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Essential Peer-Reviewed Reading in Kidney Cancer

The peer-reviewed articles summarized in this section were selected by the
Editor-in-Chief, Robert A. Figlin, MD, for their timeliness, importance,
relevance, and potential impact on clinical practice or translational research.

Updated July 2017.

Systemic Therapy for non-clear cell renal cell carcinoma. Zhang T, Gong J,
Maia MC, et al. Am Soc Clin Oncol Educ Book. 2017; 37:337-342. 
Summary: Little improvement has been made in the management of metastatic non-clear cell RCC (nccRCC). Non-clear cell disease is an umbrella term that encompasses multiple biologically distinct entities, including but not limited to papillary, chromophobe, and sarcomatoid RCC. To date, prospective studies have largely explored treatments for ccRCC (e.g., VEGF- and mTOR-directed therapies) in trials that aggregate non-clear cell histologies. However, the studies do not acknowledge the varying biology of each non-clear cell subtype.
Conclusion: Emerging studies in nccRCC should examine individual histologies and apply biologically relevant therapies. An example of this is SWOG 1500, a randomized phase II study that will compare a VEGF-inhibitor to one of three MET-directed therapies in patients with metastatic papillary RCC. Until the biologic diversity of nccRCC is appreciated, outcomes are likely to remain dismal.

Metastatic chromophobe renal cell carcinoma treated with
targeted therapies: A Renal Cross Channel Group study.
Colomba E, Le Teuff G, Eisen T, et al. Eur J Cancer. 2017; 23;80:55-62

Summary: Treatment of non-clear cell renal cell carcinoma (RCC) remains controversial despite several recent prospective studies of targeted therapies (TT). Often Vas-cular Endothelial growth Factor (VEGF) and Mammalian Target of Rapamycin (mTOR) inhibitors are used, extrapolating the data from use of these agents in clear cell RCC. This study performed a retrospective data analysis within the Renal Cross Channel Group to determine metastatic chromophobe RCC (mChRCC) outcomes in the TT era. The end-points were overall response, overall survival (OS) and time to treatment failure (TTF). The two latter were estimated using the Kaplan-Meier method. The study included 91 mChRCC patients from 26 centers. Median follow-up from the date of first metastasis was 6.1 years (range: 0-13.9). Median OS was 37.9 months from the diagnosis of metastatic disease. Among the 61 patients who received TT, 50 (82%) were treated with anti-angiogenic (AA) and 11 with mTOR inhibitors. Median TTF and OS in patients receiving a first line of AA was 8.7 months and 22.9 months vs 1.9 months and 3.2 months with mTOR inhibitors, respectively. A stratified log-rank test compared AA and mTOR inhibitors TT, while controlling the effect of the International Metastatic RCC Database Consortium risk group and no significant difference between AA and mTOR inhibitors was observed for TTF (P = 0.26) or for OS (P = 0.55).
Conclusion: This report, the largest retrospective cohort of patients with mChRCC treated with TT, found no significant difference between AA and mTOR inhibitors  for TTF and OS.

Collecting duct carcinoma of the kidney: Disease characteristics
and treatment outcomes from the National Cancer Database.
Sui W, Matulay JT, Robins DJ, et al. Urol Oncol. 2017 May 8;
pii: S1078-1439(17)30179-5. 

Summary: The National Cancer Database was queried for all cases of CDRCC and clear cell renal cell carcinoma (CCRCC) from 2004 to 2013. After removing patients with other cancer diagnoses, the analytic cohort was composed of 201,686 CCRCC and 577 CDRCC cases. Kaplan-Meier and cox proportional hazards analysis were employed to model survival. Compared to CCRCC, patients with CDRCC presented with higher grade stage, node positive, and metastatic disease (70.7% vs. 30.0% with metastasis; P<0.001). Overall median survival for CDRCC was 13.2 months for CCRCC.  Increasing T stage, high-grade disease, and metastasis were predictors of mortality. Of 184 patients with metastatic CDRCC, 113 underwent cytoreductive nephrectomy (CNx) whereas the rest were treated with chemo/radiation or observed. Survival outcomes were improved in patients who received both CNx with chemo/radiation compared to CNx alone or chemo/radiation alone.
Conclusion: CDRCC is an aggressive subtype of RCC. Median survival is 13 months after diagnosis, drastically lower than for CCRCC. More than 70% of patients have a metastatic disease at diagnosis. Chemo/radiation in addition to CNx is associated with a survival benefit over single mode therapy.

Multicenter evaluation of the tolerability of combined treatment
with PD-1 and CTLA-4 immune checkpoint inhibitors and palliative
radiation therapy. Bang A, Whilhite TJ, Pike LRG, et al.
Int J Radiat Oncol Biol Phys. 2017 Jun 1;98(2):344-351. 

Summary: Records from patients with metastatic non-small cell lung cancer, melanoma, or renal cell cancer who received at least 1 cycle of a CTLA-4 or PD-1 inhibitor and radiation were retrospectively reviewed. Immune-related adverse events, defined using Common Terminology Criteria for Adverse Events version 4.0, were tabulated in relation to treatment variables, and associations with sequencing and timing were assessed.

The study identified 133 patients, of whom 28 received a CTLA-4 inhibitor alone, 88 received a PD-1 inhibitor alone, and 17 received both classes of inhibitors either sequentially (n=13) or concurrently (n=4). Fifty-six patients received radiation within 14 days of an immune checkpoint inhibitor. Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of patients in whom radiation was administered within 14 days of immunotherapy, compared with 23% of other patients (P=.06) and more often in patients who received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However, most toxicities were mild. There were no associations between site irradiated and specific ir-AEs.
Conclusion: The data suggest the combination of focal palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with manageable ir-AEs that did not seem to be associated with the particular site irradiated. Although conclusions are limited by the heterogeneity of patients and treatments, and future confirmatory studies are needed, this information can help guide clinical practice for patients receiving immune checkpoint therapy who require palliative radiation therapy.

Correlation of genomic alterations assessed by next-generation
sequencing (NGS) of tumor tissue DNA and circulating tumor
DNA (ctDNA) in metastatic renal cell carcinoma (mRCC):
potential clinical implications. Hahn AW, Gill DM,
Maughan B, et al. Oncotarget. 2017 May 16;8(20):33614-33620.

Summary: Tumor tissue and circulating tumor DNA (ctDNA) next-generation sequencing (NGS) testing are frequently performed to detect genomic alterations (GAs) to help guide treatment in metastatic renal cell carcinoma (mRCC), especially after progression on standard systemic therapy. This report assessed whether GAs detected by ctDNA NGS are different from those detected by tumor tissue NGS, specifically in patients with mRCC, and if these platforms are interchangeable or complimentary. When controlling for genes tested by both platforms, the median mutation rate for ctDNA was similar to tissue (median 3.0 vs. 1.0, P = 0.14). However, the concordance rate between the two platforms was only 8.6%. When the study compared GAs by molecular pathway, GAs in tumor tissue were more common for the DNA repair and epigenetic pathways. Results of NGS testing from tumor tissue and ctDNA from 19 sequential mRCC patients were compared. GAs in each were statistically evaluated using the Wilcoxon signed-rank test. The Fischer’s exact test was used to compare the incidence of mutations in selected molecular pathways.
Conclusion: When controlling for genes tested by both platforms, similar number of GAs were detected by both tissue and ctDNA based NGS. However, there was discordance in the type of GAs detected suggesting that ctDNA NGS may be more reflective of dynamic tumor genomic heterogeneity. Hence, these two platforms may be con-sidered complementary to each other, rather than interchangeable, for assessment of tumor GAs to guide selection of targeted clinical trial therapies.

Evolution of circulating tumor DNA profile from first-line
to subsequent therapy in metastatic renal cell carcinoma.
Pal SK, Sonpavde G, Agarwal N, et al. Eur Urol. 2017 Apr 13.
pii: S0302-2838(17)30277-4. 

Summary: Circulating tumor DNA (ctDNA) is a platform to noninvasively ascertain temporal changes in genomic profile. The ctDNA profile was obtained in mRCC patients who received ctDNA profiling as part of routine clinical care at progression using a 73-gene Clinical Laboratory Improvement Amendments-certified ctDNA platform. Genomic alterations (GAs) were pooled for the entire cohort. A comparison of first- and post first-line was performed with grouping based on conventional practice patterns (first-line regimens included sunitinib, pazopanib, and bevacizumab, and postfirst-line regimens included everolimus, axitinib, cabozantinib, and nivolumab). ctDNA clinical results from a nationwide cohort of 220 consecutive patients with mRCC were assessed (145 men, 75 women; median age: 63 yr, interquartile range: 57-70). GAs were detected in 78.6% of patients. The most frequent GAs in the overall cohort included TP53 (35%), VHL (23%), EGFR (17%), NF1 (16%), and ARID1A (12%). Thirty-eight and 64 patients were coded as receiving first-line and later line agents, respectively. The highest disparity in GA frequencies in postfirst-line versus first-line were in TP53 (49% vs 24%), VHL (29% vs 18%), NF1 (20% vs 3%), EGFR (15% vs 8%), and PIK3CA (17% vs 8%) while ARID1A was equivalent (13% vs 11%). Restricting the analysis to later lines versus first-line vascular endothelial growth factor inhibitors, these differences were even more prominent, particularly for TP53 (64% vs 31%) and NF1 (29% vs 4%).
Conclusion: In the largest assessment of ctDNA-detected GAs prevalence in mRCC to date, the majority of patients demonstrated clinically and biologically relevant GAs. Increasing p53 and mechanistic target of rapamycin pathway (eg, NF1, PIK3CA) alterations in post first-line patients with first-line vascular endothelial growth factor-directed therapy may underlie mechanisms of resistance. Routine ctDNA assessment during the clinical course of mRCC patients may have therapeutic implications. KCJ