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Investigational Genomic Tool Identifies Consensus Molecular Subtype of Colon Tumor and May Predict Risk of Recurrence


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AN INVESTIGATIONAL TOOL called ColotypeR classifies colon cancers by molecular subtype and creates a subtype-specific risk of recurrence, according to research. Developers of the tool say it will be able to guide treatment decisions.

Colon cancer is highly heterogeneous in prognosis and response to treatment. The consensus molecular subtypes (CMS1–4 and mixed) partition colon cancers into distinct groups related to prognosis. CMS4 tumors, a mesenchymal subtype, are associated with the worst prognosis and respond poorly to standard chemotherapies. CMS1 (microsatellite instability–immune), CMS2 (canonical), and CMS3 (metabolic) tumors have a moderate-risk prognosis.

“There is a critical need for accurate molecular subtyping and subtype-specific management,” Steven Buechler, PhD, of the University of Notre Dame in Indiana, told The ASCO Post.


“With this test, we can identify about 50% of patients with stage II disease as having a poor prognosis and who therefore may benefit from additional treatment.”
— Steven Buechler, PhD

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“While we have a consensus subtyping system now, the problem is we don’t have a clinical assay for this. There are hundreds of genes involved, and it’s very complicated,” he explained. “So based on that work, I developed a 20-gene panel that can be executed in the clinic and matches the tumor subtype at about 90% accuracy. The subtype may determine what drug might be effective in an individual patient.”

“The second part of the problem is, once you know the subtype, how do you know which patients within that subtype have a better or worse prognosis?” he continued. “So my colleagues and I also developed a risk signature of 25 genes that is prognostically significant within all the subtypes. For example, among CMS1 patients, I’ll know who the poor-prognosis patients are, so I can better decide how to treat an individual.”

At the 2018 Gastrointestinal Cancers Symposium,1 Dr. Buechler and his team reported on the performance of a 20-gene score, ColotypeR-CMS, which classifies tumors into subtypes, and the 25-gene score ColotypeR-Risk, which predicts the risk of recurrence, in a training and validated data set of about 1,000 tumors.

Study Details

THE AIM OF the two assessments was to develop clinically applicable genomic tests that could identify a tumor’s CMS subtype and determine the risk of recurrence independent of the subtype. The tumor samples used in the study came largely from publicly available microarray data sets (Affymetrix U133 Plus 2.0), which were partitioned into a training set (n = 306) and validation set (n = 580). Samples from The Cancer Genome Atlas (TCGA)/Colon Adenocarcinoma (COAD) collection (n = 298) were used for further validation.

TOOL FOR COLON CANCER SUBTYPING

  • The investigational tool ColotypeR classifies colon cancers by molecular subtype and determines a subtype-specific risk of recurrence.
  • The 20-gene ColotypeRCMS classified each colon cancer sample as CMS1, CMS2, CMS3, CMS4, or mixed type. ColotypeRCMS predicted the CMS subtype with an accuracy of 81% to 90%.
  • The 25-gene score, ColotypeR-Risk, was prognostic of colon cancer recurrence, independent of CMS subtype (P = .0001) and tumor stage (P = .0019).
  • The test could someday inform treatment decisions.

A novel multistate gene methodology was used to predict CMS subtype and to prognosticate subtype-specific relapse-free survival in the training set, independent of CMS subtype. Accuracy was assessed in validation cohorts.

The 20-gene score, ColotypeR-CMS, classified each colon cancer sample as CMS1, CMS2, CMS3, CMS4, or mixed type. ColotypeR-CMS predicted the CMS subtype with an accuracy of 90% in the microarray (Affymetrix U133 Plus 2) validation set and 81% in the TCGA/COAD data set.

The 25-gene score, ColotypeR-Risk (C-Risk), was prognostic of colon cancer recurrence, independent of CMS subtype (P = .0001) and tumor stage (P = .0019). Its independent prognostic power was confirmed in the TCGA/COAD sample, Dr. Buechler reported.

Scores Correlated With Recurrence-Free Survival

IN THE KAPLAN-MEIER analysis, patients with CMS1–3 disease demonstrated a moderate relapse risk, but those with CMS4 and mixed subtype had a high relapse risk. At 5 years, recurrence-free survival was 58% in the CMS4 and mixed subtypes, compared to nearly 75% in the other subtypes (P = .0027).

The investigators defined good-prognosis and poor-prognosis stratification using a C-Risk threshold of 30, which was prognostic within each subtype. For example, within CMS1, recurrence-free survival was almost 90% for patients whose tumors had a low C-Risk score but less than 65% for those with high C-Risk scores (P = .028).

The test could be especially useful in managing patients with stage II colon cancer, according to Dr. Buechler. “There are numerous trials showing that chemotherapy is not that effective in patients with stage II disease, but that’s because this is a heterogeneous group. A lot of these patients have the CMS4 subtype, and they don’t respond well to standard chemotherapy. Patients in other subtypes may be more responsive,” he said.

“With this test, we can identify about 50% of patients with stage II disease as having a poor prognosis and who therefore may benefit from additional treatment,” he predicted. “Also, knowing the CMS subtypes of patients may assist in selection of the most effective therapy.”

Comprehensive risk assessment could be executed by combining ColotypeR-CMS and ColotypeR-Risk, he added. Researchers are currently validating their findings in additional clinical tissue samples. ■

DISCLOSURE: Dr. Buechler has stock and other ownership interests in SYSGenomics and patents, royalties, or other intellectual property in association with the University of Notre Dame.

REFERENCE

1. Buechler S, Gokmen-Polar Y, Badve SS, et al: ColotypeR: A tool to classify colon cancers by consensus molecular subtype and subtype-specific risk of recurrence. 2018 Gastrointestinal Cancers Symposium. Abstract 632. Presented January 20, 2018.


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