Combinatory Gene Signature Sets Flag High-Risk CRC Patients for Adjuvant Chemotherapy

Combinatory cancer hallmark-based gene signature sets could detect high-risk stage II colorectal cancer patients who will benefit from adjuvant fluorouracil-based chemotherapy

medwireNews: Researchers have developed combinatory cancer hallmark–based gene signature sets (CSSs) that may be able to identify the stage II colorectal cancer (CRC) patients who have the most to gain from adjuvant chemotherapy.

“To our knowledge, this is the first study to show that patients with gene expression signature–defined high-risk stage II CRC could achieve significant survival benefits through adjuvant therapy”, say Edwin Wang, from McGill University in Montreal, Quebec, Canada, and co-authors in JAMA Oncology.

“These results shed light on the controversial issue for stage II CRC treatment, which has been debated for more than 20 years.”

The CSSs were developed from eight signature sets, each based on 30 genes, and used to classify 767 stage II CRC patients, from 11 different cohorts who were not treated with adjuvant chemotherapy.

The majority (60%) of the patients were designated as low-risk, 28% were intermediate-risk and 12% were high-risk and these groups had 5-year relapse-free survival rates of 94%, 78% and 45%, respectively.

The CSSs were then applied to a further 416 patients from three cohorts where some stage II patients had received fluorouracil -based adjuvant chemotherapy, the team writes.

Patients designated as high-risk who received fluorouracil had a 30–40% reduction in 5-year recurrence compared with non-treated high-risk counterparts.

But no such benefit was found for fluorouracil-based chemotherapy among the patients classified as having low-risk CRC. Indeed, intermediate-risk patients had significantly reduced survival with adjuvant chemotherapy.

“These results suggest that these low-risk patients could have been spared the potentially toxic and costly effects of these treatments”, say Edwin Wang et al.

They therefore conclude: “Further successful validations of these results will lead to consensus recommendations for by various professional clinical organizations.”

The authors of an accompanying editorial note that the research did not include any patients treated with oxaliplatin -based chemotherapy, the adjuvant treatment of choice for many US oncologists.


“This presents a possible barrier to the clinical adoption of the cancer hallmark-based gene signature assay”, say Greg Yothers, from the University of Pittsburgh in Pennsylvania, USA, and co-authors, who argue for a prospective randomised trial of oxaliplatin regimens in CSS-identified high-risk patients.

“Since only 12% of patients with stage II colon cancer are assigned to the high-risk category via the cancer hallmark–based gene signature assay, roughly 2400 patients would need to be screened for such a study”, they write. “This might reasonably be accomplished with 3 years of screening and 3 additional years of follow-up.”


Gao S, Tibiche C, Zou J, et al. Identification and construction of combinatory cancer hallmark-based gene signature sets to predict recurrence and chemotherapy benefit in stage II colorectal cancer. JAMA Oncol 2015; Advance online publication 22 October. doi:10.1001/jamaoncol.2015.3413

Yothers G, Song N, George Jr TJ. Cancer hallmark–based gene sets and personalized medicine for patients with stage II colon cancer. JAMA Oncol 2015; Advance online publication 22 October. doi:10.1001/jamaoncol.2015.3614

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