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Background
We assessed the novel MACC1 gene to further stratify stage II colon cancer
patients with proficient mismatch repair (pMMR).
Patients and methods
Four cohorts with 596 patients were analyzed: Charité 1 discovery cohort
was assayed for MACC1 mRNA expression and MMR in cryo-preserved
tumors. Charité 2 comparison cohort was used to translate MACC1 qRT-
PCR analyses to FFPE samples. In the BIOGRID 1 training cohort MACC1
mRNA levels were related to MACC1 protein levels from
immunohistochemistry in FFPE sections; also analyzed for MMR.
Chemotherapy-naïve pMMR patients were stratified by MACC1 mRNA and
protein expression to establish risk groups based on recurrence-free
survival (RFS). Risk stratification from BIOGRID 1 was confirmed in the
BIOGRID 2 validation cohort. Pooled BIOGRID datasets produced a best
effect-size estimate.
Results
In BIOGRID 1, using qRT-PCR and immunohistochemistry for MACC1
detection, pMMR/MACC1-low patients had a lower recurrence probability
versus pMMR/MACC1-high patients (5-year RFS of 92% and 67% versus
100% and 68%, respectively). In BIOGRID 2, longer RFS was confirmed
for pMMR/MACC1-low versus pMMR/MACC1-high patients (5-year RFS of
100% versus 90%, respectively). In the pooled dataset, 6.5% of patients
were pMMR/MACC1-low with no disease recurrence, resulting in a 17%
higher 5-year RFS (95% CI (12.6-21.3%)) versus pMMR/MACC1-high
patients (P=0.037). Outcomes were similar for pMMR/MACC1-low and
deficient MMR (dMMR) patients (5-year RFS of 100% and 96%,
respectively).
Conclusions
MACC1 expression stratifies colon cancer patients with unfavorable pMMR
status. Stage II colon cancer patients with pMMR/MACC1-low tumors have
a similar favorable prognosis to those with dMMR with potential
implications for the role of adjuvant therapy.