Predicting survival

UCSD researchers use biomarkers to gauge response to chemotherapy

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SAN DIEGO—Colorectal cancer (CRC), the third-deadliest cancer in the United States, is projected to have 132,700 new cases and cause 49,700 deaths in 2015. New cytotoxic and targeted agents for patients with metastatic CRC have improved overall survival rates, but scientists at the University of California, San Diego (UCSD) wanted to do a bit better.
According to researchers at the UCSD School of Medicine, who published their findings in the June 17 issue of PLOS ONE, “In patients with metastatic colon cancer, response to first-line chemotherapy is a strong predictor of overall survival. Currently, oncologists lack diagnostic tests to determine which chemotherapy regimen offers the greatest chance for response in an individual patient.”
The researchers conducted a proof-of-principle study with a small group of metastatic colorectal cancer patients. The results revealed two genes, ERCC1 and TS, that could help physicians make more informed treatment decisions for patients with this disease. Their analysis of the results for 41 patients with de-novo metastatic colon cancer diagnosed between July 2008 and August 2013 at UCSD was designed to determine the potential clinical utility of measuring ERCC1 and TS expression in managing patients with metastatic colorectal cancer.
The researchers used a commercially available test to analyze levels of the genes ERCC1 and TS that encode proteins involved in building and repairing DNA. They found that 33 of their 41 patients had low ERCC1 levels. Those patients had much longer average survival times (36 months) compared to patients with high ERCC1 levels (10 months). They also found that 29 patients had low TS levels and significantly longer average survival times (36 months) than patients with high TS levels (15 months).
Twenty-two of the 41 patients had low levels of both ERCC1 and TS, and 20 of them responded to oxaliplatin, suggesting that this should be the first treatment choice for patients with low ERCC1 and TS. Patients responded to irinotecan at the same rate, whether they had low or high levels of these genes, implying that physicians might want to select irinotecan as the first-choice chemotherapy for patients with high ERCC1 or TS levels. These results are consistent with other studies evaluating the roles of ERCC1 and TS in metastatic colorectal cancer.
According to senior author Dr. Paul Fanta, assistant clinical professor of medicine and oncologist at UCSD’s Moores Cancer Center, “Several large trials compared oxaliplatin and irinotecan head-to-head and concluded that the response rate is about equal. How an oncologist bases his or her treatment decision can be based on experience, comfort level prescribing and the patient’s health. But in reality, the two drugs are very different. For any individual patient, one might be better than the other. As an oncologist, how do I know which is better for my patient? That’s where this study comes in.”
Co-first author Dr. John Paul Shen, a senior clinical fellow and postdoctoral fellow, added, “Our study is small, retrospective and all of the patients were located at a single medical center, but it demonstrates that it’s possible to use molecular diagnostics to identify subgroups of patients more likely to respond to a given treatment. Given this proof of principle, it’s our hope that molecular biomarkers will be included in future prospective clinical trials in metastatic colorectal cancer.”
Co-authors of this study also include Michel B. Choueiri, Andrew M. Gross, Justin K. Huang and Trey Ideker, all of UCSD. This research was funded, in part, by Arthur Athans in the name of his wife, Barbara Mae Athans, the National Institutes of Health (grants R01 ES014811 and U24 CA184427), Marsha Rivkin Center for Ovarian Cancer Research and Conquer Cancer Foundation of ASCO.
“Overall, these findings suggest that measurement of ERCC1 and TS expression has potential clinical utility in managing patients with metastatic colorectal cancer,” the report concluded.

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