Intrinsic molecular subtyping in breast cancer has become clinically applicable, and the same could be happening for gastrointestinal tumors, according to an international study reported at the 2013 Gastrointestinal Cancers Symposium in San Francisco.1
While recent efforts have yielded prognostic assays such as Oncotype and ColoPrint, this study takes genomic testing further by defining molecular subtypes with different prognoses and responses to adjuvant chemotherapy, reported Josep Tabernero, MD, Director of Vall d’Hebron Institute of Oncology in Barcelona, Spain.
“We have developed a diagnostic single-sample predictor that allows the classification of colorectal cancer tumors of different intrinsic molecular subtypes. These subtypes are potentially clinically relevant, as they differ in their underlying biology and clinical outcomes and consequently require different treatment strategies,” Dr. Tabernero said.
The classification system might be especially helpful in patients with stage II disease, since clinical and pathologic factors do not reliably indicate those at greatest risk of relapse. The information might be used not only to identify patients needing aggressive treatment but in predicting a prioriwhich particular drugs will be of most benefit in an individual patient, he said.
The researchers used gene-expression data from 188 patients with colorectal cancer (stage I–IV) to develop a molecular subtype classification system, which was subsequently validated in 543 patients with stage II or III disease. Unsupervised hierarchical clustering of the whole genome revealed three distinct patterns that were organized into patient subgroups: 21.5% of the samples were categorized as subtype A (32 genes), 62% as subtype B (53 genes), and 16.5% as subtype C (102 genes).
These subtypes differed according to three biologic hallmarks of colorectal tumors: epithelial-to-mesenchymal transition (associated with aggressive tumors), deficiency in mismatch repair genes (associated with genetic alterations), and the rate of cell proliferation. These features are known to independently affect outcomes, which the findings of the current study confirmed.
Subtypes Associated with Outcomes
“The subtypes were significantly associated with prognosis and significantly correlated with benefit from adjuvant [fluorouracil (5-FU)]–based treatment in patients with stage III disease, the standard of care at the time the patients were diagnosed,” said Dr. Tabernero. Most strikingly, after 10 years of follow-up, subtype C had the worst outcome and did not benefit from adjuvant chemotherapy.
Stage III, subtype A had a better prognosis. Ten-year survival rates were approximately 65% without chemotherapy and 80% with chemotherapy, although this difference has not achieved statistical significance (P = .183). Stage III, subtype B had a pronounced benefit from chemotherapy, with 10-year survival rates of approximately 55% vs 80%, respectively (P = .014).
In contrast, patients with subtype C derived no benefit from adjuvant chemotherapy, with 10-year survival rates of approximately 50% with chemotherapy and 65% without chemotherapy (P = .542). The 5-year overall survival difference between types A and B, vs type C, was statistically significant (P = .0166).
Directing treatment according to subtype would perhaps mean giving no 5-FU–based adjuvant chemotherapy to subtype A, giving chemotherapy to subtype B, and using a targeted approach (with companion diagnostics) in subtype C patients, he said.
The investigators believe that differences in proliferation between the subtypes might explain the differences in 5-FU–based adjuvant treatment benefits. For example, subtype C had significantly reduced expression of Ki67 and AURKA, compared to subtypes A and B.
The subtypes also differed significantly in mutation and microsatellite instability frequency (ie, mismatch repair deficiency), in mesenchymal markers (higher in subtype C) and in epithelial markers. The subtypes are currently being evaluated in stage IV colorectal cancer.
In an interview with The ASCO Post, Dr. Tabernero said the researchers will be assessing their system in other patient populations, including those treated with oxaliplatin. He noted that a number of research groups are working in this area, and considerable overlap and consistency is being observed among their findings. “Next year, I believe we will see at least four publications related to molecular subtypes in colorectal cancer,” he predicted. ■
Disclosure: Dr. Tabernero has received research funding from Agendia.
1. Simon I, Roepman P, Schlicker A, et al: Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesynchymal transition. 2013 Gastrointestinal Cancers Symposium. Abstract 333. Presented January 26, 2013.
Axel Grothey, MD, Professor of Oncology at the Mayo Clinic, Rochester, Minnesota, said that classifying colorectal cancer by intrinsic subtypes is “the right route forward,” especially if subtypes can be reliably linked to therapeutic response and survival. “We will not be treating all colorectal...