July 2019

Differential expressions of PD-1, PD-L1 and PD-L2 between primary and metastatic sites in renal cell carcinoma

Zhang X, Yin X, Zhang H, et al.
BMC Cancer April 2019
DOI: 10.1186/s12885-019-5578-4

Abstract

BACKGROUND:

In clinical practice, the detection of biomarkers is mostly based on primary tumors for its convenience in acquisition. However, immune checkpoints may express differently between primary and metastatic tumor. Therefore, we aimed to compare the differential expressions of PD-1, PD-L1 and PD-L2 between the primary and metastatic sites of renal cell carcinoma (RCC).

METHODS:

Patients diagnosed with RCC by resection or fine needle aspiration of metastasis were included. Immunohistochemistry (IHC) was applied to detect PD-1, PD-L1 and PD-L2 expressions. SPSS 22.0 was applied to conduct Chi-square, consistency tests and Cox’s proportional hazards regression models. GraphPad Prism 6 was used to plot survival curves and R software was used to calculate Predictive accuracy (PA).

RESULTS:

In the whole cohort (N = 163), IHC results suggested a higher detection rate of PD-L1 in the metastasis than that of the primary site (χ2 = 4.66, p = 0.03), with a low consistent rate of 32.5%. Among different metastatic tumors, PD-1 was highly expressed in the lung/lymph node (65.3%) and poorly expressed in the brain (10.5%) and visceral metastases (12.5%). PD-L1 was highly expressed in lung/lymph node (37.5%) and the bone metastases (12.2%) on the contrary. In terms of survival analysis, patients with PD-1 expression either in the primary or metastasis had a shorter overall survival (OS) (HR: 1.59, 95% CI 1.08–2.36, p = 0.02). Also, PD-L1 expression in the primary was associated with a shorter OS (HR 2.55, 95% CI 1.06–6.15, p = 0.04). In the multivariate analysis, the predictive accuracy of the whole model for PFS was increased from 0.683 to 0.699 after adding PD-1.

CONCLUSION:

PD-1, PD-L1 and PD-L2 were differentially expressed between primary and metastatic tumors. Histopathological examination of these immune check points in metastatic lesions of mRCC should be noticed, and its accurate diagnosis may be one of the effective ways to realize the individualized treatment.

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“At-risk” kidney: How surgical factors influence renal functional preservation after partial nephrectomy

Dagenais J, Bertolo R, Garisto J, et al.
Urology May 2019
DOI: 10.1111/iju.13930

Abstract

OBJECTIVE:

To investigate the influence of surgical modifiable factors on chronic kidney disease upstaging in a contemporary cohort of patients with normal and “at-risk” kidneys undergoing partial nephrectomy.

METHODS:

We reviewed 778 consecutive patients with (n = 634)/without (n = 144) chronic kidney disease or risk factors for chronic kidney disease in our institutional partial nephrectomy database. Chronic kidney disease upstaging was assessed using glomerular filtration rate measurements preoperatively and at 3–12 months postoperatively. Using a multivariate logistic regression, baseline clinicodemographic factors, and the operative measurements of excisional volume loss and warm and cold ischemia time on rates of chronic kidney disease upstaging were determined. Marginal effects were used to analyze the impact of ischemia time and generate interaction curves.

RESULTS:

Chronic kidney disease/risk factors for chronic kidney disease had equivalent rates of chronic kidney disease upstaging as the healthy kidney cohort (31.5% vs 38.2%, P = 0.15). Of the entire cohort, 2.8% were upstaged to stage IV–V chronic kidney disease. Multivariate analysis found a significant association between chronic kidney disease upstaging and excisional volume loss in both cohorts (no chronic kidney disease/risk factors for chronic kidney disease: odds ratio 1.63, P = 0.04; chronic kidney disease/risk factors for chronic kidney disease: odds ratio 1.42, P = 0.001). Only in the chronic kidney disease/risk factors for chronic kidney disease cohort, there was an association between ischemia type/duration and chronic kidney disease upstaging (odds ratio 1.04, P = 0.04). Warm ischemia began to predict an increased risk of chronic kidney disease upstaging at 17.6 min, which became statistically significant at 49 min.

CONCLUSION:

Chronic kidney disease upstaging is common after partial nephrectomy. Although volume loss unequivocally affects rates of upstaging irrespective of baseline renal function, warm ischemia time disproportionately influences “at-risk” kidneys. Therefore, strong consideration should be given to minimizing volume loss and using cold ischemia when extended clamp times are anticipated in “at-risk” kidneys.

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The Current State of Adjuvant Therapy Following Surgery for High-risk Renal Cell Carcinoma

Ridyard D, Buller D, Ristau B, et al.
European Urology Focus April 2019
10.1016/j.euf.2019.03.020

Abstract

Cancer recurs in up to 40% of patients following surgery for high-risk, locoregional renal cell carcinoma (RCC). To date, little progress has been made in identifying systemic adjuvant treatment options to reduce the mortality risk after surgery for high-risk RCC. Several randomized trials exploring the efficacy of adjuvant targeted therapies in the postoperative setting have recently reported results. We examine these trials to assess the contemporary role of targeted therapy following surgery in high-risk RCC and briefly consider trials that are currently accruing with a focus on immunotherapy agents in the adjuvant setting.

Patient summary

Kidney cancer often recurs despite initial surgery in patients with high-risk tumors. So far, adding systemic treatments such as targeted therapies after surgery has not resulted in improved survival outcomes. Future studies that include immunotherapy after surgery to reduce the risk of recurrence in patients with high-risk disease are eagerly anticipated.

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Systemic therapy in the management of localized and locally advanced renal cell carcinoma: Current state and future perspectives

Berquist S, Yim K, Ryan S, et al.
IJU May 2019
DOI: 10.1111/iju.13943

Abstract

Systemic therapy strategies in the setting of localized and locally advanced renal cell carcinoma have continued to evolve in two directions: (i) as adjuvant therapy (to reduce the risk of recurrence or progression in high-risk localized groups); or (ii) as neoadjuvant therapy as a strategy to render primary renal tumors amenable to planned surgical resection in settings where radical resection or nephron-sparing surgery was not thought to be safe or feasible. In the realm of adjuvant therapy, the results of adjuvant therapy phase III randomized clinical trials have been mixed and contradictory; nevertheless, the findings of the landmark Sunitinib Treatment of Renal Adjuvant Cancer study have led to approval of sunitinib as an adjuvant agent in the USA. In the realm of neoadjuvant therapy, presurgical tumor reduction has been shown in a number of phase II studies utilizing targeted molecular agents and in a recently published small randomized double-blind placebo-controlled study, and an expanding body of literature suggests benefit in select patients. Thus, large randomized clinical trial data are not present to support this approach, and guidelines for use of presurgical therapy have not been promulgated. The advent of immunomodulation through checkpoint inhibition represents an exciting horizon for adjuvant and neoadjuvant strategies. The present article reviews the current status and future prospects of adjuvant and neoadjuvant therapy in localized and locally advanced renal cell carcinoma.

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Novel Therapeutic Approaches and Targets Currently Under Evaluation for Renal Cell Carcinoma: Waiting for the Revolution

Mollica V, Di Nunno V, Gatto L, et al.
Clin Drug Investig, April 2019
DOI: 10.1007/s40261-019-00773-w

Abstract

Management of metastatic renal cell carcinoma has drastically changed in the last few years, witnessing the advent of more and more target therapies and, recently, of immune-checkpoint inhibitors. On the other hand, the adjuvant setting still lacks a clear beneficial treatment. Medical treatment still remains a compelling challenge. A large number of clinical trials is ongoing with the aim to identify new therapeutic approaches to expand the options in our repertoire. Several strategies are under investigation in renal cell carcinoma (RCC). These include new targeted agents and combinations of target therapy and immunotherapy. Programmed death receptor-1 (PD-1), programmed death receptor ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) are just part of the intricate network that regulates our immune response to cancer cells. Co-stimulators, such as glucocorticoid-induced TNFR-related protein (GITR) and tumor necrosis factor receptor superfamily, member 4 (OX40), and co-repressors, example.g. T cell immunoglobulin and mucin domain 3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3), also take part. As knowledge of the functioning of the immune system grows, so do these pathways to target with new drugs. This review is an overview of the current state of the clinical research, providing a report of ongoing Phase I, II and III clinical trials for localized and metastatic RCC, including novel target therapies, novel immunotherapy agents and new combinations strategies.

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Predictive value of single-nucleotide polymorphism signature for recurrence in localised renal cell carcinoma: a retrospective analysis and multicentre validation study

Wei J, Feng Z, Cao Y, et al.
Lancet Oncol. April 2019
DOI: 10.1016/S1470-2045(18)30932-X

Summary

BACKGROUND:

Identification of high-risk localised renal cell carcinoma is key for the selection of patients for adjuvant treatment who are at truly higher risk of reccurrence. We developed a classifier based on single-nucleotide polymorphisms (SNPs) to improve the predictive accuracy for renal cell carcinoma recurrence and investigated whether intratumour heterogeneity affected the precision of the classifier.

METHODS:

In this retrospective analysis and multicentre validation study, we used paraffin-embedded specimens from the training set of 227 patients from Sun Yat-sen University (Guangzhou, Guangdong, China) with localised clear cell renal cell carcinoma to examine 44 potential recurrence-associated SNPs, which were identified by exploratory bioinformatics analyses of a genome-wide association study from The Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) dataset (n=114, 906 600 SNPs). We developed a six-SNP-based classifier by use of LASSO Cox regression, based on the association between SNP status and patients’ recurrence-free survival. Intratumour heterogeneity was investigated from two other regions within the same tumours in the training set. The six-SNP-based classifier was validated in the internal testing set (n=226), the independent validation set (Chinese multicentre study; 428 patients treated between Jan 1, 2004 and Dec 31, 2012, at three hospitals in China), and TCGA set (441 retrospectively identified patients who underwent resection between 1998 and 2010 for localised clear cell renal cell carcinoma in the USA). The main outcome was recurrence-free survival; the secondary outcome was overall survival.

FINDINGS:

Although intratumour heterogeneity was found in 48 (23%) of 206 cases in the internal testing set with complete SNP information, the predictive accuracy of the six-SNP-based classifier was similar in the three different regions of the training set (areas under the curve [AUC] at 5 years: 0,749 [95% CI 0,660–0,826] in region 1, 0,734 [0,651–0,814] in region 2, and 0,736 [0,649–0,824] in region 3). The six-SNP-based classifier precisely predicted recurrence-free survival of patients in three validation sets (hazard ratio [HR] 5,32 [95% CI 2,81–10,07] in the internal testing set, 5,39 [3,38–8,59] in the independent validation set, and 4,62 [2,48–8,61] in the TCGA set; all p<0·0001), independently of patient age or sex and tumour stage, grade, or necrosis. The classifier and the clinicopathological risk factors (tumour stage, grade, and necrosis) were combined to construct a nomogram, which had a predictive accuracy significantly higher than that of each variable alone (AUC at 5 years 0,811 [95% CI 0,756–0,861]).

INTERPRETATION:

Our six-SNP-based classifier could be a practical and reliable predictor that can complement the existing staging system for prediction of localised renal cell carcinoma recurrence after surgery, which might enable physicians to make more informed treatment decisions about adjuvant therapy. Intratumour heterogeneity does not seem to hamper the accuracy of the six-SNP-based classifier as a reliable predictor of recurrence. The classifier has the potential to guide treatment decisions for patients at differing risks of recurrence.

FUNDING:

National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Provincial Science and Technology Foundation of China, and Guangzhou Science and Technology Foundation of China.

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