Hereditary Renal Cell Carcinoma
Abstract
BACKGROUND:
Hereditary renal cell carcinoma (RCC) is a complex and rapidly evolving topic as there is a growing body of literature regarding inherited syndromes and mutations associated with an increased risk of RCC.
OBJECTIVES:
We sought to systematically review 13 hereditary syndromes associated with RCC; von Hippel-Lindau Disease associated RCC (VHLRCC), BAP-1 associated clear cell RCC (BAPccRCC), Familial non-von Hippel Lindau clear cell RCC (FccRCC), Tuberous Sclerosis Complex associated RCC (TSCRCC), Birt-Hogg-Dube´
Syndrome associated RCC (BHDRCC), PTEN Hamartoma Tumor Syndrome associated RCC (PHTSRCC), Microphthalmia-associated Transcription Family translocation RCC (MiTFtRCC), RCC with Chromosome 6p Amplification (TFEBRCC), Autosomal Dominant Polycystic Kidney Disease associated RCC (ADPKDRCC), Hereditary Leiomyomatosis associated RCC (HLRCC), Succinate Dehydrogenase RCC (SDHRCC), Hereditary Papillary RCC (HPRCC), and ALK-Rearrangement RCC (ALKRCC).
RESULTS:
Hereditary RCC is generally associated with an early age of onset, multifocal and/or bilateral lesions, and aggressive disease course. VHLRCC, BAPccRCC, FccRCC, and certain mutations resulting in SDHRCC are associated with clear cell RCC (ccRCC). HPRCC is associated with Type 1 papillary RCC. HLRCC is associated with type 2 papillary RCC. BHDRCC is associated with Chromophobe RCC. TSCRCC, PHTSRCC, MiTFtRCC, TFEBRCC, ADPKDRCC, certain SDHRCC and ALKRCC have variable histology.
CONCLUSIONS:
There has been tremendous advancement in our understanding of the pathophysiology of hereditary RCC. Ongoing research will refine our understanding of hereditary RCC and its therapeutic targets.
“What We Have Learnt from CARMENA and SURTIME and What Should Be Done Differently in Future Trials on Cytoreductive Nephrectomy
Abstract
Upfront cytoreductive nephrectomy (CN) was the standard treatment for selected patients with metastatic Renal Cell Carcinoma (RCC) in the cytokine era for many years. In the recent ‘targeted therapy era’ it has been re-challenged by both the CARMENA and SURTIME trials. As first-line therapy for treatment-naive metastatic clear-cell RCC has now changed to immune checkpoint inhibitor combination therapy (ICI), and previous studies concerning CN were built in the targeted therapy era, the role and sequence of CN needs to be revisited. Here we address what we have learnt from both trials and how future trials should be designed to investigate CN.
Evaluating the Optimal Duration of Immunotherapy in Kidney Cancer
Abstract
Immune checkpoint inhibitor (ICI) therapy has rapidly altered the landscape of treatment of metastatic renal cell carcinoma (mRCC), resulting in significant improvements in outcomes for patients with this disease. Nivolumab, an antibody inhibiting the programmed death-1 (PD-1) receptor, was first approved for treatment of refractory mRCC, on the basis of the Phase III CheckMate 025 study comparing nivolumab to everolimus; in this study, patients were treated with nivolumab until development of progression or unacceptable toxicity [1]. More recently, several Phase III randomized controlled trials have established the benefit of incorporating ICI therapy to the first-line treatment of patients with mRCC, conferring durable responses in a subset of patients [2– 5]. For patients who do have durable responses to ICI therapy, we are often faced with a quandary of how long to continue treatment. We may be at a point now to examine this clinical question in a prospective fashion.
Immune Gene Signature Expression Differs between African American and Caucasian Patients with Renal Cell Carcinoma
Abstract
BACKGROUND:
Predictive immune signatures such as the T-effector, the 26-gene “Renal 101 Immuno signature” and the 18-gene T-cell inflamed gene expression profile were developed in clinical trials enrolling predominantly Caucasians and there is a dearth of literature comparing tumor biology between African American (AA) and Caucasian patients.
OBJECTIVE:
To compare the immune gene signature expression in AA (n = 55) and Caucasian (n = 457) patients.
METHODS:
Raw gene expression count data were downloaded from the TCGA KIRC dataset and tumor samples from “white” and “black or AA” patients were selected. The gene expression values of the immune signatures were VST-transformed normalized counts and compared between the groups.
RESULTS:
There were 457 Caucasian and 55 AA patients in the TCGA. The immune gene expression in all three signatures was significantly lower in AA patients compared to Caucasians (p < 0.05). We validated our findings in an independent dataset using Nanostring Immune Profile Panel. Since the majority of AA tumors in TCGA were stage I (71%), we compared gene expression between stage I AA tumors (n = 39) with stage I Caucasian tumors (n = 220). Once again, the immune gene expression was significantly lower in AA patients compared to Caucasians (p < 0.05), indicating differences in tumor biology between the races.
CONCLUSIONS:
Low expression of predictive immune gene signatures in AA compared to Caucasian patients indicates a possible difference in the biology of their tumors. Future studies are needed to validate our findings in other datasets and to study the predictive role of these signatures in AA patients.
A Systematic Review of Immune Checkpoint Inhibitors in Non-Clear-Cell Renal Cancer
Abstract
BACKGROUND:
Immune checkpoint inhibitors (ICI) have emerged as active therapies in the management of advanced RCC. While multiple studies have shown clinical activity of ICIs in clear cell histologies, the evidence to support their use in non-clear cell (ncc) subtypes is based on smaller prospective trials and retrospective analyses.
OBJECTIVE:
The objective of this review is to summarize the clinical outcomes of ICI-based therapies in ncc-subtypes and in tumors with sarcomatoid/rhabdoid features.
METHODS:
We performed a systematic literature search using PubMed, Google Scholar and ASCO databases. The keywords “renal cell cancer” and “immune checkpoint inhibitors” and equivalents were used and all original publications between July 2016 and July 2021 were included.
RESULTS:
We included a total of 14 publications, including two clinical trials and 12 case series. The most frequent histologies were papillary (up to 75-100%), unclassified (up to 34%) and chromophobe (up to 28%). ICI monotherapy showed some activity in both 1st and 2nd line with response rates up to 27%. ICI combination regimens yielded better activity than ICI monotherapy but, overall, a heterogeneous efficacy was noted across histologies. Overall, outcomes of ICIs were superior in tumors with sarcomatoid/rhabdoid features.
CONCLUSION:
The observed activity of ICI-based therapies was heterogeneous. Combination regimens, papillary subtype and sarcomatoid/rhabdoid features were associated with higher responses. These findings might help treatment decisions and require further validation.
Geographical Differences in Kidney Cancer Outcomes of Patients Treated with Immunotherapy: A Systematic Review
Abstract
BACKGROUND:
Immune checkpoint inhibitors (ICI) have shown clinical benefit among patients with advanced kidney cancer. Their cost burden hardens its access, especially in low- and middle-income countries. To set solutions, the impact of geographical and socioeconomic differences in the clinical outcomes and survival of renal cell carcinoma (RCC) patients needs to be explored.
OBJECTIVE:
This review aimed to understand if geographical differences affected the clinical outcomes of RCC patients receiving immunotherapy.
METHODS:
This study reviewed 45 studies that examined the OS and PFS of RCC patients undergoing ICI (2010–2020) selected from a 3028-study database search conducted on PubMed and grey literature. The selected studies were divided into groups: Asia, multicentric studies, Europe and Anglo-America. The lethality and income of the geographical locations were measured and discussed.
RESULTS:
Weighted average (WAVG) of mPFS and mOS were 8,47 months, and 40,6 months in Asia. The WAVG of mOS were 12.2 months, and 20.22 months in the Anglo-American population (15 studies; 943 patients). In multicentric studies (4 studies; 1834 patients) the WAVG mPFS was 10,06. European group (13 studies; 3143 patients) had 6.1 and 20.24 months mPFS and mOS, respectively. The exploratory analysis on income and RCC lethality has shown an absolute decline of 8.7% (CI 10.1 to 7.3% – p < 0.05) in RCC lethality, when income is raised by 100%.
CONCLUSION:
Clinical benefit from ICI varies across the globe. A wide access to ICI, and evaluation of biological aspects of the disease will allow a better understanding of the impact of geographic regions in the clinical outcome of patients receiving ICI and the etiology of potential differences.
The Current Status of Kidney Cancer Urine Markers – A Systematic Review
Abstract
BACKGROUND:
Renal cell carcinoma is the 9th most common malignant disease in the Western World. Typically, patients develop symptoms in a late stage of the disease and most of them are diagnosed by chance. Up to 30% of the patients at the time of diagnosis had metastatic disease. Therefore, highly specific and sensitive biomarkers for the detection and progression of kidney cancer are of great importance. Here, urine markers can be a major advantage and can have a huge clinical impact on the diagnosis, differentiation and prognosis of kidney cancer. At the moment there are several approaches to improve these conditions..
METHODS:
A systematic literature research was performed according to the PRISMA guidelines to identify studies reporting urine markers for kidney cancer between 2012 and 2021. A two-step process for the selection of the studies was initiated. In total 287 studies were considering for the final analysis. In total, 6 studies, which presented potential urinary biomarker were analyzed in depth.
RESULTS:
The major focus was on urinary markers for the detection, progression and differentiation of renal cell carcinoma. In total, a study population of 1099 patients were investigated in the different studies that were analyzed in depth. The median patient sample size of the different studies was 157 patients. The focus was based on the investigation of different microRNAs and proteins as urinary marker for kidney cancer detection.
CONCLUSION:
Overall, there are different approaches present for the detection, prognosis and differentiation of kidney cancer in urine but most of the studies are based on a small sample size and need to be validated in a greater collective. Furthermore, the standard should be improved to bring these biomarkers into routine clinical practice.
Clinical Trials Corner: Adding up in Adjuvant
Abstract
A Multicenter, Double-Blind, Randomized Phase 3 Study to Compare the Efficacy and Safety of Belzutifan (MK-6482) Plus Pembrolizumab (MK-3475) Versus Placebo Plus Pembrolizumab, in the Adjuvant Treatment of Clear Cell Renal Cell Carcinoma (ccRCC) Post Nephrectomy (MK-6482-022)
Status: Recruiting
Clinicaltrials.gov identifier: NCT05239728
Sponsor: Merck Sharp & Dohme LLC
Enrollment: 1600
Rationale: The KEYNOTE-564 study, a Phase 3 study evaluating the efficacy of pembrolizumab versus placebo in the adjuvant treatment of clear cell RCC post nephrectomy, extended disease-free survival (DFS) and has thus become an option for adjuvant therapy. Belzutifan, a small molecule hypoxia-inducible factor 2-alpha inhibitor, is a current treatment for patients with RCC associated with von Hippel-Lindau disease. It is possible that the combination of belzutifan and pembrolizumab may provide additive benefit to patients who are candidates for adjuvant therapy after nephrectomy.
Study design: This Phase 3 study enrolls patients with clear cell RCC (with or without sarcomatoid features) with no evidence of disease (NED) after complete resection of primary tumor, if pathology confirms intermediate-high risk (pT2, Grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0), high risk (pT4, any Grade N0, M0; pT any stage, any Grade, N+, M0), or M1 NED (complete resection of a soft tissue metastasis at time of nephrectomy or < 2 years from nephrectomy). Eligible patients must have an Eastern Cooperative Oncology Group performance status of 0 to 1 within 10 days before randomization, must have undergone nephrectomy and/or metastasectomy < 12 weeks prior to randomization, and must have adequate organ function. Patients cannot have had a prior systemic treatment or radiotherapy for RCC, have pulse oximetry of <92% at rest or require supplemental oxygen. Following enrollment, patients are randomized to receive either belzutifan (120 mg orally once daily) for up to 54 weeks plus pembrolizumab (400 mg intravenously every 6 weeks) for up to 9 administrations or placebo plus pembrolizumab for the same duration. Patients will continue to be followed after the time of treatment discontinuation or completion.
Endpoints: The primary endpoint of this trial is disease-free survival (DFS). Key secondary outcomes include overall survival (OS), disease recurrence-specific survival, rate of study treatment discontinuation and rate of participants with one or more adverse events (AEs).
