Artículos

Prognostic Molecular Signatures for Metastatic Potential in Clinically Low-Risk Stage I and II Clear Cell Renal Cell Carcinomas

Shih AJ, Murphy N, Kozel Z, et al.
Front Oncol. 2020 Aug 11;10:1383.
DOI: 10.3389/fonc.2020.01383.

Abstract

Introduction

For patients with localized node-negative (Stage I and II) clear cell renal cell carcinomas (ccRCC), current clinicopathological staging has limited predictive capability because of their low risk. Analyzing molecular signatures at the time of nephrectomy can aid in understanding future metastatic potential.

Objectives

Develop a molecular signature that can stratify patients who have clinically low risk ccRCC, but have high risk genetic changes driving an aggressive metastatic phenotype.

Patients, Materials, and Methods

Presented is the differential expression of mRNA and miRNA in 44 Stage I and Stage II patients, 21 who developed metastasis within 5 years of nephrectomy, compared to 23 patients who remained disease free for more than 5 years. Extracted RNA from nephrectomy specimens preserved in FFPE blocks was sequenced using RNAseq. MiRNA expression was performed using the TaqMan OpenArray qPCR protocol.

Results

One hundred thirty one genes and 2 miRNA were differentially expressed between the two groups. Canonical correlation (CC) analysis was applied and four CCs (CC32, CC20, CC9, and CC7) have an AUC > 0.65 in our dataset with similar predictive power in the TCGA-KIRC dataset. Gene set enrichment showed CC9 as kidney development/adhesion, CC20 as oxidative phosphorylation pathway, CC32 as RNA binding/spindle and CC7 as immune response. In a multivariate Cox model, the four CCs were able to identify high/low risk groups for metastases in the TCGA-KIRC (p < 0.05) with odds ratios of CC32 = 5.7, CC20 = 4.4, CC9 = 3.6, and CC7 = 2.7.

Conclusions

These results identify molecular signatures for more aggressive tumors in clinically low risk ccRCC patients who have a higher potential of metastasis than would be expected.

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Grading Chromophobe Renal Cell Carcinoma: Evidence for a Four-tiered Classification Incorporating Coagulative Tumor Necrosis

Avulova S, Cheville JC, Lohse CM, et al.
Eur Urol. 2020 Nov 7;S0302-2838(20)30784-3.
DOI: 10.1016/j.eururo.2020.10.007.

Abstract

Background

Although grading systems have been proposed for chromophobe renal cell carcinoma (ChRCC), including a three-tiered system by Paner et al (Paner GP, Amin MB, Alvarado-Cabrero I, et al. A novel tumor gradingscheme for chromophobe renal cell carcinoma: prognostic utility and comparison with Fuhrman nuclear grade. Am J Surg Pathol 2010;34:1233–40), none have gained clinical acceptance, and the World Health Organization (WHO) currently recommends against grading ChRCC.

Objectives

To validate a previously published grading scheme and propose a scheme that includes tumor necrosis.

Design, setting and participants

A total of 266 patients who underwent nephrectomy for nonmetastatic ChRCC between 1970 and 2012 were reviewed for ChRCC grade according to the Paner system and coagulative tumor necrosis.

Outcome measurements and statistical analysis

Associations with cancer-specific survival (CSS) were evaluated using Cox proportional hazard regression models and summarized with hazard ratios (HRs).

Results and limitations

Twenty-nine patients died from RCC; the median follow-up was 11.0 (interquartile range 7.9–15.9) yr. ChRCC grade according to the Paner system was significantly associated with CSS, including the difference in outcome between grade 1 and 2 tumors. Among patients with grade 2 tumors, the presence of tumor necrosis helped delineate patients with worse CSS. As such, the Paner system was expanded to four tiers separating grade 2 into those with and without tumor necrosis. HRs for associations of the proposed grade 2, 3, and 4 tumors with CSS were 4.63 (p = 0.007), 17.8 (p < 0.001), and 20.9 (p < 0.001), respectively. The study is limited by the lack of multivariable analysis including additional pathologic features.

Conclusions

The expansion of a previously reported ChRCC grading system from three to four tiers by the inclusion of tumor necrosis helps further delineate patient outcome and can, therefore, enhance patient counseling following surgery. It also aligns the number of ChRCC grades with the WHO/International Society of Urologic Pathology four-tiered grading systems for clear cell and papillary RCC.

Patient summary

Chromophobe renal cell carcinoma is the third most common type of renal cancer, and unlike other renal cancers, there is no accepted prognostic grading system. In this study, we found that a grading system that included a pathologic feature of tumor necrosis could better define outcomes for patients with chromophobe renal cell carcinoma.

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Acute interstitial nephritis, a potential predictor of response to immune checkpoint inhibitors in renal cell carcinoma

Patel V, Elias R, Formella J, et al.
J Immunother Cancer. 2020 Oct.
DOI: 10.1136/jitc-2020-001198.

Abstract

Immune checkpoint inhibitors (ICIs) such as nivolumab and ipilimumab have improved outcomes in metastatic renal cell carcinoma (mRCC) patients, but they are also associated with immune-related adverse events (irAEs). As observed in melanoma, we hypothesized that patients experiencing an autoimmune reaction directed against the tissue of origin may be more likely to benefit from ICI. Specifically, we asked whether patients with immune-related acute interstitial nephritis (irAIN) exhibited improved outcomes. Using Kidney Cancer Explorer (KCE), a data portal and i2b2-based central database for clinical, pathological and experimental genetic data, we systematically identified all patients with mRCC at UT Southwestern Medical Center (UTSW) from 2014-2018 who received at least one dose of ICI. More recent cases were identified through a provider query. We extracted creatinine (Cr) values at baseline and over the entirety of each patient ICI treatment course using KCE. Patients with ≥ 1.5-fold Cr increase over baseline were investigated. The likelihood of irAIN was determined based on the work-up (biopsy, if available), or by clinical criteria (timing of kidney injury, exclusion of other etiologies, treatment with immunosuppressants and response). We identified 177 mRCC patients who received at least one dose of ICI, 36 of whom had ≥ 1.5-fold increase in Cr over baseline while on treatment. Of those, two had biopsy-proven irAIN and one was clinically diagnosed, resulting in an incidence of 1.7%. One additional biopsy-proven case past 2018 was identified through a provider query, for a total of four patients. Two received combination nivolumab and ipilimumab in the first line, whereas the remaining received nivolumab after first line therapy. irAIN onset ranged from 1.5 to 12 months. All four patients stopped ICI with recovery of renal function, at least partially, three after receiving systemic steroids. Notably, all four patients had a deep response. In conclusion, irAIN is a rare event, but it may portend a higher likelihood of response. One possible explanation is antigenic overlap between normal renal tubular cells and tumor cells.

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Functional and oncological outcome of percutaneous cryoablation versus laparoscopic partial nephrectomy for clinical T1 renal tumors: A propensity score-matched analysis

Yanagisawa T, Miki J, Shimizu K, et al.
Urol Oncol. 2020 Oct 6;S1078-1439(20)30434-8.
DOI: 10.1016/j.urolonc.2020.09.024.

Abstract

Purpose

To evaluate the clinical trifecta of percutaneous cryoablation (PCA) vs. laparoscopic partial nephrectomy (LPN) for cT1 renal tumors.

Patients and methods

We retrospectively analyzed the records of patients who had undergone 2 types of nephron sparing surgeries (NSS) PCA or LPN for cT1 renal tumors between November 2011 and December 2019. The cohorts were matched by one-to-one propensity scores based on patient demographics, renal function, and tumor complexity. Perioperative and oncological outcomes and preservation of renal function following surgery were compared.

Results

After matching, a total of 180 patients who had undergone NSS for de novo renal tumors were evaluable: 90 for PCA and 90 for LPN. No statistically significant differences were noted among the measured baseline characteristics in the propensity score-matched cohorts. Overall perioperative complication rates were 5.5% in the PCA and 11.1% in the LPN groups (P = 0.28). The rate of eGFR preservation 1 to 3 months after surgery was significantly higher for PCA than for LPN (92.8 ± 11.5% vs. 88.5 ± 14.6%, P = 0.03). Median follow-up was 33 months for PCA and 18 months for LPN (P < 0.001). Three residual and 4 recurrent tumors were later diagnosed in the PCA group and 1 recurrent tumor in the LPN group. The 5-year local recurrence-free survival was lower for PCA than LPN (90.2% vs. 98.5%, P = 0.36). The 5-year metastasis-free survival rate was similar in both groups (98.4% vs. 100%, P = 0.38). The 5-year overall and cancer-specific survival rates were comparable in both groups (91.7% vs. 98.9%, P = 0.53, and 95% vs. 100%, P = 0.55, respectively).

Conclusions

Clinical T1 RCC patients are better treated with LPN if technically possible. Though PCA had a higher local recurrence rate, medium-term local control was not inferior to LPN. Additionally, PCA patients tended to retain renal function without severe complications. PCA appears to be a reasonable option for patients with high comorbidity at presentation.

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Small Renal Mass Surveillance: Histology-specific Growth Rates in a Biopsy-characterized Cohort

Finelli A, Cheung D, Al-Matar A, et al.
Eur Urol. 2020 Sep;78(3):460-467.
DOI: 10.1016/j.eururo.2020.06.053.

Abstract

Background

Most reports of active surveillance (AS) of small renal masses (SRMs) lack biopsy confirmation, and therefore include benign tumors and different subtypes of renal cell carcinoma (RCC).

Objectives

We compared the growth rates and progression of different histologic subtypes of RCC SRMs (SRMRCC) in the largest cohort of patients with biopsy-characterized SRMs on AS.

Design, setting and participants

Data from patients in a multicenter Canadian trial and a Princess Margaret cohort were combined to include 136 biopsy-proven SRMRCC lesions managed by AS, with treatment deferred until progression or patient/surgeon decision.

Outcome measurements and statistical analysis

Growth curves were estimated from serial tumor size measures. Tumor progression was defined by sustained size ≥4 cm or volume doubling within 1 yr.

Results and limitations

Median follow-up for patients who remained on AS was 5.8 yr (interquartile range 3.4-7.5 yr). Clear cell RCC SRMs (SRMccRCC) grew faster than papillary type 1 SRMs (0.25 and 0.02 cm/yr on average, respectively, p = 0.0003). Overall, 60 SRMRCC lesions progressed: 49 (82%) by rapid growth (volume doubling), seven (12%) increasing to ≥4 cm, and four (6.7%) by both criteria. Six patients developed metastases, and all were of clear cell RCC histology. Limitations include the use of different imaging modalities and a lack of central imaging review.

Conclusions

Tumor growth varies between histologic subtypes of SRMRCC and among SRMccRCC, which likely reflects individual host and tumor biology. Without validated biomarkers that predict this variation, initial follow-up of histologically characterized SRMs can inform personalized treatment for patients on AS.

Patient summary

Many small kidney cancers are suitable for surveillance and can be monitored over time for change. We demonstrate that different types of kidney cancers grow at different rates and are at different risks of progression. These results may guide better personalized treatment.

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Does renal tumor biopsies for small renal carcinoma increase the risk of upstaging on final surgery pathology report and the risk of recurrence?

Asselin C, Finelli A, Breau RH, et al.
Urol Oncol 2020 Oct;38(10):798.
DOI: 10.1016/j.urolonc.2020.06.001

Abstract

Background

Renal tumor biopsies (RTB) have been proposed as a means to diminish overtreatment of small renal masses. A potential concern of RTB is tumor seeding along the biopsy tract leading to worse clinical outcomes.

Objectives

To evaluate whether RTB was associated with greater upstaging to pT3a compared to patients without a biopsy and to determine if pathologic upstaging affects the risk of recurrence.

Design, setting and participants

The Canadian Kidney Cancer information system was used to identify patients who underwent radical or partial nephrectomy for malignant renal tumors ≤ 4cm (cT1a) between January 1, 2011 and July 2, 2019.

Intervention

RTB prior to nephrectomy or nephrectomy without biopsy.

Outcomes measurements and statistical analysis

Upstaging to pT3a and cancer recurrence were compared between subjects that had a RTB compared to those who did not. A multivariable analysis was used to evaluate factors associated with disease upstaging and recurrence.

Results and limitations

The cohort consisted of 1993 cT1a patients, followed for a median of 17.5 months. Of these patients, 502 (25%) had a preoperative RTB. There was no difference in the proportion with tumor upstaging to pT3a between patients that had RTB compared to those who did not (7.2% vs. 6.3%; P = 0.5). On multivariable analysis, RTB was not associated with pathological upstaging (Odds Ratio 0.90; 95% Confidence Interval 0.61-1.34) or recurrence (Odds Ratio 1.04; 95% Confidence Interval 0.57-1.89). The main limitation is that the study is underpowered to detect small differences between groups.

Conclusions

In this large, multi-institution cohort, RTB was not associated with increased risk of tumor upstaging or recurrence. Hence, tumor tract seeding, although possible, should not be a clinical deterrent to using RTBs as a means of personalizing renal masses management and diminishing overtreatment.

Patient summary

Recent evidence suggests that tumor seeding following RTB may be more common than initially perceived. Our results have demonstrated that RTB was not associated with an increased risk of tumor upstaging or disease recurrence.

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EAU 2020: Active Surveillance Proves Safe and Noninferior to Primary Intervention for Small Renal Masses

J.G. Cheaib, MD, MPH, and P.M. Pierorazio, MD, of the Johns Hopkins University School of Medicine, Baltimore, Maryland, and colleagues sought to describe 10-year outcomes in patients with small renal masses.
Published in Urology
News · July 17, 2020

July 17, 2020—Arnheim, The Netherlands—Active surveillance appears to be as safe as and not inferior to primary intervention in carefully selected patients with small renal masses suspected of being renal cell carcinoma.

Small renal masses were defined as solid renal masses ≤4.0 cm (clinical stage T1a).

This conclusion, based on results of an analysis of a prospective, comparative study from the large, multi-institutional Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry, which captures 10 years of experience thus far, was reported as part of the virtual 35th Annual Congress of the European Association of Urology (EAU).

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Characterization of PD-1 and PD-L1 Expression in Papillary Renal Cell Carcinoma: Results of a Large Multicenter Study

Erlmeier F, Steffens S, Stöhr C, et al.
Clin Genitourin Cancer. 2020 Jul 9
DOI: 10.1016/j.clgc.2020.07.002.

Abstract

Background

Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) play a decisive role as prognostic markers in clear-cell renal cell carcinoma (RCC). To date, the role of PD-1/PD-L1 as a prognostic marker in papillary RCC (pRCC) remains scarce.

Patients and methods

Patients’ sample collection was a joint collaboration of the nationwide PANZAR consortium – a multicenter study. Medical history and tumor specimens were collected from 245 and 129 patients with pRCC types 1 and 2, respectively. Expression of PD-1 and PD-L1 was determined by immunohistochemistry in pRCC and tumor-infiltrating mononuclear cells.

Results

Of 374 pRCC specimens, 204 type 1 and 97 type 2 were evaluable for PD-1 and PD-L1 expression analysis. In total, PD-1 and PD-L1 expression were found in 8 (4.9%) of 162 and 12 (7.2%) of 166 evaluable pRCC type 1 specimens. Comparably, PD-1 and PD-L1 expression were found in 2 (2.4%) of 83 and 5 (6.2%) of 81 evaluable pRCC type 2 specimens. Hardly any clinically relevant associations between PD-1 and PD-L1 positivity and clinicopathologic or clinical courses were observed, neither in pRCC type 1 nor type 2.

Conclusion

The analysis of a large pRCC cohort from a multicenter consortium revealed no impact of PD-1/PD-L1 expression on prognosis in patients with pRCC with predominantly limited disease status, neither for type 1 nor type 2. However, the impact of PD-1 and PD-L1 in more advanced pRCC disease needs further elucidation.

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Cabozantinib After a Previous Immune Checkpoint Inhibitor in Metastatic Renal Cell Carcinoma: A Retrospective Multi-Institutional Analysis

Iacovelli R, Ciccarese C, Facchini G, et al.
Target Oncol. 2020 Aug.
DOI: 10.1007/s11523-020-00732-y.

Abstract

Background

Angiogenesis has been recognized as the most important factor for tumor invasion, proliferation, and progression in metastatic renal cell carcinoma (mRCC). However, few clinical data are available regarding the efficacy of cabozantinib following immunotherapy.

Objective

To describe the outcome of cabozantinib in patients previously treated with immunotherapy.

Patients and methods

Patients with mRCC who received cabozantinib immediately after nivolumab were included. The primary endpoint was to assess the outcome in terms of efficacy and activity.

Results

Eighty-four mRCC patients met the criteria to be included in the final analysis. After a median follow-up of 9.4 months, median overall survival was 17.3 months. According to the IMDC criteria, the rates of patients alive at 12 months in the good, intermediate, and poor prognostic groups were 100%, 74%, and 33%, respectively (p < 0.001). The median progression-free survival (PFS) was 11.5 months (95% CI 8.3-14.7); no difference was found based on duration of previous first-line therapy or nivolumab PFS. The overall response rate was 52%, stable disease was found as the best response in 25.3% and progressive disease in 22.7% of patients. Among the 35 patients with progressive disease on nivolumab, 26 (74.3%) patients showed complete/partial response or stable disease with cabozantinib as best response after nivolumab. The major limitations of this study are the retrospective nature and the short follow-up.

Conclusion

Cabozantinib was shown to be effective and active in patients previously receiving immune checkpoint inhibitors. Therefore, cabozantinib can be considered a valid therapeutic option for previously treated mRCC patients, irrespective of the type and duration of prior therapies.

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Safety and Efficacy of Nivolumab in Patients With Advanced Clear Cell Renal Cell Carcinoma: Results From the Phase IIIb/IV CheckMate 374 Study

McFarlane JJ, Kochenderfer MD, Olsen MR, et al.
Clin Genitourin Cancer. 2020 Jun 14
DOI: 10.1016/j.clgc.2020.06.002.
Free article

Abstract

Background

The open-label, phase IIIb/IV CheckMate 374 study (NCT02596035) was conducted to validate the safety and efficacy of flat-dose nivolumab monotherapy 240 mg every 2 weeks (Q2W) in previously treated advanced/metastatic renal cell carcinoma (RCC). Three cohorts included patients with predominantly clear cell histology, non-clear cell histologies, or brain metastases. We report safety and efficacy from the CheckMate 374 advanced clear cell RCC (ccRCC) cohort.

Patients and methods

Eligible patients received prior treatment regimens (1-2 antiangiogenic; 0-3 systemic) with progression on/after last treatment and ≤ 6 months of enrollment. Patients received nivolumab 240 mg Q2W for ≤ 24 months or until confirmed progression/unacceptable toxicity. The primary endpoint was incidence of high-grade (grade 3-5) immune-mediated adverse events (IMAEs). Exploratory endpoints included objective response rate, progression-free survival, and overall survival.

Results

Ninety-seven patients had advanced predominantly ccRCC; 75.3% received only 1 prior systemic regimen in the advanced/metastatic setting. After a median follow-up of 17 months (range, 0.4-26.9 months), no grade 5 IMAEs occurred, and 9.3% of patients reported grade 3/4 IMAEs (hepatitis, 4.1%; diabetes mellitus, 2.1%; nephritis and renal dysfunction, 1.0%; rash, 1.0%; adrenal insufficiency, 1.0%). The objective response rate was 22.7% (95% confidence interval [CI], 14.8%-32.3%). Three patients had a complete response; 19 had partial responses. The median progression-free survival was 3.6 months (95% CI, 2.0-5.5 months). The median overall survival was 21.8 months (95% CI, 17.4 months to not estimable).

Conclusion

This study validates the safety and efficacy of nivolumab 240 mg Q2W flat-dose monotherapy for previously treated advanced ccRCC and adds to previous safety and efficacy data using the 3 mg/kg Q2W dose.

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