Prognostic value of MACC1 and proficient mismatch repair status for recurrence risk prediction in stage II colon cancer patients: the BIOGRID studies

U-P Rohr; P Herrmann; K Ilm; H Zhang; S Lohmann; A Reiser; A Muranyi; J Smith; S Burock; M Osterland; K Leith; S Singh; P Brunhoeber; R Bowermaster; J Tie; M Christie; H-L Wong; P Waring; K Shanmugam; P Gibbs; U Stein

doi:10.1093/annonc/mdx207

Prognostic value of MACC1 and proficient mismatch repair status for recurrence risk prediction in stage II colon cancer patients: the BIOGRID studies

Ann Oncol. 2017 Aug 1;28(8):1869-1875. doi: 10.1093/annonc/mdx207.

Authors

U-P Rohr^{1

2}, P Herrmann^{3

4}, K Ilm^{3

4}, H Zhang⁵, S Lohmann⁶, A Reiser⁶, A Muranyi⁷, J Smith^{3

4}, S Burock⁸, M Osterland^{3

4

9}, K Leith⁷, S Singh⁷, P Brunhoeber⁷, R Bowermaster⁷, J Tie¹⁰, M Christie¹⁰, H-L Wong¹⁰, P Waring⁷, K Shanmugam⁷, P Gibbs¹⁰, U Stein^{3

4

11}

Affiliations

¹ Divisional Medical and Scientific Affairs, Roche, Basel, Switzerland.
² Klinik für Innere Medizin I, Hämatologie, Onkologie und Stammzelltransplantation, University Freiburg, Germany.
³ Translational Oncology of Solid Cancer, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin.
⁴ Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
⁵ Divisional Biomarker Group, Roche, Basel, Switzerland.
⁶ Roche Diagnostics GmbH, Penzberg, Germany.
⁷ Ventana Medical Systems Inc., Tucson, USA.
⁸ Charité Comprehensive Cancer Center, Berlin.
⁹ Zuse Institute Berlin, Berlin, Germany.
¹⁰ Walter and Eliza Hall Institute, Melbourne, Australia.
¹¹ German Cancer Consortium (DKTK), Heidelberg, Germany.

PMID: 28460000
DOI: 10.1093/annonc/mdx207

Abstract

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% confidence interval (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.

Keywords: MACC1; colon cancer; pMMR; stage II; survival prognostication.

MeSH terms

Cohort Studies
Colonic Neoplasms / genetics
Colonic Neoplasms / pathology*
DNA Mismatch Repair*
Disease-Free Survival
Humans
Neoplasm Recurrence, Local / genetics*
Neoplasm Staging
Prognosis
Risk Factors
Trans-Activators
Transcription Factors / genetics*

Substances

MACC1 protein, human
Trans-Activators
Transcription Factors