Refining prognosis in early-stage colorectal cancer: one or multiple genes at a time?
Authors: J.A. Willis, E. Vilar
Journal: Annals of Oncology (2017)

Based on recent estimates, colon cancer remains the third most common newly diagnosed cancer type among both men and women in the United States [1.Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2017.CA Cancer J Clin. 2017; 67: 7-30Crossref PubMed Scopus (12753) Google Scholar]. At the time of curative surgical resection, stage II (node-negative) and stage III (node-positive) account for approximately 25% and 35% of new cases, respectively [2.Siegel R. Desantis C. Jemal A. Colorectal cancer statistics, 2014.CA Cancer J Clin. 2014; 64: 104-117Crossref PubMed Scopus (2327) Google Scholar]. However, while multiple lines of evidence support the benefit of adjuvant systemic therapy in stage III disease, its exact role in stage II disease continues to be the subject of lively debate and active investigation [3.Dienstmann R. Salazar R. Tabernero J. Personalizing colon cancer adjuvant therapy: selecting optimal treatments for individual patients.J Clin Oncol. 2015; 33: 1787-1796Crossref PubMed Scopus (250) Google Scholar]. According to the most recent National Comprehensive Cancer Network (NCCN) guidelines, stage II colon cancer patients with poor clinical prognostic factors—such as T4 disease, poorly differentiated histology, bowel obstruction, under-sampled (<12) regional lymph node status, lymphovascular or perineural invasion—can be considered for adjuvant systemic therapy to decrease the risk of metastatic recurrence. Building upon this, molecular characterization of the tumor has played a prominent role in efforts to develop novel prognostic models over the past 10 years. First, for stage II disease, deficient mismatch repair (dMMR) displayed by the tumor is associated with a favorable prognosis and lack of benefit from adjuvant single-agent fluoropyrimidine systemic therapy. As such, dMMR testing is currently recommended by both NCCN [4.National Comprehensive Cancer Network. Colon Cancer (Version 1.2017) In Clinical Practice Guidelines in Oncology. Fort Washington, PA: National Comprehensive Cancer Network 2017.Google Scholar], the European Society for Medical Oncology (ESMO) [5.Labianca R. Nordlinger B. Beretta G.D. et al.Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2013; 24: vi64-vi72Abstract Full Text Full Text PDF PubMed Scopus (654) Google Scholar] and the American Society of Clinical Oncology [6.Benson A.B. Schrag D. Somerfield M.R. et al.American Society of Clinical Oncology Recommendations on adjuvant chemotherapy for stage II colon cancer.J Clin Oncol. 2004; 22: 3408-3419Crossref PubMed Scopus (1162) Google Scholar, 7.Sepulveda A.R. Hamilton S.R. Allegra C.J. et al.Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology.J Clin Oncol. 2017; 35: 1453-1486Crossref PubMed Scopus (213) Google Scholar] to help guide prognostication and clinical decision making in early-stage disease. Second, a growing body of evidence suggests that multi-gene expression assays such as Oncotype DX Colon (12 genes) [8.Kerr D. Gray R. Quirke P. et al.A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study.J Clin Oncol. 2009; 27: 4000Crossref Google Scholar] and ColoPrint (18 genes) [9.Salazar R. Roepman P. Capella G. et al.Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer.J Clin Oncol. 2011; 29: 17-24Crossref PubMed Scopus (432) Google Scholar, 10.Kopetz S. Tabernero J. Rosenberg R. et al.Genomic classifier ColoPrint predicts recurrence in stage II colorectal cancer patients more accurately than clinical factors.Oncologist. 2015; 20: 127-133Crossref PubMed Scopus (89) Google Scholar] can further risk stratify early-stage colon cancer patients independently from other clinical risk, such assays are not currently recommended as standard of care. As a molecular subtype, dMMR colon cancer represents a relatively small proportion (approximately 15%) of all stage II cases [11.Vilar E. Tabernero J. Molecular dissection of microsatellite instable colorectal cancer.Cancer Discov. 2013; 3: 502-511Crossref PubMed Scopus (71) Google Scholar]. Thus, a challenge has existed to identify other clinically meaningful molecular subtypes of early stage disease, particularly in the proficient mismatch repair (pMMR) population. In this issue of Annals of Oncology, Rohr et al. [12.Rohr U.-P. Herrmann P. Ilm K. et al.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; 28: 1869-1875Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar] report findings from a novel comprehensive analysis of Metastasis Associated in Colon Cancer 1 (MACC1) gene expression and its prognostic utility in a total of 596 patients diagnosed with stage II colon cancer. MACC1 gene expression was determined by protein immunohistochemistry (IHC) and/or mRNA quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) assays. In the analysis of 306 patients from the Australian-based BioGrid 2 cohort, downregulation of MACC1 expression (by IHC) and MMR status were both correlated with prolonged relapse-free survival. Notably, similar rates of MACC1 up-regulation were observed in the pMMR and dMMR subgroups (95.2% versus 92.5%, respectively). However, the MACC1-low/pMMR patient subgroup (representing 3.9% of patients in the cohort) was found to have a relapse free survival rate comparable to that observed in the dMMR subgroup. Thus, MACC1 tumor expression seems to stratify patients with pMMR into those with a more favorable prognosis. Importantly, using the European-based Charité 1 and 2 cohorts and the Australian BioGrid 1 cohort, Rohr et al. [12.Rohr U.-P. Herrmann P. Ilm K. et al.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; 28: 1869-1875Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar] demonstrated similar correlations between MACC1 mRNA expression and relapse-free survival that were independent of tumor tissue source (cryopreserved versus preserved) and assay type (IHC versus qRT-PCR). MACC1 was reported by Stein et al. [13.Stein U. Walther W. Arlt F. et al.MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis.Nat Med. 2009; 15: 59-67Crossref PubMed Scopus (408) Google Scholar] in 2009 as a novel regulator of the MET pathway. The MACC1 gene product is hypothesized to act as a transductor in hepatocyte-growth factor (HGF)-MET signaling, and to promote cell growth, invasion and metastasis. Work by Stein et al. [14.Koelzer V.H. Herrmann P. Zlobec I. et al.Heterogeneity analysis of Metastasis Associated in Colon Cancer 1 (MACC1) for survival prognosis of colorectal cancer patients: a retrospective cohort study.BMC Cancer. 2015; 15: 160.Crossref PubMed Scopus (42) Google Scholar, 15.Stein U. MACC1 - a novel target for solid cancers.Expert Opin Ther Targets. 2013; 17: 1039-1052Crossref PubMed Scopus (49) Google Scholar, 16.Stein U. Burock S. Herrmann P. et al.Circulating MACC1 transcripts in colorectal cancer patient plasma predict metastasis and prognosis.PLoS One. 2012; 7: e49249Crossref PubMed Scopus (65) Google Scholar] has shown that MACC1 up-regulation correlates with increased risk of distal metastasis and poorer overall survival in colon cancer. Similar associations have been identified in other cancer types including gastric [17.Guo T. Yang J. Yao J. et al.Expression of MACC1 and c-Met in human gastric cancer and its clinical significance.Cancer Cell Int. 2013; 13: 121Crossref PubMed Scopus (53) Google Scholar], breast [18.Huang Y. Zhang H. Cai J. et al.Overexpression of MACC1 and Its significance in human Breast Cancer Progression.Cell Biosci. 2013; 3: 16Crossref PubMed Scopus (73) Google Scholar], lung [19.Shimokawa H. Uramoto H. Onitsuka T. et al.Overexpression of MACC1 mRNA in lung adenocarcinoma is associated with postoperative recurrence.J Thorac Cardiovasc Surg. 2011; 141: 895-898Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar], cervical [20.Zhou X. Xu C.-J. Wang J.-X. et al.Metastasis-associated in colon cancer-1 associates with poor prognosis and promotes cell invasion and angiogenesis in human cervical cancer.Int J Gynecol Cancer. 2015; 25: 1353-1363Crossref PubMed Scopus (25) Google Scholar], renal [21.Jin Z. Xu N. Guo K. et al.Increased expression of metastasis-associated in colon cancer-1 in renal cell carcinoma is associated with poor prognosis.Int J Clin Exp Pathol. 2015; 8: 3857-3863PubMed Google Scholar] and osteosarcoma [22.Zhang K. Zhang Y. Zhu H. et al.High expression of MACC1 predicts poor prognosis in patients with osteosarcoma.Tumor Biol. 2014; 35: 1343-1350Crossref PubMed Scopus (19) Google Scholar]. Furthermore, prior work by Ilm et al. [23.Ilm K. Kemmner W. Osterland M. et al.High MACC1 expression in combination with mutated KRAS G13 indicates poor survival of colorectal cancer patients.Mol Cancer. 2015; 14: 38.Crossref PubMed Scopus (24) Google Scholar] suggested that MACC1 up-regulation may be correlated with mutated BRAF V600E and KRAS exon 2 mutations. Hence, the pathophysiology of MACC1 up-regulation in the context of Mitogen-activated protein kinase (MAPK) pathway and other complex alterations remains unclear and warrants further investigation. The current study by Rohr et al. [12.Rohr U.-P. Herrmann P. Ilm K. et al.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; 28: 1869-1875Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar] provides novel evidence that somatic MACC1 expression may serve as a prognostic biomarker in the context of early-stage, MMR-proficient colon cancer. Given these findings, can stage II colon cancer patients with MACC1-low/pMMR tumors be considered for observation rather than adjuvant systemic therapy? Additional studies will be necessary to address this question further, using prospective and retrospective population-based data sets as well as samples from clinical trials. In particular, it remains unknown whether MACC1 expression is an independent prognostic biomarker when compared with the aforementioned clinically-relevant factors also used in stage II disease. Furthermore, because all of the analyzed patients treated with adjuvant chemotherapy in the BioGrid 2 cohort had MACC1-high tumors, the utility of MACC1 expression as a predictive biomarker remains undefined. Prospective clinical studies will be helpful in these regards. The work by Rohr et al. [12.Rohr U.-P. Herrmann P. Ilm K. et al.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; 28: 1869-1875Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar] supports the concept that molecular heterogeneity and tumor subtypes are relevant not only for metastatic but also early-stage disease. Importantly, however, the relatively small fraction of stage II patients (approximately 5%–7%) defined by an MACC1-low/pMMR molecular phenotype highlights the need to characterize additional biomarkers in this clinical setting. Moving forward, we believe that this is crucial to introduce the molecular stratification of colorectal cancer based on an orthogonal approach combining mutational, epigenetic and gene expression data utilizing the consensus molecular subtype framework [24.Dienstmann R. Vermeulen L. Guinney J. et al.Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer.Nat Rev Cancer. 2017; 17: 268.Crossref PubMed Scopus (12) Google Scholar, 25.Guinney J. Dienstmann R. Wang X. et al.The consensus molecular subtypes of colorectal cancer.Nat Med. 2015; 21: 1350-1356Crossref PubMed Scopus (2657) Google Scholar] on a prospective basis to understand the prognostic and/or predictive value of the complex molecular landscape in of early-stage colorectal cancer. None declared.