a significant challenge for risk evaluation and mitigation among cancer patients. Susceptibility to and severity of COVID-19 in cancer patients has not been studied in a prospective and broadly applicable manner. CAPTURE is a pan-cancer, longitudinal immune profiling study designed to address this knowledge gap.
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