Abstract
The genomic, transcriptomic, and immunological landscape of SGLT2 in lung cancer.
Author
person
Heng Tan
University of Miami/Jackson Memorial Hospital, Miami, FL
info_outline
Heng Tan, Samuel A. Kareff, Harris Benjamin Krause, Asaad Trabolsi, Andrew Elliott, Alex Patrick Farrell, Stephen V. Liu, Patrick C. Ma, Ari M. Vanderwalde, Milan Radovich, George W. Sledge, Gilberto Lopes
Full text
Authors
person
Heng Tan
University of Miami/Jackson Memorial Hospital, Miami, FL
info_outline
Heng Tan, Samuel A. Kareff, Harris Benjamin Krause, Asaad Trabolsi, Andrew Elliott, Alex Patrick Farrell, Stephen V. Liu, Patrick C. Ma, Ari M. Vanderwalde, Milan Radovich, George W. Sledge, Gilberto Lopes
Organizations
University of Miami/Jackson Memorial Hospital, Miami, FL, University of Miami Sylvester Comprehensive Cancer Center/Jackson Memorial Hospital, Miami, FL, Caris Life Sciences, Irving, TX, Jackson Memorial Hospital/ University of Miami, Miami, FL, Caris Life Sciences, Phoenix, AZ, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, Penn State Milton S. Hershey Medical Center, Hershey, PA, West Cancer Center and Research Institute, Caris Life Sciences, Germantown and Memphis, TN, University of Miami, Miami, FL
Abstract Disclosures
Research Funding
No funding received
None.
Background:
Retrospective data suggest that SGLT2 inhibitors, commonly used in diabetes, are associated with a lower incidence of cancer development and
in vivo
data indicate SGLT2 plays a role in the development of NSCLC. We investigated the genomic and immunological landscape of NSCLC [adenocarcinoma (AC) or squamous cell carcinoma (SCC) histology] with high and low expression of the SGLT2-coding gene
SLC5A2
and the relationship with clinical outcomes.
Methods:
NSCLC tumors of AC (N = 11,725) or SCC (N = 4,158) histology were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes or whole exome) and RNA (whole transcriptome). PD-L1 expression (22C3; Positive (+): TPS ≥1%) was assessed by IHC. High tumor mutational burden (TMB-H) was defined as ≥10 mutations/MB. Mutations were defined as pathogenic SNVs/indels
.
SLC5A2
-H and -L expression (transcripts per million) was defined as top and bottom quartile, respectively. A transcriptomic signature predictive of response to immunotherapy was applied (T cell-inflamed). The Mann-Whitney U test was applied as appropriate, with P-values adjusted for multiple comparisons (p < .05). Real-world overall survival (OS) data was obtained from insurance claims and Kaplan-Meier estimates were calculated for molecularly defined subpopulations of patients (N = 13,505).
Results:
In AC tumors,
SLC5A2
-H was associated with higher rates of
EGFR
(20.8 vs 13.5%,
p
< .05) and
STK11
mutations (20.1 vs 12.9%,
p
< .05), but lower rates of
TP53
(50.8 vs 69.5%,
p
< .05) and
ARID1A
(8.7 vs 4.6%,
p
< .05) mutations. There was no significant difference in the
KRAS
mutation rate (35.6 vs 37.1%,
p
= 1). AC and SCC
SLC5A2-
H tumors had a lower prevalence of PD-L1+ (AC: 47 vs 68%, SCC: 50 vs 67%,
p
< .05). AC
SLC5A2-
H tumors had a lower prevalence of TMB-H (30 vs 39%,
p
< .05), but not in SCC (40 vs 41%,
p
= .6).
SLC5A2
-H tumors were associated with a higher prevalence of T cell-inflamed tumors (AC: 40 vs 19%, SCC: 33 vs 11%,
p
< .05).
SLC5A2
-H AC had longer OS as compared to
SLC5A2
-L AC tumors (HR = 0.787 [.73-.85],
p
< .001) but no significant difference in time on treatment (TOT) with pembrolizumab was observed (HR .90 [.78-1.03],
p
= .13).
SLC5A2
-H SCC tumors had significantly longer OS (HR .88, [.78-1.00],
p
= .045) and they had significantly longer TOT with pembrolizumab (HR .72 [.56-.94],
p
= .01). Finally,
SLC5A2
-H,
KRAS
mutant AC tumors had significantly longer OS (HR .64 [.57-.73],
p
< .001) whereas
SLC5A2
-H KRAS mutant SCC tumors (HR 1.46 [.83-2.57],
p
= .19) trended towards shorter OS.
Conclusions:
SLC5A2
expression was associated with a highly altered genomic landscape in AC. In specific mutational and histological subgroups, differences in
SLC5A2
expression were associated with OS and responsiveness to immunotherapy. These mutational and histological subtypes should be further investigated as research on SGLT2 inhibitors progresses.
8 organizations
2 drugs
2 targets
Organization
University of Miami/Jackson Memorial HospitalOrganization
Caris Life Sciences, Irving, TXOrganization
Jackson Memorial Hospital/ University of MiamiDrug
SGLT2 inhibitorsDrug
pembrolizumabTarget
SGLT2Target
PD-1