Impact of expression of metabolic genes on patient (pts) outcomes in metastatic colorectal cancer (mCRC): Data from CALGB/SWOG 80405 (Alliance).
Authors: Battaglin Francesca , Millstein Joshua , Yang Yan , Ashouri Karam , Soni Shivani , Algaze Sandra , Mittal Pooja , Torres-Gonzalez Lesly , Jayachandran Priya , Shah Unnati Hermant , Zhang Wu , Hochster Howard S. , Ou Fang-Shu , Venook Alan P. , Innocenti Federico , Finley Stacey D , Lenz Heinz-Josef 
Published: January 2025

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Background:
Metabolic pathways are reprogrammed during CRC development, leading to increased glycolysis, glutaminolysis, and fatty acid synthesis. Understanding the impact of metabolic reprogramming on treatment outcomes is paramount. Hence, we investigated whether the tumor gene expression of 4 selected major metabolic genes (
PKM, SLC2A1
,
SLC16A1
, and
CAV1
) could affect treatment response in pts enrolled in the CALGB/SWOG 80405 trial.
Methods:
433 mCRC pts treated with either bevacizumab (bev, n = 226) or cetuximab (cet, n = 207) in combination with first-line chemotherapy were analyzed. RNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared between groups of pts categorized by tertiles of gene expression (high [H], medium [M] and low [L]). Logrank
P
-values provide a non-parametric unadjusted assessment of differences. Likelihood ratio tests (LRT) were computed from multivariate Cox proportional hazards models, adjusting for age, sex, ECOG, tumor side, number of metastatic sites,
KRAS
, CMS, and treatment.
Results:
PKM
gene expression was associated with cet treatment outcomes with
PKM-
low tumors showing significantly longer PFS and OS (median PFS: 14.3 vs 9.8 vs 8.1 months, L vs M vs H,
P
< 0.0001, LRT
P
= 0.011; median OS: 45.9 vs 31.2 vs 20.9 months,
P
< 0.0001, LRT
P
= 0.12). Low
SLC2A1
was also associated with longer OS in cet-treated pts (32.4 vs 35.8 vs 25.2 months,
P
= 0.02, LRT
P
< 0.0001). Similar results were observed in bev-treated pts where low
SLC2A1
expressing tumors had longer OS (37.4 vs 26.1 vs 29 months,
P
= 0.037, LRT
P
= 0.069) and a non-significant trend for longer PFS (13.1 vs 11 vs 9.5 months,
P
= 0.076).
CAV1
low gene expression was associated with longer OS in cet-treated pts (37.4 vs 34 vs 21.5 months,
P
= 0.0048, LRT
P
= 0.013), while no significant associations were found in bev-treated (interaction LRT
P
= 0.0009). No significant results were observed for
SLC16A1
.
Conclusions:
The intratumoral expression of metabolic genes was prognostic and predictive in mCRC pts treated with first-line therapy. GLUT1 (encoded by
SLC2A1
) and PKM2 (encoded by
PKM
) promote aerobic glycolysis of cancer cells, known as Warburg effect, supporting rapid cell proliferation and survival. CAV1 has been shown to be involved in mitochondrial bioenergetics and fatty acid metabolism and to play either a tumor suppressor or oncogenic role depending on the cancer type and stage. Lower expression of
SLC2A1
and
PKM
was associated with improved survival and increased benefit from cet treatment in our cohort. Low
CAV1
expression was also associated with increase survival suggesting a cancer-promoting role in mCRC. Our results suggest that targeting cancer cell metabolism through novel inhibitors of the aforementioned pathways may be a promising therapeutic strategy.