May 2, 2016

New Colon Cancer Prognostic Biomarker: A ‘Potentially Important Clinical Advance’

Insights from Cleveland Clinic’s Emina Huang, MD

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The recent identification of a prognostic biomarker for earlier-stage colon cancer by an international research group is a provocative finding that, if further validated, could help guide treatment decisions and suggest new therapeutic targets, says Cleveland Clinic Cancer Center colorectal surgeon and scientist Emina Huang, MD.

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The discovery that the expression status of transcription factor caudal-type homeobox transcription factor 2 (CDX2) is indicative of disease-free survival and response to adjuvant chemotherapy in a subset of stage II colon cancer patients is “biologically intriguing and a potentially quite important clinical advance,” says Dr. Huang, a colorectal surgeon and researcher in the Department of Stem Cell Biology and Regenerative Medicine.

The investigators reported in The New England Journal of Medicine that patients with CDX2-negative colon cancer had lower five-year disease-free survival (DFS) compared with those with CDX2-positive tumors. In addition, five-year DFS was higher for patients with CDX2-negative stage II disease who received adjuvant chemotherapy compared with those who did not.

Dr. Huang, who conducts translational research in colorectal cancer development and progression, was not involved in the CDX2 study but coauthored a commentary about it in Cell Stem Cell.

A lack of progress in earlier-stage colon cancer

New adjuvant chemotherapy regimens introduced during the last decade have significantly improved disease-free survival rates in patients with stage III colon cancer. But similar survival gains have not occurred in earlier-stage patients, due in part to the lack of clear benefit of adjuvant therapy when broadly applied in this group.

The most commonly used agent, fluoropyrimidine, only enhances stage II colon cancer patients’ overall survival by 5 percent or less. That slight improvement must be weighed against chemotherapy’s multiple adverse aspects, including toxicity and cost. As Dr. Huang notes in the commentary, the resulting risk/benefit ratio does not support widespread administration of adjuvant chemotherapy in stage II colon cancer, making the decision about when to employ the approach challenging.

Though some clinical and pathological criteria (tumor stage, poorly differentiated histology) and molecular features (BRAFV600E or KRAS mutations) may indicate which stage II patients are at risk of recurrence and would benefit from adjuvant chemotherapy, more reliable and precise methods are needed.

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Research design and impact

The NEJM study, led by researchers at Stanford and Columbia universities, used a systematic, multi-step approach to look for biomarkers of colon epithelial differentiation. Specifically, they sought gene-expression signatures derived from stem cells and progenitor cells, reasoning that the presence of a cancer stem cell-like state would be associated with more aggressive tumors. Cancer stem cell research involves the analysis of tumor cells removed from patients during surgery, which may be enirched – based on their expression of surface markers, for instance. They are then studied in mouse xeno-transplantation models.

Past successes with cancer stem cell research included the finding that expression of the activated leukocyte-cell adhesion molecule (ALCAM/CD166), a marker of immature colon epithelial cells, was inversely correlated with survival in colon cancer patients. Investigators built on this discovery, leveraging the power of bioinformatics to apply a Boolean algorithm focusing on potential biomarkers. Of the highest interest were genes with expression that was, at the same time, absent only in ALCAM-positive tumors and always present in ALCAM-negative tumors.

The research group mined a database containing 2,329 human gene-expression arrays from 214 normal colon tissue samples and 2,115 CRC tissue samples to identify 16 candidate genes. Only one, CDX2, encoded a protein that could be studied through immunohistochemistry via an existing clinical-grade diagnostic test. CDX2 is a “master regulator of intestinal development and oncogenesis and its expression is highly specific to the intestinal epithelium,” according to the researchers.

The researchers evaluated CDX2’s association with five-year DFS in a set of 466 patients from the National Center for Biotechnology Information Gene Expression Omnibus database. Differences between the patients with CDX2-negative tumors (n = 32) and those with CDX2-positive tumors (n = 434) were found to be significant: The five-year DFS was 41 percent vs. 74 percent, respectively (P < .001).

In the rare stage II colon cancer patients treated with adjuvant chemotherapy and whose cancers lacked CDX2 expression, the researchers found improved five-year DFS compared with those not receiving chemotherapy (91 percent vs. 56 percent (P = .006).

Biological and clinical questions for further investigation

The study “is one of the few manuscripts out there that links large databases in order to segregate cancer stem cells and then use them in a prognostic manner to inform clinicians about what to do — how to treat patients,” says Dr. Huang. In the commentary, she notes that about 25 percent of colon cancer patients present with stage II disease and that the study’s results suggest that adjuvant chemotherapy may benefit a subset of 4 to 5 percent of those stage II patients — those whose cancers lack CDX2 expression.

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“It is through this type of research that we will develop new strategies to improve the care of colon cancer patients,” she says.

The study’s authors acknowledged the exploratory and retrospective design of their research and the need for further validation using randomized, clinical trials, in conjunction with genomic DNA sequencing studies.

Should further research provide functional evidence that CDX2 directly regulates the response of colon cancer cells to adjuvant chemotherapy, strategies to antagonize CDX2 expression and function in CDX2-expressing colon cancers may be beneficial, Dr. Huang and her co-author say in their commentary.

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