Transcriptomic profiling identifies genomic markers associated with benefit from stereotactic body radiation therapy (SBRT) in oligoprogressive metastatic renal cell carcinoma (mRCC).
Authors: Zengin Zeynep Busra , Govindarajan Ameish , Muddasani Ramya , Salgia Nicholas , Sayegh Nicolas , Tripathi Nishita , Salgia Sabrina , Meza Luis A , Zhang Jiaming , Chawla Neal Shiv , Chehrazi-Raffle Alex , Malhotra Jasnoor , Dizman Nazli , Hsu Joann , Castro Daniela V. , Byron Sara A. , Dandapani Savita V. , Pal Sumanta K. 
Published: June 2022

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Background: Addition of SBRT to systemic therapy in oligoprogressive mRCC has been shown to prolong the duration of systemic treatment (Cheung et al Eur Urol 2021; De et al BJUI 2021). To date, the genomic predictors of benefit are unknown. We hypothesized that hypoxia-related genes would be associated with lesser benefit from SBRT. Methods: We retrospectively identified patients (pts) with mRCC who had oligoprogressive disease (progression of < 5 sites) while on systemic treatment and received SBRT without any systemic treatment change or interruption. Clinicopathologic characteristics, whole exome and transcriptome sequencing (Ashion Analytics) data were collected. Duration of systemic therapy (DOT) was quantified as systemic treatment duration prior to oligoprogression (DOT[P]) and after completion of SBRT (DOT[S]). The ratio of DOT[S]/DOT[P] was calculated and patients with a ratio ≥ 1.0 were considered to derive greater benefit from SBRT. The frequency of specific DNA alterations and RNA expression of pts above and below a DOT[S]/DOT[P] threshold of 1.0 was compared using a two-tailed Fischer’s exact and student’s t-test, respectively. Results: In this study, 23 mRCC pts who had oligoprogression during systemic treatment and received SBRT were identified. Within this cohort 16 pts (69.6%; M:F, 12:4) had available genomic data. Median age was 70 years and the most common histology was clear cell (87.5%). At the time of oligoprogression 11 pts (68.8%) were on immunotherapy, 4 pts (25.0%) were on targeted therapy. Median DOT[S] and DOT[P] were 12.6 months (range,0.7-46.3) and 13.4 months (range, 0.5-26.9), respectively, with a median DOT[S]/DOT[P] ratio of 1.4 (range,0.01-3.8). The most commonly mutated genes were VHL (56.3%), PBRM1 (37.5%), and SETD2 (37.5%). Alterations in VHL, PBRM1 and SETD2 were seen in 66.7% vs 42.9%, 33.3% vs 43.9%, and 44.4% vs 28.6% in patients with greater vs lesser benefit from SBRT, respectively (p≥0.05for each). Transcriptomic analysis was available in 9 pts and 1580 genes were noted to be differentially expressed between the groups (p < 0.05). Limiting scope to cancer genes in the COSMIC database, pts with lesser benefit from SBRT had higher expression of CDKN1B, CNBP, and FOXO3 whereas pts with greater benefit had higher expression of RNF43, POLD1 and PBRM1 (p < 0.05 for each). Gene set enrichment analysis showed a trend towards increased expression of hypoxia related genes in pts with lesser benefit. Conclusions: Our data align with existing studies supporting the role of SBRT in oligoprogressive mRCC. In addition, while clinical benefit from SBRT appears to be independent of DNA-level alterations, transcriptomic analysis revealed significant differences in gene expression. Hypoxia-associated signatures may be associated with lesser benefit from radiotherapy.