EURURO Vol. 73 No. 1

Introduction

Papillary renal cell carcinoma (PRCC) accounts for approxi-

mately 15–20% of cases of RCC

[1]

. For patients with

advanced PRCC, treatment options unfortunately remain

limited, and current guidelines emphasize enrollment in

clinical trials. While VEGF- and mTOR-directed therapies

have led to dramatic improvements in clinical outcome for

patients with metastatic clear-cell RCC (ccRCC) over the

past decade, the efficacy of these targeted agents appears to

be more modest in metastatic PRCC

[2,3]

. Progression-free

survival (PFS) estimates for first-line VEGF-directed agents

such as sunitinib typically range from 9 to 12 mo in patients

with metastatic ccRCC, whereas published series indicate

PFS ranging from 1.6 to 6.6 mo for metastatic PRCC in the

same setting

[4–9]

The discordant response to VEGF-directed agents among

RCC types can probably be explained by the distinct biology

of PRCC compared to ccRCC. It is generally accepted that

ccRCC is driven by alterations in

VHL

leading to upregulation

of HIF and subsequently VEGF

[10]

. By contrast, PRCC

appears to have distinct oncogenic drivers with different

aberrant pathways that vary by papillary subtype. The

Cancer Genome Atlas (TCGA) experience for PRCC has

recently been reported, and offers characterization of 161

patients

[1] .

Type 1 PRCC was characterized by alterations in

the

MET

proto-oncogene, while type 2 PRCC has been linked

to alterations in

CDKN2A

SETD2

, and

TFE3

. A subset of type

2 disease (designated CpG island methylator phenotype, or

CIMP) appears to have particularly poor survival, and several

of these patients have alterations in the

gene.

One limitation of the TCGA experience is that 73% of

patients were characterized as having M0 disease at

diagnosis. In fact, only 3% of the TCGA patients were

characterized as having M1 disease (for the remainder,

stage was unknown). With this in mind, it is challenging to

predicate clinical trial designs of targeted therapy for

advanced PRCC on this data set. In the current study, we

assess the frequency of GAs in a cohort of PRCC patients

with predominantly advanced disease for whom compre-

hensive genomic profiling (CGP) was performed in the

context of routine clinical care.

Patients and methods

Previously published methods were used to perform CGP for 169 conse-

cutive patients with PRCC sequenced between 2012 and 2016

[11,12]

. Samples from patients were submitted by clinicians in the

course of clinical care with limited accompanying information including

age, gender, stage, and disease site. In brief, formalin-fixed, paraffin-

embedded (FFPE) tissues were obtained

[13]

. Central pathology review

arbitrated by two board-certified pathologists (E.Y., S.M.A.) was used to

determine type 1 versus type 2 designation for 147 cases. Cases with

discordant assessment of subtype between the two pathologists were

arbitrated via mutual discussion; ultimately, a consensus was reached

for designation of each case. Pathology for the 22 cases that were

determined locally (3 cases of type 1, 10 of type 2, 9 unspecified) were

designated ‘‘unclassified.’’ For all cases in the current series, DNA was

extracted from 40

m of FFPE sections with at least 20% tumor cells.

Targeted next-generation sequencing was performed on hybridization-

captured, adaptor ligation-based libraries in a laboratory with Clinical

Laboratory Improvement Amendments certification and College of

American Pathologists accreditation (Foundation Medicine, Cambridge,

MA, USA). In total, up to 315 cancer-related genes were assessed along

with select introns from 31 genes frequently rearranged in cancer

[14]

. Captured libraries were sequenced to a median exon coverage

depth of 648 . Base substitutions, short insertions, deletions, copy

number changes (homozygous deletions and amplifications), and gene

fusions and rearrangements were assessed using previously published

methods

[12,15]

Wholly deidentified data were used for the current analysis.

Approval for the study, including a waiver of informed consent and a

Health Insurance Portability and Accountability Act waiver of authori-

zation, was obtained from the Western Institutional Review Board

(Protocol No. 20152817). Data from the TCGA Papillary Renal Cell

Carcinoma study were accessed using cBioPortal (February 2017);

analysis of the TCGA dataset in cBioPortal was restricted to the

161 published cases by using the patient barcodes from the appendix

of the TCGA publication

[1,16]

. Descriptive statistics were used to

compare the frequency of GAs in the current data set and the TCGA

report

[1]

. Fisher’s exact test (two-tailed) was used to compare the

frequency of GAs in primary versus metastatic samples, and in type

1 versus type 2 disease;

values are unadjusted.

Results

3.1.

Patient characteristics

Of the 169 patients with PRCC identified, 129 patients were

male and 40 were female, with a median age of 60 yr (range

19–88;

Table 1

). After central pathologic review,

39 patients were classified as type 1 and 108 patients as

type 2; 22 patients were designated as unclassified. The

distributions for age and gender were similar across these

subtypes. The majority of patients were stage IV

(103 patients, 61%). A total of 36 patients (21%) were stage

III, and only 22 patients had stage I or II disease (13%). In

association of alterations in SWI/SNF complex genes with type 2 PRCC, and observation of

frequent

CDKN2A/B

alterations in both type 1 and type 2 disease.

Conclusions:

Both the current study and the TCGA experience represent similarly sized

cohorts of patients with PRCC. Key differences in GA frequency probably underscore the

marked difference in stage distribution between these data sets. These results may inform

planned precision medicine trials for metastatic PRCC.

Patient summary:

Papillary renal cell carcinoma (PRCC) is a rare subtype of kidney cancer,

and understanding of the biology of advanced PRCC is limited. This report highlights some

of the unique biologic features of PRCC that may inform on future use of targeted therapies

for the treatment of metastatic disease.

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