The Pan-Omics Landscape of Renal Cell Carcinoma and Its Implication on Future Clinical Practice
Abstract
Renal cell carcinoma has traditionally been classified based on histological features. Contemporary studies have identified genomic, transcriptomic, epigenomic, and metabolomic signatures that correspond to or even transcend histological subtypes. Much remains to be learned about improving the algorithm of pan-omics integration for precision oncology, which will not only advance our understanding of RCC pathobiology and treatment response but also result in novel therapeutic opportunities. Accordingly, this review focuses on recent RCC multi-omics literature. Encouragingly, a few reports on omics integration into routinely employed prognostic risk models have shown early promise that could lay the foundation for future development of precision kidney cancer therapies. Hence, this article serves as a primer on what we have learned and how we might better realize the clinical potential of the burgeoning pan-omics data.
Trends in Initial Systemic Therapy for Elderly Patients with Metastatic Clear Cell Renal Cell Carcinoma
Abstract
BACKGROUND:
The treatment landscape for metastatic clear cell renal cell carcinoma (mRCC) is rapidly changing. It is unknown how adoption of new types of therapies may differ by patient age.
OBJECTIVE:
To compare trends in first-line therapy use for older (≥70 years) and younger (< 70) patients with mRCC before and after approval of nivolumab in 2015.
METHODS:
Using the National Cancer Database, we assessed trends in first-line therapy use by calculating the proportion of patients receiving targeted therapy, immunotherapy, or no systemic therapy by year of diagnosis. Initial systemic treatment was compared for patients diagnosed in 2016 with patients diagnosed in 2011 as a control group prior to nivolumab approval. Multivariable regression analysis was used to evaluate the interaction between year of diagnosis and elderly status for use of first-line immunotherapy or targeted therapy.
RESULTS:
From 2006 to 2016, the proportion of patients receiving any type of systemic therapy increased from 43.7% to 56.5%. On stratified multivariable regression analysis, older patients diagnosed in 2016 were 17.3 times more likely to receive first-line immunotherapy compared to those diagnosed in 2011, while younger patients were 2.3 times more likely. There was no change in targeted therapy use over this time regardless of patient age.
CONCLUSIONS:
The rate of adoption of first-line immunotherapy was particularly pronounced for elderly compared to younger patients. While first-line use of immunotherapy may have allowed elderly patients to receive systemic therapy that they otherwise would not, the efficacy of these drugs in elderly patients deserves further study.
Validation of the Correlation Between Single Nucleotide Polymorphism rs307826 in VEGFR3 and Outcome in Metastatic Clear-Cell Renal Cell Carcinoma Patients Treated with Sunitinib
Abstract
BACKGROUND:
Previously, we have shown a correlation between single nucleotide polymorphism (SNP) rs307826 in vascular endothelial growth factor receptor-3 (VEGFR3) and outcome in metastatic clear-cell renal cell carcinoma (m-ccRCC) patients treated with sunitinib.
OBJECTIVE:
We aimed to validate this finding in an independent patient series.
METHODS:
m-ccRCC patients receiving sunitinib as first-line targeted therapy were included in a validation cohort. Endpoints were response rate (RR), progression-free survival (PFS) and overall survival (OS). We also updated survival data of our discovery cohort as described previously.
RESULTS:
Eighty-four patients were included in the validation cohort. rs307826 AG/GG-carriers had a shorter PFS (8 versus 12 months, p = 0.04) and a trend towards a shorter OS (18 versus 27 months, p = 0.22) compared to AA-carriers. In the total series of 168 patients (from the discovery cohort, as described previously, and the validation cohort), rs307826 AG/GG-carriers had a poorer RR (29% versus 53%, p = 0.008), PFS (8 versus 15 months, p = 0.0002) and OS (22 versus 31 months, p = 0.004) compared to AA-carriers. rs307826 was independently associated with PFS and OS on multivariate analysis.
CONCLUSION:
VEGFR3 rs307826 seems to be associated with outcome on sunitinib in m-ccRCC. Its impact highlights the role of VEGFR3 in ccRCC pathogenesis and as a target of sunitinib.
Comparing the Responses of Osseous Versus Soft-Tissue Metastases of Renal Cell Carcinoma to Receptor Tyrosine Kinase Inhibitors and Immunotherapy
Abstract
BACKGROUND:
Checkpoint inhibitors and receptor tyrosine kinase inhibitors (RTKIs) have changed the standard of care for metastatic renal cell carcinoma (mRCC). Anecdotal evidence suggests these therapies may be less effective for treating bone than soft-tissue metastases.
PURPOSE:
We performed a retrospective review evaluating the relative clinical responses in soft-tissue and bone metastases in patients undergoing therapy using RTKIs and anti-programmed death-1 (PD-1) agents for mRCC.
METHODS:
Of the 2,212 patients in our institutional cancer registry with renal cell carcinoma (1997–2017), 68 (82 disease courses) were identified with measurable bone and soft-tissue metastases treated with RTKIs and/or PD-1s. Extent of metastasis was quantified at the time of therapy initiation (baseline) and at 3 months, 6 months, and 1 year. Changes in disease status were categorized as complete response, partial response, stable, mixed, or progression of disease according to RECIST v1.1 and MD Anderson criteria. These categories were further organized into “response to treatment” or “evidence of progression” to generate a generalized linear effects model with soft-tissue response as the independent variable and bone response as the dependent variable. Alpha = 0.05.
RESULTS:
Soft-tissue response correlated with bone response at 3 months (76 disease courses, p = 0.005) and 6 months (48 disease courses, p = 0.017). Of the patients with controlled soft-tissue disease, only 14 (19%) and 15 (32%) had progression in bone at 3 and 6 months, respectively.
CONCLUSION:
Contrary to anecdotal reports, osseous metastases do not appear to respond worse than soft-tissue metastases to treatment with these agents.
Race/Ethnicity and Survival in Metastatic Renal Cell Carcinoma: Outcomes for Patients Receiving First Line Targeted Therapies
Abstract
BACKGROUND:
No study to date has assessed the relationship between treatment-specific therapeutic outcomes and race/ethnicity in metastatic renal cell carcinoma (mRCC). As targeted therapies have formed the backbone of first-line treatment options for mRCC until very recently, we assessed the relationship between race/ethnicity and targeted therapy-related outcomes in mRCC.
OBJECTIVE:
To retrospectively compare response rates and survival outcomes across ethnicities in patients who received first-line targeted therapies for mRCC.
METHODS:
Patients with mRCC receiving a first-line targeted therapy were identified from an institutional database encompassing consecutive patients treated between 2009 and 2019. Patient demographics, clinical characteristics and survival outcomes were recorded. The racial/ethnic groups included for analysis were Caucasian American, Hispanic American, and Asian American. Survival and response outcomes including progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) were calculated and compared across ethnic groups using Kaplan-Meier method and Chi-square test, respectively.
RESULTS:
In total, 295 patients were included for analysis. There were 184 (62.4%) Caucasian American patients, 82 (27.8%) Hispanic American patients, and 29 (9.8%) Asian American patients. No statistically significant differences in PFS nor OS were found between groups (PFS: 5.6 vs. 4.7 vs. 4.7 months, respectively) (OS: 32 vs. 31.7 vs. 51.7 months, respectively). No significant difference was found in ORR nor DCR across groups. Univariate cox regression analyses demonstrated no independent effect of race/ethnicity on PFS or OS.
CONCLUSIONS:
The apparent lack of differences in treatment-related outcomes across racial/ethnic groups is encouraging. However, further validation is required in larger series.