Abstract 1478P
Background
The ccrcc1-4 transcriptomic subtypes that we have previously identified on fresh frozen ccRCC through unsupervised clustering, have prognostic value post-nephrectomy/metastasectomy and predictive value for 1L VEGFR-TKI. We aimed to develop a classifier for FFPE samples.
Methods
RNA sequencing of tumoral FFPE tissue was performed in ccRCC patients. The classifier assigns subtypes through relative proportions of 8 gene signatures with strong discriminative value for the molecular subtypes (ccrcc3_upregulated, ccrcc3_downregulated, ccrcc2_upregulated, cell cycle, T effector, ccrcc1-4_upregulated, ccrcc4_upregulated, ccrcc1_upregulated).
Results
214 tumors were classified. Sarcomatoid features and IMDC poor risk were enriched in ccrcc4 tumors. The favorable prognostic impact of the ccrcc2 subtype was validated after nephrectomy in localized setting, after cytoreductive nephrectomy (CN) and upon metastasectomy with curative intent (MWCI). The angiogenic ccrcc2 subtype was correlated with improved outcome on 1L VEGFR-TKI and the highly inflamed ccrcc4 subtype with improved outcome on 1L IO/IO. ccrcc2 tumors had the longest PFS on 1L VEGFR-TKI and the longest OS, as long as patients did not access to IO in later lines. In patients who could access IO in later line, OS was similar between subgroups, indicating that the ccrcc4 subtype has the largest OS benefit on IO therapy. On IO treatment in any line, ccrcc4 tumors had superior PFS. IO counteracted the poor prognosis of this subtype, resulting in OS outcomes comparable to those of less aggressive subtypes. Table: 1478P
| n | ccrcc2 | ccrcc3 | ccrcc1 | ccrcc4 | p | ||
| Prognostic impact post surgery | |||||||
| After nephrectomy in localized setting | DFS | 110 | 43 | 30 | 19 | 12 | 0.002 |
| After CN | STFS | 92 | 6 | 3 | 4 | 2 | 0.009 |
| Upon MWCI | DFS | 66 | 31 | 21 | 13 | 4 | 0.0006 |
| STFS | 73 | 25 | 40 | 16 | 0.007 | ||
| OS | 116 | 51 | 93 | 32 | 0.01 | ||
| Impact on outcome on systemic therapy | |||||||
| On 1L VEGFR-TKI | PFS | 145 | 14 | 6 | 9 | 4 | 0.003 |
| OS in patients without access to IO in later lines | 74 | 23 | 25 | 11 | 5 | 0.002 | |
| OS in patients with access to IO in later lines | 71 | 39 | NR | 56 | 79 | 0.21 | |
| On 1L IO/IO | PFS | 20 | 11 | NA | 4 | 47 | 0.04 |
| OS | 45 | NA | 23 | NR | 0.005 | ||
| On IO in any line | PFS | 93 | 4 | 13 | 0.048 | ||
| OS | 31 | 30 | 0.37 |
DFS: disease free survival. STFS: systemic therapy free survival.
Conclusions
The Clearseq1-4 classifier allows reliable ccrcc molecular subtype determination on FFPE tissues and validates previous biomarker findings for both surgical and systemic treatment approaches.
Clinical trial identification
S53479/S63833.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
“Kom op tegen Kanker” (Stand up to Cancer), Flemish Cancer Society. Unrestricted Research Grants of Pfizer and Ipsen. Bristol Myers Squibb.
Disclosure
All authors have declared no conflicts of interest.