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A biomarker for which a screening test is already available – lack of CDX2 expression – appears to identify the approximately 20% of stage II and 50% of stage III colon cancers that are at high risk of recurrence and would benefit from adjuvant chemotherapy, according to a report published online Jan. 21 in the New England Journal of Medicine.
Distinguishing the high-risk tumors from those unlikely to recur or progress would allow some patients to opt for adjuvant chemotherapy that has been shown to significantly raise the rates of overall and disease-free survival. At present, almost all patients with stage II colon cancer are treated using surgery alone, said Dr. Piero Dalerba of the Herbert Irving Comprehensive Cancer Center and the department of pathology and cell biology at Columbia University, New York, and his associates.
The investigators used a bioinformatics approach to search for biomarkers that would identify the most aggressive colon cancers: undifferentiated tumors characterized by immature, stem-like colonic epithelial cells and depleted of more mature cells. They focused on biomarkers for which clinical diagnostic tests are already available, to facilitate use in real-world clinical practice. Their search through 2,329 colon gene-expression array experiments found that when tumors do not express one particular protein, homeobox transcription factor CDX2, “a master regulator of intestinal development and oncogenesis” that is highly specifically expressed in intestinal epithelium, those tumors tend to have aggressive features such as advanced stage, vascular invasion, and BRAF mutation.
Survival outcomes were then compared in a discovery data set of 466 patients. The 5-year disease-free survival rate was significantly lower, at 41%, among the 32 patients who had CDX2-negative tumors than the 74% survival rate among the 434 patients with CDX2-positive tumors. The hazard ratio for disease recurrence among patients with CDX2-negative vs. CDX2-positive tumors was 2.73, Dr. Dalerba and his associates said (N Engl J Med. 2016 Jan 21. doi:10.1056/NEJMoa1506597).
The investigators confirmed these findings in a separate validation data set of 366 patients, of whom 48 had CDX2-negative and 318 had CDX2-positive tumors. Five-year disease-free survival (48% vs. 71%), overall survival (33% vs. 59%), and disease-specific survival (45% vs. 72%) were significantly lower with CDX2-negative tumors, and the HR for disease recurrence was 2.42.
To determine whether adjuvant chemotherapy would improve survival outcomes in patients with CDX2-negative tumors, the researchers assessed outcomes in an expanded dataset of 669 patients with stage II and 1,228 patients with stage III colon cancer. They confirmed that among patients with stage II CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (91%) than did those who didn’t receive adjuvant chemotherapy (56%). Similarly, among patients with stage III CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (74%) than those who did not receive adjuvant chemotherapy (37%).
This survival benefit was independent of many known risk factors, including tumor grade, they noted.
These results must be replicated in future prospective studies, because this study’s design was retrospective and exploratory, Dr. Dalerba and his associates added.
This work was supported by the National Comprehensive Cancer Network, the National Institutes of Health, Siebel Stem Cell Institute, the Thomas and Stacey Siebel Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the California Institute for Regenerative Medicine, the U.S. Department of Defense, the Bladder Cancer Advocacy Network, and BD Biosciences. Dr. Dalerba reported ties to Quanticel Pharmaceuticals and Oncomed Pharmaceuticals, and his associates reported ties to numerous industry sources.
These study findings give clinicians the opportunity to move beyond the existing inadequate method of selecting patients for adjuvant chemotherapy. Although this was not a perfect or definitive study, since it was retrospective and the number of patients with CDX2-negative colon cancers was relatively small, it nevertheless entailed numerous rigorous data analyses.
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Dr. C. Richard Boland |
Moreover, the results raise the important question of what mechanism might be silencing CDX2 in this subset of aggressive cancers. The answer could lead to the discovery of new approaches to treating the underlying problem.
C. Richard Boland, M.D., and Ajay Goel, Ph.D., are at the Center for Gastrointestinal Research and the Center for Epigenetics, Cancer Prevention, and Genomics at Baylor Research Institute, and at the Baylor Charles A. Sammons Cancer Center, all in Dallas. They reported having no relevant financial disclosures. Dr. Boland and Dr. Goel made these remarks in an editorial accompanying Dr. Dalerba’s report (N Engl J Med. 2016 Jan 21. doi:10.1056/NEJMe1514353).
These study findings give clinicians the opportunity to move beyond the existing inadequate method of selecting patients for adjuvant chemotherapy. Although this was not a perfect or definitive study, since it was retrospective and the number of patients with CDX2-negative colon cancers was relatively small, it nevertheless entailed numerous rigorous data analyses.
|
Dr. C. Richard Boland |
Moreover, the results raise the important question of what mechanism might be silencing CDX2 in this subset of aggressive cancers. The answer could lead to the discovery of new approaches to treating the underlying problem.
C. Richard Boland, M.D., and Ajay Goel, Ph.D., are at the Center for Gastrointestinal Research and the Center for Epigenetics, Cancer Prevention, and Genomics at Baylor Research Institute, and at the Baylor Charles A. Sammons Cancer Center, all in Dallas. They reported having no relevant financial disclosures. Dr. Boland and Dr. Goel made these remarks in an editorial accompanying Dr. Dalerba’s report (N Engl J Med. 2016 Jan 21. doi:10.1056/NEJMe1514353).
These study findings give clinicians the opportunity to move beyond the existing inadequate method of selecting patients for adjuvant chemotherapy. Although this was not a perfect or definitive study, since it was retrospective and the number of patients with CDX2-negative colon cancers was relatively small, it nevertheless entailed numerous rigorous data analyses.
|
Dr. C. Richard Boland |
Moreover, the results raise the important question of what mechanism might be silencing CDX2 in this subset of aggressive cancers. The answer could lead to the discovery of new approaches to treating the underlying problem.
C. Richard Boland, M.D., and Ajay Goel, Ph.D., are at the Center for Gastrointestinal Research and the Center for Epigenetics, Cancer Prevention, and Genomics at Baylor Research Institute, and at the Baylor Charles A. Sammons Cancer Center, all in Dallas. They reported having no relevant financial disclosures. Dr. Boland and Dr. Goel made these remarks in an editorial accompanying Dr. Dalerba’s report (N Engl J Med. 2016 Jan 21. doi:10.1056/NEJMe1514353).
A biomarker for which a screening test is already available – lack of CDX2 expression – appears to identify the approximately 20% of stage II and 50% of stage III colon cancers that are at high risk of recurrence and would benefit from adjuvant chemotherapy, according to a report published online Jan. 21 in the New England Journal of Medicine.
Distinguishing the high-risk tumors from those unlikely to recur or progress would allow some patients to opt for adjuvant chemotherapy that has been shown to significantly raise the rates of overall and disease-free survival. At present, almost all patients with stage II colon cancer are treated using surgery alone, said Dr. Piero Dalerba of the Herbert Irving Comprehensive Cancer Center and the department of pathology and cell biology at Columbia University, New York, and his associates.
The investigators used a bioinformatics approach to search for biomarkers that would identify the most aggressive colon cancers: undifferentiated tumors characterized by immature, stem-like colonic epithelial cells and depleted of more mature cells. They focused on biomarkers for which clinical diagnostic tests are already available, to facilitate use in real-world clinical practice. Their search through 2,329 colon gene-expression array experiments found that when tumors do not express one particular protein, homeobox transcription factor CDX2, “a master regulator of intestinal development and oncogenesis” that is highly specifically expressed in intestinal epithelium, those tumors tend to have aggressive features such as advanced stage, vascular invasion, and BRAF mutation.
Survival outcomes were then compared in a discovery data set of 466 patients. The 5-year disease-free survival rate was significantly lower, at 41%, among the 32 patients who had CDX2-negative tumors than the 74% survival rate among the 434 patients with CDX2-positive tumors. The hazard ratio for disease recurrence among patients with CDX2-negative vs. CDX2-positive tumors was 2.73, Dr. Dalerba and his associates said (N Engl J Med. 2016 Jan 21. doi:10.1056/NEJMoa1506597).
The investigators confirmed these findings in a separate validation data set of 366 patients, of whom 48 had CDX2-negative and 318 had CDX2-positive tumors. Five-year disease-free survival (48% vs. 71%), overall survival (33% vs. 59%), and disease-specific survival (45% vs. 72%) were significantly lower with CDX2-negative tumors, and the HR for disease recurrence was 2.42.
To determine whether adjuvant chemotherapy would improve survival outcomes in patients with CDX2-negative tumors, the researchers assessed outcomes in an expanded dataset of 669 patients with stage II and 1,228 patients with stage III colon cancer. They confirmed that among patients with stage II CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (91%) than did those who didn’t receive adjuvant chemotherapy (56%). Similarly, among patients with stage III CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (74%) than those who did not receive adjuvant chemotherapy (37%).
This survival benefit was independent of many known risk factors, including tumor grade, they noted.
These results must be replicated in future prospective studies, because this study’s design was retrospective and exploratory, Dr. Dalerba and his associates added.
This work was supported by the National Comprehensive Cancer Network, the National Institutes of Health, Siebel Stem Cell Institute, the Thomas and Stacey Siebel Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the California Institute for Regenerative Medicine, the U.S. Department of Defense, the Bladder Cancer Advocacy Network, and BD Biosciences. Dr. Dalerba reported ties to Quanticel Pharmaceuticals and Oncomed Pharmaceuticals, and his associates reported ties to numerous industry sources.
A biomarker for which a screening test is already available – lack of CDX2 expression – appears to identify the approximately 20% of stage II and 50% of stage III colon cancers that are at high risk of recurrence and would benefit from adjuvant chemotherapy, according to a report published online Jan. 21 in the New England Journal of Medicine.
Distinguishing the high-risk tumors from those unlikely to recur or progress would allow some patients to opt for adjuvant chemotherapy that has been shown to significantly raise the rates of overall and disease-free survival. At present, almost all patients with stage II colon cancer are treated using surgery alone, said Dr. Piero Dalerba of the Herbert Irving Comprehensive Cancer Center and the department of pathology and cell biology at Columbia University, New York, and his associates.
The investigators used a bioinformatics approach to search for biomarkers that would identify the most aggressive colon cancers: undifferentiated tumors characterized by immature, stem-like colonic epithelial cells and depleted of more mature cells. They focused on biomarkers for which clinical diagnostic tests are already available, to facilitate use in real-world clinical practice. Their search through 2,329 colon gene-expression array experiments found that when tumors do not express one particular protein, homeobox transcription factor CDX2, “a master regulator of intestinal development and oncogenesis” that is highly specifically expressed in intestinal epithelium, those tumors tend to have aggressive features such as advanced stage, vascular invasion, and BRAF mutation.
Survival outcomes were then compared in a discovery data set of 466 patients. The 5-year disease-free survival rate was significantly lower, at 41%, among the 32 patients who had CDX2-negative tumors than the 74% survival rate among the 434 patients with CDX2-positive tumors. The hazard ratio for disease recurrence among patients with CDX2-negative vs. CDX2-positive tumors was 2.73, Dr. Dalerba and his associates said (N Engl J Med. 2016 Jan 21. doi:10.1056/NEJMoa1506597).
The investigators confirmed these findings in a separate validation data set of 366 patients, of whom 48 had CDX2-negative and 318 had CDX2-positive tumors. Five-year disease-free survival (48% vs. 71%), overall survival (33% vs. 59%), and disease-specific survival (45% vs. 72%) were significantly lower with CDX2-negative tumors, and the HR for disease recurrence was 2.42.
To determine whether adjuvant chemotherapy would improve survival outcomes in patients with CDX2-negative tumors, the researchers assessed outcomes in an expanded dataset of 669 patients with stage II and 1,228 patients with stage III colon cancer. They confirmed that among patients with stage II CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (91%) than did those who didn’t receive adjuvant chemotherapy (56%). Similarly, among patients with stage III CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (74%) than those who did not receive adjuvant chemotherapy (37%).
This survival benefit was independent of many known risk factors, including tumor grade, they noted.
These results must be replicated in future prospective studies, because this study’s design was retrospective and exploratory, Dr. Dalerba and his associates added.
This work was supported by the National Comprehensive Cancer Network, the National Institutes of Health, Siebel Stem Cell Institute, the Thomas and Stacey Siebel Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the California Institute for Regenerative Medicine, the U.S. Department of Defense, the Bladder Cancer Advocacy Network, and BD Biosciences. Dr. Dalerba reported ties to Quanticel Pharmaceuticals and Oncomed Pharmaceuticals, and his associates reported ties to numerous industry sources.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: A biomarker for which a screening test is already available – lack of CDX2 expression – appears to identify which stage II and III colon cancers are high-risk and would benefit from adjuvant chemotherapy.
Major finding: Five-year disease-free survival rate was significantly lower (41%) in patients who had CDX2-negative tumors than in patients with CDX2-positive tumors (74%).
Data source: A series of analyses using data mining to identify (in a database of 466 patients) and validate (in databases of 366 and 1,897 patients) a biomarker for early colon cancers at high risk for recurrence/metastasis.
Disclosures: The National Comprehensive Cancer Network, the National Institutes of Health, Siebel Stem Cell Institute, the Thomas and Stacey Siebel Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the California Institute for Regenerative Medicine, the U.S. Department of Defense, the Bladder Cancer Advocacy Network, and BD Biosciences supported the work. Dr. Dalerba reported ties to Quanticel Pharmaceuticals and Oncomed Pharmaceuticals, and his associates reported ties to numerous industry sources.
