New marker flags DNA repair response to platinum therapy
A newly discovered genetic marker of DNA damage may be able to predict which patients with triple-negative breast cancer or serous ovarian cancer will respond to platinum-based chemotherapy drugs such as cisplatin or carboplatin.
“We currently do not have any targeted therapies for patients with triple-negative breast cancer, so if these laboratory findings are confirmed and an assay is created to predict sensitivity to drugs that target defective DNA repair, it would be a major step forward,” affirmed Andrea Richardson, MD, PhD, in a statement issued by the American Association for Cancer Research. Richardson, an assistant professor of medicine at Dana-Farber Cancer Institute in Boston, Massachusetts, was the lead pathologist on the study that yielded the new marker, telomeric allelic imbalance (tAI).
DNA repair status is known to be a predictor of sensitivity to therapy and thus prognosis: Whereas some cancer cells can repair DNA molecules that have been damaged by drug or radiation therapy, other cancer cells have lost this capacity, making them vulnerable to DNA-damaging agents. However, measurements of DNA repair status have been slow to arrive. Now, tAI appears to identify breast and ovarian cancer cells that can't repair the DNA damage caused by platinum drugs. This information can be used to distinguish patients who can be treated effectively with a single platinum-based drug and avoid the toxicities of other chemotherapy combinations.
Richardson and associates made the discovery while correlating genomic signatures in cell lines and tumors to platinum sensitivity. The researchers found that in some patients with serous ovarian cancer or triple-negative breast cancer (the latter is characterized by a lack of estrogen, progesterone, and HER2 receptors, making the tumors unresponsive to targeted treatments that block those receptors), tumor cells exhibited a high number of chromosome regions with an allelic imbalance that extended to the telomeres (tips of the chromosomes). This pattern was a strong indicator of defective DNA damage repair, predicting response to cisplatin therapy. In addition, the investigators found an inverse relationship between tAI level and BRCA1 expression in triple-negative breast cancer.
The report by Richardson and colleagues appears in Cancer Discovery (2012;2:366-375).