Impact of sirtuin genes expression on first-line treatment outcomes in patients (pts) with metastatic colorectal cancer (mCRC) enrolled in CALGB/SWOG 80405 (Alliance).
Authors: Mittal Pooja , Yang Yan , Ashouri Karam , Soni Shivani , Battaglin Francesca , Algaze Sandra , Jayachandran Priya , Torres-Gonzalez Lesly , Zhang Wu , Ou Fang-Shu , Venook Alan P. , Millstein Joshua , Lenz Heinz-Josef 
Published: January 2025

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Background:
Sirtuins (SIRT1-7) are class III histone deacetylases with different roles in CRC as tumor suppressive and oncogenic, mainly influencing proliferation, migration, invasion, DNA damage and chemoresistance. In the present study, we explored the association between tumor gene expression of sirtuins and first-line treatment outcomes in mCRC pts.
Methods:
We evaluated the impact of the tumor gene expression of sirtuin genes (
SIRT1
-7) on treatment outcomes (overall survival: OS; progression free survival: PFS) in 433 pts enrolled in the randomized, phase III CALGB/SWOG 80405 (NCT00265850) trial. RNA extracted from FFPE tumor samples was sequenced using the HiSeq 2500 (Illumina). Subgroup analyses were based on treatment (bevacizumab [bev] (N = 226) vs. cetuximab [cet] (N = 207)). For each gene, expression was divided into tertiles of high, medium and low. The associations between tumor gene expression and outcomes (PFS and OS) were assessed using log-rank test in univariate analysis. Multivariable Cox proportional hazards regression model was used to compute hazard ratios (HR) and 95% confidence intervals while adjusting for baseline characteristics. Treatment-gene interactions were analyzed using the likelihood ratio test.
Results:
Of the seven genes analyzed,
SIRT3
high
was associated with both longer PFS (HR: 0.59 [95% CI: 0.46-0.74],
P
< 0.001) and OS (HR:0.64 [95% CI: 0.50-0.83],
P
= 0.002) overall. Treatment-gene interaction testing found significant interactions for
SIRT1
and
SIRT5
with PFS (
P
values: 0.021 and 0.016, respectively) and OS (
P
values: 0.038 and 0.014, respectively) with targeted therapies (bev vs. cet). Multivariate analysis showed
SIRT1
high
associated with longer PFS (HR: 0.62 [95% CI: 0.42-0.89],
P
= 0.014) and OS (HR: 0.59 [95% CI: 0.40-0.89],
P
= 0.036) in cet-treated pts; in contrast with shorter observed PFS (HR: 1.38 [95% CI: 0.96-1.99],
P
= 0.22) and OS (HR: 1.31 [95% CI: 0.90-1.93],
P
= 0.23) in bev-treated pts.
SIRT5
high
showed similar results and associated with longer PFS (HR: 0.64 [95% CI: 0.45-0.91],
P
= 0.039) and OS (HR: 0.57 [95% CI: 0.39-0.83],
P
= 0.013) in cet-treated pts, with no similar associations in bev-treated pts.
Conclusions:
Our results highlight a potential role for
SIRT3
as prognostic and,
SIRT1
and
SIRT5
as predictive biomarkers for first-line treatment in mCRC, with differential effects based on targeted agents. Significant interaction favored cet treatment in
SIRT1
high
and
SIRT5
high
tumors. However, previous reports suggest an opposite role of
SIRT5
that has been linked to chemotherapy and/or cet resistance in CRC via the inactivation of succinate dehydrogenase complex subunit A. Therefore, further studies are warranted to dissect the mechanism behind the interaction of
SIRT5
with cetuximab activity and establish the potential of targeting
SIRT1/5
in CRC.