Prognostic and predictive factors of immunotherapy in metastatic renal cell carcinoma

Metastatic renal cell carcinoma has a poor prognosis. The value of immunotherapy with IFN-alpha and IL-2 both as single agent or as the combination is extensively investigated. The optimal dose and schedule is not known. In various studies response rates vary between 10 and 40%. The duration of response is variable. For a partial response a median duration between 10 and 12 months is given. Complete responses are sometimes long-lasting (a couple of years). The toxicity is drug, dose and schedule dependent. On the basis of a number of prognostic factors, such as performance score, time between the initial diagnosis and the treatment of metastases and the number of metastatic sites, patients can be divided in different prognostic groups. Patients who are classified in the good or intermediate prognostic group may have an improvement of their survival after immunotherapy and therefore they are candidates for immunotherapy.     

基于TCGA研究细胞坏死相关基因对肝细胞癌患者预后的影响

目的 研究细胞坏死相关基因对肝细胞癌(HCC)患者预后的影响。方法 自癌症基因组图谱TCGA数据库下载HCC患者mRNA水平数据及其对应的临床资料。应用LASSO Cox回归在TCGA文件中构建多坏死相关基因预后模型。结果 在单因素Cox回归分析中,23个细胞坏死相关差异水平基因与预后生存相关(P<0.05);构建一个显著相关的6个细胞坏死相关基因的预后模型,发生高风险组总体生存期显著低于低风险组(P<0.01);多因素Cox回归分析风险评分符合独立的预后因子标准(P<0.O1);对差异水平基因进行富集分析(GO/KEGG)和单样本基因集富集分析(ssGSEA),发现差异基因与免疫通路显著相关(P<0.05)。结论 通过6个细胞坏死相关基因构建的预后模型可以用于预测HCC患者的预后,或许能为HCC患者的临床治疗提供参考。     

Alternative dosing schedules for sunitinib as a treatment of patients with metastatic renal cell carcinoma

Sunitinib malate (Sutent; Pfizer, Inc., New York, NY) is an oral multitargeted tyrosine kinase inhibitor that inhibits VEGF receptors (VEGFR-1, VEGFR-2, and VEGFR-3) among a family of kinase targets and have a central role in first-line treatment of metastatic renal cell carcinoma (mRCC). The approved schedule for sunitinib is 50 mg/day oid in the so called “4 weeks on and two weeks off” (4/2 schedule). Since treatment with sunitinib can be maintained for years, adequate treatment of adverse events (AEs) and care for quality of life is essential. For this reason, several alternative schedules have been proposed in order to personalize sunitinib administration and reduce related toxicity. This review discusses the efficacy and tolerability of alternative regimens to the standard 4/2 schedule that have been investigated in RCC patients including schedule of 50 mg/day 2-weeks on/1-week off, continuous schedule of 37.5 mg daily and the “Stop and Go strategy”.     

Novel treatments for metastatic renal cell carcinoma

The mainstay of any curative treatment in renal cell carcinoma (RCC) is surgery. In case of metastatic disease at presentation a radical nephrectomy is recommended to good performance status patients prior to start of interferon-alfa treatment. Interferon-alpha (IFN-alpha) offers in a small but significant percentage of patients advantage in overall survival; interleukin-2 (IL-2) based therapy gives similar survival rates. To date hormonal and chemotherapy do not have a proven impact on survival. The recent new insights in the molecular biology of clear RCC has revealed a key-role for vascular endothelial growth factor (VEGF) in the stimulation of angiogenesis in this highly vascularized tumour. This opens interesting new treatment strategies including: blockage of VEGF with the monoclonal antibody bevacizumab and inhibition of VEGF receptor tyrosine kinases (with small oral molecules such as SU11248 or PTK787). Likewise, inhibition of the Raf kinase pathway (with oral Bay 43-9006) or inhibition of the mTOR pathway (with i.v. CCI-779) are under investigation. Preliminary clinical results with all these compounds are interesting and the results of ongoing phase III studies will become available in the next years.     

Systemic therapy for metastatic renal cell carcinoma

A better understanding of molecular biological mechanisms involved in the pathogenesis or, respectively, prognosis of renal cell carcinoma has recently led to a fundamental change in those therapeutic options that are especially effective after systemic disemination. In this context, cytokine-based therapeutic concepts have been replaced by the so-called targeted therapeutic agents that include, above all, tyrosine kinase (TK) and mTOR inhibitors. The present contribution is intended to reflect the current state of the art in the systemic therapy for renal cell carcinoma in first- and second-line use. In addition, the increasing relevance of sequential therapy under consideration of possible side effects is discussed.     

Parameters predictive of multicentricity in renal cell carcinoma

Over a 3-year period, 83 radical nephrectomies were performed for renal cell carcinoma. The preoperative radiologic investigations and pathology were reviewed. The incidence of multicentricity of the tumors was correlated with various clinical and pathologic parameters. These included polar location, histologic type, histologic grade (divided into low: Fuhrman grade 1 to 2; and high: Fuhrman grade 3 to 4), size on pathology, pathologic stage, capsular invasion, microscopic vascular invasion, renal vein or inferior vena cava (IVC) involvement, collecting system involvement, lymph node metastases and adrenal gland metastases. The incidence of multicentricity was 9/83 (11%). On univariate analysis, no factors were predictive of multicentricity. On logistic regression analysis, microscopic vascular invasion (p=0.021) and tubulo-papillary histology (p=0.049) were the only significant independent predictors of multicentricity. A model incorporating these parameters missed all multicentric tumors.     

Construction of a prognostic value model in papillary renal cell carcinoma by immune-related genes

Papillary renal cell carcinoma (PRCC) is the second most common type of renal carcinoma following clear cell renal cell carcinoma, and the role of immune-related genes (IRGs) in tumorigenesis and metastasis is evident; its prognostic value in PRCC remains unclear. In this study, we downloaded the gene expression profiles and clinical data of patients with PRCC from The Cancer Genome Atlas (TCGA) database and obtained IRGs from the ImmPort database. A total of 371 differentially expressed IRGs (DEIRGs) were discovered between PRCC and normal kidney tissues. Prognostic DEIRGs (PDEIRGs) were identified by univariate Cox regression analysis. Then, we screened the four most representative PDEIRGs (IL13RA2, CCL19, BIRC5, and INHBE) and used them to construct a risk model to predict the prognosis of patients with PRCC. This model precisely stratified survival outcome and accurately identified mutation burden in PRCC. Thus, our results suggest that these four PDEIRGs are available prognostic predictors for PRCC. They could be used to assess the prognosis and to guide individualized treatments for patients with PRCC.     

Association study identifying polymorphisms in CD47 and other extracellular matrix pathway genes as putative prognostic markers for colorectal cancer

Purpose

We identified recently the extracellular matrix (ECM) receptor interaction pathway as a consistently overrepresented category among gene expression profiling studies on colorectal cancer (CRC) prognosis.

Methods

Putative regulatory single nucleotide polymorphisms (SNPs) in genes from the ECM pathway were genotyped in 613 CRC patients from Northern Germany (PopGen cohort) and tested for association with disease progression and survival.

Results

The eSNP (SNP associated with expression) rs12695175 in CD47 associated with CRC specific survival (HR?=?2.18, 95 % CI 1.10–4.33, CC versus AA) and with overall survival (HR?=?1.99, 95 % CI 1.04–3.81, CC versus AA). This association remained significant after adjustment for age at diagnosis, tumour stage (T) and lymph node status (N). Three polymorphisms in CD47 were associated with distant metastasis in a dominant model: rs9879947 and rs3206652 in the 3′-UTR (OR?=?1.64, 95 % CI 1.01–2.64 and OR?=?1.88, 95 % CI 1.27–2.80, respectively) and the eSNP rs3804639 (OR?=?1.73, 95 % CI 1.17–2.57).

Conclusions

The novel associations of eSNPs in CD47 with worse survival and distant metastasis should be confirmed by additional studies, since increased expression of this gene has recently been shown to be an indicator of poor prognosis in cancer patients.     

Identification and validation of a hypoxia-related prognostic signature in clear cell renal cell carcinoma patients

Increasing evidence has shown that hypoxia is closely related to the development, progression, and prognosis of clear cell renal cell carcinoma (ccRCC). Nevertheless, reliable prognostic signatures based on hypoxia have not been well-established. This study aimed to establish a hypoxia-related prognostic signature and construct an optimized nomogram for patients with ccRCC.We accessed hallmark gene sets of hypoxia, including 200 genes, and an original RNA seq dataset of ccRCC cases with integrated clinical information obtained by mining the Cancer Genome Atlas database and the International Cancer Genome Consortium (ICGC) database. Univariate Cox regression analysis and multivariate Cox proportional hazards regression were performed to identify prognostic hub genes and further established prognostic model as well as visualized the nomogram. External validation of the optimized nomogram was performed in independent cohorts from the ICGC database.ANKZF1, ETS1, PLAUR, SERPINE1, FBP1, and PFKP were selected as prognostic hypoxia-related hub genes, and the prognostic model effectively distinguishes high-risk and low-risk patients with ccRCC. The results of receiver operating characteristic curve, risk plots, survival analysis, and independent analysis suggested that RiskScore was a useful tool and independent predictive factor. A novel prognosis nomogram optimized via RiskScore showed its promising performance in both the Cancer Genome Atlas-ccRCC cohort and an ICGC-ccRCC cohort.Our study reveals that the differential expressions of hypoxia-related genes are associated with the overall survival of patients with ccRCC. The prognostic model we established showed a good predictive and discerning ability in ccRCC patients. The novel nomogram optimized via RiskScore exhibited a promising predictive ability. It may be able to serve as a visualized tool for guiding clinical decisions and selecting effective individualized treatments.     

Pulmonary resection of metastatic renal cell carcinoma

Over a ten-year period, 44 patients with known primary renal cell cancer underwent thoracotomy for pulmonary metastases. The median postthoracotomy survival for all patients was 33 months. The five-year survival was 27 percent. Postthoracotomy survival was significantly better in those patients with a disease free interval of greater than 24 months and patients with metastatic lesions greater than or equal to 3 cm. No difference in survival was detected in patients with one versus more than one lesion or in patients undergoing complete resection versus incomplete resection or biopsy only. Age, sex, grade of tumor, or location of the pulmonary metastasis had no influence on survival.     

Active surveillance for metastatic or recurrent renal cell carcinoma

Purpose

Metastatic renal cell carcinoma (mRCC) sometimes presents with an indolent course without any significant symptoms. Here, the potential impact of active surveillance (AS) on clinical outcomes in asymptomatic or minimally symptomatic mRCC patients was retrospectively evaluated.

Methods

mRCC patients who were followed up with deferred treatment for the purpose of AS between 2000 and 2012 were enrolled. Patient and disease characteristics, outcomes of AS and subsequent therapies, and predictive factors for rapid disease progression were analyzed. The primary endpoint was time-to-progression (TTP).

Results

First-line systemic therapy was deliberately deferred in 58 patients. During AS, the best overall responses were stable disease for 48 patients (83 %) and progressive disease (PD) for 10 patients (17 %), and 47 patients ultimately experienced disease progression at the time of data cutoff. With a median follow-up of 31.4 months, the median TTP was 12.4 months (95 % confidence interval 8.4–16.5) and median overall survival was not reached. After univariate and multivariate analyses for TTP, Karnofsky performance status <100 %, liver metastasis, and a time from diagnosis to AS of less than 1 year were found to be predictive factors for a shorter TTP. After PD, 30 patients received systemic treatment (14 sunitinib, 11 pazopanib, 4 immunotherapy, and 1 temsirolimus). The objective response rates were 71 % for sunitinib and 46 % for pazopanib, which were deemed comparable with historical controls.

Conclusions

Asymptomatic or minimally symptomatic mRCC patients can be observed for a prolonged period of time without active treatment.     

Interdisciplinary recommendations for the treatment of metastatic renal cell carcinoma

With the introduction of targeted drug therapies, a paradigm shift for the treatment of metastatic renal cell carcinoma has taken place. New compounds like sunitinib, sorafenib, bevacizumab and temsirolimus have become established as new therapeutic standards to replace the use of cytokines as standard therapy. Recently, these substances have been complemented by everolimus and pazopanib. An interdisciplinary consensus conference was held to discuss which criteria to consider when using these drugs (treatment sequence) and what questions remain unanswered based on the current study situation (open questions). Results from the 2009 conference provided the basis for the 2010 meeting. The results of the 2010 conference are presented as short theses.